Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1](P(CC(OCC)=O)(OC1C=CC=CC=1)=O)[C:2]1C=CC=C[CH:3]=1.N12CCCN=C1CCCCC2.[Na+].[I-].[NH2:36][C:37]1[C:42]([CH:43]=O)=[C:41]([CH:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:40]=[C:39]([C:58]2[C:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][CH:67]=3)=[CH:62][CH:61]=[CH:60][C:59]=2[O:74][CH2:75][CH:76]2[CH2:78][CH2:77]2)[N:38]=1>C1COCC1>[CH:76]1([CH2:75][O:74][C:59]2[CH:60]=[CH:61][CH:62]=[C:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][CH:67]=3)[C:58]=2[C:39]2[CH:40]=[C:41]([CH:45]3[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH2:46]3)[C:42]3[CH:43]=[CH:3][C:2](=[O:1])[NH:36][C:37]=3[N:38]=2)[CH2:78][CH2:77]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C=O)c(N)n2)cc1
Reactant: CCOC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3ccc(=O)[nH]c3n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
To a solution of ethyl (diphenoxyphosphoryl)acetate (1.090 g, 3.403 mmol) in THF (15 mL) were added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.520 g, 3.403 mmol) and NaI (0.510 g, 3.403 mmol) followed by a solution of tert-butyl 3-(2-amino-6-(2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-formyl-4-pyridinyl)-1-piperidinecarboxylate (1.000 g, 1.701 mmol), obtained in the step (1) of Example 25-2, in THF (5 mL). The mixture was stirred at 0° C. for 1.5 hrs and quenched with saturated aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3:2 to 1:2) to give tert-butyl 3-(2-{2-(cyclo-propylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate as an amorphous solid (0.276 g, 27%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].Cl[CH2:23][C@H:24]1O[C@@H:27](N2C3N=CN=C(N)C=3N=C2C2C=CC=CC=2)[C@H:26](O)[C@@H:25]1O>CN.C(O)C>[CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:6]([OH:20])[C@@H:5]1[OH:21]
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: Nc1ncnc2c1nc(-c1ccccc1)n2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: CN
Solvent: CCO
Product: CNC[C@H]1O[C@@H](n2c(-c3ccccc3)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 4d was prepared by the same procedure as described for the preparation of 4a using 3d (2.00 g, 5.52 mmol) and 33% methylamine/ethanol solution (40 mL). After column chromatography (elution with 4:1:0.2 chloroform:methanol:NH4OH), a yellow glassy solid was obtained: 963 mg (49%); MS m/z 357 (M+H)+; 1HNMR (DMSO-d6) δ 8.19 (s, 1H, H-2), 7.72-7.76 (m, 2H, 8-phenyl o-H's), 7.58-7.61 (m, 3H, 8-phenyl m- and p-H's), 7.40 (bs, 2H, 6-NH2), 5.70 (d, 1H, H-1′, J1′,2′=6.4 Hz), 5.38 (d, 1H, 2′-OH, J2′-2′OH=6.2 Hz), 5.29 (ddd, 1H, H-2′, J1′,2′=6.4 Hz, J2′,3′=5.1 Hz, J2′-2′OH=6.2 Hz), 5.14 (bs, 1H, 3′-OH), 4.19 (bs, 1H, H-3′), 3.95-4.0 (m, 1H, H-4′), 2.82 (d, 2H, 5′-CH2, J=5.2 Hz), 2.34 (s, 3H, 5′NH—CH3).
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:26]([CH3:40])=[CH:25][C:24]=1[SH:41])([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[C:26]([CH3:40])=[CH:25][C:24]=1[S:41][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: Cc1cc(S)c(C(C)(C)C)cc1OCCO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and an addition funnel were added tosyl bromide (6.07 g, 26.0 mmol), CCl4 (70 mL) and NEt3 (3.59 mL, 26.0 mmol), and this solution was cooled to 0° C. The 2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzenethiol material prepared in Example OOO (4.6 g, 13.0 mmol) was dissolved in CCl4 (70 mL) and added dropwise to the tosyl bromide solution. The addition was complete in 3.5 hours, at which time the ice bath was removed and the reaction stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with saturated NH4Cl and dried (MgSO4). The solvent was then evaporated and the residue was submitted to flash chromatography (1:1 CH2Cl2 :hexane) to yield the title compound. 1H NMR (CDCl3) δ 0.04 (s, 6 H), 0.85 (s, 9 H), 1.20 (s, 9 H), 2.01 (s, 3 H), 2.37 (s, 3 H), 3.93 (t, 2 H), 3.99 (t, 2 H), 6.82 (s, 1 H), 7.03 (s, 1 H), 7.19 (d, 2 H), 7.44 (d, 2 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH:18]([OH:19])[CH2:17][N:16]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(=O)C.[NH4+]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:16]2[CH2:15][CH:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]([OH:19])[CH2:17]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2)C1
Yield: 99 %

Procedure:
The desired compound was prepared according to Boc deprotection procedures described generally above from 4-[1-(4-Chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester in 99% yield. 1H-NMR (300 MHz, D2O): δ 2.75 (1H, m), 3.0 (1H, m), 3.15 (4H, m), 3.25 (3H, m), 3.3-3.5 (2H, m), 3.7 (1 H, m), 3.9 (1H, m), 4.4 (1 H, m), 7.35 (4H, dd). Retention Time (LC, method: ammonium acetate standard):0.89 min. MS (M+H+): 310
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24]OS(C)(=O)=O)[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30]1([C:36]2([OH:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:39]2[CH2:40][CH2:41][C:36]([OH:42])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:37][CH2:38]2)[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(N(C)C(=O)CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(C)C(=O)CC(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Yield: 12.4 %

Procedure:
3,4-Dichloro-beta-(2-methanesulfonyloxyethyl)-N-methyl-N-(4-methoxyphenyl)benzene propanamide (4.2 g) in DMF (20 mL) was treated with 4-phenyl-4-hydroxypiperidine (1.53 g) and K2CO3 (1.19 g). The mixture was heated at 60° C. for 18 hours. The cooled reaction mixture was diluted the EtOAc (200 mL) and washed with H2O (3×150 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 90:10 (CH2Cl2 :MeOH) gave the title compound (0.58 g). Mass spectrum (CI): 541.
Reaction SMILES: [Br-:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[C:11]2[CH:16]3[CH2:17][CH2:18][N+:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:14][CH2:15]3)[CH2:12]2)=[CH:5][CH:4]=1.C(O)(=O)C>[Pd].O>[Br-:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH:16]3[CH2:15][CH2:14][N+:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:17]3)[CH2:12]2)=[CH:5][CH:4]=1
Reactant: CCCCCCC[N+]12CCC(CC1)C(=CCc1ccc(Cl)cc1)C2
Agent: [Pd]
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCC[N+]12CCC(CC1)C(CCc1ccc(Cl)cc1)C2

Procedure:
Combine 2.47 g (0.08 mole) of 3-[2-(4-Chlorophenyl)ethylidene]-1-heptyl-1-azoniabicyclo[2.2.2]octane bromide, 50 ml of acetic acid, 0.26 g of 10% palladium on carbon and 5 ml of water in a Parr bottle and place the mixture on a Parr hydrogenation apparatus. Pressurize the system to 40 p.s.i. and follow the reaction by the pressure drop in the system. Filter the catalyst, remove the solvent in vacuo and triturate the residue with several portions of diethyl ether. Suspend the crude solid in 100 ml of water and adjust the mixture with 10% sodium hydroxide solution to pH 10. Extract the mixture with three 50 ml portions of ether. Adjust the mixture to pH 2 with hydrobromic acid and extract with four 75 ml portions of methylene chloride. Dry the combined organic extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo. Recrystallize the residue from acetone to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C-:11]#[N:12].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[C:11]#[N:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(O)c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a stirred and cooled suspension of 438 g of 2,6-dichlorobenzaldehyde in 2000 g of glacial acetic acid there was added dropwise a solution of 203 g of potassium cyanide in 350 g of water, keeping the temperature below 25° C. Stirring was continued overnight at room temperature. The reaction mixture was concentrated and the residue, which solidified upon cooling, was filtered off and dried, yielding 438 g of (±)-2,6-dichloro-α-hydroxybenzeneacetonitrile; mp. 90° C. (interm. 1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][N:13]=1>C(O)=O>[CH:1]([NH:8][C:9]1[S:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][N:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(CC(=O)O)s1
Solvent: O=CO
Product: O=CNc1ncc(CC(=O)O)s1
Yield: 86 %

Procedure:
Formic acid (8.4 g) was added to acetic anhydride (18.7 g) under ice-cooling with stirring, and the stirring was continued at 45° to 50° C. for an hour. To the resultant solution was added 2-(2-aminothiazol-5-yl)acetic acid (5.8 g) at ambient temperature, and the mixture was stirred for 35 minutes. After the reaction mixture was evaporated to dryness, the residual product was treated with diisopropyl ether and then collected by filtration to give 2-(2-formamidothiazol-5-yl)acetic acid (5.87 g), mp 229° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:67]I>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH3:67])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CI
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(C)C(C)=O)nc1C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3R,8S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (49 mg) was reacted with methyl iodide (15 mg) according to General Procedure T to obtain (S)-2-({(3R,8S)-7-[2-(acetyl-methyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This was hydrolyzed according to General Procedures N and B to give the title compound (11 mg). LCMS: (m/z) 924.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[C:12]3[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:13]=3[N:14]=2)=[C:4]([F:27])[CH:3]=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30].N1C=CC=CC=1.[Cl-].[NH4+]>C(Cl)Cl>[C:29](=[O:30])([O:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)[O:26][CH:23]1[CH2:24][CH2:25][N:20]([C:11]2[C:12]3[CH2:17][S:16](=[O:18])(=[O:19])[CH2:15][C:13]=3[N:14]=[C:9]([C:5]3[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=3[F:27])[N:10]=2)[CH2:21][CH2:22]1
Reactant: O=S1(=O)Cc2nc(-c3cc(F)c(Cl)cc3F)nc(N3CCC(O)CC3)c2C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 112.1 %

Procedure:
A mixture of 571 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-ol, 0.30 g of 4-nitrophenyl chloroformate, 0.12 ml of pyridine, and 10 ml of methylene chloride was stirred at ambient temperature for 17 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to yield 894 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl 4-nitrophenyl carbonate as light yellow solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[C:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)C=CC=CC=1.Cl>O1CCCC1>[CH3:22][C:18]1[N:17]=[C:16]([NH:15][C:10]2[C:9]([NH2:8])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(Nc2ccccc2N=C(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(Nc2ccccc2N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
42.1 g (0.11 mol) of N1-(diphenylmethylene)-N2-(6-methylpyridine-2-yl)benzene-1,2-diamine was dissolved in tetrahydrofuran (100 ml), and 10% hydrochloric acid (45 ml) was added thereto, and was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure, and water was added to the residue thus obtained and washed with ethyl acetate. Then, the aqueous layer was adjusted to pH>11, and the aqueous layer was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 19.8 g (yield: 83%) of N-(6-methylpyridine-2-yl)benzene-1,2-diamine.
Reaction SMILES: [C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[S:16]1[CH2:22][C:20](=[O:21])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:17]1=[S:18].[Cl-].[NH4+].N>C(O)C>[C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[C:22]3[S:16][C:17](=[S:18])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:20]3=[O:21])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: Cc1ccccc1Nc1nc(C=O)cs1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccccc1Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.12 g of 2-(o-toluidino)thiazole-4-carbaldehyde, 0.87 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 15 ml of ethanol. The resulting product was an orange powder having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:14]1([S:20][CH2:21][N:5]2[C:4](=[O:13])[C:3]3[C:9](=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[S:6]2(=[O:8])=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCSc1ccccc1
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Yield: 46.3 %

Procedure:
A mixture of 1.0 g (0.005 mol) of 4-methylsaccharin, 0.33 g (0.001 mol) of TBAB and 1.2 g (0.0075 mol) of chloromethyl phenyl sulfide in 25 ml of toluene was heated under reflux for about sixteen hours and then cooled, diluted with ethyl acetate and the solution washed with aqueous bicarbonate and water. The organic layer was dried and taken to dryness to give 0.74 g of 2-phenylthiomethyl-4-methylsaccharin.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].Cl[CH2:15][C:16]#[N:17].O1CCOCCOCCOCCOCCOCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:15][C:16]#[N:17])=[O:5]
Reactant: N#CCCl
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCOC(=O)c1c(Cl)cccc1Cl
Yield: 61 %

Procedure:
This compound was prepared in the manner of Example 1, using 10.0 grams (0.052 mole) of 2,6-dichlorobenzoic acid, 2.9 grams (0.052 mole) of potassium hydroxide, 3.9 grams (0.052 mole) of chloroacetonitrile, and 1.4 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 160 ml of dry toluene. The crude product was distilled to give 7.3 grams of cyanomethyl 2,6-dichlorobenzoate; bp 107°/0.006 mm. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][C:21](C)([O-])[CH3:22].[K+].O>CN(C)C=O>[CH2:22]([S:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:21]=[CH2:20]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCSc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Yield: 43.5 %

Procedure:
1.0 g (3.6 mmol) of 2-mercapto-4-(4-trifluoromethylphenyl)benzonitrile, 0.45 g (4.0 mmol) of potassium tert-butoxide and 0.5 g (4.1 mmol) of 3-propenyl bromide were stirred in 20 ml of N,N-dimethylformamide at room temperature for 1 hour. The resulting reaction mixture was poured into 20 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.5 g of 2-(2-propenylthio)-4-(4-trifluoromethylphenyl)benzonitrile (yield 43.0%) as yellow crystals (m.p. 89-90° C.).
Reaction SMILES: [OH:1][NH:2][C:3]([CH3:10])([C:5]([NH:8][OH:9])([CH3:7])[CH3:6])[CH3:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[OH:1][N:2]1[C:3]([CH3:10])([CH3:4])[C:5]([CH3:7])([CH3:6])[N:8]([OH:9])[CH:17]1[C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(NO)C(C)(C)NO
Solvent: CO
Product: COc1ccc(C2N(O)C(C)(C)C(C)(C)N2O)cc1
Yield: 34 %

Procedure:
A solution of 2,3-bis(hydroxylamino)-2,3-dimethylbutane (1.3 g, 8.8 mmol) and 4-methoxy-benzaldehyde (1.2 g, 8.8 mmol) in methanol (10 mL) was stirred at room temperature until reactants disappeared as TLC indicated. 1,3-Dihydroxy-2-(4-methoxyphenyl)-4,4,5,5-tetramethylimidazolidine was obtained by filtration, the filtrate was evaporated under reduced pressure to obtain the second crop of the title compound. The combined compound was then washed with petroleum ether and used for the next reaction (0.8 g, 34% yield). 1HNMR (400 MHz, DMSO): δ 7.63 (s, 1H), 7.32 (d, 1H, J=6.8), 6.87 (d, 1H, J=5.8), 4.42 (s, 1H), 3.72 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[N:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([N:27]4[CH2:28][CH:29]([OH:31])[CH2:30]4)=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(N2CC(O)C2)c(F)c1
Reaction time: 48 h
Yield: 62.6 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (103 mg, 0.33 mmol, 1.0 eq) in DCM (10 mL) was added TEA (0.10 mL, 0.66 mmol, 2.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (100 mg, 0.33 mmol, 1.0 eq) at RT and stirred for 48 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (20 mL), washed with brine, dried over Na2SO4 and evaporated. The residue was purified by CC using 1.0% MeOH in EtOAc as eluent to obtain 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (100 mg; 63%, light brown solid) (TLC: EtOAc/PE 3:2; Rf: 0.3).
Reaction SMILES: [Br:1]Br.[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH3:12])=[CH:6][C:5]=2[O:4]1.N1C=CC=CC=1>ClCCl>[Br:1][C:8]1[CH:9]=[C:10]2[O:11][CH2:3][O:4][C:5]2=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1ccc2c(c1)OCO2
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
3.2 ml (62 mmol) of bromine was dropwise added at 0° C. to a solution having 7.0 ml (58 mmol) of 3,4-(methylenedioxy)toluene and 5.5 ml (68 mmol) of pyridine dissolved in 110 ml of dichloromethane, followed by stirring for 30 minutes, and the temperature was raised to room temperature, followed by stirring for 22 hours. The mixture was washed with an aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 13 g (yield 99%) of 2-bromo-4,5-(methylenedioxy)toluene.