Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:16][C@@H:17]([C@H:19]1[C:40](=[O:41])[N:21]2[CH:22]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[C:23](=O)[C@H:24]([CH3:25])[C@H:20]12)[CH3:18].FC(F)(F)S(O)(=O)=O.[SH:50][C@@H:51]1[CH2:55][N:54]([CH3:56])[C@H:53]([C:57]([N:59]2[CH2:65][CH2:64][CH2:63][N:62]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)=[O:67])[CH2:61][CH2:60]2)=[O:58])[CH2:52]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:76]([C:73]1[CH:74]=[CH:75][C:70]([CH2:69][O:68][C:66]([N:62]2[CH2:63][CH2:64][CH2:65][N:59]([C:57]([C@@H:53]3[CH2:52][C@H:51]([S:50][C:23]4[C@H:24]([CH3:25])[C@@H:20]5[C@@H:19]([C@H:17]([OH:16])[CH3:18])[C:40](=[O:41])[N:21]5[C:22]=4[C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[O:28])[CH2:55][N:54]3[CH3:56])=[O:58])[CH2:60][CH2:61]2)=[O:67])=[CH:71][CH:72]=1)([O-:78])=[O:77]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 0.67 h
Yield: 57.4 %

Procedure:
0.89 ml of diphenylphosphoryl chloride and 0.75 ml of diisopropylethylamine were simultaneously added dropwise, whilst ice-cooling, to a solution of 1.4 g of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 14 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 40 minutes. A solution of 2.68 g of (2S, 4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]pyrrolidine trifluoromethanesulfonate (prepared as described in Preparation 49) in 14 ml of dry acetonitrile and 1.64 ml of diisopropylethylamine were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 5 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The dilute solution was then washed with an aqueous solution of sodium hydrogencarbonate, with a phosphate buffer solution (pH 6.86), with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel (Merck Art No. 7734), using a gradient elution method with mixtures of ethyl acetate and methanol ranging from 85:15 to 80:20 by volume as the eluent, to give 1.7 g of the title compound, as a powder.
Reaction SMILES: N1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C[CH2:10][CH2:9][CH2:8]1.[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH:19]=O)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[C:23](=[O:24])[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][C:18](=[CH:19][C:2]#[C:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:6][CH:5]=2)[CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: C1CCNCC1
Product: CC(C)(C)C1=CC(=CC#Cc2ccccc2)C=C(C(C)(C)C)C1=O

Procedure:
In lieu of piperidine, pyrrolidine was used with 3,5-di-tert-butyl-4-hydroxybenzaldehyde to synthesize the subsequent intermediate 7-pyrrolidinyl quinone methide following the procedure in Example 1 (d). The remainder of the one-pot procedure towards 7-Phace-QM is as detailed in Example 1 (d).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[N:2]=1.[Cl:12]N1C(=O)CCC1=O>CO>[Cl:12][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=[N:2][C:3]=1[NH2:11]
Reactant: Nc1cc2ccccc2cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: Nc1ncc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To isoquinolin-3-amine (2.02 g, 14.0 mmol) in methanol (60 mL) was added N-chlorosuccinimide (2.19 g, 16.4 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours, then concentrated in vacuo. The crude material was chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield 4-chloroisoquinolin-3-amine (2.1 g, 11.8 mmol, 84% yield) as a solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.86 (s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.68 (td, J=6.7, 1.8 Hz, 1H), 7.24-7.35 (m, 1H), 6.32 (br. s., 2H). MS (LC/MS) R.T.=1.50; [M+H]+=178.96.
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[Na].Br[CH2:15][CH2:16][C@@H:17]1[O:23][C@:22](/[CH:28]=[CH:29]/[CH:30]2[CH2:32][CH2:31]2)([C:24]([F:27])([F:26])[F:25])[C:21]2[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:20]=2[NH:19][C:18]1=[O:38]>C1COCC1.C(O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:20]2[NH:19][C:18](=[O:38])[C@H:17]([CH:16]=[CH2:15])[O:23][C@:22](/[CH:28]=[CH:29]/[CH:30]3[CH2:32][CH2:31]3)([C:24]([F:25])([F:26])[F:27])[C:21]=2[CH:33]=1
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: C=C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
To a room temperature solution of 238 mg (1.05 mmol) of 2-nitrophenylselenocyanate in 3.0 mL of THF was added 9 mL of ethanol and 66 mg of sodium borchydride. After stirring 1.5 h, a solution of 153 mg of rel-(3S,5S)-trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 5 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 32 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 73 mg of the title compound as a pure solid which can be recrystallized from ethanol-hexanes: mp 165.5-166.5°; HRMS Calcd. for C17H16NO2F3Cl (M+H)+ : 358.082166. Found: 358.081658.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]2[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]2)[CH2:5][CH2:4]1.[Cl:30][C:31]1[C:44]([N:45]=[C:46]=S)=[C:43]([Cl:48])[CH:42]=[CH:41][C:32]=1[CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].CC(C)N=C=NC(C)C>CC#N>[F:29][C:2]([F:1])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]3)=[CH:13][C:14]3[N:18]([CH3:19])[C:46]([NH:45][C:44]4[C:43]([Cl:48])=[CH:42][CH:41]=[C:32]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]=4[Cl:30])=[N:17][C:15]=3[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: CNc1cc(N2CCC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CCC(F)(F)C3)cc21

Procedure:
The title compound is prepared in analogy to 6c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3,3-difluoro-pyrrolidinyl]-4-methylamino-5-amino-benzoic acid amide (140 mg, 0.33 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (93 mg, 0.29 mmol), DIC (63 μL) and MeCN (3.0 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([F:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Nc1ccc(F)cc1N
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(F)cc5N)cccc4c3)c2cc1OC
Yield: 89 %

Procedure:
The title compound (43.1 mg, 89% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.28 (s, 2H, benzene-NH2), 6.41 (td, J=2.6 and 8.5 Hz, 1H, Ar—H), 6.59 (dd, J=2.6 and 11.2 Hz, 1H, Ar—H), 7.35 (td, J=1.8 and 7.5 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.59 (dd, J=2.2 and 8.4 Hz, 1H, Ar—H), 7.63-7.67 (m, 2H, Ar—H), 7.89 (d, J=6.9 Hz, 1H, Ar—H), 7.96 (d, J=1.9 Hz, 1H, Ar—H), 8.08 (d, J=8.2 Hz, 1H, Ar—H), 8.38 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.77 (s, 1H, benzene-NH). LC-MS (m/z) 485 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7](NC(=O)C)=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.[N:13]1C=CC=C[CH:14]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:14]#[N:13])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: CC(=O)Nc1ccc(Cl)nc1Cl
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a mixture of 2,6-dichloro-3-acetamidopyridine (6.3 g, 55% pure) and pyridine (4.93 ml, 61 mmole) in dichloromethane (100 ml), trifluoroacetic anhydride (4.23 ml, 30 mmole) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with 85% hexane:15% ethyl acetate to give a pale yellow product (1.77 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH2:13]([Li])CCC.CI.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: Clc1cncc(NC2CCC2)n1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(c1cncc(Cl)n1)C1CCC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 6-chloro-N-cyclobutylpyrazin-2-amine (535 mg) in THF (30 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 2.4 mL) under an argon stream at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added dropwise a solution of methyl iodide (542 μL) in THF (1 mL), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added dropwise a saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→33% ethyl acetate/hexane) to give the title compound (492 mg, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=O)#[N:2].[NH2:21][C@@H:22]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:23]([OH:42])[CH2:24][N:25]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([NH:21][C@@H:22]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:23]([OH:42])[CH2:24][N:25]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:8])#[N:2]
Reactant: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2ccccc2)C(=O)OC(C)(C)C)c1
Reactant: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN(Cc2cccc(OC)c2)C(=O)OC(C)(C)C)c1
Reaction time: 65 h

Procedure:
To a mixture of 3-cyano-5-[(dipropylamino)carbonyl]benzoic acid (IX/XXXII, PREPARATION 7, 0.086 g, 0.314 mmol) and tert-butyl (2R,3S)3-amino-2-hydroxy4-phenylbutyl(3-methoxybenzyl)carbamate (XXXV, EXAMPLE 584, 0.126 g, 0.314 mmol) in dichloromethane (0.3 mL) is added diethylcyanophosphonate (0.062 g, 0.330 mmol) and triethylamine (0.032 g, 0.316 mmol). The mixture is stirred at 20–25 degrees for 65 hours and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is separated and dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel, 20 mL; methanol/dichloromethane, 5/95) to give several mixed fractions, which are combined and rechromatographed (silica gel; acetone/hexane, 20/80) to give the title compound, MS (ESI+) for C35H48N4O6 M/z 657.6 (M+H)+=657.6; (M+Na)=679.5 and (M—C4H9O2)=557.5.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([S:16][C:17]3[CH:24]=[CH:23][C:20](C#N)=[CH:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.[CH2:36]([N:38](CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:24]=[C:23]([C:36]4[N:31]=[N:32][NH:33][N:38]=4)[CH:20]=[CH:19][N:18]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(Sc3ccc(C#N)cn3)c2)ccc(C(C)=O)c1O
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Product: CCCc1c(OCc2cccc(Sc3cc(-c4nn[nH]n4)ccn3)c2)ccc(C(C)=O)c1O

Procedure:
Employing the procedure essentially as described in Example 1 using 6-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-nicotinonitrile (430 mg, 1.03 mmol), sodium azide (668 mg, 10.3 mmol), and triethylamine hydrochloride (1.41 g, 10.3 mmol) purify by reverse phase chromatography eluting with methanol: acetic acid: water, the title compound is obtained as a white solid (77 mg, 16%): 1H NMR (CD3CN) δ 0.83 (t, 3H), 1.48 (sextuplet, 2H), 2.53 (s, 3H), 2.60 (t, 2H), 5.24 (s, 2H), 6.62 (d, 1H), 7.11 (d, 1H), 7.56 (m, 3H), 7.71 (m, 2H), 8.11 (dd, 1H), 8.96 (dd, 1H), 12.82 (bs, 1H); MS (esi negative) m/z 460 (m−1).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.C(#N)C.[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31](=[O:34])[CH:32]=[CH2:33].[CH2:35](OCC1OC1)[CH:36]1[O:38][CH2:37]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CC(N(C)C)=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:18][C:19]([O:21][CH2:35][CH:36]([OH:38])[CH2:37][O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31](=[O:34])[CH:32]=[CH2:33])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Cl)c2c(=O)c3ccccc3sc12
Reactant: C(OCC1CO1)C1CO1
Reactant: C=CC(=O)OCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Br-]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: C=CC(=O)OCCCCOCC(O)COC(=O)COc1ccc(Cl)c2c(=O)c3ccccc3sc12
Temperature: 25 °C
Yield: 33.5 %

Procedure:
A reaction mixture containing (1-chloro-9-oxo-9H-thioxanthen-4-yloxy)-acetic acid (28.9 g, 0.09 mol), acetonitrile (345 mL), dimethylacetamide (240 ml), tetrabutylammonium bromide (2.9 g, 9 mmol), 2,6-di-tert-butyl-4-methylphenol (0.2 g, 0.9 mmol) and 4-hydroxybutylacrylate glycidylether (18.0 g, 0.09 mol) was heated to reflux. The mixture was allowed to stir at reflux temperature for 24 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residual oil was dissolved in dichloromethane (400 mL) and extracted 3 times with a mixture of an aqueous solution of sodium hydroxide (1N) (200 mL) and distilled water (200 mL). The organic layer was isolated and dried over MgSO4. The solvent was evaporated to yield 15.7 g of a brown oil. Acrylic acid 4-{3-[2-(1-chloro-9-oxo-9H-thioxanthen-4-yloxy)-acetoxy]-2-hydroxy-propoxy}-butyl ester was purified on a Merck Super Vario Prep column using dichloromethane/ethyl acetate (75/25) as eluent, yielding 13.85 g of a yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[F:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[F:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: FC[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCC[C@H]4CF)cc3c2)cc1

Procedure:
The product from Example 1C and the product from Example 164C were processed as described in Example 1D to provide the titled compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was run at 60° C. for 3 days, then worked up by pouring into toluene. The organic phase was extracted with 7:2:1 of water/N-methylpyrrolidinone/10% aqueous methanesulfonic acid, and the aqueous phase then covered with isopropyl acetate and adjusted to pH 11 with 50% aqueous NaOH. After shaking and separation of the layers, the isopropanol extract was saved, then combined with a second isopropanol extract of the aqueous layer. The combined isopropanol extract was washed three times with 5% aqueous NaHCO3, water, dried over magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The free base was converted to the mono-L-tartrate salt by addition of 1 equivalent of L-tartaric acid to the free base in ethanol. Two hours after removal of some of the ethanol under vacuum, the mixture deposited an off-white solid. The solid was collected by filtrate and dried in vacuo overnight to give the title product as the tartrate salt of 4-{2-[2-(2(R)-fluoromethyl-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-benzonitrile, mp 156.3° C., MS m/z (M+H)+349; 13C NMR (DMSO) δ 158.6, 154.2, 145.2, 133.2, 132,7, 129.4, 127.7, 122.8, 119.2, 118.9, 111.2, 109.4, 103.0, 85.6 and 84.3, 72.1, 62.8, 53.5, 52.3, 27.2, 26.4, 22.7.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[N:15]=[CH:14][S:13][C:5]=3[NH:6][C:7](=[O:12])[C:8]=2[CH:9]=[CH:10][CH:11]=1.[Cl-:16].[CH3:17][N+:18]([CH3:20])=[CH2:19]>CN(C=O)C.C(#N)C>[ClH:16].[CH3:17][N:18]([CH2:20][C:14]1[S:13][C:5]2[NH:6][C:7](=[O:12])[C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([OH:1])[C:3]=3[C:4]=2[N:15]=1)[CH3:19]
Reactant: [Cl-]
Reactant: C=[N+](C)C
Reactant: O=c1[nH]c2scnc2c2c(O)cccc12
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)Cc1nc2c([nH]c(=O)c3cccc(O)c32)s1
Product: Cl
Yield: 13 %

Procedure:
To a solution of 9-hydroxy-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one in DMF/acetonitrile (3 ml, 1:2) was added dimethyl-methylene-ammonium chloride (0.043 g, 0.46 mmol) and the resulting mixture was refluxed under Ar for 42 hours. After cooling and concentration, the residue was purified via flash chromatography on SiO2 to give the title compound (0.008 g, a 13% yield) as solid. m.p.>250° C.; 1H NMR (400 MHz, DMSO) δ 2.36 (s, 6H, N(CH3)2), 3.93 (m, 2H, CH2N), 7.24 (d, 1H, Ar), 7.44 (t, 1H, Ar), 7.74 (d, 1H, Ar), 10.23 (s, 1H, OH), 12.30 (s, 1H, NH); 13C NMR (100.6 MHz, DMSO) δ 46.83, 61.38, 119.94, 120.56, 121.00, 126.83, 129.95, 131.75, 137.39, 154.41, 162.54.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2]>CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCSCc1[nH]cnc1C
Yield: 33.6 %

Procedure:
A solution of silver nitrate (3.06 g.) in dimethyl formamide (20 ml.) was added to a solution of N-cyano-N'- [2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methyl isothiourea (4.9 g.) in dimethylformamide (30 ml.). The resultant solution was kept at room temperature for 1 hour cooled and filtered to remove silver methylmercaptide, 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.07 g.) in dimethyl formamide (10 ml.) was added and this solution was heated overnight on the steam bath. Concentration followed by chromatographic purification of the product on a column of silica gel afforded the title compound (1.2 g.), m.p. 90°-94°, containing a small amount of water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][NH:17][C:36](=[S:37])[NH:35][C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:14][CH2:15]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: O=C(NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving {1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methylamine (1325 mg, 4.84 mmol) in tetrahydrofuran (20 ml), FmocNCS (9-fluorenylmethoxycarbonyl isothiocyanate) (1498 mg, 5.32 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=85/15) to obtain N-{[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]thioxomethyl}(fluoren-9-ylmethoxy)carboxamide. The compound was identified by LC-MS.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].[NH2:11][C:12]1[C:13]([C:17](Cl)=[N:18][OH:19])=[N:14][O:15][N:16]=1>>[NH2:11][C:12]1[C:13]([C:17](=[N:18][OH:19])[NH:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[N:14][O:15][N:16]=1
Reactant: CS(=O)(=O)NCCCN
Reactant: Nc1nonc1C(Cl)=NO
Agent: Cl
Product: CS(=O)(=O)NCCCNC(=NO)c1nonc1N
Yield: 19 %

Procedure:
The desired compound was prepared according to the procedure of Example 17, step C, using N-(3-aminopropyl)methanesulfonamide hydrochloride and 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride [made according to Example 1, steps A through B] as the starting materials in 19% yield.