Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH:17]=[CH:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([CH:8]([CH:10]=[O:11])[CH3:9])[CH2:6][CH2:5]1.[CH3:26][C:27]([CH3:32])([CH2:30]O)[CH2:28][OH:29].C(OCC)(=O)C.CCCCCC>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:27]1([CH3:32])[CH2:28][O:29][CH:10]([CH:8]([C@@H:7]2[C@:12]3([CH3:25])[C@H:4]([C@H:3]4[C@H:15]([CH2:14][CH2:13]3)[C@:16]3([CH3:24])[C:21](=[CH:20][C:19](=[O:23])[CH:18]=[CH:17]3)[CH2:22][C@H:2]4[OH:1])[CH2:5][CH2:6]2)[CH3:9])[O:11][CH2:30]1
Reactant: CC(C)(CO)CO
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
In 200 ml of methylene chloride were dissolved 5.00 g (14.6 mmoles) of 7α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde and 4.56 g (43.8 mmoles) of 2,2-dimethyl-1,3-propanediol, followed by addition of 100 mg of p-toluenesulfonic acid and 20 g of molecular sieve 4A 1/16. The mixture was stirred gently at room temperature for 12 hours. From the reaction mixture thus obtained, the molecular sieve was filtered off and the solvent in the filtrate was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1:10, v/v) to give 3.14 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-7α-hydroxypregna-1,4-dien-3-one (yield: 50%).
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Br[C:50]1[N:55]=[CH:54][CH:53]=[CH:52][N:51]=1.C(N(C(C)C)CC)(C)C.C(O)(C)(C)C>O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:55]=[CH:54][CH:53]=[CH:52][N:51]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: Brc1ncccn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncccn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 86.8 %

Procedure:
To 1.21 g (1.79 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 0.90 g (5.7 mmol) of 2-bromopyrimidine, 1.0 ml (5.9 mmol) of diisopropylethylamine and 20 ml of tert-butanol were added, and the reaction solution was stirred at 65° C. for 2.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 1.17 g of the title compound as a white solid (yield: 87%).
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:32][C:33]1[N:37]([CH2:38][C:39](O)=[O:40])[N:36]=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([C@@H:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:39](=[O:40])[CH2:38][N:37]3[C:33]([CH3:32])=[CH:34][C:35]([C:42]([F:45])([F:44])[F:43])=[N:36]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (150 mg, 0.44 mmol) was dissolved in 3 mL of dry dichloromethane. To this solution was added triethylamine (30 μL, 0.22 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (83 mg, 0.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The reaction mixture was shaken overnight at ambient temperature, concentrated under reduced pressure and passed through a silica gel column (2 g) using 1:1 hexanes/ethyl acetate as eluant. The dichloromethane/hexanes/ethyl acetate solution was concentrated under reduced pressure, and the residue was purified by preparative reverse phase High Pressure Liquid Chromatography (HPLC) using a solvent gradient going from 100% water to 100% acetonitrile to give 85 mg of the title product, a compound of the present invention as an oil. 1H NMR (CDCl3) δ 0.9-1.1 (br m, 3H), 1.7-1.9 (m, 2H), 1.9-2.2 (m, 4H), 2.31 (s, 3H), 2.7-3.0 (m, 4H), 3.2-3.4 (m, 2H), 3.9-4.6 (br m, 2H), 4.96 (br s, 2H), 5.6-6.0 (m, 1H), 6.3 (s, 1H) 7.20-7.45 (m, 5H), 7.8 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH2:14])[C:6]([NH2:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:21][C:22](=O)[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:21])[NH:13][C:6]4[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:4][C:5]=4[N:14]=3)[CH:30]=[CH:29][CH:28]=2)[CH:32]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(C(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4,5-bis-trifluoromethyl-benzene-1,2-diamine [CAS-No. 30454-92-3] (244 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (297 mg, 1.0 mmol) in toluene (10 ml) under reflux conditions for 2 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (315 mg, 70%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[C:11]1(=[O:18])[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24](=[NH:26])[NH2:25])[CH3:20].C(O)C.CN(C)C=O>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)[C:12]2[C:11](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[NH:25][C:24]=1[NH2:26])=[O:27])[CH3:20]
Reactant: CCOC(=O)CC(=N)N
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=C1CCCC(=O)C1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1cccc(C#N)c1
Yield: 56 %

Procedure:
Heating a solution of 6.5 g of 3-cyanobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 6 hours yields 2-amino-4-(3-cyanophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 262°C (ethanol/dimethylformamide).
Reaction SMILES: [OH:1][CH:2]([CH3:23])[CH2:3][CH2:4][C:5]1[O:6][C:7]2[C:16]3[CH:15]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:8]=2[N:9]=1.C[N+]1([O-])CCOCC1.O>C(#N)C>[O:1]=[C:2]([CH3:23])[CH2:3][CH2:4][C:5]1[O:6][C:7]2[C:16]3[CH:15]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(CCC(C)O)oc3c21
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: O
Product: CC(=O)CCc1nc2ccc3c(c2o1)C(CCNC(C)=O)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A suspension of N-{2-[2-(3-hydroxybutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl}acetamide (72.0 mg, 0.228 mmol), 4 Å molecular sieves (72 mg), 4-methylmorpholine N-oxide (66.8 mg, 0.570 mmol) and tetra-n-propylammonium perruthenate(VII) (8.0 mg, 0.0228 mmol) in acetonitrile (3 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallized (ethyl acetate/hexane) to give the title compound (22.2 mg, yield 31%).
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd].[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11]
Reactant: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cc1NC=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN)cc1NC=O
Yield: 89.7 %

Procedure:
A solution of {5[(1R)-2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-[({[2-(trimethylsilyl)ethyl]oxy}methyl)oxy]phenyl}formamide (90 mg) in EtOAc (8 ml) and EtOH (8 ml) was hydrogenated over 10% palladium on carbon (40 mg) and 20% palladium hydroxide on carbon (20 mg). When hydrogen uptake had ceased the mixture was filtered through celite and the solvent evaporated in vacuo to give the title compound (52 mg). LCMS RT=2.31 min.
Reaction SMILES: [CH2:1]([S:9]([NH:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH2:28])[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30]([C:32](=[O:39])[CH:33](Cl)[CH2:34][CH2:35][CH2:36][CH3:37])[CH3:31].[N+](C1C=CC=CC=1)([O-])=O>CO>[CH2:1]([S:9]([NH:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:28][CH:33]([CH2:34][CH2:35][CH2:36][CH3:37])[C:32]([CH2:30][CH3:31])=[O:39])[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:10])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reactant: CCCCC(Cl)C(=O)CC
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(NC(CCCC)C(=O)CC)cccc1C2=O

Procedure:
1-(n-octylsulfonylamino)-8-aminoanthraquinone (0.25g), 1-ethylhexanoyl chloride (0.5g) and nitrobenzene (5ml) were heated at reflux for 10 mins. After addition of methanol (10ml), the mixture was heated on a steam bath for a further 10 mins to destroy excess acid chloride. 0n evaporation of low-boiling material, the remaining liquid was diluted with toluene (100ml) and separated by chromatography on a silica gel column. Nitrobenzene eluted first, and the material eluted with a 50:50 mixture of toluene:ethyl acetate was collected. The solvent was evaporated and ethanol was added to the residue, which upon trituration afforded the product as a yellow solid.
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.N([O-])=O.[Na+]>O.CCOC(C)=O>[O:9]=[C:8]1[O:10][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
To a solution of L-glutamic acid (10.07 g, 0.068 mol, J&K CHEMICA) in 20 ml of concd. HCl and 40 mL H2O was added a solution of NaNO2(7.0 g, 0.102 mol, Shantou Xilong chemical factory) in H2O (20 mL) slowly at −5° C. The mixture was continued to stir for 12 hrs at room temperature. The reaction mixture was evaporated in vacuo below 50° C. to give yellow oil, which was dissolved in EtOAc. The solid formed was filtered and washed with EtOAc. The filtrate and washing solution were combined, dried over Na2SO4. The solvent was concentrated in vacuo to give (S)-tetrahydro-5-oxofuran-2-carboxylic acid as pale yellow oil (8.1 g, 91.6%)1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:48])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([C:43]([O:45]CC)=[O:44])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CCOC(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=[O:44])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:48])=[C:16]([F:22])[CH:17]=1
Reactant: CCOC(=O)C1CCN(c2ccc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(N3CCC(C(=O)O)CC3)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of ethyl 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)piperidine-4-carboxylate (75 mg, 0.108 mmol) in THF (4 mL) was added a solution of LITHIUM HYDROXIDE monohydrate (19.2 mg, 0.458 mmol) in Water (2 mL) dropwise. The reaction mixture was stirred at rt for 2 hrs before it was neutralized with 1N HCl. it was then diluted with EtOAc, washed with water (2×10 mL), brine (2×10 mL), dried and evaporated to give 1-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid as a white solid (76 mg, 100%). MS (ES+) m/z Calcd: [(M+H)+]: 669. found: 669.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:11][C:10](=[S:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][I:22]>CCO>[IH:22].[Cl:19][C:15]1[CH:14]=[C:13]([C@H:12]2[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10]([S:20][CH3:21])=[N:11]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CI
Reactant: S=C1N[C@H](c2cccc(Cl)c2)[C@H](c2cccc(Cl)c2)N1
Solvent: CCO
Product: CSC1=N[C@@H](c2cccc(Cl)c2)[C@@H](c2cccc(Cl)c2)N1
Product: I
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A mixture of cis-4,5-bis-(3-chlorophenyl)imidazolidine-2-thione (33) (8.23 g, 0.0254 mol) and methyl iodide (3.17 mL, 0.0509 mol) in abs. EtOH (25 mL) is heated at 90° C. for 8 h. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue triturated with abs EtOH. The insoluble material is filtered to give 10.1 g of the product 50.
Reaction SMILES: Br.C1(C)C=C(C)C=C(C)C=1S([N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21](S(C1C(C)=CC(C)=CC=1C)(=O)=O)[CH2:22][CH2:23][CH2:24][CH2:25][N:26](S(C1C(C)=CC(C)=CC=1C)(=O)=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32](S(C1C(C)=CC(C)=CC=1C)(=O)=O)[CH2:33][CH3:34])[CH2:14][CH3:15])(=O)=O.C1(O)C=CC=CC=1.C(Cl)[Cl:80]>>[ClH:80].[ClH:80].[ClH:80].[ClH:80].[CH3:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:13][CH2:14][CH3:15]
Reactant: ClCCl
Reactant: CCN(CCCCCN(CCCCN(CCCCCN(CC)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Agent: Br
Solvent: Oc1ccccc1
Product: CCNCCCCCNCCCCNCCCCCNCC
Product: Cl
Yield: 81 %

Procedure:
HBr (30% in HOAc, 195 mL), 79 (12.66 g, 12.1 mmol), and phenol (33.61 g, 0.357 mol) in CH2Cl2 (135 mL) were reacted, and product was isolated by the method of 2 to provide 4.50 g (81%) of 29 as white crystals: NMR (D2O) δ 1.28 (t, 6 H, J=7), 1.40-1.52 (m, 4 H), 1.66-1.80 (m, 12 H), 3.00-3.14 (m, 16 H). Anal. (C18H46Cl4N4).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH3:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[CH3:40][O:41][C:42]1[C:47]([C:48](=[O:50])[CH3:49])=[CH:46][CH:45]=[C:44]([O:51][CH3:52])[N:43]=1>>[CH3:40][O:41][C:42]1[C:47]([C:48](=[O:50])[CH2:49][C:29]2([OH:39])[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([CH3:25])[CH:27]=3)[N:31]([CH2:35][CH2:36][CH3:37])[C:30]2=[O:38])=[CH:46][CH:45]=[C:44]([O:51][CH3:52])[N:43]=1
Reactant: COc1ccc(C(C)=O)c(OC)n1
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2ccc(OC)nc2OC)c2cc(C)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-methyl-1-propylindoline-2,3-dione and 1-(2,6-dimethoxypyridin-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 8.14 (d, 1H) 7.23 (s, 1H), 7.08 (d, 1H), 6.76 (d, 1H), 6.36 (d, 1H), 4.67 (s, 1H), 3.99 (d, 6H), 3.69 (d, 1H), 3.66 (m, 2H), 3.47 (d, 1H), 2.29 (s, 3H), 1.75 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Sn].Cl>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Sn]
Product: Cc1ccc(N)cc1C(=O)O
Yield: 75 %

Procedure:
The desired titled compound was prepared by reducing 2-methyl-5-nitrobenzoic acid using a tin/hydrochloric acid mixture (m.p. 142°-144° C.)
Reaction SMILES: [K].[F:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[CH3:10].S(=O)(=O)(O)[O-:12].[Na+].Cl.[OH2:18]>C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[C:10]([OH:12])=[O:18]
Reactant: O
Reactant: Cc1cc(I)ccc1F
Reactant: O=S(=O)([O-])O
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1cc(I)ccc1F
Temperature: 25 °C
Yield: 15 %

Procedure:
To 8.1 g (51.3 mmol) of potassium permangante in 150 mL of water are added 5.0 g (21.1 mmol) of 2-fluoro-5-iodotoluene. The reaction mixture is heated at reflux for 4 hours. After being cooled to room temperature, the reaction mixture is poured into 250 mL of methylene chloride of sodium bisulfate, and 1N hydrochloric acid. The organic layer is separated, washed with water and dried over sodium sulfate. The solvent is removed in vacuo and the solid triturated with hexane to give 0.86 g (15%) of 2-fluoro-5-iodobenzoic acid as a white solid, m.p. 161°-163° C.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CCN(CC)CC>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Yield: 63.4 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.083 g, 0.25 mmol) and 3-pentyl-8-aza-bicyclo[3.2.1]octane (104KS32-2) (0.051 g, 0.28 mmol) in Et3N (½ mL) were reacted according to GP15 to give the title compound (108LM39-36) (0.061 g, 63%). 1H NMR (CDCl3) δ 7.33-7.29 (m, 1H), 7.03-6.96 (m, 3H), 4.60 (ABq, J=14.8 Hz, J=37.1 Hz, CH2), 4.14-4.00 (m, 2H), 3.13 (bs, 1H), 3.05 (bs, 1H), 2.63-2.50 (m, 1H), 2.17-2.03 (m, 3H), 2.00-1.80 (m, 3H), 1.72-1.53 (m, 3H), 1.42-1.15 (m, 10H), 0.93-0.85 (m, 6H); 13C NMR (CDCl3) δ 165.0, 145.7 128.9, 123.7, 122.6, 117.1, 116.1, 67.9, 60.9, 58.9, 58.2, 45.3, 38.4, 37.0, 36.8, 32.2, 31.7, 28.5, 28.3, 27.2, 22.9, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=385.3.
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][C:13]([OH:15])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:17][CH2:18][Cl:19].Cl>CCCCCC.C1COCC1.C(OCC)(=O)C>[Cl:19][CH2:18][CH2:17][CH:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)Cc1ccccc1
Reactant: ClCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)C(CCCl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A 2.64 M solution of butyl lithium in hexane (28 mL) was added to a solution of phenylacetic acid (5.07 g) in THF (150 mL) in a nitrogen atmosphere at −78° C., and the reaction solution was stirred at −78° C. for 20 minutes. The reaction solution was further stirred at 0° C. for one hour. Then, 1-bromo-2-chloroethane (3.1 mL) was added at 0° C., and the reaction solution was stirred at room temperature for 14 hours. Ethyl acetate and 1 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 5.54 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1([CH:8]=[N:9][OH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[CH2:24])[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C(N(CC)CC)C>O>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2([O:10][N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24]2)[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C1CCN(Cc2ccccc2)CC1C
Reactant: ON=CC1(Cl)C=CC=CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(Cc2ccccc2)CCC12CC(c1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound C (4.49 g, 28.9 mmol, dissolved in abs. DCM (25 ml)) was added dropwise to a solution of compound S (2.5 g, 14.45 mmol) in abs. DCM (25 ml) at 0° C. within 10 min. A solution of triethylamine (16 ml, 11.7 g, 115.6 mmol) in abs. DCM (25 ml) was added to this mixture within 10 min at 0° C. As the reaction was highly exothermic, cooling was carried out in a mixture of ice/sodium chloride. The reaction mixture was stirred for 16 h at RT. For working up the mixture, DCM (50 ml) and water (70 ml) were added. The phases were separated. The aqueous solution was extracted with DCM (2×20 ml). The combined organic phases were washed successively with water (50 ml) and sat. NaCl solution (50 ml) and then dried and concentrated (4.9 g, yellow oil). The residue was purified by column chromatography [silica gel 60 (500 g); EtOAc/cyclohexane 1:2 (3 l)]. The desired product was obtained as a diastereomer mixture in a yield of (2.28 g, 50%) having a melting point of 101-108° C.