Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCCN1CCCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)piperidine
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9].[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:19]=1[S:28]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:30])=[O:29]
Reactant: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)C[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
To a solution of (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 13) (200 mg, 0.912 mmol) in DCM (10 mL) was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (295 mg, 0.912 mmol) followed by DIPEA (0.159 mL, 0.912 mmol). The reaction mixture was left stirring at room temperature for 15 h. The solvent was removed by evaporation and the crude residue was dissolved in DCM (30 ml), washed with saturated sodium bicarbonate (40 ml), dried (hydrophobic frit) and evaporated under vacuum. The crude product was purified by silica chromatography using a gradient EtOAc/iso-hexane from 20/80 to 100/0. The desired fractions were combined and concentrated under vacuum to give the title compound (216 mg).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([O:19]C(C)(C)C)=O)[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:39](=[O:51])([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[O:40][CH:41](Cl)[CH3:42].[NH:52]1[CH:56]=[C:55](C(O)=O)[N:54]=[N:53]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(N(C)C)=O>[CH:45]1([O:44][C:39]([O:40][CH:41]([O:13][C:11](=[O:12])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:56]2[NH:52][N:53]=[N:54][CH:55]=2)=[O:19])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:6][CH:5]=2)[CH3:42])=[O:51])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: O=C(O)c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC(OC(=O)OC1CCCCC1)OC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (50 mg, 120 μmol, 1.0 eq.), DMA (1 mL), DIPEA (0.13 mL, 0.75 mmol) and 1-chloroethyl cyclohexyl carbonate (52 mg, 250 μmol, 2.0 eq.) were combined. The reaction vessel was capped and microwaved at 80° C. for 2 hours. The mixture was dried under vacuum, dissolved in MeCN (2 mL), and combined with 4 M of HCl in dioxane (500 μL). The resulting mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and discarded, and the filtrate containing the intermediate was concentrated down and submitted to next step. 1,2,3-triazole-4-carboxylic acid (14 mg, 120 μmol, 0.5 eq.) and HATU (48 mg, 120 μmol, 1.0 eq) were dissolved in DMF (1 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (44 μL) and the intermediate from last step. The mixture was stirred for 5 minutes. The reaction was quenched with water and the product dried under vacuum. The product was then purified by preparative HPLC to yield the title compound (4.8 mg, 95% purity. MS m/z [M+H]+ calc'd for C30H36N4O7, 565.26. found 565.4.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[CH2:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]>CO.C(Cl)Cl>[CH2:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]3[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:31][CH:32]=1)[CH2:23][CH2:24][CH3:25]
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CCCCc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1ccc(NCc2ccc3[nH]c(C(N)=O)c(Sc4ccccc4)c3c2)cc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 4-butylaniline (74 mg, 0.50 mmol) as described in General Procedure X to afford Iah (17 mg, 23.4%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2−0.2% Et3N), m/z obs=430 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10](F)[C:11]([C:14]#[N:15])=[N:12][CH:13]=1.CN1C(=O)CCC1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:25][OH:26]>CCOC(C)=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([O:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])[C:11]([C:14]#[N:15])=[N:12][CH:13]=1
Reactant: N#Cc1ncc(Cl)cc1F
Reactant: CCOC(=O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)COc1cc(Cl)cnc1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
To a mixture of cesium carbonate (1.63 g, 5.01 mmol) and 5-chloro-3-fluoropicolinonitrile (0.784 g, 5.01 mmol) was added NMP (5 mL) and ethyl glycolate (0.52 mL, 5.49 mmol). The reaction mixture was stirred at RT for 20 min, heated to 80° C. for 1 h and additional ethyl glycolate (0.10 mL) was added. Stirring was continued at 80° C. for 2 h and the reaction mixture was cooled to RT. The reaction was and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel eluting with a gradient of 0% to 15% EtOAc in DCM gave ethyl 2-((5-chloro-2-cyanopyridin-3-yl)oxy)acetate (0.83 g, 3.46 mmol, 69% yield) as a white solid. LC/MS (ESI+) m/z=240.9 (M+H). Calculated for C10H9ClN2O3 240.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:6][CH:5]=[C:4]([F:18])[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:18])[N:3]=1
Reactant: Nc1nc(F)ccc1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(F)ccc1C(=O)O
Yield: 96.1 %

Procedure:
A solution of benzyl 2-amino-6-fluoropyridine-3-carboxylate (2.0 g, 0.008 mole) in ethanol (250 ml) containing 5 percent Palladium on charcoal was shaken in a hydrogen atmosphere (50 psi was the initial pressure) using a Paar apparatus. Hydrogen uptake ceased after 10-15 minutes. After purging the hydrogen from the system, the catalyst was removed by filtration, and the solvent evaporated to give 1.2 g (94 percent) of the desired acid. Recrystallization from water gave an analytical sample: m.p.=205-214 decompose.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)C=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and cinnamoyl chloride in a similar manner as described above to give an off-white solid (35% yield).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:8]=1[C:9]#[N:10].[C:18](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH3:18][O:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:8]=1[C:9]#[N:10]
Reactant: N#Cc1c(OC/C=C/CO)cccc1[N+](=O)[O-]
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC/C=C/COc1cccc([N+](=O)[O-])c1C#N
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of (E)-2-(4-hydroxybut-2-enyloxy)-6-nitrobenzonitrile (Example 199d) (0.50 g, 2.13 mmol) and 2,6-di-tert-butyl-4-methylpyridine (2.18 g, 10.65 mmol) in CH2Cl2 (15.0 mL) at rt, was added trimethyloxonium tetrafluoroborate (1.58 g, 10.65 mmol) under a nitrogen atmosphere. After 1 h at rt, the reaction was quenched with water (50 mL) and extracted with EtOAc (4×50 mL). The combined extract was washed with water, 1.5M HCl, saturated aqueous NaHCO3 and brine, and was dried over anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using the solvent gradient hexanes→hexanes/EtOAc (3:7), to give 0.25 g (72%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.84-7.92 (m, 2H), 7.68-7.73 (m, 1H), 5.82-6.03 (m, 2H), 4.82-4.88 (m, 2H), 3.87-3.93 (m, 2H), 3.21 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:20])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CI
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of compound 8 (22.07 g, 95 mmol) in anhydrous dimethylformamide (114 mL) under nitrogen in an ice bath was added sodium hydride (4.75 g, 119 mmol, 60% in mineral oil) and, within 15 minutes, the gas evolution had ceased. To the above reaction mixture was added a solution of methyl iodide (14.2 g, 99.8 mmol). The reaction mixture was stirred overnight and allowed to warm to room temperature. The reaction was triturated with hexane (3×150 mL) which was discarded. The reaction mixture was poured into ice water, extracted with dichloromethane (3×200 mL) which was dried with anhydrous sodium sulfate. The dry dichloromethane was concentrated to yield a solid which was triturated with a solution of ethyl acetate and hexane (1:1, 200 mL). Compound 9 was obtained as an orange solid (16.9 g, 68.6 mmol, 72%). GC/MS, m/z=246 at tR=14.63 min (100%). LC/MS, [M+H]′=247.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([I:29])C(=O)C1.C(O)(C(F)(F)F)=O>>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([I:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (50 mg, 0.17 mmol), NIS (94 mg, 0.4 mmol), TFA (20 mg, 13.4 L, 0.17 mmol) in CH2C12 (200 L) was stirred at room temperature overnight. After solvent removal, the desired product 18 (6 mg, 8.5%) was purified by silica gel column chromatography (CHC13:EtOAc at 9:1 to 4:6). 1H NMR (400 MHz, DMSO-d6) 7.6 (bs, 2H), 7.38 (s, 1H), 6.95 (s, 1H), 6.03 (s, 2H), 4.12 (s, 2H); MS m/z 414.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[ClH:27].O1CCOCC1>CO.C(Cl)Cl>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (2.3 g) in 30% MeOH/DCM (60 mL) at 0° C. was added dropwise 4M HCl/1,4-dioxane (10 mL). After all solid material had dissolved, the mixture was concentrated under reduced pressure, and to the residue was added 30% CH3CN/H2O (80 mL) and the mixture was sonicated until all solid material had dissolved. The mixture was frozen and lyophilized overnight to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol hydrochloride (100%). 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 6.02 (s, 1H), 6.20 (s, 1H), 7.27 (t, 2H), 7.60 (qt, 2H), 7.80 (t, 1H), 8.08 (t, 1H), 8.23 (d, 1H), 8.83 (d, 1H), 12.16 (s, 1H), 14.51 (b, 1H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:13][C:14]1[C:15]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30](C(OC(C)(C)C)=O)[N:29]=[CH:28]3)=[N:16][N:17](C2CCCCO2)[CH:18]=1)[CH3:12])=O)(C)(C)C.O.CC#N>O1CCCC1.Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH2:13][C:14]1[C:15]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)=[N:16][NH:17][CH:18]=1)[CH3:12]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(CCN)Cc1c[nH]nc1-c1ccc2[nH]ncc2c1
Reaction time: 0.02 h
Yield: 28.8 %

Procedure:
A solution of (R/S) tert-butyl 5-(4-(((2-(tert-butoxycarbonylamino)ethyl)(methyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indazole-1-carboxylate (50 mg, 0.09 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) and 12N hydrochloric acid (2 mL) was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum to remove most of the THF. The pH value of the solution was adjusted to 9 with 10% sodium carbonate solution. The resulting mixture was concentrated under vacuum. The residue was dissolved in 5 mL of methanol and then purified by Pre-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 7 mg (29%) of (2-aminoethyl)([[3-(1H-indazol-5-yl)-1H-pyrazol-4-yl]methyl])methylamine as a white solid. 1H-NMR (300 MHz, CD3OD): δ 8.14 (s, 1H), 8.10 (s, 1H), 7.72-7.64 (m, 3H), 3.63 (s, 2H), 3.10-3.09 (m, 2H), 2.86-2.77 (m, 2H), 2.24 (s, 3H) ppm. LCMS (method A1, ESI): RT=0.78 min, m/z=271.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([CH:17]=[CH:18][CH2:19][CH2:20][CH3:21])=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2]
Reactant: CCCC=Cc1c(CC)nc(CC)c(CO)c1-c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(CC)nc(CC)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (Example 6) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.42 (m, 3 H), 7.18 (m, 2 H), 4.34 (d, J=6 Hz, 2 H), 2.96 (q, J=7.7 Hz, 2 H), 2.84 (q, J=7.7 Hz, 2 H), 2.28 (m, 2 H), 1.34 (m, 9 H), 1.09 (m, 4 H), 0.76 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C21H29NO) 311, found 312 (M+H). mp 76-77C. Rf=0.5 (50% ethyl acetate/hexane).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3)ccc21
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Benzoyl chloride (305 μL, 1.5 eq.) was added to a solution of 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (407 mg, 1.74 mmol) and triethylamine (1.2 mL, 5.0 eq.) in dichloromethane (5 mL) at 0° C. and the resulting mixture was stirred for 15 min. The reaction was then quenched by addition of sat. NaHCO3 and the mixture was extracted with 3×EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated and the product was purified by chromatography (20 to 100% EtOAc-hexanes) to give 5-benzoylamino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (588 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[NH:24][CH:23]=[CH:22]3)[CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[NH:24][CH:23]=[CH:22]3)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccc2cc(O[C@H]3CCCNC3)ccc12
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2cc(O[C@H]3CCCN(CCOCc4ccccc4)C3)ccc12
Reaction time: 17 h

Procedure:
2-Benzyloxyethyl bromide (1 mol) was added to a suspension of (S)-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol) and potassium carbonate (70mg, 4.2 mol) in N, N-dimethylformamide (500 μl) and shaken for 17 hours. The reaction was quenched with hydrochloric acid (2M) and methanol and passed down an SCX cartridge. The products were purified by preparative HPLC under basic conditions. The clean products were isolated by evaporation under reduced pressure to afford (S)-6-[1-(2-benzyloxyethyl)piperidin-3-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=379.4[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:5]2=[CH:6][N:7]=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]2[N:29]([CH3:33])[C:30]([CH3:32])=[N:31][C:27]=2[CH:26]=1>>[CH3:33][N:29]1[C:28]2[CH:34]=[CH:35][C:25]([NH:24][C:11]([C:9]3[N:8]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:5]4=[CH:6][N:7]=[C:2]([F:1])[CH:3]=[C:4]4[CH:10]=3)=[O:12])=[CH:26][C:27]=2[N:31]=[C:30]1[CH3:32]
Reactant: CCOC(=O)c1cc2cc(F)ncc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)ccc2n1C
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ncc4n3Cc3cccc(F)c3)ccc2n1C
Yield: 51.2 %

Procedure:
The process is performed according to the method described in step 2.4 of Example 2, starting with 0.3 g (0.95 mmol) of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Example 2.3) and 0.183 g (1.14 mmol) of 5-amino-1,2-dimethylbenzimidazole. 0.21 g of expected compound is isolated.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)(C(C)(C)C)(C)C.[C:21](Cl)(=[O:25])[C:22](Cl)=[O:23].C(Cl)Cl.[CH3:30][O-:31].[Na+].CO>C(OCC)C>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](=[O:25])[C:22]([O:31][CH3:30])=[O:23])=[CH:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(=O)c1cn(CCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 1-[3-(tert-butyldimethylsilyloxy) propyl]-1H-indole (4.99 g, 17.2 mmol) in diethyl ether (20 mL) at 4° C. was added a 2.0 M solution of oxalyl chloride in methylene chloride (9.5 mL, 19.0 mmol). The resulting solution was allowed to warm to room temperature. After 2 h, the solution was cooled to −78° C. To this solution was added a 25% (w/w) solution of sodium methoxide in methanol (8.7 mL, 38.0 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with water (10 mL) and poured into EtOAc (100 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with saturated aq NH4Cl (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated. Flash chromatography (SiO2, 20% to 80% EtOAc/hexanes) gave the title compound (3.24 g, 71%) as a white solid. 1H NMR (300 MHz, CDCl3) 8.42 (m, 2H), 7.47 (m, 1H), 7.36 (m, 2H), 4.38 (m, 2H), 3.94 (s, 3H), 3.67 (m, 2H), 2.25 (m, 2H), 1.50 (m, 1H). MS (atmospheric pressure chemical ionization, m/z) 262 (M++1).
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([N+:20]([O-])=O)[CH:12]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)=[O:37])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[CH:1]1([C:4]2[O:8][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]4[N:17]=[C:42]([C:41]5[CH:40]=[CH:39][C:38]([C:36]([NH:35][C:32]6[CH:31]=[CH:30][C:29]([N:26]7[CH2:25][CH2:24][O:23][CH2:28][CH2:27]7)=[CH:34][CH:33]=6)=[O:37])=[CH:45][CH:44]=5)[NH:20][C:13]=4[CH:12]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(OCc2nnc(C3CC3)o2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3ccc(OCc4nnc(C5CC5)o4)cc3[nH]2)cc1

Procedure:
Compound 630 was prepared according to the procedure similar to that described in Scheme III from 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C30H28N6O4: 537.22; found: 537.06.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)[C:10]2=[O:19])=[N:6][C:5]=1[CH3:20])(=O)[CH3:2].COC(OC)[N:24]([CH3:26])C.O.[NH2:30]N>CN(C)C=O>[CH:16]1([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]([C:1]4[CH:2]=[CH:26][NH:24][N:30]=4)=[C:5]([CH3:20])[N:6]=3)[C:10]2=[O:19])[CH2:18][CH2:17]1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(CCC3CC3)C2=O)nc1C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1-c1cc[nH]n1
Temperature: 110 °C
Yield: 71 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(2-cyclopropylethyl)imidazolidin-2-one (0.30 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added N,N-dimethylformamide dimethyl acetal (0.30 mL, 2.25 mmol). The reaction mixture was heated for 23 hours at 110° C., followed by the addition of hydrazine monohydrate (0.30 mL, 6.16 mmol). The reaction mixture was heated for another 10 minutes at 110° C., and concentrated in vacuo. The residue was washed with water and triturated with ethyl acetate to afford the title compound as a white solid in 71% yield (0.23 g): mp 147-149° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.77-7.75 (m, 1H), 6.40 (d, J=1.2 Hz, 1H), 4.00-3.94 (m, 2H), 3.58-3.549 (m, 2H), 3.25 (t, J=6.9 Hz, 2H), 2.36 (s, 3H), 1.46-1.34 (m, 2H), 0.89-0.81 (m, 1H), 0.69-0.64 (m, 2H), 0.05-0.02 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 156.0, 155.5, 144.1, 142.3, 130.2, 117.9, 103.1, 43.8, 42.4, 42.3, 32.1, 16.9, 8.8, 4.5; MS (ES+) m/z 318.2 (M+1).