Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1>>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[C:26]([C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)[CH:25]=1)#[N:24]
Reactant: COc1ccc(C#N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Product: COc1ccc(C#N)cc1-c1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 67.4 %

Procedure:
Proceeding as in Reference 19, but substituting tert-butyl (3-bromo-benzyl)-carbamate (0.9 g, 3.2 mmol) and 4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.9 g, 3.5 mmol), gave tert-butyl (5′-cyano-2′-methoxybiphenyl-3-ylmethyl)carbamate (0.73 g, 68%) as white foam.
Reaction SMILES: [C:1](Cl)([C:3](Cl)=O)=[O:2].CN(C=O)C.[F:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]2[C:14]=1C=[CH:16][NH:17]2.CCOC(C)=O>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]2[C:14]=1[C:3]([CH:1]=[O:2])=[CH:16][NH:17]2
Reactant: N#Cc1ccc(F)c2cc[nH]c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)c2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of (COCl)2 (16.0 g) in DCM (200 mL) at 0° C. was added a solution of DMF (6 mL) in DCM (50 mL) dropwise. Half an hour later, a solution of 4-fluoro-1H-indole-7-carbonitrile (D41) (11.0 g) in DCM (60 mL) was added. The reaction was allowed to warm to RT to form a yellow precipitate. After 6 h the solvent was removed by evaporation. Then THF (100 mL) and 2M aqueous NaOH (100 L) were added to the residue obtained above. After being stirred for about 1 hour, EtOAc (1 L) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated to afford 4-fluoro-3-formyl-1H-indole-7-carbonitrile (D42) as a yellow solid (11.0 g).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH2:11]([S:13][C:14](SCC)=[C:15]1[C:20](=O)[O:19]C(C)(C)[O:17][C:16]1=[O:24])C>C(O)C>[CH3:11][S:13][C:14]1[N:10]=[C:2]2[N:3]([C:20](=[O:19])[C:15]=1[C:16]([OH:24])=[O:17])[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=1[S:1]2
Reactant: Nc1nc2c(s1)CCCC2
Reactant: CCSC(SCC)=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CSc1nc2sc3c(n2c(=O)c1C(=O)O)CCCC3
Temperature: 87.5 °C
Yield: 46.8 %

Procedure:
The suspension of 4,5,6,7-tetrahydro-benzothiazol-2-yl-amine (8 gm, 0.0519 mol) and 5-(bis-ethylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (14.2 gm, 0.0572 mol) in ethanol (60 ml) was heated at 85-90° C. for 10 hours. Reaction mixture was cooled to room temperature and filtered. The solid, thus obtained, was washed with ethanol (20 ml) followed by with diethyl ether (50 ml) and suck dried to give 7.2 gm of title compound as a solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[ClH:27]>C(O)C>[ClH:27].[NH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To benzyl trans-4-(tert-butoxycarbonylaminomethyl)cyclohexylcarbamate (18.93 g) was added concentrated hydrochloric acid (60 ml), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was mixed with ethanol and was then concentrated under reduced pressure. The residue was mixed with diethyl ether, and the precipitated crystals were collected by filtration. The crystals were washed with diethyl ether to obtain benzyl trans-4-aminomethylcyclohexylcarbamate hydrochloride (11.76 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Br)=O.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][Cl:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: O=C(Br)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with chloroacetyl bromide and after 1.5 hours with sodium acetate, then the mixture was refluxed to give 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[CH3:12][CH:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.CN(C)C=O.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:12][CH:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:3])[CH3:14]
Reactant: CC(C)c1ccccc1N
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccccc2C(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
Methyl 2-oxo-2H-pyran-3-carboxylate (3.0 g, 19 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and N,N-dimethylformamide (10 mL), and 2-(1-methylethyl)aniline (2.7 mL, 19 mmol) was added. After stirring overnight at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.5 g, 23 mmol) and 4-(N,N-dimethylamino)pyridine (120 mg, 1.0 mmol) were added, and the mixture was further stirred overnight at room temperature. The reaction system was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→60/40) to give methyl 1-[2-(1-methylethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (800 mg). Methyl 1-[2-(1-methylethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (800 mg) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The mixture was diluted with distilled water (20 mL) and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid (7 mL) and extracted twice with ethyl acetate. The collected organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. A small amount of hexane/ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to give 1-[2-(1-methylethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (760 mg, 15%) as a white solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:55])([CH3:54])[CH3:53])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:52]([OH:55])([CH3:54])[CH3:53])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48]([F:50])([F:49])[F:51])=[CH:43][CH:42]=1
Reactant: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 16c (0.24 mg, 0.31 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.18 mL, 1.55 mmol) and 10% Pd/C (72 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 30 min and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 16 as a white solid (142 mg, 90.7%, HPLC: 97.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 549 [M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.47 (d, 1H), 7.42 (d, 1H), 7.36 (dd, 2.1 Hz, 1H), 7.30 (m, 4H), 5.50 (d, 1H), 5.05 (d, 1H), 5.00 (d, 1H), 4.24 (s, 1H), 4.11 (s, 2H), 4.07-3.99 (m, 1H), 3.81 (d, 1H), 3.75-3.66 (m, 1H), 3.50-3.43 (m, 1H), 3.29-3.21 (m, 1H), 1.20 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([O:42][CH3:43])[CH:36]=1.C(N(CC)CC)C>>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([O:42][CH3:43])[CH:36]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: COc1cc(CN)ccc1O
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)CSc2ccc(Br)cc2)C3)ccc1O

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 4-aminomethyl-2-methoxyphenol hydrochloride in the presence of with one equivalent of triethylamine, m.p. 168° C. MS [(+)ESI, m/z]: 592 [M+H]+ Anal. Calcd for C29H26BrN3O4S: C, 58.79; H, 4.42; N, 7.09. Found: C, 58.65; H, 4.46; N, 6.86.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-:32])=[CH:6][C:5]=2[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2cnc3ccccc3c2n1CCCC1(C)OCCO1
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCCC1(C)OCCO1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 2-methyl-1-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinoline (6.70 g, 21.5 mmol) by reaction with m-CPBA (9.4 g) to provide 2-methyl-1-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]-5-oxido-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (7.20 g, 37.8 mmol) and ammonium hydroxide solution (100 mL) to provide 2-methyl-1-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (3.9 g) as an off-white solid after recrystallization from toluene, mp 193-195° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 3-chlorobenzyl chloride (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 307 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH3:14][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([OH:9])[CH3:14])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A cooled (0° C.) solution of 4-(trifluoromethoxy)benzaldehyde (3.000 g; 15.78 mmol) in anh. THF (50 ml) was treated dropwise with a solution of methylmagnesium bromide (3 M in Et2O; 6.30 ml; 18.90 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 4 h. The resulting reaction mixture was cooled to 0° C., and aq. sat. NH4Cl (30 ml) was added dropwise. The separated aq. layer was further extracted with AcOEt (3×20 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=40/1) afforded 1-(4-(trifluoromethoxy)phenyl)ethanol as a colorless oil. LC-MS (conditions D): tR=0.88 min.; no ionisation.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:3][CH2:4][N:5]([C:35]([C:37]2[S:41][C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[N:39][C:38]=2[CH3:48])=[O:36])[C:6]2[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:25][C:26]([O:28]CC)=[O:27])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[F:49][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:35]([C:37]2[S:41][C:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[N:39][C:38]=2[CH3:48])=[O:36])[C:6]2[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([CH2:25][C:26]([OH:28])=[O:27])[C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)C(F)(F)F)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(N(CC(=O)O)C(=O)C(F)(F)F)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 250 mg of ethyl (Z)-[(l-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)-(trifluoroacetyl)amino]acetate in 5 ml of ethanol was added a solution of 100 mg of potassium carbonate in 2 ml of water, and the mixture was stirred at room temperature for three days. After evaporation of the solvent, water was added to the residue, and the mixture was washed with ethyl acetate (a washing A) The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, and the solvent was evaporated therefrom. The resulting residue was collected by filtration to give 60 mg of (Z)-[(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)(trifluoroacetyl)amino]acetic acid as a colorless amorphous powder.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[CH3:28][N:29]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30]1>>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: Cn1cc(B(O)O)cn1
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Product: Cn1cc(-c2ccc3c(c2)[C@H]2CCCN(C(=O)C(F)(F)F)[C@H]2C3)cn1
Yield: 32 %

Procedure:
The title compound is prepared from trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and 1-methyl-pyrazol-4-yl-boronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 32% of theory; LC (method 1): tR=3.88 min; Mass spectrum (ESI+): m/z=350 [m+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Sn](C)(C)C)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=2)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Sn](C)(C)c1cc(CCCOCc2ccccc2)nc(C#N)n1
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(-c2cc(CCCOCc3ccccc3)nc(C#N)n2)cc(C(F)(F)F)c1

Procedure:
N-(3-Bromo-5-trifluoromethyl-phenyl)-methanesulfonamide (37 mg), 4-(3-benzyloxy-propyl)-6-trimethylstannanyl-pyrimidine-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium(II) (7 mg) in DMF (1 mL) were heated in a microwave to 180° C. for five minutes. The mixture was diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was washed with water (10 mL) and saturated sodium chloride solution (10 mL). Organics were separated, dried over sodium sulphate, filtered and solvent was removed under reduced pressure to yield crude product. Purification by HPLC afforded 4-(3-benzyloxy-propyl)-6-(3-methanesulfonylamino-5-trifluoromethylphenyl)-pyrimidine-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]3)=[CH:7][C:6]=2[CH:16]=1.Cl[C:18]1[CH:27]=[C:26]2[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]2[CH2:28][CH3:29])=[CH:20][C:19]=1[F:34]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[NH:11][CH2:12][CH2:13][N:14]([C:18]4[CH:27]=[C:26]5[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]5[CH2:28][CH3:29])=[CH:20][C:19]=4[F:34])[CH2:15]3)=[CH:7][C:6]=2[CH:16]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Clc1ccc2oc(C3CNCCN3)cc2c1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc5cc(Cl)ccc5o4)C3)cc21

Procedure:
A 1.45 g portion of 2-(5-chloro-2-benzofuranyl)piperazine was added to 5 ml of pyridine. A 540 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a sealed bottle, under argon, at 130°-135° C. for 18 hours, then cooled in an ice bath. The solid was collected, triturated with cold pyridine, dichloromethane, ether and dimethylformamide, giving 180 mg of the desired product, mp 262°-263° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].O1CCCC1>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccccn1
Reactant: Clc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccccn2)cn1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
In a 300 mL inner volume flask replaced by nitrogen, tetrahydrofuran solution of isopropylmagnesium chloride (19.5% by weight, 30.3 g, 57.5 mmol) as a magnesiation reagent was charged, and cooled at 10° C., then tetrahydrofuran solution (20 g) of 5-bromo-2-chloropyridine (9.6 g, 50.0 mmol) as a 2,5-dihalogenopyridine derivative (I) was added dropwise in the range of 10 to 20° C. for 1.0 hour. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 1.5 hours, then the reaction mixture was added dropwise to the solution of tetrahydrofuran (20 g) containing 2-bromopyridine (7.9 g, 50.0 mmol) as a halogenoaryl derivative (II) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.20 g, 0.25 mmol) as a palladium compound, in the range of 10 to 20° C. for 2.0 hours. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 4.0 hours, then reaction was stopped by adding saturated aqueous solution of ammonium chloride (50 g), and was left to stand to isolate organic layer. Organic layer was washed with saturated sodium chloride solution (10 g), then condensed under reduced pressure, to obtain crude 6-chloro-3,2′-bipyridine (10.6 g, purity: 81%, yield: 90%). The resultant crude 6-chloro-3,2′-bipyridine (10.6 g) was subjected to simple distillation under reduced pressure (0.9 mmHg, 124° C.), to obtain 6-chloro-3,2′-bipyridine (8.0 g, yield: 68%) as a 6-halogeno-3-arylpyridine derivative (III).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[S:3].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH:20]=[N:14][S:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([NH:1][C:2]([N:4]=[CH:17][N:18]([CH3:20])[CH3:19])=[S:3])[CH:6]=1)(=[O:12])=[O:13])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: NC(=S)Nc1cccc(S(N)(=O)=O)c1
Product: CN(C)C=NC(=S)Nc1cccc(S(=O)(=O)N=CN(C)C)c1
Yield: 82 %

Procedure:
A mixture of 2.3 g (9.9 mmol) 3-Thioureido-benzenesulfonamide and 17 ml N,N-Dimethylformamide dimethyl acetal was heated for 2 h to 90° C. The precipitate was filtered of washed with DCM/diethyl ether 1:3 and dried to yield 2.8 g (82%) of the title compound.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[C:15]([N+:24]([O-:26])=[O:25])=[C:16]([CH2:20][C:21]([OH:23])=O)[CH:17]=[CH:18][CH:19]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][CH2:29]1>C1COCC1.CCOC(C)=O>[CH2:34]([N:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:21](=[O:23])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=2[N+:24]([O-:26])=[O:25])[CH2:29][CH2:30]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1cccc(F)c1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
17.0 g (102 mmol) CDI were added at RT to 18.3 g (91.9 mmol) (3-fluoro-2-nitro-phenyl)-acetic acid in 500 mL THF and stirred for 30 min. Then 20.0 mL (95.8 mmol) 4-amino-1-benzylpiperidine were added and the mixture was stirred for a further 2 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with water and saturated sodium chloride solution. The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: CC[N:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[F:8][C:9]([F:15])([F:14])[CH2:10]CC=O>>[F:15][C:9]([F:8])([F:14])[CH2:10][CH2:7][CH2:6][NH:3][CH2:4][CH2:5][CH2:10][C:9]([F:15])([F:14])[F:8]
Reactant: O=CCCC(F)(F)F
Reactant: CCN(CC)CC
Product: FC(F)(F)CCCNCCCC(F)(F)F

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 4,4,4-trifluorobutan-1-amine, HCl (598 mg, 4.00 mmol), Et3N (550 μL, 4.00 mmol) and 4,4,4-trifluorobutanal (504 mg, 4.00 mmol) provided a colorless oil which was used directly in the preparation of Example 129. MS(ESI+) m/z 192.1 (M+H)+.