Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O-])(=O)[CH3:10].[Na+].C(OC=C)(=O)C>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir].C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Oc1ccc(Br)cc1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C=COC(C)=O
Solvent: Cc1ccccc1
Solvent: C1=CCCC=CCC1
Product: C=COc1ccc(Br)cc1
Temperature: 102 °C

Procedure:
Under nitrogen, a 250 milliliter round bottom flask was charged with 4-bromophenol (8.00 grams, 46.2 millimoles, 1.0 equivalent), sodium acetate (2.28 grams, 27.7 millimoles, 0.6 equivalent) and bis(1,5-cyclooctadiene)diiridium(I)dichloride (233 milligram, 347 micromoles, 0.0075 equivalent). Toluene (75 milliliter) was added to this and vinyl acetate (8.5 milliliter, 92 millimoles, 2.0 equivalents) was added via syringe. The reaction was heated to 102° C. for 3 hours and then allowed to cool to room temperature. The crude reaction was concentrated on a rotary evaporator and filtered through a plug of silica. The solvent was removed by rotary evaporation and the product dried under high vacuum. The final compound was obtained in form of a colorless to slightly yellow oil (6.97 gram, 35.0 millimoles, 76%). 1H NMR (500 MHz, CDCl3) δ 7.44-7.37 (m, 2H), 6.91-6.84 (m, 2H), 6.56 (dd, J=13.7, 6.1 Hz, 1H), 4.77 (dd, J=13.7, 1.8 Hz, 1H), 4.45 (dd, J=6.1, 1.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:10]1[N:11]([CH3:18])[N:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:6][C:7]([OH:9])=O)[CH:2]=[CH2:3].[C:19](Cl)(=O)[C:20](Cl)=O.CN(C=O)C.C([Sn](CCCC)(CCCC)CCCC)=C>C(Cl)Cl>[CH2:1]([O:4][CH:5]([C:10]1[N:11]([CH3:18])[N:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:6][C:7](=[O:9])[CH:19]=[CH2:20])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOC(CC(=O)O)c1c([N+](=O)[O-])cnn1C
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOC(CC(=O)C=C)c1c([N+](=O)[O-])cnn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 3-allyloxy-3-(2-methyl-4-nitro-pyrazol-3-yl)propanoic acid (4.33 g, 17 mmol) in DCM (48 mL) at 0° C. under nitrogen was added oxalyl chloride (4.37 mL, 51 mmol) followed by the cautious addition of DMF (0.05 mL) to initiate the acylation. The reaction mixture was stirred at room temperature for 3 hr and concentrated under reduced pressure. The residue was dissolved in DME (28 mL), vinyltributyltin (2.48 mL, 8.50 mmol) added and the mixture degassed with nitrogen for 30 min. trans-Benzyl(chloro)-bis(triphenylphosphine)palladium(II) (129 mg, 0.17 mmol) was added and degassing continued for 10 min. The reaction mixture was heated to 65° C. for 1 hr and cooled to room temperature. Concentration under reduced pressure and purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(allyloxy)-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)pent-1-en-3-one as a yellow syrup (2.76 g, 61%). A solution of this syrup (250 mg, 0.94 mmol) in toluene (90 mL) was degassed with nitrogen for 30 min at 35° C. Zhan 1B catalyst (26 mg, 0.04 mmol) dissolved in toluene (2 mL) was added to the reaction mixture and degassing continued for 15 min. After stirring at 35° C. for 1 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-(2-methyl-4-nitro-pyrazol-3-yl)-3,7-dihydro-2H-oxepin-4-one as a colourless solid (107 mg, 30% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 6.44 (ddd, J=12.8, 3.4, 2.3 Hz, 1H), 6.15 (m, 1H), 6.01 (dd, J=11.1, 3.4 Hz, 1H), 4.72 (ddd, J=19.8, 3.4, 1.7 Hz, 1H), 4.61 (ddd, J=19.6, 2.4 Hz, 1H), 4.08 (s, 3H), 3.20-3.12 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].I[C:19]1[CH:20]=[CH:21][C:22](C)=[C:23](O)[CH:24]=1.COCCOC>CCOC(C)=O.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccc(I)cc1O
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccccc2)cc1
Yield: 50.8 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (4.55 g, 21.38 mmol), Na2CO3 (32.1 ml 2 N aqueous, 64.2 mmol), Pd(PPh3)4 (1.24 g, 1.07 mmol), 5-iodo-2-methylphenol (Hodgson, Moore J. Chem. Soc. 1926, 2038) (5.0 g, 21.38 mmol), and ethylene glycol dimethyl ether (225 ml) was heated to reflux overnight. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Chromatography (30% EtOAc/hexanes) afforded 1.64 g (36%) product as a white solid and 2 g 4-methoxy biphenyl as an undesired by-product: mp 146–147° C.; 1H NMR (300 MHz, DMSO-d6): δ 2.13 (3H, s), 3.78 (3H, s), 6.94 (1H, dd, J=8.1 Hz, 2.7 Hz), 7.00 (3H, m), 7.09 (1H, d, J=8.1 Hz), 7.48 (1H, d, J=9.5 Hz), 9.36 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][C@@H:13]3[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=2[CH:19]=1.NC1C=CC2C[C@@H]3[C@@H](CC=2C=1)N(C(=O)CC)CCC3.[F:39][C:40]([F:52])([F:51])[C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>N1C=CC=CC=1>[F:52][C:40]([F:39])([F:51])[C:41]1[CH:42]=[CH:43][C:44]([S:47]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:14][C@@H:13]4[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]4[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=3[CH:19]=2)(=[O:49])=[O:48])=[CH:45][CH:46]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)N1CCC[C@@H]2Cc3cc(N)ccc3C[C@H]21
Agent: CCC(=O)N1CCC[C@@H]2Cc3ccc(N)cc3C[C@H]21
Solvent: c1ccncc1
Product: CCC(=O)N1CCC[C@@H]2Cc3cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)ccc3C[C@H]21
Reaction time: 2 h

Procedure:
0.792 g (3.065 mmol) of a 1:1 mixture trans-(7-amino-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-1-yl)-propan-1-one and trans-(8-amino-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-1-yl)-propan-1-one were dissolved in 20 ml pyridine. At 0-4° C., 0.75 g of 4-trifluoromethyl-benzene sulfonylchloride (3.066 mmol) were added, and the reaction stirred for 2 h under cooling. Pyridine was evaporated and the residue partitioned between 20% aqueous citric acid and diethylether. The aqueous layer was extracted twice with diethylether, the combined organic phases washed with 20% aqueous citric acid, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 1.327 g of the product. MSD: 467.1 g/mol
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([CH2:30][Cl:29])[CH:32]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(CCl)c2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (95 mg, 0.3 mmol) in anhydrous dichloromethane (3 mL) was added triethylamine (0.063 mL, 0.45 mmol) followed by 3-(chloromethyl)benzoyl chloride (0.051 mL, 0.36 mmol). The mixture was shaken overnight at room temperature, concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC, MS (APCI) m/e 472 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:14]1COCC1>C(OCC)(=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of compound 1 (10.05 g, 64.04 mmol, 1.0 eq.) in THF (30 ml) was added dropwise to a suspension NaH (1.84 g, 76.85 mmol, 1.2 eq.) in THF (90 ml) at 0° C. and the mixture was stirred at same temperature for 1 h. Triethyl phosphonoacetate (16.5 ml, 83.25 mmol, 1.3 eq.) was added to the reaction mixture at −20° C. and the reaction mixture was allowed to warm to RT and stir for 2 h. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (2×100 ml) and the organic layer dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 5% ethyl acetate/hexanes) to yield compound 2. Yield: 94% (17.28 g, 60.2 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH2:13][OH:14])=[N+:11]([O-:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:16].[SH:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1>C(Cl)(Cl)Cl>[CH3:23][N:19]1[CH:20]=[CH:21][N:22]=[C:18]1[S:17][CH2:2][C:3]1[C:12]([CH2:13][OH:14])=[N+:11]([O-:15])[C:10]2[C:5]([N+:4]=1[O-:16])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: [O-][n+]1c(CO)c(CBr)[n+]([O-])c2ccccc21
Reactant: Cn1ccnc1S
Solvent: ClC(Cl)Cl
Product: Cn1ccnc1SCc1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromomethyl-3-hydroxymethylquinoxaline-1,4-dioxide (0.01 mole) was suspended in 75 ml of chloroform and 2-mercapto-1-methylimidazole (0.01 mole) was added in one portion. The suspension was stirred at room temperature for about 2 hours. The product was collected by filtration. Yield, 3.82 grams (96%); m.p. 174-7° ).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:32])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([CH2:20][N:21]([CH3:29])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][NH:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:33][C:34]([CH3:36])=O>>[Cl:2][C:3]1[C:4]([F:32])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([CH2:20][N:21]([CH3:29])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][N:24]([CH:34]([CH3:36])[CH3:33])[CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Reactant: CC(C)=O
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(C(C)C)C1
Yield: 50 %

Procedure:
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide hydrochloride salt Example 74 was coupled with acetone using the same method as for the equivalent step in Example 76 to give the title product (50 mg, 50%) as a white powder; 1H NMR Spectrum: (CDCl3) 0.95 (d, 6H), 2.42 (s, 3H), 2.49 (brs, 1H), 3.24 (brs, 2H), 3.63 (d, 2H), 3.97 (m, 5H), 5.32 (brs, 1H), 7.14 (m, 2H), 7.24 (s, 1H), 7.65 (brs, 1H), 7.75 (brs, 1H), 7.99 (s, 1H), 8.54 (brs, 1H), 8.73 (s, 1H); Mass Spectrum: (M+H)+ 487.
Reaction SMILES: [NH2:1][C:2]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[C:3]([C:6](=[O:10])[CH2:7][C:8]#[N:9])[C:4]#[N:5].CC[O-].[Na+]>C(O)C>[NH2:9][C:8]1[NH:1][C:2]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[C:3]([C:4]#[N:5])[C:6](=[O:10])[CH:7]=1
Reactant: N#CCC(=O)C(C#N)=C(N)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(-c2ccco2)[nH]c(N)cc1=O
Temperature: 100 °C
Yield: 93 %

Procedure:
Following the method of Toledo et al. (Chem. Mater. 1994, 6, 1222), to a stirred solution 2.61 g (13.0 mmol) (E or Z)-2-(amino-furan-2-yl-methylene)-3-oxo-pentanedinitrile in 30 ml dry ethanol under argon at room temperature was added 4.86 ml (13.0 mmol) sodium ethylate solution (2.67M in ethanol) and the reaction mixture heated at 100° C. for 1 hour. The reaction mixture was then concentrated in vacuo and the residue dissolved in a minimum of water and acidified to pH 4.5 with glacial acetic acid. The resulting crystals were collected by filtration and washed sequentially with water and ether to afford 2,41 g (93%) 6-amino-2-furan-2-yl-4-oxo-1,4-dihydro-pyridine-3-carbonitrile as a white crystalline solid. ES-MS m/e (%): 200 ([M—H]−, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[Br:24]Br>Br>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Br:24]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)ccc21
Reactant: BrBr
Agent: Br
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N)c2Br
Reaction time: 1 h

Procedure:
6.6 g (0.021 mol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one, dissolved in 50 ml of concentrated aqueous hydrobromic acid, are treated slowly at between 0° and 5° with 1.2 l of bromine and stirred at 0° for 1 hour. Subsequently, the reaction mixture is poured into a mixture of ice and soda solution, extracted with methylene chloride and the organic extract is evaporated. The residue is purified on 300 g of silica gel with methylene chloride/ethyl acetate (20:1). From ethyl acetate/ether there is obtained 7-amino-6-bromo-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 217°-220°.
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[CH2:29][N:30]2[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:43].[Na+]>CO.O>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:43])[CH2:32][CH2:31]2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: CC[C@H](NC(=O)c1c(CN2CCC(=O)CC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@H](NC(=O)c1c(CN2CCC(N)CC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
0.477 g (1 mmol) of 3-(4-oxo-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (compound of Description 18), 0.462 g (6 mmol) of ammonium acetate were dissolved in 10 ml of methanol and stirred at room temperature for 1 h. Then 0.08 g of sodium cyanoborohydride were added and the mixture was stirred one night at room temperature. The reaction mixture was poured in 50 ml of water and the formed precipitate was filtered off. The aqueous phase was extracted with methylene chloride. The collected solid was dissolved in methylene chloride, both organic phases merged, washed with water, dried over MgSO4, concentrated to dryness. The residue was purified by micro flash chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 90/10/1) to afford 47 mg of the title compound as a white solid (yield ca 10%).
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 120 °C
Yield: 100 %

Procedure:
To a vial with tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (100 mg, 0.371 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (265 mg, 1.112 mmol) and cesium carbonate (362 mg, 1.112 mmol) under N2 is added DMSO (1.0 mL). The reaction is heated to 120° C. in an oil bath 1 h. The reaction was cooled to rt, added to H2O (5 mL), and extracted with Teac (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated to give tert-butyl 3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidine-1-carboxylate (175 mg) as a yellow oil which was carried on to the next step without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:19])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].C1COCC1.CO>O>[F:18][C:14]1[CH:13]=[C:12]([C:9]2[N:8]=[C:7]([CH3:19])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnc(-c2cccc(F)c2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Yield: 85.5 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (6.7 g, 27.2 mmol) and NaOH (2.1 g, 54.4 mmol) in a 1:1:1 solution of THF, MeOH and water (300 mL) is heated at reflux for 45 min. The THF/MeOH is evaporated, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The solid is filtered off, washed with water and dried in vacuo to yield 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5.4 g, 91%) as a solid. MS: 233 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.85 (s, 3H), 7.24 (m, 1H), 7.50 (m, 1H), 8.17 (m, 1H), 8.32 (m, 1H), 9.20 (s, 1H).
Reaction SMILES: C([SiH](CC)CC)C.O[C:9]1([C:29]2[C:30]([OH:40])=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH3:38])[C:33]=3[CH:39]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[C:10]1=[O:28].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[OH:40][C:30]1[C:29]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[C:10]2=[O:28])=[CH:39][C:33]2[N:34]([CH3:38])[CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1
Reactant: CN1CCOc2cc(O)c(C3(O)C(=O)N(Cc4ccc(C(F)(F)F)o4)c4ccccc43)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CCOc2cc(O)c(C3C(=O)N(Cc4ccc(C(F)(F)F)o4)c4ccccc43)cc21
Reaction time: 2 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of triethylsilane (1.1 mL, 6.9 mmol) in trifluoroacetic acid (6.5 mL) was slowly added 3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (1.00 g, 2.18 mmol) portionwise as a solid. The resulting brown solution was warmed to reflux and stirred under nitrogen for 2 h. The reaction was cooled and the solvent was removed under reduced pressure. The residue was precipitated from ethyl acetate/hexanes and collected by filtration to afford 3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one trifluoroacetate salt (1.09 g, 90%) as a light grey powder: mp 143-148° C. (hexanes); 1H NMR (300 MHz, DMSO-d6) δ8.98 (br s, 2H), 7.24-7.15 (m, 2H), 7.05-6.92 (m, 3H), 6.62 (s, 1H), 6.61 (s, 1H), 6.22 (s, 1H), 5.08 (d, J=16.7 Hz, 1H), 5.01 (d, J=16.7 Hz, 1H), 4.78 (s, 1H), 4.27-4.21 (m, 2H), 3.23-3.17 (m, 2H), 2.77 (s, 3H); MS (ES+) m/z 445.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[Li+].[OH-]>CO.O>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:13][CH2:14]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CC2)c1Cl
Yield: 94 %

Procedure:
To a solution of 5-Chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (296 mg, 1.38 mmol) in methanol (15 mL) and water (15 mL) was added LiOH (40 mg, 1.66 mmol). The reaction mixture was stirred at reflux overnight and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH=2 with concentrated HCl, and extracted with ethyl acetate. The organic extracts were evaporated in vacuo to give 5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid (242 mg, 93%) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[CH2:31]=[C:32]([CH3:34])[CH3:33]>ClCCl>[C:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:21][CH:22]=1)([CH3:34])([CH3:33])[CH3:31]
Reactant: C=C(C)C
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of 0.6 g of 5-(4-hydroxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of dichloromethane at -70° C. was added 0.29 g of trifluoromethanesulfonic acid and 2.1 g of isobutene was bubbled in a few minutes. After 1 hour of stirring at the same temperature, triethyamine was added to the solution and then the reaction mixture was warmed gradually to room temperature. The reaction mixture was poured into iced water and the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.55 g of 5-(4-t-butoxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole. nD22.8 1.5458
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 44 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (271 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.610 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 98.3 mg (44.1%) of the desired product as a solid.