Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[CH3:11][C:3]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc2scnc2cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1cc2scnc2cc1-c1ccc(N)nc1
Temperature: 85 °C
Yield: 99.2 %

Procedure:
A mixture of 5-bromo-6-methylbenzothiazole (54) (91 mg, 0.4 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (132 mg, 1.5 eq), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (42 mg, 10% mol) and K3PO4 (128 mg, 0.6 mmol) in 1 ml ACN, 1 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 1 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to silica gel flash column chromatography (0-100% B, A: hexane; B: EA) to give 5-(6-methylbenzothiazol-5-yl)-2-pyridylamine (55) (95.8 mg, yield: 99%, purity>90%) as yellow solid.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:18]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Anisole (2.16 g, 20 mmol) was dissolved in toluene (20 ml). The mixture was cooled to −10° C. and aluminum chloride (2.67 g, 20 mmol) was added. 4-Chlorobutyryl chloride (2.47 ml, 22 mmol) was added dropwise at −10° C. and stirred for 0.5 hour at −10° C. The reaction mixture was poured into iced water (40 ml). After separation, the organic layer was washed with 20%citric acid (10 ml) twice, 1N-sodium hydroxide (10 ml) and 20% brine (10 ml) twice, and was concentrated under reduced pressure to give 4-chloro-1-(4-methoxyphenyl)-1-butanone (4.21 g, yield 99%).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)C.[CH2:23]([NH:30][C:31](=[O:44])[C:32](=[N:36]NC1C=CC=CC=1)[C:33](=O)[CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Zn].C(O)(=O)C>[CH2:23]([NH:30][C:31]([C:32]1[NH:36][C:9]2[CH2:10][C@@:11]3([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C@H:6]([CH2:7][C:8]=2[C:33]=1[CH3:34])[CH2:5][N:4]([CH3:2])[CH2:13][CH2:12]3)=[O:44])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)NCc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cccc([C@@]23CCN(C)C[C@H]2Cc2c([nH]c(C(=O)NCc4ccccc4)c2C)C3)c1

Procedure:
1 g (3.3 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 2.95 g (10 mmol) of N-benzyl-2-phenylhydrazono-3-oxobutyramide, 0.82 g (10 mmol) of CH3 COONa, 2.6 g (40 mmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1. The residue was crystallised from AcOEt yielding 0.65 g of the title compound. M. p.=162°-164° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH:32]=[CH2:33])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:31]([N:25]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24](=[O:34])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)[CH:32]=[CH2:33]
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.030 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0.026 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a stirred (30 min) solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (3.52 g, 14.9 mmol), 1-Boc-4-piperidone (5.96 g, 29.9 mmol), HOAc (24.0 mL, 1M in DCM, 24.0 mmol) and TEA (2.00 mL, 14.3 mmol) in 1,2-DCE was added in one portion sodium triacetoxyborohydride (4.82 g, 22.7 mmol). The reaction was stirred for 30 min at which time sodium triacetoxyborohydride (2.00 g, 9.40 mmol) and HOAc (10.0 mL, 1M in DCM, 10.0 mmol) was added. The reaction was stirred at rt overnight. The reaction was quenched with saturated NaHCO3 (150 mL) and extracted with DCM. The organic layer was washed with H2O, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step C (6.09 g, 14.5 mmol, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.32 (m, 2H), 1.37 (s, 9H), 1.74 (d, J=10.6 Hz, 2H), 2.41 (tt, J=11.0, 3.2 Hz, 1H), 2.55-2.62 (m, 4H), 2.70 (br. s., 2H), 3.36-3.44 (m, 4H), 3.88 (s, 3H), 3.94 (d, J=13.2 Hz, 2H), 6.50 (d, J=2.6 Hz, 1H), 6.57 (dd, J=9.5, 2.6 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:12][C:13]([F:16])([F:15])[F:14])[C:7]([F:11])=[CH:8][C:9]=1[F:10])([O-])=O.[H][H]>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([O:12][C:13]([F:15])([F:16])[F:14])[C:7]([F:11])=[CH:8][C:9]=1[F:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)c(F)cc1F
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(OC(F)(F)F)c(F)cc1F
Yield: 80.3 %

Procedure:
In a hydrogenation apparatus, 27 g of 3-nitro-4,6-difluoro-trifluoromethoxy-benzene in 150 ml of tetrahydrofuran are hydrogenated at 30 to 50 bar hydrogen at 25° to 45° C., in the presence of 3 g of Raney nickel. When the hydrogen uptake is complete, the mixture is filtered, and the filtrate is distilled. 19 g of 3-amino-4,6-difluoro-trifluoromethoxy-benzene of a boiling point of 82° to 83° C. at 20 mbar are obtained.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]([CH:8]([NH3+:11])[CH2:9][OH:10])[S:6][CH:7]=1.N1C=CN=C1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]([NH2:11])[CH2:9][O:10][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[S:6][CH:7]=1
Reactant: [NH3+]C(CO)c1cc(Br)cs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(N)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(4-bromothiophen-2-yl)-2-hydroxyethanaminium chloride (300 mg, 1.35 mmol), imidazole (120 mg, 1.76 mmol), DMAP (8.25 mg, 0.068 mmol) and TEA (188 μL, 1.35 mmol) were dissolved in 13.5 mL DCM. TBSCl was then added (265 mg, 1.76 mmol) at 0° C. and the mixture was stirred for 48 hours at room temperature. The mixture was quenched with saturated NaHCO3 and the phases separated. The organic extract was concentrated and purified on silica gel (EtOAc/hexanes).
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10]1([C:16](=[O:19])[C:17]#[CH:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1.CC1[C@H]2C(C)(C)[C@H](C2)CC=1>[CH:10]1([C@H:16]([OH:19])[C:17]#[CH:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C#CC(=O)C1CCCCC1
Agent: B1C2CCCC1CCC2
Agent: CC1=CC[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: C#C[C@@H](O)C1CCCCC1
Temperature: 0 °C
Yield: 69 %

Procedure:
A mixture of 1.6 liters 0.5 M 9-borabicyclo[3.3.1]-nonane in tetrahydrofuran and 122.6 g (-)-α-pinene, 99%+pure, was heated at reflux under nitrogen for 4 hr., at which time the excess (-)-α-pinene and tetrahydrofuran were removed under vacuum to leave a thick oil. The contents of the flask were cooled to 0° C. and 80 g of 3-cyclohexylprop-1-yn-3-one, prepared as shown in Preparation 2, was added with stirring. The resulting mixture was allowed to warm to 23° C. and was stirred at that temperature for 16 hr. Excess reagent was destroyed by adding 44 ml propionaldehyde and stirring at 23° C. for 1 hr. The liberated (-)-α-pinene was removed by vacuum distillation. The resulting mixture was diluted with 400 ml tetrahydrofuran followed by 300 ml 3N sodium hydroxide. To this stirred mixture was added in dropwise fashion 300 ml 30% hydrogen peroxide over 1 hr. The mixture was heated at 40° C. for 3 hr. After cooling, the mixture was extracted with diethyl ether and this extract was dried over magnesium sulfate. Evaporation of the solvent and purification of the residue by silica gel flash chromatography using 5% ethyl acetate hexane gave 56 g of (S)-3-cyclohexyl prop-1-yn-3-ol, which by nmr analysis was shown to be 90% e.e. Recrystallization from hexane gave 45 g of the pure S isomer, mp 56°-58°, [α]D25 =-11.1°(C=0.53, Et2O)
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N+:22]([O-])=O>O.[Pd].CO.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:10]=[CH:9][C:8]=1[NH2:22]
Reactant: COc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(S(=O)(=O)c2ccccc2)ccc1N

Procedure:
A solution of ammonium formate (0.1 83 g) in water (2.5 ml) was added to a mixture of 10% palladium on carbon (0.03 g) and 2-methoxy-4-phenylsulphonylnitrobenzene (Method 22) (0.213 g) in methanol (10 ml) and ethyl acetate (1 ml). The mixture was heated and stirred under reflux under argon for 4 hours then cooled and filtered through diatomaceous earth. The filter was washed with ethyl acetate (2×5 ml) and the filtrates were combined. The solution was concentrated by evaporation to approximately 2 ml and the resultant solid was collected, washed with water (2×5 ml) and dried in vacuo to give the title compound as a solid. M.p.149-150.5° C.; NMR: 3.8 (s, 3H), 5.78 (s, 2H), 6.67 (d, 1H), 7.17 (s, 1H), 7.26 (dd, 1H), 7.5-7.62 (m, 3H), 7.84 (d, 2H); MS: 262 (M−H)−; EA: C13H13NO3S requires C, 59.3; H, 5.0; N, 5.3; S, 12.2%; found: C, 59.1; H, 4.9; N, 5.2; S, 12.2%.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[C:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)(=[O:39])[CH3:38]>>[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7](/[C:15](/[CH3:16])=[CH:44]/[C:43]3[CH:46]=[CH:47][C:40]([C:37](=[O:39])[CH3:38])=[CH:41][CH:42]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: CC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 4-acetyl-benzaldehyde there can be obtained 4'-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-acetophenone of melting point 148°-149° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:15][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[Cl:15][C:16]1[O:20][C:19]([CH:21]([OH:22])[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2ccc(Cl)o2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 117.6 %

Procedure:
To a solution of THF (40 mL) and 4-iodobenzonitrile (2.0 g) was added isopropylmagnesium chloride (2M, 6.1 mL) dropwise at −78° C. under a nitrogen atmosphere, which was stirred for 1 hour and 10 minutes at 0° C. After cooling to 78° C., 5-chloro-2-furaldehyde (1.4 g) was added dropwise thereto, which was stirred for 15 minutes at room temperature. A saturated aqueous ammonium chloride solution was added at room temperature, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Br-:14].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[Br:14][CH:7]1[C:6](=[O:13])[C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][CH2:8]1
Reactant: [Br-]
Reactant: O=C1CCOc2c1ccc(Cl)c2Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C1c2ccc(Cl)c(Cl)c2OCC1Br
Reaction time: 0.5 h

Procedure:
A mixture of 100 mg. (0.46 mmol) 7,8-dichlorochroman-4-one was dissolved in anhydrous ethanol (5 ml) and Chloroform (5 ml). To this solution was added pyridinium tribromide (0.442 g, 1.38 mmol, 3 equiv). The reddish brown mixture was heated with stirring at 50 C for 30 min. The reaction mixture was then cooled and the solvent was evaporated. Then water (20 ml) was added to the residue and it was then extracted with 20 ml of dichloromethane. The dichloromethane layer was then washed with 5% sodium bicarbonate solution followed by water (20 ml). The organic layer was then dried and the solvent was evaporated in vacuum to yield the crude product which was purified by column chromatography.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1([C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[C:22]3[CH2:39][CH2:40][CH2:41][C:21]=3[N:20]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.[CH:51]1([NH2:56])[CH2:55][CH2:54][CH2:53][CH2:52]1>CN(C)C=O>[CH:51]1([NH:56][C:36]([C:32]2([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23]4[C:22]5[CH2:39][CH2:40][CH2:41][C:21]=5[N:20]=[C:19]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[N:24]=4)=[CH:31][CH:30]=3)[CH2:33][CH2:34][CH2:35]2)=[O:37])[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: NC1CCCC1
Reactant: O=C(O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCC1)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Reaction time: 16 h
Yield: 46.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.48 g, 2.5 mmol) was added to a mixture of 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid (0.5 g, 1.2 mmol), 1-hydroxybenzotrialzole (0.09 g, 0.65 mmol), diisopropylethylamine (0.43 mL, 2.5 mmol), and cyclopentylamine (0.13 mL, 1.3 mmol) in anhydrous dimethylformamide and stirred at a temperature in the range of 15° C. to 25° C. under N2 for 16 hours. The reaction was quenched by addition of water. The precipitated solid was filtered, washed with water and dried in vacuo. The crude was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.26 g, 45% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[NH2:12])#[C:2][CH2:3][CH3:4].O>CN1CCCC1=O>[CH2:3]([C:2]1[NH:12][C:6]2[C:5]([CH:1]=1)=[CH:10][C:9]([F:11])=[CH:8][CH:7]=2)[CH3:4]
Reactant: CCC#Cc1cc(F)ccc1N
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
Under argon 4.9 g potassium-tert-butoxide are suspended in 25 ml N-methyl-2-pyrrolidinone and a suspension of 3.4 g 2-but-1-ynyl-4-fluorophenylamine in 25 ml N-methyl-2-pyrrolidinone is added dropwise thereto. The reaction mixture is stirred for 3 hours at ambient temperature and mixed with water. The product is extracted with diethyl ether and purified by chromatography (silica gel, cyclohexane/ethyl acetate 100/0-90/10). 2.83 g product are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 2.72 (2H, q); 1.27 (3H, t).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:5][C:4]=1[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[CH3:29])[C:15](=O)[CH3:16])#[N:2].B1([O-])O[O:31]1.O.O.O.O.[Na+].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CO.O>[CH3:16][C:15]1[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=2[CH3:29])[C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:7][C:3]=2[C:1](=[O:31])[N:2]=1
Reactant: CC(=O)N(Cc1cccc(C(F)(F)F)c1C)c1nc(N2CCOCC2)sc1C#N
Reactant: [O-]B1OO1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cn2c(C)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 55 °C
Reaction time: 8 h

Procedure:
In a 2 L round bottom flask equipped with a magnetic stir bar, N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]-N-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}acetamide (42.5 g, 100 mmol), sodium perborate tetrahydrate (46.2 g, 300 mmol), and potassium carbonate (27.64 g, 200 mmol) were taken up in Methanol (233 mL), Tetrahydrofuran (THF) (233 mL), and Water (233 mL) and the resulting reaction mixture was heated to 55° C. and stirred overnight at 55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[C:6]3[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:18])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: N#CCCCBr
Product: OC1(c2ccccc2)C2=NCCCCN2c2ccc(Cl)cc21

Procedure:
Reaction of 5-chloro-3-hydroxy-3-phenyl-2-indolinone with 4-bromobutyronitrile by a procedure analogous to that in Example 3(a) followed by hydrogenation of the resulting nitrile by a procedure analogous to that of Example 3(b) gives 9-chloro-11-phenyl-2,4,5,11-tetrahydro-3H-1,3-diazepino[1,2-a]indol-11-ol [m.p. of hydrobromide is 298°-300°C(decomp.)].
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:14][CH:13]=3)=O)(C)C.C(N(CC)CC)C.Cl[Si](C)(C)C>C1(C)C=CC=CC=1>[CH2:23]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][C:7]([CH:5]=[O:4])=[C:19]([CH2:20][O:21][CH3:22])[C:18]2=1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(CCc4ccccc4)cc3c12
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCc1c(C=O)ncc2[nH]c3ccc(CCc4ccccc4)cc3c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
1.2 g of 6-phenethyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 25 ml of dry toluene with 2.5 ml of triethylamine and 0.78 ml of chlorotrimethylsilane and heated for 1 hour to 50° C. solution temperature. After concentration by evaporation to about half it is cooled to -78° C. and 5 ml of a 1.2 molar diisobutylaluminium hydride solution is instilled. It is stirred for 30 minutes at -78° C., mixed with 1.2 ml of ethanol and allowed to come to room temperature. 10.2 ml of 0.5-N NaOH and 10.2 ml of ethanol are added to the batch and stirred for 2.5 hours at room temperature. The batch is added to 35 ml of glacial acetic acid and extracted three times from ethyl acetate. The organic phase is washed in succession with dilute ammonia and saturated common salt solution, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=1:1 and 720 mg of 6-phenethyl-4-methoxymethyl-β-carboline-3-carbaldehyde is obtained, that in 8 ml of dimethylformamide is mixed in succession with 322 mg of hydroxylaminehydrochloride, 1.6 ml of ethanol, 322 mg of powdered potassium hydroxide and refluxed for 3 hours. Suctioning off yields 740 mg of 6-phenylethyl-4-methoxymethyl-β-carboline-3-carbaldehyde aldoxime of a melting point of 197°-198° C. This oxime is dissolved in 26 ml of dimethylformamide and mixed with a solution of 381 mg of N-bromosuccinimide in 3.4 ml of dimethylformamide and stirred for 15 minutes at room temperature. 1.38 ml of triethylamine and 0.26 ml of methylpropargly ether is added to the batch and stirred for 7 hours at room temperature. After concentration by evaporation it is spread in ethyl acetate/water and the organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with toluene:ethanol=9:1. After combining and concentrating by evaporation the corresponding fractions and recrystallization 251 mg (30% of theory) of 6-phenethyl-4-methoxymethyl-3-(5-methoxymethyl-isoxazol-3-yl)-β-carboline, of a melting point of 133°-135° C. (ethyl acetate) is obtained.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([NH:28]C(=O)C(F)(F)F)[N:27]=4)[CH:24]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].O>C(O)C>[NH2:28][C:26]1[N:27]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([C:3]5([C:1]#[N:2])[CH2:4][CH2:5]5)[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:24][N:23]2[CH:25]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C(F)(F)F)cn5c4)c3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5c4)c3)c2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]benzamide (450 mg, 0.89 mmol) in ethanol (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.9 mL), and the mixture was stirred at 45° C. for 8 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and fractions containing the object product was concentrated under reduced pressure to give N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 55%) as a colorless solid.