Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H].CC(C)=O.[ClH:24]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:24].[F:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: [H][H]
Reactant: Fc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: Fc1ccc2c(c1)CNC2
Temperature: 25 °C

Procedure:
A suspension of 20% palladium hydroxide on carbon (4.0 g) and N-benzyl-5-fluoroisoindoline (D7) (44.6 g) in ethanol (475 ml) and conc. hydrochloric acid (d=1.18, 25 ml) was stirred with hydrogen at 50 psi for 18 h at 45° C. The mixture was cooled to ambient temperature and filtered to remove the catalyst. The filtrate was evaporated in vacuo to give a solid which was stirred with acetone (300 ml) for 0.5 h and filtered to give the title compound (D8) as a solid (29.3 g). 1H NMR δ (D6-DMSO): 10.0 (2H, br, s), 7.41-7.46 (1H, m), 7.15-7.29 (2H, m), 4.49 (2H, s), 4.46 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([CH2:36][CH2:37][CH2:38][OH:39])[CH2:15][CH2:14][CH2:13][CH:12]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[Cl:27])[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=[CH:20]3)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:44].CO>C1COCC1>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([CH2:36][CH2:37][CH2:38][O:39][CH3:44])[CH2:9][CH2:10][CH2:11][CH:12]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[Cl:27])[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=[CH:20]3)[CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(CCCO)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCC1(NC(=O)OC(C)(C)C)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 405 mg (0.71 mmol) of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (59) in 5 mL of THF was dropped into a suspension of 31.3 mg (0.78 mmol) of sodium hydride (60%) in 5 mL THF at 0° C. 88.6 μL (1.42 mmol) of iodomethane were added, and after stirring for 1 h at room temperature another 88.6 μL (1.42 mmol). The reaction mixture was stirred at room temperature until LCMS indicated complete conversion, then 5 mL of methanol were added and the volatiles removed in vacuo. The crude material was purified by silica gel chromatography. 196 mg of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-methoxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (61) as diastereomeric mixture could be isolated. Rt=1.89 min, 2.02 min (Method I). Detected mass: 583.3 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:33][C@@H:34]2[C@@H:38]([OH:39])[CH2:37][CH2:36][O:35]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:33][C@@H:34]3[C@@H:38]([OH:39])[CH2:37][CH2:36][O:35]3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2OCC[C@@H]2O)cc1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3OCC[C@@H]3O)c3ccc(C#N)cc23)C1
Temperature: 65 °C
Yield: 72.7 %

Procedure:
A mixture of ((S)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (2.50 g, 8.82 mmol), [(2R,3S)-3-hydroxytetrahydrofuran-2-yl]methyl 4-methylbenzenesulfonate (3.10 g, 11.38 mmol), and cesium carbonate (5.00 g, 15.35 mmol) in N-methylpyrrolidine (25 mL) is heated in a 65° C. oil bath overnight. After cooling to ambient temperature, the reaction is diluted with ethyl acetate (120 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with ethyl acetate. Fractions containing pure product are combined and concentrated to afford 2.46 g (72%) of the title compound. LC-ES/MS m/z 384.2 [M+H]+, TR=1.90 min. (Symyx Draw 3.1 (IUPAC Name) provides the following name for the compound of Example 1: Isopropyl N-[(2S)-7-cyano-4-[[(2R,3S)-3-hydroxytetrahydrofuran-2-yl]methyl]-2,3-dihydro-1H-cyclopenta[b]indol-2-yl]carbamate.)
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:31][CH:32]2[CH2:36][CH:35]=[CH:34][CH2:33]2)(=O)=O)=CC=CC=1>>[CH:32]1([CH2:31][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC=CC2)c1
Yield: 62.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (cyclopent-3-en-1-yl)methyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][CH:23]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: COc1ccc(CN(CCNC(=O)OC(C)(C)C)Cc2cnc(Cl)s2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(CCN)Cc2cnc(Cl)s2)cc1

Procedure:
This compound was made in a manner analogous to that set forth in Step C of Example 1, using 0.3 gram (0.0007 mole) of (tert-butoxy)-N-(2-{[(2-chloro(1,3-thiazol-5-yl))methyl][(4-methoxyphenyl)methyl]amino}ethyl)carboxamide and 3 mL (excess) of trifluoroacetic acid in 20 mL of methylene chloride. The yield of subject compound was 0.20 gram. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[NH:12])SC)[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[NH2:15][NH2:16].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:12])=[N:15][NH2:16])[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14]
Reactant: NN
Reactant: CSC(=N)Nc1cc(Cl)c(C)c(Cl)c1
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)cc(NC(N)=NN)cc1Cl

Procedure:
To 7.18 g of 1-(2,6-dichloro-4-tolyl)-2-methylisothiourea.HJ (C), suspended in 26 ml of ethanol, 1.3 ml of hydrazine.hydrate is added after which the mixture is refluxed for 20 hours. The precipitate formed is filtered off and the filtrate evaporated to dryness. Yield: 6.35 g. Melting point HJ salt: 203°-205°C; melting point HCl salt: 149°-150°C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([OH:3])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>ClCCl>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:5][C:4]=1[C:1](=[O:3])[NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Yield: 95.3 %

Procedure:
Using methyl 3-(3-carboxy-4-methoxyphenyl)-2,2-dimethylpropanoate (204 mg, 0.766 mmol), triethylamine (135 ml, 0.969 mmol), ethyl chlorocarbonate (82.0 ml, 0.843 mmol), 4-(trifluoromethyl)benzylamine (120 ml, 0.842 mmol) and 8 ml of dehydrated dichloromethane and conducting the procedure similar to Example 7, 309 mg (95%) of the title compound were obtained as a colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:5].[OH-].[Na+]>O.C(O)C>[CH2:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:2][OH:3])=[CH:9][CH:8]=1)[CH3:5]
Reactant: CCOc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
A solution of 34.8 g of hydroxylamine hydrochloride in 50 ml of water was added in one portion to a solution of 37.5 g of 4-ethoxybenzaldehyde in 100 ml of ethanol in a 500-ml Erlenmeyer flask equipped with a magnetic stirrer. The reaction mixture was stirred for approximately 5 minutes, until clear. A room-temperature solution of 15.2 g of sodium hydroxide in 20 ml of water was added in several portions during 15 minutes. The reaction mixture was stirred for 5 minutes and then heated to boiling. After the cloudy reaction mixture had cooled to room temperature, water was added and product separated from solution as an oil. The mixture was extracted four times with 50-ml portions of chloroform. The chloroform extracts were combined, washed twice with 75-ml portions of saturated aqueous sodium chloride solution and dried over sodium sulfate. The dry chloroform solution was filtered, the filtrate was evaporated, and the residue crystallized with a slight amount of cooling. The crude solid was recrystallized from cyclohexane to give 35.4 g of 4-ethoxybenzaldoxime, m.p. 81°-86°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([N:3]([CH2:65][CH3:66])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:45])[N:20]([CH3:44])[CH2:21][CH2:22][N:23]([CH3:43])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:46]2[CH:51]=[C:50]([C:52](=[O:64])[NH:53][C@@H:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH2:57][CH2:56][CH2:55]3)[CH:49]=[CH:48][N:47]=2)[CH:5]=1)[CH3:2].[ClH:67]>O1CCOCC1>[ClH:67].[ClH:67].[ClH:67].[ClH:67].[NH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][N:23]([CH3:43])[CH2:22][CH2:21][N:20]([CH3:44])[C:19](=[O:45])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:65][CH3:66])=[CH:5][C:6]=2[C:46]2[CH:51]=[C:50]([C:52](=[O:64])[NH:53][C@@H:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH2:57][CH2:56][CH2:55]3)[CH:49]=[CH:48][N:47]=2)=[O:12])[CH:14]=1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN(C)CCOCCOCCOCCNC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN(C)CCOCCOCCOCCN)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
(S)-tert-Butyl 1-(3-(4-(diethylamino)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-2,5-dimethyl-1-oxo-8,11,14-trioxa-2,5-diazahexadecan-16-ylcarbamate Example 339 (1.08 g, 1.23 mmol) and hydrochloric acid in dioxane (4N, 20 mL) were stirred for 4 hours at room temperature and then evaporated to dryness to give the intermediate (S)—N1-(14-amino-3-methyl-6,9,12-trioxa-3-azatetradecyl)-N3-(4-(diethylamino)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)-NI-methylisophthalamide tetrahydrochloride 340a as a foam (1.2 g, quantitative); MS (ES, m/z): 808 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=1)=[O:11].Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=1)=[O:11]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2F)n(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
A mixture of N-(2-fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (9.80 g, 39.3 mmol), 5-bromo-2-nitropyridine (7.14 g, 35.1 mmol), cesium carbonate (14.8 g, 45.3 mmol) and N,N-dimethylformamide (80 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10→0/100) to give N-{2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.68 g, 59%) as a white solid. To a solution of N-{2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.68 g, 20.7 mmol) thus-obtained in methanol (50 mL) was added palladium carbon (50% water-containing product, 700 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (6.20 g, 88%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.B(O)(O)[C:17]1[CH:22]=[N:21][CH:20]=[N:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[N:19]1[CH:18]=[C:17]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccnc(-c3cncnc3)c2)cn1
Temperature: 95 °C
Yield: 21.7 %

Procedure:
A solution of Example A9 (0.25 g, 1.128 mmol) and pyrimidinyl-5-boronic acid (0.196 g, 1.579 mmol) in dioxane (8 mL) was treated with a solution of K2CO3 (0.156 g, 1.128 mmol) in water (2 mL), Pd(PPh3)4 (0.130 g, 0.113 mmol) and heated at 95° C. for 20 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2-(pyrimidin-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (65 mg, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 2H), 9.24 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.32 (dd, J=8.9, 3.0 Hz, 1H), 6.83 (dd, J=5.7, 2.4 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.04 (s, 2H); MS (ESI) m/z: 266.1 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N:42]=[N+:43]=[N-:44])(C)C>C1COCC1.CCOC(C)=O>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[N:44]=[N:43][N:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of 2-oxo-2-{[5-(trifluoromethyl)-2-pyridinyl]amino}ethyl acetate (Intermediate 56, 3.30 g, 12.6 mmol) in THF at 0° C. were added triphenylphosphine (8.24 g, 31.4 mmol) and diisopropyl azodicorboxylate (6.30 g, 31.2 mmol). The reaction mixture was stirred for 30 min and trimethylsilyl azide (3.60 g, 31.2 mmol) was added dropwise at room temperature. The reaction mixture was heated to reflux for 4 hr. The reaction mixture was diluted with EtOAc and washed with ice water, aq. NaHCO3 solution and saturated brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 mesh silica gel), eluting with 20% ethyl acetate/pet ether, to give the title compound (1.80 g) as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cncnc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (32 mg, 41%), MS (ISP) m/z=313.5 [(M+H)+], mp 306° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]1([S:16][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Sc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Sc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
To a solution of 4-phenylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.11 g, 3.45 mmol) in 10 mL of DCM, was added 2 mL of TFA. The reaction mixture was stirred at ambient temperature for 2.5 hours then solvent was removed by reduced pressure to yield the title product (0.75 g, 3.4 mmol). MS (ESI) m/z 221.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.29 min.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>>[C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:17][N:16]=2)(=[O:19])=[O:20])[CH:2]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1

Procedure:
prepared by reaction of m-tolylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O)=[O:25].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.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>[CH:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1)=[O:25]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C=O)c1
Yield: 40.5 %

Procedure:
To a solution of tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.600 g, 1.59 mmol) in DME (35 mL) was added 2-formyl-4-methoxybenzeneboronic acid (0.344 g, 1.91 mmol), tetrakis(triphenylphosphine)palladium(0) (0.110 g), barium hydroxide octahydrate (0.753 g, 2.39 mmol), and H2O (10 mL). The combined mixture was refluxed for 20 h. Once at room temperature, the mixture was taken up in H2O (300 mL) and extracted with EtOAc (3×100 mL). The combined extracts were dried over MgSO4 and stripped of solvent under reduced pressure. Purification by normal phase HPLC using 25% EtOAc in hexanes afforded 0.280 g (41%) of tert-butyl (6aS,10aR)-2-(2-formyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-2-ylmethyl-ethylamine (1.06.; 3.2 mmol, from Example 13) in dichloromethane (40 mL) at 0° C. was added triethylamine (0.90 mL; 6.5 mmol) and a solution of 1-methyl-1-cyclohexanecarbonyl chloride (520 mg.; 3.2 mmol) in dichloromethane (6 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to yield the free base of the title compound as a clear oil (1.0 g.; 70%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as a white amorphous solid, m.p. 135–139° C.; MS (+) FAB [M+H]+ @ m/z 451; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2.C4H4O4 Calculated: C, 65.70; H, 7.47; N, 9.89 Found: C, 65.29; H, 7.69; N, 9.77
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:5]([NH:8]C=O)([CH3:7])[CH3:6].Cl.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:5]([NH2:8])([CH3:6])[CH3:7]
Reactant: CC(C)(NC=O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(N)c1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
A mixture of 1.16 g (5 mmol) of N-(3,5-dichloroα,α-dimethylbenzyl)formamide and 8 ml of 2N hydrochloric acid was refluxed for 30 minutes. After cooling, the reaction solution was alkalified with a sodium hydroxide aqueous solution and extracted with diethyl ether. The ether solution was washed with water, dried and then concentrated to obtain 1.0 g (yield: 98.0%) of the desired compound.