Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.[O-:8][N+:9]1[C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:13]=2[N:12]=[C:11]([CH2:22][CH2:23][CH:24]=O)[N:10]=1)[CH2:19][CH2:18][CH2:17]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([CH2:24][CH2:23][CH2:22][C:11]2[N:10]=[N+:9]([O-:8])[C:14]3[CH:15]=[C:16]4[C:20]([CH2:19][CH2:18][CH2:17]4)=[CH:21][C:13]=3[N:12]=2)[CH2:5]1
Reactant: COC1CNC1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC1CN(CCCc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
3-Azetidinyl methyl ether hydrochloride (275) (MacKenzie et al., PCT Int Appl. WO 9605193, 1996) (0.60 g, 4.9 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 82 (930 mg, 60%) as a yellow oil: 1H NMR δ 8.24 (s, 1H, H-9), 7.74 (s, 1H, H-5), 4.27-4.39 (m, 3H, CH2N, CHO), 3.49-3.53 (m, 2H, CH2N), 3.30 (s, 3H, OCH3), 3.21-3.27 (m, 2H, CH2N), 3.09-3.16 (m, 4H, H-6, H-8), 3.05 (t, J=7.2 Hz, 2H, CH2), 2.14-2.26 (m, 4H, H-7, CH2); 13C NMR δ 163.9, 155.1, 149.3, 147.3, 132.3, 122.7, 144.2, 68.3, 60.9, 58.7, 56.6, 56.5, 33.5, 33.1, 32.8, 25.7, 23.8; HRMS calcd for C17H22N4O2 (M+) m/z 314.1743, found 314.1742.
Reaction SMILES: [C:1]([O:6]CC[N:9]=C=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:12]([O:15][CH2:16][CH3:17])(=[O:14])C>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:9][C:12]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(C)=O
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C=C(C)C(=O)O
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.0027 mol of alcohol and 0.00284 mol of isocyanatoethyl methacrylate, 20 mL ethyl acetate, and two drops of dibutyltin dilaurate were added to a polymerization bottle with a stirrer. At room temperature the solution was stirred for 2 days. The solvent was then evaporated, and the solid was redissolved in acetone and precipitated from water. The collected solid was dissolved in ethyl acetate and washed by water and sodium carbonate, and dried by anhydrous magnesium sulfate. Evaporation of solvent by a rotary evaporator gave the desired urethane methacrylate.
Reaction SMILES: C(O[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=O)C=C.[C:14]([OH:20])(=[O:19])[CH2:15]C(O)=O.N1CC[CH2:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[CH2:24]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[CH:15][C:14]([OH:20])=[O:19])[CH:23]=[CH2:22]
Reactant: C=CCOc1cc(C=O)ccc1O
Reactant: C1CCNCC1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: C=CCc1cc(C=CC(=O)O)ccc1O

Procedure:
48.5 g (0.27 mol) of 3-allyloxy-4-hydroxy-benzaldehyde, 104 g (1 mol) of malonic acid, 140 ml of pyridine and 4 ml of piperidine are heated to 100° C for 2 hours, whilst stirring. The volatile constituents are distilled off under reduced pressure at 80° C and the residue is stirred with 800 ml of water. The crystals obtained are filtered off and recrystallised from methylene chloride. 3-Allyl-4-hydroxy-cinnamic acid of melting point 132°-133° C is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1.CO>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)Nc2nc3nc(NCCCN4CCN(C)CC4)ncc3cc2-c2c(Cl)cccc2Cl)cc1
Yield: 87 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 4-methoxyphenyl isocyanate (0.334 g) according to the general procedure of Example 37 to give 1.16 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(4-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CM+0.1% AcOH): M+ +H=595; mp 93.5°-100.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[NH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:23][C:24]1[C:40](F)=[CH:39][CH:38]=[C:37]([N+:42]([O-:44])=[O:43])[C:25]=1[O:26][C:27]1[CH:28]=[C:29]([C:35]#[N:36])[CH:30]=[C:31]([CH:34]=1)[C:32]#[N:33].O>C1COCC1.CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:40]1[CH:39]=[CH:38][C:37]([N+:42]([O-:44])=[O:43])=[C:25]([O:26][C:27]2[CH:28]=[C:29]([C:35]#[N:36])[CH:30]=[C:31]([C:32]#[N:33])[CH:34]=2)[C:24]=1[F:23])[C:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[NH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)n[nH]c1=O
Reactant: N#Cc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])c(Oc3cc(C#N)cc(C#N)c3)c2F)n[nH]c1=O
Temperature: 0 °C
Reaction time: 19 h
Yield: 62.4 %

Procedure:
A 5 L three-neck round bottom flask was charged with (5-methyl-6-oxo-1,6-dihydro-pyridazin-3-3-yl)-acetic acid tert-butyl ester (10; 223 g, 0.996 mol) and THF (700 mL). The resulting solution was cooled to 0° C. and potassium tert-butoxide (1.2 L, 1.66 M in THF, 1.99 mol) was added dropwise over approximately 30 min. After cooling the reaction mixture to −55° C., a solution of 5-(2,3-difluoro-6-nitro-phenoxy)-isophthalonitrile (22; 150 g; 0.498 mol) in THF (1.0 L) was added dropwise over approximately 1 h. Following a THF rinse (500 mL), the cooling bath was removed, and the reaction mixture was stirred for 19 h with warming to ambient temperature. The reaction mixture was then quenched by the addition of 1N HCl (1.75 L). Following removal of the aqueous layer (2 L, pH of 3-4) the organic phase was washed with water (1.0 L) and brine (750 mL). The resulting THF solution was filtered through CELITE® and the filter aid washed with THF (500 mL). The solution was then concentrated in vacuo to afford a dark oil which was dissolved in NMP (850 mL) and warmed to approximately 50° C. Water (425 mL) was added dropwise. The cloudy solution was stirred slowly, seeded with a crystal and cooled to 0° C. After stirring at 0° C. for 30 min, the product was filtered. The filter cake was then washed with MeOH (100 mL, 200 mL) and dried in a vacuum oven (50° C., 25 Torr) to afford [3-(3,5-dicyano-phenoxy)-2-fluoro-4-nitro-phenyl]-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl ester (23; 157 g, 62% theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[C:22]1[C:26]([NH2:27])=[CH:25][NH:24][N:23]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][C:26]3[C:22]([C:16]4[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=4[CH3:14])=[N:23][NH:24][CH:25]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cc1ccc(C)c(-c2n[nH]cc2N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3ccc(Cl)nc23)c1
Reaction time: 14 h

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (400.4 mg, 1.853 mmol, 1.16 equiv) in dichloromethane (6 mL) was added 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine (300.0 mg, 1.602 mmol, 1.0 equiv) and triethylamine (0.70 mL, 5.0 mmol, 3.1 equiv) at room temperature. After 14 hours, the reaction mixture was partitioned between dichloromethane and half-saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic portions are dried over magnesium sulfate, filtered, and concentrated to yield 5-chloro-N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=367.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccnc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromobenzenesulfonyl chloride (3.19 g, 12.5 mmol) was added to a solution of 4-amino-2-chloropyridine (642 mg, 5 mmol) in pyridine (5 ml) and dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue suspended in 2M NaOH (25 ml) and heated at 60° C. for 1 h. The reaction mixture was extracted with ethyl acetate (2×25 ml). The extracts were washed, dried and evaporated. The residue was suspended in methanol and filtered. Evaporation of the filtrate and trituration with diethyl ether afforded the title compound (D3), 1H NMR (DMSO) δ: 6.54 (1H, d), 6.62 (1H, s), 7.60-7.63 (4H, m), 7.66 (1H, d).
Reaction SMILES: CN(C)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C([O-])(=O)C.[Na+]>ClCCCl>[C:3]([C:19]1[NH:18][CH:22]=[CH:21][CH:20]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: CN(C)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N-dimethylbenzamide (48.0 g, 0.32 mol) in 1,2-dichloroethane (500 mL) was added oxalyl chloride (48.0 g, 0.38 mol). The reaction mixture was stirred for 24 hours at room temperature. To the reaction mixture was then added pyrrole (22.0 g, 0.33 mol). The reaction mixture was again stirred for 24 hours at room temperature. Aqueous sodium acetate (20%, 200 mL) was added to the reaction mixture and vigorous stirring was continued for 24 hours at room temperature. The organic layer was filtered through a silica gel column and concentrated under reduced pressure to yield 2-benzoylpyrrole which was used without further purification. Yield 43.0 g (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[O:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:42][C:39]4[CH:40]=[CH:41][O:37][N:38]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 133.5 %

Procedure:
A RBF was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.0 g, 1.763 mmol), isoxazol-3-amine (0.143 ml, 1.939 mmol), and THF (8.81 ml) to give a clear solution. The flask was cooled to 0° C. for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.88 ml, 3.88 mmol) was added dropwise. The reaction was stirred for 30 minutes. The reaction was diluted with 1N aq. HCl and EtOAc. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with 1N aq. HCl, washed with brine, dried with sodium sulfate, filtered, and concentrated to afford crude 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.10 g, 2.354 mmol, 100% yield) as an orange solid. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>CO>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[N:2][NH2:3])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NN=Cc1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of 80% hydrazine hydrate (1.64 g, 26.2 mmol) and methanol (5.0 ml) was dropwise added a solution of 4-(pyridin-2-yl)benzaldehyde (1.5 g, 8.2 mmol) in methanol (5.0 ml) at 25° C. over 10 minutes. After the dropwise addition, the mixture was stirred for 30 minutes. Methanol and excess hydrazine hydrate were evaporated under reduced pressure. The residue was crystallized and 4-(pyridin-2-yl)benzaldehyde hydrazone was obtained as crude crystals at a yield of 1.6 g (yield:100%). The percentage of the area of 4-(pyridin-2-yl)benzaldehyde hydrazone in the crude crystals as determined by liquid chromatography was 94.30%.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].O>CN(C)C(=O)C>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:8](=[O:9])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nncs1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1nncs1)Oc1ccccc1
Yield: 75.6 %

Procedure:
1,3,4-Thiadiazol-2-amine (253 mg, 2.50 mmol) in N,N-dimethylacetamide (3 mL) was stirred with phenyl chloroformate (392 μL, 3.13 mmol) at room temperature for one day. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and hexane and dried under reduced pressure to give the title compound as a colorless solid (418 mg, yield 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23]S[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:39][S:40]([O-:42])=O.[K+]>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:40](=[O:42])(=[O:39])[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCSCC3)c2=O)cc1OC
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Yield: 77.7 %

Procedure:
0.55 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-thiopyran-4-yl)-quinazoline-2,4(1H,3H)-dione and 0.196 g of Oxone® in 100 ml of an MeOH/water mixture (10/1) (v/v) is stirred at room temperature overnight. The resulting mixture is evaporated under reduced pressure. Water is added and the resulting mixture is extracted with DCM. The organic phase is dried over Na2SO4. The resulting solution is filtered and the filtrate is then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture from (50/50, v/v) to (0/100, v/v) to give 0.454 g of the expected product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.C(N(CC)CC)C.CS(C)=O>ClCCl>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1
Reactant: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc2[nH]cc(CCCC=O)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
18 g of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile and 34 ml of triethylamine are dissolved in 300 ml of dichloromethane and cooled to about 0° C. in an ice/methanol bath. A solution of 39 g of sulfur trioxide/pyridine complex and 140 ml of dimethyl sulfoxide is subsequently metered in at 2 to 5° C. The mixture is stirred at 2 to 3° C. for approximately a further 20 min., then the reaction solution is warmed to 22-23° C. (room temperature) over the course of 2 hrs. The reaction mixture is diluted by addition of a further 200 ml of dichloromethane and then extracted with water, 10% citric acid solution and 10% sodium chloride solution. The organic phase is concentrated to an oily residue in vacuo, then chromatographed on silica gel using a mixture of dichloromethane and MTB ether.
Reaction SMILES: [CH3:1][S:2][CH3:3].[C:4](OOC(=O)C1C=CC=CC=1)(=[O:11])C1C=CC=CC=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2][CH2:3][O:11][CH:4]1[CH2:26][CH2:25][NH:24][CH2:22][CH2:23]1
Reactant: CCNCC
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: CSC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSCOC1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
To a solution of alcohol E (1.0 g, 3.1 mmol) and methyl sulfide (1.8 mL, 24.8 mmol) in acetonitrile (31 mL) at 0° C. was added benzoyl peroxide (3.0 g, 12.4 mmol) in four equal portions over 10 min, and the mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h until no E was observed by TLC. The mixture was diluted with ethyl acetate (100 mL), washed with 10% Na2CO3 (100 mL) and then brine (100 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for the next step without purification. The resulting residue was dissolved in acetonitrile (10 mL) and followed by addition of diethyl amine (6.2 mL, 60 mmol). The mixture was stirred at room temperature for overnight until no starting material was observed by TLC and concentrated in vacuo. The residue was flash chromatographed on silica gel with 5% MeOH/DCM to provide intermediate H (270 mg, yield 54% over two steps). MS (ESI) m/z 162.83 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:55]=[CH:54][C:51]([CH2:52][Cl:53])=[CH:50][CH:49]=2)[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45]>>[ClH:53].[ClH:53].[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:15][CH2:16]3)[CH2:52][C:51]3[CH:54]=[CH:55][C:48]([C:40]4[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=4)=[CH:49][CH:50]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2ccc(CCl)cc2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN(c3ccc4c(c3)CCC4)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cc2)cc(OC)c1OC
Product: Cl

Procedure:
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])[CH3:2].C(Cl)[Cl:16].C(Cl)(=O)C(Cl)=O>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([Cl:16])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1OC
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOc1cc(C(=O)Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-ethoxy-4-methoxybenzoic acid (5 g, 25.5 mmol) was added to a solution of CH2Cl2 (40 mL) and benzene (20 mL) in a flame-dried 150 mL round bottom flask. Anhydrous DMF (9 drops) was added and the solution was cooled on ice. Oxalyl chloride (11 mL, 128 mmol) was added dropwise, and the reaction was then allowed to warm to RT. The reaction was stirred at RT for 90 minutes, then concentrated in vacuo yield an off-white solid. The solid was placed on a high-vacuum line for 2 hours, and then taken onto the next step without further characterization.
Reaction SMILES: C(OC(=O)[N:7]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:8]1[S:9][C:10]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[C:11]([Cl:13])[N:12]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(#N)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:7][C:8]2[S:9][C:10]([CH2:14][C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[C:11]([Cl:13])[N:12]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc(CNc2nc(Cl)c(Cc3c[nH]c4ncccc34)s2)cc1
Yield: 13.1 %

Procedure:
A mixture of (4-Chloro-benzyl)-{4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (97, 76 mg, 0.11 mmol), triethylsilane (0.5 mL, 3 mmol), and trifluoroacetic acid (0.25 mL, 3.2 mmol) in acetonitrile (5 mL) was refluxed for 3 hours. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a yellow solid (P-0083, 5.6 mg, 14%). MS (ESI) [M+H+]=389.35, 390.36.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:24][C:25]([F:39])([F:38])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[O:27]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]3[N:16]([CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[C:25]([F:24])([F:38])[F:39])[CH:14]([CH2:13][CH2:12]3)[CH2:15]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(N2CC3CCC(C2)N3)cc1
Reactant: CS(=O)(=O)OCCCCNC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2)C(F)(F)F
Yield: 39 %

Procedure:
3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octane hydrochloride salt (1.5 g, 5.79 mmol), triethylamine (1.77 mL, 12.73 mmol) and methanesulfonic acid 4-(2,2,2-trifluoro-acetylamino)-butyl ester (2.29 g, 8.68 mmol) were combined in tetrahydrofuran (25 mL). The resulting white heterogeneous reaction was heated at reflux for 24 hours. The mixture was cooled diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown oil. Silica gel flash chromatography using 5% methanol/ chloroform as eluent yielded N-{4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-2,2,2-trifluoro-acetamide (0.88 9, 39%) as an off-white solid which had the following properties: Mp. 83-85° C., 1H NMR CDCl3 δ: 7.77 (brd s, 1H), 7.16 (d, J=9.1 Hz, 2H), 6.68 (d, J=9.1 Hz, 2H), 3.44-3.35 (m, 4H), 3.29 (d, J=9.6 Hz, 2H), 3.02 (d, J=9.6 Hz, 2H), 2.51 (t, J=6.2 Hz, 2H), 2.10-1.90 (m, 2H), 1.83-1.76 (m, 2H), 1.73-1.57 (m, 6H).