Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(C)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 74-4 (100 mg, 0.54 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (140 mg, 0.64 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (220 mg, 0.58 mmol) in DMF (2 mL) was added DIEA (280 μL, 1.62 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into ethyl acetate, washed with saturated NaHCO3 then brine, dried over Na2SO4. The solvent was removed by rotary evaporation to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 148-1 (210 mg, 100%). MS m/z 388.1 (M+1).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](O)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=C2N=C(SSC3SC4C(=CC=CC=4)N=3)SC2=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 0.74 g. of t-butanol, 1.22 g. of benzoic acid, 3.32 g. of 2,2'-dibenzothiazolyl disulfide and 50 ml. of methylene chloride is added dropwise a solution of 2.62 g. of triphenyl phosphine in 20 ml. of methylene chloride while stirring at room temperature. After completion of the addition, the mixture is stirred at room temperature for an additional 5 hours. The reaction mixture is treated with the same procedure as in Example 1 (1) to give 1.35 g. of the desired product boiling at 75°C/3 mmHg.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:33]=[CH:32][C:27](C(OC)=O)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].BrC1C=CC([C:44](OC)=[O:45])=CC=1>>[CH3:44][O:45][C:25]1[CH:26]=[CH:27][CH:32]=[CH:33][C:24]=1[N:21]1[CH2:20][CH2:19][CH:18]([N:15]2[CH2:16][CH2:17][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:34]=[CH:35][CH:36]=[C:3]([C:2]([F:37])([F:38])[F:1])[CH:4]=3)[CH2:14]2)[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reactant: COC(=O)c1ccc(Br)cc1
Product: COc1ccccc1N1CCC(N2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was synthesized in similar fashion to methyl 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoate, substituting bromo-2-methoxybenzene for methyl 4-bromobenzoate, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.50-2.20 (m, 5H), 2.25-2.40 (m, 1H), 2.50-2.70 (m, 3H), 2.82 (dd, J=11.1, 6.9 Hz, 1H), 3.13-3.20 (m, 1H), 3.30-3.40 (m, 1H), 3.49-3.51 (m, 2H), 3.84 (s, 3H), 4.00-4.21 (m, 2H), 4.60-4.71 (m, 1H), 6.81-6.90 (m, 2H), 6.93-7.02 (m, 1H), 7.10-7.28 (m, 4H), 7.56 (t, J=8.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.25 (s, 1H). MS m/z: 505 (M+1).
Reaction SMILES: [N+]([N:4](CCCC)[C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[NH:4][CH2:5][CH2:18][CH2:17][CH3:16])[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: [H][H]
Reactant: CCCCN(c1cccc(C(=O)c2ccccc2)c1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCCNc1ccc(C(=O)c2ccccc2)cc1N
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of 3-(nitro-4-n-butylamino)-benzophenone (5.96 g.; 0.02 mole) in ethanol (200 ml.) is added palladium on charcoal (5%; 0.1 g.). The mixture is hydrogenated until theoretical uptake of hydrogen has occurred (about 3 hours) and then let stand at room temperature overnight. The reaction mixture is filtered to remove the catalyst and the filtrate concentrated under vacuum to afford 4.75 g. (88.6% yield) of 3-amino-4-n-butylaminobenzophenone.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[C-]#[N:21].[Na+].[C:23]([O:26]CC)(=O)[CH3:24]>CS(C)=O>[NH2:14][C:11]1[N:10]=[C:9]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:24][C:23]([NH2:21])=[O:26])[CH:7]=2)=[CH:13][N:12]=1
Reactant: CCOC(C)=O
Reactant: Nc1ncc(-c2ccnc(F)c2)c(-c2ccco2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)Cc1cc(-c2cnc(N)nc2-c2ccco2)ccn1
Temperature: 150 °C
Reaction time: 46 h
Yield: 3 %

Procedure:
A suspension of 5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (300 mg, 1.17 mmol) and sodium cyanide in dimethylsulfoxide (3 ml) was stirred at 150° C. for 46 hours. After cooling as it was, the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of saturated ammonium chloride twice. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel plate (developing solvent; dichloromethane:methanol=10:1) and then washed with diethyl ether, to give the title compound (10 mg, 3%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:24]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CC#N.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11](=[O:22])[N:12]([CH2:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CO
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1C(=O)C(Nc2ccc(OC)cc2)=C(c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
To a solution of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.34 mmol, 100 mg) in dry THF (1.0 mL) under an atmosphere of N2 at room temperature was added ethyl glycolate (0.34 mmol, 35 mg). The reaction mixture was cooled to 0° C. and tributylphosphine (0.17 mmol, 34 mg) was added followed by 1,1′-(azodicarbonyl)dipiperidine (0.36 mmol, 84 mg). After stirring at 0° C. for 10 min., the reaction mixture was brought to room temperature and the stirring was continued for 26 h. The reaction mixture was diluted with CH3CN:water 1:1 (2 mL) and purified using HPLC (95% 0.1M ammonium acetate buffer:5% CH3CN→100% CH3CN, 38.5 min., 25 mL/min.) to give 53 mg (41%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22-7.17 (bs, 1H), 7.15-7.05 (m, 3H), 7.01-6.96 (m, 2H), 6.63-6.52 (m, 4H), 4.36 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 3.69 (s, 3H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:12]=[C:11]([CH:24]=O)[C:10]=2[OH:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>>[ClH:1].[C:27]([NH:31][CH2:24][C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[OH:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(CCc2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: CC(C)(C)NCc1cc(CCc2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
3-((tert-Butylamino)methyl)-3′,4′-dichloro-5-(4-chlorophenethyl)-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 3′,4′-dichloro-5-(4-chlorophenethyl)-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:17]S(C2C=CC(C)=CC=2)(=O)=O)=[C:9]([CH:16]=1)/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])([CH3:4])([CH3:3])[CH3:2].ClC1C=C2C(C(CC(O)=O)=[C:34]([C:38]([C:40]3[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=3)=[O:39])N2)=CC=1>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:10]1[C:9]2[C:8](=[CH:7][CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:16]=2)[NH:17][C:34]=1[C:38]([C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=1)=[O:39]
Reactant: COC(=O)/C=C/c1cc(C(C)(C)C)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2ccc(C(C)(C)C)cc12

Procedure:
The compound was prepared according to the procedure described in Example of 57 from methyl trans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[CH:38]=[C:37]1B(O)O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)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](=[O:35])[CH:4]([N:12]([CH:27]([C:37]1[O:36][C:40]2=[CH:41][CH:42]=[CH:43][C:44]2=[CH:39][CH:38]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)C(Cc1ccccc1)N(Cc1ccc(I)cc1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
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
Solvent: O
Product: COC(=O)C(Cc1ccccc1)N(C(c1ccccc1)c1ccc2cccc-2o1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a degassed solution of 2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (40 mg, 0.068 mmol) and benzofuran-2-boronic acid (20 mg, 0.124 mmol) in a mixture of DME (3 mL) and 2M aqueous Na2CO3 (1.5 mL), Pd(PPh3)4 (4 mg) was added and the reaction mixture was stirred at 65° C. for 2 h under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (Na2SO4), concentrated. The residue was purified by column chromatography using ethyl acetate and hexane (1:9) to obtain 2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (39 mg, 100%) as a thick syrup. 1H NMR (af-2783) (CDCl3, 400 MHz): δ7.2 (d, 2H), 7.62 (d, 1H), 7.55 (d, 1H), 7.30-7.15 (m, 7H), 7.12 (d, 2H), 6.96 (s, 1H), 6.51 (s, 1H), 4.72 (m, 3H), 3.80, 3.40 (2s, 6H), 3.28 (dd, 1H), 3.02 (dd, 1H), 2.71, 2.58, 2.12 (3s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH3:15][N:16]([CH3:36])[C:17]([C@@H:19]1[C@H:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH2:33])[C:27]=2[NH2:34])[C@@H:23]2[CH2:35][C@H:20]1[CH:21]=[CH:22]2)=[O:18].C([O-])(=O)C.[NH4+]>>[CH3:15][N:16]([CH3:36])[C:17]([C@@H:19]1[C@H:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]3[NH:33][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:34][C:27]=23)[C@@H:23]2[CH2:35][C@H:20]1[CH:21]=[CH:22]2)=[O:18]
Reactant: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1sc(N2CCOCC2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCOCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 15.7 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-morpholin-4-yl-thiazole-5-carbaldehyde (75.00 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid dimethylamide (93.35 mg, 0.2901 mmol) and Ammonium acetate (44.72 mg, 0.5802 mmol) were reacted to produce 24.34 mg (16%) of the title compound. (300 MHz, DMSO-d6) 12.80 (s, 1H), 7.96 (s, 1H), 6.42-6.32 (m, 2H), 5.11 (t, J=17 Hz, 8.5 Hz, 1H), 3.73 (m, 4H), 3.48 (m, 4H), 3.01 (d, J=9 Hz, 1H), 2.94 (s, 3H), 2.86 (m, 4H), 2.82 (s, 1H), 2.11 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS=533 (M+H), HPLC: 2.73 min. (G Method)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([N:11]([CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=3[CH:16]=2)[CH:12]=O)=[C:4]([F:26])[CH:3]=1.CC(O)=O>[Fe].CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]2[N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[CH:12]=[N:8][C:6]=2[CH:7]=1
Reactant: CSc1nc2ccc(CN(C=O)c3c(F)cc(Br)cc3[N+](=O)[O-])cc2s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CSc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Temperature: 80 °C
Yield: 0 %

Procedure:
To a stirred mixture of N-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide (4.8 g, 10.55 mmol) from the previous step, HOAc (15 mL) and EtOH (50 mL) at rt was added portionwise iron powder (1.77 g, 31.65 mmol). The mixture was heated at 80° C. for 2.5 h. After cooling to rt, the mixture was partitioned between saturated aq NaHCO3 and a 10:1 mixture of EtOAc and MeOH. The biphasic mixture was filtered through Celite, and the layers of the filtrate were separated. The aqueous layer was extracted with a 10:1 mixture of EtOAc and MeOH. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residual solid was purified by trituration with diethyl ether to afford 6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.39 mg, 39%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.87 (m, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.75 (m, 1H), 7.30-7.34 (m, 2H), 5.66 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 408 and 410 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([C:11]1[CH:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:13]1[C:14]([S:16][CH3:17])=[CH:15][C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:12]1)=[O:4]
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CSc1cc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 62 %

Procedure:
Dimethylcarbamoyl chloride (10.7 g, 9.1 ml) was added to a solution of 3-t-butyl-5-(methylthio)pyrazole (17.0 g) and pyridine (8 ml) in benzene (100 ml). The reaction mixture was refluxed (at 80°) for 24 hours, allowed to cool, and washed with water (50 ml), 2 N HCl, (25 ml) and water again (50 ml). The organic layer was dried, and evaporated to give an oil which soon crystallised. Recrystallisation from petrol afforded 1-(dimethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole, 15.1 g, 62% yield, of melting point 58°-60°.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccoc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccoc2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (335 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 220 mg, 76%).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:11][C:12]1[CH:13]=[C:14]([NH:19][NH2:20])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:2]([C:1]1[CH:7]=[C:8]([NH2:9])[N:19]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[N:20]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc(NN)cc1C
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1C
Yield: 66.9 %

Procedure:
To a solution of pivaloylacetonitrile (400 mg) in toluene (10 mL) were added 3,4-dimethylphenylhydrazine hydrochloride (520 mg) and triethylamine (0.4 mL) and refluxed with heating for 5 hours. The reaction mixture was added with a saturated sodium hydrogen carbonate aqueous solution. The obtained organic layer was washed with a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=4:1) to give the titled compound (490 mg) having the following physical data.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[K].O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(NC1C=CC=CC=1)=O>C1(C)C(C)=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=CNc1ccccc1
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Yield: 92 %

Procedure:
The highest yields at minimum reaction temperature are attained from essentially anhydrous potassium formanilide, but small amounts of water have little effect. From a reaction mixture of 31.8 parts by weight (0.2 mole) of dry potassium formanilide, 24.2 parts by weight (0.154 mole) of para-nitrochlorobenzene, 9.3 parts by weight (0.077 mole) of formanilide and 25 parts by weight of xylene there is obtained after heating at 137°-149° C. for about 125 minutes a 92% yield of 4-nitrodiphenylamine and 97% conversion. The addition of 0.5% weight and 1.0% by weight of water respectively based on the potassium formanilide results in little or no reduction in yield and conversion. Addition of 1.0% by weight 45% potassium hydroxide improves the yield slightly. The innocuous effect of a little free water is to be contrasted with the adverse effect of bound water. Potassium formanilide forms a monohydrate which hydrolyzes rapidly when heated above temperatures of 85°-90° C. Replacing about half the formanilide with aniline in the foregoing procedure gives comparable result. The presence of aniline reduces the by-product carbon monoxide about 40% with formation of formanilide by mechanism imperfectly understood.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].C(Cl)Cl>O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
Added 3′-fluoroacetanilide (3.06 g, 20 mmol) cautiously to conc sulfuric acid (6 mL) at 5° C. To the resulting solution, added fuming nitric acid (1.05 mL, 25 mmol) dropwise while maintaining temperature at 5-10° C. After 30 min, added ice (50 g), later diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated NaHCO3 and brine, dried (Na2SO4) and concentrated to give the crude product (4.0 g) as a mixture of isomers (1:1.4 ratio of 4′-nitro/2′-nitro). The desired isomer, 3′-flouro-4′-nitroacetanilide, was isolated by flash chromatography (DCM-5% MeOH/DCM) in low yield (1.2 g, 30%) as a yellow solid. 1H-NMR (CDCl3): δ 8.08 (1H, app t), 7.82 (1H, dd), 7.41 (1H, br s), 7.21 (1H, m), 2.25 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[N:8]2[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: CC1(C)C(=O)Nc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(C)(C)c2ccc(Br)cc21
Temperature: 80 °C

Procedure:
To a suspension of 6-bromo-3,3-dimethylindolin-2-one (example 14a, 1.68 g, 7.00 mmol) in DMF (30 ml) were added 2-bromopropane (2.15 g, 1.64 ml, 17.5 mmol) and cesium carbonate (5.02 g, 15.4 mmol). The reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was treated with 1 M HCl and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as orange solid (2.00 g, 70% purity) and was used for the next reaction without further purification.