Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:24])([CH3:23])[C@H:7]1[OH:25].[CH:26]([C:28]1[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](OC)=O)=[O:27].C(=O)([O-])O.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:24][C:8]1([CH3:23])[C@@H:7]([OH:25])[C@H:6]([N:5]2[CH2:30][C:29]3[C:28](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:26]2=[O:27])[C:11]2[CH:12]=[C:13]([S:16]([C:19]([F:21])([F:22])[F:20])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9]1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A solution of 0.18 g of zinc chloride and 0.083 g of sodium cyanoborohydride in 3 ml of methanol was added to a solution of 0.40 g of trans-4-amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran-3-ol (prepared from its hydrochloride prepared as described in Preparation 9) and 0.20 g of methyl 2-formylbenzoate in 6 ml of methanol, and the resulting mixture was stirred at room temperature for 1 hour and then at 50° C. for 24 hours. At the end of this time, the mixture was cooled with ice and then mixed with a saturated aqueous solution of sodium hydrogencarbonate. The methanol was then removed by distillation under reduced pressure, and the resulting residue was diluted with water and extracted with methylene chloride. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was recrystallized from ethyl acetate, to afford 0.34 g of the title compound, melting at 279°-281° C.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[C:34]4[C@H:41]([CH3:42])[CH2:40][C@H:39]([OH:43])[C:35]=4[N:36]=[CH:37][N:38]=3)[CH2:29][CH2:28]2)=[O:26])[CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:11][C:10]=1[F:44]>O1CCOCC1.C(Cl)Cl>[ClH:8].[ClH:1].[NH2:17][CH2:16][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([F:44])[CH:11]=1)[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[C:34]3[C@H:41]([CH3:42])[CH2:40][C@H:39]([OH:43])[C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:29][CH2:28]1)=[O:26]
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)c4ccc(Cl)c(F)c4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@H](CN)c4ccc(Cl)c(F)c4)CC3)c21
Temperature: 25 °C
Reaction time: 13 h
Yield: 179.7 %

Procedure:
4M HCl/dioxane (2.46 ml, 9.85 mmol) was added to a solution of tert-butyl (S)-2-(4-chloro-3-fluorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.263 g, 0.492 mmol) in dioxane (3 mL) and DCM (2 mL). The reaction mixture was stirred at room temperature for 13 hours and then concentrated to dryness. The residue was dissolved in minimal MeOH, and the solution was added dropwise to vigorously stirring ether (40 mL), which caused a fine precipitate to form. The solids were isolated by filtration through a medium frit funnel with nitrogen pressure, rinsed with ether, dried under nitrogen pressure, and dried further in vacuo to give (S)-3-amino-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.224 g, 0.442 mmol, 89.7% yield) as a pale yellow powder. LC/MS (APCI+) m/z 434 [M+H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19]CC4C=CC=CC=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:27]([O:29][CH3:30])=[O:28])[C:8]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:3][CH:2]=1>C(O)(=O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:27]([O:29][CH3:30])=[O:28])[C:8]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Reaction time: 3 h
Yield: 97.5 %

Procedure:
1-(4-Pyridyl)-2,3-bis(methoxycarbonyl)-6-benzyloxy-7-methoxynaphthalene (2.3 g) is dissolved in acetic acid (50 ml), and thereto is added 10% palladium-carbon. The mixture is subjected to hydrogenation for 3 hours with shaking by using a moderate-pressure reduction apparatus (Parr). The palladium-carbon is removed by filtration, and the filtrate is concentrated. The precipitated crystal is washed with diethyl ether to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene (1.8 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[Si]([N:27]1[CH2:32][CH2:31][N:30](C)[CH2:29][CH2:28]1)(C(C)(C)C)(C)C>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
In a manner similar to that of Example 1, 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (II, R1 : cyclopropyl; X: fluoro) is reacted with 1-butylmethylsilyl piperazine (III, R2 : hydrogen; R3 and R4 : methyl; R5: t-butyl) to give a solid compound.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)ccc1O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)ccc1O
Temperature: 90 °C
Yield: 92 %

Procedure:
Vanillin (40 g, 263 mmol) was dissolved in pyridine (120 ml), and malonic acid (41 g, 395 mm ol) was added, followed by piperidine (4 ml). The mixture was heated at 90° C. for 6 hs under N2. After removal of pridine, the residue was poured into water (500 ml), acidified to PH=3 by aq.HCl. The precipitate was collected, washed by water (150 ml×3), and dried to give product (47 g, 91.8%). LC-MS: m/e 193 (M−1)
Reaction SMILES: [Br:1]C1C=NC=NC=1.[NH4+].[Cl-].[F:10][C:11]([F:27])([F:26])[O:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17]C2C=NC=NC=2)=[CH:15][CH:14]=1>C1COCC1.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:11]([F:27])([F:26])[O:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][Br:1])=[CH:15][CH:14]=1
Reactant: Brc1cncnc1
Reactant: FC(F)(F)Oc1ccc(Cc2cncnc2)cc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(CBr)cc1
Reaction time: 0.17 h

Procedure:
A suspension of zinc dust (15 g, excess) in THF (100 mL) was treated with LiCl (10.00 g, 238 mmol) and 1,2-dibromoethane (0.5 mL, catalytic). The warm mixture thus formed was treated dropwise with a solution of 4-(trifluoromethoxy)benzyl bromide (10a) (50.00 g, 209 mmol) in THF (200 mL) over a period of 3 hours. The resulting mixture was stirred for an additional hour, affording a solution of the lithium zincate 11, and then treated with (Ph3P)2NiCl2 (300 mg, 0.1 mol or 0.001 equivalents). The red suspension was treated drop wise with a solution of 5-bromopyrimidine (4) (33.23 g, 200 mmol) in THF (50 mL) over a period of one hour. The mixture was stirred for another 10 minutes and then poured into 300 mL of saturated aq. NH4Cl. The aqueous layer was washed with 200 mL of THF-ether (1:1), the combined organic layers washed with saturated aqueous NaHCO3, filtered, dried (MgSO4) and evaporated under reduced pressure to afford a pale yellow oily residue weighing 51.00 g (96%) and was found to be pure 5-[4-(trifluoromethoxy)benzyl]pyrimidine (12). 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (s, 1H, pyrimidine), 8.84 (s, 2H, pyrimidine), 7.19 (s, 4H, Ar, no para-pattern observed), 4.06 (s, 2H, methylene); 13C NMR (100 MHz, CDCl3) 156.3, 157.1, 147.4, 139.6, 134.8, 131, 121.7, 35.0. ESI-MS (low-res) 255.0 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].Cl[C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[C:17]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])[N:18]2[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([N:18]2[C:17]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[N:16][C:15]3[C:19]2=[N:20][CH:21]=[N:22][C:14]=3[O:10][CH2:9][C:8]([F:12])([F:11])[F:7])=[CH:28][CH:27]=1
Reactant: OCC(F)(F)F
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: FC(F)(F)COc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Potassium tert-butoxide (1 M in THF; 0.73 ml, 0.73 mmol) and 2,2,2-trifluoroethanol (2 ml) were stirred at room temperature and to this mixture was added 6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (100 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 3 days then quenched with H2O and diluted with chloroform. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC using 20% ethyl acetate/hexanes as the eluant to give title compound 5A-1 (20 mg, 17%): +ACPI MS (M+1) 473.1; 1H NMR: (400 MHz, CD3OD): δ 8.58 (s, 1H), 7.64 (d, 1H), 7.57 (d, 1H), 7.50–7.41 (m, 3H), 7.36 (d, 2H), 5.23 (q, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([C:21]([CH:23]2[CH2:27][CH2:26][C@@H:25]([N:28]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24]2)=O)=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[NH2:43][NH2:44].CC(O)=O.CC(C)([O-])C.[Na+]>CCO.CN1C(=O)CCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C(C)(C)C)F)CCCCC1>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:25]1[CH2:26][CH2:27][C@@H:23]([C:21]2[C:3]3=[C:4]4[CH:10]=[CH:9][NH:8][C:5]4=[N:6][CH:7]=[C:2]3[NH:44][N:43]=2)[CH2:24]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CC[C@@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Reactant: NN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(F)C1CCCCC1
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(CN(Cc2ccccc2)C2CC[C@@H](c3n[nH]c4cnc5[nH]ccc5c34)C2)cc1
Temperature: 90 °C
Yield: 99.6 %

Procedure:
A mixture of (5-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanone (1.5 g, 2.5 mmol), hydrazine (0.24 mL, 7.5 mmol), and AcOH (0.14 mL, 2.5 mmol) in EtOH (40 mL) was heated to reflux for about 8 h and at about 90° C. for about 16 h. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL). The organic phase was separated and washed with brine (40 mL), dried over anhydrous MgSO4, filtered, and concentrated to yield crude (3R)-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine (1.14 g, 100%) as a yellow amorphous solid that was used without purification. To a solution of the hydrazone (1.14 g, 2.5 mmol) in NMP (4 mL) were added sodium tert-butoxide (0.58 g, 6.0 mmol), palladium (II) acetate (0.0056 g, 0.025 mmol), and CyPFt-Bu (0.014 g, 0.025 mmol). The mixture was heated at about 140° C. for about 15 min in a microwave, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (25 mL) and water (25 mL), and the organic solution was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give crude (3R)—N,N-dibenzyl-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine (1.05 g, 100%) as a dark brown solid that was used without purification. To a solution of the protected amine (1.05 g, 2.5 mmol) in MeOH (15 mL) was added Pd(OH)2 (0.23 g, 1.6 mmol) and ammonium formate (1.58 g, 25.0 mmol). The mixture was heated at about 65° C. for about 1 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give crude (3R)-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine (0.60 g, 100%) as a brown solid that was used without purification: LC/MS (Table 2, Method a) R=1.12 min; MS m/z: 242 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:34](OCCCC)(=O)[CH:35]=[O:36].CC(O)=O>CCO>[C:24]([O:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:6]=[CH:7][C:2]4[N:1]=[CH:34][C:35](=[O:36])[N:28]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)[C:3]=4[N:4]=3)=[CH:14][CH:13]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)C1
Reactant: CCCCOC(=O)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)C1
Yield: 28.5 %

Procedure:
A mixture of 0.70 g (1.5 mmol) of 5-amino-2-[[4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]phenyl]amino]-4-(cyclopentylamino)-pyrimidine, 0.52 g (4 mmol) of butyl glyoxylate (F. J. Wolf, J. Weijlard, Org. Synth. Coll., 1963;4:124–125) and 0.5 mL HOAc in 15 mL of EtOH is heated under reflux for 14 hours, and the solvent is removed under vacuum. The residue is diluted with aqueous ammonia solution and extracted into EtOAc. Chromatography on silica, eluting with hexane/EtOAc (3:2), gives 0.21 g (28%) of the title compound (Compound 53): mp (MeOH) 226–228° C.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl>CO>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(Br)ccc32)C1
Agent: Cl
Solvent: CO
Product: Brc1ccc2c(c1)CCCCN2C1CCNC1
Yield: 90.8 %

Procedure:
A solution of compound 3 (2.2 g, 5.56 mmol) in methanol (solvent grade, 25 mL) was treated with 1 N HCl (40 mL) and the resulting mixture was refluxed for 30 minutes. The reaction was brought to room temperature, methanol was evaporated and the solution basified with 6 N NaOH (pH ˜14). The product was extracted into CH2Cl2 (3×50 mL) and the combined organic layers were dried (Na2SO4) and concentrated to give crude product 4 (1.49 g, 91%) as a syrup. 1H NMR (DMSO-d6) δ 1.47-1.62 (m, 6H), 1.97-2.08 (m, 1H), 2.59-2.68 (m, 3H), 2.73-2.79 (m, 2H), 2.84-2.88 (m, 2H), 3.08-3.09 (m, 1H), 3.78-3.87 (m, 1H), 6.85 (d, 1H, J=8.4 Hz), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.26 (d, 1H, J=2.4 Hz); ESI-MS (m/z, %): 297, 295 (M+, 100).
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:21][CH2:22][O:23][CH3:24])/[C:5](=[N:9]/[C:10]([C:12]23[CH2:19][CH:18]4[CH2:20][CH:14]([CH2:15][CH:16]2[CH2:17]4)[CH2:13]3)=[O:11])/[S:6][C:7]=1[CH3:8])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:4]([CH2:21][CH2:22][O:23][CH3:24])/[C:5](=[N:9]/[C:10]([C:12]23[CH2:19][CH:18]4[CH2:20][CH:14]([CH2:15][CH:16]2[CH2:17]4)[CH2:13]3)=[O:11])/[S:6][C:7]=1[CH3:8]
Reactant: COCCn1c(C=O)c(C)s/c1=N\C(=O)C12CC3CC(CC1C3)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCn1c(CO)c(C)s/c1=N\C(=O)C12CC3CC(CC1C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of Example 127 (47.0 mg, 0.14 mmol) in methanol (3 mL) was added a solution of sodium borohydride (6.0 mg, 0.15 mmol) in methanol (3 mL). The reaction mixture was stirred at 0° C. for 30 minutes and then warmed to reflux for 1 hour. The reaction mixture was then cooled, quenched with aqueous 1 M aqueous HCl, neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.48-1.65 (m, 4H), 1.66-1.82 (m, 4H), 2.08 (s, 1H), 2.12 (s, 1H), 2.23 (s, 3H), 2.26 (s, 2H), 2.52-2.59 (m, 1H), 3.24 (s, 3H), 3.66 (t, J=5.6 Hz, 2H), 4.34 (t, J=5.8 Hz, 2H), 4.46 (d, J=4.4 Hz, 2H), 5.29 (t, 1H); MS (ESI+) m/z 351 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8][CH2:7]1>N1C=CC=CC=1>[CH3:27][N:13]([CH2:12][C@H:9]1[CH2:8][CH2:7][C@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:11][CH2:10]1)[S:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CN(C[C@H]1CC[C@H](CCCCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CN(C[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
1.22 g (3.0 mmol) trans-N-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide were dissolved in 4.0 ml of pyridine, cooled to −10° C. and treated with 0.687 g methanesulfochloride. The reaction mixture was then stirred at room temperature for 2 hours. It was subsequently poured into 50 ml of an ice/water/diluted hydrogen chloride mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure giving 1.35 g (92.8%) trans-methanesulfonic acid 4-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-butyl ester as colorless solid, MS: 486 (MH+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]([OH:18])[CH3:17].O.CCOC(C)=O>N1C=CC=CC=1>[C:1]([O:18][CH:16]([CH3:17])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Br:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)Cc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(C)Cc1ccccc1Br

Procedure:
Acetic acid anhydride (1.2 mL) was added to a solution of 1-(2-bromophenyl)-2-propanol (529 mg) in pyridine (1.0 mL) at 20° C. under stirring. The reaction mixture was stirred overnight, then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with water (×3), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7]CCC)=[O:6].O.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[C:5]([OH:7])=[O:6]
Reactant: CCCOC(=O)c1ccc(OCCC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1C
Temperature: 0 °C
Yield: 84 %

Procedure:
The crude propyl 3-methyl-4-propoxybenzoate was dissolved in methanol (25 mL) and water (50 mL) and treated with solid sodium hydroxide (31.6 g, 789 mmol). The reaction mixture was refluxed for 1 h. The reaction mixture cooled to 0° C. and acidified with 12 M HCl (74 mL, 890 mmol). The resulting solid filtered to provide 3-methyl-4-propoxybenzoic acid (3.22 g, 16.6 mmol, 84%) as a light pink solid. ESI-MS m/z calc. 194.0943. found 195.3 (M+1)+; Retention time: 1.41 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.77 (dd, J=8.5, 2.2 Hz, 1H), 7.73 (d, J=1.4 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 4.01 (t, J=6.4 Hz, 2H), 2.18 (s, 3H), 1.82-1.69 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.O.[Cu]Br>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: Brc1cccnc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2-c2cccnc2)c1
Yield: 86.4 %

Procedure:
A mixture of 5-nitroindole (0.49 g, 3 mmol), 3-bromopyridine (0.95 g, 6 mmol), copper (I) bromide (60 mg, 0.42 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in pyridine (2 mL) and nitrobenzene (0.6 mL) was heated under reflux for 4 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried and evaporated. The residue was chromatographed on silica gel eluted with ethyl acetate to give the tide compound (0.62 g, 86.5%), mp. 164-5° C.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH:6]=1)C=C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])[CH:6]=[C:5]2[NH2:4])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: C=CCNc1cc(NCc2cc(F)ccc2OC)nc2ccc(Cl)cc12
Product: COc1ccc(F)cc1CNc1cc(N)c2cc(NCc3ccccc3)ccc2n1

Procedure:
The title compound, MS: m/e=403.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine and benzylamine
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>C1(C)C=CC=CC=1>[C:15]([C:3]1[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:20][N:21]([CH3:23])[CH3:22])#[N:16]
Reactant: Cc1cccc(Nc2n[nH]c(N)c2C#N)c1
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2n[nH]c(N=CN(C)C)c2C#N)c1
Temperature: 25 °C

Procedure:
A suspension of 10.71 g (50.22 mmol) of 5-amino-4-cyano-3-(3-methyl-phenylamino)-pyrazole [for preparation see: Arch. Pharm. (Weinheim) 326, 245 (1993)], 9.9 ml (57.8 mmol) of N,N-dimethylformamide diethyl acetal and 150 ml of toluene is heated under reflux for 4 hours. The reaction mixture is then cooled to RT and filtered and the filter residue is washed with toluene and diethyl ether, yielding the title compound; m.p. 260-261° C.