Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[H][H]>O1CCCC1.CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:11])[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)cccc1O

Procedure:
2-Methyl-3-nitrophenol (70 g) in 100 ml of tetrahydrofuran and 400 ml of methanol at room temperature was hydrogenated under 5 psi of hydrogen gas using 3.5 g of 5% palladium on carbon as catalyst. After removal of catalyst by filtration, the filtrate was concentrated to give 56 g of analytically pure 3-amino-2-methylphenol. This aminophenol was then converted to the title compound (7.9 g) using the general method of Example 2, except that the hydrochloride salt was formed by adding hydrogen chloride/dioxane to a methanol solution of the free base. The nmr spectrum and elemental analysis were in agreement with those of title compound prepared by Example 3 (Method A).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.N[C:39]1C=CC(OC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:39][CH2:12][C@H:13]([C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[O:17])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)[C@H]3CCN(C(=O)OCc4ccccc4)C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 1A, substituting (S)-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid and tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(CCl)c(CCNC(=O)C(F)(F)F)cc1OC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC#N)c(CCNC(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
In a three-necked flask stir, at ambient temperature, a suspension of sodium cyanide (9.8 g, 200 mmoles) in 160 mL of DMSO. Add to the suspension, dropwise, a solution of N-{2-[2-(chloromethyl)-4,5-dimethoxyphenyl]ethyl}-2,2,2-trifluoroacetamide (26 g, 798 mmoles) in 80 mL of DMSO. After being in contact for 1 hour 30 minutes at ambient temperature, hydrolyse the mixture using 300 mL of water and extract the mixture with dichloromethane (3×150 mL). Combine the organic phases and wash them with 10% aqueous solution of NaOAc (150 mL) and saturated aqueous NaCl solution (4×150 mL), then dry them over MgSO4 and carry out drying in vacuo. The product obtained is recrystallised from toluene (66 mL) to obtain 12.8 g of a white powder corresponding to the title compound.
Reaction SMILES: NC1OC=C(C(OCC)=O)N=1.CC(OC(C)=O)=O.[C:19]([NH:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=1)(=[O:21])[CH3:20].[Li+].[OH-]>CCO>[C:19]([NH:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1coc(NC(C)=O)n1
Agent: CCOC(=O)c1coc(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(C(=O)O)co1
Temperature: 25 °C

Procedure:
1.0 g (6.41 mmol) ethyl 2-aminooxazole-4-carboxylate and 9.10 mL (96.3 mmol) Ac2O are stirred at r.t. over the weekend. Then the solvent is removed in vacuo. Some toluene is added and all volatile components are removed in vacuo again. This procedure is repeated three times. The crude product is used without further purification. b) 1.31 g (6.60 mmol) of ethyl 2-acetamidooxazole-4-carboxylate are added to 33 mL EtOH. 0.55 g (13.2 mmol) LiOH are added and the resulting mixture is stirred at r.t. over night. Then the EtOH is removed in vacuo and diluted aq. HCl is added and the resulting precipitate is collected, washed with cold water and dried. The resulting product is used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.Cl.C(=O)=O.CC(C)=O.N>CCO.CO>[Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][OH:22])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)Cn1cc([N+](=O)[O-])nc1Br
Agent: Cl
Agent: N
Agent: O=C=O
Solvent: CO
Solvent: CCO
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cn(CC(CO)CO)c(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A suspension of silyl ether 178 (7.35 g, 14.5 mmol) in a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (150 mL) was stirred at room temperature for 4 h, and then kept at 4° C. for 12 h. The resulting solution was cooled (CO2/acetone), neutralised by dropwise addition of 7M NH3 in MeOH (9.8 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 33-75% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 75% EtOAc/petroleum ether and EtOAc gave 2-[(2-bromo-4-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol (179) (3.42, 85%) as a white solid: mp (MeOH/CH2Cl2/hexane) 110-112° C.; 1H NMR [(CD3)2SO] δ 8.50 (s, 1H), 4.65 (t, J=5.0 Hz, 2H), 4.07 (d, J=7.3 Hz, 2H), 3.41 (m, 4H), 2.06 (m, 1H). Anal. (C7H10BrN3O4) C, H, N.
Reaction SMILES: [C:1]1([CH:7]2[N:11]([CH2:12][CH2:13]O)[N:10]=[C:9]3[C:15](=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][S:17][CH2:18][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH3:48]>N1C=CC=CC=1.C(O)C.O>[C:1]1([CH:7]2[N:11]([CH2:12][CH2:13][NH2:48])[N:10]=[C:9]3[C:15](=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][S:17][CH2:18][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: NCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1
Reaction time: 16 h

Procedure:
3a,4,6,7-Tetrahydro-3-phenyl-7-(phenylmethylene)thiopyrano[4,3-c]pyrazole-2(3H)-ethanol is suspended in pyridine and treated with one equivalent of tosyl chloride. After standing at room temperature for about 16 hours, the mixture is poured into water and the tosylate is dissolved in ethanol, cooled and saturated with ammonia gas. After standing for 3 days, the excess ammonia and solvent are removed by evaporation to give the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](Cl)=[O:14].C(=O)=O.[CH3:19][C:20](C)=O.C(OCC)C>ClCCl.CCCCCC>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][C:13](=[O:14])[CH2:20][CH2:19]2
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C1CCc2cccc(Cl)c2C1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a slurry of 46.5 gm (0.348 mole) AlCl3 in 400 mL dichloromethane at -78° C. was added a solution of 32.76 gm (0.174 mole) of the previously prepared o-chlorophenylacetyl chloride in 100 mL dichloromethane dropwise over 1 hour. The dry ice/acetone bath then was replaced with an ice/water bath and ethylene was bubbled into the reaction mixture during which time the temperature rose to 15° C. The ethylene addition was discontinued at the end of the exotherm and the reaction mixture was stirred at about 5° C. for 4 hours. Ice was then added to the reaction mixture to destroy aluminum complexes. Upon termination of the exotherm, the reaction mixture was diluted with 500 mL of water and stirred vigorously until all solids had dissolved. The phases were separated and the organic phase was washed with 3×400 mL 1N hydrochloric acid and 2×400 mL saturated aqueous sodium bicarbonate. The remaining organic phase was then dried over sodium sulfate and concentrated in vacuo to give a pale orange residue. The residue was dissolved in 1:1 hexane:diethyl ether and was poured over a flash silica column which was then eluted with 1:1 hexane:diethyl ether to give a light yellow residue which was crystallized from 4:1 hexane:diethyl ether to give 10.55 gm of the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@@H:34]4[CH2:39][CH2:38][C@H:37]([C:40]([O:42]CC)=[O:41])[CH2:36][CH2:35]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:50])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@@H:34]4[CH2:35][CH2:36][C@H:37]([C:40]([OH:42])=[O:41])[CH2:38][CH2:39]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:48])([F:50])[F:49])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)O)CC4)c4[nH]cc(C)c(=O)c34)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of ethyl cis-4-(5-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Example 305, 61.7 mg, 0.083 mmol) in THF (0.11 mL) and MeOH (0.11 mL) was charged with a solution of lithium hydroxide, monohydrate (17.4 mg, 0.41 mmol) in H2O (0.11 mL) and allowed to stir at rt for 30 hrs. The reaction was concentrated under reduced pressure. The material was purified on an Isco combi-flash unit using DCM/MeOH (100:0→95:5) as eluent to afford 22.3 mg (38%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 1.24-1.30 (m, 6 H) 1.76-1.89 (m, 6 H) 2.11-2.15 (m, 3 H) 2.34 (d, J=4.80 Hz, 2 H) 2.73 (br. s., 1 H) 2.99 (s, 1 H) 3.29 (br. s., 1 H) 3.34 (s, 1 H) 3.89-3.94 (m, 3 H) 4.02-4.13 (m, 4 H) 6.87 (dt, J=8.21, 2.34 Hz, 1 H) 7.03 (t, J=2.02 Hz, 1 H) 7.41 (d, J=8.59 Hz, 1 H) 7.84 (d, J=0.76 Hz, 1 H) 8.03 (d, J=8.34 Hz, 1 H) 8.33 (s, 1 H) 8.49 (d, J=6.32 Hz, 1 H). MS (ES+): m/z 718.15/719.19 (100/98) [MH+]. HPLC: tR=1.47 min (Micromass TOF: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:56][C:57]([F:66])([F:65])[C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1>C1COCC1.CN(C=O)C>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:62][C:61]3[CH:63]=[CH:64][C:58]([C:57]([F:56])([F:65])[F:66])=[CH:59][CH:60]=3)=[O:24])=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cc3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 14.7 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.100 g, 0.254 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.163 g, 0.509 mmol), N-methyl morpholine (1.0 mL), DMF (1.5 mL), THF (7.0 mL) and 4-trifluoro methyl aniline (0.082 g, 0.509 mmol) to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 3.07 (s, 2H), 7.25 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 8.45 (s, 2H), 9.91 (s, 1H), 10.99 (s, 1H), 11.55 (s, 1H); MS [M+H]+: 536.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.[CH:21]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH:10]([CH3:21])[C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cc(OC)c2c(c1)OC1(CCCCC1)CC2=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(OC)c2c(c1)OC1(CCCCC1)C(C)C2=O
Reaction time: 2 h
Yield: 69.6 %

Procedure:
A solution of 5,7-dimethoxyspiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 8) (1.38 g, 5 mmol) in dry tetrahydrofuran (10 ml) is added dropwise at -78° C. to a solution of lithium diisopropylamide (prepared from diisopropylamine (0.77 ml, 7.6 mmol) and 1.3N butyl lithium solution in hexane (3.85 ml, 5.0 mmol)) in tetrahydrofuran. To the mixture is added hexamethyl phosphoric triamide (1.05 ml) and then a solution of methyl iodide (0.78 g, 5.5 mmol) in tetrahydrofuran (1 ml) at -70° C. After the mixture is reacted at -78° to 0° C. for 2.5 hours and then at 0° to 3° C. for 2 hours, an aqueous solution of ammonium chloride is added thereto. The mixture is then extracted with diethyl ether and the organic layer is separated, washed twice with saturated brine, dried and the solvent is removed by distillation. The residue is loaded onto a Lober column and eluted with a mixture of acetonitrile and dichloromethane (1:9) to obtain the title compound as an oil (1.01 g, yield 69.6%).
Reaction SMILES: CCCN([C:8]1[C:9]([N+:21]([O-:23])=[O:22])=[CH:10][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])CCC.FC(F)(F)C1C=CC([Cl:32])=CC=1.[N+]([O-])(O)=O.S(=O)(=O)(O)O>>[F:18][C:17]([F:20])([F:19])[C:11]1[CH:10]=[C:9]([N+:21]([O-:23])=[O:22])[C:8]([Cl:32])=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=1
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
The preparation of, for example, trifluralin is carried out by nitrating 1-trifluoromethyl-4-chlorobenzene with nitric acid in the presence of sulfuric acid to give 1-trifluoromethyl-3,5-dinitro-4-chlorobenzene, from which 2,6-dinitro-4-trifluoromethyl-N,N-dipropylaniline is obtained by amination with the secondary amine, di-n-propylamine. This synthesis can be represented by the following reaction scheme: ##STR1##
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]2[C:15](=[O:16])[CH:14]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: CCOC(=O)CC(=O)CCl
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Product: O=c1cc(CCl)nc2scc(C(F)(F)F)n12

Procedure:
This compound was synthesized from 2-amino-4-trifluoromethylthiazole, Step 1 intermediate (3.70 g, 22.541 mmol) and ethyl chloroacetoacetate (5.194 g, 31.558 mmol) in polyphosphoric acid (30.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 4.0 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 269.22 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)c(C)cc3ccc(OC)cc23)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(C)cc3ccc(OC)cc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1

Procedure:
Synthesized in a manner similar to Example 46 (Step 7) using ethyl (2E)-3-[4-({3-methyl-7-(methyloxy)-2-[4-(methyloxy)phenyl]-1-naphthalenyl}oxy)phenyl]-2-propenoate (265). 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, J=9.0 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.60 (s, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.14 (dd, J=8.7, 2.4 Hz, 1H), 7.06-7.04 (m, 3H), 6.81 (d, J=8.7 Hz, 2H), 6.63 (d, J=8.7 Hz, 2H), 6.24 (d, J=15.9 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.24 (s, 3H). TLC (90:10; CHCl3/MeOH): Rf=0.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Temperature: 25 °C

Procedure:
A suspension of 2-chloro-4-nitrotoluene (10.0 g, 58.3 mmol), N-bromosuccinimide (NBS, 10.9 g, 61.2 mmol), and 2,2′-azobis(2-methylpropionitrile) (AIBN, 0.29 g, 1.75 mmol) in 120 mL of CCl4 was heated at reflux under an atmosphere of N2 for 12 h. The reaction mixture was cooled to ambient temperature, and the solid was filtered and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried over Na2SO4, filtered, concentrated on rotovap, and further dried under vacuum. 1H NMR indicated the ratio of desired product to unreacted 2-chloro-4-nitrotoluene to be 50:50. This material was used directly in the next step.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:27]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(CCc1ccccc1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
1-[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-3-phenyl-propan-1-one was prepared from phenanthridine, hydrocinnamoyl chloride, and indole according to GP 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CS(C)=O>[Cl:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:17])=[CH:18][CH:19]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)cc1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(-c3cc4c(-c5cnc(C6(O)CCC6)s5)c(Cl)cnc4[nH]3)cc2)CC1
Temperature: 45 °C

Procedure:
To a solution of 4-(5-chloro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (Example 16C) (100 mg, 0.235 mmol) in N,N-dimethylformamide (1.17 mL) was added 1-methylpiperazine (78 μl, 0.704 mmol), 4-methylmorpholine (71.2 mg, 0.704 mmol), hydroxybenzotriazole (53.9 mg, 0.352 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (67.5 mg, 0.352 mmol). The solution was heated to 45° C. for 3 hours. The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 m column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.67 (bs, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.10-8.05 (m, 2H), 7.51-7.44 (m, 2H), 7.17 (s, 1H), 6.68 (s, 1H), 3.76-3.48 (m, 4H), 2.69-2.58 (m, 2H), 2.47-2.25 (m, 6H), 2.20 (s, 3H), 2.05-1.91 (m, 2H); MS ESI(+) m/z 508.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:13]([C:29]([F:32])([F:31])[F:30])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[N:41]=[C:42]=[O:43].C(N(CC)CC)C.O>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42]([NH:10][C:8]1[N:7]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:13]([C:29]([F:30])([F:32])[F:31])[N:12]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)=[O:43]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)c1cc(N)n(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2c(Cl)cccc2Cl)n(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 3-t-butyl-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazol-5-amine (0.23 mmol) in dichloromethane (3 ml) was treated with 2,6-dichlorophenyl isocyanate (0.056 g, 0.3 mmol) in the presence of triethylamine (0.05 ml), and the reaction was mixture was stirred at room temperature, overnight. Subsequently water (15 ml) was added to above and it was extracted with ethyl acetate (25 ml). The organic layer was evaporated and the crude material purified by column chromatography; elution with 1.5% of ethyl acetate in hexane yielded the title compound. 1H-NMR (CDCl3) δ: 0.86 (s, 9H), 6.58 (s, 1H), 7.02-7.05 (m, 3H), 7.14 (d, 2H), 7.24-7.33 (m, 8H), 8.43-8.44 (br, 1H, D2O exchangeable), 10.52 (br, 1H, D2O exchangeable); MS m/z: 625 (M+).