Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(O)c1cncc(Br)c1
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
Solvent: O
Product: O=C(O)c1cncc(-c2cccc(Cl)c2)c1
Temperature: 25 °C

Procedure:
A three neck flask was charged with 5-bromonicotinic acid (2 g, 9.90 mmol), 3-chlorophenylboronic acid (1.55 g, 9.90 mmol), a 0.4 M solution of sodiumcarbonate in water (37 mL, 14.8 mmol) and Acetonitrile (37 mL). The solution was degassed under vacuum and tetrakistriphenylphoshine Pd(0) (0.57 g, 0.495 mmol) was added and the reaction refluxed overnight under nitrogen. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was partially evaporated under reduced pressure and the remaining solution acidified to pH=2 with 1N HCl. The resulting solid was collected by filtration and dried under vacuum. 1H NMR [(CD3)2SO]: δ 9.15-9.05 (m, 2H), 8.45 (s, 1H), 7.85 (s, 1H), 7.80-7.65 (m, 1H), 7.60-7.42 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:13])[CH2:30][CH2:29]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Temperature: 50 °C

Procedure:
A solution of quinoline-4-carboxylic acid (173 mg, 1 mmol), and 1,1′-carbonyldiimidazole (162 mg, 1 mmol) in dimethylformamide (2 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (150 mg, 1 mmol), and N,N-diisopropylethylamine (0.262 mL, 1.5 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with chloroform (10 mL). The organic solution was washed with water (3×10 mL), 1 N NaOH (10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 156 mg (58%) of 403:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[C:14]1([N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)c1csc(NC(=O)N(c2ccccc2)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 13, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 7 g of diphenylcarbamoyl chloride, 30 ml of triethylamine and 20 ml of dimethylformamide. The resulting product was a brown oil having the following physical properties.
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][N:19]=[C:18](F)[N:17]=1)[C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])#[N:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:18]1[N:17]=[C:16]([N:4]([CH2:3][C:1]#[N:2])[C:5](=[O:15])[C@H:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:7])[CH:21]=[CH:20][N:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(F)n1
Reactant: NCc1ccccc1
Product: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(NCc2ccccc2)n1

Procedure:
The title compound was prepared from the product from step (ii) (0.2 g) and benzylamine (0.37 ml) by the method of example 1 step (iv). Yield 0.11 g.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].C(OC(OCC)CNC(N)=O)C.[OH:23][C@H:24]1[CH2:44][C@@:43]2([CH3:45])[C@@H:35]([CH2:36][C@@H:37]([OH:47])[C@:38]2([OH:46])[C:39](=[O:42])[CH2:40][OH:41])[C@H:34]2[C@H:25]1[C@:26]1([CH3:49])[C:31]([CH2:32][CH2:33]2)=[CH:30][C:29](=[O:48])[CH2:28][CH2:27]1>CCOCC.CCCCC.CO>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][O:47][C@@H:37]1[CH2:36][C@@H:35]2[C@:43]([CH3:45])([CH2:44][C@H:24]([OH:23])[C@H:25]3[C@H:34]2[CH2:33][CH2:32][C:31]2[C@:26]3([CH3:49])[CH2:27][CH2:28][C:29](=[O:48])[CH:30]=2)[C@@:38]1([OH:46])[C:39](=[O:42])[CH2:40][OH:41])[CH3:2]
Reactant: CCOC(C=[N+]=[N-])OCC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Agent: CCOC(CNC(N)=O)OCC
Solvent: CCCCC
Solvent: CO
Solvent: CCOCC
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)OCC
Temperature: 0 °C

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and B. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3:2 ether pentane is diluted with 100 ml of methanol and cooled to 0°C. 11β,16α,17,21-Tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is recrystallized from methanol to yield the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:12]>>[Br:12][CH2:11][C:10]1[CH:9]=[C:8]([O:7][C:6]([F:5])([F:16])[F:17])[CH:15]=[CH:14][C:13]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1CBr
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Fuming nitric acid (5 mL) was cooled to 0° C. and 3-(trifluoromethoxy)benzyl bromide (1 mL, 6.16 mmol) was added. After 15 minutes, the reaction was poured into ice water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water, saturated NaHCO3, and brine (75 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatograpy on silica gel (0 to 15% EtOAc/hexanes) afforded 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene Rf=0.54 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.14 (d, J=8.9 Hz, 1H), 7.43 (m, 1H), 7.31 (m, 1H), 4.82 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]([CH2:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of commercially available methyl 2-amino-5-bromobenzoate (10.0 g, 43.5 mmol) in dichloromethane (100 mL) was added 2-phenoxyacetyl chloride (6.60 mL, 47.8 mmol). The white suspension formed was cooled to 0° C. and treated with triethylamine (13.3 mL, 95.6 mmol) dropwise. The resulting solution was stirred at room temperature for 0.5 hours. The mixture was diluted with CH2Cl2 and was washed with water and saturated aqueous NH4Cl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 7% EtOAc-heptane), to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:44])[CH2:11][NH:12][CH2:13][C:14](=[O:43])[NH:15][C:16]1[CH:21]=[C:20]([N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[N:24]([CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:23]2=[O:37])[CH:19]=[CH:18][C:17]=1[O:38][C:39]([F:42])([F:41])[F:40].[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:28][C:25]1([CH3:29])[C:26](=[O:27])[N:22]([C:20]2[CH:19]=[CH:18][C:17]([O:38][C:39]([F:40])([F:41])[F:42])=[C:16]([NH:15][C:14]([CH2:13][NH:12][CH2:11][C:10]([OH:44])=[O:9])=[O:43])[CH:21]=2)[C:23](=[O:37])[N:24]1[CH2:30][C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1
Reactant: COC(=O)CNCC(=O)Nc1cc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)ccc1OC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CNCC(=O)O)c2)C(=O)N1Cc1ccncc1
Temperature: 50 °C

Procedure:
100 mg (0.16 mmol) ({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenylcarbamoyl]-methyl}-amino)-acetic acid methyl ester trifluoro acetate were dissolved in 5 ml dioxane/water (9/1) and treated with 9.3 mg (0.39 mmol) lithium hydroxide. After stirring for 1H at 50° C., the solvent was evaporated and the residue was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid)/acetonitrile gradient) Yield: 10 mg.
Reaction SMILES: OC1C=CC([CH:8]([CH:16]2[CH2:20]C[CH2:18][CH2:17]2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.O.CN([CH:34]=[O:35])C>>[Cl:21][C:22]1[C:23]([O:35][CH2:34][C:22]2[CH:23]=[CH:24][CH:27]=[CH:28][CH:29]=2)=[C:24]([CH:25]2[CH2:18][CH2:17][CH:16]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:20]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)C(c1ccc(O)cc1)C1CCCC1
Reactant: Clc1cccc(CBr)c1
Solvent: O
Product: CC(C)(C)OC(=O)CC1CCC(c2cccc(Cl)c2OCc2ccccc2)C1

Procedure:
1 g of tert-butyl 2-(4-hydroxyphenyl)-2-cyclopentyl-acetate (U.S. Pat. No. 834,734) and 1.2 ml of 3-chlorobenzyl bromide are dissolved in 10 ml of DMF and heated at 60°-70° C. for 14 h with 0.9 g of K2 CO3. After cooling, the mixture is treated with water and extracted by shaking with ether and the ether extract is dried. 1.3 g of the title compound are obtained as an oil. Rf =0.48 (cyclohexane / ethyl acetate 9:1)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][OH:23])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=[O:29])=[N:25][C:26](Cl)=[O:27].CO.[NH3:32]>C(Cl)Cl.O>[NH:25]([C:24]([O:23][CH2:22][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:29])[C:26]([NH2:32])=[O:27]
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Reactant: N
Reactant: O=C=NC(=O)Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COC(=O)NC(N)=O)COc1noc2ccc(Cl)cc12

Procedure:
A solution of 1.00 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole in 5 ml of methylene chloride is added to a solution of 0.31 g of N-(chlorocarbonyl) isocyanate in 10 ml of methylene chloride at -50° to -40° C. This solution is added to 10 ml of a methanol solution (8.0N) of ammonia at -20° C. over 20 minutes, and the temperature is elevated to 0° C., at which they are subjected to reaction for 30 minutes. Water is added to the reaction mixture, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure, to obtain 3-(3-ureidocarbonyloxy-2-tert-butoxycarbonylaminopropoxy)-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4].I[CH2:14][CH2:15][CH3:16]>O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][CH2:15][CH3:16])[CH3:4]
Reactant: CCOc1ccccc1O
Reactant: CCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOc1ccccc1OCC
Temperature: 80 °C

Procedure:
The reaction was conducted in a 500-ml 3-neck flask equipped with a reflux condenser, an addition funnel, and a magnetic stirring bar. Into the flask was introduced 75 ml water, 11.5 grams of 50% aqueous sodium hydroxide, 19.3 grams (0.14 moles) 2-ethoxyphenol, and 23.8 grams (0.14 moles) 1-iodopropane. The flask contents were maintained at 80° C. for a period of 7 hours and were then cooled to room temperature. After the addition of 100 ml of water the reaction mixture was transferred to a 250-ml separatory funnel and washed twice with 100-ml quantities of hexane. The organic layer was washed twice with 10 ml of 15% aqueous sodium hydroxide and dried over anhydrous magnesium sulfate. Most of the solvent was removed by simple distillation. A liquid was isolated which boiled at 63-67° C. @ 0.05 mm. It was labeled example 8, and the structure confirmed by glpc and NMR analysis.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.BrC1N2N=C(N[C:32]3[CH:39]=[CH:38][C:35](C#N)=[CH:34][CH:33]=3)N=C2C=CC=1.[OH2:40].[OH-].[Na+]>P(=O)(O)(O)O>[OH:40][C:32]1[CH:33]=[C:34]([C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:35]=[CH:38][CH:39]=1
Reactant: N#Cc1ccc(Nc2nc3cccc(Br)n3n2)cc1
Reactant: NC(=O)c1ccc(Nc2nc3cccc(Br)n3n2)cc1
Reactant: O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccc(Nc2nc3cccc(-c4cccc(O)c4)n3n2)cc1
Yield: 71 %

Procedure:
4-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzamide. A pale yellow solution of 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzonitrile (0.909 g, 2.89 mmol) in 85% phosphoric acid (15 mL) was heated at 100° C. for 2 h. Upon completion of the reaction as indicated by LCMS the reaction mixture was poured into minimum water, and made neutral with 1N sodium hydroxide (pH 6-7). The mixture was extracted with 20% isopropanol in chloroform several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by silica gel chromatography using a gradient of 0-8% of saturated methanolic ammonia in chloroform to give the title compound as a pale yellow solid (0.677 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.20 (s, 1H), 7.84 (d, 2H, J=8 Hz), 7.78-7.75 (m, 3H), 7.66 (d, 1H, J=8 Hz), 7.53 (t, 1H, J=8 Hz), 7.7.45-7.42 (m, 1H), 7.16 (br s, 1H); MS (ESI) m/z 332.16 and 334.16 [M]+ and [M+2]+
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])=[N:8]1)=[O:6])[CH:2]=C.I([O-])(=O)(=O)=[O:27].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CCOCC.O.[Os](=O)(=O)(=O)=O>[CH:2]([CH2:1][NH:4][C:5]([N:7]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:22])([F:23])[F:24])=[CH:16][C:15]=2[Cl:25])=[N:8]1)=[O:6])=[O:27]
Reactant: C=CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NCC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
N-allyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (4.3 g, 10.9 mmol) was dissolved in a solution mixture of ether (50 ml) and water (50 ml), an aqueous solution (60 ml) of osmium tetraoxide (254 mg, 1.0 mmol) and sodium periodate (4.7 g, 21.8 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, a 10% sodium thiosulfate aqueous solution (100 ml) and ethyl acetate (100 ml) were added to the reaction solution, and an organic layer was separated and an aqueous layer was extracted with ethyl acetate (50 ml×2). These organic layers combined were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/5), to give a white solid of N-formylmethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (2.12 g, yield: 49.1%). mp: 111-113° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (d, J=0.8 Hz, 3H), 4.17 (d, J=5.5 Hz, 2H), 5.81 (q, J=0.8 Hz, 1H), 7.21 (br t, J=5.5 Hz, 1H), 7.67 (s, 2H), 9.66 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:26][C:27]1[C:28](F)=[C:29]([CH:37]=[CH:38][C:39]=1F)[C:30]([N:32]([CH2:34][CH2:35][OH:36])[CH3:33])=[O:31].S(Cl)(Cl)=O>C(#N)C.CO>[Cl:26][C:27]1[C:28]2[O:36][CH2:35][CH2:34][N:32]([CH3:33])[C:30](=[O:31])[C:29]=2[CH:37]=[CH:38][C:39]=1[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
Cesium carbonate (41.2 g, 126.4 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (10.9 g, 42.25 mmol) and 3-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (11.6 g, 46.4 mmol) in acetonitrile (210 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 8 hours. The mixture was cooled to RT and pressure, the acetonitrile evaporated in vacuo, and the residue partitioned between water (500 mL) and ethyl acetate (300 mL). The mixture was adjusted to pH 2, the organic layer washed with brine, dried (MgSO4) and evaporated to a residue (shown to contain a large amount of acid). The mixture was added to a solution of thionyl chloride (11.7 mL, 160 mmol) in methanol (120 mL) at −35° C., the solution stirred at −35° C. for 1 hour then allowed to come to RT and stirred for 18 hours. The methanol was evaporated in vacuo to a residue which was partitioned between ethyl acetate (250 mL) and a saturated sodium hydrogen carbonate solution (175 mL). The organic layer was washed with a saturated sodium hydrogen carbonate solution (3×75 mL), brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (8.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:18][C:19]([CH3:21])=O.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][CH:12]([NH:15][CH:19]([CH3:21])[CH3:18])[CH2:13][CH2:14]3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)=O
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (335 mg), acetone (92 ul), acetic acid (0.1 mL) and methanol (3 mL) was stirred at room temperature for 5 minutes. To the reaction solution was added triacetoxy sodium boron hydride (332 mg). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. Aqueous sodium hydrogencarbonate was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (160 mg). Yield: 41%.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[P:31](Cl)(=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34].C(N(CC)CC)C>O1CCCC1>[CH2:33]([O:32][P:31]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:29][CH:30]=1)([O:35][CH2:36][CH3:37])=[O:38])[CH3:34]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52693.6 %

Procedure:
2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (268 mg), diethyl phosphorochloridate (0.16 mg), and triethylamine (0.28 ml) were dissolved in tetrahydrofuran (8 ml) and the solution was stirred at room temperature for 14 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was then washed with water, dried, and concentrated, and the residue was crystallized from hexane to provide the title compound as colorless solid (270 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)O)[CH:10]=2)[N:5]=[C:4]([O:26]C(C)(C)C)[CH:3]=1.Cl.Cl[Sn]Cl.O>CC(O)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:14]3[S:15][CH:16]=[CH:17][N:18]=3)[CH:10]=2)[N:5]=[C:4]([OH:26])[CH:3]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
Into a 250-mL round-bottom flask, was placed [4-bromo-2-(tert-butoxy)quinolin-6-yl](4-chlorophenyl)1,3-thiazol-2-ylmethanol (5.5 g, 10.92 mmol, 1.00 equip), AcOH (78 mL), hydrogen chloride (13 mL), and SnCl2.2 H2O (7.4 g, 32.80 mmol, 3.00 equip). The resulting solution was stirred for 40 min at 100° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with water (200 mL). The resulting solution was extracted with DCM (3×200 mL) and the organic layers combined. The resulting mixture was washed with water (2×200 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with dichloromethane:methanol (10:1) to yield 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]quinolin-2-ol as a white solid. (ES, m/z): [M+N]+ 433