Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:26])(=[O:25])[NH2:24])=[CH:13][C:12]=2[F:27])=[C:8]([C:28]#[N:29])[N:7]([C:30]2[CH:35]=[C:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:32][C:31]=2[Cl:41])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl[C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH2:46]([O:45][C:43]([NH:24][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]([C:30]3[CH:35]=[C:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:32][C:31]=3[Cl:41])[C:8]=2[C:28]#[N:29])=[C:12]([F:27])[CH:13]=1)(=[O:26])=[O:25])=[O:44])[CH2:47][CH2:48][CH3:49]
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: CCCCOC(=O)Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CCCCOC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cc2c(CCCC)nn(-c3cc(NC(=O)CC)ccc3Cl)c2C#N)c(F)c1
Yield: 30 %

Procedure:
This material was prepared by reaction of 3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-1H-pyrazole-5-carbonitrile (from Example 4, Step K) according to the method of Example 6, except that n-butyl chloroformate was substituted for di-t-butyl dicarbonate, and the overnight reaction was conducted at 50° C. The crude product was purified by reverse phase HPLC, as described in Example 6, to give a 30% yield of the title compound as a nearly white solid; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 694 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.81 (t, J=7.4 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.15 (m, 2H), overlapping 1.21 (t, J=7.5 Hz, 3H), 1.38-1.46 (m, 2H), 1.72 (m, 2H), 2.38 (q, J=7.5 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H), 3.97 (t, J=6.5 Hz, 2H), overlapping 4.04 (br s, 2H), 7.06-7.12 (m, 2H), 7.27-7.35 (m, 2H), 7.40-7.68 (m, 5H), 7.97 (s, 1H), 8.26 (dd, J=8.0, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:6]2[N:7]([N:24]=[CH:25][CH:26]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:9]([C:11](N(OC)C)=[O:12])[CH:10]=1>O1CCCC1>[Cl:4][C:5]1[C:6]2[N:7]([N:24]=[CH:25][CH:26]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:9]([C:11](=[O:12])[CH3:1])[CH:10]=1
Reactant: CON(C)C(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
3.0 M Methylmagnesium bromide in tetrahydrofuran (0.87 mL) was added dropwise to a solution of 4-chloro-7-(3-fluorophenyl)-N-methoxy-N-methylpyrazolo[1,5-a]pyridine-6-carboxamide (0.25 g, 0.75 mmol) in tetrahydrofuran (3.038 mL) under N2 cooled to 0° C. The solution was stirred at 0° C. for 30 minutes. The reaction solution was quenched at 0° C. with 1.0 M hydrogen chloride in water (2.996 mL), poured into 25 mL of water saturated sodium bicarbonate solution and was extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethanone (0.15 g, 68%) as an oil. LCMS calculated for C15H11ClFN2O (M+H)+: m/z=289.1. found: 288.9.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].N=[C:20](CCCC)C(OCC)=O>CO>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[N:6]=1)[CH2:2][CH2:3][CH2:4][CH3:20]
Reactant: CCCCC(=N)C(=O)OCC
Reactant: CCCCc1nc(CNC(=O)OC(C)(C)C)n[nH]1
Solvent: CO
Product: CCCCCc1nc(CNC(=O)OC(C)(C)C)n[nH]1

Procedure:
Under nitrogen, a solution of 18.9 g (100 mmol) of N-Boc glycine hydrazide (from step 2 of Example 3) in 100 mL of methanol is treated with 14.3 g (100 mmol) of ethyl iminocaproate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)]. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-pentyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:47][CH:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NC2CCN(C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 83.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (10 mg, 0.018 mmol) in THF (5 mL) were added 1-methyl-4-piperidinamine (10 mg, 0.088 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over might. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (9 mg, 83%). LC-MS m/z 602 (M+H)+; 1H-NMR (MeOD) δ 1.47 (m, 2H), 1.84 (m, 4H), 2.24 (s, 3H), 2.33 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:33][C@H:34]3[C@H:38]4[O:39][CH2:40][C@@H:41]([O:42][CH2:43][CH:44]=[O:45])[C@H:37]4[O:36][CH2:35]3)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:33][C@H:34]3[C@H:38]4[O:39][CH2:40][C@@H:41]([O:42][CH2:43][CH2:44][OH:45])[C@H:37]4[O:36][CH2:35]3)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OCC=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OCCO)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (3.1 mg, 0.082 mmol) was added to a stirred solution of 2-[[(3R,3aR,6R,6aR)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]acetaldehyde (11.1 mg, 0.018 mmol) in MeOH (0.3 ml) that had been cooled to 0° C. in an ice bath. After 1.5 hours, the reaction mixture was removed from the ice bath and allowed to warm to room temperature. The reaction mixture was evaporated under reduced pressure to give the desired product as a white residue. LC-MS: calculated for C32H38ClN3O6Si 623.22 observed m/e: 624.37 (M+H)+ (Rt 1.35/2 min)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4].C(NC(C)C)(C)C.[N:23]1([C:29]2[N:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:31]([C:30]1[C:29]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=3)=[O:4])[CH2:27][CH2:28]2)=[N:36][CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: N#Cc1cccnc1N1CCN(CC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
2-Chloro-N-(4-trifluoromethylphenyl)acetamide (820 mg, 3.45 mmol, Maybridge) and N,N-diisopropylamine (2.5 mL) in toluene (50 mL) were treated with 2-piperazin-1-ylnicotinonitrile (800 mg, 4.25 mmol, Chess) and heated to 60° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution with 20% to 40% ethyl acetate:hexanes) to provide 1.05 g (78% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.69 (m, 4H), 3.26 (s, 2H), 3.68 (m, 4H), 6.93 (dd, 1H, J=7.5, 4.7 Hz), 7.68 (AA′BB′, 2H, J=8.8 Hz), 7.88 (AA′BB′, 2H, J=8.5 Hz), 8.07 (dd, 1H, J=7.8, 2.0 Hz), 8.42 (dd, 1H, J=4.7, 2.0 Hz), 10.14 (br s, 1H); MS (DCI/NH3) m/e 390 (M+H)+;
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH:3](O)[CH:4]=[CH2:5].C[O:10][C:11](=O)[CH:12](C=O)[CH3:13]>>[CH3:13][CH:12]([CH2:5][CH:4]=[CH:3][CH:2]([CH3:1])[CH2:7][CH3:8])[CH:11]=[O:10]
Reactant: C=CC(O)C(C)CC
Reactant: COC(=O)C(C)C=O
Product: CCC(C)C=CCC(C)C=O
Yield: 75.2 %

Procedure:
57 g (0.5 mole) of 4-methyl-hex-1-en-3-ol and 70 g of α-formylpropionic acid methyl ester (0.6 mole) are heated at from 140° to 200° C whilst stirring; at the same time the methanol liberated is distilled off through a 20 cm column and the carbon dioxide is measured using a gas flow meter. 11.5 liters of carbon dioxide are liberated in the course of three hours. When the elimination of methanol and carbon dioxide has ceased, the mixture is fractionated. 58 g of the above aldehyde (yield: 75% of theory) are obtained. B.p. = 75° - 80° C at 11 mm Hg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]C(=O)C)=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)=O)C>O1CCCC1>[CH3:10][NH:12][CH2:13][CH2:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)NCCc1ccc(Oc2ccc(OC(C)=O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
1.0M Lithium aluminum hydride in tetrahydrofuran (5 mL) was added to a solution of acetic acid 4-[4-(2-ethoxycarbonylamino-ethyl)-phenoxy]-phenyl ester (330 mg, 1.0 mmol) in tetrahydrofuran (25 mL). Refluxed overnight, cooled to room temperature, then quenched the reaction with saturated aqueous ammonium chloride and stirred for 3 hours. Decanted the organic layer. Washed the remaining solid with ethyl acetate (2×30 mL). Combined all the organic washes then concentrated on a rotary evaporator to yield 4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol (200 mg): HPLC=98% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. 1H NMR (CDCl3, 300.00 MHz): 7.42-6.77 (m, 8H), 4.32 (s, 1H), 2.95-2.79 (m, 4H), 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[Cl:17]N1C(=O)CCC1=O>C1COCC1>[Cl:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Cn1nccc1-c1ccc(C(=O)O)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)O)cc1F
Reaction time: 1 h

Procedure:
A solution of 3-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzoic acid (196 mg, 0.89 mmol) and N-chlorosuccinimide (119 mg, 0.89 mmol) in THF (5 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM, the aqueous phase was adjusted to pH 3 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (192 mg, 85%): LC-MS (ES) m/z=255 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].[C:12]1([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH:1]([CH:4]1[CH2:5][C:6](=[O:11])[CH:7]([C:22](=[O:23])[NH:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:19])=[O:20])[C:8](=[O:10])[CH2:9]1)([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CC(C)C1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CC(C)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccccc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-isopropyl-1,3-cyclohexanedione with benzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ISOPROPYL-2-(N-BENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 112.5°-114° C. (corr.).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:13][C:12]#[CH:11])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: C#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCOc1ccc(C)cc1

Procedure:
To a solution of 10.8 g (0.1 mol) of p-cresol in 70 ml of absolute ethanol,there were added 4 g of sodium hydroxide. The reaction mixture was refluxeduntil complete dissolution and then treated with 16.36 g (0.1 mol) of propargyl bromide (80% in toluene). Reflux was resumed for 14 additional hours. The reaction mixture was then cooled, poured into water and extracted with hexane (3×100 ml). The combined organic extracts werewashed with 20% aqueous sodium hydroxide solution and water, dried over sodium sulfate and the solvent removed by evaporation. The residue was distilled at 102° C./15 mm to yield 3-(p-methylphenoxy)-1-propyne, identical to an authentic sample.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1([P:23](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][PH3+:23])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CNS(=O)(=O)c1ccc(CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)CNS(=O)(=O)c1ccc(C[PH3+])cc1
Product: [Br-]
Yield: 156.5 %

Procedure:
A mixture of 4-bromomethyl-N-isobutyl-benzenesulfonamide (1.08 g, 3.53 mmol) and triphenylphosphine (1.39 g, 5.29 mmol) in toluene (20 mL) was heated at reflux for 18 hours. The precipitate was collected from the cooled mixture, washed with toluene and air dried to give 4-isobutylsulfamoyl-benzyl-phosphonium bromide (1.88 g, 94%). 1H NMR (300 MHz, DMSO) δ 7.96-7.88 (m, 2H), 7.79-7.56 (m, 15H), 7.20-7.13 (m, 2H), 5.29 (d, J=16.1 Hz, 2H), 2.53-2.46 (m, 2H), 1.64-1.48 (m, 1H), 0.77 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 488.1 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][CH:9]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:30]=[N:31][CH:32]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Yield: 16 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with 5-chloropyridin-3-ylboronic acid yielded the title compound (16% yield) as a grey solid. MS (ISP): m/z=442.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(Sc2ccccc2)c(Cl)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Yield: 74.1 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 6.07 g (25.6 mmol) 3-chloro-4-thiophenoxyaniline was heated to reflux under N2. Removed heat at about 8 hours, made basic with saturated sodium bicarbonate, stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Dissolved nearly completely in 400 ml ethyl acetate, stirred with Darco and filtered. Stripped solvent and boiled in hexane to remove last of the excess aniline. Dried in vacuo, giving 6.90 g of red solid: mass spectrum (electrospray m/e): M+H=433.1, 435.1.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1.N>ClCCl>[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1
Reactant: COc1ccc2c(N)nccc2c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Nc1nccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.2 %

Procedure:
A solution of boron tribromide (18.2 mL; 370 mmol) in 20 mL of dichloromethane was added dropwise to a stirred solution of 1-amino-6methoxy-isoquinoline (1d, 11.0 g; 63 mmol) in 150 mL of dichloromethane at 10° C. After stirring for 4 d at ambient temperature the reaction mixture was poured into ice and the pH was adjusted to 9 by adding concentrated aqueous ammonia. The precipitated material was collected by filtration and dried in vacuo to give 8.9 g (88%) of the title compound as a white solid; m.p. 258-260° C.; El-MS: 160 (M+). 1H NMR (DMSO-d6): δ 8.11 (d, 1H), 7.65 (d, 1H), 6.99 (dd, 1H), 6.86 (d, 1H), 6.80-6.63 (m, 4H), 5.2 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:28][N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH:25]1([C:21]2[CH:22]=[C:23]([CH3:24])[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:32][CH2:33][N:29]([CH3:28])[C:30]5=[O:34])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2C#N)CC1
Yield: 81.9 %

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 189 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (364 mg) was obtained.
Reaction SMILES: [CH:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:20](=[O:21])[C@@H:9]2[N:8]([C@@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:32]1=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](C2CCCCC2)N1
Reactant: O=C=NCc1ccccc1
Product: O=C1[C@H]2Cc3c([nH]c4ccccc34)[C@H](C3CCCCC3)N2C(=O)N1Cc1ccccc1

Procedure:
The same method as employed in the preparation of Example 1 but starting from cis methyl 1,2,3,4-tetrahydro-1-cyclohexyl-9H-pyrido[3,4-b]indole-3-carboxylate (see J. Cook et al., Heterocycles, 4(7), 1249-1255 (1976)) and benzyl isocyanate gave after recrystallization from methanol, the title compound as white crystals m.p.: 170-173° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][CH:16]=[O:17])=[CH:10][CH:9]=1.[CH3:19][Mg]Br.[Cl-].[NH4+]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][CH:16]([OH:17])[CH3:19])=[CH:10][CH:9]=1
Reactant: C[Mg]Br
Reactant: CC(CC=O)c1ccc(-c2ccccc2F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)CC(C)c1ccc(-c2ccccc2F)cc1
Temperature: 0 °C

Procedure:
A solution of 96.9 gm (0.4 mol) of 3-(2'-fluoro-4-biphenylyl)-butanal (b.p. 112°-114°C at 0.04 mm Hg) in 200 ml of anhydrous ether was added dropwise to a stirred solution of 0.5 mol of methyl magnesium bromide in 200 ml of ether, and the resulting mixture was heated for two hours on a water bath, while stirring. Thereafter, the reaction mixture was cooled, then hydrolized by addition of 50 gm of crushed ice, and subsequently an aqueous 50% ammonium chloride solution was added until the initially formed precipitate dissolved again. The ethereal phase was separated, the aqueous phase was extracted twice with ether, the ethereal extracts were combined with the ether phase, thoroughly washed with water and dried over sodium sulfate, the ether was distilled off, and the residue was distilled in a high vacuum. 55.8 Gm (54% of theory) of a mixture of diastereoisomers of 4-(2'-fluoro-4-biphenylyl)-2-pentanol was obtained as a colorless oil having a boiling point of 122° -124°C at 0.06 mm Hg.
Reaction SMILES: [CH3:1]N(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+].O.[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH:24]1[C:33]2[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[N:31][N:30]([CH3:40])[C:29]=2[CH2:28][C:27](=[O:41])[CH2:26][CH2:25]1)[C:18]([OH:20])=[O:19]>C1COCC1.CCOCC>[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH:24]1[C:33]2[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[N:31][N:30]([CH3:40])[C:29]=2[CH2:28][C:27](=[O:41])[CH2:26][CH2:25]1)[C:18]([O:20][CH3:1])=[O:19]
Reactant: Cc1cc(C(=O)O)ccc1C1CCC(=O)Cc2c1c(-c1ccccn1)nn2C
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(C2CCC(=O)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
In an Erlenmeyer flask, 1-methyl-3-nitro-1-nitrosoguanidine (1.20 g, 8.16 mmol, TCI) was added portionwise to 45% KOH (10 mL)/H2O (5 mL) and Et2O (24 mL) at 0° C. The mixture was stirred until the yellow color of the ether layer did not change in intensity. The solution was poured into a separatory funnel and the aqueous layer was drained. The ether layer was poured into an Erlenmeyer flask and then decanted into another to remove some residual water. The yellow ether solution was poured slowly into a solution of 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoic acid (0.240 g, 0.639 mmol) in THF (12 mL) cooled to about 0° C. in an ice bath. The ice bath was allowed to melt. The mixture was diluted with THF (12 mL) and a nitrogen stream was blown over the surface until the solution turned from yellow to colorless. The mixture was concentrated in vacuo to give methyl 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoate (0.220 g, 88%): LC-MS (Table 1, Method g) Rt=2.09 min, m/z 390 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.30-8.24 (m, 1H), 7.71-7.64 (m, 2H), 7.62-7.57 (m, 1H), 7.45-7.41 (m, 1H), 7.08-7.01 (m, 1H), 6.73-6.69 (m, 1H), 5.30-5.26 (m, 1H), 4.28-4.17 (m, 1H), 3.96 (d, J=15.6 Hz, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 2.63-2.56 (m, 4H), 2.39-2.30 (m, 2H), 2.19-2.07 (m, 1H).