Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:26]([C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([CH3:38])=[CH:40][CH:41]=1)[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C)C(=O)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate (500 mg, 1 eq.) in methylene chloride (5 ml), was added 4-methyl benzoyl chloride (380 ul, 3 eq.) and triethylamine (660 ul, 5 eq.). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude product was dissolved in ethyl acetate. Ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated to yield crude tert-butyl 3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([N+:33]([O-])=O)[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[OH:32])[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:36]=[C:37]([F:41])[C:38]([F:40])=[CH:39][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine prepared above, 10% palladium-activated carbon (45 mg), and methanol (5 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The Pd catalyst was filtered off and the filtrate was concentrated to afford 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (100 mg, 60%).
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:22])[CH2:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:20][C:19]1[C:14]([C:13]2[C:12]([OH:22])=[N:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[C:3]=2[OH:4])=[N:15][CH:16]=[C:17]([Cl:21])[CH:18]=1
Reactant: COC(=O)c1nccnc1NC(=O)Cc1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1nc2nccnc2c(O)c1-c1ncc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-[2-(3,5-dichloro-pyrid-2-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (Example 1.1) (5.78 g) and potassium carbonate (2.4 g) in dry N,N-dimethylformamide (100 ml) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated. The residue was triturated with diethyl ether and the organic phase decanted. The solid was dissolved in water and pH value adjusted to pH 5 by addition of aqueous hydrochloric acid (2M). The aqueous phase was concentrated. The residue was dissolved in methanol, the insoluble salts were removed by filtration and the filtrate was concentrated to give Compound No. A1 of Table A (4.9 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.Br[C:60]1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1.CC1C(B2OC(C)(C)C(C)(C)O2)=CN(CC2(CO)COC2)N=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]6)[C:42]([CH3:60])=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: Cc1nn(CC2(CO)COC2)cc1B1OC(C)(C)C(C)(C)O1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(C)n2)COC1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 124 mg, 0.200 mmol) and (3-{[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}oxetan-3-yl)methanol (Compound 60B, 75 mg, 0.24 mmol) to give the desired product. MS (ESI): m/z 909.76/911.76 [M+H]+. UPLC: tR=1.63 min (analytical 2 min).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])=[N:26]2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccc(OCc3ccccc3)cc2)n1

Procedure:
The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrile and 4-benzyloxyphenylhydrazine hydrochloride, using the same method as that described for preparation 7, as a pale pink powder in quantitative yield.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]1[C:10]([N+]([O-])=O)=[CH:9][N:8]=[C:7]([C:14]2[CH:15]=[CH:16][C:17]([F:38])=[C:18]([CH:37]=2)[CH2:19][N:20]([CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:6]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([N:20]([CH2:19][C:18]2[CH:37]=[C:14]([C:7]3[CH:6]=[C:5]4[CH:4]=[CH:3][NH:2][C:10]4=[CH:9][N:8]=3)[CH:15]=[CH:16][C:17]=2[F:38])[CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:29])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CN(C)/C=C/c1cc(-c2ccc(F)c(CN(CCN3CCCC3)C(=O)c3ccc(F)cc3)c2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)N(CCN1CCCC1)Cc1cc(-c2cc3cc[nH]c3cn2)ccc1F
Yield: 55.5 %

Procedure:
N-{5-[4-((E)-2-Dimethylamino-vinyl)-5-nitro-pyridin-2-yl]-2-fluoro-benzyl}-4-fluoro-N-(2-pyrrolidin-1-yl-ethyl)-benzamide (485 mg, 0.9 mmol) in 30 mL of ethyl acetate was treated with 100 mg of 10% Pd/C under 3 bar of hydrogen for 18 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was chromatographed (alumina, elution with 2% methanol/dichloromethane) to afford 230 mg of product. LC/MS: Retention time, 1.79 min; (M+H)=461. 1H NMR (400 MHz, DMSO-D6) δ ppm: 1.61 (br s, 4H) 2.37 (br ss, 2H) 2.56-2.71 (br s, 2H) 3.45 (t, J=6.26 Hz, 2H) 4.75 (s, 2H) 6.55 (s, 1H) 7.17-7.28 (m, 3H) 7.45-7.52 (m, 2H) 7.56 (t, J=2.64 Hz, 1H) 8.00 (ddd, J=8.30, 5.44, 2.31 Hz, 2H) 8.07 (d, J=7.47 Hz, 1H) 8.82 (s, 1H) 11.40 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCNCC1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(c2nc(Cl)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To a solution of 2,4-dichloro-thieno[3,2-d]pyrimidine (0.20 g, 1.0 mmol) in EtOH (3.2 mL) was added K2CO3 (0.31 g, 2.2 mmol) followed by N-methylpiperazine (0.13 mL, 1.2 mmol). After stirring at rt for 12 h, the mixture was filtered to afford 0.23 g of the desired product. MS: 269.0. 1H NMR (400 MHz, CD3OD) 8 ppm 8.06 (d, J=5.6 Hz, 1H), 7.27 (d, J=5.6 Hz, 1H), 4.05-4.00 (m, 4H), 2.62-2.56 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]([F:35])([F:34])[F:33])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:36][NH2:37]>>[CH3:36][NH:37][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:32]([F:35])([F:34])[F:33])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:15]=2[O:14]1
Reactant: COc1ccc(-c2cc(C(F)(F)F)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3ccc(OC)cc3OC)c2O1

Procedure:
The title compound was prepared (0.048 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.080 g, 0.16 mmol) and methylamine (0.12 g, 3.9 mmol). mp 234-236° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]1.CNC([C@@H]1CCCNC1)=O>>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: O[C@@H]1CCNC[C@@H]1O
Agent: CNC(=O)[C@@H]1CCCNC1
Product: Cc1c(-c2ccc(C(=O)N3CC[C@@H](O)[C@@H](O)C3)s2)noc1C(F)(F)F
Yield: 81 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3S,4R)-3,4-Piperidinediol (CAS [868051-84-7]) in the same manner as the (3R, 4S) isomer (Example 87) to afford product as a colorless solid (303 mg, 81%). LC/MS 5.43 min, [M+1]+ 377.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[O:32][CH2:30][CH3:31])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CCOc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OCC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100.1 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-ethoxybenzaldehyde (570 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was unified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (402 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[C:7](Br)[C:6]([CH3:11])=[C:5]([F:12])[C:3]=1[NH2:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:34]2[CH2:39][CH2:38]CCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:8]([F:9])=[C:7]([CH:38]2[CH2:39][CH2:34]2)[C:6]([CH3:11])=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: Cc1c(F)c(N)c(Cl)c(F)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(F)c(N)c(Cl)c(F)c1C1CC1
Temperature: 95 °C

Procedure:
A mixture of 2-chloro-4-bromo-5-methyl-3,6-difluoroaniline (7.0 g, 27 mmol) cyclopropylboronic acid (3.5 g, 41 mmol), palladium(II) acetate (0.67 g, 3.0 mmol), potassium phosphate (17.5 g, 82 mmol) and tricyclohexylphosphine (0.83 g, 3.0 mmol) is dissolved in 100 mL of 4:1 toluene/water. The mixture is degassed by repeated alternating applications of vacuum and positive nitrogen pressure (10×). The mixture is heated to 95° C. for 2 days and then cooled to room temperature. Most of the toluene is removed by rotary evaporator and the residual mixture is partitioned between Et2O (250 mL) and water (250 mL). The organic phase is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (10% EtOAc/hexanes) to give 2-chloro-4-cyclopropyl-5-methyl-3,6-difluoroaniline as a tan oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1)[NH2:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 g of 4,6-dichloropyrimidine were dissolved in 100 ml of methanol, mixed dropwise with 12 ml of hydrazine hydrate (80%) and stirred for 1 hour at room temperature. After sucking off the precipitate and washing with H2O, 10 g of 4-hydrazino-6-chloropyrimidine were obtained.
Reaction SMILES: [OH-].[K+].[N+](C1C=CC(O[CH2:11][C:12]2O[N:15]=[C:14]([CH2:17][C:18]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=3[Cl:29])=[O:19])[N:13]=2)=CC=1)([O-])=O.[N+:32]([C:35]1[CH:60]=CC(OCC(NC2CC(=O)N(C3C(Cl)=CC(Cl)=CC=3Cl)N=2)=O)=[CH:37][CH:36]=1)([O-:34])=[O:33]>CO>[N+:32]([C:35]1[CH:60]=[CH:11][C:12]([NH:13][C:14]2[CH2:17][C:18](=[O:19])[N:20]([C:21]3[C:22]([Cl:29])=[CH:23][C:24]([Cl:28])=[CH:25][C:26]=3[Cl:27])[N:15]=2)=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=C(Cc1noc(COc2ccc([N+](=O)[O-])cc2)n1)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(Nc2ccc([N+](=O)[O-])cc2)=NN1c1c(Cl)cc(Cl)cc1Cl

Procedure:
To a solution of 5 g of potassium hydroxide in 75 ml of anhydrous methanol was added 10 g of 2-[5-(p-nitrophenoxymethyl)-1,2,4-oxadiazol-3-yl]-2',4',6'-trichloroacetanilide. The mixture was heated under reflux for 2 hours. The reaction did not stop with 3-[(p-nitro-phenoxy)acetamido]-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one but proceeded further (Smiles rearrangement) to give 3-(p-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one. At the end of the reaction, the mixture was allowed to cool to room temperature, acidified with 10 ml of acetic acid, diluted with 70 ml of water, and then allowed to stand at room temperature overnight. The product was collected, washed with water and ethanol, and dried. There was obtained 3.8 g (43%) of 3-(p-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one as yellow crystals, mp 295°-298° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(cc(C)c(Cl)c2C)OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(c(C)c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Yield: 94.8 %

Procedure:
To a suspension of ethyl 6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (4.00 g, 11.9 mmol) in 40 mL of EtOH was added a solution of NaOH (1.2 g, 30 mmol) in 18 mL of H2O. The reaction was heated at reflux for 1.5 h. Once cooled, the reaction was neutralized with 2 N HCl. The product that precipitated from solution was filtered and washed with H2O. After drying in the vacuum oven at 50° C., a pale yellow solid, 6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (3.46 g, 95%) was isolated.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:19]([F:28])[CH:18]=2)=[CH:15][CH:16]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1>C(O)C.C1(C)C=CC=CC=1.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.O>[F:28][C:19]1[CH:18]=[C:17]([C:14]2[S:13][C:12]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:16][CH:15]=2)[CH:22]=[CH:21][C:20]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCCCc1ccc(-c2ccc(Br)s2)cc1F
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc(-c3ccc(C)cc3)s2)cc1F
Temperature: 80 °C

Procedure:
A mixture of 3.54 g (26.0 mmol) of p-tolylboronic acid, 8.50 g (26.0 mmol) of 2-bromo-5-(3-fluoro-4-pentylphenyl)thiophene, 1.50 g (1.30 mmol) of tetrakis(triphenylphosphine)palladium(0) and 33 ml of 2 M sodium hydrogencarbonate solution in 80 ml of ethanol/toluene=3:2 is heated at 80° C. for 20 h. Toluene and water are added to the mixture, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(3-Fluoro-4-pentylphenyl)-5-p-tolylthiophene is obtained as a solid having an m.p. of 115° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH:13]1[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Clc1nc2ccncc2nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nc2cnccc2nc1NC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (3.55 g, 17.75 mmol) in dioxane (71.0 mL) at room temperature was treated with cyclopropanamine (1.63 mL, 23.07 mmol), followed by dropwise addition of DIPEA (6.51 mL, 37.3 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. Purification by flash silica gel chromatography using a gradient of 25% to 100% EtOAc in hexanes gave the title compound (3.15 g, 80%) as an orange solid. ESI-MS m/z [M+H]+ 221.1.
Reaction SMILES: ClC(Cl)(Cl)[C@@H](O)C=C(C)C.[CH3:11][C:12]1([CH3:23])[C@@H:17]2[C@H:13]1[C@@H:14]([C:19](Cl)([Cl:21])[Cl:20])[O:15][C:16]2=[O:18]>>[Cl:20][C:19]([Cl:21])=[CH:14][C@@H:13]1[C@H:17]([C:16]([OH:18])=[O:15])[C:12]1([CH3:11])[CH3:23]
Reactant: CC1(C)[C@@H]2[C@@H](C(Cl)(Cl)Cl)OC(=O)[C@@H]21
Agent: CC(C)=C[C@H](O)C(Cl)(Cl)Cl
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O

Procedure:
In the manner of Examples IA.1.(a), IA.2.(a), IA.4.(a), IA.8.(a), and IIIC., (1S,3S)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid is prepared from (2S)-1,1,1-trichloro-4-methyl-3-penten-2-ol via (1S,4S,5R)-6,6-dimethyl-2-oxo-4-trichloromethyl-3-oxabicyclo[3.1.0]hexane.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[N:32]1([C:38]2[N:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([S:44]([C:41]6[CH:42]=[N:43][C:38]([N:32]7[CH2:33][CH2:34][O:35][CH2:36][CH2:37]7)=[CH:39][CH:40]=6)(=[O:46])=[O:45])[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(S(=O)(=O)c3ccc(N5CCOCC5)nc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) in DMF (1 mL), was added 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (21 mg, 80 μmol) and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added and the resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method A to afford 18.7 mg of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:10]([N+:25]([O-])=O)=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[NH2:25][C:10]1[C:9]([OH:8])=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 40 °C
Yield: 89.6 %

Procedure:
To 7.44 g of 3-benzyloxy-N-(5-chloro-2-pyridyl)-2-nitrobenzamide were added 40 ml of trifluoroacetic acid and 3.72 g of pentamethylbenzene and the mixture was stirred at 40° C. for one night. The reaction solution was concentrated in vacuo, a saturated aqueous solution of sodium bicarbonate was added to the resulting residue to such an extent that the residue did not become alkaline and the mixture was extracted with chloroform. The organic layer was extracted with a 1N aqueous solution of sodium hydroxide and the aqueous layer was acidified by adding hydrochloric acid thereto and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and 200 ml of an ethanolic suspension of Raney nickel was added to the resulting residue. The mixture was stirred a hydrogen atmosphere for 6 hours, N,N-dimethylformamide was added and the insoluble matters were filtered off. The solvent was evaporated in vacuo and water was added to the resulting residue. The resulting precipitate was filtered and dried in vacuo to give 4.58 g of 2-amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.