Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[O:18][CH3:19].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([N:5]([CH2:4][C:3]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[C:10]([O:18][CH3:19])[CH:11]=1)(=[O:43])=[O:42]
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCO)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-difluorobenzyl)-N-heptyl-2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]acetamide (A)(132 mg, 0.294 mmol) was dissolved in DCM (10 ml). It was cooled in an ice-bath. Triethylamine (0.05 ml, 0.352 mmol) was added and then methanesulfonyl chloride (37 mg, 0.323 mmol) was dropped in. The cooling-bath was removed after 30 minutes. The mixture was stirred at room temperature overnight. LS-MS showed that ca 50% of A was not reacted. The mixture was cooled in an ice-bath and 0.05 ml of triethylamine was added, followed by 0.025 ml of methanesulfonyl chloride. After addition, the cooling-bath was removed and the mixture was stirred for 5 hours more. It was then washed with water (×2) and brine, dried (magnesium sulphate) and evaporated. Oil product 138 mg was left and used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:51].Cl>>[ClH:1].[ClH:51].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH:38][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCC(CCCCN2CCCCC2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CCCCN3CCCCC3)CC2)c2ccccc21
Yield: 40 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[4-(piperidin-1-yl)butyl]-piperidin-1-yl]ethanamine in a yield of 40% of theory. The colourless dihydrochloride melted at 231°-233° C.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2C[CH2:26][NH:25][CH2:24][C:23]2=O)=[CH:18][CH:17]=1.C=O.O>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH3:26])[CH2:12][C:11]2=[O:13])=[CH:20][CH:21]=1
Reactant: O=C1CNCCN1c1ccc(Br)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added to a solution of 1-(4-bromophenyl)piperazin-2-one (200.0 mg, 0.7840 mmol, from J&W PharmLab product) and 11.0 M formaldehyde in water (0.21 mL, 2.4 mmol) in methylene chloride (3 mL, 50 mmol) and then the reaction was stirred at rt for 1 hour. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated to provide the product which was used in the next step. LCMS calculated for C11H14BrN2O (M+H)+: m/z=269.0. Found 269.0.
Reaction SMILES: [C:1]1([CH:11]=[C:12]2[CH2:17][C:16](=[O:18])[O:15][C:13]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>ClCCl>[C:1]1([CH:11]=[C:12]([CH2:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Solvent: ClCCl
Product: O=C(O)C(=Cc1cccc2ccccc12)CC(=O)N1CCOCC1
Yield: 80.5 %

Procedure:
A solution of 1.00 g of 2-(1-naphthylmethylene)succinic anhydride and 0.37 g of morpholine in 31 ml of dry dichloromethane was stirred for 2 hours at room temperature. The reaction mixture was evaporated under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate, benzene and hexane (1:1:1) to obtain 1.10 g of 2-(1-naphthylmethylene)-3(morpholinocarbonyl)propionic acid as colorless crystals. A solution of 1.00 g of the propionic acid compound was hydrogenated over 0.1 g of a 10% palladium charcoal under a hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure. The residue was crystallized from hexane to give 0.90 g of 2-(1-naphthylmethyl)-3(morpholinocarbonyl)propionic acid as a white powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH:14]=[CH2:15])[S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:10]1[CH:11]=[N:12][C:8]([S:5](=[O:7])(=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][CH:14]=[CH2:15])=[N:9]1)=[O:20])[CH3:17]
Reactant: CCN(CC)C(=O)Cl
Reactant: C=CCN(CC=C)S(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)S(=O)(=O)c1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 6.9 g. 3-diallylsulphamoyl-1,2,4-triazole, 4.5 g. diethylcarbamoyl chloride, 6 ml. triethylamine and 25 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 1.5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The solid residue was recrystallized from petroleum ether, b.p. 60° - 80°C., to give 1-diethylcarbamoyl-3-diallylsulphamoyl-1,2,4-triazole, m.p. 49° - 51°C. Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:18])[C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:19])=[N:6][C:5]=2[N:20]=1.Br[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:18])[C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:19][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[N:6][C:5]=2[N:20]=1
Reactant: CC(C)C[C@H](CO)N(C)c1nc(S)nc2nc(N)sc12
Reactant: CC(Br)c1ccccc1
Product: CC(C)C[C@H](CO)N(C)c1nc(SC(C)c2ccccc2)nc2nc(N)sc12
Yield: 62 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)(methyl)amino]-4-methylpentan-1-ol (31.4 mg, 0.1 mmol) with 1-bromoethylbenzene (13.5 μL, 0.1 mmol) to give 26 mg (62% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[NH:43]1[C:47]2=[N:48][CH:49]=[CH:50][CH:51]=[C:46]2[CH2:45][C@H:44]1[C:52]([O:54][CH2:55][CH3:56])=[O:53]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([N:43]1[C:47]2=[N:48][CH:49]=[CH:50][CH:51]=[C:46]2[CH2:45][C@H:44]1[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (270 mg, 1.04 mmol, Eq: 1.00) was combined with DCM (10 mL) to give a colorless solution. Diisopropylethylamine (0.73 mL, 4.16 mmol, Eq: 4) was added followed by N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (824 mg, 3.12 mmol, Eq: 3). The reaction was stirred at rt for 1 h and then (S)-ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (200 mg, 1.04 mmol, Eq: 1.00) was added. After stirring overnight at rt, the reaction mixture was washed with saturated aqueous NaHCO3 (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 30% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (220 mg), m/z=434 (M+H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1I.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)O1>O1CCOCC1.C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1[C:46]1[CH:47]=[CH:48][C:49]([CH:52]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:60])([F:59])[F:61])[CH2:53]2)=[CH:50][CH:51]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Reactant: CC1(C)OB(c2ccc(C3CCN(CC(F)(F)F)C3)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(C4CCN(CC(F)(F)F)C4)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Tripotassium phosphate 2.0 M aqueous solution (0.6 ml, 1.200 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (25.2 mg, 0.031 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (147.1 mg, 0.266 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrrolidine (94.6 mg, 0.266 mmol) in dioxane (2.1 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. After 18 hours, the reaction mixture was cooled to room temperature before being partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was separated and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. The residue was dissolved in DCM, loaded onto a 5 g silica solid load cartridge, and purified using an ISCO Rf and a 12 g silica column (CV=16.8 ml) by eluting as follows: 100% Hex (5 CV), 0-70% EtOAc/Hex gradient (50 CV), 70% EtOAc/Hex (35 CV) at 30 ml/min. The product fractions were combined and evaporated under reduced pressure to give the desired product as a yellow residue. LC-MS: calculated for C30H38ClF3N4O5Si 654.23 observed m/e: 655.32 (M+H)+ (Rt 1.37/2 min)
Reaction SMILES: C(OC([N:8]([CH2:42][CH3:43])[C:9]1[C:10]([CH2:37][O:38]C(=O)C)=[N:11][CH:12]=[C:13]([C:15]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][C:19]4[N:25]([CH3:36])[C:26](=[O:35])[N:27]([C:28]5[C:29]([CH3:34])=[N:30][N:31]([CH3:33])[CH:32]=5)[C:18]=4[C:17]=3[CH:16]=2)[CH:14]=1)=O)(C)(C)C.[Li+].[OH-]>O1CCOCC1.CCOC(C)=O>[CH3:33][N:31]1[CH:32]=[C:28]([N:27]2[C:18]3[C:17]4[CH:16]=[C:15]([C:13]5[CH:12]=[N:11][C:10]([CH2:37][OH:38])=[C:9]([NH:8][CH2:42][CH3:43])[CH:14]=5)[CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][C:19]=3[N:25]([CH3:36])[C:26]2=[O:35])[C:29]([CH3:34])=[N:30]1
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-2-ylmethyl ester 155.1.1, 0.041 mmol) in dioxane (0.33 ml) was treated with 1 M aqueous LiOH (0.082 ml) for 1.5 h at rt then was added 1 M aqueous LiOH (0.082 ml) and the RM was stirred for 2 h at rt. The RM was diluted with EtOAc and washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The pure fraction was basified with NaHCO3, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a film. (HPLC: tR 2.10 min (Method A); M+H=444 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.12-8.08 (m, 2H), 7.97-7.90 (m, 2H), 7.63-7.60 (m, 1H), 6.87 (s, 1H), 5.49 (t, 1H), 5.31 (t, 1H), 4.57 (d, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.19 (qt, 2H), 1.96 (s, 3H), 1.25 (t, 3H))
Reaction SMILES: BrCC1C=CC=CC=1F.ClC1N=C2NN=CC2=CN=1.Cl[C:21]1[N:26]=[C:25]2[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[N:28]=[CH:29][C:24]2=[CH:23][N:22]=1.C[N:39]1[CH:43]=[C:42]([NH2:44])[CH:41]=[N:40]1>>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:27]1[C:25]2=[N:26][C:21]([NH:44][C:42]3[CH:43]=[N:39][NH:40][CH:41]=3)=[N:22][CH:23]=[C:24]2[CH:29]=[N:28]1
Reactant: Fc1ccccc1Cn1ncc2cnc(Cl)nc21
Reactant: Cn1cc(N)cn1
Agent: Clc1ncc2cn[nH]c2n1
Agent: Fc1ccccc1CBr
Product: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21

Procedure:
The following compound was made according to the procedures in Example 1 (Step ii) using 1-(bromomethyl)-2-fluorobenzene and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine followed by Example 1 (Step i) using 6-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-1H-pyrazol-4-amine:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CN(C)C(=O)N1CCOCC1
Reactant: Nc1ccccc1N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)C(=Nc1ccccc1N1CCOCC1)N1CCOCC1

Procedure:
Reaction of 4-dimethylcarbamoylmorpholine (3.8 g) in benzene (25 ml) with 4-(2-aminophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride (2.1 ml) for 40 hours at 80°-85° C. gave N,N-dimethyl-N'-(2-morpholinophenyl)morpholine-4-carboxamidine (m.p. 126°-128° C.) which was recrystallised from hexane.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([S:12]([NH:15][C:16]1[S:17][C:18]([F:21])=[CH:19][N:20]=1)(=[O:14])=[O:13])[CH2:7]2.[N:22]1([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2C2C=CC=C3C=2CNCC3)[CH:26]=[CH:25][N:24]=[CH:23]1.Cl.BrC1C=CC=C2C=1CCNC2>>[N:22]1([C:27]2[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=2[C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([S:12]([NH:15][C:16]2[S:17][C:18]([F:21])=[CH:19][N:20]=2)(=[O:14])=[O:13])[CH2:7]3)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CNCC3)c(-n2ccnc2)c1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(Br)cccc2C1
Agent: Brc1cccc2c1CCNC2
Agent: Cl
Product: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2-n2ccnc2)C1

Procedure:
The title compound was prepared in a procedure analogous to Intermediate I, wherein 8-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate R) was substituted for 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride [M+H]+=524.0 1H NMR (400 MHZ, Acetone-d6) δ ppm: 7.97 (s, 1H), 7.91 (dd, J=7.9, 1.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.48 (d, J=1.0 Hz, 1H), 7.44 (t, J=1.3 Hz, 1H), 7.10-7.19 (m, 2H), 6.97-7.02 (m, 3H), 4.28-4.41 (m, 2H), 3.68-3.77 (m, 1H), 3.21-3.32 (m, 1H), 2.44-2.54 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[OH:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:44]4[CH2:45][CH2:46][C@@H:42]([OH:41])[CH2:43]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: O[C@H]1CCNC1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CN4CC[C@@H](O)C4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.7 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (0.075 g, 0.14 mmol), (S)-3-hydroxypyrrolidine (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of (S)-3-hydroxypyrrolidine (0.1 mL) and sodium triacetoxyborohydride (0.084 g, 0.40 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the reaction mixture was concentrated in vacuo. The residue was dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 16.5-18.4 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(3R)-3-hydroxytetrahydro-1H-1-pyrrolyl]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.027 g, 0.043 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.89 (1H, s), 8.30-8.33 (2H, m), 8.13-8.14 (2H, m), 7.90-7.80 (1H, m), 7.84 (1H, d, J=10.8 Hz), 7.70 (1H, d, J=7.6 Hz), 7.35-7.59 (4H, m), 4.64 (1H, bs), 4.14-4.23 (1H, m), 3.91 (3H, s), 3.62 (2H, s), 2.61-2.62 (2H, m), 2.27-2.28 (2H, m), 2.27-2.28 (2H, m), 2.02 (1H, m), and 1.60 (1H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.41 min. MS: MH+ 622.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:27]1[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=[C:26]1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][N:36]=1
Reactant: CCOc1ccc(C(=Nc2ccccc2Cl)NN)nc1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nnc(/C=C/c3nnc(-c4ccnc(OC)c4)o3)n2-c2ccccc2Cl)nc1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (0.30 g, mmol) in 20 mL of PhMe was added 0.5 mL of POCl3. The mixture was stirred at reflux for 2 h. After removal of solvent, the residue was dissolved in 20 mL of dichloromethane and added to 240 mg (0.68 mmol) of N-amino-N′-(2-chlorophenyl)-5-ethoxy-pyridine-2-carboxamidine 5. The mixture was stirred at ambient temperature for 2 h. After removal of solvent, the residue was suspended in 20 mL of PhMe and refluxed for 3 h. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-ethoxypyridine as a solid. Yield: 20 mg, 3.5%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10](=[CH:15][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Methane sulphonyl chloride (7.0 g) was added to a stirred, cooled mixture of methyl 4-chlorosalicylate (10.0 g) and triethylamine (8.0 g) in dichloromethane while maintaining the temperature at 0° C. The mixture was then stirred at room temperature for one-half hour and left to stand overnight. The mixture was washed with hydrochloric acid (2M), saturated aqueous sodium bicarbonate solution, water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-(methylsulphonyloxy)benzoate (11.7 g) as an orange solid m.p. 82.5°-84.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=O)[CH:2]=1.[NH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:26][O:25][CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[N:18]=[C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1CCCCC1c1cnc2ccccc2c1
Reactant: COC[C@@H]1CCCN1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC[C@@H]1CCCN1N=C1CCCCC1c1cnc2ccccc2c1

Procedure:
A mixture of (±)-2-(3-quinolinyl)cyclohexanone (0.5 g, 2.2 mmol), (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (`SAMP`)(0.28 g, 2.2 mmol) and p-toluenesulphonic acid (10 mg) was refluxed in toluene (15 ml) for 2.5 hours. The toluene was removed in vacuo (40° C./14 mmHg,) to give a crude oil which was partitioned between water (20 ml) and ethyl acetate (25 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml) and the combined organic extracts were dried over sodium sulphate then concentrated in vacuo to give (2S)-(+)-2-(methoxymethyl) -1-[2-(3-quinolinyl)cyclohexylideneamino]pyrrolidine and (2S)-(-)-2-(methoxymethyl)-1-[2-(3-quinolinyl)cyclohexylideneamino]pyrrolidine as a 50:50 mixture of diastereoisomers (0.69 g, 2 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][N:19]1[CH:23]=[N:22][N:21]=[CH:20]1>>[N:19]1([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:23]=[N:22][N:21]=[CH:20]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nn1cnnc1
Product: FC(F)(F)c1cc(Nn2cnnc2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 1-amino-1,3,4-triazole (24 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.61 (brs, 1H), 8.71-8.66 (m, 4H), 7.41 (m, 2H), 6.69 (s, 1H), 5.18 (s, 2H).