Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][C@H:20]2[O:25][CH:24](OC)[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([C@@H:24]2[O:25][CH:20]([CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:29][CH:28]=3)[CH2:21][CH2:22][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O)c1ccccc1
Reactant: COC1CCC[C@@H](COc2ccc(F)cc2)O1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)[C@H]1CCCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (2.0 g), till the solid dissolved. This mixture was extracted with ethyl acetate (30 ml), dried (Na2SO4) and concentrated to give benzenesulfinic acid (1.5 g). To an ice-cooled mixture of benzenesulfinic acid (1.48 g, 10.5 mmol) and calcium chloride (1.15 g, 10.5 mmol) in dry CH2Cl2 a solution of (2RS, 6S)-6-(4-fluorophenoxymethyl)-2-methoxytetrahydropyran (0.5 g, 2.1 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layer was washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS, 6S)-6-benzenesulfonyl-2-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H) 4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][NH:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:30]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(O)=O.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][N:23]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:24][CH:25]4[CH2:27][CH2:26]4)=[CH:28][CH:29]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCCC1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc(OCCNCC4CC4)cc3)nc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN(CC4CC4)C4CCCC4)cc3)nc2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 80.6 mg (0.20 mmol) of (2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)cyclopropylmethylamine, 35 μL (0.40 mmol) of cyclopentanone, and one drop of AcOH in 10 mL of THF was stirred for 15 minutes. 169.5 mg (0.80 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred for 24 hours at RT. A further 17.5 μL of cyclopentanone and 85 mg of sodium triacetoxyborohydride were added and the mixture was again stirred for 24 hours at RT. The reaction mixture was diluted with water, made basic with saturated aqueous potassium carbonate solution, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, EtOAc/MeOH/conc. aqueous ammonia 98:2:0.2) and stirred with DIPE. Yield: 22 mg (23% of theoretical); C30H31ClN2O (M=471.033); calc.: molpeak (M+H)+: 471/473 (Cl); found: molpeak (M+H)+: 471/473 (Cl); HPLC-MS: 5.83 minutes (method B).
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:17]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:17]([NH:27][C@H:28]([C:36]([CH:4]1[C:3]2([NH2:2])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]1([C:13]([O:15][CH3:16])=[O:14])[CH2:6]3)[CH2:10]2)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C2
Reaction time: 24 h

Procedure:
To 30 ml of a 1 N sodium hydroxide solution is added 4.95 g of L-phenylalanine. The solution is cooled and stirred in an ice bath and 5.4 ml of a 6.1 M solution of carbobenzoxychloride is added dropwise along with additional 1 N sodium hydroxide solution so that the pH remains at 11.0-11.5. The reaction mixture is washed with ether. The aqueous layer is acidified to pH 1.0 with 12 N hydrochloric acid, then the solution is extracted with ethyl acetate. The ethyl acetate extract is separated and is washed three times with water then dried over magnesium sulfate. The solvent is removed under vacuum. The residue crystallizes on rubbing with water to give N-carbobenzoxy-L-phenylalanine. 3.99 Grams of methyl 3-amino-1-adamantanecarboxylate hydrochloride and 4.78 g of carbobenzoxy-L-phenylalanine are dissolved in 40 ml methylene chloride. To this solution is added 1.8 ml of N-methylmorpholine followed immediately by 2.19 g of dicyclohexylcarbodiimide. The reaction mixture is allowed to stand for 24 hours at room temperature, then the treatment with carbobenzoxy-L-phenylalanine and dicyclohexylcarbodiimide is repeated. The reaction mixture is again allowed to stand for 24 hours at room temperature. The dicyclohexylurea is removed by filtration and washed with methylene chloride. The combined filtrates are washed twice with 0.5 M potassium bisulfate, water and 1 M solution of potassium bicarbonate and dried over magnesium sulfate. The dicloromethane is removed under vacuum and the residue is purified by low pressure chromatography on silica gel using mixtures of hexane and chloroform as eluting solvent to give methyl carbobenzoxy-L-phenylalanyl-3-amino-1-adamantanecarboxylate which has the following structural formula ##STR13## wherein Cbz represents carbobenzoxy.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)/C=C\C(O)=O.C(O)(=O)/C=C\C([O-])=O>C(O)C.O.CCOCC>[CH3:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNC(=O)c1ccccc1Sc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])/C=C\C(=O)O
Agent: [Al+3]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CNCc1ccccc1Sc1ccccc1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride, 1.52 g. (0.04 mole), is weighed under nitrogen, transferred to a dry nitrogen-flushed reaction flask, and suspended in 50 ml. of absolute ether. A solution of 5.34 g. (0.04 mole) of aluminum chloride in 60 ml. of absolute ether is added dropwise. The mixture, containing a white precipitate, is stirred at room temperature while a solution of 4.87 g. (0.02 mole) of N-methyl-2-(phenylthio)benzamide in 1 l. of absolute ether is added dropwise. The mixture is stirred at reflux for about 18 hours. After cooling, hydrolysis is effected by the dropwise addition of 60 ml. of water. After decantation of the ethereal layer and washing of the gelatinous precipitate with boiling ether, the precipitate is suspended in 40 ml. of 40% aqueous sodium hydroxide and 200 ml. of water. The mixture is extracted repeatedly with ether-benzene (1:1). Evaporation of solvents under reduced pressure from the washed and dried organic extract leaves the product as the residual oil. The base is converted to the hydrogen maleate salt by treating an ethereal solution with a slight excess of maleic acid dissolved in absolute ethanol. The hydrogen maleate separates in white crystals, m.p. 121°-122.5° C. The melting point in unchanged upon further recrystallization.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:15]([S:17][C:18]1[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:16].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH2:15]([S:17][C:18]1[C:19]([C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][N:3]=2)=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:16]
Reactant: Nc1ccc(C(F)(F)C(F)(F)F)cn1
Reactant: CCSc1cccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A mixture of 0.63 g of 2-amino-5-pentafluoroethylpyridine, 0.55 g of 3-ethylsulfanylpicolinic acid, 1.0 g of EDCI hydrochloride, 0.04 g of HOBt and 5 mL of pyridine was stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.33 g of 3-ethylsulfanyl-N-(5-pentafluoroethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 46).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:15]1[C:16]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([Cl:42])=[CH:36][C:35]=2[Cl:43])=[C:17]2[S:23][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)=[CH:21][C:18]2=[N:19][CH:20]=1)#[N:14]>CN(C)C=O>[C:13]([C:15]1[C:16]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([Cl:42])=[CH:36][C:35]=2[Cl:43])=[C:17]2[S:23][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:3])=[O:30])=[CH:26][CH:25]=3)=[CH:21][C:18]2=[N:19][CH:20]=1)#[N:14]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(=O)O)cc4)sc23)c(Cl)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(N)=O)cc4)sc23)c(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
1,1′-Carbonyldiimidazole (100 mg, 0.61 mmol) is added to a suspension of 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl]benzoic acid (130 mg, 0.28 mmol) in 10 mL of N,N-dimethylformamide. After stirring at 60° C. for 2 hours the reaction mixture is allowed to cool to room temperature and ammonia gas is bubbled through the mixture for 15 minutes. The mixture is stirred at room temperature for an additional 60 minutes and poured into 50 g of ice and stirred for 30 minutes. The mixture is adjusted to pH 4 with concentrated hydrochloric acid and stirred for 60 minutes. The resulting precipitate is collected by filtration washing with water and dried under reduced pressure. The resulting solid is purified by flash column chromatography eluting with a gradient of ethyl acetate to 20% methanol in ethyl acetate to provide 12.3 mg of 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzamide as a gray solid, mp>300° C.; 1H NMR (DMSO-d6) δ3.86 (s, 3H), 7.40 (s, 1H), 7.48 (s, 1H), 7.78 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 2H), 8.06 (s, 2H), 8.08 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS 468.9, 471.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25]Br)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:28].[C:29]1([C:35]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:28].[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:38]2[CH2:39][CH2:40][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:36][CH2:37]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 41.5 %

Procedure:
2.35 g of 3-methyl 5-(2-bromoethyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 1.46 g of 4,4-diphenylpiperidine hydrochloride and 1.55 g of finely powdered potassium carbonate in 15 ml of anhydrous dimethylformamide are stirred for 6 h at 80° C. After the mixture has cooled, 100 ml of water are added and the mixture is then extracted with ether. The ether phase is washed twice with water, dried over sodium sulphate and then evaporated in vacuo. The residue is chromatographed over a silica gel column using a 95:5 chloroform/ethanol as the mobile phase. The chromatographically pure fractions are collected and evaporated. The residue is dissolved in ether and 2 ml of a saturated solution of hydrogen chloride in ether are added to the solution, crystallisation occurring. The product is filtered off under suction, washed with ether and dried. 1.4 g of the title compound of m.p. 155°-158° C. (decomp.) and [α]22D =+68.4° (c=1, methanol) are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]#[N:22])([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[OH-].[Na+].O>C1COCC1.O1CCOCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:14]3[C:19](=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:22][CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2F)CC1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1cnccc12
Temperature: 130 °C
Yield: 24 %

Procedure:
A mixture of 4-cyano-3′-fluoro-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acid tert-butyl ester (1 g) and lithium tri-tert-butoxyaluminohydride (12.7 ml), 1M solution in THF) in 1-4-dioxane (15 ml) was stirred at 130° C. (sealed tube) for 1 hr. After cooling, 1 N NaOH (100 ml) and H2O (100 ml) were added slowly at 0° C. Ethyl acetate was added to the mixture. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with saturated sodium bicarbonate, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography [SiO2; hexane-ethyl acetate (7:3)] to give 230 mg g (24%) of 6-aza-spiro[indoline-3,4′-piperidine]-1′-carboxylic acid tert-butylester; MS (ES+) 290 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3.[OH-].[Na+].O>C(O)C>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)c1cnc2c3ccccc3ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2c3ccccc3ccn2c1=O

Procedure:
A mixture of ethyl 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (2.78 g., 0.010 mole), 1.0 N NaOH (15.0 ml.), H2O (40 ml.) and ethanol (30 ml.) was refluxed for 15 minutes. The mixture was filtered and the cooled filtrate acidified with 15.0 ml. of 1.0 N HCl to precipitate crude acid (2.36 g.), m.p. 193°-223°. Two recrystallizations from 2-methoxyethanol gave peach needles, m.p. 252°-253.5°.
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: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
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: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[C:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)(Cl)Cl.O>[C:18]([N:23]1[CH2:28][CH2:27][N:26]([CH:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:10]2)[CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Clc1ccc2c(c1)CC(Cl)c1ccccc1S2
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
100 g of 2,10-dichloro-10,11-dihydro-dibenzo[b,f]thiepin in 300 ml of chloroform are heated at reflux for 24 hours together with 182 g of 1-carbethoxy-piperazine. The mixture is then diluted with chloroform and water. The organic phase is washed several times with water and dried over magnesium sulphate. After filtration, the filtrate is concentrated under reduced pressure and the residue crystallised from acetone/hexane. There is obtained 1-carbethoxy-4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine of melting point 92°-93° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:37]1([C@H:43]([NH:45][C:46]([NH2:48])=[O:47])[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CC(N(C)C)=O>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:8]2[C:5]3[CH:6]=[N:7][C:2]([NH:48][C:46]([NH:45][C@@H:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH3:44])=[O:47])=[CH:3][C:4]=3[N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)=[CH:35][CH:34]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 92.5 %

Procedure:
6-chloro-3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 4a, 73 mg, 0.147 mmol), (R)-1-(1-phenylethyl)urea (37 mg, 0.225 mmol), Cs2CO3 (120 mg, 0.367 mmol), BrettPhos precatalyst (11.7 mg, 0.015 mmol) and DMA (1.1 mL) were charged in a vial. The mixture was evacuated and purged with nitrogen six times and heated at 100° C. for 55 min. The mixture was diluted with EtOAc and washed with water, brine, dried (Na2SO4) and concentrated to afford a residue, which was purified by chromatography on silica gel (0-100% ethyl acetate in hexane, 20 CV) to afford (R)-1-(3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (85 mg, 0.136 mmol, 92%) as a yellow solid. MS ESI calcd. For C40H32FN5O [M+H]+ 618, found 618.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1-c1ccccc1C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
To a stirred solution of methyl 2-ethoxy-2′-methyl-1,1′-biphenyl-4-carboxylate (11 g, 40.6 mmol) in a mixture of THF (100 mL) and water (10 mL) was added lithium hydroxide (6.82 g, 162.7 mmol) in portions. After 24 hours at RT, the reaction mixture was evaporated and the residue was taken up with water. The aqueous layer was acidified with a concentrated aqueous solution of HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under vacuum affording of the title compound as pale yellow solid (9.7 g, 93%). LC/MS (Method B): 255.0 (M−H)−. 1H-NMR (DMSO-d6, 400 MHz) δ 13.02 (br s, 1H), 7.57 (m, 2H), 7.18-7.25 (m, 4H), 7.09 (d, 1H), 4.05 (q, 2H), 2.05 (s, 3H), 1.18 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1I)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[C:21]([C:35]2[S:39][C:38]3[C:40](B4OC(C)(C)C(C)(C)O4)=[CH:41][CH:42]=[CH:43][C:37]=3[CH:36]=2)=[N:22][C:23]([NH:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:24][CH:25]=1.C([O-])(O)=O.[Na+]>C(#N)C.O.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:17][C:13]1[N:12]=[CH:11][C:10]([CH:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:9])=[C:15]([C:40]2[C:38]3[S:39][C:35]([C:21]4[C:20]([F:19])=[CH:25][N:24]=[C:23]([NH:26][CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][NH:31][C:30]5=[O:34])[N:22]=4)=[CH:36][C:37]=3[CH:43]=[CH:42][CH:41]=2)[CH:14]=1
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)c1cnc(Cl)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 100 °C
Yield: 55.3 %

Procedure:
In a microwave vial, combine [1-(6-chloro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (250 mg, 0.65 mmol) and 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (380 mg, 0.78 mmol), bis(diphenylphosphino)ferrocene)dichloro palladium (53 mg, 0.07 mmol) and NaHCO3 (110 mg, 1.31 mmol) in acetonitrile (7 mL) and water (3 mL). Purge the mixture with nitrogen for 5 min. Heat the mixture at 100° C. for 15 min in a microwave. Remove solvent on a rotovap. Purify by normal phase column chromatography using 0.5% to 5% MeOH in dichloromethane to get off white solid product (220 mg). MS (ES) m/z 612 [M+1]+