Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(NOS(C1C(C)=CC(C)=CC=1C)(=O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[N:38]O)=[N:34][CH:35]=1>C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:38]=[C:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[CH:36]=2)[CH:35]=1
Reactant: ON=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Agent: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2cc3ccc(Cl)cn3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine (8.45 g 26.8 mmol) was added portionwise with stirring to TFA (100 ml) over 10 min then stirred for a further 30 minutes. The solution was poured onto ice (˜250 ml) and left until the ice melted. The resulting white solid was filtered off, washed with water, and dissolved in chloroform (200 ml). The solution was dried over 4 Å mol. sieves for 1.5 hours, filtered and 2-(5-chloropyridin-2-yl)-1-(4-fluorophenyl)ethanone oxime (3.56 g 13.4 mmol) in chloroform (100 ml) was added. The reaction was stirred at room temperature for 18 hours, washed with water (2×50 ml) and dried. Removal of solvent gave a brown solid which was purified by Biotage chromatography. Elution with cyclohexanelethyl acetate (35/1) gave the title compound as a yellow solid (2.476 g 75%). NMR (CDCl3) δ 6.76 (1H, s, H-3); 7.08 (1H, dd, J 9 & 2 Hz, H-5); 7.13 (2H, t, J 9 Hz, H-3′); 7.45 (1H, d, J 9 Hz, H-4); 7.9 (2H, dd, J 9 & 5 Hz, H-2′); 8.5 (1H, d, J 2 Hz, H-7);
Reaction SMILES: F[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:21]1([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: Fc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: FC(F)(F)c1cc(N2CCOCC2)c2c(c1)ncn2-c1ccccc1
Temperature: 245 °C
Yield: 13.1 %

Procedure:
To 7-fluoro-1-phenyl-5-trifluoromethylbenzimidazole (400 mg, 1.4 mmol) was added morpholine (1 ml, 1.1 mmol) and the mixture heated in a Personal Chemistry Smith Creator™ microwave for ten 30 minute periods at 245° C. The residue was chromatographed over silica gel to give the title compound as a solid (50 mg, 10%) m/z, 348.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:25]=[C:26]([C:16]2[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccccc1Cl
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(Cl)c1
Yield: 44.4 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.032 g (44%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[CH:26]12[NH:33][C:30]([C:34]([OH:36])=[O:35])([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:33]2[C@@:30]3([C:34]([OH:36])=[O:35])[CH2:31][CH2:32][C@@H:26]2[CH2:27][O:28][CH2:29]3)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C(O)C12CCC(COC1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1=C(CN2[C@@H]3CC[C@@]2(C(=O)O)COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (compound C, 61 mg, 0.138 mmol), 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a (20 mg, 0.127 mmol) and DIPEA (0.07 mL, 0.4 mmol) in DCM (5 mL) was stirred at 25° C. for 16 h. Then the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford a pair of diastereomers, Example 81 and Example 82.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:11][N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:19]=2)[CH2:16][CH2:17]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)CC1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.2 mL, 1M in THF, 0.23 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole (24.9 mg, 0.12 mmol) in THF (2.5 mL) at −78° C. and the mixture stirred for 1 h. Benzenesulfonyl chloride (30 μL, 0.24 mmol) was added and the mixture stirred at room temperature for 2 h, prior to quenching with water (4 drops) and silica gel (˜1 g). Purification using solid phase extraction tubes (1000 mg silica, eluting with 0-10% 2M methanolic ammonia in dichloromethane) yielded 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-7-azaindole (21.3 mg, 51%, HRMS-FAB+ for C19H19N3O2S: calculated MH+:354.12762; found:354.12896).
Reaction SMILES: C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.Cl.CO[C:17]1[CH:41]=[CH:40][C:20]([C:21]([NH:34][CH2:35][CH2:36][NH:37][CH:38]=[O:39])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.COC1C=CC(C(NCCNC=O)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(Cl)Cl.CO>[C:21]([NH:34][CH2:35][CH2:36][NH:37][CH:38]=[O:39])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:19]=[CH:18][CH:17]=[CH:41][CH:40]=1
Reactant: COc1ccc(C(NCCNC=O)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(C(NCCNC=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Solvent: CO
Product: O=CNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
C22H22N2O (330.42); RF=0.87 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); 2-(4-monomethoxytrityl)aminoethylformamide; C23H24N2O2 (360.46); RF=0.86 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); 1H NMR (CDCl3, 250.133 MHz):=1.70 (br s, 1 H); 2.32 (tr, 2H, J=6.0 Hz); 3.37 (m, 2H); 3.76 (s, 3H); 5.99 (br s, 1H); 6.78-7.49 (m, 14H); 8.17 (s, 1H). 13C NMR (CDCl3, 62.896 MHz):=38.7 (CH2); 43.1 (CH2); 55.2 (CH3); 70.2 (C); 113.2 (CH); 126.4 (CH); 127.9 (CH); 128.3 (CH); 129.7 (CH); 137.8 (C); 145.9 (C); 158.0 (C); 164.7 (CHO). 2-(4,4′-dimethoxytrityl)aminoethylformamide; C24H26N2O3 (390.49); RF=0.92 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl).
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(N)C[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:15]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][CH2:4][CH2:3][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:7][C:8]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: CN(C)CCNc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: NCCc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(NCCc3ccccc3)sc2c1

Procedure:
The title compound was prepared following the procedure for N,N-dimethyl-N′-(6-nitrobenzothiazol-2-yl)-ethane-1,2-diamine, using 4 eq of phenethylamine. Modified workup: Solid that had precipitated during course of reaction (amine salt) was filtered; no aqueous workup was conducted. 1H NMR (400 MHz, CDCl3): δ=3.03 (t, J=6.4 Hz, 3H), 3.77 (q, J=6.4 Hz, 2H), 7.23-7.30 (m, 3H), 7.33-7.38 (m, 2H), 7.52 (d, J=8.8 Hz, 1H), 8.21 (dd, J=8.8, 2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 300.10 [MH+]. HPLC: tR=3.57 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[O:39])=[CH:36][C:35]=1[O:48][CH3:49]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])=[O:39])=[CH:36][C:35]=4[O:48][CH3:49])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 39.4 %

Procedure:
A mixture of 0.0663 g (0.219 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0625 g (0.33 mmole) of toluenesulfonic acid monohydrate, 0.052 g (0.219 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) and then recrystallization from acetonitrile to give 0.0434 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide (I-8) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[CH2:7][C:6]1[CH:19]=[CH:20][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:12]([O:14][CH3:15])=[O:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2ccc(C(=O)OC)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (1.28 g) in N,N-dimethylformamide (14 mL) were added potassium carbonate (0.98 g) and benzyl bromide (0.62 mL), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was poured into water, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[C:6](S(O)(=O)=O)(S(O)(=O)=O)[CH:5]=1)([O-])=O.[NH2:27]C1C=C(S(O)(=O)=O)C2C(C=1)=CC=CC=2.[NH:42]1[CH:46]=[CH:45][N:44]=[N:43]1>>[NH2:27][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[N:43]1
Reactant: Nc1ccc(C=CC2C=CC([N+](=O)[O-])=CC2(S(=O)(=O)O)S(=O)(=O)O)cc1
Reactant: Nc1cc(S(=O)(=O)O)c2ccccc2c1
Agent: c1c[nH]nn1
Product: Nc1ccccc1C=Cc1ccccc1

Procedure:
Diazotized 4-nitro-4′-aminostilbene-2,2-disulfonic acid and 3-aminonapthalene-1-sulfonic acid were subjected to coupling. The resultant was turned into a triazole, and a nitro group of the triazole was reduced to an amino group by means of a conventionally known method to produce aminostilbene-triazole. Aminostilbene-triazole was dissolved into water, and sodium nitrite and hydrochloric acid were added dropwise to the solution to perform diazotization. The resultant was added dropwise to an aqueous solution of a compound represented by Compound (1) below, and the whole was subjected to coupling, followed by dialysis with sodium chloride. The compound was diazotized with an aqueous solution of sodium nitrite, and was turned into a triazole by adding an aqueous solution of 6-aminonaphthalene-2-sulfonic acid. The triazole was dialyzed with sodium chloride to prepare a coloring material represented by Exemplified Compound 1 below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(-c4cccc(Cl)c4)s3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnc(-c2cccc(Cl)c2)s1)c1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Reaction time: 18 h
Yield: 65.5 %

Procedure:
150 mg of methyl cis-4-{4-[5-(3-chlorophenyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}-cyclohexanecarboxylate (0.32 mmol, 1 eq.) is placed in 1 mL of tetrahydrofuran. 27 mg of lithium hydroxide monohydrate (0.64 mmol, 2 eq.) dissolved in 1 mL are added and stirring is continued for 18 hours. The reaction medium is diluted with water, washed with ethyl acetate and acidified with aqueous 6% sulfur dioxide solution. The solid obtained is filtered off by suction and washed successively with water, ethanol and diethyl ether. 96 mg of cis-4-{4-[5-(3-chlorophenyl)[1.3.4]thiadiazol-2-ylcarbamoyl]-phenoxy}cyclohexanecarboxylic acid are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.O>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:27][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccco1
Temperature: 80 °C
Yield: 97.1 %

Procedure:
The product of Example 255a (1.00 g, 2.89 mmol) was dissolved in DMF to which K2CO3 (801 mg, 5.79 mmol), and 4-mercapto-phenol (366 mg, 2.89 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.00 g, 99%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:12]3[N:11]=[N:10][C:9]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(N2CCN(c3ccc(Oc4ccccc4)nn3)CC2)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 1.9 parts of phenol, 2.9 parts of 3-chloro-6-[4-(3-methylpheyl)-1-piperazinyl]pyridazine and 2.76 parts of potassium carbonate was stirred and heated for 7 hours in an oil bath at 150° C. After cooling, water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (60%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-phenoxypyridazine: mp. 123.4° C. (compound 264).
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][NH:4][CH2:5][CH:6]([NH2:8])[CH3:7].[C:10](=S)=S.S>CC1C2C(=CC=CC=2)C=CC=1>[CH3:9][CH:2]1[CH2:3][N:4]2[CH2:5][CH:6]([CH3:7])[N:8]=[C:10]2[NH:1]1
Reactant: S=C=S
Reactant: CC(N)CNCC(C)N
Agent: S
Solvent: Cc1cccc2ccccc12
Product: CC1CN2CC(C)NC2=N1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
In a 100 mL flask, 0.4078 g of di-(2-aminopropyl)amine (0.00311 mol) was dissolved in 50 mL of 1-methylnaphthalene. Carbon disulfide (0.18 mL, 0.00298 mol) was added. The reaction was stirred for three hours then heated to 200° C. The reaction was heated for four days until production of hydrogen sulfide stopped. The solvent was then removed by distillation. The product was then dissolved in approximately 5 mL of hexanes and 0.5 mL of a 2.0 M ether solution of hydrogen chloride was added. The yield of the precipitate was 0.278 g (53%). The NMR had a doublet at 1.19 ppm, a multiplet at 3.44 ppm, a multiplet at 3.92 ppm and a multiplet at 4.15 ppm.
Reaction SMILES: C([NH:3][C:4]1[N:8]([CH2:9][CH2:10][OH:11])[N:7]=[CH:6][CH:5]=1)=O.ClS([N:16]=[C:17]=[O:18])(=O)=O.O.[OH-].[Na+]>C(#N)C>[NH2:3][C:4]1[N:8]([CH2:9][CH2:10][O:11][C:17](=[O:18])[NH2:16])[N:7]=[CH:6][CH:5]=1
Reactant: O=CNc1ccnn1CCO
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: NC(=O)OCCn1nccc1N
Reaction time: 3 h

Procedure:
To a suspension of 5-formamido-1-(2-hydroxyethyl)pyrazole (1 g) in acetonitrile (50 ml) was added dropwise chlorosulfonyl isocyanate (0.77 ml) at -15° C.~-20° C. The mixture was stirred for 3 hours under ice-cooling. To the reaction mixture was added water (1 ml) and kept to stand overnight. The solution was adjusted to pH 7.5 with 5N-sodium hydroxide solution and then adjusted to pH 8.5 with 1N-sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran. The extract and said organic layer were combined and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate to give 5-amino-1-(2-carbamoyloxyethyl)pyrazole (0.60 g).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:25]>>[Br:25][C:14]1[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:10]=2)[N:15]=1
Reactant: BrP(Br)Br
Reactant: O=C(c1ccccc1)c1ccc2[nH]c(=O)c(C(F)(F)F)nc2c1
Product: O=C(c1ccccc1)c1ccc2nc(Br)c(C(F)(F)F)nc2c1
Temperature: 0 °C

Procedure:
A mixture of 6-benzoyl-3-trifluoromethylquinoxalin-2(1H)-one (1.0 g, 3.13 mmol) [J. Org. Chem. 57(21). 5630,1992] and 10 ml of phosphorous tribromide was refluxed for 5 hours. The mixture was cooled and poured into ice water and the precipitate was isolated, washed with water and dried. Yield 0.87 g (73%) of the title compound as beige crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:11][OH:12])[CH3:10])=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].CO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][NH:15][C:16]([NH2:18])=[S:17])[C:9](=[N:11][OH:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: CC(=NO)C(=O)c1ccc(Cl)cc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NO)C(=NNC(N)=S)c1ccc(Cl)cc1
Yield: 86.5 %

Procedure:
A mixture of 4'-chloro-2-hydroxyiminopropiophenone (252.3 g), thiosemicarbazide (151.3 g), methanol (650 ml) water (300 ml), and acetic acid (9 ml) was refluxed for 31 hours with stirring. After cooling, the resulting precipitates were collected by filtration, washed successively with methanol, water and methanol, and then dried to give 4'-chloro-2-hydroxyiminopropiophenone thiosemicarbazone (298.88 g).
Reaction SMILES: COC[O:4][C:5]([CH2:7][N:8]([S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:9]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:10]=1[O:11][CH2:12][C:13]1[CH:24]=[CH:23][C:16]([C:17]([O:19][CH2:20][O:21][CH3:22])=[O:18])=[CH:15][CH:14]=1)=O.[CH3:42][NH:43][CH3:44]>C1COCC1>[CH3:42][N:43]([C:5]([CH2:7][N:8]([S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:34])=[O:35])[C:9]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:10]=1[O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][O:21][CH3:22])=[O:18])=[CH:23][CH:24]=1)=[O:4])[CH3:44]
Reactant: COCOC(=O)CN(c1ccc(C(F)(F)F)cc1OCc1ccc(C(=O)OCOC)cc1)S(=O)(=O)c1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: COCOC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2N(CC(=O)N(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[2-(N-methoxymethoxycarbonylmethyl-phenylsulfonylamino)-5-trifluoromethylphenoxymethyl]benzoic acid. methoxymethyl ester (476 mg; prepared in Reference Example 35) in THF (2 ml), dimethylamine(0.8 ml) was added. The mixture was stirred for 3 days at room temperature. The solvent was distilled off. The residue was purified on silica gel column chromatography (hexane:AcOEt=2:1→1:1) to give the title compound (290 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:15][CH:13]1[CH2:14][N:11]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:12]1
Reactant: OC1CNC1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CC(O)C2)nc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
To a solution of 6-chloronicotinamide (0.16 g, 1 mmol) and azetidin-3-ol (73 mg, 1 mmol) in DMF (5 ml) under nitrogen was added K2CO3 (0.41 g, 3 mmol). The resulting solution was stirred under nitrogen at 125° C. for 24 h. After all the starting materials were consumed, the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was then filtered and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated to afford the title compound (50 mg, 25%) as a yellow solid. [LCMS RtA=0.81 min, [M+H]+=194.1].