Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:15]#[CH:16].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl-].[Na+].O.CC#N.CC#N.Cl[Pd]Cl.C(#N)C>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:16]#[C:15][CH2:14][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:3]=1
Reactant: C#CCOC1CCCCO1
Reactant: Cc1cc(Br)cs1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C#CCOC2CCCCO2)cs1
Temperature: 90 °C
Reaction time: 11 h

Procedure:
A mixture of 4-bromo-2-methylthiophene(5.00 g), cesium carbonate (23.9 g), 2-(2-propynyloxy)tetrahydropyran (5.96 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (806 mg), bis(acetonitrile)palladium(II) dichloride (147 mg) and acetonitrile (90 ml) was stirred at 90° C. for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (1.48 g) as a brown oil.
Reaction SMILES: CS(C)=O.[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15](F)[C:16]=3[O:18][CH3:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH2:7][CH2:6]1.C(OC([NH:33][C@H:34]1[C@@H:38]([CH2:39][F:40])[CH2:37][NH:36][CH2:35]1)=O)(C)(C)C>C(N(CC)CC)C>[NH2:33][C@H:34]1[C@@H:38]([CH2:39][F:40])[CH2:37][N:36]([C:15]2[C:16]([O:18][CH3:19])=[C:17]3[C:12]([C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9][N:8]3[CH:5]3[CH2:6][CH2:7]3)=[CH:13][C:14]=2[F:21])[CH2:35]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@@H]1CF
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N2C[C@H](CF)[C@H](N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a dimethyl sulfoxide (2 ml) solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3carboxylic acid EF2 complex (345 mg, 1.00 mmol) were added 3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (327 mg, 1.00 mmol) and triethylamine (400 μl), subsequently carrying out 1 day of stirring at room temperature. Triethylamine was evaporated, the resulting residue was mixed with 10% citric acid aqueous solution and then the thus precipitated material was collected by filtration and washed with water. This was dissolved in 80% water-containing ethanol (50 ml), mixed with triethylamine (5 ml) and then heated overnight under reflux. The solvent was evaporated, and the thus obtained residue was mixed with concentrated hydrochloric acid and stirred at room temperature for 15 minutes. The reaction solution was washed with chloroform and then, while cooling in an ice bath, alkalified with 50% sodium hydroxide aqueous solution. This was adjusted to pH 7.4 with concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (300 ml×3). The organic layer was dried over sodium sulfate, the solvent was evaporated, and the resulting residue was isolated and purified by a preparative TLC through its development with a lower layer of chloroform:methanol:water=7:3:1 and then recrystallized from 28% aqueous ammonia-ethanol to give 185 mg (47%) of the title compound in the form of light yellow crystals.
Reaction SMILES: CN[C@@H]1[C@@H](O)[C@H](O[C@H]2O[C@H](CN)CC[C@H]2N)[C@@H](N)C[C@H]1O.C[NH:23][CH2:24][C@H:25]1[O:30][C@H:29]([O:31][C@H:32]2[C@H:37]([OH:38])[C@H:36]([NH:39][CH3:40])[C@H:35]([O:41][CH3:42])[CH2:34][C@@H:33]2[NH2:43])[C@H:28]([NH2:44])[CH2:27][CH2:26]1.CNC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@H](NC)[C@@H](OC)C[C@@H]2N)[C@H](N)CC1>>[CH3:40][NH:39][C@@H:36]1[C@@H:37]([OH:38])[C@H:32]([O:31][C@H:29]2[O:30][C@H:25]([CH2:24][NH2:23])[CH2:26][CH2:27][C@H:28]2[NH2:44])[C@@H:33]([NH2:43])[CH2:34][C@H:35]1[O:41][CH3:42]
Reactant: CNC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@H](NC)[C@H](OC)C[C@@H]2N)O1
Agent: CNC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@H](NC)[C@@H](OC)C[C@@H]2N)O1
Agent: CN[C@@H]1[C@@H](O)[C@H](O[C@H]2O[C@H](CN)CC[C@H]2N)[C@@H](N)C[C@H]1O
Product: CN[C@@H]1[C@@H](O)[C@H](O[C@H]2O[C@H](CN)CC[C@H]2N)[C@@H](N)C[C@H]1OC

Procedure:
Active fractions Nos. 96 to 112 were lyophilized to afford 0.65 g of a crude powder containing substance KA-7038. Lyophilization of active fractions Nos. 113 to 134 afforded 0.4 g of a crude powder of substance KA-7038 I and substance KA-7038 VII. Lyophilization of fractions Nos. 135 to 149 afforded 0.36 g of a crude powder of a mixture of substance KA-7038 I, substance KA-7038 II and substance KA-7038 VI. Furthermore, 0.9 g of a free base of substance KA-7038 III was obtained from fractions Nos. 150 to 172.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([OH:35])=[O:34])(C)[CH:27]=1.O.[OH-].[Li+].Cl.[CH3:40]O>O.C(OCC)(=O)C>[OH:14][C:5]1[C:4]([CH2:25][C:26]2[CH2:30][CH2:29][CH:28]([CH2:32][C:33]([OH:35])=[O:34])[C:27]=2[CH3:40])=[C:3]([O:2][CH3:1])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2
Reactant: CO
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC(=O)O)CC1)C(=O)OC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C)c2c(c(O)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Reaction time: 4 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy -5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetic acid obtained in Example ZC-1G was dissolved in a mixture of methanol (8 mL) and water (2 mL) and treated with lithium hydroxide monohydrate (0.15 g). After 4 hours, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the product was washed out of the combined organic layers with 2M NaOH. Acidification of the basic layers with 5% hydrochloric acid and extraction of the product into ethyl acetate was followed by drying the organic layer with magnesium sulfate. Filtration and solvent removal was followed by two flash chromatographies (hexanes/ethyl acetate, 4/1 with 1% HOAc; then methylene chloride/methanol 25/1) to provide 3-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid (0.010 g) m.p. 153°-159° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](Cl)=[N:28][CH:27]=1)[CH3:23]>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)=[N:28][CH:27]=1)[CH3:23]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC2CCN(Cc3ccc(OC)c(OCC)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.0 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 6-chloro-nicotinic acid ethyl ester (46.4 mg, 0.25 mmol, 1.67 equiv; commercially available) was added and the mixture heated by microwave irradiation to 220° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (18%) of the title compound. MS (ISP): 414.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(F)cc1F
Product: COC(=O)C(=O)Nc1ccc(F)cc1F

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 2,4-difluoroaniline and methyl chlorooxoacetate.
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH3:6][S:7][C:8]1[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:9]=1[CH2:10][N:11]([CH3:13])[CH3:12]>C(OCC)C>[BrH:1].[CH3:13][N:11]([CH2:10][C:9]1[C:8]([S:7][CH3:6])=[C:17]([OH:18])[CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: COc1cccc(CN(C)C)c1SC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CSc1c(O)cccc1CN(C)C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
30% Hydrogen bromide in acetic acid (7 mL, 34 mmol) was added to (2-methylsulfanyl-3-methoxybenzyl)-dimethylamine (1.44 g, 6.8 mmol) and heated with stirring at 100° C. After 17 h, the reaction was complete by LC/MS analysis and was then allowed to cool to room temperature. Diethyl ether (100 mL) was added with stirring. After 20 min, the orange diethyl ether solution was decanted off. This was repeated until a tan solid precipitated. 3-Dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 90%) was filtered off as a brown solid.
Reaction SMILES: O[CH2:2][C@@H:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C:4]([NH:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:15]([C@@H:3]1[CH2:2][N:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:5])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCCC[C@H](CO)C(=O)NOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCC[C@@H]1CN(OCc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
To a mixture of (2R)-2-(hydroxymethyl)-N-benzoxy-7-octenamide (1.51 g, 5.47 mmol) and triphenylphosphine (1.72 g, 6.56 mmol) in THF (50 mL) was added dropwise diisopropyl azodicarboxylate (1.3 mL, 6.56 mmol) at 0° C. The reaction mixture was stirred and allowed to warm to room temperature overnight. The reaction was then quenched with water (50 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine, and dried over MgSO4. After removing the solvent under vacuum, the residue was purified by flash column chromatography (hexane:EtOAc 6/1) to provide the title compound. MH+260.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)([CH3:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([CH3:26])([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]3[N:34]=[N:7][NH:6][C:5]=3[Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:28]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(c2cccc(C#N)c2)CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2cccc(-c3nn[nH]c3[Si](C)(C)C)c2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 0.55 mL, 1.10 mmol) in tetrahydrofuran (5 mL) at 0° C. under an atmosphere of nitrogen was added n-butyllithium (1.6 M in hexane, 0.69 mL, 1.10 mmol) dropwise. After 1 h, a solution of 1-benzyl-4-(3-cyanophenyl)-4-methylpiperidine (Preparation 9, 300 mg, 1.03 mmol) in tetrahydrofuran (10 mL) was added such that the internal temperature remained at 0° C. After 4.5 h, the reaction was quenched with saturated sodium hydrogencarbonate (25 mL) and the mixture was extracted with diethyl ether (3×25 mL). The extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a foam (360 mg, 86%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:36])[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40].Cl>C1COCC1.CCCCCC>[CH2:13]([CH:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:36])[CH:27]([CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH2:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCCC1CCCCC1)N1C(=O)OCC1Cc1ccccc1
Reactant: O=C(CBr)N1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(CC(CCC1CCCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)N1CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.92 mL, 13.68 mmol) in dry THF (50 mL) was cooled to −20° C. A 2.5M solution of n-butyl lithium in hexane (4.4 mL) was added with a syringe. The mixture was stirred for 30 min and then cooled to −78° C. A solution of 4-benzyl-3-(4-cyclohexyl-butyryl)-oxazolidin-2-one (3 g, 9.12 mmol) in THF (10 mL) was added slowly over 3 min. Stirring was continued for 30 min, then a solution of 2-Bromo-1-morpholin-4-yl-ethanone (2.28 g, 10.94 mmol) in THF (4 mL) was added over 3 min. The mixture was allowed to come to room temperature over 5 h. 1N HCl (50 mL) was added and the product was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried with MgSO4 and evaporated under vacuum. The product (1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-butane-1,4-dione) was obtained after purification by flash chromatography as a single diastereomer (2.5 g). 1H NMR: (CDCl3) 7.35–7.22(m, 5H), 4.69–4.62 (m, 1H), 4.28–4.10 (m, 3H), 3.76–3.46 (m, 8H), 3.37 (d, J=13.6 Hz, 1H), 2.91 (ddd, J=16.4 Hz, J=13 Hz, J=3 Hz, 1H), 2.76 (ddd, J=13.5 Hz, J=11 Hz, J=3 Hz, 1H), 2.51 (dt, J=13.6 Hz, J=3 Hz, 1H), 1.76–0.80 (m, 15H). MS: (M+H)+ 457.
Reaction SMILES: O=[C:2]([CH2:25][CH3:26])[CH:3]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19])[C:4](=[O:15])[NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:9]1([C@@H:6]([NH:5][C:4]([C:3]2[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18](=[O:19])[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:2]=2[CH2:25][CH3:26])=[O:15])[CH2:7][CH3:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC(=O)C(C(=O)N[C@@H](CC)c1ccccc1)c1ccccc1C(=O)O
Reactant: Nc1ccccc1
Solvent: CC#N
Product: CCc1c(C(=O)N[C@@H](CC)c2ccccc2)c2ccccc2c(=O)n1-c1ccccc1
Yield: 39 %

Procedure:
A sealed mixture of 2-[2-oxo-1-((S)-1-phenyl-propylcarbamoyl)-butyl]-benzoic acid (82 mg, 0.2 mmol) and aniline (0.3 ml, 3.3 mmol) in acetonitrile (0.3 ml) was heated under microwave irradiation at +160° C. for 10 min. The mixture was partitioned between ethyl acetate (20 ml) and 3M aq. HCl (2×8 ml), sat. aq. NaHCO3 (2×10 ml and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (SiO2, gradient heptane-ethyl acetate) to give 32 mg of the title compound. LC-MS (m/z) 411.5 (MH+); tR=1.48. 1H NMR (500 MHz, DMSO-d6): a mixture of two atropisomers.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH2:32])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[N:12][N:11]=2)[CH2:3]1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>N1C=CC=CC=1>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:43]([CH3:42])(=[O:45])=[O:44])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:34])=[O:35])=[N:12][N:11]=2)[CH2:3]1
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O

Procedure:
To a solution of 5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinamine (200 mg, 0.347 mmol) in pyridine (1 ml) was added, dropwise, methanesulphonyl chloride (0.054 ml, 0.695 mmol) and the mixture stirred at 20° C. for 18 hr. Water (10 ml) was added and the title compound was collected by filtration as a brown solid (106 mg).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][N:7]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:8][CH:4]2[CH2:3][NH:2]1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1>>[F:26][C:24]([F:25])([F:27])[C:21]1[N:19]2[N:20]=[C:15]([N:2]3[CH2:3][CH:4]4[CH:5]([CH2:6][N:7]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:8]4)[CH2:1]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CCCC(=O)N1CC2CNCC2C1
Product: CCCC(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1

Procedure:
A mixture of 1-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)butan-1-one and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.2% aqueous ammonia) and acetonitrile as eluents to give 1-[2-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]butan-1-one.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([O-])=[O:23])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:38]1([C:41]2[C:49]3[C:48]([NH2:50])=[CH:47][CH:46]=[CH:45][C:44]=3[N:43]([CH2:51][C:52]3[CH:56]=[CH:55][N:54]([CH2:57][CH3:58])[N:53]=3)[N:42]=2)[CH2:40][CH2:39]1.CCOCC>CN1C(=O)CCC1>[CH:38]1([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[NH:50][C:22]([C:19]3[N:16]4[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]5)=[CH:14][C:15]4=[N:21][CH:20]=3)=[O:23])[N:43]([CH2:51][C:52]3[CH:56]=[CH:55][N:54]([CH2:57][CH3:58])[N:53]=3)[N:42]=2)[CH2:39][CH2:40]1
Reactant: CCn1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Reactant: CC(C)N1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCn1ccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(C)C)CC6)ccn45)cccc32)n1
Temperature: 88 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of lithium 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (531 mg, 1.57 mmol) in NMP (6 mL) at 0° C. was added 2,4,6-trichlorobenzoyl chloride (250 μL, 1.56 mmol). The cold bath was removed once the addition was complete. The mixture was stirred for a further 1 hour. 3-Cyclopropyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (310 mg, 1.10 mmol; prepared as in Example 61, step E) was added and the reaction mixture was heated to 88° C. for 11 hours. The mixture was cooled to ambient temperature. Vacuum distillation was set up and NMP was removed until the reaction mixture became a thick oily residue, to which 10% NaOH aqueous solution (10 mL) was added and the resulting clear solution was stirred at 80° C. for 30 minutes. The solution was cooled to ambient temperature and extracted with DCM. The organic extracts were combined, dried (Na2SO4) and concentrated under vacuum to give a residual oil, which was triturates with Et2O (50 mL). The resulting solids were washed with Et2O (40 mL) to give the final product (492 mg). MS (ES+APCI) m/z=596 (M+H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2-pyridyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 90% overall yield. FDMS m/e=352 (M+ of free base). α[D]589 =-31.14 (c=0.86, methanol).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F:26][C:27]1([F:52])[CH:32]([NH:33][C:34]2[N:51]=[C:37]3[C:38]([C:42]4[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[C:43]=4[F:50])=[CH:39][CH:40]=[CH:41][N:36]3[N:35]=2)[CH2:31][CH2:30][NH:29][CH2:28]1.Cl[C:54]1[S:58][N:57]=[C:56]([CH3:59])[N:55]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:52][C:27]1([F:26])[CH:32]([NH:33][C:34]2[N:51]=[C:37]3[C:38]([C:42]4[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[C:43]=4[F:50])=[CH:39][CH:40]=[CH:41][N:36]3[N:35]=2)[CH2:31][CH2:30][N:29]([C:54]2[S:58][N:57]=[C:56]([CH3:59])[N:55]=2)[CH2:28]1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Reactant: Cc1nsc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5F)cccn4n3)C(F)(F)C2)n1
Temperature: 150 °C

Procedure:
A degassed solution of 2-(dicyclohexylphosphino)biphenyl (12.7 mg, 36.3 μmol) and palladium(II) acetate (4.08 mg, 18.2 μmol) in dioxane (2 mL) was stirred for 10 minutes at room temperature, then a solution of N-(3,3-difluoropiperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (87 mg, 227 μmol), 5-chloro-3-methyl-1,2,4-thiadiazole (30.5 mg, 227 μmol) and sodium tert-butoxide (32.7 mg, 340 μmol) in dioxane (2 mL) was added. Through the solution was bubbled argon for 5 minutes, then heated to 150° C. in the microwave for 60 minutes. Again a degassed solution of 2-(dicyclohexylphosphino)biphenyl (12.7 mg, 36.3 μmol) and palladium(II) acetate (4.08 mg, 18.2 μmol) in dioxane (2 mL) was added, followed by 5-chloro-3-methyl-1,2,4-thiadiazole (30.5 mg, 227 μmol) and heated to 150° C. in the microwave for further 60 minutes. Again a degassed solution of 2-(dicyclohexylphosphino)biphenyl (12.7 mg, 36.3 μmol) and palladium(II) acetate (4.08 mg, 18.2 mmol) in dioxane (2 mL) was added, followed by 5-chloro-3-methyl-1,2,4-thiadiazole (30.5 mg, 227 μmol) and heated to 150° C. in the microwave for further 60 minutes. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) and then by preparative HPLC. The title compound was obtained as white foam (42 mg, 38%).