Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>C(Cl)Cl>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]3[C:42]4[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=4[C:36]([C:46]4[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=4)=[N:35]3)[CH2:13][CH2:12]2)=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccccc23)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3noc4ccccc34)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 82 mg (0.27 mmol) of 4-benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester in 2 mL of CH2Cl2 was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in EtOH and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperazine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 105 mg (68%) of a white solid. MS (electrospray), exact mass calculated for C29H31F3N6O3, 568.24; m/z found, 569.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.41 Hz, 1H), 7.69 (m, 2H), 7.67-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.45-7.42 (m, 1H), 7.23-7.18 (m, 1H), 4.93 (br m, 1H), 4.87 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.27-4.15 (m, 2.3H), 4.09-3.95 (m, 1.7H), 3.91-3.82 (m, 0.7H), 3.81-3.66 (m, 1.3H), 3.62-3.49 (m, 4H), 3.01-2.85 (m, 1.5H), 2.85-2.74 (m, 2.5H), 2.71-2.60 (m, 2H), 2.58-2.45 (m, 2H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[C:28]([OH:36])(=[O:35])[CH:29]([CH2:31][C:32]([OH:34])=[O:33])[OH:30].CN1CCN(C(OC2N(C3C=CC(Cl)=CN=3)C(=O)C3N=CC=NC2=3)=O)CC1>C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[C:28]([O-:36])(=[O:35])[C@H:29]([CH2:31][C:32]([O-:34])=[O:33])[OH:30]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Agent: CN1CCN(C(=O)O[C@H]2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Solvent: CCOC(C)=O
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A 250 mL reactor was charged with 1.5 g (S)-zopiclone and 90 mL of ethyl acetate (EtOAc). The contents were heated to 40° C. to dissolve. A 125 mL flask was charged with 540 mg malic acid and 60 mL of ethyl acetate. The contents were heated to 40° C. and the acid solution was transferred slowly to the zopiclone solution. The reaction was stirred for 3 h. The slurry was filtered and washed with ethyl acetate in an appropriate filter. The wet cake was dried under vacuum, isolated and packaged in appropriate container. Isolated yield=96%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][NH:49][CH3:50])=[CH:44][CH:43]=2)[CH:41]=[CH:40][N:39]=[CH:38]1>C1COCC1.C(Cl)Cl>[N:37]1([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][N:49]([CH3:50])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:46][CH:47]=2)[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: CNCc1ccc(-n2ccnc2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-n4ccnc4)cc3)co2)c(C)c1
Reaction time: 2 h

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (53 mg, 0.15 mmol) was dissolved in THF (0.5 mL) and CDI (24 mg, 0.15 mmol) added. The reaction was stirred for 2 h prior to addition of 1-[4-(1H-imidazol-1-yl)phenyl]-N-methylmethanamine (25 mg, 0.135 mmol). The reaction was stirred at ambient temperature for 3 days, and diluted with DCM (1 mL) and washed with 2M aqueous K2CO3 (1 mL). The organic layer was dried over MgSO4, the solvent removed in vacuo and a portion of the crude product purified using prep method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=[O:14].C(Cl)Cl.CC#N.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:55]([NH:62][C:63](=[NH:66])[S:64][CH3:65])([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>>[C:5]([N:62]([C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])[C:63](=[NH:66])[S:64][CH3:65])([CH3:9])([CH3:6])[CH3:4].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([O:15][C:55](=[O:56])[NH:62][C:63]([S:64][CH3:65])=[NH:66])=[O:14]
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2[nH]cc(CC(=O)OC(=O)NC(=N)SC)c2c1
Product: CSC(=N)N(C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
Step 2 (A): To a mixture of 2-(5-methoxy-1H-indol-3-yl)acetic acid (205 mg, 1.0 mmol)) and CH2Cl2/CH3CN/DIPEA (4.0 mL/0.5 mL/0.5 mL) was added HATU (418 mg, 1.1 mmol). The mixture was stirred at rt for 5 min, and then N-Boc-S-methylisothiourea (preparation C, 190 mg, 1.0 mmol) was added. The reaction was stirred at rt overnight. The resulting crude product was purified by silica gel chromatography to give 280 mg (yield 74%) of tert-butyl N-Boc-S-methylisothiourea-(2-(5-methoxy-1H-indol-3-yl)acetyl)(methylthio)-carbonoimidoylcarbamate. MS (ESI) (M+H)+=378.08. 1H-NMR (500 MHz, CDCl3) δ 7.22 (d, J=8.85 Hz, 1 H), 7.13 (s, 1 H), 6.92-6.99 (m, 1 H), 6.85 (dd, J=8.70, 2.29 Hz, 1 H), 3.83 (s, 5 H), 2.31 (s, 3 H), 1.26-1.51 (m, 9 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[F:1]
Reactant: COc1ccc(C(=O)O)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 5.0 g (29.4 mmol) of 2-fluoro-4-methoxybenzoic acid in methanol (50 mL) at room temperature are added 2.13 mL (29.4 mmol) of thionyl chloride. The reaction is stirred at room temperature for 16 h and the solvent is removed under reduced pressure. The residue is dissolved in DCM and washed with brine. The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to give 5.04 g (27.1 mmol) of 2-fluoro-4-methoxybenzoic acid methyl ester. Yield: 92%, ES-MS: m/z 185 [M+H].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:28]=2[N:29]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH:34][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[CH:19][CH:18]=3)=[O:22])=[CH:30][C:28]=2[N:29]=1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
Add oxalyl chloride (0.16 mL, 1.82 mmol) and 3 drops of DMF to a stirring suspension of 4′-fluoro-biphenyl-4-carboxylic acid (0.197 g, 0.910 mmol) in CH2Cl2 (2.0 mL). Stir the reaction mixture at room temperature for 2 h, Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4′-fluoro-biphenyl-4-carbonyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.05 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (2×20 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.106 g, 38%). mass spectrum (m/e): 459.0 (M+1), 457.0 (M−1). 1H NMR (400 MHz, CDCl3): δ 7.95-7.90 (m, 3H), 7.63 (d, J=8.0 Hz, 2H), 7.60-7.54 (m, 2H), 7.52 (d, J=1.2 Hz, 1H), 7.36 (dd, J=8.8, 1.6 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.18-7.11 (m, 2H), 4.21-4.11 (m, 1H), 3.07 (s, 3H), 2.97 (d, J=11.6 Hz, 2H), 2.32 (s, 3B), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.83-1.75 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].O>CS(C)=O>[CH2:19]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 90 %

Procedure:
3-(5,6-Oxidohexyl)-1-methylthymine was synthesized as follows: A mixture of sodium hydride (343 mg, 14 mmol) and 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (30 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (2.30 g, 14 mmol) was added. After stirring for 69 hours, the reaction mixture was poured into water (100 ml) and extracted with dichloromethane (4×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (40 ml), dried over sodium sulfate, and then the solvent was evaporated under vacuum to give a residue which was recrystallized (dichloromethane-ethyl ether) to give 3-(5-hexenyl)-1-methylthymine (2.80 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N:6]=1.[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH:16]([CH3:18])[CH3:17]>COCCO>[ClH:1].[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=3[N:6]=2)[CH2:24][CH2:23]1)=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: COc1cc2nc(Cl)[nH]c2cc1OC
Reactant: CC(C)COC(=O)N1CCNCC1
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)OCC(C)C)CC3)[nH]c2cc1OC
Product: Cl

Procedure:
3.40 g 2-chloro-5,6-dimethoxy benzimidazole, 7.50 g piperazine N-carboxylic acid isobutyl ester (described in U.S. 3,635,979, Example LVII) and 25 ml 2-methoxyethanol were reacted as in Example I to give the base of the desired product as a gum. This was washed free of starting amine with water, then dissolved in isopropyl alcohol and acidified with HCl gas to give 5.30 g product HCl salt, mp 248°-250° C
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](C=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.[C:58](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:51][N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH:14]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: CN1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1-methylpiperazine (23.4 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). The combined organic extracts were washed with sat. aq. NaCl, dried (Na2SO4) and concentrated to a glassy foam (98.9 mg). Purification was carried out on Gilson instrument with an acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase back-extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a white solid [43.9 mg (36%)]. LC-MS m/z 769.7 (M+H)+.
Reaction SMILES: [Cl:1]Cl.[CH:3]1[C:13]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[Cl:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9](=[O:19])[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[C:13]=2[CH:3]=1
Reactant: ClCl
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)c2ccccc12

Procedure:
Chlorine gas is bubbled into a mixture (partial suspension) of 1.0 g (450 mmol) of 5H-dibenz[b,e]azepine-6,11-dione in 50 ml of glacial acetic acid. The temperature of the mixture rises to 38° C. On standing, as the temperature of the solutions decreases, a white solid precipitates. The mixture is filtered to give 0.40 g of solid (mixture of starting material and product in ratio of 1:8). The filtrate on standing gives 0.10 g of product as crystals, m.p. 289°-293° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(N)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 80.1 %

Procedure:
53.0 g of ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0161 mol), 15.4 ml of benzyl amine, and 37.0 g of anhydrous K2CO3 in 220 ml of acetonitrile were stirred at 100-110° C. for 1 hour. The reaction was monitored by TLC. After the solvent was evaporated, the residue was re-crystallized from ethanol to give 53.7 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.129 mol) in 80.0% yield, mp 133-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)[Cl:17]>Cl.O>[ClH:17].[N+:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[NH:8][NH2:12])([O-:11])=[O:10]
Reactant: Cl[Sn]Cl
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
The commercially available 4-methyl-2-nitro-phenylamine (40 g, 0.23 mol) was dissolved in 12N-hydrochloric acid (100 mL), to which sodium nitrite (16 g, 0.23 mol) dissolved in water (50 mL) was slowly added in drops at 0° C. The reaction mixture was stirred for 30 min at 0° C. After lowering the temperature of the reaction mixture to 0° C., tin (II) chloride (132 g, 0.70 mol) dissolved in 100 mL of 12N-hydrochloric acid was slowly added in drops thereto. The reaction mixture was stirred for 3 h at 0° C. to room temperature. The resulting yellow solid was filtered, washed with a small amount of 6N-HCl, and dried to give the title compound (30 g, Yield 63%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1.IC1C2C(=CC(C#N)=CC=2)NN1C.C([Mg]Cl)(C)C.Cl[Sn:33]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[CH3:13][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]([Sn:33]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:34][CH2:35][CH2:36][CH3:37])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2ccc(C#N)cc21
Agent: CC(C)[Mg]Cl
Agent: CN1Nc2cc(C#N)ccc2C1I
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C#N)ccc12
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
A mixture 3-iodo-1-methyl-1H-indazole-6-carbonitrile and 3-iodo-2-methyl-1H-indazole-6-carbonitrile (160 mg, 0.565 mmol) was dissolved in THF (6 mL). The solution was cooled to −40° C. Isopropylmagnesium chloride 2M in THF (0.34 mL, 0.678 mmol) was added drop-wise at −40° C. The reaction mixture was stirred at −40° C. for 20 min, then chlorotributyltin (0.18 mL, 0.678 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with EtOAc (3×10 mL), combined organics were washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated. The residue was used in the next step without further treatment.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23].S(Cl)(Cl)=O.[CH3:32][C:33]1[S:37][C:36]([NH2:38])=[N:35][N:34]=1>COCCOC.ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:38][C:36]1[S:37][C:33]([CH3:32])=[N:34][N:35]=1)=[O:23]
Reactant: O=C(O)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Reactant: Cc1nnc(N)s1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: Cc1nnc(NC(=O)c2cccc(-c3c(O)ccc4cc(-c5cccc(O)c5)ccc34)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To 3-(2-hydroxy-6-(3-hydroxyphenyl)naphthalene-1-yl)benzoic acid (220 mg, 0.62 mmol, 1 eq), which is dissolved under a nitrogen atmosphere in 5 ml of dry DME, thionyl chloride (600 μl) is added, and the mixture is stirred at RT for 2 h. After the excess thionyl chloride has been removed in vacuum on a rotary evaporator, the residue is dissolved in dry THF and added dropwise to a suspension of 5-methyl-1,3,4-thiadiazole-2-amine (42.6 mg, 0.74 mmol, 1.2 eq) in dry dichloromethane cooled at 0° C. The reaction mixture is stirred at RT over night, followed by removing the solvent on a rotary evaporator. Purification of the raw product by column chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired compound in a yield of 47%, 132 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]2=[N:9][C:8]=1[CH:16]([NH2:18])[CH3:17].[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:9]=[C:10]3[N:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ncccn2c1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ncccn2c1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrimidin-2-yl)-ethylamine (800 mg, 3.34 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (520 mg 3.34 mmol) in n-butanol (5 mL) was added DIEA (1.7 mL, 10.04 mmol) at rt. The reaction mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-30% acetone in hexane to provide 4-amino-6-[1-(3-pyridin-2-yl-imidazo[1,2-a]pyrimidin-2-yl)-ethylamino]-pyrimidine-5-carbonitrile: 1H NMR: (DMSO-d6, 400 MHz) δ 1.547 (d, J=6.4 Hz, 3H), 5.807-5.841 (br s, 1H), 7.150-7.176 (m, 1H), 7.289 (br s, 2H), 7.429-7.466 (m, 2H), 7.847-7.867 (m, 1H), 7.998 (s, 2H), 8.653 (s, 1H), 8.789 (s, 1H), 9.419 (d, J=6.4 Hz, 1H); LC-MS (ESI) m/z 358.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[CH:21]=1>>[F:30][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Reactant: N#Cc1cccnc1-c1cc(Br)ccc1F
Product: N#Cc1cccnc1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 45.5 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 2-(5-bromo-2-fluorophenyl)nicotinonitrile (208 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 2-[2-fluoro-5-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)phenyl]-nicotinonitrile (91 mg, 45%) as a white solid: δH (360 MHz, CDCl3) 6.98 (1H, dd, J 7 and 6), 7.44-7.54 (2H, m), 7.67-7.72 (1H, m), 7.79 (1H, dd, J 7 and 2), 7.88 (1H, s), 8.15 (1H, dd, J 7 and 2), 8.24 (1H, d, J 7), 8.95 (1H, d, J 2); m/z (ES+) 401 (100%, [MH]+).