Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].[NH3:13]>C(O)C.CO>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1)[C:6]([NH2:13])=[NH:7]
Reactant: N
Reactant: COc1cc(C#N)cc(OC)c1
Solvent: CCO
Solvent: CO
Product: COc1cc(OC)cc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry HCl gas was bubbled through a cooled (−15° C.) solution of 3,5-dimethoxybenzonitrile (1.50 g, 9.20 mmol) for 30 minutes. The reaction mixture was placed in a refrigerator overnight. After evaporation of the solvent, a white solid was obtained which was dissolved in ethanol. 9.2 ml of a 2 molar solution of ammonia in Methanol was added and the reaction mixture was stirred at room temperature overnight. After evaporation of the solvent, the title compound, MS: m/e=181.2 (M+H+), (1.21 g, 71%) was obtained by chromatographic purification of the residue (silica gel, MeOH, DCM). 1H-NMR (300 MHz, d6-DMSO, 25° C.): δ(ppm)=3.80 (6H, s), 6.82 (1H, t, J=2 Hz), 7.05 (2H, t, J=2 Hz), 9.35 (3H, bs).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (325 mg, 2.37 mmol) from Step 2 of this Example in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 100 mg, 2.49 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (600 mg, 2.61 mmol) from Step 4 of Example 36 in DMF (2 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (250 mL) and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (356 mg, 45%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.41 (t, J=2.0 Hz, 1H), 8.10 (dd, J=2.6, 9.4 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.3, 8.3 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 331 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:37][CH2:36][C:35]1[N:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:45])[NH:21][C:9]4[CH:10]=[C:11]([C:19]#[N:20])[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[N:32]=[N:33][CH:34]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-cyano-5-(isopropyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M96) (0.45 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (236 mg, 77%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]([CH2:30][CH2:31][CH2:32]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCOc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCOc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 3-phenoxypropyl chloride were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(3-(phenoxy)propyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [N:1]1[N:2]=[C:3]([CH2:6][C:7]([O:9]CC)=O)[NH:4][CH:5]=1.[CH2:12]([C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([CH2:37][CH3:38])=[N:30][N:31]3[CH:34]([CH3:36])[CH3:35])=[CH:27][CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:20][N:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([CH2:37][CH3:38])=[N:30][N:31]3[CH:34]([CH3:35])[CH3:36])=[CH:27][CH:26]=2)[CH2:22][CH2:23][N:24]1[C:7](=[O:9])[CH2:6][C:3]1[NH:4][CH:5]=[N:1][N:2]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: CCOC(=O)Cc1nnc[nH]1
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4nnc[nH]4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 39 %

Procedure:
Prepared by the method outlined for Example 275 using ethyl 2-(4H-1,2,4-triazol-3-yl)acetate and 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole as starting materials. Product was obtained as an off-white solid (39%). LC/MS (Method B) 3.34 min, [M+1]+ 472.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([C:16](OC)=[O:17])=[C:6]2[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:17][CH2:16][C:7]1[C:8]([CH3:15])=[N:9][C:10]2[C:5]([C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(CO)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
A solution of methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylate (0.4 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of lithium aluminium hydride (LiAlH4) (0.114 g) in tetrahydrofuran (10 ml) at room temperature. The mixture was stirred at room temperature for 1.5 hours, and water was added. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, the solvent was evaporated, and the resulting crystals were collected by filtration and recrystallized from methanol to give 3-hydroxymethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline (0.326 g, 88%). mp. 200°-201° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[S:40](Cl)(=[O:42])=[O:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:40]([C:36]3[S:35][CH:39]=[CH:38][CH:37]=3)(=[O:42])=[O:41])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 103 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with thiophene-2-sulfonylchloride to give 95 mg 4-tert.-butyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=5.60 min, [M+1]+=633.60, [M−1]−=631.70.
Reaction SMILES: C(N[C:10]1[CH:41]=[CH:40][N:13]([C@@H:14]2[O:29][C@H:18]([CH:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[OH:20])[C@@:16]([C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:17])[C@:15]2([F:39])[CH3:38])[C:12](=[O:42])[N:11]=1)(=O)C1C=CC=CC=1.CC(O)=[O:45]>>[C:30]([C@@:16]1([OH:17])[C@@H:18]([CH:19]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:20])[O:29][C@@H:14]([N:13]2[CH:40]=[CH:41][C:10](=[O:45])[NH:11][C:12]2=[O:42])[C@@:15]1([F:39])[CH3:38])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@]1(F)[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@H](C(O)C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Reactant: CC(=O)O
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@H](C(O)C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Yield: 91 %

Procedure:
N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, 1 eq) was refluxed in 80% aqueous AcOH overnight. After cooling and standing at room temperature (15° C.), most of the product precipitated and then was filtered through a sintered funnel. White precipitate was washed with water and co-evaporated with toluene to give a white solid. The filtrate was concentrated and co-evaporated with toluene to give additional product which was washed with water to give a white solid. Combining the two batches of white solid gave 1.50 g of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (Yield: 91%).
Reaction SMILES: F.[Cl:2][C:3]([Cl:6])([Cl:5])[CH3:4].B(F)(F)[F:8]>>[Cl:2][C:3]([Cl:6])([Cl:5])[CH3:4].[Cl:2][C:3]([Cl:6])([F:8])[CH3:4]
Reactant: FB(F)F
Agent: F
Solvent: CC(Cl)(Cl)Cl
Product: CC(F)(Cl)Cl

Procedure:
The data indicates that using a 3.3:1 molar ratio of hydrogen fluoride to 1,1,1-trichloroethane, in the presence of 1.4 mole % boron trifluoride, based upon the combined amounts of hydrogen fluoride and boron trifluoride, results in 60% conversion of 1,1,1-trichloroethane at 60° C., with 97.3% selectivity for 1,1-dichloro-1-fluoroethane. At 75° C., conversion increased to 98.1%, while selectivity for 1,1-dichloro-1-fluoroethane was still 67.5%, with the only by-product being 1-chloro-1,1-difluoroethane. Vinylidene chloride was not a by-product at either 60° C. or 75° C. In the absence of the catalyst, however, conversion of 1,1,1-trichloroethane was only 20% at 70° C., and the product contained 1 mole % vinylidene chloride. Increasing the concentration of boron trifluoride to 2.4 mole % increased the rate of conversion of 1,1,1-trichloroethane to 84%, while selectivity for 1,1-dichloro-1-fluoroethane decreased to 58.4%. No vinylidene chloride was produced.
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:18]>COC(OC)C1C=CC=CC=1>[CH3:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[N:8]3[CH2:16][CH2:15][CH2:14][CH:9]3[C:10](=[O:13])[N:11]3[CH:18]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:12][CH:2]=4)[O:1][C:2]=1[C:12]=23
Reactant: Cc1ccc2c(c1O)NC(=O)C1CCCN1C2=O
Agent: COC(OC)c1ccccc1
Product: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Yield: 176.8 %

Procedure:
2.0 g of 2,3,5,10,11,11a-hexahydro-9-hydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5,11-dione was admixed with 300 ml of benzaldehyde dimethyl acetal and heated at 190° to 200° C. for 2 hours with stirring under a stream of nitrogen gas. The liquid reaction mixture was concentrated at 130° to 150° C. under reduced pressure. The concentrate was dissolved in a small quantity of chloroform, passed through a silica gel chromatographic column and eluted with ether. Thus, there was obtained 2.4 g of 6,8,9,10,10a,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo(5,4,3-jk)pyrrolo(2,1-C)(1,4)benzodiazepin-6,11-dione as a colorless crystal. Recrystallization of the resulting product from ether gave a colorless needle-like crystal having a melting point of 158.5° to 162.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]1([NH:65][CH2:66][CH2:67][C:68]#[N:69])[CH2:64][CH2:63][CH2:62]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:65]([CH2:66][CH2:67][C:68]#[N:69])[CH:61]2[CH2:64][CH2:63][CH2:62]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: N#CCCNC1CCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.2 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 3-(cyclobutylamino)propionitrile (0.038 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.042 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: Clc1cncc(Cl)n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2ccccc2-c2ccccc2)n1
Yield: 65 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 2-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (238 mg). Yield: 65%. 1H NMR (250 MHz, DMSO-d6) δ 7.31-7.61 (m, 9H, Harom), 8.43 (s, 1H, HPz 5), 8.46 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.[O:22]([CH2:29][CH2:30][CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:22]([CH2:29][CH2:30][CH2:31][S:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:4]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CSCCCOc2ccccc2)S1
Yield: 95.6 %

Procedure:
The product of Example 1 (2.0 g, 0.006 mol) and 3-phenoxy-1-bromopropane (1.3 g, 0.006 mol) were dissolved in methyl ethyl ketone (20 ml). Anhydrous potassium carbonate (2.5 g) was added and the reaction was run and worked up as described in the procedure of Example 2. Chromotography of the resulting oil on silica gel using 15% ethyl acetate/hexane as eluent gave 2.70 g (96%) of the title compound as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>>[N:19]1([C:17]([C:15]2[S:14][C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[CH:16]=2)=[O:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)N3CCOCC3)cc2C1
Agent: Cl
Product: O=C(c1cc2c(s1)CCNC2)N1CCOCC1
Temperature: 25 °C

Procedure:
5-t-Butoxycarbonyl-2-(morpholine-4-carbonyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (610 mg, 1.7 mmol) was mixed with hydrochloric acid-saturated methanol and stirred at room temperature for two nights. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the residue was mixed with sodium hydroxide aqueous solution (1 N). The reaction product was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. By evaporating the solvent from the organic layer under a reduced pressure, 270 mg (1.1 mmol, 63% in yield) of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[N:24]([C:25]([C:27]4[C:28]([CH3:32])=[N:29][O:30][CH:31]=4)=[O:26])[CH2:23][CH2:22][N:10]2[C:11](=[O:21])[C:12]2[N:13]([CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.[OH-].[NH4+]>CO.O.S([O-])([O-])(=O)=O.O.O.O.O.O.O.O.[Fe+2]>[NH2:18][C:16]1[CH:17]=[C:12]2[C:11](=[O:21])[N:10]3[CH2:22][CH2:23][N:24]([C:25]([C:27]4[C:28]([CH3:32])=[N:29][O:30][CH:31]=4)=[O:26])[C:9]3([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14][N:13]2[CH:15]=1
Reactant: COc1ccc(C23Cn4cc([N+](=O)[O-])cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccc(C23Cn4cc(N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 50 °C
Yield: 38.9 %

Procedure:
To a solution of 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-nitro-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (107 mg, 0.24 mmol) in MeOH (2.4 mL) was added Iron(II) heptahydrate sulfate (544 mg, 2 mmol) in water (2.4 mL). A solution of ammonium hydroxide (28%, 0.7 mL) was added and the mixture was heated at 50° C. for 45 min. The reaction mixture was then partially concentrated in vacuo (half volume), neutralized with a saturated aqueous solution of NH4Cl and then extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtrated and concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4 gradient 0-7% MeOH in EtOAc) to give 7-amino-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (111) (38 mg, yield 39%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:33])[N:15]([CH3:32])[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[N:19]=[CH:18][N:17]=1>C1COCC1.CO.[Ni]>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]([N:15]([CH3:32])[C:14]([NH:13][C:3]2[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[Cl:12])=[O:33])[CH:21]=1
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(2-nitro-phenylamino)-pyrimidin-4-yl]-urea (50 g, 0.1 mmol) in THF (10 mL) and MeOH (10 mL) was added Raney-Ni (suspension in water) at room temperature, the resulting mixture was stirred for 2 hours under hydrogen atmosphere. The reaction was filtered and concentrated to obtain the title compound (38 mg, yield: 82%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 3.28 (s, 3H), 3.85 (s, 2H), 3.94 (s, 6H), 5.86 (s, 1H), 6.52 (s, 1H), 6.78-6.87 (m, 3H), 7.16-7.20 (m, 2H), 8.39 (s, 1H), 12.62 (s, 1H); MS (ESI): 463 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C@@H:51](O)[CH2:50]2>C1COCC1>[O:16]=[C:15]([O:17][C@@H:51]1[CH:52]2[CH2:55][CH2:56][N:49]([CH2:54][CH2:53]2)[CH2:50]1)[CH:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: C=CCOC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C=CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 2-(3-(allyloxycarbonyl)phenylamino)-2-phenylacetic acid (I3) (2.69 g, 8.64 mmol) in dry THF (80 ml), were added DCC (3.57 g, 17.3 mmol) and HOBt (2.65 g, 17.3 mmol). After 30 minutes, (R)-quinuclidin-3-ol (3.30 g, 25.9 mmol) was added and reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the crude residue was purified by flash-chromatography (DCM/MeOH=97/3+0.3% NH4OH) to obtain allyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (2.40 g, 66.1% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CNCCN>O1CCCC1>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:16][CH2:15][NH:14][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Agent: CNCCN
Solvent: C1CCOC1
Product: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of 24.0 g (100.0 mmol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole (see U.S. Pat. No. 4,029,816 as an example of how to obtain this material) and 13.6l g (183.5 mmol) of N-methylethylenediamine in 100 ml of tetrahydrofuran was stirred at ambient temperature for 18 hours. The reaction mixture was filtered and evaporated. The residue was crystallized from 2-propanol to give 20.8 g (85.0 mmol, 85%) of 3,5-diamino-6-chloro-N-(2-methylaminoethyl)pyrazine-2-carboxamide; mp 142.5°-143° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].C([O-])([O-])OC.[CH2:28](O)[CH2:29][OH:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:16]([O:15][C:7]1[CH:6]=[CH:5][C:4]([C:1]2([CH3:2])[O:30][CH2:29][CH2:28][O:3]2)=[CH:9][C:8]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCO
Reactant: COC(=O)Cc1cc(C(C)=O)ccc1OCc1ccccc1
Agent: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(C2(C)OCCO2)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
Methyl 2-(5-acetyl-2-benzyloxyphenyl)acetate (9.0 g), 18 ml of methyl orthoformate and 18 ml of ethylene glycol were dissolved in 300 ml of methylene chloride, 60 mg of p-toluenesulfonic acid monohydrate was added to the solution, and the mixture was heated under reflux for 12 hours. After cooling, 0.14 ml of triethylamine was added to the reaction solution and the mixture was stirred for 15 minutes. The reaction solution was partially purified by silica gel flash column chromatography (eluent: methylene chloride) and then further purified by silica gel medium pressure liquid column chromatography (eluent: hexane/diethyl ether=3/2) to give 9.2 g of methyl 2-[2-benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]acetate in an oily form.