Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]([F:50])([F:49])[F:48].COP(OC)OC>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:50])([F:49])[F:48])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC1(C)OB(c2cccc3[nH]c4c(c23)CCN(C(=O)c2ccccc2)CC4)OC1(C)C
Agent: [Pd]
Agent: COP(OC)OC
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4C(F)(F)F)c3c2CC1
Yield: 95.1 %

Procedure:
3-Benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.50 g, 6.00 mmol), triturated potassium phosphate (3.01 g, 14.2 mmol) and tris(dibenzylideneacetone) dipalladium(0) (0.562 g, 0.613 mmol) were combined in dioxane (63 mL) at rt under N2. 2-Bromobenzotrifluoride (0.98 mL, 1.62 g, 7.21 mmol) and trimethylphosphite (0.22 mL, 0.231 g, 1.86 mmol) were added to the reaction mixture by syringe. Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was heated to reflux for 22 h. The reaction mixture was concentrated and the residue was taken up in toluene (150 mL) and H2O (200 mL). The layers were separated and the aqueous layer was extracted with toluene (1×100 mL, 1×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product (3.90 g) was chromatographed (SiO2 250 g, eluted with 2:1 toluene:EtOAc) to yield 3-benzoyl-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.48 g) in 95% yield. IR (diffuse reflectance) 3294, 1617, 1575, 1461, 1439, 1423, 1346, 1334, 1316, 1276, 1266, 1259, 1178, 1170, 1126, 1113, 1105, 1058, 1034, 792, 775, 755, 719, 701, 626 cm−1; MS (ESI+) for C26H21F3N2O m/z 435.0 (M+H)+; Anal. Calcd for C26H21F3N2O: C, 71.88; H, 4.87; N, 6.45; found: C, 71.94; H, 4.93; N, 6.48.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluoronitrobenzene (2.09 g, 13.1 mmol) in EtOH (10 mL) at ambient temperature was added piperidine (3.35 g, 39.4 mmol) dropwise. The reaction was allowed to stir overnight and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (2×100 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography afforded 1.10 (37%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C11H13FN2O2, 225.1 (M+H), found 225.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][N:15]2[CH:22]=1)=[O:11])[CH2:2][CH3:3].C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO.O>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:38][C:34]3[NH:33][CH:37]=[CH:36][N:35]=3)[CH2:16][N:15]2[CH:22]=1)=[O:11])[CH2:24][CH3:25]
Reactant: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CN)C2
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CNCc1ncc[nH]1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
The compound (28.3 mg) obtained in Example 19-3 was dissolved in methanol (1.0 ml) and added with trimethyl orthoformate (0.030 ml) and 2-imidazole carboxaldehyde (11.7 mg), and the whole was stirred at room temperature for 3 hours. After having been cooled to 0° C., the solution was added with sodium borohydride (4.6 mg) and the whole was warmed to room temperature and stirred for additional 15 minutes. The resultant was added with water to stop the reaction and subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (30.5 mg) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1(Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:14].C[OH:17].O>>[Cl:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2](=[O:17])[C:3](=[O:14])[NH:4]2
Reactant: COc1ccc2c(c1Cl)C(Cl)(Cl)C(=O)N2
Reactant: CO
Solvent: O
Product: COc1ccc2c(c1Cl)C(=O)C(=O)N2

Procedure:
Hydrolysis of 3,3,4-trichloro-5-methoxy-1,3-dihydro-indol-2-one in MeOH-water mixture according to the procedure published in Tetrahedron 27, 3263-70 (1971) provided 4-chloro-5-methoxy-1H-indole-2,3-dione as a deep-brown shiny crystals in 96% Y.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C1COCC1>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH3:10]
Reactant: C1CCNC1
Reactant: CCOc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccnc(N2CCCC2)n1

Procedure:
To a solution of 2-chloro-4-ethoxypyrimidine (3 g, 19 mol) in THF (410 mL) was added pyrrolidine (2.7 g, 38 mmol) and Et3N (5.8 g, 57 mmol) and the reaction mixture was heated to reflux overnight. The solvent was evaporated and the residue was partioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:7]3)=[CH:22][CH:21]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: Cc1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Temperature: 125 °C

Procedure:
24.16 g (91.9 mmole) 7-Chloro-2-cyclohexylmethyl-indan-1-one, 15.0 g (1.2 eq.) 4-methylphenyl boronic acid, 19.49 g sodium carbonate, 303 ml ethylene glycol and 57 ml water were placed in a 1 l-roundbottom flask equipped with a mechanical stirrer and a reflux condenser. The mixture was degassed three times by slight evacuation and recharging with argon. A premixed catalyst solution consisting of 41 mg (0.2 mole %) palladium acetate, 1.2 ml NaTPPTS (2.6 M in water, 0.8 mole %) and 2 ml of water was added and the mixture was refluxed at 125° C. until complete conversion (approx. 8 h). 100 ml of water were added and the mixture was extracted three times with 100 ml of toluene each. The combined organic layers were washed twice with 100 ml water and once with 100 ml of a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent in vacuo yielded 30.57 g (quant.) of the desired product as a yellow sticky oil. 1H-NMR (400 MHz, CDCl3): δ=7.60-7.19 (m, 7H, aromatic), 3.31 (m, 1H, (C═O)CH), 2.91-2.61 (m, 2H, benzylic), 2.38 (s, 3H, Ph-CH3), 1.80-0.85 (m, 10H, aliphatic) ppm.
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13].C[Li]>CCOCC.O>[CH3:8][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]
Reactant: c1cc[cH-]c1
Agent: [Ti+2]
Agent: [Cl-]
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: C[c-]1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 197 %

Procedure:
A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 ml of ether in the dark at 0° C. was treated with 17.5 ml of 1.4M methyllithium solution in ether maintaining the internal temperature below 5° C. The resulting yellow/orange mixture was stirred at room temperature for 30 minutes and the reaction was quenched by slowly adding 25 g of ice. The quenched reaction mixture was diluted with 50 ml of ether and 25 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 2.03 g (98%) of the title compound as a light-sensitive solid. The dimethyl titanocene could be stored as a solution in toluene at 0° C. for at least 2 weeks without apparent chemical degradation. 1H NMR (200 MHz, CDCl3) δ−0.15 (6H, s), 6.06 (10H, s).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[S:17][N:16]=[C:15](Cl)[C:14]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:15]1[C:14]2=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[CH:10]=[CH:11][CH:12]=[C:13]2[S:17][N:16]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2snc(Cl)c12
Reactant: NCCCN
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc2snc(NCCCN)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of N-tert-butyl-3-chlorobenzo[d]isothiazole-4-sulfonamide (280 mg, 0.92 mmol) in 1,3-diaminopropane (1 mL) was allowed to stir at room temperature for 2.5 h. The reaction mixture was then poured over water (10 mL), extracted with ethyl acetate and the combined organic layers was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give, upon trituration with ethyl ether, 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-4-sulfonamide (257 mg) as an off-white solid. 1H NMR (300 MHz, CD3OD): 8.02 (d, 1H), 7.85 (d, 1H), 7.70 (t, 1H), 3.74 (t, 2H), 3.02 (t, 2H), 1.87-1.95 (m, 2H), 1.24 ppm (s, 9H). MW=342 confirmed by LC-MS, tr=8.22 min (Method Y) MH+=343.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:21]([O:25][C:26]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[NH2:35])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([NH:35][C@H:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]2[NH:28][C:26](=[O:27])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
To a solution of 4.80 g of 2,4-dichloro-6-methylquinazoline in 100 ml of methylene chloride, 9.12 g of triethylamine and 5.31 g of (1S,2R)-2-(t-butoxycarbonylamino)cyclohexylamine were added, and then the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated, mixed with water, extracted with methylene chloride and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 8.30 g of the desirable compound.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-fluorobenzoate (6.0 mL, 41 mmol), 1,4-dioxa-8-azaspiro(4,5)decane (13.5 mL, 102 mmol), and K2CO3 (5.7 g, 41 mmol) in NMP (35 mL) was stirred at 150° C. for 4 hours, cooled to room temperature, treated with water (0.5 L) and filtered. The filter cake was washed with water and dried briefly. The crude product was triturated with hexane, filtered, and dried under vacuum to provide the desired product. MS (DCI) m/e 292 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34][OH:35]>>[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: COCCOCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (200 mg, 0.48 mmol) and sodium hydride (42 mg 55% dispersion in mineral oil, 0.96 mmol) were dissolved in 2-methoxy-ethanol (3.8 ml, 48 mmol) and stirred at ambient temperature for 18 h. Workup and purification as described in the general procedure C afforded the title compound as white solid (70%), MS: m/e=458 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH:15]([NH2:17])=[O:16].C(O)=O.O>C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][CH:15]=[O:16])=[CH:4][C:3]=1[C:2]([F:14])([F:13])[F:1]
Reactant: NC=O
Reactant: COc1ccc(C=O)cc1C(F)(F)F
Solvent: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC=O)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 9 h

Procedure:
A mixture of 5.8 g 3-trifluoromethyl-p-anisaldehyde, 8.6 ml formamide, and 13.6 ml formic acid was stirred at 130° C. for 9 hr. After cooling, water and ethyl acetate were added thereto. The ethyl acetate layer was recovered and washed with brine. It was dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography to give 3.8 g of N-[4-methoxy-3-(trifluoromethyl)benzyl]formamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: ClCCCBr
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccccc1NCCCCl
Yield: 33 %

Procedure:
A mixture of 13.6 parts of 2-aminobenzamide, 31.5 parts of 1-bromo-3-chloropropane, 21 parts of sodium carbonate and 200 parts of ethanol is stirred and refluxed over week-end. The reaction mixture is filtered and the filtrate is evaporated. The oily residue is stirred in methylbenzene. The mixture is filtered till clear and the solvent is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 7 parts (33%) of 2-[(3-chloropropyl)amino]benzamide; mp. ±100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH:13]1([Mg]Br)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:13]2[CH2:15][CH2:14]2)[OH:11])=[CH:6][CH:5]=1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(C(O)C2CC2)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and Cyclopropyl magnesium bromide following the general method exemplified in Preparation 1.
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=O)=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH3:15][N:16]([CH2:24][CH2:25][NH:26][CH3:27])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[I:1][C:2]1[C:6]([CH2:7][N:26]([CH3:27])[CH2:25][CH2:24][N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (21.5 g, 70.24 mmol, 1.00 equiv), tert-butyl N-methyl-N-(2-(methylamino)ethyl)carbamate (20 g, 106.23 mmol, 1.51 equiv) and NaBH(OAc)3 (29.8 g, 137.98 mmol, 1.96 equiv) in dichloroethane (300 mL) was stirred for 1 h at room temperature. The reaction was diluted with 300 mL of dichloromethane and then washed with 3×300 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-7% methanol in dichloromethane to give 31 g (92%) of tert-butyl (2-(((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 5.34-5.30 (m, 1H), 4.06-4.02 (m, 1H), 3.68-3.62 (m, 1H), 3.42-3.38 (m, 4H), 2.85 (s, 4H), 2.62-2.53 (m, 2H), 2.47-2.46 (m, 2H), 2.13-1.97 (m, 3H), 1.74-1.69 (m, 3H), 1.46 (s, 9H) ppm. LCMS (method A, ESI): RT=1.17 min, m/z=479.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:20])[C:10]([F:19])=[C:11]([NH:15][CH2:16][CH2:17][OH:18])[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C.C(#N)C>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:20])[C:10]([F:19])=[C:11]([N:15]4[CH2:16][CH2:17][O:18][CH2:27]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(NCCO)c(F)c(F)c2c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCOCC
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)c(F)c2c1=O
Reaction time: 3 h

Procedure:
A mixture of 0.74 g of ethyl 1-cyclopropyl-5,6,8-trifluoro-7-(2-hydroxyethylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.08 g of p-toluenesulfonic acid, 2.08 g of diethoxymethane and 20 ml of acetonitrile was stirred for 3 hours under reflux. The reaction mixture was allowed to cool down, followed by the addition of 100 ml of chloroform. The resultant mixture was washed successively with 5% aq. sodium carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH:31]=[O:32].O>O1CCCC1.ClCCl>[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH:31]([OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: COC(=O)CCCC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCC(O)/C=C/c1cccc(C(O)CCCC(=O)OC)n1
Reaction time: 0.17 h

Procedure:
A solution of 326 mg of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 5 ml of tetrahydrofuran is mixed with 1.25 ml of n-butyllithium (1.6 molar in hexane) at -78° C. with stirring and under argon atmosphere. After 10 minutes, a solution of 5-oxo-pentanoic acid methyl ester in 1 ml of tetrahydrofuran is added at -78° C. and stirred for 2 hours at this temperature. The reaction mixture is mixed with water, shaken out with dichloromethane, dried on sodium sulfate, concentrated by evaporation and the crude product is chromatographed on silica gel With hexane/ethyl acetate 98/2. 188 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([CH2:23][CH3:24])[C:7]1=[O:25])=O)C.[NH2:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>>[C:33]1([NH:32][C:30]([C:29]2[CH:28]=[C:27]([NH:26][C:4]([CH:6]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=4)[N:8]([CH2:23][CH3:24])[C:7]3=[O:25])=[O:3])[CH:41]=[CH:40][CH:39]=2)=[O:31])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccccc3)c2)c2cc(C(=O)c3ccccc3)ccc21

Procedure:
Prepared as in Example 1, Step A, from 5-benzoyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid ethyl ester (U.S. Pat. No. 4,686,224) and 3-amino-N-phenyl-benzamide. Purified by trituration in ethyl acetate/hexanes. mp 129-135° C.
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[C:11]1([CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])=[CH:24][C:20]=2[C:21]([OH:23])=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=C(N)C=1.C(Cl)CCl>CN(C)C=O.O>[C:11]1([CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:29])=[CH:24][C:20]=2[C:21]([NH:7][C:5]2[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=2)=[O:23])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Agent: Nc1cccnc1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Neat HOBT (94 mg, 0.62 mmol) was added in one charge to a stirred solution of 2-[(phenylmethyl)oxy]-5-(1-pyrrolidinylcarbonyl)benzoic acid (may be prepared as described in Description 55; 200 mg, 0.62 mmol), 3-pyridinamine (57.9 mg, 0.62 mmol) and EDC (118 mg, 0.62 mmol) in N,N-dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water (50 ml). The precipitate was collected by filtration, washed with ether (5 ml), and dried to yield the title compound as a white solid. 88 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[CH3:20][N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cnc(NC2CCCCO2)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(C)C2CCCCO2)s1
Yield: 40.4 %

Procedure:
Ethyl 2-(tetrahydro-2H-pyran-2-ylamino)thiazole-5-carboxylate (4.73 g, 18.5 mmol) was added to a suspension of NaH (740 mg, 18.5 mmol) in THF (20 mL) at 0° C., followed by methyl iodide (1.15 mL, 18.5 mmol). The resulting mixture was heated at reflux during 3 hrs. After quenching with water and extracting with AcOEt, the crude product was purified by column chromatography (50% AcOEt/PE), yielding ethyl 2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carboxylate (2.02 g, 40%) as an oil.