Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.ClCCCl>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[C:10]=3[OH:11])[C:31]2=[O:40])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Oc1cccc2c1OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1O)OCCO2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.3 %

Procedure:
To a solution of 2,3-dihydro-1,4-benzodioxin-5-ol (3.60 g, 23.7 mmol) in anhydrous tetrahydrofuran (80 mL) at 0° C. was added isopropylmagnesium chloride (11.8 mL, 2 M solution in tetrahydrofuran, 23.7 mmol). The mixture was stirred at 0° C. for 45 min, concentrated in vacuo, and 1,2-dichloroethane (60 mL) was added. The mixture was cooled to 0° C. and a solution of 1-benzhydrylindoline-2,3-dione (4.94 g, 15.8 mmol) in 1,2-dichloroethane (70 mL) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 60 h, and heated to 83° C. and stirred for 3.5 h. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo and saturated aqueous ammonium chloride (250 mL) was added. The mixture was extracted with ethyl acetate (250 mL followed by 2×100 mL). The organic phase was washed with water (150 mL) and brine (150 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and a solid was precipitated by the addition of hexanes to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (5.10 g, 69%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.14 (s, 1H), 7.43-7.30 (m, 9H), 7.22 (d, J=8.7 Hz, 1H), 6.97-6.79 (m, 3H), 6.52 (s, 1H), 6.44 (d, J=8.7 Hz, 1H) 6.26 (d, J=7.8 Hz, 1H), 4.22 (s, 4H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH:18]=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=CCc1ccc2nc(-c3ccccc3)ccc2c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1
Reaction time: 3 h

Procedure:
A solution of 2.5 g of crude 2-phenyl-6-quinolineacetaldehyde in 3 ml of ethanol is slowly added dropwise at room temperature to a suspension of 3.4 g of silver nitrate and 1.6 g of sodium hydroxide in 12 ml of water. After completion of the addition, the mixture is stirred for a further 3 hours. Thereafter the suspension is clarified by filtration and the filtrate is washed with ether and adjusted to a pH of 6. The emulsion thereby produced is extracted with ethyl acetate. The ethyl acetate extracts, after drying, evaporation and recrystallisation of the residue from methanol-pentane, yield 2-phenyl-6-quinolineacetic acid of melting point 176°-179°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-methyl-2-nitroaniline (4 mmol) and pyridine (8 mmol) in dry dichloromethane (15 mL) was added dropwise benzoyl chloride (8 mmol). The reaction mixture was stirred at room temperature for 8 h. The solvent was evaporated in vacuum, and the residue was subjected to flash chromatography on silica gel using a mixture of hexanes and CH2Cl2 (7:3) as eluent to afford N-(5-methyl-2-nitrophenyl)benzamide as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.[Br:58][C:59]1[CH:68]=[CH:67][C:62]([C:63](=[N:65]O)[NH2:64])=[CH:61][CH:60]=1>CN(C)C=O>[Br:58][C:59]1[CH:68]=[CH:67][C:62]([C:63]2[N:65]=[C:10]([C@@H:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[O:12][N:64]=2)=[CH:61][CH:60]=1
Reactant: NC(=NO)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)no1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a solution of N-Boc-L-proline (2.5 g, 11.6 mmol) in N,N-dimethylformamide (18 mL), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (TBTU, 3.73 g, 11.6 mmol), HOBt.H2O (0.36 g, 2.32 mmol) and DIPEA (10.2 ml, 58.1 mmol) were added. After the reaction mixture was stirred at room temperature for 5 minutes, 4-Bromo-N′-hydroxybenzimidamide 15 (2.5 g, 11.6 mmol) was added. The mixture was then stirred at 110° C. for 2.5 hours. After cooled to room temperature, the resulting mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to yield a crude yellow liquid, which was purified with chromatography (ethyl acetate: n-hexane=1:10) to give the desired product 16a (2.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][C:14](O)=[O:15])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.N1([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31](=[O:39])[N:30]=2)CCCCC1.C(N(CC)CC)C.CCOP(ON1N=[N:65][C:60]2C=[CH:62][CH:63]=[CH:64][C:59]=2C1=O)(OCC)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][C:14]([N:65]2[CH2:62][CH2:63][CH:64]([N:30]3[CH2:29][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:39])[CH2:59][CH2:60]2)=[O:15])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=c1nc(N2CCCCC2)c2ccccc2[nH]1
Reactant: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Reactant: Cc1cc(CC(CC(=O)O)c2ccccn2)cc2cn[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccccn2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 4-(7-methyl-1H-indazol-5-yl)-3-pyridin-2-yl-butyric acid (white solid, 0.028 mmol) in methylene chloride (2 mL) was added 3,4-dihydro-3-(4-piperidinyl-2(1H)-quinazolinone (7.2 mg, 0.031 mmol, 1.1 equiv). Triethylamine (30 μL) was added followed by 3-(diethoxyphosphoryloxy)-1,2,3-benzotriain-4(3H)-one (DEPBT, 9.4 mg, 0.031 mmol 1.1 equiv). The resulting yellow solution was stirred at room temperature for 1 h and LCMS. A further 1 equivalent of the amine and DEPBT were added. After stirring for another 4 h, LCMS indicated complete conversion. The reaction mixture was diluted with ethyl acetate and quenched with 0.5 N sodium hydroxide. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (10% methanol in methylene chloride) to afford the desired product (9.0 mg, 62% for two steps) as a glassy solid. MS (ESI) [M+H]+=509, 1H-NMR (400 MHz, CDCl3) δ 11.5 (br., 1H), 8.61-8.52 (m, 1H), 7.93 (d, J=4.8 Hz, 1H), 7.50-7.38 (m, 1H), 6.90 (m, 8H), 6.66 (d, J=7.6 Hz, 1H), 4.72-4.62 (m, 1H), 4.59-4.48 (m, 1H), 4.24 (s, 1H), 4.09 (s, 1H), 4.07-3.94 (m, 1H), 3.80-3.66 (m, 1H), 3.20-2.80 (m, 4H), 2.72-2.46 (m, 2H), 2.45 (d, J=4.8 Hz, 3H), 1.85-1.48 (m, 4H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Br:49]C1C=C(C=CC=1)N>C(O)(=O)C>[Br:49][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1cccc(Br)c1
Yield: 12 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), 3-bromoaniline (280 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 40 mg (0.10 mmol, 12% yield) of the title compound.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[CH:20]([C:23]1[S:27][C:26]([NH2:28])=[N:25][N:24]=1)([CH3:22])[CH3:21]>N1C=CC=CC=1>[CH:20]([C:23]1[S:27][C:26]([NH:28][S:16]([C:13]2[CH:14]=[CH:15][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[NH:4][C:1](=[O:3])[CH3:2])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[N:25][N:24]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1nnc(N)s1
Reactant: CC(=O)N[C@@H]1CCC[C@H]1c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1CCC[C@H]1c1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1

Procedure:
608 mg of trans-4-(2-acetylamino-cyclopentyl)-benzenesulfonyl chloride, 3 ml of pyridine and 286 mg of 5-Isopropyl-1,3,4-thiadiazol-2-ylamine were stirred at room temperature for 30 minutes. The solvent was evaporated, the residue was treated with 20 ml 2n hydrochloric acid and the product extracted with 30 ml ethyl acetate and purified by column chromatography (silca gel, DCM:methanol=96:4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:21]1C=C(NS(C2C=CC(NC(=O)C)=CC=2)(=O)=O)C=C(C)[N:22]=1>CN.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:22][CH3:21])[N:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(C)nc(Br)c2)cc1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Agent: CN
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(C)n1
Yield: 48 %

Procedure:
0.94 g (0.00275 mol) of 4-amino-N-(2-bromo-6-methyl-pyridin-4-yl)-benzenesulfonamide was stirred in 50 ml of 8M methylamine in ethanol in an autoclave at 135° C. for 40 hours. The methylamine was allowed to evaporate, the residue was dissolved in ethanol, treated with 2 g of silica gel, concentrated and the residue was chromatographed on silica gel, firstly with ethyl acetate/hexane 1:1, then 9:1. There was obtained 0.39 g (48%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide as colourless crystals; m.p.: 173-175° C. 0.081 g (0.00028 mol) thereof was recrystallized from methanol, diethyl ether and hexane, dried in a high vacuum, dissolved in 3 ml of methanol and treated with 2.8 ml of 0.1N NaOH. The methanol was distilled off and the residue was freeze-dried twice. There was obtained 0.084 g (97%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide sodium salt (1:1) as white crystals; MS (ISP): me/e=293 (C13H17N4O2S+). 0.31 g (0.0011 mol) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide was dissolved in 2 ml of methanol, treated with 1 ml of 2.4N HCl in diethyl ether and freed from solvent. The residue was dissolved in 1 ml of methanol and slowly added dropwise to diethyl ether while stirring vigorously. A colourless precipitate thereby separated and this was isolated and dried in a high vacuum. There was obtained 0.33 g (87%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide hydrochloride (1:1.86) as white crystals; m.p.: >170° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[NH:8][C:7]=2[CH:22]=1.[CH2:31](Br)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[N:8]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:7]=2[CH:22]=1
Reactant: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Reactant: BrCCc1ccccc1
Product: COc1ccccc1-c1cc2c(cc1OC)N(CCc1ccccc1)C(=O)CN=C2c1cccc(C#N)c1
Yield: 87 %

Procedure:
Prepared from 3-[8-methoxy-7-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile Example 10 using the same method described for Example 35 using phenethyl bromine instead of hexyl bromine. The title compound (110 mg) was obtained as a white solid, (yield=87%).
Reaction SMILES: [C:1](O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[NH:26][N:25]=[N:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].IC>CN1C(=O)CCC1.O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[N:23]=[N:24][N:25]([CH3:1])[N:26]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[CH:10][CH:11]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(-n2ccc3cc(Cc4nnn[nH]4)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1nnc(Cc2ccc3c(ccn3-c3ccc(F)cc3)c2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the cyanomethyl compound, sodium azide, triethylamine hydrochloride in 1,2-dimethoxyethane was boiled at reflux for 2 days. After cooling to room temperature, the reaction mixture was filtered and the volatile solvents were evaporated in vacuo. Water (100 mL) and glacial acetic acid (15 mL) were added and the resulting mixture was extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with water (200 mL) and brine (200 mL) and subsequently dried (Na2SO4). Evaporation of the solvents in vacuo gave 1-(4-fluorophenyl)-5-(tetrazol-5-ylmethyl)-1H-indole as an oil containing some residual acetic acid (14 g). A solution of the crude tetrazole in NMP (200 mL) was cooled with ice and potassium tert-butoxide (6.4 g) was added cautiously at 10-20° C. over 20 minutes. When the addition was complete the reaction mixture was cooled at 0° C. and iodomethane (7 mL) was added. After stirring at room temperature for 2 h, water (200 mL) was added and the resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water (2×200 mL) and brine (2×250 mL), dried (Na2SO4) and the volatile solvents evaporated in vacuo. The resulting mixture of 1- and 2-methyl-substituted tetrazoles was separated by column chromatography on silica gel (ethyl acetate/heptane 1:2). Evaporation of the fastest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(2-methyltetrazol-5-ylmethyl)-1H-indole (11a) as an oil (3.7 g): 1H NMR (CDCl3) δ 4.25 (s, 3H), 4.30 (s, 2H), 6.60 (d, 1H), 7.10-7.20 (m, 3H), 7.20 (d, 1H), 7.30-7.45 (m, 3H), 7.60 (broad s,1H).
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4].[NH2:10][NH2:11]>>[CH:2](=[N:10][NH2:11])[C@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@H](O)[C@H](O)C=O
Reactant: NN
Product: C[C@H](O)[C@H](O)[C@H](O)C=NN

Procedure:
reacting 5-deoxy-L-ribose with a hydrazine compound to form a 5-deoxy-L-ribose hydrazone compound; and
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:19]([O-])=O)=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2]>CO.[Pt].C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:1]1[NH:19][C:6]2[C:5](=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[C:15]([O:17][CH3:18])=[O:16])[N:4]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1C(=O)OC
Agent: [Pt]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C)[nH]c2c1C(=O)OC
Yield: 60.1 %

Procedure:
A mixture of dimethyl 4-acetamido-3-nitrophthalate (142.1 g, 0.480 mol) in methanol with 5% platinum on carbon catalyst is hydrogenated on a Parr hydrogenator at room temperature. The reaction mixtures is filtered through diatomaceous earth and concentrated in vacuo to afford a solid residue. This solid is dispersed in glacial acetic acid and toluene, and heated with stirring at reflux temperatures for 4 hours with azeotropic removal of water. The resultant hot reaction mixture is slowly added to a saturated sodium bicarbonate solution with vigorous stirring, filtered and the filter cake dried to give the title product as a white solid (71.6 g, 60.1%), mp 97°-103° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[F:14][C:15]([F:37])([F:36])[C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=3)[CH:25]=[CH:24][N:23]=2)=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCCl.O1CCOCC1>[F:37][C:15]([F:14])([F:36])[C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:33][CH:34]=3)[CH:25]=[CH:24][N:23]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(Oc2ccnc(-c3ccc(C(F)(F)F)nc3)c2)cn1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3ccc(C(F)(F)F)nc3)c2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.029 g, 0.284 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.025 mL, 0.284 mmol), stirred at RT for 5 min, then heated at 80° C. for 0.5 h. The mixture was cooled to RT, added to a mixture of 5-((6′-(trifluoromethyl)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (0.063 g, 0.190 mmol) and pyridine (0.123 mL, 1.517 mmol) in dioxane (4 mL) and stirred at RT for 3 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN and the solid collected via filtration to afford N-((5-((6′-(trifluoromethyl)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (57 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H); 10.47 (s, 1H); 9.41 (s, 1H); 8.67-8.66 (m, 2H), 8.31-8.30 (m, 1H), 8.11 (d, J=9.0 Hz, 1H); 8.00 (d, J=8.3 Hz, 1H); 7.84 (d, J=2.4 Hz, 1H); 7.79 (dd, J=9.0, 2.9 Hz, 1H); 7.01 (dd, J=5.7, 2.4 Hz, 1H); 1.21 (s, 9H); MS (ESI) m/z: 460.2 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.48 g) was added to a solution of 2-butyl-4-chloro-5-hydroxymethylimidazole (prepared as described in U.S. Pat. No. 4,355,040) (0.56 g) and 5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (1.3 g) in DMF (15 ml) and the mixture was stirred under an atmosphere of argon at 60° C. for 5 hours. The mixture was cooled to ambient temperature, water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were washed with satured sodium chloride solution, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole (180 mg) as a pale yellow solid, m.p. 182°-186° C.; NMR (CDCl3) 0.87(t,3H), 1.32(m,2 H), 1.65(m,2H), 2.49(t,2H), 4.57(s,2H), 5.15(s,2H), 6.58(d,2H), 6.75(d,2H), 6.90(dd,2H), 7.36(dd,1H), 7.65(m,2H), 7.85(dd,1H), 8.00(dd,2H); mass spectrum (+ve FAB, DMSO/CH3OH/m-nitrobenzyl alcohol): 544 (M+H)+.
Reaction SMILES: [C:1](/[C:3](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:17]=2)=[CH:12][CH:11]=1)/[C:4]([O:6]CC)=[O:5])#[N:2].[OH-].[Li+]>O1CCCC1.CO.O>[C:1](/[C:3](=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)[N:17]=2)=[CH:14][CH:15]=1)/[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)/C(C#N)=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#C/C(=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To (Z)-ethyl 2-cyano-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C46) (2.5 g, 5.8 mmol) in tetrahydrofuran/methanol/water (3:2:1, 42 mL) was added lithium hydroxide (2.5 mL, 7.5 mmol) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, cooled in an ice bath, and acidified with hydrogen chloride (2 N). The precipitate was filtered and washed with cold water to afford the title compound as a brown solid (2.2 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.39 (s, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.18 (d, J=8.5 Hz, 2H), 8.13-8.08 (m, 2H), 7.64 (d, J=8.4 Hz, 2H); ESIMS m/z 401 ([M+H]+).
Reaction SMILES: OC[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C1(CO)C=CC([CH2:17][OH:18])=CC=1.C(=O)C1C=CC(C=O)=CC=1>>[OH:18][CH2:17][C:5]1[CH:4]=[CH:3][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1ccc(CO)cc1
Reactant: OCc1ccc(CO)cc1
Agent: O=Cc1ccc(C=O)cc1
Product: O=Cc1ccccc1CO
Reaction time: 0.17 h

Procedure:
167.0 g of sodium carbonate and 1200 g of distilled water were placed in a four-necked flask equipped with a reflux condenser, a lagged dropping funnel, a thermometer and a stirrer, and the atmosphere in the flask was replaced with nitrogen and then adjusted to 100° C. Next, 100 g of α,α,α'-trichloro-p-xylene having a purity of 90% by weight obtained in the same manner as in Preparation Example 1 were added dropwise thereto over 10 minutes. After an aging reaction was carried out for 10 hours, the resultant reaction solution was analyzed by the use of gas chromatography. As a result, it was found that the reaction solution was composed of 85% by weight of p-hydroxymethylbenzaldehyde, 4.8% by weight of p-xylylene glycol, 2.8% by weight of terephthalaldehyde and 7.4% by weight of the others.