Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:10]=1)C.[OH2:24].[OH2:25].[OH-].[Li+].S(=O)(=O)(O)O.[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C(OCC)(=O)C>[C:17]([CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([C:8](=[O:22])[CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:23])[CH:14]=[CH:13][C:12]=1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:14][CH2:13][O:24][C:35]1[CH:34]=[CH:4][C:5]2[C:6](=[O:25])[CH2:7][CH2:8][O:33][C:37]=2[C:36]=1[CH2:15][CH2:16][CH3:17])([OH:19])=[O:18]
Reactant: C1CCOC1
Reactant: CCOC(=O)CCCC(=O)c1cccc(CCC(=O)OCC)c1
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCc2ccc(C(=O)CCCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 19.3 h
Yield: 77 %

Procedure:
To a mixture of 0.442 g (0.73 mmol) of 4-[6-[3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]-3-(3-ethoxy-3-oxopropyl)-δ-oxobenzenepentanoic acid ethyl ester from the preceding example, in 7 mL of tetrahydrofuran and 7 mL of water was added 91.7 mg (2.19 mmol) of lithium hydroxide monohydrate and the reaction was stirred for room temperature for 19.3 hr. After being acidified with 16 mL of 3N aqueous sulfuric acid, the mixture was worked-up with ethyl acetate in the usual manner. The crude product thus obtained was recrystallized from hexane-ethyl acetate to give 0.309 g (77%) of the title compound as a white solid, mp 136°-139° C.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[CH2:28][OH:29].N1C=CN=C1>C(Cl)Cl>[C:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:29][CH2:28][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[C:25]([F:26])[C:20]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(F)c(F)c1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1ccc(F)c(F)c1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
tert-Butylchlorodiphenylsilane (8.86 ml, 34 mmol) was added slowly via syringe to a solution of (2,3,4-trifluorophenyl)methanol (5.0 g, 31 mmol) and imidazole (2.53 g, 37.2 mmol) in CH2Cl2 (30 ml) cooled in an ice water bath. The mixture warmed to room temperature and stir overnight. Solvent was removed and the residue was partitioned between Et2O and water. The Et2O was separated and washed with brine, and the combined aqueous layers were twice more extracted with Et2O, which was washed with brine. Drying (MgSO4) and removal of solvent gave an oil that was chromatographed on silica gel (50% CH2Cl2 in hexanes followed by gradient elution to 100% CH2Cl2) to isolate an oil that slowly solidified to afford 11.9 g (96%) of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([P:9]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[C:10]2[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[CH3:8][C:6]1[CH:5]=[C:4]([P:9]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[C:10]2[N:15]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:14]([NH2:16])[CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cccc(N)n2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(P(C2=CC=CC(N)N2C(=O)C(C)(C)C)c2cc(C)cc(C)c2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.6 %

Procedure:
To a solution of 6-bis(3,5-dimethylphenyl)phosphino-2-aminopyridine (0.19 g, 0.58 mmol) in dichloromethane (45 mL) at 0° C., triethylamine (152 μL, 1.1 mmol) and pivaloyl chloride (107 μL, 0.87 mmol) are added consecutively. The solution is slowly warmed to ambient temperature, stirred for 40 hours, and concentrated under reduced pressure. The remaining suspension is stirred with activated charcoal (0.25 g) and filtered through a Celite pad. The filtrate is concentrated under reduced pressure and the white residue is purified by column chromatography to yield 6-bis(3,5-dimethylphenyl)phosphino-N-pivaloyl-2-aminopyridine (0.16 g, 65%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 64.2 %

Procedure:
A mixture of methyl thiosalicylate (1.15 g, 6.8 mmol), 2-cyano-4-methylpyridine (0.81 g, 6.8 mmol), triethylamine (1.50 ml, 10.8 mmol) and toluene (2.0 ml) was refluxed for 8 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (1.11 g, 64%).
Reaction SMILES: O[CH:2]1CN(C(=O)C2C=CC3OCOC=3C=2)C(C(O)=O)C1.[OH:21][CH:22]1[CH2:26][N:25]([C:27](=[O:40])[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[CH:24]([C:41]([OH:43])=[O:42])[CH2:23]1>>[CH3:2][O:42][C:41]([CH:24]1[CH2:23][CH:22]([OH:21])[CH2:26][N:25]1[C:27](=[O:40])[C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1)=[O:43]
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Reactant: COc1cc(C(=O)N2CC(O)CC2C(=O)O)cc(OC)c1OC
Product: COC(=O)C1CC(O)CN1C(=O)c1cc(OC)c(OC)c(OC)c1
Yield: 40 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid by the 4-hydroxy-1-(3,4,5-trimethoxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 8, the title product is obtained.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:20])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1.[NH2:23][C:24]1[NH:28][N:27]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:25]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[C:29]([C:26]1[CH:25]=[C:24]([NH:23][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:8]=2)=[O:20])[NH:28][N:27]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: O=C(Nc1cccc(Oc2cccnc2)c1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3cccnc3)c2)[nH]n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl-3-(pyridin-3-yloxy)phenylcarbamate (0.040 g, 0.11 mmol), 5-amino-3-t-butylpyrazole (0.031 g, 0.22 mmol) and i-Pr2NEt (0.029 g, 0.22 mmol) in DMF (2 mL) was stirred at 100° C. overnight. Water (20 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (26 mg, 67% yield) of the desired product as a red-brown oil. 1H-NMR (400 MHz, CDCl3): δ 10.1 (brs, 1H), 8.40 (s, 1H), 8.35 (d, J=3.6 Hz, 1H), 8.02 (s, 1H), 7.35-7.28 (m, 4H), 6.71 (dt, J=6.4, and 2.2 Hz, 1H), 5.67 (brs, 1H), 1.32 (s, 9H), urea protons not visible; MS (EI) m/z: 352.3 (M+H+).
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[C:16]([CH3:21])([CH3:20])[C:17](N)=O.[OH2:25].[OH-:26].[Na+]>CO>[C:12]([C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([OH:2])=[C:4]([C:16]([CH3:20])([CH3:17])[C:21]([OH:26])=[O:25])[CH:5]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: [OH-]
Reactant: O
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1C(C)(C)C(N)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C(=O)O)c(O)cc1[N+](=O)[O-]

Procedure:
To a mixture of compound 17 (7.3 g, 21.6 mmol) in methanol (180 mL) was added water (18 mL) and NaOH (8.64 g, 216 mmol). The solution was heated and maintained at reflux for 3 days. The solvent was evaporated in vacuo and the residue was dissolved in 140 mL of water. Then the solution was acidified to pH 2 by the addition of 2N HCl. The aqueous phase was extracted with ethyl acetate (100 mL×3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and then concentrated to give compound 18 as a yellow solid, which was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[NH:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:21]2[CH:22]=[N:18][NH:19][CH:20]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cn[nH]c2)CC1
Yield: 66.9 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), 1H-pyrazole-4-boronic acid pinacol ester (12 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (18 mg, 67%), LC-MS (ESI, 3.5 min) Rt 1.06 min, m/z 306 (100%, [M+H]+); m/z (ESI) C14H17ClN5O requires 306.1116 found [M+H]+ 306.1114.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][CH:15]([NH:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:16].C(N=C=NCCCN(C)C)C>>[CH3:16][CH:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=3[CH:5]=2)=[O:13])[CH2:28][CH2:29]1)[CH3:14]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(Br)ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-bromoindole-2-carboxylic acid (0.51 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.47 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.49 g), the title compound is obtained, mp 229°-230°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[S:8].[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[OH:21])#[N:15]>C(#N)C>[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[S:8])#[N:15]
Reactant: COP(=S)(Cl)OC
Reactant: CCCCOc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=S)(OC)OC)c(C#N)s1
Temperature: 20 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
7 g of potassium carbonate and 8 g of O,O-dimethyl chlorothiophosphate were added to a solution of 9.8 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 24 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with benzene yielded 11 g of 2-cyano-3-(dimethoxythiophosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 =1.5375.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7](O)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:29])CC)C.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]([F:29])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(Cc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2-(4-Chlorobenzyl)1,3-bis(1,2,4-triazol-1-yl)2-propanol (0.318g) was added to a solution of diethylamino sulphur trifluoride (0.128g) in chloroform (15ml), and the resulting yellow solution was stirred at room temperature for 3.5 hr. The mixture was then poured into water and the organic layer was separated, washed with water, dried, and evaporated to dryness. The yellow oil so obtained was purified by chromatography on a 25cm silica (Merck "Lobar") column, eluting with 3% v/v methanol in chloroform, to give a colourless oil which was crystallised from diethyl ether to give 2-(4-chlorobenzyl)-2-fluoro-1,3-bis(1,2,4-triazol-1-yl) propane, m.p. 161-163°.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][O:35][CH3:36])=[CH:30][CH:31]=2)[O:26][CH2:25][C:24]1([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:40][CH:39]=1)[CH3:37].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:8]([O:12][C:6]([NH:5][S:2]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][O:35][CH3:36])=[CH:30][CH:31]=2)[O:26][CH2:25][C:24]1([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:42][CH:43]=1)[CH3:37])(=[O:4])=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)O
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCNS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 35.3 %

Procedure:
To a solution of chlorosulfonylisocyanate (25 μl, 0.292 mmol) in dichloromethane (1 ml) was added t-butanol (27 μl, 0.292 mmol) at −38° C. for 10 minutes, which was then stirred for 2.5 hours. Then, the reaction mixture was cooled down to −78° C., 4-(9-aminononyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (118 mg, 0.243 mmol) dissolved in triethylamine (50 μl, 0.364 mmol) and dichloromethane (1 ml) was slowly added thereto, and the resulting mixture was stirred overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloride solution, water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was subjected to preparative TLC (chloroform:methanol=10:1) to give the title compound (57 mg, yield 36%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH3:2].[OH-].[Na+].[CH2:14](O)[CH3:15].BrCC>ClCCl>[CH2:14]([O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[O:3][CH2:1][CH3:2])[CH3:15]
Reactant: CCOc1c(O)cccc1F
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCBr
Product: CCOc1cccc(F)c1OCC
Temperature: 10 °C
Yield: 75 %

Procedure:
To a 250 ml reactor were added 12.5 (0.08 mol) of 2-ethoxy-3-fluorophenol [F1], 3.2 g (0.08 mol) of sodium hydroxide and 20 ml of ethanol. After cooling to around 10° C., 20 ml of an ethanol solution of 9.6 g (0.088 ml) of bromoethane was slowly added. After the termination of the addition, they were reacted under a reflux temperature for 3 hours and, after the termination of the reaction, dichloromethane was added, followed by extraction. The extraction liquid was washed with water and dried, and the solvent was removed by distillation to obtain 11.0 g of an oily product [G1]. The process yield was 75%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:19][CH:20]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1OCc1ccc(/C=C/c2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 66 %

Procedure:
To a mixture of [4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]phenyl]methanol (0.50 g), methyl 2-(2-hydroxyphenyl)acetate (0.27 g), triphenylphosphine (0.63 g) and tetrahydrofuran (30 mL) was dropwise added a solution (40%, 1.04 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. To the reaction mixture was added ethyl acetate, the mixture was washed successively with water, a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]benzyloxy]phenyl]acetate as a pale-yellow oil (0.4-6 g, 66%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[C:4]([NH:6][C:7]1[S:8][C:9]2[CH2:20][CH2:19][CH2:18][CH2:17][C:10]=2[C:11]=1[C:12]([O:14]CC)=O)=[O:5])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:12]([C:11]1[C:10]2[CH2:17][CH2:18][CH2:19][CH2:20][C:9]=2[S:8][C:7]=1[NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:21][CH3:22])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1c(NC(=O)C(CC)CC)sc2c1CCCC2
Product: CCC(CC)C(=O)Nc1sc2c(c1C(=O)NCc1ccccc1)CCCC2

Procedure:
The product of Example 14 and benzylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 0.91 (t, J=7.5 Hz, 6H), 1.52-1.71 (m, 4H), 1.77-1.89 (m, 4H), 2.16-2.29 (m, 1H), 2.64-2.75 (m, 4H), 4.56 (s, 2H), 7.21-7.29 (m, 1H), 7.31-7.37 (m, 4H); MS (DCI/NH3) m/z 385 (M+H)+; anal. calculated for C22H28N2O2S: C, 68.72; H, 7.34; N, 7.28. Found: C, 68.45; H, 7.49; N, 7.17.
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C(#N)C>[CH3:9][C:2]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[N:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=O)C(C)Br
Reactant: Nc1ccccn1
Solvent: CC#N
Product: COC(=O)c1nc2ccccn2c1C
Yield: 30.7 %

Procedure:
Methyl 3-bromo-2-oxobutanoate (6.5 g, 34.3 mmol) was added to a stirred solution of 2-aminopyridine (4.0 g, 42.5 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated in vacuo and the residue was diluted with water and the pH was to 7.5 using sodium bicarbonate solution. The mixture was extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 8% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 25.1%) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 7.95 (d, 1H), 7.7 (d, 1H), 7.25 (t, 1H), 6.8 (t, 1H), 4.0 (s, 3H), 2.8 (s, 3H). MS: [M+H]+: m/z=191.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[Cl:25][C:26]1[CH:32]=[C:31]([P:33]([CH3:36])([CH3:35])=[O:34])[CH:30]=[CH:29][C:27]=1[NH2:28]>>[Cl:25][C:26]1[CH:32]=[C:31]([P:33]([CH3:35])([CH3:36])=[O:34])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])[C:5]([C:21]([F:24])([F:22])[F:23])=[CH:4][N:3]=1
Reactant: CP(C)(=O)c1ccc(N)c(Cl)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2Cl)ncc1C(F)(F)F

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 2-chloro-4-(dimethylphosphoryl)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:7][CH2:6][C:5]2=[N:22][OH:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[S:32]([OH:34])(=[O:21])(=[O:33])[CH3:31].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:7][CH2:6][C:5]2=[N:22][OH:23]
Reactant: CS(=O)(=O)Cl
Agent: O=C(c1ccc(Cl)cc1Cl)N1CCC(=NO)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O

Procedure:
To a mixture of 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime (10.0 g), triethylamine (4.1 g) and dichloromethane (150 ml) was added dropwise methanesulfonyl chloride (3.5 g) at -20° C. with stirring. The mixture was stirred at -20° C. for 30 minutes and dichloromethane (300 ml) was added. The reaction mixture was sequentially washed with 1N HCl, saturated aqueous sodium bicarbonate solution, then with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. Solvent was removed in vacuo and the residue was recrystallized with ether and n-hexane to obtain 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime mesylate (yield 11 g) as white crystal.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH2:15]O)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:19])=O>C(Cl)Cl>[ClH:19].[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH2:15][Cl:19])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: OC/C=C/c1ccc(Cn2ccnc2)cc1
Solvent: ClCCl
Product: Cl
Product: ClC/C=C/c1ccc(Cn2ccnc2)cc1

Procedure:
In 11 ml of methylene chloride was dissolved 2.11 g of (E)-3-[4-(imidazol-1-ylmethyl)phenyl]allyl alcohol, and 3.57 ml of thionyl chloride was dropped into the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction under reflux for one hour. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure to obtain oily (E)-3-[4-(imidazol-1-ylmethyl)phenyl]allyl chloride hydrochloride. This was dissolved in 8 ml of methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=2[C:15]#[N:16])[CH2:7][CH2:6]1.C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:14]=2[C:15]([NH2:16])=[N:32][C:31]([NH2:33])=[N:30]3)[CH2:9][CH2:10]1
Reactant: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2Cl)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCC(Cc4ccccc4Cl)CC3)cccc2n1
Yield: 79 %

Procedure:
Cyclization of 2-[4-(2-chlorobenzyl)cyclohexylmethoxy]-6-fluorobenzonitrile (100 mg; 0.28 mmol) was carried out using Method F using guanidine carbonate (100 mg; 0.55 mmol) in 1.5 mL of dimethylacetamide. Title compound was obtained as a white solid. (88 mg; 79% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.27 (m, 7H), 6.75 (d, J=8.0 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.97 (br s, 2H), 3.92 (d, J=5.6 Hz, 2H), 2.52 (d, J=7.2 Hz, 2H), 1.83 (m, 3H), 1.68 (m, 3H), 1.06 (m, 4H). MS m/z (ESI) 398 (M+H)+.