Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]Br.O>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[CH:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 100 mg), potassium carbonate (172 mg), and 1,2-dibromoethane (0.086 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.17 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 70 mg (yield 54%) of the title compound.
Reaction SMILES: [C:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8])#[N:2].[CH2:22]1[O:25][CH:23]1[CH3:24]>CO>[C:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:5][CH2:6][N:7]([CH2:22][CH:23]([CH3:24])[OH:25])[CH3:8])#[N:2]
Reactant: CC1CO1
Reactant: CNCCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Solvent: CO
Product: COc1ccc(C(C#N)(CCCN(C)CC(C)O)C(C)C)cc1OC
Temperature: 20 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
A solution of 18.9 g of 4-cyano-4-(3,4-dimethoxyphenyl)-5,N-dimethyl-hexylamine and 4.5 g of propylene oxide in 40 ml of methanol was allowed to stand for 24 hours at 20° C. A further 0.75 g of propylene oxide was then added, and after 24 hours at 20° C. the solution was refluxed for 1 hour and then evaporated to dryness in vacuo. The oil thus obtained was purified by silica gel chromatography using chloroform containing increasing amounts of methanol as eluent. The unitary TLC fractions (chloroform:methanol:5N methanolic ammonia 95:5:0.5 by volume) were evaporated to dryness to give 18.78 g of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[NH2:38][C@H:39]1[CH2:45][CH2:44][S:43][C@H:42]2[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([F:53])([F:52])[F:51])[N:41]2[C:40]1=[O:54]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH3:16])[C:17]([NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])=[O:35])[C:8]([NH:38][C@H:39]2[CH2:45][CH2:44][S:43][C@H:42]3[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([F:51])([F:53])[F:52])[N:41]3[C:40]2=[O:54])=[O:9])=[CH:36][CH:37]=1
Reactant: N[C@H]1CCS[C@H]2CCC[C@@H](C(F)(F)F)N2C1=O
Reactant: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O
Product: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(F)(F)F)N2C1=O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O

Procedure:
(2R,5S)-2-(4-Fluorobenzyl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N1-((4S,7S,10aS)-5-oxo-7-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-5-propylhexanediamide was synthesized as described in General Procedure H using Intermediate 76 (22 mg, 0.043 mmol) and Intermediate 77 (12 mg, 0.045 mmol) to give a white solid (14 mg, 43% yield). Anal. Calcd. for C39H50F4N4O5S m/z 762.7. found: 763.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.42-7.22 (3H, m), 7.15-7.02 (3H, m), 7.01-6.94 (2H, m), 6.86 (2H, t, J=8.5 Hz), 5.28-5.15 (2H, m), 4.99-4.83 (2H, m), 4.05-3.88 (1H, m), 3.81 (3H, s), 3.54-3.34 (1H, m), 3.28-3.09 (1H, m), 2.85-2.60 (3H, m), 2.42-2.30 (1H, m), 2.22-1.72 (12H, m), 1.71-1.20 (11H, m), 0.87 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH:37]1([O:43][C:44](Cl)=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:44](=[O:45])[O:43][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.87 g, 0.002 mol) and sodium bicarbonate (5%, 1 mL) in toluene (10 mL) at 0° was added, dropwise, a solution of cyclohexylchloroformate (0.32 g, 0.002 mol) in toluene (5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The solvent was removed under vacuum. The residue (1.0 g) was chromatographed with 7:3 hexane-ethyl acetate to give the title compound (0.61 g, 0.0011 mol) as a yellow oil. 1H NMR (CDCl3) δ 11.1(bs,1H), 7.7-7.2(m,10H), 4.6(bs,1H), 3.3(t,2H,J=5.1 Hz), 3.2(t,2H,J=7.5 Hz), 3.0(t,2H,J=5.2 Hz), 1.9-1.2(m,26H), 0.9-0.8(m,3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[NH:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20](=[O:21])[C:19]([OH:24])([C:18]([F:26])([F:25])[F:17])[C:13]1[C:14](=[O:15])[N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[NH:11][C:12]=1[CH3:16]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Cc1cc(=O)n(-c2ccc(C(C)C)cc2)[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C(C)C)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-isopropylphenyl)-3-methyl-5-pyrazolone (108 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (186 mg).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19]2)[CH2:14][CH2:13]1)=[O:10].[O-:25][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([N:18]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19]2)[CH2:16][CH2:17]1)=[O:10]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C=O)c3)CC2)c(Cl)c1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C(=O)O)c3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Solutions of 3,4-dichloro-N-[1-(3-formyl-1H-pyrrol-1-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 259, 90 mg, 0.24 mmol) in 10 ml acetone and KMNO4 (39 mg, 0.24 mmol) in 3 ml water were combined and stirred at ambient temperature overnight. Due to incomplete conversion, solutions of KMnO4 (15 and 20 mg) in 3 ml water were added at 5 hour intervals. The mixture was quenched with aqueous NaHSO3 and partitioned between EtOAc and water. The EtOAc was separated and washed with brine. Drying (MgSO4) and removal of solvent gave product as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>C(Cl)Cl>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH:14][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(I)c2oc(C3CC3)cc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(I)c2oc(C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of the title compound from Step 2 (1.0 g, 3.3 mmol) in 20 mL of dry DCM was added a solution of pyridine (793 mg, 10 mmol) in DCM (10 mL), followed by addition of EtSO2Cl (473 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 1 h. It was diluted with DCM (20 mL) and washed with water (20 mL×2) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (1.3 g, 100% yield) that was used directly in the next step. 1H NMR (CDCl3, 400 MHz): δ 7.42 (d, J=2.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 6.88 (br, 1H), 6.40 (s, 1H), 3.09 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H), 2.04-2.08 (m, 1H), 1.06-0.97 (m, 4H). LCMS: 409 (M+18)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:8]1[C:6]2=[N:7][C:2]([Br:1])=[CH:3][C:4]([CH3:13])=[C:5]2[N:10]=[C:9]1[CH2:11][CH3:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCc1nc2nc(Br)cc(C)c2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(Br)nc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-ethyl-7-methylimidazo[4,5-b]pyridine (10 g, 39 mmol) in DMF (70 mL) at room temperature was added NaH (1.3 g of an 80% dispersion, 43 mmol). After 20 min benzyl bromide (5.15 mL, 43 mmol) was added and the reaction was stirred for 16 h. The mixture was poured onto 500 g of ice and the solid residue was filtered, washed with water and air dried to afford 3-benzyl-5-bromo-2-ethyl-7-methylimidazo[4,5-b]pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[F:8][C:9]1[C:10]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:12]=[CH:13][C:14]=1[CH:15]=[O:16]
Reactant: O=Cc1cccc(B(O)O)c1F
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1cccc(-c2ccccn2)c1F
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromopyridine (200 mg; 1.26 mmol), (2-fluoro-3-formylphenyl)boronic acid (212 mg; 1.26 mmol), K2CO3 (699 mg; 5.06 mmol), and PdCl2(dbpf) (11 mg; 0.017 mmol) in MeCN (5 ml) and water (5 ml) was heated to 80° C., under nitrogen, for 2 h. After cooling to rt, MeCN was removed under reduced pressure, and the aq. layer was extracted with AcOEt (2×). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (toluene/AcOEt=8/2) afforded 2-fluoro-3-(pyridin-2-yl)benzaldehyde as a yellow solid. LC-MS (conditions C): tR=0.78 min.; [M+H]+: 202.20 g/mol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[O:21]=[C:22]1[NH:26][C:25]2[CH:27]=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:24]=2[NH:23]1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:24]4[NH:23][C:22](=[O:21])[NH:26][C:25]=4[CH:27]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Product: COc1cccc(Nc2nc(-c3ccc4[nH]c(=O)[nH]c4c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with 2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 115. NMR: (CDCl3): 3.84 (s, CH3), 4.01 (s, CH3), 6.72 (dd, H, ArH, J=2.1, 8.28), 7.04 (d, H, ArH, J=8.2), 7.35 (t, H, ArH, J=8), 7.47 (d, H, ArH, J=8), 7.72 (s, H, NH), 8.06 (s, H, NH), 8.18 (dd, H, ArH, J=1.4, 8.3), 8.25 (s, H, NH), 10.03 (s, H, ArH), 10.81 (s, H, ArH), 10.86 (s, H, ArH). MS: (ESI+) MH+=388.21
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH3:25])[CH3:24]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Trifluoromethylphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:19]([CH3:20])[C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=1[C:24]([N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:18]1[N:19]([CH3:20])[C:15]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:7]=2[F:6])=[C:16]([C:24]([N:26]2[CH2:29][CH:28]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27]2)=[O:25])[CH:17]=1)(=[O:23])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(C(=O)N2CC(O)C2)c(Nc2ccc(I)cc2F)n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N2CC(OS(C)(=O)=O)C2)c(Nc2ccc(I)cc2F)n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
Methane sulfonyl chloride (0.026 ml, 0.33 mmol) was added dropwise at 0° C. to a stirred solution of Example 27 (102 mg, 0.22 mmol) and triethyl amine (0.047 ml, 0.33 mmol) in CH2Cl2 (1.2 mL). After stirring for 10 min at 0° C., the reaction mixture was allowed to warm up at room temperature. After stirring for 2 hours, the reaction mixture was washed with a saturated solution of NaHCO3, extracted with CH2Cl2. The organics were washed with and brine, dried (MgSO4), and concentrated. Purification by silica gel chromatography gave 100 mg (84%) of the title compound as beige solid. MS (ES) [m+H] calc'd for C18H19FIN3O5S, 536; found 536.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][S-:15].[Na+].Cl>CN(C)C=O>[CH3:14][S:15][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[S-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(F)(F)F)cc1C#N
Yield: 67.1 %

Procedure:
(Step 1) A mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (10 g) and sodium methanethiolate (4.08 g) was stirred in N,N-dimethylformamide (30 ml) at 80° C. for 14 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-(methylsulfanyl)-5-(trifluoromethyl)benzonitrile (7.71 g) as a solid.
Reaction SMILES: [C:1](=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:3][C:1](=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)=C(C)CBr

Procedure:
Diethyl isopropylidenemalonate (4, 50g, 0.25 mol) was refluxed with stirring with N-bromosuccinimide (44.3 g, 0.25 mol) and dibenzoyl peroxide (1.0 g, 4.1 mmol) in carbon tetrachloride (100 mL) with illumination using Kodak Ectagraphic slide projector lamp ELH (300 Watt) for 1.5 h. The reaction was completed as indicated by a negative starch-iodine test for N-bromosuccinimide. The resulting mixture was diluted with carbon tetrachloride (100 mL) and it was cooled in an ice-bath. The precipitated succinimide was filtered off and the filtrate was evaporated in vacuo at room temperature. The residual pale yellow oil of diethyl bromo-isopropylidene-malonate (5, 71.1 g) was used without purification in the Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C1C(=O)N([Br:18])C(=O)C1.C(O)(C(F)(F)F)=O>C(#N)C>[Br:18][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2nccn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc2ncc(Br)n2n1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (5 g, 32.6 mmol) in acetonitrile (300 mL) was added NBS (6.37 g, 35.8 mmol) and TFA (0.75 mL). The resulting solution was allowed to stir at it overnight. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc, washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7.2 g (92%) of the title compound as a light yellow solid. 1H-NMR (400 MHz, CDCl3) ppm 7.91 (d, 1H), 7.79 (s, 1H), 7.12 (d, 1H). LCMS (method A): [MH]+=232/234, tR=4.48 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:16]1[CH2:18][CH2:17]1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH:16]1[CH2:18][CH2:17]1)[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H](C(=O)O)C1CC1)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)C1CC1)OCc1ccccc1
Reaction time: 4 h
Yield: 49.8 %

Procedure:
A solution of (S)-benzyloxycarbonylamino-cyclopropyl-acetic acid (3.2 g, 12.8 mmol) in THF (20 mL) was cooled in an ice/water bath and treated with a 1 M solution of BH3 in THF (16.7 mL, 16.7 mmol). The reaction was stirred for 4 hours and then treated with 1 M HCl until the bubbling ceased. The reaction was stirred overnight and the organic solvent was removed by rotary evaporation. The residue was treated with ethyl acetate and transferred to a separatory funnel. The aqueous phase was discarded and the organics were washed twice with 1 M NaOH, dried over MgSO4 and the solvent was removed. The residue was purified on silica gel using a gradient of 0-100% ethyl acetate in hexane to afford 1.5 g (50% yield) of (S)-(1-Cyclopropyl-2-hydroxy-ethyl)-carbamic acid benzyl ester as a white solid; 1H NMR (CDCl3, 400 MHz) δ 0.26-0.37 (m, 1H), 0.34-0.44 (m, 1H), 0.47-0.61 (m, 2H), 0.83-0.94 (m, 1H), 2.95-3.04 (m, 1H), 3.70 (dd, 1H, J1=5.8, J2=11.1), 3.79-3.88 (m, 1H), 5.00-5.12 (m, 1H), 5.10 (s, 2H), 7.29-7.31 (m, 5H); HPLC-MS calcd. for C13H17NO3 (M+H+) 236.1, found 236.3.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:26]1(=[O:35])[C:29]2([CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:28][O:27]1>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][S:4][CH2:28][C:29]2([C:26]([OH:27])=[O:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:10][CH:11]=1
Reactant: CC(=O)SCCCOc1ccc(Cl)cc1
Reactant: O=C1OCC12CCOCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1(CSCCCOc2ccc(Cl)cc2)CCOCC1
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A solution of Intermediate 3 (0.80 g) in methanol was treated with a solution of sodium hexamethyldisilazide (1 M in THF, 3.3 ml) at 0° C. and the resulting mixture was stirred for 2 h, then a solution of Intermediate 1 (460 mg) in methanol was added. The mixture was stirred for 18 h, then evaporated and the residue dissolved in water and washed with diethyl ether. The aqueous phase was acidified with citric acid and extracted with dichloromethane; the organic layer was then washed with brine, dried over MgSO4 and evaporated to give the title compound (0.12 g) as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=O.[C:24]([NH2:27])(=[S:26])[CH3:25].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:23][N:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]1[N:27]=[C:24]([CH3:25])[S:26][CH:2]=1)=[CH:13]2)[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: CC(N)=S
Reactant: CN(c1cccc2cc(C(=O)CCl)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)cs1
Yield: 10.6 %

Procedure:
A mixed solution of N-[2-(2-chloroacetyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (570 mg), thioacetamide (0.20 g) and N,N-dimethylacetamide (15 ml) was stirred at 80° C. for 2 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-4:6), the obtained crude product was purified by preparative HPLC, and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (64 mg, yield 11%) as colorless needle crystals. melting point 161-162° C. MS:390 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:15]=[C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:26]=[CH:27][C:28]=3[S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Sc2ccccc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (557 mg, 3.12 mmol) was reacted with the product from Example 90b (1.032 mg, 3.12 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (310 mg, 17%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (s, 9H) 2.76 (s, 3H) 4.19 (d, J=6.25 Hz, 2H) 6.29 (d, J=6.99 Hz, 1H) 7.25 (s, 5H) 7.31 (s, 1H) 7.37 (d, J=3.31 Hz, 2H) 7.44-7.56 (m, 1H) 7.79 (d, J=8.82 Hz, 1H) 8.42 (d, J=6.99 Hz, 1H) 8.94 (d, J=8.46 Hz, 1H) 11.05 (s, 1H) 14.43 (s, 1H); MS (ESI+) m/z 473 (M+H)+.