Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([OH:23])=[CH:18][C:17]=2[N+:24]([O-:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>O1CCCC1.C(OCC)(=O)C>[C:39]([O:23][C:19]1[CH:20]=[C:21]2[C:16](=[C:17]([N+:24]([O-:26])=[O:25])[CH:18]=1)[NH:15][C:14]([C:12]([NH:11][CH2:10][CH:9]([S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:27]([O:28][CH3:29])[O:30][CH3:31])=[O:13])=[CH:22]2)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(OC)C(CNC(=O)c1cc2cc(O)cc([N+](=O)[O-])c2[nH]1)SCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(OC)C(CNC(=O)c1cc2cc(OC(=O)C(C)(C)C)cc([N+](=O)[O-])c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-5-hydroxy-7-nitro-1H-indole-2-carboxamide (1.0 g) in tetrahydrofuran (10 mL) were added dropwise triethylamine (0.38 mL) and pivaloyl chloride (0.30 mL) under ice-cooling. The mixture was stirred overnight at room temperature, diluted with ethyl acetate, washed with water, 1N hydrochloric acid and saturated brine, dried (MgSO4), and concentrated. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.18 g, yield 99%) as a pale-yellow amorphous powder.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([C:11]1[C:12]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[N:13][N:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([CH3:32])=[N:22][C:23]([O:30][CH3:31])=[C:24]([CH:29]=3)[C:25]([O:27][CH3:28])=[O:26])=[C:16]([F:33])[C:15]=12)=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:16]1[C:15]2[N:14]([N:13]=[C:12]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[C:11]=2[C:9](=[O:10])[NH:8][CH3:6])[CH:19]=[CH:18][C:17]=1[C:20]1[C:21]([CH3:32])=[N:22][C:23]([O:30][CH3:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(-c2ccn3nc(-c4ccc(F)cc4)c(C(=O)N(C)C(=O)OC(C)(C)C)c3c2F)c(C)nc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cc(C(=O)OC)c(OC)nc3C)c(F)c12

Procedure:
To a solution containing methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinate (0.07 g, 0.13 mmol) and dichloromethane (2.5 mL) was added TFA (0.39 mL, 5.0 mmol) at room temperature. The solution was maintained for 15 minutes and concentrated to dryness to afford Methyl 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinate as a tan solid which was used without further purification. LCMS retention time: 1.777 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 489 (MNa+).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([O:13][CH: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)[CH:5]=1.[NH2:27][C:28]1[C:29]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=2)=[O:35])=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][C:28]2[C:29]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=3)=[O:35])=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:10])=[C:6]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:5]=1
Reactant: CSCc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: CSCc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 43 %

Procedure:
Using a procedure analogous to Example 1-G, 3-[4-(methylthiomethyl)-2-(1-t-butoxycarbonylpiperidin-4-yloxy)-benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white solid (751 mg, 43%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[C:17]([F:20])([F:19])[F:18])=[O:5])C.[OH-].[Na+].Cl.O>CO>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:17]([F:19])([F:20])[F:18])[N:8]=2)[CH:12]=1
Reactant: CCOC(=O)c1sc(-c2cccnc2)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(-c2cccnc2)nc1C(F)(F)F
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
To a solution of 2-pyridin-3-yl-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (13.9 g, 46 mmol, ca. 85% pure) in methanol (150 mL) was added an aqueous solution of sodium hydroxide (total volume 75 mL, 140 mmol), and the mixture was stirred for 40 min. Upon addition of 2 N HCl (70 mL, ca pH=3) to the reaction mixture, a precipitate was formed. Water (300 mL) was then added and the heterogeneous mixture was filtered under reduced pressure. The precipitate was rinsed further with water and dried in vacuo to give the desired product as an off-white solid (7.37 g, 58%): mp 209° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.21 (d, J=2.5 Hz, 1H), 8.77 (dd, J=4.9, 1.7 Hz, 1H), 8.41 (dt, J=8.0, 1.7 Hz, 1H), 7.60 (dd, J=8.0, 4.9 Hz, 1H), 3.4 (br s, 1H); ESIMS m/z 276.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-bromobenzoic acid (500 mg, 2.49 mmol) in DCM (12 mL) was added morpholine (260 mg, 2.99 mmol), EDCI (1.43 g, 7.47 mmol) and HOBt (1.0 g, 7.47 mmol). The mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water and extracted with DCM. The organic layer was concentrated to give the desired (3-bromophenyl)(morpholino) methanone as a crude product which was used in next step without further purification. LCMS (m/z): 270.1/271.1 [M+H]+/[M+2H]+
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:10]([O:32][CH2:33][CH2:34][CH3:35])[N:9]=2)[CH2:3]1.[CH3:36][C:37]1[S:41][C:40]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)=[N:39][CH:38]=1.CCN(CC)CC>C1COCC1.C(Cl)Cl.CO>[CH3:36][C:37]1[S:41][C:40]([NH:42][C:43](=[O:44])[NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:16]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][CH:19]=4)[C:11]([C:12]([NH2:14])=[O:13])=[C:10]([O:32][CH2:33][CH2:34][CH3:35])[N:9]=3)[CH2:3]2)=[N:39][CH:38]=1
Reactant: CCCOc1nc(N2CCC[C@@H](N)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Reactant: Cc1cnc(NC(=O)Oc2ccccc2)s1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1nc(N2CCC[C@@H](NC(=O)Nc3ncc(C)s3)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A mixture of (R)-6-(3-aminopiperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)-2-propoxynicotinamide (50 mg, 0.104 mmol), phenyl 5-methylthiazol-2-ylcarbamate (29.1 mg, 0.124 mmol), and Et3N (0.014 mL, 0.104 mmol) in THF (3 mL) in a scintillation vial was stirred at 60° C. for 2 hrs, during which time a white precipitate forms. Left standing overnight at rt. The solid were dissolved in a mixture of CH2Cl2 and MeOH and crude mixture was chromatographed (loaded onto an ISCO Companion 40 g silica gel column and eluted with (90:9:1 CH2Cl2:MeOH: NH4OH)/CH2Cl2 gradient (20-100%) to give 40 mg (R)-6-(3-(3-(5-methylthiazol-2-yl)ureido)piperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)-2-propoxynicotinamide as a white solid. LCMS: (M+H)+=623.37. 1H NMR (400 MHz, CDCl3) δ ppm 11.51 (1H, s), 7.93 (1H, br. s.), 7.38 (2H, d, J=8.57 Hz), 7.24 (2H, d, J=8.57 Hz), 6.80 (1H, s), 6.03 (1H, s), 5.94 (1H, br. s.), 4.23-4.37 (2H, m), 3.85-4.05 (2H, m), 3.55-3.82 (8H, m), 3.25-3.53 (4H, m), 2.32 (3H, s), 1.65-1.90 (5 H, m), 0.97 (3H, t, J=7.47 Hz).
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccncc1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccncc1C#N
Reaction time: 2 h
Yield: 83.6 %

Procedure:
The compound (25) (0.73 g, 5.61 mmol) was dissolved in ethyl acetate (15 ml) and 10% palladium carbon (20 mg) was added. The mixture was stirred at normal temperature and normal pressure under a hydrogen atmosphere for 2 hrs. for hydrogenation. The reaction mixture was passed through celite and the filtrate was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, and the extract was combined and dried (MgSO4). The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless oil (0.62 g, 84%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].[F:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([F:30])[CH:25]=[CH:24][C:23]=1[NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33].[OH-].[K+].Cl>CO>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:20]([CH:28]([C:27]4[C:26]([F:30])=[CH:25][CH:24]=[C:23]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])[C:22]=4[F:21])[OH:29])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: CCNC(=O)c1ccc(-c2cnc3[nH]ccc3c2)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4ccc(C(=O)NCC)nc4)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
In a round bottom flask, 5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide (38, 71 mg, 0.27 mmol), propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (58, 84.2 mg, 0.32 mmol) and potassium hydroxide (44.9 mg, 0.80 mmol) were combined with 1.1 mL of methanol. The reaction was stirred for 2 hours at room temperature. The reaction solution was neutralized with 0.1 N hydrochloric acid, then extracted 3× with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to provide the desired compound (73, 55 mg). MS (ESI) [M+H+]+=530.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:14])[CH3:13])[C:6]([NH2:8])=O.O=P(Cl)(Cl)Cl.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:13])[CH3:14])[C:6]#[N:8]
Reactant: COc1cc(C(N)=O)ccc1N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1N(C)C
Temperature: 105 °C
Yield: 90.8 %

Procedure:
A mixture of the above benzamide (0.220 g, 1.25 mmol), POCl3 (1 mL) and diisopropylethylamine (0.5 mL) was heated to 105° C. for 16 hours and then cooled to room temperature. The solution was poured into ice water and neutralized with sodium carbonate, then extracted with EtOAc (2×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography eluting with hexanes/EtOAc (2:1) afforded 3-methoxy-4-dimethylaminobenzonitrile as an oil (0.20 g).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[N:28]([O:29][CH3:30])[CH3:27])=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:23])(=[O:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CNOC
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C1=C(C(=O)c2ccc3c(c2Cl)S(=O)(=O)CCC3(C)C)C(=O)CCC1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
0.5 g (1.25 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one was dissolved in 10 ml of tetrahydrofuran, and 0.13 g (1.37 mmol) of N,O-dimethylhydroxylamine hydrochloride and 0.28 g (2.74 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for 25 hours, stirred into water and extracted with ethyl acetate, the organic phases were extracted with 1N hydrochloric acid and dried and the solvent was removed. This gave 0.4 g of beige crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].ClC1C2C(=CC=CC=2)C=CC=1.[C:21](Cl)(Cl)=[O:22]>>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:21]=[O:22])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(Cl)Cl
Solvent: Clc1cccc2ccccc12
Product: O=C=Nc1ccc(F)c(F)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
At -10° to 0° and while stirring, 120 g of 3,4-difluoroaniline (J. Chem. Soc., 73, 5884-5, 1951) is metered into a solution of 180 parts by weight of phosgene in 1,100 parts by weight of chloronaphthalene. The reaction mixture is then slowly heated to 150° C. while passing in additional phosgene, and phosgenated for 2 hours at this temperature. Excess phosgene is expelled with nitrogen and the isocyanate distilled from the solution; b.p. (30 mm Hg): 79°-85° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]>C(O)(C)(C)C.[Rh]>[NH2:1][CH2:2][CH:3]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC
Agent: [Rh]
Solvent: CC(C)(C)O
Product: CCOC(OCC)P(=O)(CC(CN)C1CCCCC1)OCC
Reaction time: 20 h

Procedure:
A solution of 3.45 g of ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate in 25 ml of tertiary butanol is added to 2.0 g of 5% rhodium in alumina, suspended in 25 ml of tertiary butanol. The resulting mixture is hydrogenated at an atmosphere of 150 bar and temperature of 100° C. for a period of 20 hours. The mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product is chromatographed on silica gel using ethanol as eluent to give ethyl 3-amino-2-cyclohexylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=47.1 and +47.0 ppm (CDCl3).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:47](=[O:48])[C:46]([CH3:51])([CH3:50])[CH3:45])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Title compound in example 659. A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give 1-((1R,5S)-8-{2-[4-(1,3-benzodioxol-5-yl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a foam (0.18 g, 82%). 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 1H), 7.29 (m, 3H), 6.83 (m, 2H), 6.75 (m, 1H), 6.21 (m, 1H), 6.00 (s, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.38 (m, 2H), 2.98 (m, 2H), 2.86 (s, 3H), 2.56 (m, 2H), 2.31 (m, 4H), 2.07-2.21 (m, 4H), 1.82 (m, 4H), 1.26 (s, 9H). HRMS C34H44N4O3 m/z 557.3492 (M+H)Cal., 557.3495 (M+H)Obs..
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:20])[CH2:13][CH2:14][CH:15]1[O:18][C:16]1([CH3:19])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CCC1OC1(C)C)COCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@@H](CCCC(C)(C)O)COCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of the epoxide 6 (2.5 g, 9 mmol) in anhydrous ether (75 mL) at 0° C. was added lithium aluminum hydride (1.7 g, 67.5 mmol). The cooling bath was removed and the reaction was stirred at room temperature overnight. The reaction was then quenched with cold water and aqueous NH4Cl, and extracted with CH2Cl2. The solvents were removed under reduced pressure and the crude oil was chromatographed on a silica gel using hexane/EtOAc (9:1) as an eluent to give an oily alcohol 7 (2 g, 80%).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O>C1COCC1>[CH2:26]([O:25][C:23]([NH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.50 g (1.66 mol) of ethyl (3-(4-(aminoiminomethyl)phenyl)ureido)acetate in 20 ml of THF is treated with 2.7 ml of 1N NaOH and cooled to 0° C. 0.29 ml (1.99 mmol) of benzyl chloroformate is added to this mixture and it is stirred at room temperature for 2 h. The pH is kept between 9 and 10 using 1N NaOH. The mixture is then treated with 50 ml of water and extracted with ethyl acetate. After drying (MgSO4), the solvent is removed in vacuo and the residue is stirred with ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([C:36]1[CH:40]=[CH:39][S:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:40]=[CH:39][S:38][CH:37]=3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccsc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccsc1
Temperature: 85 °C

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (110 mg, 0.5 mmol) was dissolved in DMF (3 mL). potassium phosphate (212.4 mg, 1 mmol), Copper (I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.51 mg, 0.1 mmol) were added. 3-(1-bromoprop-1-en-2-yl)thiophene (121.8 mg, 0.6 mmol) dissolved in DMF (2 mL) was added dropwise to it. Nitrogen was purged for 2 min and the reaction mixture was heated at 85° C. overnight (prolonged heating required in some cases). DMF was evaporated and water added. The precipitate obtained was filtered and purified through silica gel chromatography (100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified through reverse phase purification. Yield: 110 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.62 (s, 1H), 7.56 (m, 3H), 7.20 (s, 2H), 7.16 (s, 1H), 4.58 (s, 2H), 3.70 (m, 2H), 3.16 (m, 5H), 1.98 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH3:14].[CH2:15](I)[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([NH:1][CH2:15][CH2:16][CH3:17])[O:3][N:4]=[C:5]2[N:6]([CH3:14])[C:7]1=[O:13]
Reactant: Cn1c(=O)c2c(N)onc2n(C)c1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNc1onc2c1c(=O)n(C)c(=O)n2C
Temperature: 100 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of 0.588 g of 3-amino-5,7-dimethyl-isoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, 15 ml of dimethylformamide, 2.5 g of propyl iodide and 1.0 g of potassium carbonate was stirred at 100° C. for 3 hours. From the reaction solution was removed the solvent under reduced pressure. To the residue was added water, which was subjected to extraction with chloroform. The chloroform layer was taken and dried over anhydrous sodium sulfate, from which was removed the solvent. The resultant residue was chromatographed on a column of silica gel (30 g), and the column was eluted with chloroform:acetone:formic acid (20:1:0.1). From the elute was recovered the desired compound, which was recrystallized from isopropyl ether-acetone to give 0.217 g of colorless prisms, melting point: 164°-166° C.