Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26](=O)[CH3:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]([NH:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH3:27])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)=O)c3ccccc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25° C. solution of 4-(4-acetyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 39 (45 mg, 0.11 mmol) in MeOH (4 mL) was added cyclohexylamine (31 mg, 0.22 mmol) and sodium cyanoborohydride (34 mg, 0.69 mmol). After stirring for 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The resultant solid was purified by reverse phase HPLC providing the title compound (G-30). 1H NMR (300 MHz, MeOD) δ 8.84 (m, 1H), 8.42 (s, br, 1H), 8.35 (m, 2H), 7.82 (m, 3H), 5.55 (d, 1H), 4.02 (q, 2H), 3.80 (d, 2H), 3.22(m, 1H), 3.00 (m, 1H), 2.77(s, br, 2H), 2.19 (d, 1H), 2.05 (d, 1H), 1.78 (m, 4H), 1.50 (m, 5H), 1.24 (m, 9H); LC/MS m/z 488 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:22][C@@H:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=3)[CH:16]=2)[CH2:22][C@@H:23]([OH:28])[C:24]([F:26])([F:27])[F:25])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: Oc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)C[C@@H](O)C(F)(F)F)c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O[C@H](CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(OCc2cccc(C(F)(F)F)c2)c1)C(F)(F)F
Temperature: 60 °C
Yield: 47 %

Procedure:
To a solution of (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol) from EX-20B and 3-trifluoromethylbenzyl bromide (70.0 mg, 0.27 mmol) in 2.5 mL of acetone was added cesium carbonate (100 mg, 0.31 mmol). The reaction mixture was heated at 60° C. for 18 h then cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 63.3 mg (45%) of the desired (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H21F10NO3: 586.1440 [M+H]+, found: 586.1419. 1H NMR (acetone-d6) δ 7.61-7.82 (m, 4H), 7.41 (t, 1H), 7.25 (d, 1H), 7.10-7.21 (m, 3H), 6.34-6.67 (m, 4H), 5.73 (d, 1H), 5.19 (s, 2H), 4.82 (s, 2H), 4.34-4.48 (m, 1H), 3.99 (dd, 1H), 3.68 (dd, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:31].[OH-].[Na+]>O>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[N:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:31]
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(N)=O
Temperature: 70 °C
Yield: 98.2 %

Procedure:
A mixture of crude 5-cyano-4-(2-methylphenyl)-2-(4-methylpiperazinyl) pyridine (16.85 g, 57.6 mmol), 18 mL of toluene, and 27 mL (49.7 g, 507 mmol) of concentrated sulfuric acid was heated at 70° C. for 12 hours. The mixture was cooled and quenched with 200 mL of cold H2O. Ethyl acetate was added followed by a solution of 45.6 g (1.14 mol) of sodium hydroxide in 200 mL of H2O. Water (200 mL) was added and the layers were separated. The aqueous layer was extracted several times with 100 mL of ethyl. The organic layers were combined and concentrated to afford 17.55 g (98.1%) of 4-(2-methylphenyl)-6-(4-methylpiperazinyl)-3-pyridinecarboxamide as a colorless solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[C:18]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:17][N:16]=[C:15]3[C:13]2[CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=[N:11][CH:12]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.4 %

Procedure:
N-(tert-Butyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridine-3-sulfonamide (0.0300 g, 0.0570 mmol) was dissolved in TFA (5.00 mL, 64.9 mmol) and stirred at room temperature for 12 h. TFA was removed under reduced pressure and reaction mixture was diluted with saturated NaHCO3 (50 mL). The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 16 as described in general methods) to afford 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridine-3-sulfonamide (10.0 mg, 37.3%) as a white solid. LCMS (Condition 4): retention time 2.25 min, [M+1]=469.2. HPLC (Condition 28): retention time=5.73 min, purity 99.07%. 1H NMR (400 MHz, CD3OD) δ 4.68 (s, 2 H), 7.24 (dd, J=4.8 Hz, J=7.6 Hz, 1 H), 7.27 (d, J=7.6 Hz, 1 H), 7.52 (br s, 5 H), 7.71-7.77 (m, 2 H), 7.88 (dd, J=1.6 Hz, J=8.4 Hz, 1 H), 7.95 (dd, J=7.2 Hz, J=8.4 Hz, 1 H), 8.30-8.31 (m, 1 H), 8.57 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 9.07 (d, J=2.0 Hz, 1 H), 9.21 (d, J=2.4 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:22][CH:21]=3)=[O:18])=[CH:7][C:6]=2[CH:35]=1.B([O-])([O-])O[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:48]([O:47][CH2:46][CH2:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:22][CH:21]=4)=[O:18])=[CH:7][C:6]=3[CH:35]=2)=[CH:43][CH:42]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CC(C)CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
In toluene/ethanol/water (=10/1/1, 31.5 ml) was dissolved 7-bromo-1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.66 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.35 g) and potassium carbonate (0.37 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was heated to reflux for 16 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1). The purified residue was dissolved in ethyl acetate and filtered to give a solution. The solvent was removed under reduced pressure, followed by recrystallization from isopropyl ether/ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 87) (74 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:22][CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].C(C1C=C(C(C)C)C2OC(C3C=CC(C(O)=O)=CC=3)=NC=2C=1)#N>>[C:1]([C:3]1[CH:4]=[C:5]([S:22][CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(SC)c3o2)cc1
Agent: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CSc1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12

Procedure:
The title compound was prepared from methyl 4-[5-cyano-7-(methylthio)-1,3-benzoxazol-2-yl]benzoate by a procedure analogous to that described in INTERMEDIATE 2, Step C. Mass spectrum (ESI) 311.0 (M+1).
Reaction SMILES: [Br-].[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])=[CH:10][CH:11]=2)[C:6]([CH3:35])([CH3:34])[CH2:5][CH2:4]1.C([Li])CCC.[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.CCCCCC>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([CH3:14])=[CH:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:10][CH:11]=2)[C:6]([CH3:34])([CH3:35])[CH2:5][CH2:4]1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCN2C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=Cc1ccccc1)c1ccc2c(c1)C(C)(C)CCN2C
Temperature: -20 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
5.1 g of [1-(1,2,3,4-tetrahydro-1,4,4-trimethyl6-quinolinyl)ethyl]triphenylphosphonium bromide were suspended in 40 ml of tetrahydrofuran and treated at -20° C. with 5.9 ml of a 1.6 molar solution of n-butyllithium in hexane. After stirring at -20° C. for 1 hour, 1 g of benzaldehyde was added thereto and the mixture was stirred at room temperature for an additional 1 hour. After working-up in analogy to Example 49 and recrystallization from hexane, there were obtained 1.2 g of 1,2,3,4-tetrahydro-1,4,4-trimethyl-6-(α-methylstyryl)quinoline, melting point 69°-71° C.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>CC#N>[Cl:24][C:23]1[C:18]([O:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[N:19][CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: Oc1ccnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(Oc2ccnc3[nH]ccc23)c(Cl)c1
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridin-4-ol (210 mg, 1.56 mmol, see: Thibault, C. et al. Org. Lett. 2003, 5, 5023) in 3 mL of MeCN was added K2CO3 (240 mg, 1.74 mmol). The suspension was stirred for 10 min and treated with 2,3-dichloro-5-nitropyridine (270 mg, 1.40 mmol, see: Koch, V. and Schnatterer, S. Synthesis, 1990, 499). The reaction mixture was stirred for 12 h and quenched with 20 mL of H2O. The solution was extracted with EtOAc and the organic layer was washed with brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (ISCO RediSep® silica gel cartridge) to give the title compound (220 mg, 54%). MS (ESI) m/z 291.1 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[N:32][C:31]([C:34](OC)=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][N:9]=1)[CH:5]([CH3:7])[CH3:6]>CCO>[CH3:3][C:4]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[N:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][N:9]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(C)(c1ccc(-c2ccc(CO)nn2)cc1)c1ccc(OCc2ccccn2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium borohydride (14.0 mg, 0.362 mmol) was added to a stirred solution of 5c (113 mg, 0.241 mmol) in EtOH (2.00 mL) at 0° C., and the resulting mixture was allowed to warm to rt. After approximately 12 h, the reaction mixture was cooled to 0° C. and quenched by the addition of aqueous 1N HCl. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 30%-100% EtOAc/hexanes as eluent) afforded the title compound 5d. m/z (ES) 441 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.61 (d, 1H, J=3.2 Hz), 8.40 (m, 1H), 7.97 (d, 2H, J=8.2 Hz), 7.83 (d, 1H, J=8.7 Hz), 7.75 (m, 1H), 7.52 (m, 4H), 7.26 (m, 1H), 7.19 (m, 2H), 5.23 (s, 2H), 3.09 (m, 1H, J=6.6 Hz), 1.72 (s, 3H), 0.88 (d, 3H, J=6.6 Hz), 0.83 (d, 3H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH2:17][CH2:16][O:15][N:14]=2)=[C:10]([CH:18]=[S:19](=[O:21])=[O:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH2:17][CH2:16][O:15][N:14]=2)=[C:10]([CH:18]=[S:19](=[O:20])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(CC2=NOCC2)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C=S(=O)=O)c(CC2=NOCC2)c1Cl

Procedure:
At 5° C., a solution of 2.3 g (7 mmol) of methyl 2-chloro-3-(4,5-dihydro-3-isoxazolylmethyl)-4-sulfonylmethylbenzoate in 40 ml of tetrahydrofuran is treated with 0.3 g (13 mmol) of lithium hydroxide. The reaction mixture is taken up in 300 ml of diethyl ether and adjusted to pH 1 using 10% strength aqueous hydrochloric acid. The aqueous phase is extracted with diethyl ether. The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. Yield: 1.7 g; 1H NMR, δ [ppm], DMSO-d6; 3.0 (t), 3.3 (s), 4.2 (t), 4.3 (s), 7.8 (d), 8.1 (d).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH:9]=2)[CH:4]=1.C(O)(=O)C.Br>O>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCC[C@H]1CC[C@H](c2ccc3cc(OC)ccc3c2)CC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCC[C@H]1CC[C@H](c2ccc3cc(O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
To 28.0 g of 2-methoxy-6-(trans-4-propylcyclohexyl) naphthalene were added 280 ml of acetic acid and 280 ml of 48% hydrobromic acid. The reaction mixture was then heated under reflux for 12 hours. The reaction solution was then allowed to cool to room temperature. To the reaction solution was then added 500 ml of water to cause crystallization. The crystal thus precipitated was then filtered off. The crystal was washed with water, and then dried under reduced pressure to obtain 26.8 g of 6-(trans-4-propylcyclohexyl)-2-naphthol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].Cl>C1C=CC=CC=1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)cc(NC(=O)CCl)c(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture consisting of 0.8 g of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid, 20 ml of dry benzene, and 0.5 ml of pyridine was added dropwise with stirring a solution of 0.4 ml of chloroacetyl chloride in 5 ml of benzene. The mixture was stirred overnight and then, shaken with dilute hydrochloric acid. The layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, dried over sodium sulfate, and evaporated. The residue was recrystallized from ethyl ether/n-hexane to give 0.65 g of 2-chloroacetylamino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid (m.p. 124°-125° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([O:37]C)=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>CO.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:25]([C:35]([OH:37])=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc(C#Cc2cn([C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
The (2S,4S)-1-tert-butyl 2-methyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate (393.8 mg) obtained in Example 66 (Step 6) was dissolved in methanol (6 ml). After cooling to 0° C., 4N aqueous sodium hydroxide (3 ml) was added thereto. The reaction suspension was stirred at room temperature for 3 hours. 5N hydrochloric acid was added to the reaction mixture to a pH of 5, and ethyl acetate and water were added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow solid (280 mg). Physical properties: m/z[M+H]+ 508.3
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:6][C@@H:5]2[O:7][C@H:8](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[C@@H:4]2[O:3]1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:35])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(C(F)(F)F)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2O[C@H](CCc3ccc(C(F)(F)F)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Reaction time: 4 h

Procedure:
10% Palladium on charcoal (0.2 g) was added to the solution of compound obtained from step d above (0.25 g) in ethyl acetate (20 mL) at room temperature, and the reaction mixture was hydrogenated at 50 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad, and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.225 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]=1.ClC1C=CC=CC=1Cl>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Brc1ccccc1C1=NCCc2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: Brc1ccccc1-c1nccc2ccccc12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A mixture of 28.6 g (100 mmol) of 1-(2-bromophenyl)-3,4-dihydroisoquinoline, 86.9 g (1 mol) of manganese dioxide and 200 ml of 1,2-dichlorobenzene was stirred at 180° C. for 5 h. After cooling, the mixture was diluted with 500 ml of toluene and filtered through silica gel. After the solvent had been removed, the product was obtained as a yellow oil. The yield at a purity of approx. 99.0% was 26.0 g (91 mmol), 91.4% of theory.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][O-:13].[Na+].O>O1CCOCC1>[CH3:12][O:13][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccnc(OC)c1
Yield: 75 %

Procedure:
A mixture of methyl 2-chloroisonicotinate (5.23 g, 0.030 mol) and sodium methoxide (2.47 g, 0.045 mol) in 15 mL of dioxane was heated at reflux for 1.5 hours. After the reaction mixture was cooled, water was added and the resulting mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 3.76 g (75%) of product as a yellow oil: Anal. Calc'd. for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.07; H, 5.54; N, 8.34.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3ccc(Br)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 47.5 %

Procedure:
290 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 200 mg of 5-bromoisoindoline, 290 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 220 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[CH2:8]O.[Br:11]P(Br)Br>ClCCl>[Br:11][CH2:8][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[CH:5][C:6]=1[CH3:10]
Reactant: Cc1cncc(C)c1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1cncc(C)c1CBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3,5-dimethylpyridin-4-yl)methanol (2.55 g, 18.6 mmol) in anhydrous dichloromethane (130 mL) was added tribromophosphane (2.0 mL, 21.1 mmol). The mixture was stirred at room temperature for 5 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 4-(bromomethyl)-3,5-dimethylpyridine. The crude product was used without further purification.