Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[NH:5][C:6](=O)[CH3:7].C(Cl)(=O)C(Cl)=O>ClCCl.[Fe](Cl)(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH:4]([C:3]([O:2][CH3:1])=[O:18])[N:5]=[C:6]2[CH3:7])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(C)=O
Agent: Cl[Fe](Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1Cc2ccc(OC)cc2C(C)=N1
Temperature: 10 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of N-acetyl-O-methyltyrosine methyl ester (10 g, 39.8 mmol) in anhydrous dichloromethane (350 mL) was added oxalyl chloride (44 mL, 2 M solution). The reaction mixture was stirred for 1 hr and then cooled to - 10° C. and to it anhydrous iron (III) trichloride (7.75 g, 47.8 mmol) was added portionwise. The stirring was continued overnight at room temperature and then the reaction mixture was treated with 2 M HC1 (100 mL) for 2 hrs. The organic phase was separated, washed with water and brine, dried (MgSO4) and concentrated in vacuo. Methanol (130 mnL) and concentrated sulfuric acid (6 niL) were added to the foamy residue and reaction was heated to reflux for 8 hrs. The reaction mixture was concentrated in vacuo, diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The water layer was basified with ammonium hydroxide to pH >9 and extracted with dichloromethane (3×50 mL). The organic phase was washed with water, brine, dried (MgSO4) and concentrated in vacuo. The dark yellow product (8.7 g) was purified by a silica gel column chromatography eluting with (1: 1) ethyl acetate/ hexane to yield 5.61 g (60 %) of yellow product: 1H-NMR (CDCl3, δ): 2.45 (d, J=2 Hz, 3H), 2.82- 3.00 (m. 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.19 (qq. J=2. 6.8 Hz, I H), 6.93 (dd, J=2.7, 7.5 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 7.14 (d, J=7.5 Hz- 1H): MS showed (M+H) +@ 234; Anal. Calcd for C13H15NO3 : C, 66.94; H, 6.48; N, 6.00; Found: C, 66.78; H, 6.36; N, 5.96.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][NH:16][CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:25](C)=O.[Na+].CC(O)=O.[OH-].[Na+]>CO>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:25])[CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCNC3)c1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2cc(Nc3nc(Br)cn(C)c3=O)ccc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 221a (2.75 g, 7.5 mmol), formaldehyde (37% in H2O, 30 mL, 375 mmol), NaBH(OAc)3 (4.75 g, 22.5 mmol), and AcOH (25 ml, 150 mmol) in methanol (125 ml) was stirred for 4 hours at room temperature. The mixture was then brought to basic condition with saturated NaOH solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 4:1 ethyl acetate/methanol to give 221b. (0.9 g, 34.4%) LC/MS: m/z 350 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:12][C:13](=[O:30])[CH:14]([NH:22]C(OC(C)(C)C)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][S:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:12][C:13](=[O:30])[CH:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][S:7][C:8]([CH3:11])([CH3:9])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CSC(C)(C)C)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CSC(C)(C)C)NC(=O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 23 (6.63 g, 25.0 mmol) in CH2Cl2 (30 mL) was added TFA (30 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h, then concentrated. EtOAc (150 mL) was added, washed successively with sat. NaHCO3 (2×20 mL) and brine (20 mL), dried (Na2SO4), and concentrated to give D as a light yellow oil (6.83 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.94 (br d, 1H), 7.30 (m, 5H), 4.80 (m, 1H), 4.21 (q, 2H), 3.70 (dd, 1H), 3.28 (dd, 1H), 2.99 (m, 2H), 2.74 (dd, 1H), 2.25 (br s, 2H), 1.30 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[O:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:21])=[CH:23][CH:24]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 99.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{[5-(4-chlorophenyl)-2-methyl-3-furyl](cyclohexyl)methoxy}benzoic acid (120 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (143 mg, 93%) as an amorphous compound.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:13]O.S(=O)(=O)(O)O>>[O:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2c1OCC2
Temperature: 80 °C

Procedure:
2,3-Dihydrobenzofuran-7-carboxylic acid (8 g, 48.7 mmol) was dissolved in methanol (39.6 mL, 975 mmol) and concentrated sulfuric acid (2.6 mL, 48.7 mmol) was slowly added. The mixture was refluxed at 80° C. for 17 h. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was evaporated to give the title compound as a beige solid. Yield: 8.6 g (99%). HPLC purity 93%, RT=1.72 min (System A; 10-97% MeCN over 3 min); 96%, RT=1.67 min (System B; 10-97% MeCN over 3 min). MS (ESI+) for C10H10O3 m/z 179 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[NH:8][N:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[N:8]([C:45](=[O:46])[NH:44][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NNC(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=NN(C(=O)Nc2ccc(Cl)cc2)C(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.520 g) in methylene chloride (12 ml) was added pyridine (4 equiv.) and 4-chlorophenyl isocyanate (1.25 equiv.). Stirred at room temperature for 16 hours. Evaporated and recorded crude 1H: 80156×134 RM1—revealed expected product and relatively clean. Purified by silica gel chromatography, eluant 10-100% EtOAc in hexane over 25 mins. Collected 1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.480 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:36]=[C:6]2[N:7]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:8]([CH3:25])=[C:9]([C:23]#[N:24])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=3[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]2[N:4]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>N1C=CC=CC=1>[C:23]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]2[N:4]=[C:3]([NH:2][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])[N:36]=[C:6]2[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:8]=1[CH3:25])#[N:24]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)n2nc(NC(=O)C3CC3)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7S)-2-amino-7-[4-cyano-2-(methylsulfonyl)phenyl]-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (16 mg, 30 μmol) was dissolved in abs. pyridine (1 ml). At room temperature, cyclopropanecarbonyl chloride was added in two portions (in each case 3.7 mg, 36 μmol, 1.2 eq.). Once HPLC showed substantial conversion (12 h), the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Macherey & Nagel Gravity C18 column, 21×300 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (11.2 mg, 66% of theory).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>[Ti](Cl)(Cl)(Cl)Cl.CCOCC>[CH3:1][N:2]([CH3:3])[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1
Reactant: CNC
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(C)C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Titanium tetrachloride (237 g., 1.25 mole) is added in small portions over 4 hrs. to a solution of dimethyl amine (307 g., 6.82 mole) and cyclohexanone (223 g., 2.27 mole) in 600 ml. ether. Temperature is maintained below 5° during the addition. The mixture is stirred overnight at room temperature. The precipitate is collected and washed with ether. The ether is removed by distillation and the residual oil distilled at reduced pressure. After a small forerun, 243 g. (86% yield) of enamine (title compound) is obtained, b.p. 79°-80° (33 mm. Hg.) The nmr (CDCl3) is in accord.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH2:27][CH3:28]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:27][CH3:28])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1
Reactant: CCBr
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Product: CCOc1ccc(CN2C(=O)CCCC2c2c(OC)cccc2OC)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available bromoethane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.76 min.; [M+H]+: 370.17 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:15])[CH3:14])[NH:7]2.[C:17]1([S:23]([N:26]=C=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:26][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH:5]=[C:6]([C:13](=[O:15])[CH3:14])[NH:7]2
Reactant: CC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-acetyl-1,4-dihydroquinol-4-one (0.28 g, 1.1 mmol) and benzenesulfonyl isocyanate (0.16 mL, 1.2 mmol) in acetonitrile (5 mL). Heat at reflux for 3 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel eluting with dichloromethane to obtain a solid. Recrystallize the solid from ethyl acetate/hexane to give the title compound; mp, 163°-164° C. Rf =0.32 TLC/silica gel/dichloromethane. Elem. Anal. Calcd. for C17H12Cl2 N2O3S: C, 51.65; H, 3.04; N, 7.09.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([C:18]1[CH:43]=[CH:42][C:21]([O:22][C:23]2[CH:32]=[C:31]3[C:26]([CH:27]=[C:28]([C:39](Cl)=[O:40])[N:29]=[C:30]3[CH2:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[CH2:6]([N:5]([CH2:4][C:3]([OH:2])=[O:13])[C:39]([C:28]1[N:29]=[C:30]([CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:31]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([O:22][C:21]1[CH:42]=[CH:43][C:18]([C:14]([CH3:16])([CH3:17])[CH3:15])=[CH:19][CH:20]=1)[CH:32]=2)=[O:40])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CNCc1ccccc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)Cl)nc(CC4CCCC4)c3c2)cc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N(CC(=O)O)Cc4ccccc4)nc(CC4CCCC4)c3c2)cc1
Yield: 70.8 %

Procedure:
The title compound (39 mg) was prepared following the same procedures that was described for example 432 from benzyl glycine methyl ester (17.9 mg, 0.1 mmol) and 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl chloride (46 mg, 0.1 mmol).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccc(C(F)(F)F)cc3)c12

Procedure:
The title compound, grey solid (88 mg, 97%), MS (ISP) m/z=363.2 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH3:11])[CH:7]=[CH:8][CH:9]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[Cl:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[N:16][OH:17])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccc(OC(F)(F)Cl)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1cccc(OC(F)(F)Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 106.4 %

Procedure:
A mixture of 3.3 g of 1-(3-(chloro-difluoro-methoxy)-phenyl)-ethanone, 1.4 g of hydroxylamine hydrochloride and 10 ml of pyridine is stirred at 50° C. for 2 hours. It is then poured into ice-water, extracted with diethyl ether and concentrated using a rotary evaporator, and any pyridine still present is removed azeotropically by means of toluene. Drying under reduced pressure at 60° C. yields 3.75 g of the desired oxime in the form of an oil.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:22]1[CH:29]2[CH:23]1[CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=12.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][Si](C)(C)C)=[N:39][CH:40]=1>O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38](=[O:41])[N:39]([C@@H:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][CH2:25][CH2:24][C@H:23]2[OH:22])[CH:40]=1
Reactant: C[Si](C)(C)Oc1ccc(Cl)cn1
Reactant: c1ccc2c(c1)OCCC1OC21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=c1ccc(Cl)cn1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 90 °C

Procedure:
22.7 g (72 mmol) of tetrabutylammonium fluoride trihydrate are added to a mixture of 10.54 g (65 mmol) of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin and 19.4 g (96 mmol) of 5-chloro-2-trimethylsilyloxy-pyridine, and the mixture is heated at 90° C. for 3 hours. The mixture is stirred into water and extracted several times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, and the solvent is evaporated off in vacuo. The residue is crystallized in n-butyl acetate. Crystals of melting point 175.5°-177.5° C. are obtained.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](COCC[Si](C)(C)C)[CH:14]=[CH:13]2)[C:6]([OH:8])=[O:7])[CH2:2][CH3:3].C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([CH2:9][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]([OH:8])=[O:7])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CCCOC(Cc1ccc2c(ccn2COCC[Si](C)(C)C)c1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
0.96 g rac-2-propoxy-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-5-yl]-propionic acid were dissolved in 40 ml N,N-dimethylformamide. 0.94 ml Ethylene diamine were added, followed by 7.63 ml of a tetra-butylammonium fluoride solution (1 molar in tetrahydrofuran); a small amount of molecular sieves was then added to the reaction mixture and it was heated to 80° C. After 6 hours, the mixture was cooled to r.t., filtered and the filtrate was poured into ice water and extracted 3 times with dichloromethane. The organic phases were washed with water, dried over MgSO4, filtered again and evaporated. The crude rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[CH3:15][CH:16]([C:29](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:30])[C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:18].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:29]([OH:30])=[C:16]([CH3:15])[C:17](=[O:18])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1nnc(SCc2ccccc2)s1
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: Cc1c(O)nc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of 19.3 g of 2-amino-5-benzylthio-1,3,4-thiadiazole, 41.3 g of bis(2,4,6-trichlorophenyl) 2-methylmalonate and 60 ml of chlorobenzene was stirred at 135°-140° C. for 1 hour. After cooling, n-hexane was added to the reaction mixture and the formed precipitate was separated by filtration. The separated precipitate was washed with n-hexane and thus 23.9 g of 2-benzylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 247°-250° C. Yield 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:18][CH2:17][CH:13]([C:14](O)=O)[CH2:12][CH2:11]1.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:14]([CH:13]3[CH2:17][CH2:18][NH:10][CH2:11][CH2:12]3)[O:9][C:3]=2[CH:4]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc2nc(C3CCNCC3)oc2c1
Temperature: 190 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
2-amino-5-bromophenol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixture was heated to 190° C. for 3 h. After 3 h, reaction mixture cooled to rt and basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the title compound (500 mg) as a black solid. It was used in the next step without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][O:27][CH3:28])=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][O:27][CH3:28]
Reactant: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Yield: 106.9 %

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(methoxymethyl)cyclohexylcarbamate (64 mg, 0.163 mmol) in methanol (3 mL) was stirred with Pearlman's catalyst (20% Pd(OH)2 on charcoal, 65 mg) under hydrogen at atmospheric pressure and rt for 22 h. The mixture was filtered through Celite and the solids were washed with methanol. The filtrate was concentrated to provide tert-butyl (1R,3R,4S)-4-amino-3-(methoxymethyl)cyclohexylcarbamate as a pale yellow glassy foam (45 mg) which was used without further purification. MS found: (M+H)+=259.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(F)c1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
3-Fluorophenylacetic acid (4.90 g, 32.07 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (3.5 ml, 40.08 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 50 ml dichloromethane. To this mixture, 4-bromoanisole (5.0 g, 26.72 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (5.3 g, 40.08 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (6.6 g, 80% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 12.02 (s, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.57 (dd, J=8.9, 2.4.1 Hz, 1H), 7.36 (m, 1H), 7.04 (m, 3H), 6.90 (d, J=8.9 Hz, 1H), 4.28 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2].[H-].[Na+].[CH:28](I)([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:28]([CH3:30])[CH3:29])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(C)c(C)cc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(OC(C)C)nc2cc(C)c(C)cc2c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-chlorophenyl)-1,2-dihydro-6,7-dimethyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (2.0 g) in DMF (20 ml) was added sodium hydride (60% in oil) (270 mg), followed by stirring at room temperature for 30 minutes. To this solution was added isopropyl iodide (0.9 ml), followed by stirring at 70° C. for 5 hours. After the mixture was cooled, ethyl acetate was added, and this mixture was washed successively wfth dilute hydrochloric acid, aqueous potassium carbonate and Water and then dried, after which the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1), to yield 4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylic acid ethyl ester as colorless crystals (1.72 g).