Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](Cl)=[O:38]>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:37](=[O:38])[CH2:36][C:35]([CH3:41])([CH3:40])[CH3:34])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
80.0 mg (0.217 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in 1 ml of dichloromethane. 75.9 mg (0.750 mmol) of triethylamine was added to the obtained solution. Then a solution of 35.1 mg (0.260 mmol) of 3,3-dimethylbutanoyl chloride in 0.5 ml of dichloromethane was slowly added to the obtained mixture. After stirring for 30 minutes, the product was purified by the silica gel chromatography (hexane:ethyl acetate=93:7 to 3:1) to obtain the title compound.
Reaction SMILES: O[CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[C:7]([O:13]CC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.C(O)C>[Cl-].[Zn+2].[Cl-].O>[CH3:11][C:9]1[O:5][C:3]([CH3:4])=[C:2]([CH3:6])[C:8]=1[C:7]([OH:13])=[O:12]
Reactant: CC(=O)C(C)O
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Product: Cc1oc(C)c(C(=O)O)c1C
Yield: 96 %

Procedure:
A mixture of 3-hydroxy-2-butanone (90g.) ethyl acetoacetate (175g.), absolute ethanol (150 ml.) and anhydrous zinc chloride (100g.) was heated under reflux for 24 hours. The cooled solution was poured into water and extracted with benzene. The benzene extract was washed successively with 30% aqueous sodium bisulfite, 5% sodium hydroxide, dilute hydrochloric acid and finally with water. The solvent was removed and the residual ester saponified with aqueous-alcoholic alkali as in example 18 to yield 149 g. or 96% yield of the 2,4,5-trimethyl-3-furoic acid.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:35])[CH:8]([N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1)(C)(C)C.C(O)C>C(Cl)Cl>[OH:5][NH:6][C:7](=[O:35])[CH:8]([N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(Cc2nnn(C)n2)C(=O)NOC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(Cc2nnn(C)n2)C(=O)NO)cc1
Temperature: 0 °C

Procedure:
N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide (0.77 g, 1.55 mmol) is dissolved in methylene chloride (2.0 mL) and ethanol (0.1 mL) in a glass sealed tube, and the reaction is cooled to 0° C. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes, and then the tube is sealed at room temperature for 3 days. After that time, the solvent is removed, and the reaction is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase is dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (2% methanol/methylene chloride) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide, m.p. 72°-75° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)c1

Procedure:
The title compound was prepared from 2′-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.94) (0.349 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.267 g, 50%). MS (ISP) 532.1 [(M+H)+]; mp 209° C.
Reaction SMILES: [Sn](Cl)Cl.[F:4][C:5]1[CH:6]=[CH:7][C:8]2[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[S:10][C:9]=2[CH:25]=1.O>Cl.C(O)C>[NH2:14][C:13]1[C:12]2[C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:25][C:9]=3[S:10][C:11]=2[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]=1
Reactant: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2cc(F)ccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccccc2Nc2sc3cc(F)ccc3c21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Tin(II) chloride (50 g) was dissolved in a 18% hydrochloric acid (250 ml) solution heated to 50° C., and a suspension of 6-fluoro-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile (20 g) in ethanol (280 ml) was added. The mixture was refluxed under heating for 4 hours. Then, the reaction mixture was cooled to 40° C. and poured into water (1 L) and the mixture was stood still for 30 minutes. The precipitated crystals were filtered by suction and washed with water (500 ml) to give 12-amino-3-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 hydrochloride (15 g).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2cncs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(O)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 60, Step B) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:22]Br>ClCCl>[NH2:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH2:9][C:10]([Br:22])([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1=CCC(Br)(C(=O)OC)C=C1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
10.5 g (50 mmol) dimethyl amino-terephthalate and 8.1 ml (100 mmol) pyridine are dissolved in 175 ml dichloromethane and at −16° C. a solution of 2.7 ml (52.5 mmol) bromine in 25 ml dichloromethane is added dropwise. It is stirred for 4 hours at 0° C. and then heated overnight to ambient temperature. The mixture is added to ice water, washed three times with water and then dried over magnesium sulphate and evaporated down. The crude product is recrystallised from ethanol.
Reaction SMILES: O1CCCC1.[CH3:6][NH:7][CH3:8].Cl.Cl[C:11]([N:13]1[C:19]2[S:20][C:21]([CH2:23][CH3:24])=[CH:22][C:18]=2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16][CH2:15][CH2:14]1)=[O:12]>O>[CH2:23]([C:21]1[S:20][C:19]2[N:13]([C:11](=[O:12])[N:7]([CH3:8])[CH3:6])[CH2:14][CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[CH:22]=1)[CH3:24]
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccccc1

Procedure:
To 50 ml of 25%(W/V) tetrahydrofuran solution of dimethylamine is added 7.1 g of 1-chlorocarbonyl-7-ethyl-5-phenyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring, and stirred at room temperature for 2 hours. The reaction mixtureis transferred to water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is treated with ethanolic hydrogen chloride to give 7-ethyl-1-dimethylcarbamoyl-5-phenyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloric as yellow crystals, melting at 237°-238° C with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=O.CN1CCOCC1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CN1CCOCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Yield: 75.3 %

Procedure:
To a suspension of 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (13.3 mmol) in ethanol (60 ml) was added 4-(2-bromoacetyl)-benzoic acid (13.3 mmol) and 4-methylmorpholine (13.9 mmol). The reaction was heated at reflux for 2.5 h. The reaction was concentrated in vacuo and the solid washed with water (200 ml) to yield the title compound as a white solid (3.9 g). 1H NMR (400 MHz, CDCl3) 1.45 (9H, s), 3.58 (8H, m), 4.86 (1H, s), 6.95 (1H,s), 7.97 (2H, d, J 8 Hz), 8.1 (2H, d, J 8 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl>>[ClH:1].[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:14][CH:15]=1)[CH3:20]
Reactant: CCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CNCCN1
Agent: Cl
Product: CCc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 39 %

Procedure:
2-Chloro-1-(4-ethylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-ethylphenyl)-2-(piperazin-1-y)-1H-indole-3-carboxaldehyde hydrochloride (39% yield) as a cream solid. ESI/MS 334 (M+H); RT=2.67 min; NMR 10.13 (1H, s); 8.11 (1H, d, J=6 Hz); 7.50 (4H, s); 7.24 (2H, m); 6.94 (1H, d, J=6 Hz); 3.42 (4H, m); 2.95 (4H, m); 2.76 (2H, q); 1.30 (3H, t).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:49])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[S:35][C:36]([CH2:39][CH2:40][O:41]C3CCCCO3)=[N:37][N:38]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[S:35][C:36]([CH2:39][CH2:40][OH:41])=[N:37][N:38]=4)[CH:29]=3)[CH2:26][C:25](=[O:49])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nnc(CCO)s3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (0.15) and crude 3-oxo-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-phenyl)-propionic acid tert-butyl ester (0.24 g) (Example K30) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:21][N:20]=2)=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Br)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and 4-bromophenyl acetohydroximoyl chloride (150 mg, 0.602 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 2 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (85 mg, 66%).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([O:12][CH3:13])(=[O:11])[C:8]([CH3:10])=[CH2:9]>CO>[CH3:13][O:12][C:7](=[O:11])[CH:8]([CH3:10])[CH2:9][NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)CCN
Solvent: CO
Product: COC(=O)C(C)CNCCC(C)C
Yield: 76.4 %

Procedure:
A solution of 8.72 g (0.10 mole) of isoamylamine, 12.01 g (0.12 mole) of methyl methacrylate and 50 mL of methanol was heated at reflux under an argon atmosphere for 22 hours. After cooling the mixture was concentrated, then distilled under vacuum to give 14.31 g of (rac)-2-methyl-3-(3-methyl-butylamino)-propanoic acid methyl ester as colorless oil. b.p. 73-75 degrees, 2 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:9](=[C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:11]=1[CH3:12])[NH:8][CH2:7][CH2:6]2.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:22]([N:8]1[C:9]2[C:5](=[C:4]([CH3:20])[C:3]([CH2:2][OH:1])=[C:11]([CH3:12])[C:10]=2[NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:6][CH2:7]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCI
Reactant: Cc1c(CO)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CCc2c(C)c(CO)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
N-(5-Hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.5 g) was dissolved in DMF (15 ml) and 1-iodooctane (2.6 g) and K2CO3 (1.5 g) were added, which was followed by stirring under a nitrogen atmosphere at 50° C. for 2 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=1/0-10/1) to give 1.0 g of the title compound.
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH3:17])[C:4](=[NH:8])[O:5]CC.[C:18](Cl)(Cl)=[O:19]>>[CH2:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:3]1[O:2][C:18](=[O:19])[NH:5][C:4]1=[O:8])[CH3:17]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1ccccc1OCC
Agent: Cl
Product: CCOc1ccccc1C1OC(=O)NC1=O
Yield: 70 %

Procedure:
Ethyl 1-hydroxy-1-(2-ethoxyphenyl)methanecarboximidate hydrochloride (20 g.) was reacted with phosgene according to the procedure of Example 3. To isolate the product, the reaction mixture was evaporated to dryness and the solid residue partitioned between 500 ml. of water and 500 ml. of chloroform. The aqueous phase was washed with two fresh portions of chloroform. The combined chloroform phase and washes was dried over anhydrous magnesium sulfate, filtered, evaporated to solids and recrystallized from toluene to yield 5-(2-ethoxyphenyl)oxazolidine-2,4-dione (11.9 g., 70%; m.p. 165°-167° C., m/e 221).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl)[C:9]([N+:23]([O-:25])=[O:24])=[C:8]([CH3:26])[NH:7][C:6]=1[NH2:27])=[O:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH2:21][N:39]2[CH2:38][CH2:37][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[CH2:41][CH2:40]2)[C:9]([N+:23]([O-:25])=[O:24])=[C:8]([CH3:26])[NH:7][C:6]=1[NH2:27])=[O:4]
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCCCl
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCCN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5 liter 4-neck round-bottom flask fitted with mechanical stirrer, reflux condenser and thermowell, under a nitrogen atmosphere, was added 37.87 g of 2-amino- 1,4-dihydro-4-(2-[(4-chlorobutyl)thio]phenyl)-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester, 3.5 liters of isopropanol, 35.35 g of 1-(2-methoxyphenyl)piperazine, 27.57 g of sodium iodide and 15.45 g of sodium bicarbonate. The reaction mixture was heated at reflux for 6.5 hr., then stirred overnight at room temperature. The solvent was removed by rotary evaporation and the residue was partitioned between dichloromethane and water. The aqueous layer was washed with dichloromethane (2×300 ml), the organic layers combined, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography, eluting with 5% methanol in ethyl acetate. The product (Ex. No. 1, Table 1) was isolated as an orange solid, 37.23 g. 1H-NMR (d6 -DMSO) δ 1.60(m,4H); 2.33(m,2H); 2.40(s,3H); 2.45(m,4H); 2.92(m,6H); 3.43(s,3H); 3.76(s,3H); 5.59(s,1H); 6.73-6.95 (m,6H); 7.09(m,2H); 7.35(m,1H); 9.50(br s,1H). Mass spectrum: 568 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][C:10]#[N:11])[CH3:7])=[O:5].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:10]([CH2:9][CH2:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[NH:1][C:19]1[C:20]([Cl:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)#[N:11]
Reactant: CN(CCC#N)C(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCC#N)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 96 h
Yield: 50.6 %

Procedure:
2-Amino-N-(2-cyano-ethyl)-N-methyl-benzamide (5.73 g, 28.2 mmol) in N,N-Dimethylformamide (50 mL) was treated with 2,4,5-Trichloro-pyrimidine (4.00 mL, 34.9 mmol) and Potassium carbonate (5.8 g, 42 mmol). The mixture was heated at 80° C. for 4 h, then cooled to room temperature and stirred for 4 days. The reaction was diluted with 200 mL water, extracted with DCM (200 mL, then 2×50 mL). The combined organics were washed 1×100 mL brine, dried over sodium sulfate and conc. in vacuo to give an oil, which was chromatographed (ISCO 330 g silica gel, 0-80% EtOAc:Hex). The product eluted with ˜60% EtOAc to afford N-(2-Cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide as an oil (5.0 g, 50%). 1H-NMR (CDCl3): 9.36 (s, 1H), 8.34 (d, 1H, J=8.4 Hz), 8.22 (s, 1H), 7.53 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 3.81 (m, 2H), 3.22 (s, 3H), 2.80 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][S:12][C:13]#[N:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:16].[OH-].[Na+].O>C(O)(=O)C>[Br:16][C:13]1[S:12][CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:14]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2csc(Br)n2)cc1
Yield: 45 %

Procedure:
2-(4-Nitrophenyl)-2-oxoethyl thiocyanate (3.0 g; 15.4 mmol) and 50 mL of 30% HBr in acetic acid were stirred at room temperature under nitrogen overnight. The yellow paste was neutralized with 60 mL of 2N NaOH and 60 mL of H2O. The residue was collected by suction filtration. Purification of the residue on silica gel using a stepwise gradient of 5-50% ethyl acetate:hexane gave 2-bromo-4-(4-nitrophenyl)-1,3-thiazole (2.0 g, 45%), MS (ES) m/z 286[M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[Si:24]([O:31][CH2:32][C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:34]1[CH:35]=[CH:36][N:37]=[C:33]1[CH2:32][O:31][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1ncc[nH]1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1CO[Si](C)(C)C(C)(C)C
Yield: 91.2 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methylsulfonyloxy-2-(2-methylsulfonyloxyethyl) pyrrolidine (28.8 g) and 2-(t-butyldimethylsilyloxymethyl)imidazole (18.1 g) were reacted in substantially the same manner as that of Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(2-(t-butyldimethylsilyloxymethyl) imidazol-1-yl)ethyl]-4-methylsulfonyloxypyrrolidine (34.5 g) as a yellow paste.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2>C1C=CC=CC=1.[Zn]>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([OH:12])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C

Procedure:
To a refluxing solution of zinc dust (0.15 g, 20 mesh, activated prior to use by washing with 2% of hydrochloric acid, water, 95% ethanol, acetone and anhydrous ether, then dried in vacuum for several hours) in 6 ml of dry benzene was slowly added a mixture of bromo ethyl acetate (0.082 ml, 0.74 mmol) and ethyl 4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate (Compound D10, 0.13 g, 0.371 mmol) in 6 ml of dry benzene. The resulting mixture was refluxed for 2 h then cooled to room temperature. The precipitate was filtered through celite and the filtrate was washed with cold 15% sulfuric acid. The organic phase was washed with saturated sodium bicarbonate, brine, dried over Na2SO4, filtered and concentrated to give a red oil. Purification by flash chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound as a red oil.