Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[C:36]([F:47])=[C:37]2[C:42](=[C:43]([O:45][CH3:46])[CH:44]=1)[O:41][CH2:40][CH2:39][CH2:38]2)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:44][C:43]([O:45][CH3:46])=[C:42]2[C:37]=1[CH2:38][CH2:39][CH2:40][O:41]2
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
After adding 23 mg of 2-hydrazinopyrimidine and 35 μl of triethylamine to a solution of 113 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (82 mg) as a light brown solid.
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26](/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([Cl:43])[CH:42]=2)[C:5](=[O:6])[NH:4][CH2:3]1.ClN1C(=[O:52])CCC1=O>COCCOC.O>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:52][CH:29]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([Cl:43])[CH:42]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)/C=C/c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)/C=C/c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl

Procedure:
Likewise, cryptophycin 3 (about 40 mg, 0.063 mmol) is put into 2:1 DME/H2O (about 6 mL) and N-chlorosuccinimide (0.075 mmol) is added and is heated at about 60-70 C for about 24 hours. A further quantity of NCS (8 mg) is added and continue heating for about another 24 hours. The solvent is removed and the residue subject to HPLC (35% H2O/CH3CN 6 mL/min) to give the desired cryptophycin compounds. The resulting mixture is further purified by HPLC using methanol/water (about 4:1) to obtain the desired purified cryptophycin compounds.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: Cc1cc(O)cc(C)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OC(=O)C(C)(C)C)cc(C)c1O
Yield: 61 %

Procedure:
By using 6.90 g of 2,6-dimethylbenzene-1,4-diol, 6.63 g of pivaloyl chloride, 11.85 g of pyridine and 60 ml of dichloromethane, reaction and purification were carried out in a similar manner to that described in Reference Example 9, whereby 6.77 g of the title compound were obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].S(Cl)([Cl:18])(=O)=O.C(O)=O>O>[Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH2:13][Cl:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOCCBr)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: O=CO
Product: CCOC(=O)C(=NOCCBr)C(=O)CCl
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 82.2 %

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-3-oxobutyrate (syn isomer, 168 g.), sulfuryl chloride (87.3 g.) and formic acid (168 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hours. After adding water (1 l.) to the resultant solution, the mixture was extracted with methylene chloride. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, and then concentrated in vacuo to give ethyl 2-(2-bromoethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 156 g.), oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][CH:15]=1.[C:22](=[S:24])=[S:23].O>C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:16]2[S:23][C:22]([SH:24])=[CH:19][C:18](=[O:20])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: S=C=S
Reactant: CC(=O)CC(=O)c1cccc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc(S)sc(-c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(3-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warm warmed slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (4.28 g, 72%); m.p. 188° C. (decomp); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.07 (d, 1H, J=1.4 Hz, H-3), 7.36 (d, 1H, J=1.4 Hz, H-5), 7.47–7.52 (dd, 1H, J1=J2=7.9 Hz, Ar-5), 7.69–7.72 (d, 1H, J=7.9 Hz, Ar-4/6), 7.76–7.78 (d, 1H, J=7.9 Hz, Ar-4/6), 7.92 (s, 1H, Ar-2); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:4][NH:5][C:6]3[N:26]=[C:10]([NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([CH:25]=4)[CH2:17][CH2:18][CH2:19][O:20][C:21]([CH:24]=2)=[CH:22][CH:23]=1)[N:9]=[CH:8][C:7]=3[Cl:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:27][C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH:25]=3)[CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:24]=[C:3]([CH2:4][NH:5][C:6]=1[N:26]=2)[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:23][CH:22]=3
Reactant: Clc1cnc2nc1NCc1cc(ccc1Br)OCCCc1cccc(c1)N2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1cnc2nc1NCc1cc(ccc1-c1ccccc1)OCCCc1cccc(c1)N2
Yield: 27 %

Procedure:
A mixture of 11-bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene (30.0 mg, 0.067 mmol) (prepared according to Example 14, Step E), phenylboronic acid (9.8 mg, 0.081 mmol), tetrakis(triphenylphosphine)palladium(0) (7.8 mg, 0.0067 mmol), 1,2-dimethoxyethane (0.50 mL), and a solution of sodium carbonate in water (0.17 mL, 2.0 M) was sealed into a microwave vial and the resultant suspension was de-gassed by bubbling with N2. After degassing, the vial was microwaved at 150° C. for 20 min. The reaction mixture was diluted with EtOAc, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to provide the desired product (8 mg, 27%) as a white powder. LCMS for C26H23ClN4O (M+H)+: m/z=443.1. 1H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.41 (dd, J=6.0, 1.2 Hz, 2H), 7.32 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 6.87 (m, 2H), 6.75 (m, 1H), 5.70 (t, 2H), 4.62 (m, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 2.68 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: [C:1]([CH:3]=[C:4]([C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)#[N:2].N[C:28]1C=C(C(C2C=CC(OC)=C(OCC)C=2)=CC#N)C=CC=1OC.C(Cl)(=O)C>CCCCCC>[C:1]([CH:3]=[C:4]([C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH3:28])[CH:6]=1)#[N:2]
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1NC(C)=O
Solvent: CC(=O)Cl
Solvent: CCCCCC
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(C)=O)c2)ccc1OC
Yield: 41 %

Procedure:
N-{5-[2-Cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide (E and Z isomers) were prepared analogously to N-{5-[2-cyano-1-(3,4-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide using 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.4 g, 1.1 mmol) and acetyl chloride (1.1 mL). The crude product was slurried with hexane to give N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide (0.2 g, 41%) as a white solid: mp 155-157° C.; 1H NMR (CDCl3) δ 9.25 (d, J=2 Hz, 1H), 7.90 (d, 13.5 Hz, 1H), 7.17-6.90 (m, 3H), 6.75 (d, J=1 Hz, 1H), 6.13 (s, 1H), 5.97 (s, 1H), 4.02-3.97 (m, 2H), 3.94-3.97 (m, 6H), 2.07 (d, J=7 Hz, 3H), 1.70 (t, 3H); 13C NMR (CDCl3) δ 161.29, 151.18, 150.02, 147.76, 147.32, 130.47, 130.23, 129.18, 128.91, 127.26, 127.22, 122.40, 122.18, 118.77, 118.70, 113.81, 122.20, 111.43, 111.34, 111.04, 110.77, 92.73, 92.45, 63.76, 63.71, 55.87, 55.41, 23.80, 23.68, 14.57; Anal Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.94, 5.93; N, 7.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]([CH2:12][CH:13]=[CH:14][CH2:15][CH3:16])[C:7](=[O:11])[CH:8](Cl)[Cl:9].C(NCCCC)CCC.[ClH:29]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:12][CH:13]([CH:14]([Cl:29])[CH2:15][CH3:16])[CH:8]([Cl:9])[C:7]1=[O:11]
Reactant: CCC=CCN(Cc1cccc(Cl)c1)C(=O)C(Cl)Cl
Reactant: Cl
Solvent: Cc1ccccc1C
Solvent: CCCCNCCCC
Product: CCC(Cl)C1CN(Cc2cccc(Cl)c2)C(=O)C1Cl
Temperature: 90 °C

Procedure:
N-(3-chlorobenzyl)-N-(2-pentenyl)-2,2-dichloroacetamide was added by 1 g into 15 ml of xylene, to which 2 g of di-normal-butylamine and 0.5 g of cuprous chloride were added under stirring at 90° C. After continuing stirring for one hour, 40 ml of 20% hydrochloric acid was added and extracted with toluene. The extract was dried with anhydrous magnesium sulfate, concentrated by an evaporator and then purified on silica gel chromatography (hexane/ethyl acetate=3/1, v/v) to obtain 0.6 g of an oily product. This was a mixture of four isomers.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[C:23]([CH3:24])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[C:23]([CH3:24])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1nc2ccccc2nc1C
Product: Cc1nc2ccccc2nc1CCC#Cc1cccc(CF)n1
Yield: 16.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (24 mg, 0.13 mmol) and 2-but-3-ynyl-3-methyl-quinoxaline (25 mg, 0.13 mmol). Reaction time: 14 hours. The crude residue was purified by preparative chromatography plate (Et2O/pentane 7:3) to yield 6.4 mg (21 μmol, 13%) of 2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methylquinoxaline as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]CC1C=CC=CC=1)[C:6]#[N:7])[CH3:2]>CCOC(C)=O.CCO.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7])[CH3:2]
Reactant: CCc1cc(C#N)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
3-ethyl-4-[(phenylmethyl)oxy]benzonitrile (Intermediate 112, 334 mg) was dissolved in 15 mL of EtOAc/EtOH (2/1) and 10% mol Pd/C (0.1 equiv) was added to the solution. The resulting mixture was stirred overnight at room temperature under hydrogen gas atmosphere. The reaction mixture was filtered under argon and the solvent was removed. The residue obtained was purified by chromatography on silica gel (Companion system, 40 g Si cartridge) using as eluent a gradient cyclohexane/ethyl acetate from 100:0 to 80:20. Evaporation afforded the title compound (148 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:35][C@H:36]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[NH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH:36]([NH:35][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)=[N:9][C:10]=2[CH:15]=1)=[O:17])[C:49]([OH:51])=[O:50]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCCCCC(NC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1)C(=O)O
Yield: 15 %

Procedure:
Compound 232 was synthesized from Compound 201 as described for Compound 235, except H-Lys(Boc)-OtBu was used instead of L-5-hydroxytryptophane. In the 3rd step the protected intermediate was treated with a mixture of TFA-anisol 8:2 for 2 hours then the product was precipitated with ether and purified on RP-HPLC. Yield 15%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:13][N+:14]1[N:15]([CH3:26])[C:16](Cl)=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:26][N+:15]1[N:14]([CH3:13])[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:16]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Cn1c(Cl)cc(-c2ccccc2)[n+]1C
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cn1c(-c2ccccc2)cc(N2CCCCC2)[n+]1C

Procedure:
Piperidine (2.56 g, 0.03 mole) is added to 1,2-dimethyl-3-chloro-5-phenylpyrazolium methyl sulfate (4.77 g, 0.015 mole) in absolute ethanol (30 ml) and the mixture stirred with a bar magnet and heated under reflux for 4 hours. After cooling, the reaction mixture is evaporated under reduced pressure to a brown oil, and then dissolved in 50 ml of aqueous saturated sodium bicarbonate solution. The aqueous layer is extracted with ether and this organic layer discarded, then with chloroform (3×100 ml). Evaporation of the chloroform layer affords 1,2-dimethyl-3-phenyl-5-piperidinopyrazolium methyl sulfate as a viscous oil. The oil is redissolved in water and saturated aqueous potassium iodide solution is added. (Sodium iodide is also equally effective). An immediate copious white precipitate of 1,2-dimethyl-3-phenyl-5-piperidinopyrazolium iodide is formed, then filtered and washed with ice cold water to give 3.37 g, (56%) of product mp 179°C to 180°C. The melting point is unchanged by dissolving in chloroform, filtering and reprecipitating with diethyl ether and filtering off the solid. For analysis see Table I, compound 1.
Reaction SMILES: P(OCC)(OCC)OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21](O)[C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1>CN(C=O)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[NH:21][C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1
Reactant: CCCc1c(-c2ccc(Br)cc2)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1O
Agent: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1[nH]c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
The triethyl phosphite (0.9 mL, 5.33 mmol) was added to a solution of (S)-tert-butyl 2-(4-(4-bromophenyl)hydroxy-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.776 mmol) in DMF (2 mL) and stirred for 18 hours at 80° C. Add second 0.8 mL and the reaction was continued an additional 8 hours, cooled, and taken up in ethyl acetate (400 mL) and washed with water and brine. Apply in CH2Cl2 to a 25 (M) Biotage silica gel column. Gradient elution, 15-100%, over 750 mL (A=Hexanes; B=ethyl acetate) gave (S)-tert-butyl 2-(4-(4-bromophenyl)-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 585 mg (76%). 1H NMR (500 MHz, DMSO-d6) δ 7.55-7.53 (m, 4H), 4.80-4.69 (m, 1H), 3.53-3.51 (m, 1H), 3.38-3.32 (m, 1H), 2.71 (t, J=7.0 Hz, 2H), 2.24-2.11 (m, 1H), 2.0-1.79 (m, 1H), 1.89-1.79 (m, 2H), 1.63-1.59 (m, 2H), 1.41/1.17 (s, 9H). 0.91 (t, J=7.6 Hz, 3H). RT=1.8 min, (Condition 1) LRMS: Anal. Calcd. for C21H28BrN3O2 434.14. found: 434.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:7]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(OCC)(=O)C>[CH3:16][NH:17][C:18]([N:2]([CH3:1])[C:3]1[S:4][C:5]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][N:7]=1)=[O:19]
Reactant: CN=C=O
Reactant: CNc1nnc(SCc2ccccc2)s1
Solvent: CCOC(C)=O
Product: CNC(=O)N(C)c1nnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylamino-5-benzylthio-1,3,4-thiadiazole (4.0 g) in ethyl acetate (100 ml) was added 1.5 g of methyl isocyanate. The reaction was stirred at room temperature for 2 hrs. then heated at reflux for an additional 2 hrs. The product, 1,3-dimethyl-3-(5-benzylthio-1,3,4-thiadiazol-2-yl)urea, crystallized upon the addition of petroleum ether, was collected, washed with ether and dried to give 4.7 g, MP 139°-142° C.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]12[CH2:8][OH:9].[OH-:10].[Na+]>S(=O)(=O)(O)O.O1CCOCC1.O>[OH:10][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:1]
Reactant: OCC12CCCCC1O2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCC1(O)CCCCC1O

Procedure:
A stirred mixture of 10.6 g of 1,2-epoxycyclohexanemethanol and 8 drops of concentrated sulfuric acid in 100 ml of p-dioxane and 100 ml of water was heated at 60°-70° for 18 hours. The reaction mixture was neutralized with sodium hydroxide, and evaporated under reduced pressure to a viscous residue. The residue was taken up in methanol and dried with sodium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to a residue. The residue was distilled to give 10.8 g of 1,2-dihydroxycyclohexanemethanol; bp 170°-240°/0.02 mm. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([O:37]CC5C=CC=CC=5)=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:45])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:45])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:15])=[O:16])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)[C@@H](c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Reaction time: 3 h
Yield: 90.6 %

Procedure:
(+)-Benzyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate (from (f), 374 mg) was dissolved in aqueous ethanol (20 ml of 9:1 ethanol/water) and 50 mg of 5% palladium on carbon was added. After 3 h at 414 kPa (60 psi) of hydrogen at room temperature a further 50 mg of catalyst was added and the hydrogenation continued for a further 3 h. The catalyst was removed by filtration and the filtrate evaporated. The residue was azeotroped several times with dichloromethane to give the title compound (290 mg) in >98%ee (determined by chiral HPLC).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH3:27][C:28]1[C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[C:31]([CH3:45])[O:30][N:29]=1>ClCCl>[CH3:27][C:28]1[C:32]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([NH:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([CH:9]4[CH2:13][CH2:12][N:11]([CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:10]4)=[CH:5][CH:6]=3)(=[O:43])=[O:42])=[CH:39][CH:40]=2)=[C:31]([CH3:45])[O:30][N:29]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 65 °C
Yield: 70.6 %

Procedure:
To a solution of 2-methyl-6-[1-(phenylmethyl)-3-pyrrolidinyl]-3-pyridinamine (150 mg, 0.561 mmol) in dichloromethane (DCM) (4 mL) and pyridine (0.045 mL, 0.561 mmol) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (169 mg, 0.561 mmol). The reaction vessel was sealed and heated at 65° C. for 2 hours. Additional 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (169 mg, 0.561 mmol) and pyridine (0.045 mL, 0.561 mmol) were added and the reaction mixture was heated for a further 4 hours at 65° C. The reaction mixture was then cooled and separated between DCM (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic phase was passed through a hydrophobic frit and evaporated in vacuo. The sample was purified by flash silica (Si) chromatography (0-25% methanol-dichloromethane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product (211 mg) as a brown gum (approx 71% pure). LCMS (2 min, formic) Rt 0.80 min, m/z (ES+) 533 (M+H)