Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:6]([CH2:4][OH:3])[N:7]([CH3:22])[N:8]=2)=[CH:12][C:13]=1[C:18]([F:20])([F:19])[F:21]
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cn1nc(-c2ccc(F)c(C(F)(F)F)c2)cc1CO

Procedure:
In analogy to the procedure described for example 1 a], 5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol as white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])Cl.[OH:23][Ge:24][OH:25].[CH:26]1[CH:27]=[CH:28][C:29]2[C:30](=[C:32]3[N:64]=[C:63]4[N:65]=[C:56]([C:57]5[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=54)[N:55]=[C:53]4[NH:54][C:46]([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:52]=54)=[N:45][C:43]4=[N:44][C:36]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=54)=[N:35][C:34]=2[NH:33]3)[CH:31]=1>N1C=CC=CC=1>[CH3:1][Si:2]([CH3:22])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:23][Ge:24][O:25][Si:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH3:56])([CH3:1])[CH3:22].[CH:27]1[CH:26]=[CH:31][C:30]2[C:29](=[C:34]3[N:35]=[C:36]4[N:44]=[C:43]([C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=54)[N:45]=[C:46]4[NH:54][C:53]([C:52]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=54)=[N:55][C:56]4=[N:65][C:63]([C:62]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=54)=[N:64][C:32]=2[NH:33]3)[CH:28]=1
Reactant: CCCCCCCCCCCCCCCCCC[Si](C)(C)Cl
Reactant: O[Ge]O
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC[Si](C)(C)O[Ge]O[Si](C)(C)CCCCCCCCCCCCCCCCCC

Procedure:
In analogy to a procedure by Wheeler et.al., J. Am. Chem. Soc. 106, 7404 (1984)] 3.3 g (9.5 mmol)of dimethyl-octadecyl-chlorosilane and 0.5 g (0.8 mmol) of dihydroxygermanium-phthalocyanine in 50 ml of pyridine are stirred for 2 hours at 50°. The solution is cooled and filtered using a suction filter. The solvent is removed in vacuo, and 250 ml of hexane are added to the residue. The resulting precipitate is filtered off with suction and washed fast with hexane, then in portions with 200 ml of acetone/water (1:1). The residue is dried overnight under a high vacuum, then extracted with toluene in a Soxhlet, freed of solvent and dried, yielding bis(dimethyl-octadecyl-siloxy)germanium-phthalocyanine; NMR (pyridine-d5): δ=9.8-9.9 (m, 8H); 8.3-8.5 (m,8H): aromatic H's; 0.75-1.46 (various m's); 0.45(m); -0.03 (m); -0.88 (m); -1.91 (m); -2.48 (m, 4×CH3 : silyl side chains) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([O:29][CH2:33][CH2:34][O:35][CH3:36])([CH3:27])[CH3:28])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOC(C)(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 70 °C
Reaction time: 17 h
Yield: 10.5 %

Procedure:
In a 10 mL pear flask, 2-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.100 g, 0.252 mmol, Example #37) and NaH (60% in mineral oil, 0.025 g, 0.631 mmol) in THF (5 mL) and DMF (1 mL) were added to give an off-white suspension. 1-Bromo-2-methoxyethane (0.140 g, 1.01 mmol) was then added and the suspension was stirred at about 70° C. for about 17 h. The mixture was concentrated under reduced pressure and was purified by flash chromatography on silica gel MeOH/DCM (gradient 1-5% over 14 min) and then further purified by RP-HPLC (Table 1, Method m) to afford the title compound (0.012 g, 11%) as a white fluffy solid: LC/MS (Table 1, Method g) Rt=2.02 min; MS m/z 455.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[O:4].[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[O:4]
Reactant: COC(=O)CCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: COC(=O)CCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2-methoxycarbonyl-ethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].Cl.[NH2:33][OH:34].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:33][OH:34])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 25 °C
Yield: 58.5 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (1.5 g, 3.64 mmol) obtained in Example 7 was dissolved in ethanol (100 mL), hydroxylamine hydrochloride (759 mg, 10.92 mmol) and pyridine (1.15 g, 15.56 mmol) were added thereto, refluxed for 1 hr, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 0.91 g of the titled compound (yield: 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>O1CCCC1>[NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:4]([NH:8][C:25]([NH:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])=[S:26])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: Nc1cccc(N)c1NCCCCCO
Solvent: C1CCOC1
Product: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCCCO
Yield: 32.1 %

Procedure:
To a solution of 5-[(2,6-diaminophenyl)amino]pentan-1-ol (Reference Example 110; 873 mg, 4.17 mmol) in tetrahydrofuran (30 mL) was added a solution of 2,4-dichlorophenyl isothiocyanate (936 mg, 4.59 mmol) in tetrahydrofuran (10 mL) at 0° C. The resultant mixture was stirred at 0° C. for 2 hr and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-90% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (554 mg, 1.34 mmol, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 72 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (55 mg, 72%) which was obtained as a white solid. MS: m/e=384.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]([BH3-])#N.[Na+].C(O)=O.C=O.C(=O)(O)[O-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:26])[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: [BH3-]C#N
Reactant: COc1ccc([N+](=O)[O-])cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 27.5 °C
Reaction time: 0.08 h
Yield: 112.6 %

Procedure:
Placed 2-Methoxy-5-nitro-N-(1-Boc piperidin-4-yl)phenylamine (5 grams, 14.24 mmol) obtained at step (I) into a round bottom flask containing methanol (10 mL) and stirred at 25-30° C. for 5 minutes. Added sodium cyanoborohydride (1.06 grams, 17.09 mmol) and formic acid (1.96 grams, 42.7 mmol) and stirred the reaction mass for 10 minutes. White solid mass separated out. Then the reaction mass was cooled to 0-5° C. in an ice bath and added formaldehyde (2.84 mL, 28.4 mmol, 30-50%). A clear solution was obtained. The mass was further stirred for 6 hours at 20-25° C. After completion of reaction (thin layer chromatography), solvent was distilled off to obtain oily mass. Added water (100 mL) and basified to pH: 8 using saturated solution of sodium bicarbonate solution. Extracted the product with ethyl acetate (3×100 mL) and layers separated. The combined organic layer was washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain 5.86 grams of dark yellow colored oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2-methoxyaniline by a procedure similar to example 28 (35% yield). 1H NMR (CDCl3): 8.76-8.79 (m, 1H), 8.50 (s, broad, 1H), 7.77-7.88 (m, 3H), 7.54-7.59 (m, 1H), 7.09-7.13 (m, 2H), 6.95-6.99 (m, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH2:32])[CH3:31]>ClCCl.C(N(CC)C(C)C)(C)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH:32][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1)[CH3:31]
Reactant: C[C@H](N)c1ccccc1F
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1F
Yield: 97 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 111 mg of (S)-1-(2-fluorophenyl)ethylamine were dissolved in 1 ml of dichloromethane and 0.10 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (194 mg) with a molecular weight of 328.4 g/mol (C15H21FN2O3S); MS (ESI): m/e=329 (M+H+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[C:14]1([CH3:23])[C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[CH2:23]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([OH:22])=[O:21])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24]
Reactant: CCCCCCCCCCCBr
Reactant: Cc1ccccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C(=O)O
Reaction time: 0.08 h

Procedure:
A solution containing lithium diisopropylamide (0.1 mole) was prepared by treating a solution of dissopropylamine (14.1 ml, 0.1 mole) in tetrahydrofuran (200 ml) at 0° C. with n-butyl lithium (41.2 ml of a 2.43 M solution, 0.1 mole), and stirring for 5 minutes. To this was added a solution of o-toluic acid (6.8 g, 0.05 mole) in tetrahydrofuran (50 ml). The ice bath was removed and the intense red solution was stirred for 30 minutes. This solution was slowly pipetted into a solution of undecylbromide (11.8 g, 0.05 mole) in tetrahydrofuran (50 ml) at -20° C. After the addition, the cooling bath was removed and the solution stirred for 30 minutes. A small amount of water was added and most of the tetrahydrofuran was removed under reduced pressure. The residue was poured into water, acidified with 3N hydrochloric acid and extracted with ether. The ether was dried, evaporated and the residue was recrystallized from acetonitrile, then from hexane, to give the product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CS(C)=O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 5.86 g (0.05 mol) of indole in 25 ml of DMSO is added to a mixture of 1.32 g of sodium hydride (0.055 mol, mineral oil suspension) in 50 ml of dimethyl sulfoxide. The resultant mixture is heated at 60° C. for 1.3 hours; after that, it is allowed to cool down and 17.7 g (0.11 mol) of 4-chlorobenzyl chloride are added dropwise. The solution is heated to 60° C. and allowed to stand overnight; it is then poured into 200 ml of water while stirring. This mixture is extracted several times with a total of 75 ml of CH2Cl2, after which the organic phase is dried with anhydrous sodium sulfate and filtered and the filtrate is evaporated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:18]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:18]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN(C)c1cccc(Br)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(N(C)C)c2)CCN(C)C1
Temperature: 25 °C

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), (3-bromo-phenyl)-dimethyl-amine (600 mg, 3 mmol), K3PO4 (636 mg, 3 mmol), L-Proline (69 mg, 0.6 mmol) and CuI (57 mg, 0.3 mmol) in dry DMF (4 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by column chromatography using neutral alumina and 10% EtOAc-Hexane to yield [3-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-phenyl]-dimethyl-amine as an off white solid (11 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 7.40 (t, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 7.86 (d, 1H), 6.64 (m, 2H), 4.58 (m, 2H), 3.64 (m, 2H), 3.16 (s, 3H), 3.08 (m, 2H), 2.96 (s, 6H), 2.42 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:21]([NH:23][C@H:24]([C:26]5[N:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:30](=[O:38])[C:29]6=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]6[N:27]=5)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=4[N:16](COCC[Si](C)(C)C)[CH:15]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:21]([NH:23][C@H:24]([C:26]5[N:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:30](=[O:38])[C:29]6=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]6[N:27]=5)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=4[NH:16][CH:15]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(-c6cccc(O)c6)n5)c34)n(-c3ccccc3)c(=O)c12
Yield: 73.6 %

Procedure:
(S)-2-(1-((5-(1-(3-Methoxyphenyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (9 mg, 0.01 mmol) was treated with boron tribromide (1M in dichloromethane, 1 mL, 1.00 mmol) in dichloromethane (1.0 mL) and then with a solution of ammonia (7N in methanol, 5.0 ml, 35.0 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (reverse phase, 0% to 100% water-methanol/acetonitrile 1:1) to obtain 4 mg (47% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COc1cccc(C(O)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(=O)C(F)(F)F)c1

Procedure:
4.82 g (0.023 mol) of 2,2,2-trifluoro-1-(3-methoxyphenyl)ethanol and 0.4 g (0.0012 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 100 ml of methylene chloride at room temperature. 14.4 ml (0.028 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 15 minutes with vigorous stirring and the mixture is stirred for a further 6 hours during which the reaction temperature rises to 26° C. The reaction mixture is added to 100 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.2 mbar, 60°-70° C. bath temperature), 2.1 g (44% of theory) of 3-trifluoroacetylanisole are obtained. nD20 : 1.4773.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[NH:17][C:18](=[O:20])[CH3:19])[CH3:3]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[NH:17][C:18](=[O:20])[CH3:19])[CH3:3]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCCN(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1cc(N)ccc1OCCCN(C)C
Reaction time: 0.5 h

Procedure:
7 g of 2-acetylamino-4-nitrophenyl γ-N,N-dimethylaminopropyl ether are dissolved in 35 ml of absolute ethanol. 0.5 g of 10% strength palladium-on-charcoal is added as a catalyst and the reduction is carried out in a reaction bomb under a hydrogen pressure of 40 bars, at 60° C., for 30 minutes. After the catalyst has been removed by filtration, the alcohol is driven off in vacuo to give the expected product in the form of an oil, which will be used as such for the following step.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])=[CH:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.C(O)C>[C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([CH3:21])[CH2:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To an oven-dried 100 mL round-bottomed flask containing 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (EXAMPLE 147) (200 mg, 0.69 mmol) in 50 mL 2:1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx 1 mol %), and the mixture was stirred under an atmosphere of H2 for 4 h. The reaction mixture was then filtered, and concentrated under diminished pressure to give 201 mg (quant) of 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline as a white oily solid. Data for (R/S)-7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.02 (d, J=8.7, 1H, 5-H), 6.73 (br s, 1H, HNBoc), 6.39 (dd, J=8.3, 2.2, 1H, 6-H), 6.29 (br s, 1H, 8-H), 3.62 (br s, 1H, NH), 2.85 (ddq, J=12.5, 12.3, 6.4, 1H, 4-H), 1.70 and 1.39 [d of ABq, JAB =12.8, JA =5.5 Hz (3-Hequiv), JB =12.6 Hz (3-Hax)2H], 1.49 [s, 9H, (CH3)3CO)], 1.29 (d, J=6.7, 3H, 4-CH3), 1.21 (s, 3H, 2-CH3), 1-14 (s, 3H, 2-CH3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=O)=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(OCC)(=O)C.O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]=[N:20][OH:21])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CSc1ncc(C=O)c(OCc2ccccc2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CSc1ncc(C=NO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 4-(benzyloxy)-2-(methylthio)pyrimidine-5-carbaldehyde (S20, 223 mg) in pyridine (4.0 mL), hydroxylamine hydrochloride (95.8 mg) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-2-(methylthio)pyrimidine-5-carbaldehyde oxime (S21, 233 mg).
Reaction SMILES: C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:11])(=O)=O)=CC=1.[H-].[Na+].[CH2:23]1[S:31](=[O:33])(=[O:32])[O:30][CH2:29][CH2:28][O:27][S:24]1(=[O:26])=[O:25].C(Cl)Cl>O1CCCC1.C(#N)C>[F:11][CH:23]1[S:24](=[O:25])(=[O:26])[O:27][CH2:28][CH2:29][O:30][S:31]1(=[O:33])=[O:32]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S1(=O)OCCOS(=O)(=O)C1F
Reaction time: 0.25 h

Procedure:
The fluorinating agent used was N-fluorobenzenesulfonimide obtained from PCR Chemicals (Gainesville Fla.). To a suspension of 0.34 g of NaH in 50 mL of tetrahydrofuran was added 2.45 g of ethylene methanedisulfonate followed by 3.8 g of N-fluorobenzenesulfonimide in 25 mL of acetonitrile. After about 15 min, 25 mL of CH2Cl2 was added, the solution was filtered, and the product was isolated by crystallization from CH2Cl2-cyclohexane to give 0.49 g of ethylene fluoromethanedisulfonate, m.p. 84-86° C. (93-2).