Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]#[N:20])([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.O1CCC[CH2:22]1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([C:19]#[N:20])[CH2:14][CH2:15][C:16]1=[O:18])([O:13][CH3:22])=[O:12]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Yield: 96 %

Procedure:
A reaction mixture consisting of 34.97 g. (0.108 mole) dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid (prepared in Part a, above) dissolved in 700 ml. tetrahydrofuran with 24.4 gm. (0.218 mole) potassium tert-butoxide added is heated at the reflux temperature for 41/2 hours. After cooling, the reaction mixture is chilled in an ice-bath and 175 ml. 2.5 N acetic acid is added. The organic and aqueous phases separate and the organic phase is recovered. It is diluted with 600 ml. benzene before being washed successively with aqueous sodium bicarbonate, water, and brine. The organic solvents are then removed by distillation under reduced pressure. There is thus obtained 30.2 gm. (96% yield) of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone having a melting point at 139° to 143° C.
Reaction SMILES: Cl[C:2]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[C:12]3[C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[S:9][N:8]=[CH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Clc1cccc2c1-c1ccccc1SN=C2
Reactant: C1CNCCN1
Product: C1=NSc2ccccc2-c2c1cccc2N1CCNCC1

Procedure:
EP 0282236-A1 reports that a dibenzothiazepine derivative can be processed to give 11-[4-(2-(2-hydroxyethoxy)-ethyl]-1-piperadinyldibenzothiazepine derivative, which is of value as, for example, an antipsychotic pharmaceutical. In more detail, dibenzo-[b,f][1,4]thiazepin-11-one, which is a representative compound of the dibenzothiazepine derivatives reported therein, is reacted with phosphorus oxychloride to yield a 11-chloro-dibenzothiazepine derivative. To the 11-chloro-dibenzothiazepine derivative is added piperazine to yield a 11-piperazinyl-dibenzothiazepine derivative, which is subsequently reacted with 2-chloroethoxyethanol under basic conditions to give the desired 11-[4-(2-(2-hydroxyethoxy)-ethyl]-1-piperadinyldibenzothiazepin.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1.O>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1Cc1cc2ccccc2nc1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(2-Aminoquinolin-3-yl)methyl]-3-methoxyphenol (40 mg, 0.14 mmol), triphenylphosphine (56 mg, 0.21 mmol) and methanol (7 μL, 0.22 mmol) were placed in THF (2 mL) at 10° C. and then mixed slowly with azodicarboxylate diisopropyl ester (44 mg, 0.22 mmol) in THF (1 mL). Then the mixture was stirred for 12 hours at room temperature. The batch was mixed with water and extracted with ethyl acetate. The combined organic phases were washed with water, dried (sodium sulfate) and concentrated. The crude product was purified chromatographically (silica gel, dichloromethane, methanol). To remove traces of triphenylphosphine oxide, the slightly contaminated product was dissolved in diethyl ether and extracted with 2N aqueous hydrochloric acid. The aqueous phase was alkalized with dilute sodium hydroxide solution and extracted with dichloromethane. The combined dichloromethane extracts were washed with water until neutral, dried (sodium sulfate) and concentrated (yield: 5 mg, 9%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][C:24](=[O:49])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:46][CH2:47][CH3:48])([CH3:22])([CH3:21])[CH3:20]>CC#N.CCOC(C)=O.O>[C:19]([O:23][C:24](=[O:49])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=3[C:2]([F:12])([F:11])[F:1])[S:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)(=[O:37])=[O:38])=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:46][CH2:47][CH3:48])([CH3:22])([CH3:21])[CH3:20]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc2cc(N(Cc3ccccc3C(F)(F)F)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Trifluoromethylbenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [S:1]([C:7]([C:10]([C:13]([C:16]([S:19](F)(=O)=[O:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])([F:5])([F:4])([F:3])[F:2].[OH:23][Li:24].[OH2:25]>CO>[S:1]([C:7]([C:10]([C:13]([C:16]([S:19]([O:23][Li:24])(=[O:20])=[O:25])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:5])([F:4])([F:3])([F:2])[F:6]
Reactant: [Li]O
Reactant: O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(F)(F)(F)F
Solvent: CO
Product: [Li]OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(F)(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 10-gram mixture of F5S(CF2)4SO2F (47.5 wt %) and cyclo-SF4C4F7SO2F (52 wt %) was charged to a flask containing LiOH.H2O (2.3 g) slurried in 30 g methanol. The reaction mixture was refluxed 18 hrs and then cooled to room temperature. The LiF was then filtered away. The cake was washed with an additional 30 mL methanol. The filtrate was placed in a dish and placed in an oven at 80° C. overnight. A total of 5.5 g of lithium salt, an off-white solid, was removed from the dish. IR analysis of the solid was consistant for the desired lithium salt: F5S(CF2)4SO3Li.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][N:28]([CH3:42])[CH2:29][CH2:30][NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33]>>[CH3:27][N:28]([CH3:42])[CH2:29][CH2:30][NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33]
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCN(C)C
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCN(C)C

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.15) according to general procedure II.
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23]CC)=[O:22])=[CH:6]1)(C)(C)C>C(O)C.Cl.C(OCC)C>[O:20]=[C:8]1[C:9]2[C:14](=[N:13][C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:11][CH:10]=2)[NH:5][CH:6]=[C:7]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)c1c[nH]c2nc(N3CCCC3)ccc2c1=O

Procedure:
A solution of Example 74A (63.2 mg) in ethanol (2.5 mL) and 6M HCl (2.5 mL) was heated in a sealed tube at 130° C. for 18 hours then cooled, diluted with diethyl ether, and filtered. NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.22 (m, 1H), 6.80 (m, 1H), 3.55 (m, 4H), 2.00 (m, 4H).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=O)C.S(Cl)([Cl:20])=O>CN(C)C=O>[Cl:20][C:9]1[C:8]2[C:13](=[CH:14][C:5]([OH:4])=[C:6]([O:16][CH3:17])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1O
Temperature: 80 °C
Yield: 75 %

Procedure:
7-Acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1 g, 4.3 mmol) was suspended in thionyl chloride (10.5 ml). One drop of dimethylformamide was added and the reaction was heated to 80° C. for two hours, during which time the solid dissolved. The reaction mixture was cooled and the thionyl chloride was removed in vacuo. The residue was azeotroped with toluene before being suspended in methylene chloride. A solution of 10% ammonia in methanol (40 ml) was added and the reaction mixture was heated to 80° C. for 15 minutes. After cooling the solvents were removed in vacuo and the residue redissolved in water (10 ml) and the pH adjusted to 7.0 with 2M hydrochloric acid. The resulting solid was filtered, washed with water and dried over phosphorus pentoxide yielding 4-chloro-7-hydroxy-6-methoxyquinazoline as a white solid (680 mg, 75%).
Reaction SMILES: [CH:1]([OH:3])=O.Cl.CN(C)CCCN=C=NCC.[C:16]([NH:19][C:20]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:25][CH2:24][N:23]([CH:26]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)[CH2:27][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:29][NH2:30])[CH2:22][CH2:21]1)(=[O:18])[CH3:17].CN1CCOCC1>ClCCl.Cl.O>[C:16]([NH:19][C:20]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:21][CH2:22][N:23]([CH:26]([CH2:39][C:40]2[CH:41]=[C:42]([C:50]([F:51])([F:53])[F:52])[CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=2)[CH2:27][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:29][NH:30][CH:1]=[O:3])[CH2:24][CH2:25]1)(=[O:18])[CH3:17]
Reactant: O=CO
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CNC=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of formic acid (0.09 mL) in dichloromethane (3 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g) and the mixture stirred for 15 minutes. To this mixture was added a solution of 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butyl amine (0.40) and N-methylmorpholine (0.13 mL) in dichloromethane (5 mL). The mixture was allowed to warm to room temperature overnight, and was diluted with 1N hydrochloric acid (5 mL), dichloromethane, and water (5 mL). The layers were separated and the the aqueous phase was extracted with dichloromethane (10 mL). The combined organic layers were washed (brine), dried, and evaporated to afford material which was purified by chromatography with dichloromethane:methanol (20:1) as eluent, to give a hydrate of the title compound (0.206 g); mp 108-110° C.; NMR: 8.1-7.5 (m,6), 7.3 (m,6), 4.75-4.40 (m,2), 3.75-3.3 (m,4), 3.3-3.0 (m,4), 2.85 (m,1), 1.95 (s,3), 2.25-1.80 (m,4); MS: m/z=688(M+l,100%); TLC: Rf=0.46 (10:1 dichloromethane:methanol). Analysis for C33H33C2F6N3O2.1.50 H2O: Calculated: C, 55.39; H, 5.07; N, 5.87; Found: C, 55.38; H, 4.77; N, 5.84.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[CH:29]=O)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[NH2:32][OH:33]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:26])[CH3:27])=[C:19]5/[CH:29]=[N:32]\[OH:33])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NO
Reactant: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C=O
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1/C=N\O
Reaction time: 48 h
Yield: 77.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5-yl)cyclopropanecarboxamide (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added hydroxylamine hydrochloride (21 mg, 0.30 mmol). After stirring for 48 h, the mixture was evaporated to dryness and purified by column chromatography (0-100% ethyl acetate/hexanes) to yield (Z)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)methyl)-1H-indol-5-yl)cyclopropanecarboxamide (81 mg, 77%). ESI-MS m/z calc. 419.5, found 420.5 (M+1)+; retention time 3.42 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 0.5H), 10.55 (s, 0.5H), 8.56-8.50 (m, 2H), 8.02 (m, 1H), 7.24-7.22 (m, 1H), 7.12-7.10 (m, 1H), 7.03 (m, 1H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 43 (s, 9H), 1.40-1.38 (m, 2H), 1.04-1.01 (m, 2H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[CH:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:42][CH3:43]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[C:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([CH2:42][CH3:43])[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCI
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
LiHMDS (20 mL, 0.020 mol) was added dropwise to a stirred solution of methyl 2-(4-(tert-butoxycarbonylamino)-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)acetate (4.32 g, 0.010 mol) in THF (80 mL) and HMPA (20 mL) at −78° C. The resulting mixture was stirred for another 1 h at −78° C. Iodoethane (2.3 g, 0.015 mol) was added to the above solution. The reaction mixture was warmed to −20° C. and stirred for 20 min. The mixture was quenched with sat. ammonium chloride and extracted with EA, washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=8:1) to afford the title compound. LC/MS m/z=405.1 [M-tBu+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]1C=CC(S(O)=O)=C[C:17]=1C(O)=O.ICCC>C(O)CC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH2:16][CH3:17])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: CCCO
Solvent: CCCI
Product: CCCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 3 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and 1-iodopropane in 20 ml propanol/20 ml water and obtained in 3% yield. MS (m/e): 261.1 (MH−, 100%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[NH:11][C:10]2=[O:32])[CH:6]=[CH:7][CH:8]=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH:12]2[C:13]3[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][C:18]=3[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)[C:10](=[O:32])[N:11]2[C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:37])=[C:21]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=1)#[N:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C

Procedure:
A microwave vessel is charged with a mixture of 4-(1-(3-(trifluoromethyl)phenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18, 50 mg, 0.10 mmol), 4-nitrophenyl chloroformate (31 mg, 0.15 mmol) and a tip of a spatula of 4-dimethylaminopyridine in toluene (3 mL). Triethylamine (0.1 mL) is added, and the mixture is heated in a microwave at 150° C. for 10 min. Another portion of 4-nitrophenyl chloroformate (31 mg, 0.15 mmol) is added and the mixture is heated again at 150° C. for 20 min. All volatiles are evaporated and the residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 32 mg; ESI mass spectrum M+H]+=655, Retention time HPLC: 1.10 min (Z017_S04).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1)[C:6]([OH:8])=O.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:8])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 161.1 %

Procedure:
To a mixture of 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzoic acid (0.15 g), tert-butyl hydrazinecarboxylate (0.17 g) and triethylamine (0.18 mL) in DMF (2 mL) was added HATU (0.49 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.36 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([N:17]3[CH:21]=[N:20][N:19]=[CH:18]3)[CH:16]=[C:11]2[C:10](C=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:26][CH2:27][CH3:28])=[O:25].[C:49]1(C)C=CC=CC=1>>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([N:17]3[CH:21]=[N:20][N:19]=[CH:18]3)[CH:16]=[C:11]2[C:10]([CH:49]=[CH:29][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cc(-n3cnnc3)ncc21
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=Cc1cn(C(=O)OC(C)(C)C)c2cnc(-n3cnnc3)cc12

Procedure:
A solution of 1-tert-butyloxycarbonyl-3-formyl-5-(1,2,4-triazol-4-yl)pyrrolo[2,3-c]pyridine (0.71 g, 2.3 mmol) and (carboethoxymethylene)triphenylphosphorane (0.95 g, 2.7 mmol) in toluene (25 mL) was heated at 80° C. under nitrogen for 2 hours. The mixture was allowed to cool and the solvent evaporated in vacuo. The residue was chromatographed on silica eluting with 20% EtOAC in DCM, followed by a gradient of 2 to 5% MeOH in DCM to afford ethyl 3-[1-tert-butyloxycarbonyl-5-(1,2,4-triazol-4-yl)pyrrolo[2,3-c]pyridin-3-yl]prop-2-enoate (0.93 g), contaminated with minor impurities, as a cream solid. 1H NMR (360 MHz, CDCl3) δ 1.38 (3H, t, J=7.1Hz), 1.73 (9H, s), 4.32 (2H, q, J=7.1Hz), 6.51 (1H, d, J=16.2Hz), 7.76 (1H, s), 7.80 (1H, d, J=15.7Hz), 8.09 (1H, s), 8.95 (2H, s) and 9.33 (1H, s). This was used without further purification.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:27][CH2:26]2)=O)=[CH:19][CH:18]=1.[Cl-].[Na+]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:26][CH2:27]2)=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(C(=C2SCCCS2)C2CC2)cc1
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
A solution of 16.0 grams (0.083 mole) of 2-trimethylsilyl-1,3-dithiane in 80 mL of tetrahydrofuran was cooled to 0° C., and 39 mL (0.083 mole) of n-butyllithium (2.1M in hexane) was added. The reaction mixture was stirred for 15 minutes, and 15.0 grams (0.083 mole) of cyclopropyl (4-chlorophenyl) ketone in 40 mL of tetrahydrofuran was added via syringe during a five minute period. Upon completion of addition, the reaction mixture was stirred at 0° C. for 15 minutes and then was allowed to warm for 30 minutes. The reaction mixture was stirred with 100 mL of an aqueous solution saturated with sodium chloride, and then the two phases were separated. The aqueous phase was extracted with one portion of diethyl ether. The ether extract was combined with the organic phase, and this mixture was dried with magnesium sulfate and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure, yielding 24.0 grams of 2-[(4-chlorophenyl)cyclopropylmethylene]-1,3-dithiane as a solid, m.p. 91°-95° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.CN(C)C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH:13]([O:12][C:10]1[C:9]([O:16][CH3:17])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:11]=1)([CH3:14])[CH3:15]
Reactant: COC(=O)c1cc(OC)c(OC(C)C)cc1N
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(OC(C)C)cc1NCc1ccc(OC)cc1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A mixture of methyl 2-amino-4-isopropoxy-5-methoxybenzoate (12.67 g), 4-methoxybenzaldehyde (7.90 g), N,N-dimethylformamide (150 ml) and acetic acid (3 ml) was stirred for 8 hours. After stirring, the sodium triacetoxyborohydride (13.4 g) was added thereto. The reaction mixture was stirred for 1 night. To the reaction mixture was added 4-methoxybenzaldehyde (1.98 g) and sodium triacetoxyborohydride (3.35 g) and stirred for 1 day. The reaction mixture was concentrated under reduced pressure until the amount was concentrated to a half, adjusted to pH 8˜9 by adding 5% sodium carbonate. Water was added thereto, the precipitated solid was collected by filtration, washed with water and dried to obtain the target compound (18.9 g).