Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][C@H:28]([NH2:31])[C@H:27]([F:32])[CH2:26]2)=[CH:21][C:20]=1[O:33][CH3:34].Cl[C:36]1[N:41]=[C:40]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44][CH:43]=2)[C:39]([Cl:51])=[CH:38][N:37]=1>>[NH2:31][C@H:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:36]3[N:41]=[C:40]([C:42]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[NH:44][CH:43]=4)[C:39]([Cl:51])=[CH:38][N:37]=3)=[C:20]([O:33][CH3:34])[CH:21]=2)[CH2:26][C@H:27]1[F:32]
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCO
Product: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Yield: 34.9 %

Procedure:
1-Pentanol (2 mL) was injected into a microwave vial charged with p-toluenesulfonic acid (0.180 g, 0.95 mmol), (3R,4S)-1-(4-amino-3-methoxyphenyl)-3-fluoropiperidin-4-amine (Intermediate 48) (0.091 g, 0.38 mmol), and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 2) (0.1 g, 0.38 mmol). The reaction was microwaved at 140° C. for 1 h. The solution was concentrated under reduced pressure. The crude residue was dissolved in DCM (15 mL) and washed with a sat. Na2CO3 solution. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give a crude liquid. The crude material was purified using silica gel chromatography (2-10% MeOH and 1% NH4OH in DCM) to give the title product (0.062 g, 35.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.Cl[CH2:14]Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a suspension of 3-bromo-5-iodobenzoic acid (993 g, 3.04 mol) in methanol (6.0 L) was added hydrochloric acid (37%; 20.0 mL, 244 mmol). The mixture was heated to 70° C. After 72 h, the mixture was cooled to ambient temperature. Dichloromethane (2.5 L) was added and the mixture was partially concentrated. The suspension was filtered and the filtered cake was washed with cold methanol to give the title compound as a white solid (846 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20]C)=O)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.O.[NH2:23][NH2:24]>CCO>[NH2:1][C:2]1[C:3]([C:18]([NH:23][NH2:24])=[O:20])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCC(=O)N1CCC(c2cnc(N)c(C(=O)OC)n2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCC(=O)N1CCC(c2cnc(N)c(C(=O)NN)n2)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
Methyl 3-amino-6-(1-propanoyl-4-piperidyl)pyrazine-2-carboxylate (110 mg, 0.38 mmol) was suspended in EtOH (2 mL) and hydrazine hydrate (94 mg, 92 μL, 1.9 mmol) was added and the reaction mixture was heated at 70° C. for 1.5 h, followed by 16 h heating at 35° C. forming a thick yellow solid. The solid was isolated by filtration, washed with water (20 mL) and ethanol (40 mL). The solid was dried under high vacuum to yield 3-amino-6-(1-propionylpiperidin-4-yl)pyrazine-2-carbohydrazide (105 mg, 95%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.12 (s, 1H), 7.27 (bs, 2H), 4.57-4.43 (m, 3H), 3.94 (d, J=13.6 Hz, 1H), 3.33 (bs, 2H), 3.13-2.97 (m, 1H), 2.90-2.76 (m, 1H), 2.58 (t, J=11.7 Hz, 1H), 2.34 (q, J=7.4 Hz, 2H), 1.83-1.70 (m, 3H), 1.69-1.55 (m, 1H), 1.01 (t, J=7.4 Hz, 3H). LC/MS m/z 293.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:10]([F:11])=[C:9]([NH:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[C:7]([CH:32](OCC)[O:33]CC)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.CC#N>O>[NH2:12][C:9]1[C:10]([F:11])=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=[C:7]([CH:32]=[O:33])[CH:8]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C(C)(C)C)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1nc(C=O)cc(N)c1F
Yield: 76.2 %

Procedure:
Using the procedure for Example 12, 2-(tert-butyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2461 mg, 4.8 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-6-(tert-butyl)-5-fluoropicolinaldehyde (718 mg, 73.2%) as a white solid: mp 129-130° C.; 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.26 (d, J=6.3 Hz, 2H), 4.37 (s, 2H), 1.43 (d, J=1.5 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 193.06, 149.83 (d, J=14.8 Hz), 148.90 (d, J=253.5 Hz), 148.71 (d, J=5.5 Hz), 141.32 (d, J=12.6 Hz), 107.56 (d, J=3.7 Hz), 33.32 (d, J=1.4 Hz), 21.85 (d, J=1.2 Hz), 13.90; 19F NMR (376 MHz, CDCl3) δ −137.45 (d, J=4.6 Hz); HRMS-ESI (m/z) [M+H]+ calcd for C10H13FN2O, 196.1012. found, 196.0994.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][N+:23]([CH3:25])=[CH2:24].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:22][N:23]([CH2:25][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:2]=1[CH3:1])[CH3:24]
Reactant: C=[N+](C)C
Reactant: COC(=O)c1ccc(Cn2c(C)cc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C)c(CN(C)C)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
Methyl 4-((2-methyl-1H-indol-1-yl)methyl)benzoate 3 (0.500 g, 1.90 mmol) and dimethylformiminium chloride (0.200 g, 2.15 mmol) were heated to reflux in a solution of DCM (5 mL) and DMF (2 mL) for 20 h. The reaction was then cooled to RT and DCM (50 mL) was added along with sat. NaHCO3 (20 mL). The organic fraction was isolated and the aqueous solution was further extracted with DCM (2×20 mL). The combined organic fractions were washed with H2O (20 mL), brine (20 mL), dried with Na2SO4 and concentrated in vacuo. The desired product was purified via automated column chromatography method 2 (0.221 g, 37%). 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J=8.1 Hz, 2H), 7.69 (m, 1H), 7.14 (m, 3H), 7.02 (d, J=8.0 Hz, 2H), 5.38 (s, 2H), 3.90 (s, 3H), 3.62 (s, 2H), 2.35 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([C:10]1([CH2:27][CH2:28][OH:29])[C:23]2[CH:22]=[C:21]([Cl:24])[N:20]=[C:19]([F:25])[C:18]=2[O:17][C:16]2[C:11]1=[CH:12][C:13]([Br:26])=[CH:14][CH:15]=2)=[N+]=[N-]>C1COCC1>[NH2:7][C:10]1([CH2:27][CH2:28][OH:29])[C:23]2[CH:22]=[C:21]([Cl:24])[N:20]=[C:19]([F:25])[C:18]=2[O:17][C:16]2[C:11]1=[CH:12][C:13]([Br:26])=[CH:14][CH:15]=2
Reactant: [N-]=[N+]=NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of LAH (1.0 M solution in tetrahydrafuran; 90 ml, 90 mmol) in THF (50 mL) at rt was added drop wise a solution of 2-(5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (24 g, 60.1 mmol) in THF (150 mL). The resulting mixture was stirred at RT for 1 h. The reaction mixture was quenched with sodiumsulfate decahydrate and stirred for 30 min. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography (0-50% EtOAc/hexanes) to afford 2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (16.5 g, 44.2 mmol) as a colorless oil.
Reaction SMILES: N1C=CC=CC=1.F.[CH2:8]([N:10]([CH2:54][CH3:55])[C:11](=[O:53])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]1[C@@H:22](/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si](C(C)(C)C)(C)C)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:21]([O:39][Si](C(C)(C)C)(C)C)[CH2:20][C:19]=1[O:47][C:48](=[O:52])[CH2:49][CH2:50][CH3:51])[CH3:9]>>[CH2:54]([N:10]([CH2:8][CH3:9])[C:11](=[O:53])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]1[C@@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:21]([OH:39])[CH2:20][C:19]=1[O:47][C:48](=[O:52])[CH2:49][CH2:50][CH3:51])[CH3:55]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)N(CC)CC)=C(OC(=O)CCC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)N(CC)CC)=C(OC(=O)CCC)C[C@H]1O
Yield: 87.2 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.2 ml) and N,N-diethyl(11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienamide (169 mg), the same procedure as in Example 2 was performed to obtain N,N-diethyl(11R,12S,13E,15S)-9-butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienamide (101 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:15]([C:11]2[C:12]([CH3:14])=[CH:13][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=2)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccccc1-n1cc(C)c(C=O)n1
Solvent: C1CCOC1
Product: COc1ccccc1-n1cc(C)c(C(O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution (10 mL) of 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde (0.97 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (5.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.56 g, 40%) as a pale-yellow oil.
Reaction SMILES: [C:1]1(=O)[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1(=[N:15][OH:16])[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CCc2oc3ccccc3c21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: ON=C1CCc2oc3ccccc3c21
Yield: 101.2 %

Procedure:
A mixture of 2,3-dihydro-1H-cyclopenta[b]benzofuran-1-one (1.0g) and hydroxylamine hydrochloride (1.21g), in dry pyridine was stirred at 60° under nitrogen for 24h. The solution was poured into 8% sodium bicarbonate solution (150ml) and extracted with dichloromethane (3×50 ml). The combined extracts were washed with water (2×10 0 ml), dried, and evaporated to give the title compound (1.1 g) as a foam, t.l.c. (System B, 1:2) Rf 0.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][N:23]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:24]=1)=[CH:16][CH:15]=3
Reactant: ClCCN1CCOCC1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCN5CCOCC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 36, using compound 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from Example 39 above and chloroethylmorpholine
Reaction SMILES: COC1C=C2C(=CC=1OC)CNCC2.C([O:17][C:18](=[O:57])[C:19]([NH:49]C(OC(C)(C)C)=O)([CH2:33][CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([O:47][CH3:48])=[C:40]([O:45][CH3:46])[CH:41]=2)[CH2:36]1)[CH2:20][CH2:21][CH2:22][CH2:23][B:24]1[O:28]C(C)(C)C(C)(C)[O:25]1)C.[ClH:58]>O>[ClH:58].[ClH:58].[NH2:49][C:19]([CH2:33][CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([O:47][CH3:48])=[C:40]([O:45][CH3:46])[CH:41]=2)[CH2:36]1)([CH2:20][CH2:21][CH2:22][CH2:23][B:24]([OH:28])[OH:25])[C:18]([OH:57])=[O:17]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN1CCc2cc(OC)c(OC)cc2C1)NC(=O)OC(C)(C)C
Agent: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: O
Product: COc1cc2c(cc1OC)CN(CCC(N)(CCCCB(O)O)C(=O)O)CC2
Temperature: 25 °C

Procedure:
2-Amino-6-borono-2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-hexanoic acid dihydrochloride is prepared in a manner analogous to that set forth in Example 16, except 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is used as the amine in step 6. The final step is as follows: a solution of 2-tert-butoxycarbonylamino-2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (108 mg) in 6 N hydrochloric acid (5 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give the title compound as a colorless foam (66 mg); 1H NMR (D2O, 300 MHz) δ 6.75 (s, 1H), 6.66 (s, 1H), 4.39 (d, J=15 Hz, 1H), 4.14 (d, J=15 Hz, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.18-3.46 (m, 4H), 2.97 (m, 2H), 2.31 (t, J=8 Hz, 2H), 1.82 (m, 2H), 1.27 (m, 3H), 1.12 (m, 1H) and 0.64 (m, 2H); MS (+CI): m/z for C19H31BN2O6: expected 394.2. found 395.5 (M+H)+, 377.4 (M+H−H2O)+, 359.4 (M+H-2H2O)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:3]1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:14][N:3]1[C:2](=[O:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a mixture of 1,1-dimethylethyl 3-oxo-1-pyrazolidinecarboxylate (1.00 g, 5.37 mmol) and potassium carbonate (0.89 g, 6.44 mmol) in DMF (10 ml) was added iodomethane (2 M in MTBE, 3.22 ml, 6.44 mmol). The reaction mixture was stirred at rt for 2 h. LCMS indicated completion of the reaction. The mixture was diluted with ethyl acetate/hexanes (1:1, 150 ml) and washed with water (5×50 ml), brine (50 ml), dried (Na2SO4) and concentrated to provide 1,1-dimethylethyl 2-methyl-3-oxo-1-pyrazolidinecarboxylate (0.57 g, 53.0%). LCMS: (M+H)+ 201.0.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl.[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>COCCOC>[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(Nc1ccc(C(=O)Cl)cc1)C1CCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccc(NC(C)C2CCCC2)cc1

Procedure:
A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-(1-cyclopentylethylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords ethyl 2-[4-(1-cyclopentylethylamino)benzoyl]acetoacetate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([Cl:15])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc([N+](=O)[O-])c1
Product: O=C(Cl)c1ccnc([N+](=O)[O-])c1

Procedure:
1.8 g. of 2-nitroisonicotinic acid and 30 ml. of thionyl chloride were refluxed for 3 hours. An excess of thionyl chloride was distilled off to leave 2-nitroisonicotinoyl chloride as an oil. The obtained acid chloride was added to 5 ml. of pyridine at -15° C., and to the resulting solution was added 1.5 g. of m-toluylamide. The mixture was stirred at room temperature for one hour and the solvent was evaporated at 40° C under reduced pressure. The residue was then purified by silica gel chromatography and recrystallized from ethyl acetate-n-hexane to yield 250 mg. of the desired crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.[CH3:30][Mg]Cl.Cl.O.C([O-])(O)=O.[Na+]>O1CCCC1>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=[O:9])[CH3:30]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Into a microwave vial was placed a solution of tert-butyl 4-(8-chloro-6-{[methoxy(methyl)amino]carbonyl}imidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxylate (31 mg, 0.073 mmol) in anhydrous tetrahydrofuran (0.5 mL) under N2 at 0° C. A solution of 3.0 M methylmagnesium chloride in tetrahydrofuran (85 μL, 0.26 mmol) was added dropwise. The solution was stirred at 0° C. for 30 minutes. It was stirred for 2 hours at room temperature. The reaction solution was quenched at 0° C. with 1.0 M hydrogen chloride in water (0.5 mL, 0.5 mmol), poured into 25 mL of saturated NaHCO3 solution and was extracted into ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude which was purified on silica gel with ethyl acetate (0-60%) to give desired product (22 mg, 78%). LCMS calculated for C18H24ClN4O3 (M+H)+: m/z=379.2. found: 378.9.
Reaction SMILES: C(O)(=O)C.Cl.C(OC(=O)[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([S:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([NH:30]C(=O)C2C=CC=CC=2)=[N:25][CH:24]=[CH:23]3)[CH2:15][CH2:14]1)(C)(C)C>CO>[NH2:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([S:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([NH2:30])=[N:25][CH:24]=[CH:23]3)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Sc2ccc3c(NC(=O)c4ccccc4)nccc3c2)CC1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nccc2cc(S[C@H]3CC[C@H](N)CC3)ccc12

Procedure:
Potassium carbonate (160 mg) and methanesulfonic acid cis-4-tert-butoxycarbonylaminocyclohexyl ester (140 mg, 0.47 mmol) were added to a solution of N-(6-mercaptoisoquinolin-1-yl)benzamide residue in DMA (4 ml). The mixture was irradiated in a microwave at 120° C. for 600 s then concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give trans-[4-(1-benzoylaminoisoquinolin-6-ylsulfanyl)cyclohexyl]carbamic acid tert-butyl ester. Glacial acetic acid (1 ml) and 6M hydrochloric acid (2 ml) were added to the trans-[4-(1-benzoylaminoisoquinolin-6-ylsulfanyl)cyclohexyl]carbamic acid tert-butyl ester and the mixture was refluxed for 24 h. The mixture was then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and then eluted with 2M ammonia in methanol to give cude trans-6-(4-aminocyclohexylsulfanyl)isoquinolin-1-ylamine, which was further purified using prep-HPLC (9 mg), EIMS: m/z=274.5 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[C:3]=1[S:13](Cl)(=O)=O>O1CCCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[C:3]=1[S:13][S:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:5][C:4]=1[CH3:12]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)cc(C)c1SSc1c(C)cc(C(C)(C)C)cc1C
Temperature: 60 °C
Yield: 64.1 %

Procedure:
A two liter, three-neck flask, was obtained. A condenser with a drying tube, a thermometer, and a dropping funnel were each attached to the flask. Zinc dust (<10 micron, 43.6 g, 0.667 mol) and anhydrous tetrahydrofuran (400 mL) were added to the flask. The mixture was stirred and cooled on an ice-water bath and 58.6 ml (0.534 mmol) of titanium tetrachloride added drop wise (˜45 min). During the entire addition of titanium tetrachloride, the temperature of the mixture was maintained below 25° C. Once the addition was complete, a solution of 2,6-dimethyl-4-tert-butylbenzenesulfonyl chloride (69.48 g, 0.267 mol) in 200 mL of anhydrous tetrahydrofuran was added drop wise (˜60 min). During the entire addition of the material, the temperature of the mixture was maintained below 20° C. At the conclusion of the 2,6-dimethyl-4-tert-butylbenzenesulfonyl chloride addition, the ice-water bath was removed, the mixture was allowed to stir an additional 30 min. The mixture was then heated on an oil bath at 60° C. for 4 hours. The mixture was then cooled to room temperature and 800 mL of 1N hydrochloric acid and 300 mL of ice water added. The resultant pale yellow precipitates were collected by filtration and washed with water (300 mL×3). The precipitate was then dried under vacuum and the precipitates recrystallized from hexanes, giving 33.1 g bis(2,6-dimethyl-4-tert-butylphenyl)disulfide (see Formula III, Table 3). The yield of the reaction was 70% and the material had the following spectral data: 1H NMR (CDCl3) δ 7.04 (s, 4H, aromatic protons (Ar—H)), 2.23 (s, 12H, CH3), 1.30 (s, 18H, C(CH3)3).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C@@H:7]2[CH2:22][N:10]3[CH2:11][CH2:12][N:13]([CH2:15]C4C=CC=CC=4)[CH2:14][C@@H:9]3[CH2:8]2)=[CH:4][CH:3]=1.ClC1[N:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CC(O)C>CO.C([O-])=O.[NH4+].[Pd].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:22][N:10]3[CH2:11][CH2:12][N:13]([C:15]4[N:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=4)[CH2:14][C@@H:9]3[CH2:8]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(O[C@H]2C[C@H]3CN(Cc4ccccc4)CCN3C2)cc1
Reactant: Fc1cnc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: Fc1ccc(O[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.1 %

Procedure:
A solution of 0.83 g (2.5 mmol) of (7S,8aS)-7-(4-fluorophenoxy)-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine in 10 mL of methanol and 1.8 mL of aqueous ammonium formate (5 M) was treated with an aqueous slurry of 0.325 g of 10% palladium on carbon and the mixture was stirred at room temperature for 24 hours. The mixture was filtered through Celite, evaporated, re-evaporated with another 100 mL of chloroform, dissolved in 100 mL of chloroform, dried (magnesium sulfate), filtered and evaporated. The crude amine (0.61 g, ca. 2.5 mmol), 0.50 g (3.75 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), 0.86 g (6.2 mmol) of potassium carbonate and 15 mL of 2-propanol were refluxed for 5.5 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×). The combined organic phase was washed with water (2×) and brine (1×), dried (magnesium sulfate), filtered and evaporated. Purification by silica gel MPLC starting with 70:30 ethyl acetate:hexane and ramping to 50:50 ethyl acetate:hexane at 30 minutes, gave 0.30 g (36%) of the title compound. Mp (.HCl) 90-95° C. 13C NMR (base, CDCl3): δ 36.6, 43.6, 48.7, 60.5, 62.1, 75.6, 115.67, 115.98, 116.08, 116.18, 144.97, 145.26, 149.9, 153.2, 153.8, 155.6, 158.8. HRMS calc'd for C17H19F2N4O (MH+): 333.1527, found: 333.1556.