Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C:20]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]3)=[O:16])=[N:10]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])(=[O:53])[CH3:52]>CN(C=O)C.C(OCC)(=O)C>[C:55]([O:54][C:51](=[O:53])[CH2:52][N:5]1[CH2:4][CH2:3][C:2]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@H:17]3[C@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@:20]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]3)=[O:16])=[N:10]2)([OH:1])[CH2:7][CH2:6]1)([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC3(O)CCNCC3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC3(O)CCN(CC(=O)OC(C)(C)C)CC3)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(4-hydroxy-piperidin-4-ylmethyl)-1H-pyrazol-3-yl]-amide (80 mg, 0.12 mmol) was dissolved in DMF (3 mL) with cesium carbonate (100 mg, 0.31 mmol) then t-butyl acetate (0.1 mL, 0.677 mmol) was added stirred 16 hours at 25° C. The reaction mixture was diluted with ethyl acetate and separated with water (3×), the organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by reverse phase column chromatography (20-95% acetonitrile/water) to yield compound rac-[4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidin-1-yl]-acetic acid tert-butyl ester (68 mg, 74.7%).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=4[C:38]([O:40]C)=[O:39])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=4[C:38]([OH:40])=[O:39])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3C(=O)OC)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3C(=O)O)oc2C)c(OC)c1)OCC
Yield: 67 %

Procedure:
To a mixture of methyl 2-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 2-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless amorphous form (0.26 g, yield 67%).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)([O:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Yield: 95 %

Procedure:
This compound was synthesized as a colorless oil from cyclopentylmethanol (235.0 mg, 2.35 mmol), TsCl (581.5 mg, 3.05 mmol), Et3N (473.2 mg, 4.70 mmol), and DMAP (287.1 mg, 2.35 mmol) in 95% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.77 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 3.88 (d, J=7.1 Hz, 2H), 2.44 (s, 3H), 2.18 (dt, J=15.0, 7.5 Hz, 1H), 1.80-1.62 (m, 2H), 1.62-1.41 (m, 4H), 1.25-1.09 (m, 2H); 13C NMR (100 MHz, CDCl3, δC) 144.83, 133.40, 130.02, 128.07, 74.51, 38.79, 29.19, 25.45, 21.86. ESI-MS: 255.1 (M+H+), 277.1 (M+Na+).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[CH2:11]([C:18]1[O:19][CH:20]=[C:21]([CH2:23]O)[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([C:18]1[O:19][CH:20]=[C:21]([CH2:23][Cl:3])[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCc1coc(Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 13 g of thionyl chloride in toluene was added dropwise over 15 minutes to a mixture of 15.8 g pyridine and 18.8 g 2-benzyl-4-hydroxymethylfuran, in toluene, at a temperature of 0°-5° C. The mixture was slowly warmed to 80° C. and stirred for 11/2 hours and then cooled in an ice-bath, poured into ice and filtered. The resulting solution was extracted with diethyl ether, washed with water and then with sodium bicarbonate solution, and dried over magnesium sulphate. The solution was then stripped of solvent, yielding a brown oil, which was chromatographed over silica gel using toluene as eluent to give 2-benzyl-4-chloromethylfuran (1A) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Temperature: 140 °C

Procedure:
A mixture of 98.3 g (0.504 mol) of methyl 4-methyl-3-nitrobenzoate, 78.0 g (0.655 mol) of N,N-dimethylformamide dimethylacetal and 1 1 of dimethylformamide was heated to 140° C. for 3 hours. The solvent was distilled off in vacuo, the residue was triturated thoroughly with 1 1 methanol. After drying in vacuo 119.5 g (94.7% of theory) of a red amorphous substance was obtained, which was further processed without any more purification.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]2[N:11]([CH:15]=[N:16][CH:17]=2)[CH:12]=[CH:13][CH:14]=1)=[O:4]>C(O)C.[OH-].[Na+].O>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]2[N:11]([CH:15]=[N:16][CH:17]=2)[CH:12]=[CH:13][CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCc1cccn2cncc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCc1cccn2cncc12

Procedure:
A solution of 8-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine (30 mg) in 0.3 ml of ethanol and 0.3 ml of 1 N sodium hydroxide is refluxed for 2 hours, cooled, diluted with 2 ml of water and extracted with ethyl acetate (1×5 ml). The aqueous phase is brought to pH=6 and is extracted with methylene chloride (4×10 ml). The extracts are dried and evaporated to yield 8-(4-carboxybutyl)imidazo[1,5-a]pyridine, melting at 195°-197°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22](N(C2CC2)CC2C=CC(OC)=CC=2)[C:23]2[N:24]([C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[N:25]=1>CO>[Cl:19][C:20]1[CH:21]=[C:22]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:23]2[N:24]([C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[N:25]=1
Reactant: COc1ccc(CNCCN2CCOCC2)cc1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CO
Product: COc1ccc(CN(CCN2CCOCC2)c2cc(Cl)nn3c(C#N)cnc23)cc1

Procedure:
17A was prepared from 1F and N-(4-methoxybenzyl)-2-(4-morpholinyl)ethanamine following the procedure employed in the preparation of 1G. HPLC: Rt=2.95 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=427.1 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[O:14]=[C:13]1[NH:8][C:7]2[C:6](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:1]2[CH:2]=[CH:3][CH:4]=[C:5]12
Reactant: Nc1ccccc1-n1cccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2n2cccc12

Procedure:
15 g (0.095 mol) of 2-(1-pyrrolyl)aniline is brought to reflux for 1 h 30 min, in 200 cm3 of toluene, in the presence of 50 cm3 of a 20% solution of phosgene in toluene. After cooling, the precipitate formed is filtered off, washed with ethyl ether, dried and recrystallized from acetonitrile (white powder sublimed at 270° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][C:10]([CH3:18])=[N:11][C:12]=1[NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CC(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]1[N:13]([C@H:14]([CH3:17])[CH2:15][OH:16])[C:12]2[C:7]([N:6]=1)=[C:8]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)[N:9]=[C:10]([CH3:18])[N:11]=2
Reactant: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(N[C@H](C)CO)n1
Reactant: CN1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n([C@H](C)CO)c2n1
Temperature: 160 °C

Procedure:
Combine 2-chloro-N-[4-chloro-6-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]-2-methyl-pyrimidin-5-yl]benzamide (13.0 g), IPA (11 mL), of N-methylpiperizine (7.1 mL) and diisopropylethylamine (7.0 mL) in a 300 mL Parr autoclave with mechanical stirrer. Seal the reaction vessel and heat to 160° C. for 24 h. Evaporate all volatile materials, dissolve in dichloromethane (100 mL) to give a dark solution. Wash with water (2×50 mL), dry using a hydrophobic frit, and evaporate all the solvent under reduced pressure. Take the resulting solid and dissolve in acetonitrile (85 mL) and stir. After 1.5 h collect the solids by filtration and air dry, before dying under vacuum to provide the title compound (10.73 g). Determine optical purity by chiral SFC to show a single enantiomer. ES/MS m/z 401.2 (M+1). Chiral HPLC conditions: Diacel AD-H, 10% IPA, 0.2% isopropylamine, 89.8% supercritical carbon dioxide, UV (220 nm), TR=4.22 min, 100% ee.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[CH:11][C:12]3[CH:13]=[C:14]4[C:20]([C:21]5[CH2:22][N:23]([CH3:26])[NH:24][CH:25]=5)=[CH:19][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]4=[N:16][CH:17]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:20]([C:21]5[CH2:22][N:23]([CH3:26])[NH:24][CH:25]=5)=[CH:19][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:15]4=[N:16][CH:17]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CN1CC(c2cn(COCC[Si](C)(C)C)c3ncc(C=C4CCC5(CC4)OCCO5)cc23)=CN1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CC(c2cn(COCC[Si](C)(C)C)c3ncc(CC4CCC5(CC4)OCCO5)cc23)=CN1
Reaction time: 48 h
Yield: 79 %

Procedure:
To a solution of 86 (389 mg, 0.81 mmol) in MeOH (15 mL) was added 20% Pd(OH)2 on carbon (50 mg, cat.), and the reaction mixture was stirred vigorously under H2 for 48 h. The mixture was then filtered through Celite, which was then washed with MeOH:CH2Cl2=1:1 (v/v; 200 mL). The solutions were combined and concentrated to afford 87 as a clear oil (307 mg, 0.64 mmol, 79%). 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.99 (t, J=8.1 Hz, 2H), 1.34-1.46 (m, 2H), 1.56 (dt, J=13.9, 4.8 Hz, 2H), 1.61-2.12 (m, 5H), 2.74 (d, J=7.1 Hz, 2H), 3.64 (t, J=8.3 Hz, 2H), 4.00 (s, 4H), 4.07 (s, 3H), 5.76 (s, 2H), 7.47 (s, 1H), 7.70 (s, 1H), 7.82 (s, 1H), 7.88 (s, 1H), 8.23 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](N1CCN(C2C(Cl)=CN=CC=2Cl)CC1)(=[O:10])=[O:9].[Cl:25]C1C=NC=C(Cl)C=1N1CCNCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([Cl:25])(=[O:10])=[O:9]
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: O=S(=O)(c1ccccc1Cl)N1CCN(c2c(Cl)cncc2Cl)CC1
Product: O=S(=O)(Cl)c1ccccc1Cl
Yield: 59 %

Procedure:
In an analogous manner to Example 1F, step 1Q 1-[(2-chlorophenyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43 mmol) and 2-chlorobenzene sulfonyl chloride (59% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([N:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[N:38][CH:39]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:39]=[N:38][C:37]([N:40]5[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]5)=[N:36][CH:35]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(N6CCN(C(=O)OC(C)(C)C)CC6)nc5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate, (Frontier., Cat. P1821). LCMS (M+H)+: m/z=587.5.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1cnc2cn[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.7 %

Procedure:
To a solution of methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate (3.52 g, 20 mmol) in methanol (250 mL) and water (190 mL) at 0° C. was added aqueous sodium hydroxide (2M, 64 mL, 128 mmol), dropwise. The suspension was then allowed to warm to ambient temperature and stirred for 18 hours. The methanol was then removed in vacuo and the aqueous mixture extracted with ethyl acetate (250 mL). The aqueous layer was acidified (to pH 5-6) with 2 N aqueous hydrochloric acid (70 mL). The cream solid which had precipitated out was then filtered off and dried in a desiccator to yield the title compound (0.675 g, 21%). 1HNMR (400 MHz, DMSO-d6, δ): 8.97 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:31])[C:6](=[O:30])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[CH:11][C:10]([O:26][CH3:27])=[C:9]([O:28][CH3:29])[CH:8]=2)(O)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C)C=O.C(OCC)(=O)C.O>[CH3:27][O:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:28][CH3:29])[C:6](=[O:30])[N:5]([CH3:31])[C:4]([C:1]([CH:59]1[O:60][CH2:61][CH2:62][NH:57][CH2:58]1)=[O:2])=[C:13]2[C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)n(C)c(=O)c2cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)C3CNCCO3)n(C)c(=O)c2cc1OC
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of the compound obtained in Example 128 (1.50 g), 1,3-dicyclohexylcarbodiimide (793 mg) and 1-hydroxybenzotriazole (588 mg) in dimethylformamide (30 ml) is stirred at room temperature for one hour, and thereto is added morpholine (335 mg), and the mixture is stirred for two hours. The mixture is further stirred at 50° C. for four hours. To the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether-ethyl acetate to give 6,7-dimethoxy-2-methyl-3-morphlino-carbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (893 mg) as listed in Table 12.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(F)n2)CC1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(F)n2)CC1

Procedure:
A solution of tert-butyl 4-cyano-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (250 mg, 0.82 mmol) in methanol (20 mL) with triethylamine (1 mL) was reacted with Raney nickel (0.5 mL of 50% slurry in water) under 40 psi hydrogen for 5 hours. The catalyst was filtered off and washed thoroughly with methanol. Evaporation of the solvent afforded the desired product: tert-butyl 4-(aminomethyl)-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate: m/z (ES) 310 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(O)c(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a solution of example 84 (0.100 g, 0.190 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 1 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale green solid (0.061 g, 63% yield). MP: 244-247° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.19(s,1H), 8.04(s, 1H), 8.04(dd, J=8.0,1.4 Hz, 1H), 7.85(m,1H), 7.68(d, J=8.4Hz, 1H), 7.52(t, J=7.2Hz, 1H), 7.33(m,2H), 7.24(dd, J=8.2,1.4 Hz, 1H), 7.09-6.91(m,4H), 6.00(q, J=7.0 Hz, 1H),1.88(d, J=7.0 Hz, 1H). Mass: 511.94(M+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([C:15]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)([CH:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=1[OH:32])[CH2:19][CH:20]=[CH2:21])[CH2:16]O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1.O1CCOCC1>[CH2:13]([C:15]1([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=2)[CH:18]([CH2:19][CH:20]=[CH2:21])[C:22]2[C:23](=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=2)[O:32][CH2:16]1)[CH3:14]
Reactant: C=CCC(c1ccc(OCOC)cc1O)C(CC)(CO)c1ccc(OCOC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCC1c2ccc(OCOC)cc2OCC1(CC)c1ccc(OCOC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A 40% solution of diethyl azodicarboxylate in toluene (21.9 ml) was added dropwise to an ice-cold solution of (2RS,3RS)-2-ethyl-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxy-phenyl)-5-hexenol (9.5 g) and triphenylphosphine (15.0 g) in dry 1,4-dioxane (150 ml) over 25 minutes under nitrogen atmosphere. The reaction mixture was stirred for 10 minutes on ice and for 30 minutes at room temperature. Under ice-cooling, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and then concentrated to give a crude product, which was then purified by flash column chromatography (silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=50/1→20/1→10/1) to give (3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman (8.4 g, Yield 92.6%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:32]1([C:38]#[CH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CCOC(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.[Cu](I)I>[F:1][C:2]1[C:3]([C:39]#[C:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(C#Cc2ccccc2)cc1=O)S(C)(=O)=O
Yield: 82.8 %

Procedure:
A solution of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (500 mg, 1.12 mmol) and diisopropylethylamine (6.0 mL, 30 mmol) in tetrahydrofuran (15 mL) was degassed with nitrogen. Pd(PPh3)4 (65.4 mg, 0.056) and copper iodide (21.8 mg, 0.112 mmol) were added to the solution, followed by phenylacetylene (150 uL, 1.4 mmol). The reaction was allowed to stir until complete via TLC. The reaction was diluted with EtOAc (100 mL) and washed with saturated aq NH4Cl (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude residue was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in hexanes (30-80%) to afford the title compound as a yellow solid (389 mg, 82.6%). MS (LCMS) m/z 420.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.35 (t, 3 H) 1.75 (s, 3 H) 2.42-2.61 (m, 2 H) 3.11 (s, 3 H) 3.91-4.00 (m, 1 H) 4.19-4.27 (m, 1 H) 4.30 (q, J=7.02 Hz, 2 H) 6.72 (d, J=6.63 Hz, 1 H) 7.27 (t, J=2.34 Hz, 2 H) 7.35-7.44 (m, 2 H) 7.55-7.60 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[OH:24][CH2:23][CH2:22][C:19]1[N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]2=[N:21][N:20]=1
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated with repeated additions of paraformaldehyde in an oil bath to give 1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.