Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:26])[C:7]([S:15][C@@H:16]1[CH2:20][NH:19][C@H:18]([CH2:21][O:22][CH2:23][CH2:24][OH:25])[CH2:17]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:34](=[NH:39])(OCC)[CH3:35].Cl>P([O-])([O-])([O-])=O>[C:34]([N:19]1[CH2:20][C@@H:16]([S:15][C:7]2[C@H:6]([CH3:26])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:17][C@H:18]1[CH2:21][O:22][CH2:23][CH2:24][OH:25])(=[NH:39])[CH3:35]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCO)C3)[C@H](C)[C@H]12
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Product: CC(=N)N1C[C@@H](SC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)C[C@H]1COCCO
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(2-hydroxyethyloxymethyl)pyrrolidin-4-ylthio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (300 mg) in 0.05M phosphate buffer (pH 7, 30 ml) was adjusted to pH 8.5 with 30% potassium carbonate at 0° C., and ethyl acetimidate hydrochloride (3 g) was added in portions, while adjusting the mixture to around pH 8.5. After stirring for 1 hour, the reaction mixture was neutralized with 1N hydrochloric acid and washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" eluting successively with water and 5% aqueous acetone. The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-1-acetimidoyl-2-(2-hydroxyethyloxymethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]- 4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (290 mg).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1>CN(C)C=O.[Pd]>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[CH:16][N:15]=2)=[N:6]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21
Yield: 78.5 %

Procedure:
Under an argon atmosphere, 225 mg (approx. 0.112 mmol) of the compound from example 107 were dissolved in 15 ml of dimethylformamide, admixed with 150 mg of 10% palladium on charcoal and hydrogenated under standard hydrogen pressure overnight. The reaction mixture was filtered through Celite and concentrated, and the residue was purified by means of preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, gradient 60:35:5→35:60:5). 33 mg of the title compound were obtained (76% of theory).
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]#[CH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.O>O1CCCC1>[C:6]1([C:12]#[C:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ICCCCCOC1CCCCO1
Reactant: C#Cc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
BuLi (33.3 mL, 50 mmol, 1.5 M) was added in drops to a magnetically stirred solution of phenyl acetylene (5.11 g, 50 mmol) in dry tetrahydrofuran (200 mL) at 0° C. in a nitrogen atmosphere. After all the BuLi had been added, the reaction mixture was stirred at 0° C. for 30 minutes. A solution of 2-(5-iodpentyloxy)tetrahydro-2H-pyrane (9) (14.91 g, 50 mmol) in dry tetrahydrofuran (100 mL) was added in drops at 0° C. Adding completed, the reaction mixture was allowed to reach room temperature in order then to be refluxed over night. The reaction was monitored by thin-layer chromatography (TLC). When all the base material had been converted, water (300 mL) was added and the aqueous phase was extracted with petroleum ether (boiling point 40-60° C.) (6×50 mL). The combined organic phases were washed with water (4×25 mL) and dried (MgSO4). Petroleum ether was distilled out on a rotary evaporator, yielding 11.6 g (85%). NMR indicated a pure product, and further purification was therefore not necessary.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+]([O-])=O)[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].[N+:36](C1C=CC(C(Cl)=O)=CC=1)([O-:38])=[O:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([N+:36]([O-:38])=[O:37])=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
3,4-Dimethoxy-4′-nitrobenzophenone was prepared analogously to 3,4-dimethoxy-3′-nitrobenzophenone using veratrole (3.8 mL, 30 mmol), aluminum chloride (4.4 g, 33 mmol) and 4-nitrobenzoyl chloride (5.7 g, 30 mmol) with a reaction time of 48 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 1.69 g (78%) of the product as a white solid: mp 172-173° C.; 1H NMR (CDCl3) δ 8.43-8.31 (m, 2 H), 7.97-7.86 (m, 2 H), 7.55-7.46 (m, 1 H), 7.40-7.30 (m, 1 H), 7.00-6.89 (m, 1 H), 3.99 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ 193.4, 153.8, 149.4, 149.3, 143.8, 130.2, 130.0, 125.8, 123.4, 111.7, 109.9, 56.1, 56.0; Anal. Calcd for C15H13NO5. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.49; H, 4.68; N, 4.86.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[S:32][CH:31]=[N:30][C:29]=4[CH:33]=3)=[N:11][CH:12]=[C:13]([C@H:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:23])[CH3:16])[CH:14]=2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[S:32][CH:31]=[N:30][C:29]=4[CH:33]=3)=[N:11][CH:12]=[C:13]([C@H:15]([N:17]3[CH2:22][CH2:21][N:20]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:19][C@@H:18]3[CH3:23])[CH3:16])[CH:14]=2)[N:3]=1
Reactant: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCNC[C@@H]3C)cnc2Nc2ccc3scnc3c2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cnc2Nc2ccc3scnc3c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.1 %

Procedure:
A mixture of N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((R)-1-((S)-2-methylpiperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.100 g, 0.217 mmol) in THF (5 mL) was chilled to 0° C. in an ice bath, then sodium carbonate (0.115 g, 1.083 mmol) was added to the mixture while stirring. After 10 min, methanesulfonyl chloride (0.051 mL, 0.650 mmol) was added into the mixture slowly via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (25 g), eluting with a 20% mixture of 10:1 methanol/ammonium hydroxide in dichloromethane to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((R)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.012 g, 0.022 mmol, 10.26% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H) 8.92 (s, 1H) 8.65 (s, 1H) 8.60 (s, 1H) 8.26 (d, J=2.35 Hz, 1H) 7.79-7.83 (m, 1H) 7.72 (dd, J=8.61, 1.56 Hz, 1H) 5.55 (s, 2H) 4.05 (q, J=7.04 Hz, 1H) 3.21 (s, 2H) 3.11 (s, 1H) 2.87 (s, 2H) 2.61-2.73 (m, 4H) 2.47-2.60 (m, 4H) 1.34-1.46 (m, 3H) 1.02-1.22 (m, 3H). m/z (ESI, +ve ion) 540.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH3:10])=[O:4].CCN(C(C)C)C(C)C.[CH2:22]([O:29][C:30](N1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30](=[O:31])[N:8]([CH2:9][CH3:10])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:11])([F:12])[F:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNCCNC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
A solution of compound M (24.6 g, 82.4 mmol) and DIEA (14.3 ml, 82.4 mmol) in THF (100 ml) was cooled to ˜5° C., followed by the addition of a solution of N-(benzyloxycarbonyl)succinimide (20.3 g, 81.6 mmol) in THF (75 ml) dropwise over 20 min The temperature of the reaction mixture was raised to room temperature and stirring was continued for an additional 30 min. Solvents were evaporated and the residue was dissolved in EtOAc (500 ml). The organic layer was extracted with 5% aqueous NaHCO3 (2×100 ml) and brine (100 ml). The organic layer was evaporated to provide compound N (24.9 g, 78.2 mmol) as yellowish oil. LC-MS [M+H] 319.0 (C14H17F3N2O3+H, calc: 319.2). Compound N was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][OH:14])=[N:3][CH:4]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(NCCO)nc1
Yield: 64.4 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with 2-aminoethanol (213 mg, 3.5 mmol) followed by reduction to afford the desired product (306 mg, 65%) as a purple solid: ESI MS m/z 154 [C7H11N3O+H]+.
Reaction SMILES: [O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:8]4[CH2:7][CH:6]5[O:1][CH2:2][CH2:3][O:4][CH:5]5[CH2:9]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCCl
Reactant: C1COC2CNCC2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CC2OCCOC2C1
Temperature: 70 °C
Yield: 18 %

Procedure:
A mixture of hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (0.39 g, 3.0 mmol, 1.0 eq), N-(4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (868 mg, 2.40 mmol, 0.80 eq), anhydrous K2CO3 (2.07 g, 15.0 mmol, 5.0 eq) and tetrabutylammonium iodide (55 mg, 0.15 mmol, 0.05 eq) in DMF (10 mL) was heated at 70° C. for 11 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The resulted mixture was diluted with EtOAc (20 mL) and the organic phase was separated from the mixture. The water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (196 mg, 22.00%), HPLC:96.21%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 455.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.00 (2H, m), 2.63 (2H, m), 2.72 (2H, m), 2.90 (2H, dd, J=2.8, 6.1 Hz), 3.28 (1H, br s), 3.52 (2H, m), 3.76 (2H, m), 3.91 (3H, s), 4.05 (4H, d, J=4.4 Hz), 7.03 (1H, t, J=8.4 Hz), 7.18 (1H, s), 7.29 (1H, s), 7.63 (1H, dd, J=4.8, 8.4 Hz), 8.42 (1H, br s), 8.60 (1H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:45]([CH3:46])=[CH:44][C:39]([O:40][CH2:41][C:42]#[N:43])=[CH:38][C:37]=1[CH3:47]>>[C:42]([CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:47])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:45]([CH3:46])[CH:44]=1)#[N:43]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC#N)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC#N)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(4-bromo-3,5-dimethylphenoxy)acetonitrile following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.71 min; Mass spectrum (ESI+): m/z=502 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][CH:4]=1.CS(C)=O.O.[C-:20]#[N:21].[K+]>CC(OC)(C)C.O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][CH:4]=[C:3]2[CH2:2][C:20]#[N:21])=[CH:8][CH:9]=1
Reactant: [C-]#N
Reactant: COc1ccc2cccc(CCl)c2c1
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2cccc(CC#N)c2c1
Temperature: 65 °C

Procedure:
To a solution of the compound obtained in Step B (100 g) in 30 mug of DMSO and 5 ml/g of water there are added 1.2 equivalents of potassium cyanide (37.8 g). The reaction mixture is heated to 65° C. and maintained at 65° C. for 3 hours. After returning to ambient temperature, an MTBE/water (1/1) binary system is added to the mixture. The aqueous phase is removed. The organic phase is washed several times with water and then with saturated NaCl solution. The solvents are distilled off and the title compound is obtained in a quantitative yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:32][O:33][CH2:34][C@@H:35]([NH:42][C:43]([NH2:45])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1>[CH3:32][O:33][CH2:34][C@@H:35]([NH:42][C:43]([NH:45][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC[C@@H](NC(=O)Nc1cc2c(cn1)c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
6-Chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Example 40, Step 1; 151 mg, 0.355 mmol), (S)-1-(2-methoxy-1-phenylethyl)urea (Intermediate 16B; 108 mg, 0.556 mmol), BrettPhos pre-catalyst (17.6 mg, 0.022 mmol), and cesium carbonate (337 mg, 1.034 mmol) were taken up in 1,4-dioxane (3.5 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 100° C. for 6 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave (S)-1-(2-methoxy-1-phenylethyl)-3-(3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C36H33N5O3 [M+1]+ 584. found 584.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](=O)([OH:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 18 h

Procedure:
4-Methyl-3-nitroaniline (5.0 g, 32.86 mmol) was dissolved in anhydrous THF (25 mL). t-Butyl bicarbonate (7.5 mL, 32.86 mmol) dissolved in anhydrous THF (25 mL) was added slowly to the reaction mixture, which was stirred at 65° C. for 18 hours. After the reaction was completed the remaining organic solvent was distilled under reduced pressure, and water was added thereto. The resulting yellow solid was filtered and dried to obtain the title compound without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][NH:9]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccccc2Cl)c1=O
Yield: 77.7 %

Procedure:
In the same manner as in Reference Example 63 and using (2-chlorophenyl)hydrazine•hydrochloride (5 g, 28 mmol), water (100 mL), potassium carbonate (8.5 g, 62 mmol) and diethyl ethoxymethylenemalonate (7.3 g, 34 mmol) as starting materials, the title compound (5.8 g, 78%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=C1Cc2[nH]c3cc(F)ccc3c2CCN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc2c3c([nH]c2c1)CCNCC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flask containing THF (10 mL) at −78° C. under argon was added a 1 M solution of iBU2AlH in CH2Cl2 (16.3 mL). After 5 min, a solution of 8-fluoro-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0.175 g, 0.80 mmol) in THF (16 mL) was added. The reaction mixture was allowed to warm to rt, stirred for 48 h, cooled to 0° C., then quenched with MeOH (4.5 mL). It was partitioned between CH2Cl2 and aqueous 1 M KO2CC(OH)C(OH)CO2Na. The CH2Cl2 extracts were washed with brine, dried, filtered, and concentrated to give a solid. The solid was purified by silica chromatography (92.5:7.5 CH2Cl2/satd NH3 in MeOH) to give the free amine. A solution of this amine (0.094 g, 0.46 mmol) in dry MeOH (4.0 mL) at rt under argon was mixed with a solution of fumaric acid (0.027 g, 0.23 mmol) in dry MeOH (2.2 mL). The turbid solution was stirred overnight at rt. The MeOH was evaporated. The residue was dissolved in hot MeOH, and the salt was permitted to crystallize. The crystalline salt was collected: mp 266° C.; MS (ESI+) m/z 205.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.94 (1H), 7.34 (1H), 7.00 (1H), 6.77 (1H), 6.40 (1H), 3.11 (4H), 2.91 (4H); Anal. C 63.90, H 5.83, N 10.63.
Reaction SMILES: [CH3:1][NH2:2].C([NH:6][C:7]1[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[N:9][N:8]=1)(=O)C>C1COCC1>[CH3:1][NH:2][S:12]([C:10]1[S:11][C:7]([NH2:6])=[N:8][N:9]=1)(=[O:14])=[O:13]
Reactant: CC(=O)Nc1nnc(S(=O)(=O)Cl)s1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nnc(N)s1
Temperature: 25 °C

Procedure:
Methylamine (2M in THF, 40 mmol) was added to a suspension of 5-acetylamino-1,3,4-thiadiazole-2-sulfonyl chloride (10 mmol) (prepared as described in Bioorg. Med. Chem. 5, 515, 1997) in THF (10 mL) at −20° C. The mixture was stirred at room temperature over night and evaporated to dryness. The crude methylsulfonamide was suspended in EtOH (15 mL) and added 4N HCl in dioxane (15 mL) and heated for 4 h at 80° C. and then cooled to room temperature and evaporated to dryness to give crude 5-amino-1,3,4-thiadiazole-2-sulfonic acid methylamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C(N)=O)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pd]
Solvent: CCO
Product: CC(C(N)=O)c1ccc(N)cc1
Yield: 100.4 %

Procedure:
2-(4-Nitrophenyl)propionamide (5.3 g) in ethanol (250 ml) was hydrogenated over palladium oxide on charcoal (5%, 0.5 g) at atmospheric pressure. The reaction was terminated after 1775 ml of hydrogen had been absorbed and the catalyst was removed by filtration. Removal of the solvent gave the title compound as a white solid (4.5 g), m.p. 120°-122°.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].Cl.[OH-].[NH4+:13]>>[O:10]=[C:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[NH:13][C:2]([CH3:3])([CH3:1])[CH2:4]1
Reactant: [NH4+]
Reactant: CC(C)=CC(=O)C=C(C)C
Agent: Cl
Agent: [OH-]
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 60 %

Procedure:
In a 500 mL erlenmeyer flask, 25 gm (0.182 moles) of phorone (Aldrich Chemical Company) and 250 mL of ammonium hydroxide are stirred in a water bath at 50° C. for 14 hours. Upon cooling in an ice bath, the reaction is acidified with conc. HCl and extracted (four times) with ether. The remaining water solution is first made basic with ammonium hydroxide, then saturated with NaCl and finally, extracted with ether. The ether solution is dried over anhydrous MgSO4 and evaporated to dryness, giving a pale yellow solid (I), (17 gm, 60%). A small portion of this material is recrystallized from cyclohexane, mp 34°-36° C. (lit. ref. 1) mp 35.5°-36° C.). The NMR and i.r. (1750 cm-1) confirm the presence of 4-oxo-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.Cl[C:30]1[C:31]2[N:32]([CH:36]=[N:37][N:38]=2)[CH:33]=[CH:34][N:35]=1>>[N:38]1[N:37]=[CH:36][N:32]2[CH:33]=[CH:34][N:35]=[C:30]([NH:2][CH2:3][C:4]3([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]4[C:13]([CH3:22])=[C:14]5[C:15](=[CH:20][CH:21]=4)[C:16](=[O:19])[O:17][CH2:18]5)[OH:11])[CH2:5]3)[C:31]=12
Reactant: Clc1nccn2cnnc12
Reactant: Cc1c([C@@H](O)CN2CCC(CN)(c3ccccc3)C2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCC(CNc3nccn4cnnc34)(c3ccccc3)C2)ccc2c1COC2=O

Procedure:
5-((1R)-2-(3-(([1,2,4]Triazolo[4,3-a]pyrazin-8-ylamino)methyl)-3-phenylpyrrolidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 5-[(R)-2-[3-(Aminomethyl)-3-phenylpyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 15] and 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]\[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(/C=C\c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a solution of methyl 4-[(Z)-2-(4-pyridyl)vinyl]-benzoate (570 mg) in methanol (5.7 ml) was added 10% palladium on carbon, and the mixture was stirred for 4 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was crystallized with n-hexane to give methyl 4-[2-(4-pyridyl)ethyl]benzoate (539 mg).