Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:9]1([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncccc1C1=CCCCC1
Yield: 96.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 3-bromopyridin-2-amine (0.42 g, 2.40 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), cesium carbonate (1.72 g, 5.29 mmol), 1,4-dioxane (8.0 mL) and water (4.0 mL), to yield the title compound (403.3 mg, 96%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[N+:31]([O-])=O)[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.[Pt]>[CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)Nc1c(N)cnc2ccccc12
Reaction time: 5.5 h
Yield: 97.8 %

Procedure:
N-[(1S)-2-(Benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-3-nitroquinolin-4-amine (1.81 g, 3.88 mmol) was dissolved in 30 mL of acetonitrile and the solution was placed in a pressure bottle. Platinum on carbon (5%, 180 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 5.5 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give 1.66 g of N4-[(1S)-2-(benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]quinoline-3,4-diamine as an orange solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.N(C(OCC)=O)=NC(OCC)=O.[C:43]([O:47][C:48]([NH:50][CH:51]1[CH:56](O)[CH2:55][CH2:54][N:53]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:52]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>O.C1COCC1>[C:43]([O:47][C:48]([NH:50][CH:51]1[CH:56]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH2:55][CH2:54][N:53]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:52]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
PPh3 (412 mg), phthalimide (252 mg), and diethyl azodicarboxylate (40% in toluene solution) (0.712 ml) were added to a THF (5 ml) solution containing benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidin-1-carboxylate (500 mg), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 15:7). Colorless oily matter of benzyl 3-((tert-butoxycarbonyl)amino)-4-(1,3-dioxoisoindolin-2-yl)piperidin-1-carboxylate (205 mg) was thus obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N)([CH3:3])[CH3:2].Cl.[CH3:13][C:14]([CH3:16])=O>CCO>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[NH:10][C:14]([CH3:16])=[CH:13]2)([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)c1ccccc1NN
Agent: Cl
Solvent: CCO
Product: Cc1cc2cccc(C(C)C)c2[nH]1
Temperature: 140 °C
Yield: 20 %

Procedure:
To a solution of (2-isopropyl-phenyl)-hydrazine 7.60 g, 0.0506 mol) (Asselin et al., J. Med. Chem. 1976, 19, 787-792) and acetone (100 mL) is added 1M HCl in EtOH (2 drops). The solution is heated at a reflux overnight. The solution is concentrated, dissolved in toluene (100 mL) and concentrated. The residue is dissolved in o-xylene (100 mL) and ZnCl2 (8.3 g) is added. The solution is heated at 140° C. for 2 hours, cooled to ambient temperature, diluted with EtOAc (200 mL), washed with sat. NH4Cl, dried over Na2SO4, filtered and concentrated. The residue is purified by ISCO (5%-15% EtOAc gradient to furnish the title compound (1.76 g, 10.16 mmol, 20%). 1H NMR (CDCl3), δ 1.43 (d, J=7.0 Hz, 6H), 2.50 (s, 3H), 3.17-3.29 (m, 1H), 6.24-6.27 (m, 1H), 7.02 (d, J=7.1 Hz, 1H), 7.07 (dd, J=7.5, 7.1 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.85 (bs, 1H) ppm. LC/MS (m/z): calcd. for C12H15N (M+H)+: 174.1. found: 174.1.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C(C)(C)C)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 90 mg (0.74 mmol) 2,2-dimethylpropanoyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[CH3:14][C:15](=[N:19][OH:20])[C:16](=O)[CH3:17]>CC(O)=O.CCOCC>[CH3:14][C:15]1[N+:19]([O-:20])=[C:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[O:3][C:16]=1[CH3:17]
Reactant: CC(=O)C(C)=NO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
HCl gas was bubbled through a solution of methyl 4-formylbenzoate (8.20 g, 50.0 mmol) and 2,3-butanedione 2-oxime (5.05 g, 50 mmol) in HOAc (25 mL) at 0° C. and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with Et2O (300 mL) and the resulting precipitate was filtered, washed with Et2O (50 mL) and dried in vacuo to give N-oxide 1 (12.05 g, 97%) as a white powder: mp (Et2O) 127-128° C.; 1H NMR (CDCl3) δ 8.44 (br d, J=8.8 Hz, 2H, H-2, H-6), 8.23 (br d, J=8.8 Hz, 2H, H-3, H-5), 3.98 (s, 3H, OCH3), 2.50 (s, 2H, CH3), 2.47 (s, 3H, CH3); MS m/z 248.6 (MH+, 100%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:21](=[CH:22][CH:23]=1)[C:13]1[N:14]([CH2:17][CH:18](O)[CH3:19])[CH:15]=[CH:16][C:12]=1[CH2:11]2.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:31]([CH:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][CH:23]=[C:8]([O:7][CH3:6])[CH:9]=3)=[N+:32]=[N-:33]
Reactant: COc1ccc2c(c1)Cc1ccn(CC(C)O)c1-2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)Cc1ccn(CC(C)N=[N+]=[N-])c1-2
Yield: 48.2 %

Procedure:
1.9 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.41 g of (RS)-1-(6-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.24 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 558 mg of sodium azide and the reaction mixture was heated to 60° while stirring for 7 hours. After cooling the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 140 ml of water and once with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.75 g (48%) of (RS)-1-(2-azido-propyl)-6-methoxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a colorless oil.
Reaction SMILES: CC(C)(C)C([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=[N:24][N:23]=2)[CH:8]=1)=O>CO.O>[F:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][OH:5])=[CH:8][C:9]=1[C:22]1[N:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=[N:24][N:23]=1
Reactant: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2-c2nncn2C(C)C)c1
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO)cc2-c2nncn2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 213.5 %

Procedure:
To a room temperature solution of 29.4 (50 mg, 118 μmol) in MeOH (3.0 mL) was added LiOH monohydrate (1.0 M, 494 μL, 494 μmol). The mixture was stirred at room temperature for 30 minutes, diluted with water, and extracted with 30% IPA/chloroform. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-10% MeOH/DCM for elution gave 29.5 as colorless solid (86 mg, 89%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:26][C:27]1[CH:28]=[C:29]([S:36](Cl)(=[O:38])=[O:37])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]>C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([S:36]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=2)[C:9]2[S:13][N:12]=[CH:11][N:10]=2)(=[O:37])=[O:38])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: COc1ccc(CNc2ncns2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 250-mL round bottom flask was charged with N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE H, 2.032 g, 9.18 mmol) and THF (30 mL). The flask was cooled to −78° C. and lithium bis(trimethylsilyl)amide (1M in THF) (10.02 mL, 10.02 mmol) was added dropwise, rapidly. The flask was placed in an ice/water bath for 10 minutes, and then returned to −78° C., at which time a solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (Matrix Scientific, Columbia, S.C., 2.000 g, 8.35 mmol) in THF (5 mL with a 1 mL wash) was added dropwise. After 15 minutes, the reaction was complete, and was quenched with aqueous saturated ammonium chloride solution. The mixture was warmed to RT and extracted with EtOAc. The organics were combined and dried over sodium sulfate, filtered and concentrated. The solids were taken up in methanol, and after triturating, were filtered and washed with methanol to yield 3-fluoro-N-(4-methoxybenzyl)-4-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide. (INTERMEDIATE I) (2.76 g, 6.50 mmol) as a light yellow solid. m/z (ESI) 446.7 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([OH:16])=O)=[CH:10][N:9]1[CH3:17].[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([NH:18][C:19]2[CH:40]=[CH:39][C:22]([O:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]5[CH2:38][CH2:37]5)=[O:35])[N:32]=4)[CH:29]=3)=[C:21]([F:41])[CH:20]=2)=[O:16])=[CH:10][N:9]1[CH3:17]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1Cl
Yield: 60.2 %

Procedure:
In the same manner as in Example 46 and using 2-(2-chlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (330 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (260 mg, 60%) was obtained as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=1)[CH:13]=[CH2:14]>C(Cl)Cl>[C:21]([C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:18]=1[OH:25])[CH2:12][CH:13]1[CH2:14][O:9]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: C=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O

Procedure:
A solution of 22.4 g [0.11 mol] of m-chloroperbenzoic acid [85% strength] in 300 ml of dry methylene chloride is added dropwise to a solution of 24.6 g [0.10 mol] of 4-allyl-2,6-di-tert.-butylphenol of boiling point6 : 134°-36° C [manufactured according to the datain Journ. Org. Chem. USSR 1967, 95] in 175 ml of dry methylene chloride at room temperature, at a speed such that the temperature of the reaction solution does not exceed room temperature. Stirring is continued at room temperature until a sample of the reaction solution indicates that 1 equivalent of peracid has been consumed. Thereafter, excess peracid is destroyed by adding 10% strength aqueous sodium sulphate solution and the organic phase is successively extracted with 5% strength sodium bicarbonate solution and with water, dried over sodium sulphate and evaporated. Crude 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane is obtained as a brownish oil which, when recrystallized from petroleum ether, yields colorless crystals of melting point 86°-87° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:30])[C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: CN
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Yield: 84 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (210 mg, 0.46 mmol) was reacted with methylamine to give the title compound as a white solid (178 mg, 84%); NMR Spectrum 1.66 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.39 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.70 (br s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH3:19])=[N:5][CH:4]=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[H][H]>[Pd].C(O)C>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH3:19])=[N:5][CH:4]=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc(-c2cc([N+](=O)[O-])ccc2OCC)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cc(N)ccc2OCC)[nH]c1=O
Yield: 31.4 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-ethoxy-5-nitrophenyl)pyrimidine-5-carboxylate (0.42 g., 1.26 mmoles) and 10% palladium on carbon (0.07 g.) in ethanol (200 ml.) was treated with hydrogen at a pressure of about 3.5 kg./cm2 until uptake of hydrogen ceased. The mixture was filtered and the filtrate reduced to dryness. The residue was recrystallized from water followed by aqueous ethanol to give the title compound (0.12 g., 31.6%), m.p. 107°-110°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O[CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].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>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:15][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH3:13]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc([N+](=O)[O-])c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a mixture of 3-fluoro-4-nitrophenol (2.02 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5.62 g), triphenylphosphine (8.41 g) and THF (60 mL) was added dropwise a toluene solution (1.9 M, 16.9 mL) of diisopropyl azodicarboxylate at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow solid (4.03 g).
Reaction SMILES: BrC1C=C(NC(=O)CC)C=C(C(C2C=NC=CC=2)=O)C=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:29]2[CH:30]=[C:31]([NH:54][C:55](=[O:58])[CH2:56][CH3:57])[CH:32]=[C:33]([C:35]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:36]=3[CH:37]=[CH:38][N:39]4[Si](C(C)C)(C(C)C)C(C)C)[CH:34]=2)=[O:28])[CH:22]=1>>[NH:39]1[C:40]2[C:36](=[C:35]([C:33]3[CH:32]=[C:31]([NH:54][C:55](=[O:58])[CH2:56][CH3:57])[CH:30]=[C:29]([C:27]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)=[O:28])[CH:34]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CCC(=O)Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Product: CCC(=O)Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3[nH]ccc23)c1

Procedure:
N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-propionamide was converted to N-[3-(pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-propionamide, and the triisopropylsilyl group was removed with tetra n-butylammonium fluoride to give N-[3-(1H-indol-4-yl)-5-(pyridine-3-carbonyl)-phenyl]-propionamide as described in Example 35. 1H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 10.20 (s, 1H), 8.95 (s, 1H), 8.82 (d, J=3.5 Hz, 1H), 8.32 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.60 (dd, J=7.7, 5.0 Hz, 1H), 7.45-7.41 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.10 (d, J=6.6 Hz, 1H), 6.62 (s, 1H), 2.35 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([CH3:8])[N:7]=1.ClC1C(C#N)=NC(C)=C(CC)N=1.Cl.[CH2:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][NH:28][CH2:27]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:9]([C:5]1[N:4]=[C:3]([C:11]#[N:12])[C:2]([N:28]2[CH2:27][CH2:26][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][CH2:29]2)=[N:7][C:6]=1[CH3:8])[CH3:10]
Reactant: CCc1nc(C#N)c(Cl)nc1C
Reactant: c1ccc2c(c1)CCNCC2
Agent: CCc1nc(Cl)c(C#N)nc1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(C#N)c(N2CCc3ccccc3CC2)nc1C
Temperature: 0 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
A solution of 0.300 g (1.65 mmol) of the 1:1 mixture of the 3-chloro-6-ethyl-5-methyl-pyrazine-2 -carbonitrile and the 3-chloro-5-ethyl-6-methyl-pyrazine-2-carbonitrile, of 0.395 g (1.30 mmol) of 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and of 0.566 g (2.60 mmol) of N-ethyl-diisopropylamine in 1.0 ml of N,N-dimethylformamide was stirred at room temperature for 60 hours and then at 60° C. for 18 hours. The reaction mixture was subsequently poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was then chromatographed on silica gel using dichloromethane as eluent giving 0.086 g (0.29 mmol, 18% of theory) of the 6-ethyl-5-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellowish solid after crystallization from dichlormethane/pentane; MS: 293 (M+H)+; and 0.074 g (0.25 mmol, 15% of theory) of the 5-ethyl-6-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellowish solid; MS: 293 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.OCCSCCO>CO.C1(C)C=CC=CC=1.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Agent: [Ni]
Agent: OCCSCCO
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CCc1ccc(Cl)cc1

Procedure:
Hydrogenation of 139 g of 5-(4-chlorophenyl)-2,2-dimethylpent-4-en-3-one in 245 g of methanol or toluene at 100° C. on 5.6 g of Raney nickel with and without addition of bis-(2-hydroxyethyl) sulphide to give 5-(4-chlorophenyl)- 2,2-dimethylpentan-3-one (final product).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 28 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone, 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (28%).