Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][C:9](=[CH:14][C:15]([O:17]C)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[O:3]1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[O:17]=[C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[NH:8][C:7]2[C:2](=[O:1])[O:3][C:4]3[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=3[C:6]1=2
Reactant: COC(=O)C=C(Nc1cc2ccccc2oc1=O)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Yield: 93.5 %

Procedure:
A solution of 2-[(2-oxo-2H-1-benzopyran-3-yl)amino]-2-butenedioic acid, dimethyl ester (3.0 g, 0.0099 mole) in diphenyl ether (50 ml) is heated at 274-285 for 60 minutes under nitrogen. The reaction mixture is cooled and diluted with hexane. The product is filtered off and washed with ethyl acetate. Recrystallization from dimethyl formamide gives white crystals (2.51 g, 93%), mp 225-227.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:10][CH2:9][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[NH:38][C:37]2=[O:45])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:11]1([C:8]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7][CH2:6][CH:5]([N:30]3[CH2:31][CH2:32][CH:33]([N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[NH:38][C:37]4=[O:45])[CH2:34][CH2:35]3)[CH2:10][CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccccc3)(c3ccccc3)CC2)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CCC(c3ccccc3)(c3ccccc3)CC2)CC1
Temperature: 55 °C
Reaction time: 47 h

Procedure:
A mixture of 4.1 g of 4,4-diphenylcyclohexyl tosylate, 2.2 g of 4-piperidyl-2-benzimidazolinone, 1.5 g of potassium carbonate, 1.5 g of potassium iodide and 50 ml of dimethylformamide is stirred at 55° C for 47 hours. The reaction mixture is cooled to room temperature and poured into ice water. The precipitate is collected by filtration and dissolved in chloroform under warming. The solution is washed with water and dried over sodium sulfate, and the chloroform is removed under reduced pressure. To the residue is added ether, and the mixture is cooled. The precipitated crystals are collected by filtration and recrystallized twice from a mixture of methanol and chloroform. The crystals are dried at 100° C under reduced pressure for many hours, because the solvent is not easily removable. Thus is obtained 1-[1-(4,4-diphenylcyclohexyl)-4-piperidyl]-2-benzimidazolinone as light gray crystals, melting at 289°-293° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1)=O)(C)(C)C.Cl.CO>O1CCOCC1>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1
Reactant: COC(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C1CCCC(N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask, methyl 3-(tert-butoxycarbonylamino)cyclohexanecarboxylate (5.13 g, 19.94 nmol) in 1,4-dioxane (15 ml) was reacted with hydrochloric acid in dioxane (4M) (15 mL). Methanol (2 mL) was added to aid in solubility. The reaction was stirred at room temperature for 1 hour. Upon completion the reaction was concentrated, and the crude (3.86 g) was progressed to the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1)[CH3:2].O.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[CH:50]=O>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:5]2[CH:50]([C:49]([O:53][CH2:54][CH3:55])=[O:52])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C=O
Reactant: CCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
2-Ethyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (7.48 g) is dissolved in tetrahydrofuran (60 ml) to which is added ethyl glyoxylate hydrate (1.56 g). The reaction mixture is stirred overnight at room temperature and then refluxed for one hour. The solution is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(1-trityl- 1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.54 g) as a foam, characterized as its oxalate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:50])[C:22]([C:24]5[S:28][C:27]([NH:29]C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)=[N:26][C:25]=5[CH3:49])=[O:23])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:51])[N:7]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[F:59])[C:6]2=[O:60])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]([CH3:50])[C:22]([C:24]5[S:28][C:27]([NH2:29])=[N:26][C:25]=5[CH3:49])=[O:23])=[CH:19][CH:20]=4)[NH:10][C:9]=3[C:8](=[O:51])[N:7]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[F:59])[C:6]2=[O:60])[CH2:3][CH2:2]1
Reactant: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)sc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
A solution of 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (74.0 mg, 0.09 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was treated with triethylsilane (16 μL, 0.10 mmol). The reaction was concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 2-amino-4-methyl-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (3.0 mg, 5.8%) as a white solid: (ES)+-HRMS m/e calcd for C29H28N7O3SF (M+H)+ 574.2031, found 574.2035.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].CC[O-:15].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>CO.CCCCCC.C1(C=CC(O)=CC=1)O>[C:10]([OH:11])(=[O:15])[CH:8]=[CH2:6].[C:17]([OH:20])(=[O:3])[CH:18]=[CH2:19].[CH2:10]([OH:11])[C@H:8]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:12])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: C=CC(=O)Cl
Reactant: CC[O-]
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: C=CC(=O)O
Temperature: 17 °C
Reaction time: 10 h

Procedure:
9.1 g mannitol (D(-)-Mannitol, Merck, for determination of boric acid) is mixed to an emulsion in 120 ml methanol (Merck, dried for analysis purposes) in a round flask, and is subsequently dissolved through boiling in reflux. 18 g of sodium ethylate is then slowly added (Merck, 30% in methanol) and boiled in reflux for one hour. A felt of long needles is formed. Methanol is then evaporated off in a vacuum and the mixture is mixed to an emulsion four times in n-hexane and once again the solvent is removed and the mixture is dried in a desiccator. 11.5 g of a light yellow crystaline substance is obtained. This is mixed to an emulsion in 120 ml n-hexane in a 250 ml round flask and maintained at 17 degrees C. Under heavy agitation, 9.1 g acryloyl chloride is slowly added (Merck, stabilised for synthesis). After 5 hours of agitation and 10 hours standing, 0.1 g of hydroquinone is added and the mixture is dried in a vacuum. 21.3 g of a mannitol diacrylate and common salt mixture is formed. The mixture is dissolved in 200 ml deionised water and subsequently, by means of an ion exchanger, (Amberlite IR 120, acidic) separated from the common salt. 0.1 g hydroquinone is introduced into the eluate, the water is removed and drying in a desiccator is then undertaken. 15.3 g of a light yellow substance remains. This is completely soluble in water or in acrylic acid. It is hard to dissolve in acetone, methanol, ethanol or ethyl acetate.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[OH:26]>C(Cl)Cl>[OH:26][C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[NH:18][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(N)c(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C)cc2O)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Pyridine (810 μl) and then, a little at a time, p-toluenesulfonyl chloride (1.91 g, 10 mmol) are added to a solution of 2-amino-5-methylphenol (1.23 g, 10 mmol) in CH2Cl2 (20 ml). The reaction mixture is stirred at 40° C. for 4 h. The solvent is distilled off under reduced pressure, ethyl acetate is added to the residue and the solid is filtered off with suction.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)=[O:4].[CH3:32]I>CN(C)C=O.C(OCC)(=O)C.[Ag]>[CH3:1][O:2][C:3]([CH:5]([N:24]([CH3:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)C(CCc1cn(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C
Agent: [Ag]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1cn(C(=O)OC(C)(C)C)c2ccccc12)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
295 g of silver(l) oxide are added, with stirring, to a solution of 75 g of N-tert-butyloxycarbonyl-amino-3-(1-tert-butyloxycarbonyl-indol-3-yl)-propanecarboxylic acid methyl ester in 770 ml of N,N-dimethylformamide. 75 ml of methyl iodide are then added dropwise. The reaction mixture rises to a temperature of 40° and is stirred at room temperature for 2 days and then diluted with 800 ml of ethyl acetate, filtered and concentrated by evaporation. The residue is purified by chromatography (silica gel, hexane/ethyl acetate 3:2). In this way the title compound is obtained in the form of a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 64 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-phenyl-5-methyl-oxazole, the title compound was obtained in 64% yield as a pale yellow solid. MS: (M−H)− 403.3.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]=[N+:26]=[N-:27])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([O:30][C:31](=[O:38])[CH:32]=[C:33](NC)NC)[CH3:29]>O1CCOCC1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[CH:33]=[C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:38])[N:27]=[N:26]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=C(NC)NC
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N=[N+]=[N-])ccc32)n1)c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)nn1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution containing 12.5 mg of 2-[(S)-1-phenylethylamino]-4-[5-azidobenzimidazol-1-yl]pyrimidine and about 100 μL ethyl-3,3-dimethylaminoacrylate in 2 mL 1,4-dioxane was stirred at 90° C. for 48 hours. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 6.0 mg of the title compound. RF: 0.4 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, 1:1 CD3OD/CDCl3): δ 1.42 (t, J=7.1 Hz, 3H), 1.59 (d, J=7.1 Hz, 3H), 4.44 (q, J=7.1 Hz, 2H), 5.16 (m, 1H), 6.92 (d, J=5.5 Hz, 1H), 7.24 (br s, J=7.3 Hz, 1H), 7.36 (br s, J=7.3 Hz, 2H), 7.45 (d, J=7.3 Hz, 2H), 7.68-7.8 (m, 1H), 7.95 (m, 1H), 8.14 (br s, 1H), 8.38 (br s, J=5.3 Hz, 1H), 8.77 (m, 1H), 8.92 (s, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 455.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C1COCC1.[BH4-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CO)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 50 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde in 200 ml of an ethanol:THF=1:1 mixed solvent there was added 16.4 g of sodium borohydride while cooling on ice. After stirring at room temperature for 2 hours, 1N hydrochloric acid was added to the reaction mixture while cooling on ice. The organic layer was washed with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (50 g) as a crude product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:4][C:5](=[O:14])[N:6]([C@H:8]([C:9]([NH2:11])=[O:10])[CH2:12][CH3:13])[CH2:7]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C(N)=O)N1CC(COS(C)(=O)=O)CC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 4 l three necked flask fitted with mechanical stirrer, dropping funnel and reflux condenser under inert atmosphere, 114 g (569 mmoles, 1 eq) of (2S)-2-[4-hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 are dissolved in 2 l of CH2Cl2 and cooled down to 0° C. 158.5 ml (115 g, 2 eq) of dry triethylamine are added in one portion, followed by dropwise addition of a solution of 66.3 ml (96.2 g, 1.5 eq) of methanesulfonyl chloride in 190 ml of CH2Cl2 over 1 hour, all the while maintaining the temperature below 4° C. After 4 hours, 7.5 ml of methanesulfonyl chloride and 15 ml of triethylamine are added and the mixture is kept overnight in the refrigerator. The mixture is filtered, the residue washed with CH2Cl2 and the combined organic phases concentrated to dryness to give 216 g of crude 37. It is purified by Prep LC in several batches (1 kg SiO2, CH2Cl2/EtOH, 100:0->96:4) to give 109 g of pure 37, 69%.
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C1NCCc2c(-c3ccc(F)c(Cl)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-chloro-4-fluorophenylboronic acid (217 mg, 1.24 mmol) were coupled to yield 2-(3-chloro, 4-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 217 mg (61%), as a pale-yellow solid. mp 234-235° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H, J=7.8 Hz), 7.57 (dd, 1H, J=8.1, 0.9 Hz), 7.61 (m, 2H), 7.69 (dd, 1H, J=7.5, 0.9 Hz), 7.85 (dd, 1H, J=7.2, 2.1 Hz), 8.10 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H13ClFN2O: 315.0700, Found: 315.0704; Anal. (C17H12ClFN2O.1.0 H2O.0.5 MeOH) C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[S:17])SC)[CH2:6][CH2:5]1.[N-:18]=[N+:19]=[N-:20].[Na+]>O.C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:14]([SH:17])=[N:20][N:19]=[N:18]2)[CH2:6][CH2:5]1
Reactant: CSC(=S)NCCCN1CCN(CCO)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCN1CCN(CCCn2nnnc2S)CC1
Reaction time: 4 h
Yield: 28.6 %

Procedure:
To a solution of methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]-propyl]-dithiocarbamate (4.8 g) in a mixture of water (15 ml) and ethanol (10 ml) as added sodium azide (1.5 g). The resulting mixture was refluxed with stirring for 4 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was disolved in water and the solution was washed successively with ethyl acetate and diethyl ether and then evaporated. To the residue was added ethanol and the mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was recrystallized from isopropyl alcohol to give 1-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]-1H-tetrazole-5-thiol (1.35 g).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[N:22]=3)[N:17]=[CH:16][C:15]=2[C:25](=[O:27])[CH3:26])[CH2:9][CH2:8]1)(=O)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:24][C:21]1[N:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25](=[O:27])[CH3:26])=[C:14]2[NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCOCC2)CC1

Procedure:
Following general procedure V, {trans-4-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)-amino]cyclohexyl}methyl methanesulfonate (230 mg, 0.56 mmol) was reacted with morpholine (72 mg, 0.84 mmol) to afford the desired product (85 mg, 38%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.90 (br s, 1H), 8.94 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 5.11-4.88 (m, 1H), 3.77-3.65 (m, 4H), 2.68 (s, 3H), 2.46-2.38 (m, 4H), 2.36-2.21 (m, 2H), 2.21-2.15 (m, 2H), 2.01-1.89 (m, 2H), 1.64-1.50 (m, 1H), 1.46-1.07 (m, 4H); ESI MS m/z 403 [M+H]+
Reaction SMILES: C(Cl)(=O)C.[S:5]1[C:9]([C:10]23[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]2[CH2:13][O:12][N:11]3CC2C=CC(OC)=CC=2)=[CH:8][CH:7]=[N:6]1.FC(F)(F)C(O)=O.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.CCCC(C)C.C(OCC)(=O)C>Cl.O1CCCC1.CC(OC)(C)C.C(Cl)Cl.C(O)(C)C>[S:5]1[C:9]([C:10]23[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]2[CH2:13][O:12][NH:11]3)=[CH:8][CH:7]=[N:6]1
Reactant: COc1ccc(CN2OCC3CN(C(=O)OC(C)(C)C)CC32c2ccns2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CONC2(c2ccns2)C1
Temperature: 45 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Isopropyl alcohol (5.66 L) is cooled to 5° C. and acetyl chloride (941.23 mL, 13.23 mol) is added drop wise (exothermic). The mixture is heated to 45° C., and tert-butyl 6a-isothiazol-5-yl-1-[(4-methoxyphenyl)methyl]-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (460.17 g, 1.10 mol) is added to the reactor in portions. The resulting white suspension is stirred at 45° C. for 1 hour. Most of the solvent is evaporated to give a wet, off-white solid, which is dissolved in trifluoroacetic acid (2.76 L, 36.52 mol). The resulting dark solution is heated to 70° C. and stirred at this temperature for 1 hour. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is azeotroped with toluene (2×2.5 L) to give a light brown solid. The residue is dissolved in 2 M aq. HCl solution (4.6 L) and DCM (4.6 L) and stirred vigorously at 40° C. for 30 minutes until full dissolution. The mixture is cooled to room temperature and separated. The aqueous layer is washed with DCM (2×500 mL). The acidic aqueous layer is cooled to 5° C. and the pH is adjusted to 10.5 by the addition of 50% wt/wt aq. NaOH solution. The mixture is cooled to 10° C. and a solution of BOC2O (252.57 g, 1.16 mol) in tetrahydrofuran (2.30 L) is added slowly. The mixture is stirred for 5 minutes and warmed to 25° C. and then stirred 1 hour longer. MTBE (2 L) is added and the resulting phases are separated. The aqueous layer is extracted with MTBE (2×1 L) and the combined organic layers are washed with brine solution (2 L), dried over MgSO4, filtered, and evaporated under reduced pressure to give the crude product as an off-white solid (347.2 g). The crude solid is dissolved in boiling 7:3 v/v isohexane/ethyl acetate (2.8 L) and the resulting clear solution is allowed to slowly cool to room temperature and then cooled in an ice-bath. The resulting white suspension is filtered and washed with cold 7:3 isohexane:ethyl acetate. The white solid is dried under vacuum and nitrogen for 2 days to give the title compound as a white solid (291.30 g, 88.9%). ES/MS (m/e): 298 (M+H).