Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2([CH:23]([CH3:28])[CH2:24][N:25]([CH3:27])[CH3:26])[OH:22])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl>[C:35]([O:22][C:17]1([CH:23]([CH3:28])[CH2:24][N:25]([CH3:26])[CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:11][CH:12]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC(CN(C)C)C1(O)CCCCC1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1(C(C)CN(C)C)CCCCC1c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
2-(p-Benzyloxyphenyl)-1-(2-dimethylamino-1-methylethyl)cyclohexanol hydrochloride (11.3 g) is stirred with 140 ml chloroform and 26 g potassium carbonate. Acetyl chloride (6.5 ml) is added and the mixture is stirred overnight, washed with water, and the chloroform dried. The chloroform solution is stirred for 6 hours with 6.5 ml acetyl chloride and 26 g potassium carbonate, then washed with water, dried and concentrated to give 14 g crude product.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:32][C:33]1[CH:38]=[C:37]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:22])=[O:23])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(N)c3)c2c1
Yield: 26.6 %

Procedure:
N-[3-(3-Aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 276 mg of 3-aminophenylboronic acid, 20 ml of dimethylformamide, 1.6 ml of a saturated aqueous sodium hydrogencarbonate solution and 25 mg of tetrakis(triphenylphosphine)palladium[0]. 102 mg of N-[3-(3-aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 220° C. (analysis C20H18N4O4S2 % calculated C, 54.29; H, 4.10; N, 12.66; O, 14.46; S, 14.49. % found C, 53.48H, 4.11; N, 12.50; S, 13.95).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:18])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)O
Product: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)Cl

Procedure:
The title compound was prepared from 3-chloro-2,4,5-trifluoro-6-methylbenzoic acid and oxalyl chloride following the same procedure used in Example F.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]=[C:10]=[O:11])[CH:4]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>ClCCl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
In a round bottom flask under nitrogen, α,α,α-trifluro-m-tolyl isocyanate (3 g, 16 mmol) was dissolved in anhydrous dichloromethane (40 mL). 3-(Trifluoromethyl) aniline (2 g, 12.4 mmol) was added through a syringe at room temperature. A precipitate was formed 15 minutes after the completion of the addition. The reaction was left to stir overnight at room temperature. The next day the white solid was collected by filtration, washed with dichloromethane and dried. This solid corresponds to the desired urea. (4.2 g, 97% yield). 1H NMR (400 MHz, DMSO) δ 7.35 (d, 2H), 7.55 (m, 2 H), 7.6 (d, 2H), 8.05 (s, 2H). MS calculated=m/e 348, found=m/e 348.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH3:20])([CH3:19])[NH:14]1.C(O)(=O)C(C)=[O:23].O>O1CCOCC1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:19](=[O:23])[C:15]([CH3:20])=[N:14]1
Reactant: CC(=O)C(=O)O
Reactant: CC(C)Oc1cc(N2NC(C)(C)NC2=O)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a stirred mixture of 1.0 g (0.0031 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3,3-dimethyl-1,2,4-triazolidin-5-one in 10 mL of p-dioxane was added 0.29 g (0.0031 mole) of pyruvic acid and one drop of concentrated sulfuric acid. The mixture was stirred at room temperature for one hour, then an additional 0.25 g (0.0029 mole) of pyruvic acid was added. The mixture was heated at 90° C. for three hours, then poured into water. The mixture was extracted with ethyl acetate, and the solvent was evaporated from the extract under reduced pressure to give an oil. The oil was purified by thin-layer preparative chromatography on silica gel, eluting with ethyl acetate:heptane (1:1). Extraction of the appropriate bands gave 0.6 g of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid (mp 163°-164° C.), Compound 10 in the tables.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[Cl:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(Cl)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (1.02 g, 3 mmol) is initially charged in 15 ml of dimethylformamide. N-Chlorosuccinimide (0.550 g, 4 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 4 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 7:3). This gives 0.45 g of product (35.9% of theory).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:17]([O:24][P:25]([CH2:34][C@H:35]([OH:45])[CH2:36][NH:37][C:38](=[O:44])[C@@H:39]([NH2:43])[CH:40]([CH3:42])[CH3:41])([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][P:25]([CH2:34][C@H:35]([OH:45])[CH2:36][NH:37][C:38](=[O:44])[C@@H:39]([NH:43][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:40]([CH3:42])[CH3:41])([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1

Procedure:
The title compound was prepared substantially in a similar manner as in Step 1 of Example 10 using N-Cbz-glycine and [(R)-3-((S)-2-amino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride as the starting materials. The title compound thus obtained was purified by SiO2 chromatography using 0-4% MeOH/CH2Cl2 as the eluent. 1H NMR (CD3OD, 300 MHz): δ 7.20-7.15 (m, 10H), 5.17 (s, 2H), 5.02 (m, 2H), 4.19 (d, 1H), 4.09 (m, 1H), 3.80 (s, 2H), 3.23-3.15 (m, 2H), 2.08 (m, 1H), 2.01-1.90 (m, 2H), 1.88-1.78 (m, 6H), 1.70-1.59 (m, 2H), 1.30-1.11 (m, 2H), 1.03 (m, 1H), 0.95-0.88 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 60.61, 59.94. LCMS m/z: [M+H]+=616.26.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].C(Br)(Br)(Br)[Br:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(4-Bromo-3-methylphenyl)methanol (14.4 g, 71.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (26.1 g, 79.0 mmol) is added. The reaction mixture is cooled to 0° C. and PPh3 (20.7 g, 79.0 mmol) is added in small portions. The reaction mixture is stirred 2 h and the triphenylphosphine oxide that forms is filtered off and the solvent removed in vacuo. The resulting semi solid is filtered on a silica gel pad and rinsed with hexane/EtOAc (9:1) to provide the expected product 1-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.39-4.44 (m, 3H) 7.07 (dd, J=8.20, 2.34 Hz, 1H) 7.26 (t, J=1.17 Hz, 1H) 7.49 (d, J=8.20 Hz, 1H)
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([CH3:12])=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[BH4-].[Na+]>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:13])[C:6]([CH3:12])=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1cc2c(c(C)c1C)C(=O)C(C)C2
Agent: [BH4-]
Agent: [Na+]
Product: CC1=Cc2c(cc(C)c(C)c2C)C1
Yield: 63.9 %

Procedure:
Analogously to Example D, 1.50 g (8 mmol) of 2,5,6,7-tetramethyl-1-indanone (9) were reduced with 0.45 g (12 mmol) of NaBH4. The alcohol, which was not purified further, was then further reacted in the presence of 0.1 g of p-toluenesulfonic acid in 100 ml of toluene. Chromatography on 100 g of silica gel (hexane/methylene chloride 9:1) gave 0.88 g (65%) of 2,4,5,6-tetramethyl-indene (10).
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.CO.[ClH:31].C[CH2:33][O:34]CC>C(Cl)(Cl)Cl>[ClH:31].[C:4]1(=[O:23])[N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:34][CH3:33])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: N#Cc1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=N)c1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 6 g of 4-[2-(4-phthalimidomethylphenyl)ethyl]benzonitrile in 300 ml of chloroform, was added at room temperature slowly dropwise 50 ml of anhydrous methanol saturated with anhydrous hydrogen chloride. The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 6 g of methyl 4-[2-(4-phthalimidomethylphenyl)ethyl]benzimidate hydrochloride; m.p. 238°-240° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)(=O)C>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[O:11][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[N:3]=1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc3ccsc23)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 62.8 %

Procedure:
To a solution of 2-chloro-4-(mesityloxy)thieno[3,2-d]pyrimidine (32.4 mg, 0.11 mmol), TFA (0.13 mL, 1.71 mmol) in TFE (0.7 mL) was added 4-aminobenzonitrile (100 mg, 0.88 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC afforded the product as a white solid (26.7 mg, 63%):
Reaction SMILES: Cl.Br[CH:3]([CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15])=[CH:9][CH:8]=1)=[O:5].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH3:24])[CH:3]([CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15])=[CH:9][CH:8]=1)=[O:5])[CH3:21]
Reactant: CCNCC
Reactant: CC(=Nc1ccc(NC(=O)C(C)Br)cc1)N(C)C
Agent: Cl
Product: CCN(CC)C(C)C(=O)Nc1ccc(N=C(C)N(C)C)cc1

Procedure:
Following the procedure described in Example 3, reaction of 27.5 g of N'[4-(α-bromopropionyl)aminophenyl]-N,N-dimethylacetamidine hydrochloride with 40 g of diethylamine gives N'-[4-(α-diethylaminopropionyl)aminophenyl]-N,N-dimethylacetamidine, which is converted, in the crude form, into the naphthalenedisulphonate by means of one equivalent of naphthalenedisulphonic acid. Yield 16 g, melting point >260° C (decomposition) (recrystallized from ethanol/H2O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH:24][CH2:25][CH2:26][OH:27])[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][OH:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNCCO
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CCN(CCO)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 2-(ethylamino)ethanol were converted to yield 2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-ethyl-amino]-ethanol, MS: 436 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.C1COCC1>[Br:1][C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[N:7]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1Br)c1ccsc1c(=O)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a suspension of 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (2.2 g, 6.8 mmol) in a mixture of DMF (15 mL) and THF (15 mL) at 0° C. was added sodium hydride (60%, 0.54 g, 13.6 mmol). The reaction mixture was stirred at 0° C. for 30 min before (2-(chloromethoxy)ethyl)trimethylsilane (3.4 g, 20 mmol) was added. The resulting mixture was stirred at rt overnight and then poured into ice-water (50 mL). The resulting precipitate was filtered and purified by column chromatography (silica, heptane/ethyl acetate) to afford the desired product (2.7 g, 87%) as a light yellow solid: ESI MS m/z 454 [C19H24BrNO3SSi+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1.CN(C)[CH:19]=[O:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:20]1[C:19]2([CH2:6][CH2:5][C:4]([C:2]3[N:7]=[CH:6][C:5]([N:8]4[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]4=[O:16])=[CH:4][CH:3]=3)=[CH:3][CH2:2]2)[O:10][CH2:11][CH2:12]1
Reactant: COCC1CN(c2ccc(Br)nc2)C(=O)O1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COCC1CN(c2ccc(C3=CCC4(CC3)OCCO4)nc2)C(=O)O1
Reaction time: 22 h

Procedure:
A suspension of 8.9 g of (RS)-3-(6-bromo-pyridin-3-yl)-5-methoxymethyl-oxazolidin-2-one, 6.5 g of 8-tributyl-stannyl-1,4-dioxaspiro[4,5]dec-7-ene and 1.4 g of bis(triphenylphosphine)palladium(II) dichloride in 40 ml of dimethylformamide was stirred at 85° under argon for 22 h. Then, the mixture was cooled, filtered over a Celite® pad, the filter cake was washed with a large amount of ethyl acetate and the organic phase was washed several times with semi-saturated sodium chloride solution. The aqueous phases were extracted with ethyl acetate, the organic phases were combined, concentrated to a volume of 250 ml, treated with 250 ml of saturated potassium fluoride solution and stirred for 30 minutes. The mixture was again filtered over a Celite® pad, the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, concentrated and chromatographed over silica gel 60 with diethyl ether as the eluent. There were obtained 1.2 g of (RS)-3-[6-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-pyridin-3-yl]-5-methoxymethyl-oxazolidin-2-one. 1H-nmr (CDCl3) ppm: 8.48 (s, 1H), 8.19 (d, 1H), 7.56 (d,1H), 6.50 (m, 1H), 4.79 (m, 1H), 4.12 (t, 1H), 4.02 (s, 4H), 3.98 (t, 1H), 3.64 (m, 2H), 3.44 (s, 3H), 2.80 (m, 2H), 2.52 (m, 2H), 1.96 (t, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=O)[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[K+].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1.N1C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[N:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Reactant: CC(C)(C)OC(=O)CON
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (14.5 g) was added to a solution of 1 N aqueous potassium hydroxide (110 ml) at ambient temperature, and the mixture was stirred for 10 minutes to prepare the solution of potassium (υ-formamido-5-chlorothiazol-4-yl)glyoxylate. After this solution was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, thereto were added pyridine (20 ml) and a solution of tert-butyl 2-aminooxyacetate (10.3 g) in tetrahydrofuran (50 ml), followed by stirring at ambient temperature for 5 hours. After the reaction mixture was washed with ethyl acetate, the remaining aqueous solution was adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (8.5 g), mp 166° to 167° C. (dec.).
Reaction SMILES: [C:1](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.CC[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[C:1](=[N:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:35][CH:34]1[CH2:31][CH2:32][CH2:33]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: Clc1ccc(N(CC2CCC2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
Rf=0.77. (30/70 EtOAc/heptane (v/v)) (immediate deprotection). N-Benzhydrylidene-N′-(4-chlorophenyl)hydrazine is described in example 28.
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:39])[C@@H:16]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:37])[CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:19]2=[O:38])[CH3:17])[CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([N+](CC)(CC)CC)C>C(Cl)Cl>[Cl:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@@H:16]([CH3:17])[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][CH2:1][CH3:2])[CH2:10]3)=[O:39])[C:19]1=[O:38])(=[O:26])=[O:25])[CH:36]=[CH:35]2
Reactant: CC=O
Reactant: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[N+](CC)(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of acetaldehyde (0.041 ml from a stock solution made up from 0.0127 l acetaldehyde dissolved in 1 ml DCM)) in dry DCM (0.4 ml) treated with acetic acid (0.1 ml from a stock solution made up from 0.0054 ml acetic acid dissolved in 1 ml DCM) was added N-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl }-6-chloronaphthalene-2-sulfonamide [Example 365] (0.045 g) followed by tetraethylammonium triacetoxyborohydride (0.005 g). The mixture was stirred at room temperature, under nitrogen, for 60 h. DCM (1 ml) was added and the resultant solution washed with saturated sodium bicarbonate (1 ml) in a hydrophobic frit. The solvent was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.8 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:23].O>ClCCl>[CH3:14][C:13]([C:7]1[CH:8]=[C:9]([S:11]([CH3:12])=[O:23])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:17])([CH3:16])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2,6-bis(1,1-dimethylethyl)-4-(methylthio)phenol (2.0 g, 3.9 mmole) and meta-chloroperoxybenzoic acid (0.86 g, 4.1 mmole) in dichloromethane (25 ml) was stirred at room temperature for 20 hours. Water was added and the phases were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel gave the title compound, m.p. 171°-173°.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][C:13]([CH3:28])=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[OH:29]O.[OH-]>CO>[O:29]1[C@:14]2([C@:18]3([CH3:27])[C@@H:11]([CH2:12][C@@:13]12[CH3:28])[C@H:10]1[C@@H:21]([C@:22]2([CH3:25])[CH:7]([CH2:8][CH2:9]1)[CH2:6][C@H:5]([OH:4])[CH2:24][CH2:23]2)[C:20](=[O:26])[CH2:19]3)[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=C(C)C[C@@H]32)C1
Reactant: OO
Agent: [OH-]
Solvent: CO
Product: CC(=O)[C@@]12O[C@]1(C)C[C@H]1[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]12C
Reaction time: 0.67 h

Procedure:
A solution of 20.0 g. of 3α-acetoxy-16-methyl-16-pregnene-11,20-dione dissolved in 600 ml. of methanol, is cooled to 18°C., and 80 ml. of 30% hydrogen peroxide followed by 80 ml. of 2.5 N sodiim hydroxide are added. Considerable material precipitates from solution, but all redissolves on stirring the reaction mixture at 25°-30°C. for 40 minutes. The solution is kept at 15°-20°C. for 18 hours at which time the ultraviolet maximum at 249 has completely disappeared. Then 600 ml. of saturated salt water is slowly added, the crystalline precipitate is filtered, washed with water, and dried in air and in vacuum. The 16α,17α-epoxy-3α-hydroxy-16β-methyl-pregnane-11,20-dione thus formed weighs about 17 g.