Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: Cc1cccc2cc[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c1NCC2
Reaction time: 1 h
Yield: 111.5 %

Procedure:
To a stirred solution of 7-methylindole (10.27 g, 78.3 mmol) in glacial acetic acid (50 mL) is added sodium cyanoborohydride (6.33 g, 100.7 mmol) portionwise over a 5 minute period. The reaction solution is allowed to stir for 1 hour. The solution is diluted with water (500 mL) and basified with 50% sodium hydroxide solution. The basic solution is extracted with three 250 mL portions of diethyl ether. The organic fractions are combined, dried over anhydrous potassium carbonate, filtered and evaporated to give a pink oil. The oil is purified by silica gel column chromatography using 20% ethyl acetate/hexanes as eluent to give 11.63 g of 2,3-dihydro-7-methylindole as a colorless oil (94% yield).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:20])OC(C)(C)C)=[N:10][C:9]=2[C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCOCC1>[CH:1]1([C:6]([C:8]2[S:12][C:11]([NH:13][C:14]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:20])=[N:10][C:9]=2[C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCCC2)s1
Solvent: C1COCCO1
Product: O=C(c1sc(NC(=O)N2CCOCC2)nc1-c1ccco1)C1CCCC1
Reaction time: 8 h
Yield: 64.6 %

Procedure:
Compound 432 (251 mg, 0.693 mmol) was dissolved in 1,4-dioxane (5 mL), and morpholine (6.19 mL, 70.9 mmol) was added thereto, followed by stirring overnight under heating and reflux. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the entitled Compound 435 (168 mg, 64%) as a pale brown solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[OH:50][CH2:51][C@H]1[C@H](O)CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@@H:51]([OH:50])[C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC[C@@H]1NCC[C@H]1O
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CC[C@@H](O)[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,3R)-2-(hydroxymethyl)pyrrolidin-3-ol and isolated as light-yellow gum (9.6 mg, 49%). MS (m/e): 417.4 (MH+).
Reaction SMILES: [Br-].C[O:3][C:4](=[CH:25][C:26]([O:28][CH3:29])=[O:27])[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[CH:33](=O)[CH:34]1[CH2:39][CH:38]=[CH:37][CH2:36][CH2:35]1.S(=O)(=O)(O)O>CO.O1CCOCC1>[CH:37]1[CH2:36][CH2:35][CH:34]([CH:33]=[CH:5][C:4](=[O:3])[CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:39][CH:38]=1
Reactant: COC(=O)C=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OC
Reactant: O=CC1CC=CCC1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC(=O)C=CC1CC=CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
In 100 ml of methanol was dissolved 25.7 g of [2-methoxy-3-(methoxycarbonyl)allyl]triphenylphosphonium bromide, and to this solution was added dropwise 10.5 g of a 28% by weight solution of sodium methoxide in methanol with stirring at room temperature over 10 minutes. To the mixed solution was then further added 5 g of 1,2,3,6-tetrahydrobenzaldehyde at room temperature and the resulting mixture was subjected to reaction at the same temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and to the residue was added 50 ml of water. The resulting mixture was extracted with 50 ml of chloroform. The extract was dried with anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: benzene/n-haxane (3:1 by volume) mixture) to obtain an oily substance. This oily substance was dissolved in 100 ml of dioxane, and to the solution was then added 100 ml of 0.1N sulfuric acid. The resulting mixture was subjected to reaction at 100° C. for 1.5 hours. The solvent was then removed by distillation under reduced pressure, and to the residue was added 100 ml of chloroform. The resulting mixture was washed with 100 ml of water. The organic layer was separated, and dried with anhydrous magnesium sulfate and then the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: benzene/n-hexane (3:1 by volume) mixture) to obtain 7.5 g of oily methyl 5-(cyclohexen-4-yl)-3-oxo-4-pentenoate.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In acetonitrile (80 ml), tert-butyl 1-piperazine carboxylate (2.50 g) was dissolved. Under ice cooling, benzyl bromide (1.59 ml) and triethylamine (1.87 ml) were added dropwise to the resulting solution, followed by stirring at room temperature for 90 minutes. After the solvent was distilled off under reduced pressure, distilled water and dichloromethane were added to the residue to separate the organic layer. The organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (ethyl acetate:hexane=1:20 to 1:5), whereby the title compound (3.12 g, 84%) was obtained as colorless powder.
Reaction SMILES: Br[C:2]([Br:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[Si](CC)(CC)CC.[C:18]1(=[O:23])[CH2:22][CH2:21][CH:20]=[CH:19]1>[Zn].C(#N)C>[Br:9][C:2]([F:8])([CH:20]1[CH2:21][CH2:22][C:18](=[O:23])[CH2:19]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(Br)Br
Reactant: O=C1C=CCC1
Agent: CC[Si](Cl)(CC)CC
Agent: [Zn]
Solvent: CC#N
Product: CCOC(=O)C(F)(Br)C1CCC(=O)C1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 40.4 g of ethyl dibromofluoroacetate was added dropwise to a suspension of 22.4 mL of chlorotriethylsilane, 8.0 g of zinc, and 250 mL of acetonitrile, over 2 hours at −20° C. The mixture was further stirred for 1.5 hours at −20° C. 2-cyclopenten-1-one in an amount of 5.0 g was added dropwise to the reaction solution, and the mixture was stirred for 15 hours at −20° C. The reaction was quenched with 1M hydrochloric acid, followed by concentration under reduced pressure. After extraction of the residue with diethyl ether twice, the organic layers were combined. The combined organic layer was washed with a saturated aqueous solution of sodium chloride, and was subsequently dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=10:1 to 8:1), thereby yielding 6.2 g of (2SR)ethyl 2-bromo-2-fluoro-2-[(1RS)-3-oxocyclopentyl]acetate and 4.4 g of (2RS)ethyl 2-bromo-2-fluoro-2-[(1RS)-3-oxocyclopentyl]acetate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-methylpyridazine. ESI-MS (m/z): 406 [M+1]+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH:14]=[CH:13]2
Reactant: [N-]=[N+]=NC[C@H]1C=Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1C=Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
To a solution of ((R)-2-azidomethyl-8-(2,6-dichloro-phenyl)-6-fluoro-2H-chromene (300 mg, 0.85 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.85 g, 2.6 mmol) and the reaction mixture stirred at room temperature for 43 hours. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under vacuum. Chromatography with 0–10% methanol in methylene chloride plus 1% NH4OH afforded {[(2R)-8-(2,6-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}amine as a colorless oil. The oil was dissolved in ethyl acetate and made into its hydrochlorde salt (83 mg, 27%) as a white crystalline solid using excess ethereal hydrochloric acid, mp 153–155° C.; [α]D25=+220.67° (c 1% solution in MeOH); MS (ES) m/z 324.0 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 4-chloro-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3): δ 7.20 (dd, 2H, J=4.4 Hz, 2.0), 7.31 (m, 2H), 7.53 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.65 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.79 (dd, 2H, J=4.4 Hz, 1.6 Hz), 10.00 (s, 1H). MS: m/z 407.1 (M++1).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=O)[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.P(Cl)(Cl)(OC1C=CC(Cl)=CC=1)=O.CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[N:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: c1nc[nH]n1
Agent: O=P(Cl)(Cl)Oc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(-n3cncn3)nc2=O)C[C@@H]1N=[N+]=[N-]
Yield: 60 %

Procedure:
5'-O-Acetyl-3'-azido-3'-deoxythymidine was reacted with 5 equivalents of 1,2,4-triazole and two equivalents of 4-chlorophenyl dichlorophosphate in dry pyridine at ambient temperature for 10 days. Silica gel chromatography of the crude product using 1:1 EtOAc/hexane (v/v) followed by combination and evaporation of the appropriate fractions yielded an oil. Crystallization from EtOAc afforded the title compound as a solid 2.7 g (7.5 mMol; 60%); m.p.=143°-145° C. UV (nm): at pH 1λmax =324,245,215 (ε=9300, 10000, 20500), λmin =282,233 (ε=2100,8200); at pH 13λmax =276 (ε=6000), λmin =242 (ε=2000), H1NMR (DMSO-d6) δ9.34, 8.40(2s,2H, triazolyl), δ8.23(s,1H,H6), δ6.12(t, 1H, H1', J=6.16 Hz), β4.48-4.17(m, 4H, H3', H4', H5'), δ2.35(s, 3H, 5'-acetyl), δ2.07(s, 3H, 5CH3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[CH:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:22][CH2:23]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: C1CCC(C2CCNCC2)CC1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)nnn2CCCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-cyclohexyl)piperidine (5.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.5 g compound (I-155) with a yield of 63.7%. ESI-MS [M+H]+: m/z 341.3.
Reaction SMILES: C1(C(O)=O)C2C(=CC=CC=2)C=CC=1.S(Cl)(Cl)=O.N.[CH3:19][O:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:33](=O)[NH2:34])[CH:29]=2)[CH:24]=1)=[O:22].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.COP(OC)(OC)=O>[CH3:19][O:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:33]#[N:34])[CH:29]=2)[CH:24]=1)=[O:22]
Reactant: COC(=O)c1ccc2cc(C(N)=O)ccc2c1
Agent: N
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: COP(=O)(OC)OC
Product: COC(=O)c1ccc2cc(C#N)ccc2c1

Procedure:
Compounds of formula II, where T is a bond, B is H, each of-e and g is C—H, f is a bond, V is a substituted carbonyl group, and Z′ is NH can be prepared as follows. Hydrolysis of naphthalene-2,6 dicarboxylic acid dimethyl ester with one equivalent of a base such as KOH, followed by acidification of the product with an acid such as HCl, affords the naphthalene mono carboxylic acid. After conversion of the carboxylic acid to an acid chloride with a reagent such as thionyl chloride and subsequent reaction with ammonia in methylene chloride, the resulting 6-carbamoyl-naphthalene-2-carboxylic acid methyl ester is reacted with triphosgene in trimethylphosphate to provide 6-cyano-naphthalene-2-carboxylic acid methyl ester. Hydrolysis of the ester with LiOH in aqueous THF solution, followed by reaction with thionyl chloride, affords 6-cyano-naphthalene-2-carbonyl chloride, which can then be coupled with alcohols or amines to provide compounds of the formula XX. The amidine, hydroxyamidine, or aminoamidine groups can be obtained from the nitrile as described previously to afford compounds the formula XXI, where R19 is H, and R22 is H, alkyl, OH, or NH2, and V is an alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, aralkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, or heteroaralkyloxycarbonyl.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][CH2:31][CH2:32]I>C(#N)C.O>[F:30][CH2:31][CH2:32][N:22]1[CH2:21][CH2:20][C:6]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)\[CH3:13])[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[CH2:23]1
Reactant: FCCI
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(CCF)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
8-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (60 mg, 0.19 mmol) was dissolved in acetonitrile (1 mL). Potassium carbonate (82 mg, 0.9 mmol) and 1-Fluoro-2-iodo-ethane (45 mg, 0.25 mmol) were added and stirred at RT for 1 h. The reaction mixture was heated at 80° C. for 1 h. After 1 h the reaction mixture was cooled to RT, diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtained 33 mg of desired product. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.62 (d, 2H), 7.80 (d, 2H), 7.42 (s, 1H), 7.36 (s, 1H), 7.10 (m, 2H), 5.05 (m, 1H), 4.92 (m, 1H), 4.65 (s, 2H), 3.82 (m, 3H), 3.78 (m, 1H), 3.20 (m, 2H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])[CH:7]=[C:8]([NH:10][C:11](=[O:17])[C:12]([O:14]CC)=[O:13])[CH:9]=1)(=[O:3])[NH2:2].[OH-].[Na+].O>C(Cl)Cl>[OH2:3].[C:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:17])[C:12]([OH:14])=[O:13])[CH:7]=[C:6]([NH:18][C:19](=[O:25])[C:20]([OH:22])=[O:21])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)C(=O)Nc1cc(NC(=O)C(=O)OCC)cc(C(N)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cc(NC(=O)C(=O)O)cc(NC(=O)C(=O)O)c1

Procedure:
A mixture of 5.26 gm. (0.015 mole) of diethyl (5-carbamoyl-m-phenylene)dioxamate, 33 ml. of 1N sodium hydroxide solution and 50 ml. of water is stirred for twenty minutes. Methylene chloride (85 ml.) is added and stirring continued for an additional thirty minutes. The aqueous layer is separated and acidified by the addition of dilute hydrochloric acid. The precipitate is removed by filtration and washed with water. The solid is purified by dissolving it in a dilute solution of THAM, filtering the solution and reprecipitation by the addition of a filtered solution of dilute hydrochloric acid. There is obtained 4.7 gm. of material melting at 220° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[C:19]([O:38][CH2:39][CH2:40][OH:41])=[N:20][N:21]([CH3:37])[C:22]=3[NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:17][C:12]=2[O:11][CH2:10]1>>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[C:19]([O:38][CH2:39][CH2:40][O:41][C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=4)=[N:20][N:21]([CH3:37])[C:22]=3[NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Clc1ncc(Br)cn1
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (45 mg) of 5-bromo-2-chloropyrimidine was used and that N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 17) (70 mg) was used in place of 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude was purified by HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (19.6 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]([CH:13]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:14]1)=[O:12].Cl.[NH2:28][CH2:29][C:30]1[C:35]([Cl:36])=[N:34][CH:33]=[CH:32][N:31]=1>ClCCl>[Cl:36][C:35]1[C:30]([CH2:29][NH:28][C:11]([CH:13]2[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14]2)=[O:12])=[N:31][CH:32]=[CH:33][N:34]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(Cl)C1CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
N,N-diisopropylethylamine (109 mmol, 18.01 ml) and a solution of benzyl 3-(chlorocarbonyl)azetidine-1-carboxylate (5.53 g) in dichloromethane (32.5 ml) were added to a stirred suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 21.80 mmol, 5.10 g) in dichloromethane (55 ml) at room temperature to give a dark brown solution. After stirring at room temperature for two hours the reaction mixture was quenched with water and filtered over decalite. Layers were separated and to the aqueous layer saturated aqueous sodium hydrogencarbonate solution was added and the layer was extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol gradient 10/0 to 9/1) to give benzyl 3-((3-chloropyrazin-2-yl)methylcarbamoyl)azetidine-1-carboxylate (6.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:26]1[O:29][CH:27]1[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=2[F:18])[CH2:26][CH:27]([OH:29])[CH3:28])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Reactant: CC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)CC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-(4-Chloro-benzenesulfonylmethyl)-1,3,4-trifluoro-benzene (Example 8, step 2, 305 mg, 0.95 mmol) was dissolved in 4 mL THF. The solution was cooled to −78° C. and butyllithium (2.5M in hexane, 0.4 mL) was added slowly. The solution was stirred at −78° C. for 2 h then warmed to 0° C. and stirred for 0.5 h. The solution was then cooled to −78° C. again and propylene oxide (178.0 mg, 3.1 mmol) in 3.25 mL of THF was added slowly and the reaction mixture was allowed to stir and warm to room temperature overnight. The reaction mixture was quenched with a saturated NH4Cl solution (50 mL). The reaction mixture was extracted three times with EtOAc (50 mL each) and the combined organics were washed with water (100 mL) and brine (100 mL). The organic layer was then dried over Na2SO4 and concentrated. The product was purified using column chromatography (hex./EtOAc 100/0 to 70/30 in 60 min. 0.19 g, 52%). 1H NMR (CDCl3 400 MHz) δ 7.59 (m, 2H), 7.42 (m, 2H), 7.10 (m, 1H), 6.81 (m, 0.5H), 6.66 (m, 0.5H), 4.83-4.99 (m, 1H), 4.06 (m, 0.5H), 3.51 (m, 0.5H), 2.50-2.74 (m, 1H), 2.26 (m, 1H), 1.03-2.24 (m, 3H). The product is a mixture of diastereomers.