Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[N:24][OH:25])=[CH:12][CH:13]=1)=[O:6].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:25][N:24]=[C:19]1[C:20]2[C:16](=[C:15]([O:14][C:11]3[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=4)=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=NO)nc1)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)ON=C1CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
650 mg of N1-{6-[(1-hydroxyimino-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 47 was dissolved in 10 ml of tetrahydrofuran. To the resulting reaction solution, 1.2 ml of pyridine and 0.7 ml of acetic anhydride were added and the mixture was stirred at room temperature. After 17 hours, the reaction solution was distilled off under reduced pressure and 15 ml of ethyl acetate and 15 ml of water were added to the resulting residue. Then, the deposited powder was isolated by filtration and washed in turn with water and ethyl acetate to obtain the titled compound (310 mg).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]1[N:22]3[CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:21]3=[N:20][C:12]=1[C:13]([NH2:19])=[N:14]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>CN(C=O)C>[CH3:28][S:29]([N:26]1[CH2:25][CH2:24][CH2:23][N:22]2[C:11]3[C:10]4[C:15](=[CH:16][CH:17]=[CH:18][CH:9]=4)[N:14]=[C:13]([NH2:19])[C:12]=3[N:20]=[C:21]2[CH2:27]1)(=[O:31])=[O:30]
Reactant: Nc1nc2ccccc2c2c1nc1n2CCCNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (2.32 mL, 16.7 mmol) was added to a suspension of 9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine hydrochloride (1.61 g, 5.56 mmol, Example 7 Part A) in DMF (20 mL). The mixture was sonicated for ten minutes at 80° C., and methanesulfonyl chloride (764 mg, 6.67 mmol) was slowly added. The mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure. Unsuccessful attempts were made to purify the product, and ultimately, the product was isolated by filtration to provide 894 mg of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine containing some impurities.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:14]=3)[CH2:16][CH2:17]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a stirred solution of {4-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (80 mg, 0.17 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (35 mg, 0.83 mmol) in water (1 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (57 mg, 65%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (br s, 1H), 7.95 (dd, J=9.0, 6.1 Hz, 1H), 7.88 (d, J=10.3 Hz, 1H), 7.76-7.85 (m, 4H), 7.68 (s, 1H), 7.34-7.41 (m, 2H), 3.80 (d, J=11.2 Hz, 2H), 3.71 (s, 2H), 2.59 (t, J=11.2 Hz, 2H), 1.87-1.94 (m, 3H), 1.73-1.82 (m, 2H); MS cald. for C23H20ClFNO4S [(M−H)−]: 460, obsd. 460.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:26])([C@H:16]([N:18]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[N:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>CO.[Pd]>[NH2:23][C:21]1[CH:20]=[N:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:26])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:22]=1
Reactant: C[C@@H](n1cc([N+](=O)[O-])cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CO
Product: C[C@@H](n1cc(N)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 4 h
Yield: 87 %

Procedure:
(2R,3R)-2-(2,4-difluorophenyl)-3-(4-nitro-1H-pyrazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol obtained in Step 1 (0.2 g, 0.55 mmol) was dissolved in methanol (15 mL) and 5% palladium on charcoal (5% Pd/C, 0.02 g) was added thereto, and the resulting mixture was stirred for 4 hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated by evaporation under a reduced pressure to obtain the title compound (0.16 g, yield 87%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1>[F:12][C:9]1([F:13])[CH2:10][CH2:11][CH:6]([CH:4]=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=CC1CCC(F)(F)CC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of 173 g (0.900 mol) of 4,4-difluorocyclohexanecarboxylic acid ethyl ester in 1.0 L toluene, 945 ml (0.945 mol) of 1.0 M diisobutyl aluminum hydride-toluene solution was added dropwise at −55° C. or lower temperatures and then the reaction solution was stirred at −65° C. for 30 minutes. After completion of the reaction, saturated ammonium chloride aqueous solution was added at −40° C. or lower temperatures to the reaction solution and then 1.0 L of 4 N hydrochloric acid was added at 0° C. or lower temperatures. The organic layer was separated and then the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg) to provide 75.3 g of the title compound as a colorless oil (yield: 57%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[N:8]2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27]>C(OCC)(=O)C>[Cl:31][C:30]([Cl:33])([Cl:32])[CH2:29][O:28][C:26](=[O:27])[NH:12][C:11]1[N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)[N:8]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc([Si](C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc([Si](C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 96 %

Procedure:
Place 2-p-tolyl-5-trimethylsilanyl-2H-pyrazol-3-ylamine (170 mg, 0.693 mmol) in ethyl acetate (10 mL). Add potassium carbonate (191 mg, 1.38 mmol) and water (2 mL). Stir the reaction and add trichloroethyl chloroformate (0.114 mL, 0.831 mmol). Stir at room temperature for 18 hours. Add water and ethyl acetate. Separate organic layer and wash with saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-30% EtOAc:hexane to yield 280 mg (96%) of the title compound. MS(ES+): m/z=420.2 [M+H].
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[Br:16][CH2:17][C:18](O)=[O:19].[CH3:21][O:22][C:23](=[O:41])[CH:24]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:25][NH:26][CH2:27][C:28]#[CH:29]>C(Cl)Cl.CCOCC>[CH3:21][O:22][C:23](=[O:41])[CH:24]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:25][N:26]([C:18](=[O:19])[CH2:17][Br:16])[CH2:27][C:28]#[CH:29]
Reactant: O=C(O)CBr
Reactant: C#CCNCC(NC(=O)OCc1ccccc1)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCN(CC(NC(=O)OCc1ccccc1)C(=O)OC)C(=O)CBr
Reaction time: 8 h
Yield: 47.9 %

Procedure:
DCC (2.27 g, 11.0 mmol) and bromoacetic acid (1.48 g, 10.7 mmol) is added to a solution of 2-benzyloxycarbonylamino-3-(prop-2-ynylamino)-propionic acid methyl ester (3.10 g, 10.7 mmol) in CH2Cl2 at RT. The mixture is stirred overnight then diluted with ether. The white solid which precipitates out is filtered and the filtrate is concentrated to give a yellow oil. The crude product is purified by chromatography eluting with a gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to yield the title product (2.1 g, 5.12 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7.30 (m, 5H), 5.70 (d, 1H), 5.10 (s, 2H), 4.63 (m, 1H), 4.15 (d, 2H), 4.00 (m, 1H), 3.80 (s, 3H), 3.75 (s, 2H), 3.70 (dd, 1H), 2.27 (bs, 1H). Ion spray MS, [M+H]+=411, 413, Br pattern.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:22][CH3:23])[CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=2)=[C:17]([O:22][CH3:23])[CH:16]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(Cl)ncc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cnc(Cl)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 137.5 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (211 mg, 1 mmol), 6-chloro-4-methoxypyridin-3-amine (150 mg, 0.95 mmol) and para-toluenesulphonic acid (190 mg, 1 mmol) in 1,4-dioxane (2 mL) was heated at 100° C. for 1 h. The mixture was cooled and filtered, the solid was washed with dioxane and dried in vacuo to give the product as a cream coloured solid (436 mg, >100%). 1H NMR (400 MHz, DMSO): δ 9.82 (s, 1H); 8.76 (s, 1H); 8.44 (s, 2H); 7.38 (s, 1H); 4.00 (s, 3H); 2.99-2.92 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:50])[CH2:5][CH2:6][NH:7][C:8]([N:10]1[C:14]2[N:15]=[C:16]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[N:17]=[C:18]([C:19]3[CH:20]=[N:21][C:22]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[N:23][CH:24]=3)[C:13]=2[CH2:12][CH2:11]1)=[O:9])C.[OH-].[Na+]>C1COCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[C:22]2[N:23]=[CH:24][C:19]([C:18]3[C:13]4[CH2:12][CH2:11][N:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:50])=[O:3])=[O:9])[C:14]=4[N:15]=[C:16]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[N:17]=3)=[CH:20][N:21]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)NCCC(=O)O)cn2)cc1
Yield: 97.1 %

Procedure:
To a THF solution (3 ml) of 3-[(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbonyl)-amino]-propionic acid ethyl ester (84 mg) obtained in Step A in Example 1-D-30, 5M-NaOH aqueous solution (1.5 ml) was added, followed by refluxing for 1 hour. The resulting solid was filtered, to obtain a crude product of the desired compound (78.2 mg, 97%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([SH:38])[CH:33]=1.CCCCP(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:10]=[N:11][C:12]=3[CH:26]([CH3:27])[CH3:28])=[CH:17][C:18]=2[CH3:25])[CH3:23])[CH:33]=1
Reactant: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)O
Reactant: COC(=O)c1cccc(S)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(SC(C)c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a room temperature solution of 1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanol (70 mg, 0.167 mmol) in toluene (2 mL) are added 3-mercapto-benzoic acid methyl ester (28 mg, 0.167 mmol) and tri-N-butylphosphine (62 μL, 0.251 mmol). The reaction mixture is cooled to 0° C. To the reaction mixture is added 1,1′-(azocarbonyl)-dipiperidine (63 mg, 0.251 mmol). The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is concentrated and the residue is chromatographed (40 g SiO2, 0% to 30% EtOAc/Hexanes) to yield 3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoic acid methyl ester (62 mg, 65%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:23])([F:24])[F:25])[CH:16]=1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cccc(OC(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1cccc(NC[C@@H]2CCCN2)c1

Procedure:
A solution of (S)-2-[(3-trifluoromethoxy-phenylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.277 mmol) and TFA (1 mLl) in CH2Cl2 (2 mL) was stirred at RT for 2 h. Solvent was concentrated and the residue was co-evaporated twice with CH2Cl2 and dried under high vacuum overnight to give the crude title compound as a TFA salt. MS: 261.1 [MH−Boc]+, tR (HPLC conditions a): 2.61 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-2-carboxylate (300 mg, 0.76 mmol) from Example 95, Step E in methanol (6 mL) was added 5N sodium hydroxide (0.300 mL, 1.5 mmol). The reaction was stirred at rt for 20 h and was then concentrated in vacuo. The residue was partitioned between methylene chloride and 2N hydrochloric acid. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to give the crude title compound as a yellow foam. HPLC/MS: 378 (M+1), 380 (M+3); Rt=3.73 min
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.[NH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C>C(#N)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCc1ccccc1CC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 78.9 %

Procedure:
To a solution of tert-butyl [2-(chloromethyl)phenyl]acetate (2.31 g) in acetonitrile (23.1 mL) were added tert-butyl glycinate hydrochloride (2.41 g) and triethylamine (4.01 mL), followed by heating at 60° C. for 3 hours. The reaction suspension was concentrated under reduced pressure, then to the residue were added water and ethyl acetate, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[2-(2-tert-butoxy-2-oxoethyl)benzyl]glycinate (2.54 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([OH:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)O)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([OH:27])[CH3:26])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN(CCCCCC(C)O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC/C=C/c1ccc(NS(C)(=O)=O)cc1)CCCCCC(C)O

Procedure:
In the process as described in Example 2 the product of Example 5 is treated with trifluoroacetic acid to give the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:33])(=[N:27][C:28](=[O:32])[NH:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1>>[CH2:30]([NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:33])=[O:26])=[O:32])[CH3:31]
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CCNC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CCNC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (296.3 mg, 1.1 mmol) with (RS)—S-(4-aminophenyl)-N-(ethylcarbamoyl)-S-methylsulphoximide (241 mg, 1 mmol) according to procedure 5c, the desired product is obtained in 26% yield (133 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [NH2-].[Na+].C1(C)C=CC=CC=1.[C:10]1([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:25][C:26]([CH2:28]Cl)=[CH2:27]>C(OCC)C.CN(C)C=O>[Cl:25][C:26](=[CH2:27])[CH2:28][C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:17]#[N:18]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C=C(Cl)CCl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(Cl)CC(C#N)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
A 40.3 g. portion of sodium amide was suspended in 400 ml. of dry toluene at 70° C. and 199.6 g. of diphenylacetonitrile, dissolved in 600 ml. of hot dry toluene, was added dropwise. The mixture was stirred at 70°-100° C. for 4 hours, and an additional 500 ml. of dry toluene and 100 ml. of dimethylformamide were added. The mixture was stirred for 27 hours more. The slurry was cooled to 10° C., and 114.6 g. of 2,3-dichloropropene was added. The mixture was warmed to ambient temperature and stirred for 40 hours, and was then stirred at 90°100° C. for one hour. The mixture was then cooled to ambient temperature, diluted with a large amount of diethyl ether, washed with water and dried over magnesium sulfate. The solution was evaporated to give 265 g. of crude liquid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:8]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[N:12]=1.[OH-].[Na+].Cl>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:8]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:12]=1
Reactant: COC(=O)CCc1nc(NCc2ccc(OC)c(Cl)c2)c2c(n1)sc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: COc1ccc(CNc2nc(CCC(=O)O)nc3sc4ccccc4c23)cc1Cl
Reaction time: 5 h

Procedure:
Methyl 3-[4-(3-chloro-4-methoxybenzylamino)-benzothieno[2,3-d]pyrimidin-2-yl]propionate is dissolved in ethylene glycol monomethyl ether and; after addition of 32% strength NaOH, stirred at 110° for 5 hours. 20% strength HCl is added, and the mixture is then extracted with dichloromethane. Addition of petroleum ether affords 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]propionic acid, m.p. 218°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([N:12]2[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]2)[N:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:21][C:20]([F:23])([F:22])[C:6]([C:5]1[C:4]([N:12]2[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]2)=[N:3][C:2]([CH3:1])=[CH:11][CH:10]=1)=[O:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(C)nc1-n1ccc(C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C(F)(F)F)c(-n2ccc(C)n2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate (3.7 g, 16 mmol) and trimethyl(trifluoromethyl)silane (11.4 g, 80.2 mmol) in toluene (60 ml), was added dropwise at −78° C. and then the solution of tetrabutyl ammonium fluoride (1.6 mL, 1.0 M in THF) was added dropwise to the reaction mixture at −78° C. After addition, the mixture was warmed slowly up to RT and stirred for 12 h. The reaction mixture was concentrated and the resulting residue was dissolved in methanol (30 mL). 6 N HCl (30 mL) was added to the reaction mixture and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated, adjusted to pH 6 with sat.NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/hepate) to provide 2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone as a brown semi-solid.