Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[ClH:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[O:25]([CH2:32][CH2:33][CH2:34]Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[OH2:25].[ClH:2].[ClH:2].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:34][CH2:33][CH2:32][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][CH2:13]2)=[CH:8][CH:9]=1.[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:34][CH2:33][CH2:32][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][CH2:13]2)=[CH:8][CH:9]=1.[ClH:2].[ClH:2]
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: BrCCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
A mixture of 3.92 g (10.5 mmol) of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine hydrochloride hydrate, 2.77 g (13.0 mmol) of 3-phenoxy propyl bromide, 3.80 g (36.0 mmol) of sodium carbonate, and 0.61 g (3.7 mmol) of KI in 400 mL of 1-butanol was heated at reflux for 69 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected to flash column chromatography (silica gel, elution with 1 to 3% CH3OH in CH2Cl2) to give the free base of the title compound. This was converted to the HCl salt, and the salt was recrystallized from CH3OH/ether to give 3.59 g (65.9%) of the title compound as a white crystalline solid, mp 222°-226° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[F:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:19]=1.C(N(CC)CC)C>CN(C)C=O>[F:17][C:18]1[C:23]([NH:24]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)=[CH:22][CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:19]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CCN(c2ccc(N)c(F)n2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)c(F)n2)CC1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
(4E)-6-Iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.26 g, 0.80 mmol), 2-fluoro-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine (contaminated with triethylammonium trifluoroacetate, approximately 0.80 mmol) were coupled in N,N-dimethylformamide (10 mL) with triethylamine (0.66 mL). The mixture is heated in a 100° C. oil bath for one hour. The reaction mixture is purified by reverse phase HPLC and then flash silica gel chromatography (methanol/chloroform) to give (4Z)-4-({[2-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione (0.20 g, 49%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH:32]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[NH2:33]>C(Cl)Cl>[CH2:37]([O:36][C:34]([NH:32][NH:33][C:14]([C@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)O
Reactant: NNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of (R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (1.146 g, 5.00 mmol) in dehydrated methylene chloride (25 mL) was cooled to 0° C. under an argon atmosphere and gradually added dropwise isobutyl chloroformate (0.682 g) so that the temperature does not exceed 0° C. Then, triethylamine (0.505 g) was gradually added so that the temperature does not exceed 0° C., followed by stirring 30 minutes, thereby a mixed acid anhydride was prepared in the reaction system. To this reaction mixture was gradually added benzyl hydrazinecarboxylate (0.830 g), after the addition, followed by raising the temperature to room temperature and stirring for 1 hour. This reaction mixture was washed with 0.5M hydrochloric acid and saturated brine, the organic layer was dried over magnesium sulfate and then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=30/1) to afford 1.53 g of the title compound (yield 80.1%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#N)=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.Cl.[OH2:25]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:25])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)c2ccccc12
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of 4-(bromomethyl)-1-naphthonitrile (8 g, 33 mmol) in toluene (100 mL) at 0° C. was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0° C. for 1 h. 3 N HCl in H2O (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116° C.; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)=[CH:40][CH:41]=1
Reactant: [H][H]
Reactant: CCCCCCC(Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(Cc1ccc(Cc2ccc(N)cc2)cc1)Cc1ccc(Cc2ccc(N)cc2)cc1
Yield: 96.9 %

Procedure:
In a 1-liter three-necked flask having a fit equipped with a stirring device and a nitrogen substituting device, 40.9 g of 1,3-bis(4-(4-nitrobenzyl)phenyl)-2-n-hexyl propane, 5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and 300 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Residues were dissolved in chloroform, and then subjected to a separating operation by a column chromatography with silica gel. By removing off the solvent again, 35.3 g of 1,3-bis(4-(4-aminobenzyl)phenyl)-2-n-hexyl propane was obtained as yellow oil.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][O:44][C:45]([CH3:66])([CH3:65])[CH2:46][N:47]1[C:59]2[C:58]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N:52]=[C:51]([NH2:60])[C:50]=2[N:49]=[C:48]1[CH2:61][O:62][CH2:63][CH3:64]>CN(C=O)C>[NH2:60][C:51]1[C:50]2[N:49]=[C:48]([CH2:61][O:62][CH2:63][CH3:64])[N:47]([CH2:46][C:45]([CH3:66])([O:44][CH2:43][CH2:42][NH:41][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH3:65])[C:59]=2[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N:52]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Nicotinic acid (11.4 mg, 92.3 μmol) was combined with DMF (1.0 mL) to give a colorless solution. To this solution was added TBTU (29.6 mg, 92.3 μmol), and DIEA (54.2 mg, 71.8 μl) were added. Finally 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (30 mg, 83.9 μmol) was added and the reaction mixture was stirred for 1 hour at room temperature. Volatiles were removed in high vacuum at 40° C. The residue was dissolve in a mixture of ethyl acetate (5 mL) and methanol (0.5 mL). 1N sodium hydroxide solution (1.5 mL) was added and after a few minutes stirring the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic phases were combined dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 10% methanol in DCM) to give the title product (33 mg, 85%) as white foam; LC-MS (UV peak area, ESI) 88%, 463.2459 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[CH:15][C:16]4[O:17][CH2:18][CH2:19][O:20][C:21]=4[C:12]=3[O:11][CH2:10]2)[C:2]1=[O:22].Cl.CO.Cl.[F:27][C:28](F)([F:37])[C:29]1[C:30]([CH2:35]O)=[N:31][CH:32]=[CH:33][CH:34]=1>>[F:27][CH:28]([F:37])[C:29]1[C:30]([CH2:35][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:13]4[C:12](=[CH:21][C:16]5[O:17][CH2:18][CH2:19][O:20][C:15]=5[CH:14]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2
Reactant: OCc1ncccc1C(F)(F)F
Agent: Cl
Solvent: CO
Product: O=C1N(Cc2ncccc2C(F)F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 11.78 and making non-critical variations using (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one, and 3-(difluoromethyl)pyridin-2-yl]methanol hydrochloride to replace (3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride, (8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (50%) as a colorless solid: mp 181-182° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=4.9 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.52-7.50 (m, 1H), 7.52-7.42 (m, 1H), 7.25-7.15 (m, 2H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.42 (s, 1H), 5.18 (ABq, 2H), 4.72 (ABq, 2H), 4.19-4.12 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 152.9 (t, JC-F=4.3 Hz), 151.4, 144.6, 143.2, 138.2, 135.0 (t, JC-F=7.0 Hz), 132.5, 129.1, 128.0 (t, JC-F=22.6 Hz), 123.9, 123.5, 123.3, 122.0, 113.8 (t, JC-F=236.6 Hz), 112.3, 109.7, 99.1, 79.7, 64.7, 64.1, 57.8, 42.3; MS (ES+) m/z 436.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[C:6]([CH2:8][NH:9][C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26]Br)[CH:19]=3)[N:11]=2)[CH:7]=1.O1CCCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:5]=[C:6]([CH2:8][NH:9][C:10]3[N:11]=[C:12]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH:19]=4)[CH2:24][CH2:25][CH2:26][O:28]2)[N:13]=[CH:14][C:15]=3[Cl:16])[CH:7]=1
Reactant: Oc1cc(Br)cc(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc2nc1NCc1cc(Br)cc(c1)OCCCc1cccc(c1)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.9 %

Procedure:
Into a reaction flask were added 3-bromo-5-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]methyl}phenol (2.97 g, 5.64 mmol), tetrahydrofuran (30 mL), and a solution of sodium hydroxide in water (33.8 mL, 1.0 M). The reaction mixture was stirred at rt over two days. The mixture was filtered, and then the cake was washed with water, MeOH, and EtOAc successively to provide the desired product (1.33 g, 53%) as an off-white powder. LCMS for C20H18BrClN4O (M+H)+: m/z=444.9, 446.9. 1H NMR (400 MHz, DMSO-d6): δ 9.04 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.36 (s, 1H), 7.10 (m, 1H), 7.07 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J=7.5 Hz, 1H), 4.42 (d, J=5.5 Hz, 2H), 4.18 (t, 2H), 3.60 (m, 1H), 2.65 (m, 2H), 1.65 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].[NH2:40][C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([S:47](=[O:49])(=[O:48])[NH2:50])[CH:42]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(S(N)(=O)=O)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide, (50 mg, 0.09 mmol), prepared as in reference 3, in glacial acetic acid (2 mL) is mixed with 3-aminobenzenesulfonamide (31 mg, 0.18 mmol) and shaken at 80° C. for 24 hours. The resulting mixture is directly purified by preparative HPLC-MS to give 4-(3-sulfamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (35.3 mg, yield 57%); 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 10.64 (s, 1H), 10.10 (s, 1H), 9.58 (s, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 8.14 (s, 1H), 7.87 (d, J=3.9 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.53 (d, 5.9 Hz, 1H), 7.37 (s, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.11 (d, J=3.9 Hz, 1H), 2.44 (s, 3H), 2.33 (s, 3H); ESIMS m/z 690.1 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][C@@H:8]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH2:7][C:6]2=1)#N.C(O)=[O:31]>[Al].[Ni].CO>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][C@@H:8]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([CH:1]=[O:31])[CH:4]=2
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Agent: [Ni]
Agent: [Al]
Solvent: CO
Product: O=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Yield: 95 %

Procedure:
Combine (R)-cyclopropanecarboxylic acid[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amide (Example 194) (3.70 g, 9.55 mmol) and nickel-aluminum catalyst (10.0 g) in 90% formic acid and heat at 90-100° C. for 18 h. Dilute with methanol, filter to remove catalyst, and concentrate the filtrate in vacuo. Neutralize the filtrate by addition of solid NaHCO3 after taking up in ethyl acetate/water. Dry the ethyl acetate portion over Na2SO4, filter, and evaporate to give 3.53 g (95%) of the title compound as a foam. MS (ES): n/z 391 (M+1); 1H NMR(DMSO-d6): δ 9.90 (s, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.61 (d, 1H), 7.57 (d, 1H), 7.37 (dd, 1H), 7.15 (m, 1H), 6.81-6.92 (m, 2H), 5.44 (s, 2H), 4.08 (m, 1H), 3.03 (dd, 1H), 2.57-2.82 (m, 4H), 2.00 (m, 1H), 1.82 (m, 1H), 1.59 (m, 1H), 0.65 (m, 4H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:14]([NH:13][C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 39.1 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate (56 mg, 0.18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg, 0.22 mol), EDCI (42 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), and Et3N (22 mg 0.20 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%–5%–10% (NH4OH/MeOH)/CH2Cl2) to give 34 mg of the title product, (1R,2S,5R)-methyl 5-(tert-butylamino)-2-((S)-2-oxo-3-(3-(trifluoromethyl)-benzamido)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=484.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CN(C)CCN(C)C.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:24]([OH:29])[OH:25])=[CH:7][C:6]=2[CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc2occc2c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc2cc(Cl)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of 5-chlorobenzofuran (14 g, crude) in dry tetrahydrofuran (250 mL) were added tetramethylethylenediamine (12.82 g, 110 mmol). The solution was kept below −60° C. under argon, while the solution of butyllithium in hexane (44 ml, 2.5 M) was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (51.88 g, 276 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (70 ml, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 ml). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5-chlorobenzofuran-2-ylboronic acid (7.5 g) which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][N:29]3[CH2:32][CH2:31][CH2:30]3)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1
Reactant: C1CNC1
Reactant: CCC(=O)Nc1ccc(Sc2nc(CCBr)cc(Nc3cc(C)[nH]n3)n2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ccc(Sc2nc(CCN3CCC3)cc(Nc3cc(C)[nH]n3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-(4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(2-bromoethyl)pyrimidin-2-ylthio)phenyl)propionamide (100 mg, 0.21 mmol) and azetidine (36 mg, 0.63 mmol) in dimethylformamide (2 ml) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml). The organic layer was washed with a saturated solution of sodium bicarbonate (10 ml) and brine (10 ml), then dried over magnesium sulfate. The residue was purified by Gilson HPLC to afford the title compound as a bis-trifluoro acetic acid salt (0.5 mg, 1%). 1H NMR (CD3OD): 1.30-1.37 (3H, m), 2.15-2.20 (3H, s), 2.40-2.50 (4H, m), 2.80-2.90 (2H, t), 3.50-3.55 (2H, t), 4.00-4.15 (4H, s), 6.50-6.55 (1H, s), 7.55-7.65 (2H, m), 7.75-7.80 (2H, m). ES+438
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][OH:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:29][CH2:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: OCc1ccc2ccccc2c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccc3ccccc3c2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-naphthalenemethanol and DBU in DME. ES-MS m/e (%): 365 (M+Na+, 100), 343 (M+H+, 40).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)C.[F:21][C:22]([F:26])([F:25])[CH2:23]I.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:11]1[N:12]=[C:13]2[S:19][CH:18]=[CH:17][N:14]2[C:15](=[O:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:23][C:22]([F:26])([F:25])[F:21])=[CH:9][CH:8]=1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a solution of Step 1 intermediate from Intermediate 10 (400 mg, 2.712 mmol) in DMF (4 ml) was added 1,1,1-trifluoro-2-iodoethane (1.131 g, 5.413 mmol) at room temperature followed by Cs2CO3 (2.63 g, 8.120 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography using 1% methanol in chloroform to afford the desired compound; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 4.79 (q, J=9.3 Hz, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J=4.8 Hz, 1H), 7.98 (d, J=4.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])[CH2:45][CH2:44]1)=[O:20]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 64.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (538 mg, 1.19 mmol, 65%) was obtained.