Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([I:25])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[C:12]([I:25])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2sc3c(c2c(I)c1C(OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of Methyl tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 10, 63.95 g, 135 mmol) in tetrahydrofuran (1 L) and methylated spirit (1 L) was dropwise added aqueous sodium hydroxide (1 M, 811 mL, 811 mmol). The resulting mixture was stirred at 60° C. for 90 minutes and then allowed to cool to room temperature overnight. The volatile solvents were removed in vacuo, and the remaining aqueous residue was diluted with water (400 mL) and extracted with tert-butyl methyl ether (600 mL). The organic layer was washed with water (400 mL) and then cooled on ice. 2 M hydrochloric acid was added to pH 5 and the resulting solids were collected by filtration, washing with water. The solid was dissolved in 2-methyl tetrahydrofuran (300 mL) and stirred for 10 minutes. An aqueous layer had appeared and this was separated. The aqueous layer was extracted with 2-methyl tetrahydrofuran (2×300 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound as a pale yellow solid, 54.35 g, in an 88% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (s, 9H), 1.81-1.93 (m, 4H), 2.65 (s, 3H), 2.76-2.88 (m, 2H), 3.20-3.27 (m, 2H), 6.13 (s, 1H), 9.66 (br s, 1H).
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=O)C.[OH-].[K+].[Cl-].[Na+]>CO.O>[OH:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(C)cc(C)nc2n(C)c1=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c2c(=O)n(CCCC[C@@H](C)O)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of the crude (R)-3-(5-acetoxyhexyl)-1,5,7-trimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione in methanol (10 ml) and was added a solution of potassium hydroxide (200 mg) in water (1 ml) was added. After stirring at room temperature for 3 hours, saturated aqueous sodium chloride solution (5 ml) and water (5 ml) were added. The methanol was evaporated under reduced pressure and the aqueous mixture was extracted with ethyl acetate (20 ml). The organic layer was applied to a short column of silica gel. Elution with ethyl acetate afforded (R)-3-(5-hydroxyhexyl)-1,5,7-trimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (227 mg, 84% yield) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.19 (d, 3H), 1.33-1.79 (m, 6H), 2.53 (s, 3H), 2.77 (s, 3H), 3.68 (s, 3H), 3.80 (m, 1H), 4.04 (t, 2H), 6.82 (s, 1H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:2].[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=C=O)[CH:30]=[C:31]([Cl:33])[CH:32]=1>C1COCC1.C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[NH:34][C:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC=O)CC2)c1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)Nc3cc(Cl)cc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-(3-{1-[4-(formylamino)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,5-dichlorophenyl isocyanate: ESMS m/e: 505.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1ccccc1S
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1cccc(Sc2ccccc2C(C)C)c1
Yield: 93.3 %

Procedure:
The general procedure in example 39 was followed. 3-Iodoanisole (234 mg, 1.0 mmol), 2-Isopropylbenzenethiol (90% purity, 168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-(2-isopropylphenyl)sulfanylanisole (241 mg, 93% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=40/1). Rf=0.3 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.29-7.36 (m, 3 H), 7.09-7.17 (m, 2 H), 6.67-6.73 (m, 3 H), 3.72 (s, 3 H), 3.54 (hept, 1 H, J=6.9 Hz), 1.22 (s, 3 H), 1.19 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 160.1, 150.9, 139.0, 134.5, 132.1, 129.9, 128.9, 126.8, 126.3, 121.4, 114.4, 111.9, 55.6, 31.1, 24.0. IR (neat, cm−1) 3060, 2962, 2867, 2834, 2362, 2343. MS (EI) m/z (relative intensity) 258 (100), 241 (30), 225 (30). HRMS (EI), Cald. for C16H18OS 258.1078; Found 258.1080.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-])=O)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>[Ni].C(O)C>[NH2:17][C:9]1[C:10]([F:16])=[C:11]([F:15])[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Yield: 34.7 %

Procedure:
A suspension of 1.9 g (5.3 mmoles) of ethyl 1-cyclopropyl-5-nitro-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.5 g of Raney nickel and 100 ml of ethanol was shaken in a hydrogen atmosphere at pressures of 42.5-50 psi and temperatures of 24-26.5° C. for ten hours. The mixture was filtered through Celite and some insoluble product was dissolved in tetrahydrofuran with filtration. The combined filtrates were evaporated in vacuo and the residue was chromatographed on silica gel to give 600 mg of the title compound, mp 223-225° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>CN(C=O)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:21]=[CH2:22])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOP(=O)(COc1ccc(Br)cc1[N+](=O)[O-])OCC
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OCP(=O)(OCC)OCC)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Example 31, Step A from 2-fluoro-5-bromonitrobenzene) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 6 h. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was subjected to Step B of Example 31, Step B of Example 29, and Step D of Example 27 to give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (34.1). mp>167° C.(dec.). Anal. calcd. for C11H12N3O4PS2: C: 38.26; H: 3.50; N: 12.17. Found: C: 37.87; H: 3.47; N: 11.93.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[OH2:13]>>[C:10](=[O:11])([OH:13])[OH:12].[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: O=C(O)O

Procedure:
40 grams of powder L-arginine of Ajinomoto C-grade are mixed with 40 grams of deionized water in a 1:1 weight ratio for reaction. After reaction, 60% (w/w) arginine bicarbonate aqueous solution was obtained. The reaction temperatures are 45, 60, and 75° C., and the pressures are 68948 Pa (10 psi), 137895 Pa (20 psi), 275790 Pa (40 psi), 413685 Pa (60 psi), and 551580 Pa (80 psi) as shown on the gauge on the CO2 tank regulator. The thermo-equilibrium time is for 5 minutes and the reaction time is for 10 minutes. Detailed compositions and conditions utilized for the reactions performed at high pressure and temperature are listed in Table 1.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[CH:42]/[S:43]([CH3:46])(=[O:45])=[O:44])/[C:15]([CH:17]2[C:40](=[O:41])[N:19]3[C:20]([C:33]([O:35]C(C)(C)C)=[O:34])=[C:21]([CH2:25][S:26][C:27]4[N:31]([CH3:32])[N:30]=[N:29][N:28]=4)[CH:22]([NH2:24])[S:23][C@H:18]23)=[O:16])[N:13]=1)=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[CH:42]/[S:43]([CH3:46])(=[O:45])=[O:44])/[C:15]([CH:17]2[C:40](=[O:41])[N:19]3[C:20]([C:33]([OH:35])=[O:34])=[C:21]([CH2:25][S:26][C:27]4[N:31]([CH3:32])[N:30]=[N:29][N:28]=4)[CH:22]([NH2:24])[S:23][C@H:18]23)=[O:16])[N:13]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(C(=O)/C(=C\S(C)(=O)=O)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1N
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(C(=O)/C(=C\S(C)(=O)=O)c3csc(N)n3)[C@H]2SC1N

Procedure:
When the product prepared in Example 6 is treated with trifluoroacetic acid as described in Example 5, the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[OH:13]>C(OCC)(=O)C.[C].[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[OH:13])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(O)c1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1C(O)c1ccccn1
Yield: 90.4 %

Procedure:
(2-methoxy-4-nitrophenyl)(pyridin-2-yl)methanol (0.5 g) was dissolved in ethyl acetate (25 ml), and the solution was reduced by catalytic hydrogenation overnight with 10% palladium-carbon of 50% hydration (50 mg). The catalyst was removed, and the solvent of the filtrate was distilled off to give (4-amino-2-methoxyphenyl)(pyridin-2-yl)methanol (0.4 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:15][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=3)[CH2:30][CH2:29]2)[CH:23]=1)=[O:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CCCOc1ccc(C=O)c2ccccc12
Product: CCCOc1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc12

Procedure:
Prepared by Procedure F and Scheme R using 4-propoxy-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 445.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=2)[N:30]=1>>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]2[CH2:9][CH2:10][N:11]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C:34]([F:35])([F:37])[F:36])=[N:32][N:33]=4)[N:30]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1ccc(C(c2ccccc2)N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-[phenyl-[4-(trifluoromethyl)phenyl]methyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[phenyl-[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[O:5][N:4]=1.CN(C)C=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+:25]>CO>[N:18]1([CH2:2][C:3]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[O:5][N:4]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[Na+:25]
Reactant: C1COCCN1
Reactant: O=C(O)CCc1nc(CCl)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C([O-])CCc1nc(CN2CCOCC2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A 25 mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with 3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)propionic acid (1.48 g, 7.77 mmol), dimethylformamide (4 mL) and morpholine (2.0 g, 22.9 mmol). The reaction mixture was then stirred for 4 h at ambient temperature. The resulting suspension was filtered, and the filter cake was washed with ether and dried to afford 2.52 g of the crude product. A portion (1.49 g) of this material was dissolved in methanol (6 mL) and treated with sodium hydroxide (399 mg, 9.98 mmol). After 1 h, the reaction mixture was concentrated to dryness under vacuum, and then triturated with ethyl acetate. The precipitate was filtered and dried under reduced pressure affording a 68% yield of sodium 3-[3-(morpholin-4-ylmethyl)-1,2,4-oxadiazol-5yl]propionate, contaminated with a small amount of sodium acetate, as a white solid. This material was used directly. m.p. 155-161° C. (dec.); 1H NMR (DMSO-d6) δ (ppm) 3.56 (m, 6H), 2.98 (t, 2H,J=7.2 Hz), 2.46 (t, 4H,J=4.3 Hz), 2.36 (t, 2H,J=7.2 Hz): m/z=263 (M−Na).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl.[CH3:19][CH:20]([CH3:27])[CH2:21][O:22][CH2:23][CH2:24][NH:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:25]([CH2:24][CH2:23][O:22][CH2:21][CH:20]([CH3:27])[CH3:19])[CH3:26]
Reactant: CNCCOCC(C)C
Reactant: CC1(C)[C@H]2CC[C@@H](CCOCCCCCCl)[C@@H]1C2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COCCN(C)CCCCCOCC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
15 g of 5-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethoxy]pentyl chloride were dissolved in 100 ml of dimethylformamide. 5.13 g of N-[2-(2,2-dimethylethoxy)ethyl]-N-methylamine (Example 12 B)), 12 g of potassium carbonate and 1 g of potassium iodide were added to the solution. The reaction mixture was stirred at a temperature of 80° C. for 12 hours. The reaction mixture was worked up by concentrating it under reduced pressure, adding 100 ml of water to the residue, and extracting the mixture three times with 80 ml portions of dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate, filtered and concentrated. The crude product remaining as a residue was purified by chromatography on silica gel using dichloromethane/methanol as the eluent. 4.1 g of oily N-(5-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethoxy]pent yl)-N-[2-(2,2-dimethylethoxy)ethyl]-N-methylamine were obtained.
Reaction SMILES: C(OC(N1C[C@@H](S[C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H](O)C)[C:14]=2[C:25]([O:27]CC=C)=[O:26])C[C@H]1COCCF)=O)C=C.N1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[CH3:20][CH:19]1[CH:18]2[N:15]([C:16](=[O:24])[CH2:17]2)[C:14]([C:25]([OH:27])=[O:26])=[CH:13]1
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCO
Product: CC1C=C(C(=O)O)N2C(=O)CC12
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) [0.32 g) was added to a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.35 g), morpholine (0.84 ml) and triphenylphosphine (0.24 g) in a mixture of water (3 ml), ethanol (12 ml) and tetrahydrofuran (35 ml) at ambient temperature in a stream of nitrogen, and the mixture was stirred at the same condition for 2 hours to give precipitates. The precipitates were collected by filtration, washed with tetrahydrofuran, and dried over phosphorus pentoxide to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)1-hydroxyethyl[-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.67 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:8].O[CH2:10][P+:11]([CH2:16]O)([CH2:14]O)[CH2:12]O>C(O)C>[Cl-:8].[NH:1]([CH2:10][P+:11]([CH2:16][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: CCO
Product: c1ccc(NC[P+](CNc2ccccc2)(CNc2ccccc2)CNc2ccccc2)cc1
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Aniline (7.70 g) was added to a solution of 3.83 g of tetrakis(hydroxymethyl)phosphonium chloride (THPC) in 75 ml of ethanol. There was a mild exotherm, followed immediately by the separation of solids. The mixture was stirred for 2 hours and then filtered, giving 9.15 g (93.0 percent yield) of tetrakis(anilinomethyl)phosphonium chloride, m.p. 129°-130°, as a white crystalline solid that yellowed rapidly on exposure to light. No further solids separated from the filtrate in the next 5 hours. The filtrate and washings, stripped under vacuum, left 1.15 g of a yellow oil containing the remainder of the product and the unreacted aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:12]=2)=[CH:7][C:4]=1[CH:5]=O.[OH-].[NH4+:31].II>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:31]
Reactant: [NH4+]
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)cc1C=O
Agent: II
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The aldehyde 36 (98 mg, 241 μmol) was dissolved in tetrahydrofuran (5 ml). To this was added 30% aqueous ammonium hydroxide (3 ml) and iodine (79 mg, 313 μmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with ether and ethyl acetate. The organics were washed with aqueous sodium sulfite (50 mg) in water (10 ml). The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 37 (95.8 mg, 98%).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:19]([CH3:20])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C@H:2]1[C@H:19]([CH3:20])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)[C@H](C)NC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1NC(=O)c2cc3ccc(C(=O)O)cc3n2[C@H]1C
Temperature: 80 °C
Yield: 94.6 %

Procedure:
To a suspension of ethyl trans-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (930 mg, 3.2 mmol) in ethanol (40 mL) is added 1M NaOH solution (10 mL, 10 mmol). The reaction mixture is heated at 80° C. for 1 h and then cooled to room temperature. The reaction mixture is acidified using concentrated HCl and ethanol is removed under vacuum. The resulting solid is filtered, rinsed with water and dried to afford the title compound (782 mg, 93%).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)C.[OH-].[K+].Cl>CO>[O:17]=[C:14]1[CH:13]=[CH:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:18])=[O:3])=[CH:6][CH:7]=2)[CH:16]=[CH:15]1
Reactant: CCOC(=O)c1ccc(-n2ccc(=O)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-n2ccc(=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
A mixture of 4-(4-oxo-4H-pyridin-1-yl)benzoic acid ethyl ester (10.0 gm, 41.1 mmol), potassium hydroxide (6.92 g, 123 mmol) and methanol (250 ml) was stirred overnight at room temperature. The mixture was acidified by dropwise addition of concentrated hydrochloric acid and the precipitate was collected by suction filtration to give the product as a white powder (9.08 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1([CH3:34])[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][N:15]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=O>C(O)(=O)C>[C:8]([C:7]1[C:2]2[N:1]=[C:12]([C:14]3([CH3:34])[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][N:15]3[C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[NH:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)(=[O:10])[NH2:9]
Reactant: CC1(C(=O)Nc2cccc(C(N)=O)c2N)Cc2ccccc2CN1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: CC1(c2nc3c(C(N)=O)cccc3[nH]2)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Step-5: A solution of benzyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (40 mg, 0.087 mmol) in acetic acid (2 ml) was heated to 80° C. and stirred overnight. The reaction was further heated to 120° C. for 3 h. The reaction mixture was concentrated, neutralized with aq. NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Purification of the crude product by preparative TLC using hexane/ethyl acetate (1:1) mixture as eluent afforded benzyl 3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 441.22 [M+H]+