Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:3][CH2:2]1.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:21][N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1nccc2cc(OC3CCNCC3)ccc12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc3c(N)nccc3c2)CC1
Reaction time: 72 h
Yield: 52.7 %

Procedure:
Three drops of glacial acetic acid was added to a solution of 6-(piperidin-4-yloxy)-isoquinolin-1-ylamine (35 mg, 0.14 mmol) in N, N-dimethylformamide (1 ml), followed by addition of formaldehyde (37% aqueous solution, 200 mL). Sodium triacetoxyboro-hydride (150 mg) was added to the mixture, which was shaken for 72 h. Saturated aqueous sodium hydrogen carbonate was added and then the mixture acidified with acetic acid. The mixture was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 6-(1-methylpiperidin-4-yloxy)-isoquinolin-1-ylamine (19 mg), EIMS: m/z=258.5 [M+H]+
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:37]1[CH2:43][CH2:42][CH2:41][C@H:38]1[CH2:39][OH:40].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:37]3[CH2:43][CH2:42][CH2:41][C@H:38]3[CH2:39][OH:40])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 79.3 %

Procedure:
A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.23 g (2.3 mmol) L-prolinol and 0.15 g (1.1 mmol) potassium carbonate in 0.5 ml dimethyl sulfoxide was heated at 180° C. under microwave irradiation for 30 min. in a sealed tube. After cooling to room temperature the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.18 g (78%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[N:11]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[C:3]1=O.Cl.O>C1COCC1>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2[N:11]3[C:10]4[C:9]([C:13]=2[CH2:14]1)=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]([CH3:23])[CH2:3][C:2]3([CH3:1])[CH3:25])=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)C(=O)N4C)C1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)CN4C)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a solution of ethyl 1,1,3-trimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (240 mg, 0.7 mmol) in THF (20 mL) at 25° C. was added BH3/THF complex (0.7 mL, 0.7 mmol). The mixture was stirred at 80° C. for 5 hours then cooled to rt and added 6N HCl (10 mL) with stirred for another 1 hr. About 30 mL of H2O was added and then was extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give ethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as an oil (152 mg, 66%). MS [M+H]+ 327. 1H NMR (CDCl3, 300 MHz) δ 7.01 (t, 1H, J=7.7 Hz), 6.97 (d, 1H, J=7.7 Hz), 6.41 (d, 1H, J=7.7 Hz), 4.68 (s, 2H), 4.23 (m, 2H), 3.84 (m, 2H), 3.11 (m, 2H), 2.99 (s, 3H), 1.54 (s, 6H), 1.27 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1C[CH2:37][CH2:36][CH2:35]1>O>[CH2:20]([NH:19][N:16]1[C:17](=[O:18])[C:12]([C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:28])[N:3]=2)=[C:13]([OH:27])[C:14]2[S:26][CH:25]=[CH:24][C:15]1=2)[C:21]1[CH:22]=[CH:37][CH:36]=[CH:35][CH:23]=1
Reactant: C1CCOC1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 269A (0.116 g, 0.257 mmol) in tetrahydrofuran (5 mL) and methanol (0.021 mL, 0.514 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.19 mL, 0.386 mmol). The reaction was stirred at 25° C. for 2 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.97 (d, J=5.54 Hz, 2 H) 6.17 (t, J=6.43 Hz, 1 H) 7.08 (d, J=5.52 Hz, 1 H) 7.21 (d, J=8.09 Hz, 1 H) 7.33 (m, 4 H) 7.47 (d, J=6.62 Hz, 2 H) 7.55 (t, J=6.99 Hz, 1 H) 7.66 (d, J=7.35 Hz, 1 H) 7.73 (d, J=5.52 Hz, 1 H) 15.92 (s, 1 H). MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1>[CH3:14][N:13]([CH2:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[C:21]([OH:23])=[O:22])[CH3:15]
Reactant: O=C=O
Reactant: CN(C)Cc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]-N,N-dimethylmethanamine (2 g, 7.1 mmol) in THF (40 mL) at −78° C. was dropwise added a solution of n-butyllithium (2.50 M in hexane, 3.12 mL, 7.81 mmol). The resulting mixture was stirred at −78° C. for 20 min. Excess crushed solid CO2 was added and the mixture was stirred at −78° C. for another 15 min. The reaction was quenched by the addition of water (0.156 mL), and allowed to warm to room temperature. The solvents were evaporated and the solid was dried overnight under vacuum to give 3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzoic acid.Li salt as a white solid contaminated with valeric acid. The crude acid was dissolved in aqueous hydrochloric acid (1M in water, 5 eq) and water (20 vols). Dissolution was not complete. The solids were removed by suction filtration, washed with methylene chloride and set aside. The resulting aqueous solution was transferred to a separatory funnel and washed with methylene chloride (3×). The washed aqueous phase was transferred to a round bottom flask. The filtered solids were added to the aqueous phase. The mixture was concentrated to dryness under reduced pressure. On heating in the water bath, the mixture turned homogeneous. On concentration, the solution afforded a gummy solid, which was azeotropically dried in toluene it was a free-flowing solid. The resulting powder was suspended in ether and filtered. The filter cake was briefly dried under suction. The product was transferred to a round bottom flask and dried under high vacuum at 40° C. overnight. LC-MS: (AA) ES+248; 1H NMR (400 MHz, CD3OD) δ ppm 8.46 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 4.51 (s, 2H), 2.89 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 496 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[C:7]([CH3:10])[C:6]([NH2:11])=[C:5]([CH2:12][CH3:13])[CH:4]=1)[CH3:2].O>[Pt].C(C(C)=O)C>[CH:1]([NH:11][C:6]1[C:5]([CH2:12][CH3:13])=[CH:4][C:3]([CH2:1][CH3:2])=[C:8]([NH:9][CH:5]([CH2:6][CH3:7])[CH3:12])[C:7]=1[CH3:10])([CH2:3][CH3:4])[CH3:2]
Reactant: CCc1cc(CC)c(N)c(C)c1N
Agent: [Pt]
Solvent: O
Solvent: CCC(C)=O
Product: CCc1cc(CC)c(NC(C)CC)c(C)c1NC(C)CC
Temperature: 130 °C
Reaction time: 0.62 h
Yield: 88.8 %

Procedure:
Diethyl(methyl)-1,3-benzenediamine, as a mixture of its 2,4-diethyl-6-methyl- and 4,6-diethyl-2-methyl-isomers (5 g; Ethacure® 100, Albemarle Corporation), Pt(S)/C (0.5 g), water (1 g) and methyl ethyl ketone (50 g) were charged into a 100 mL metal autoclave at 22° C. The autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. The reaction mixture was then heated at 130° C. under 125 psig (9.63×105 Pa) of H2. After 30-45 minutes, H2 uptake was observed. The reaction mixture was stirred at 130° C. for 8 hours (until no further H2 uptake was observed). The product mixture was cooled to 22° C. and degassed. A diluted product sample was analyzed by GC (100° C. for 5 minutes at 10° C. per minute rate; final temperature, 270° C.). The GC data (normalization method) showed 100% conversion of diethyl(methyl)-1,3-benzenediamine, and an 88.8% yield of N,N′-di-sec-butyl-[diethyl(methyl)-1,3-benzenediamine].
Reaction SMILES: [N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34]O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C@@H:31]3[CH2:32][C@@H:30]3[CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[N:20]=[CH:19][C:18]([CH2:16][CH3:17])=[CH:23][N:22]=4)[CH2:29][CH2:28]3)=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: O=C(Cc1ccc(O)c(F)c1)N1CCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(azetidin-1-yl)-2-(3-fluoro-4-hydroxyphenyl)ethanone (65.0 mg, 0.236 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (59.0 mg, 0.283 mmol), triphenylphosphine (polymer-bound, 186 mg, 0.534 mmol), and di-tert-butyl azodicarboxylate (109 mg, 0.472 mmol). The reaction mixture as stirred at RT for 3 hours. The mixture was filtered by Celite and concentrated. The residue was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-100% acetonitrile in 0.1% formic acid in water gradient), to give the title compound. LC/MS (m/z) 467.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:29])=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[C@H:12]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(=O)=O.CO>>[NH2:1][C:2]1[C:3]([Cl:29])=[C:4]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[C@@H:12]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C=O
Solvent: CO
Product: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 43.8 %

Procedure:
(+/−)-methyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyl dimethylsilyl)oxy) piperidin-4-yl)carbamate (Example 171E, 927 mg, 2.112 mmol) was separated by chiral SFC (Berger SFC MGIII, Column: Lux Cel-4 25×3 cm ID, 5 μm; Flow rate: 85.0 mL/min; Mobile Phase: 85/15 CO2/methanol; Detector Wavelength: 220 nm). Methyl ((3S,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (406 mg) was obtained as a white foaming solid. The enantiomeric purity of each fraction was estimated to be greater than 99.5%.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][NH2:10].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:10][CH2:9][C:2]3[C:1]([CH3:11])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=3[CH3:8])=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Cc1cc(C)c(CN)c(C)c1
Product: Cc1cc(C)c(CNC(=O)c2cn3cc(Br)ccc3n2)c(C)c1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using mesitylmethanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[C:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])[O:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][CH:2]([C:12]1[CH:13]=[C:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])[O:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)c1cc(C(O)CCCc2ccccc2)co1
Solvent: c1ccncc1
Product: CC(=O)OC(CCCc1ccccc1)c1coc([Si](C)(C)C)c1

Procedure:
A solution of 4-(1-hydroxy-4-phenylbutyl)-2-trimethylsilylfuran (0.249 g., 0.862 mmol), acetic anhydride (1 ml, excess) and pyridine (3 to 4 drops, excess) was stirred at room temperature until no starting material remained (as monitored by TLC). The reaction mixture was then partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed repeatedly with saturated sodium bicarbonate solution, twice with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale yellow oil (0.396 g). This material was further purified by flash chromatography (silica, 5% ethyl acetate/hexane) to give the desired acetate.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:29])[C:15]=1[Sn](CCCC)(CCCC)CCCC>>[F:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:29])[C:15]=1[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][N:7]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Product: Nc1ccc(-c2c(F)cncc2F)nc1
Yield: 50 %

Procedure:
Obtained (50% yield) following the procedure described in example 34 (step A), starting with 6-bromopyridin-3-amine and 3,5-difluoro-4-(tributylstannyl)pyridine.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CNC
Solvent: CO
Product: CN(C)C1CCC2(CC1)OCCO2

Procedure:
Prepared from 1,4-dioxaspiro[4.5]decan-8-one and dimethylamine. Pale brown oil, Rf : 0.28 (silica gel; methylene chloroide/methanol/concentrated ammonia=9:1:0.1)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[C:14]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:16]=[N:17][C:13]=4[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1cc(-c2cccc(CCl)c2)c2c(c1)ncn2-c1ccccc1
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cc(-c2cccc(CN3CCOCC3)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
This was prepared analogeously to the above product from 7-(3-(chloromethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.97 g, 2.5 mmol) and morpholine (0.74 ml, 7.5 mmol) in NMP (5 ml) to yield 0.81 g (74%), m/z, 382.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([S:25]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([S:25]([CH:22]5[CH2:24][CH2:23]5)(=[O:27])=[O:26])=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: O=S(=O)(c1ccc2[nH]ccc2c1)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(=O)(=O)C5CC5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(Cyclopropylsulfonyl)-1H-indole (intermediate 24).
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14](Br)[CH:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30]>CN(C=O)C.O.ClCl.[Cu]I>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:29]#[N:30])=[C:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCCN(CCC)C1CC2CN(C(=O)c3ccccc3)C3=C2C(C1)C(Br)C=C3
Agent: [Cu]I
Agent: ClCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of (±)-1-benzoyl-6-bromo-4-(di-n-propylamino) hexahydrobenz[cd]indole (5.5 g, 12.5 mmol) in DMF (100 mL) under a N2 atmosphere was added 3.4 g (37.5 mmol) of CuCN and 7.1 g (37.5 mmol) of CuI. The reaction mixture was then stirred at 140° C. for 6 hr. The reaction mixture was poured onto ice, diluted with water, CH2 Cl2 added and stirred for 30 minutes. The mixture was filtered through a Celite pad and the filtrate was extracted twice with CH2 Cl2. The organic solution was washed twice with saturated NaCl solution. The CH2Cl2 solution was dried over MgSO4 and then evaporated to provide 4 g of a solid. Chromatography of this crude product over silica gel with 1:19 MeOH/CH2Cl2 as eluent gave 3 g (62%) of product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[S:7][C:8]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[C:9]([C:11](Cl)=[O:12])[N:10]=1>ClCCl>[Cl:5][C:6]1[S:7][C:8]2[CH2:14][CH2:15][C:16]3[CH:17]=[C:18]([Cl:22])[CH:19]=[CH:20][C:21]=3[C:11](=[O:12])[C:9]=2[N:10]=1
Reactant: O=C(Cl)c1nc(Cl)sc1CCc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2sc(Cl)nc21

Procedure:
Aluminium chloride (5.3 g) was added to a solution of the product from step (iv) in dichloromethane (30 ml) at room temperature. After 3 h the mixture was poured onto 2M HCl/ice and the product extracted into ethyl acetate. The organic phase was collected, dried, (MgSO4) and solvent evaporated under reduced pressure to leave a brown solid. This was triturated with isohexane/ethyl acetate and filtered to leave the subtitle product as a beige solid.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=O>>[F:15][C:16]([F:21])([F:20])[C:17]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(NN)nccc2c1
Product: COc1ccc2c(ccn3c(C(F)(F)F)nnc23)c1
Yield: 20 %

Procedure:
A solution of 1-hydrazino-6-methoxyisoquinoline and excess trifluoroacetic acid was held at reflux for four hours. After removal of the excess acid, the residue was treated with potassium bicarbonate solution until neutral and filtered. The filter cake was recrystallized from ethanol to provide the product in a yield of 20%; m.p. 214°-215°C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.51) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.022 g, 11%). MS (ISP) 412.4 [(M+H)+]; mp 248° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3ccccc3C)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-o-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32](=[O:34])[NH2:33])([CH3:31])[CH3:30])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C1C=CC(P([N:56]=[N+:57]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([CH3:31])([CH3:30])[C:32]([N:33]=[N+:56]=[N-:57])=[O:34])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(CC(C)(C)C(N)=O)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(CC(C)(C)C(=O)N=[N+]=[N-])C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 1-02 [see step 4 SC-174] (110 mg, 0.223 mmol) in dry toluene (4 mL) was added Et3N (62 μL, 0.446 mmol) and DPPA (63 μL, 0.290 mmol). The reaction mixture was stirred overnight and concentrated in vacuo to give the desired product as a yellow oil.