Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:29]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:30])=[C:10]([O:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[N:11]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CC(=O)OCC>[F:27][C:25]1[CH:24]=[CH:23][C:22]([CH3:28])=[C:21]([CH:26]=1)[O:20][C:10]1[N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]2[C:8]([C:9]=1[C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2
Reactant: COC(=O)c1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccc(C(=O)O)cc2n1-c1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
The compound of example 27, step 1 (18 mg, 30.6 μmol) was dissolved in MOH (1 ml), a 2 N sodium hydroxide solution (300 μl) was added, and the mixture was stirred at 40° C. for 3 h. The mixture was diluted with EA and washed with a saturated solution of ammonium chloride. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in DCM (1 ml), TFA (0.3 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated and the obtained solid residue was purified by preparative HPLC. The eluate was lyophilized overnight. The residue was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 3.6 mg of the title compound were obtained in the form of the 2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carboxylic acid hydrochloride.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[CH:23]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21
Product: CC(C)COCCc1ccc(OCC(O)CNCCn2cnc3cc(-c4ccc(=O)[nH]n4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([C:23](=[O:25])[CH3:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]([OH:25])[CH3:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:1]
Reactant: CC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-one (500 mg, 1.48 mmol) in THF (50 mL) was added LiAlH4 (0.282 g, 7.37 mmol), then the mixture was heated at 60° C. for 1 h. After cooling to room temperature, the reaction was quenched with a piece of ice cube. The solid was filtered off and washed with ethyl acetate (3×10 mL). The combined filtrate was concentrated to give the crude product, which was purified by silica gel chromatography eluting with DCM/MeOH (50:1) to give 1-{4-[1-(Propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-ol (420 mg, 83% yield) as a white solid. LCMS (ESI) m/z: 340.3 [M+H+].
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH:11][S:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:20]=1)(=[O:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccc1SCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 80.3 %

Procedure:
Following General Procedure B, the title compound (890 mg, 80%) was prepared from 2-(benzylthio)-5-chloroaniline (560 mg, 2.25 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (628 mg, 2.25 mmol).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[C:19]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[CH3:38])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[SH:43][CH2:44][CH2:45]O.B(F)(F)F.CCOCC>ClCCl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:18]2[CH:23]=[N:22][C:21]([N:24]3[CH2:29][CH2:28][C:27]4([O:30][CH2:45][CH2:44][S:43]4)[CH2:26][CH2:25]3)=[CH:20][C:19]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(F)ccc1-c1cc(N2CCC3(CC2)OCCS3)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of 0.20 g (0.34 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 5 ml dichloromethane were added 0.03 g (0.4 mmol) 2-mercaptoethanol and 0.11 g (0.34 mmol) boron trifluoride etherate at 0° C. After 1 h the reaction mixture was allowed to warm to room temperature and stirred over night. Dilution with a 2 N aqueous sodium hydroxide solution was followed by extraction with 3 portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.22 g (98%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1NCC(=O)O
Temperature: 25 °C
Yield: 106.2 %

Procedure:
A mixture of 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (40 mg, 0.0.084 mmol), potassium carbonate (23 mg, 0.167 mmol), methanol (5 mL) and water (1 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 40 mg (99%) of 3-[3-(carboxymethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)cc2)C1=O
Yield: 70.4 %

Procedure:
Using (4-bromophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 185 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (189 mg) was obtained.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Sc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfophenylthio)anthraquinone-2-sulfonic acid (23.7 parts), cyanuric chloride (9.3 parts) and 1-aminobenzene-3-β-sulfatoethylsulfone (14.1 parts) were subjected to condensation reactions one after another in an aqueous medium in a usual manner, followed by a further condensation reaction with 3-aminobenzenesulfonic acid (8.7 parts) at 50° to 60° C. under a weak acid condition. Thereafter, salting out of the reaction mixture gave an anthraquinone compound of the following formula (free acid form). ##STR519##
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9]Br.[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C@H:22]([NH2:24])[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C@H:22]([N:24]3[CH2:9][C:4]4[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:2]3)[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:32][CH:33]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: BrCc1ccccc1CBr
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](N2Cc3ccccc3C2)CN1C(=O)Cn1cncn1
Yield: 11 %

Procedure:
Proceeding as in Example 7, but substituting 1,2-bis(bromomethyl)benzene and (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide gave Compound 260, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(isoindolin-2-yl)pyrrolidine-2-carboxamide (47 mg, 0.088 mmol, 11%). 1H-NMR (400 MHz, DMSO-d6): 10.10 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.60 (d, J=10.0 Hz, 2H), 7.29-7.17 (m, 6H), 7.03-6.95 (m, 4H), 5.34-5.30 (m, 2H), 4.56-4.52 (m, 1H), 3.95 (s, 4H), 3.71-3.60 (m, 1H), 3.52-3.46 (m, 2H), 2.31-2.24 (m, 1H), 2.17-2.09 (m, 1H). MS (EI) for C29H27FN6O3. found 527.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.[Cu]Cl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)=[CH:36][CH:35]=1
Reactant: Oc1ccc(F)cc1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)cn3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) (0.2 g, 0.397 mmol), 4-fluorophenol (0.089 g, 0.794 mmol), cesium carbonate (0.259 g, 0.794 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (TMHD) (0.008 g, 0.040 mmol) were combined in NMP (3 mL) under argon. Copper (I) chloride (0.02 g, 0.199 mmol) was added and the mixture heated at 120° C. overnight. A second portion of 4-fluorophenol, copper (I) chloride, cesium carbonate and TMHD was added and heating continued at 120° C. overnight. After cooling to room temperature, the mixture was partially concentrated, the residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and water. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-50% ethyl acetate/petroleum ether yielded the title compound as a yellow oil (0.161 g). δH (CDCl3, 400 MHz) 8.04 (1H, br.s), 7.49 (1H, br.d), 7.20 (2H, d), 7.00 (7H, m), 4.17 (1H, br.s), 3.79 (1H, d), 3.51 (3H, s), 3.47 (1H, d), 3.33 (1H, d), 3.08 (1H, td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.99 (1H, m), 1.46 (9H, s), 1.19 (3H, d). MS (ES): MH+ 535.4.
Reaction SMILES: C1(N)C=CC=CC=1.[N+:8]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-:23])=[O:22])[C:12]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH:26]=1)([O-:10])=[O:9].[Cl:39]Cl>ClCCl>[N+:21]([C:13]1[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:35])[F:36])[C:26]=1[Cl:39])([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1cccc(OC(F)(F)C(F)(F)F)c1
Reactant: ClCl
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1cccc(OC(F)(F)C(F)(F)F)c1Cl

Procedure:
When desired, the above described halogenation reaction can be carried out utilizing less than one molar quantity of halogenating agent, thereby effecting monohalogenation instead of dihalogenation. The monohalogenated product can be further halogenated if desired with the same or a different halogenating agent. For instance a benzenamine such as N-(2,6-dinitro-4-trifluoromethylphenyl)-3-(1,1,2,2,2-pentafluoroethoxy)benzenamine can be reacted with about a 0.5 molar amount of chlorine in dichloromethane at about 25° C. to give N-(2,6-dinitro-4-trifluoromethylphenyl)-2-chloro-3-(1,1,2,2,2-pentafluoroethoxy)benzenamine. The latter compound can be further halogenated, for instance by reaction with about a 0.5 to 1.0 molar amount of bromine in dichloromethane, to provide the corresponding dihalogenated derivative, for example N-(2,6-dinitro-4-trifluoromethylphenyl)-2-chloro-4-bromo-5-(1,1,2,2,2-pentafluoroethoxy)benzenamine.
Reaction SMILES: [CH2:1]([C:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:1]([C:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:22][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:34][CH:35]=2)=[O:21])=[CH:18][CH:17]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
{circle around (3)}: A mixture comprising 2.14 g of 4-n-dodecylcarbonyloxybenzoic acid, 1.40 g of 4-benzyloxyphenol, 1.44 g of DCC and 20 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, and dichloromethane was distilled off from the filtrate under reduced pressure. The resultant residue was purified by means of silica gel column chromatography, whereby 3.3 g of 4-(4′-n-dodecylcarbonyloxyphenylcarbonyloxy)-1-benzyloxybenzene was obtained in the form of a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])=[C:12]([NH:31][CH3:32])[CH:11]=2)[CH:6]=[C:5]([CH3:33])[N:4]=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]3[N:16]=[C:17]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=4)[C:23]([O:25][CH3:26])=[O:24])[N:31]([CH3:32])[C:12]=3[CH:11]=2)[CH:6]=[C:5]([CH3:33])[N:4]=1
Reactant: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1NC(=O)COc1cccc(C(=O)OC)c1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4cc(C)nc(OC)c4)cc3n2C)c1
Yield: 96.7 %

Procedure:
The reaction and post-treatment were carried out according to Example (16f) using methyl 3-[2-({4-[(2-methoxy-6-methylpyridin-4-yl)oxy]-2-(methylamino)phenyl}amino)-2-oxoethoxy]benzoate produced in Example (17d) (4.44 g, 9.83 mmol) and acetic acid (50 mL) to obtain the title compound (4.12 g, 99%) as a white powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[O-2].[Ba+2].[OH-].[Ba+2].[OH-].I[CH3:25]>CN(C=O)C>[CH3:25][O:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CI
Agent: [Ba+2]
Agent: [O-2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CO[C@H]1Cc2ccccc2[C@H]1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A mixture of tert-butyl [(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-carbamate (680. mg, 2.73 mmol), DMF (21.1), barium monoxide (5.02 g, 32.7 mmol), barium hydroxide (2.80 g, 16.4 mmol) and iodomethane (1.70 mL, 27.3 mmol) was stirred overnight. LC/MS showed no starting material. The reaction was quenched via addition of a saturated solution of NaHCO3 and was extracted with DCM. The organic layer was washed with H2O (3×), dried over sodium sulfate and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the title compound (178 mg, 25%). LC/MS: Rt=1.24 min, ES+ 264 (AA standard).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[CH:17]1(C2C=CC(NN)=CC=2)[CH2:22][CH2:21]C[CH2:19][CH2:18]1>>[ClH:1].[CH:2]1([C:3]2[CH:14]=[C:13]3[C:6]([NH:7][CH:8]=[C:9]3[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=2)[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]1
Reactant: NNc1ccc(C2CCCCC2)cc1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: NCCc1c[nH]c2ccc(C3CCCCC3)cc12

Procedure:
5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-cyclohexylphenylhydrazine hydrochloride as starting material.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11]([NH2:13])=O)[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11]#[N:13])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2ccc(C(N)=O)cc21
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C)COc2ccc(C#N)cc21

Procedure:
The product of stage (c) was boiled under reflux in benzene (5 ml) with thionyl chloride for 6 hours. Washing with water, drying over magnesium sulphate and running down gave, after recrystallisation from petroleum ether (bp 60°-80° C.), 0.6 g of title product, mp 70°-72° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:2]1([C:1]([OH:12])=[O:11])[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: [H][H]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)C1CCCC(C(=O)O)C1
Yield: 94.9 %

Procedure:
To a suspension of isophthalic acid (5.0 g, 30.1 mmol) in 45 ml of acetic acid was added a slurry of 0.1 g of platinum oxide in 5 ml of acetic acid. The resulting mixture was stirred under 50 psi of hydrogen at 25° C. for 16 hours. NMR analysis (DMSO-d6) at this time showed complete reduction of starting material. The reaction mixture was filtered through Celite and the filter cake was rinsed with methanol. The combined filtrate and washes were concentrated under reduced pressure, using heptane to azeotropically remove residual acetic acid. Trituration of the resultant semi-solid with heptane and filtration of the precipitate provided 4.92 g (95%) of the title compound as a white powder. mp: 163-165° C.
Reaction SMILES: C(OCC)(=O)C.[CH3:7][O:8][C:9](=[O:42])[CH:10]=[CH:11][CH:12]([C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)[CH2:13][C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:15]=1>[Ni].C(O)C>[CH3:7][O:8][C:9](=[O:42])[CH2:10][CH2:11][CH:12]([C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)[CH2:13][C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:15]=1
Reactant: COC(=O)C=CC(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCC(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Reaction time: 2 h
Yield: 91 %

Procedure:
To a flask containing ethyl acetate (1.0 mL), ethanol (1.0 mL) and a catalytic amount of Raney nickel was added 5-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pent-2-enoic acid methyl ester (92 mg, 0.17 mmol). The reaction mixture was stirred under H2 (˜1 atm) for 2 h and then filtered through a CELITE® pad. The filtrate was concentrated under reduced pressure, and the crude residue was purified by reversed-phase HPLC giving the desired ester (81 mg, 91%). HPLC: Rt=3.68 (Method B). MS (ESI): mass calculated for C29H28Cl2N3O3, 522.15; m/z found, 523.3 [M+H]+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][CH2:10][C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[C:18]([S:20](=[O:23])(=[O:22])[NH2:21])[O:19][C:13]=2[CH:12]=1>C(#N)C.C(Cl)(Cl)Cl>[CH3:6][N:4]([CH3:5])[CH:3]=[N:21][S:20]([C:18]1[O:19][C:13]2[CH:12]=[C:11]([CH2:10][OH:9])[N:16]=[CH:15][C:14]=2[CH:17]=1)(=[O:22])=[O:23]
Reactant: NS(=O)(=O)c1cc2cnc(CO)cc2o1
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2cnc(CO)cc2o1
Temperature: 25 °C
Reaction time: 40 h
Yield: 48.5 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (1.0 ml, 0.007 mole) was added dropwise (10 minutes) to a suspension of 6-hydroxymethyl-2-sulfamoylfuro[3,2-c]pyridine (1.33 g, 0.005% mole) in acetonitrile (25 ml). The mixture was stirred at room temperature under N2 for 40 hours. The reaction mixture was diluted with CHCl3 and washed with water. The organic phase was separated, dried (Na2SO4) and filtered through charcoal. The filtrate was concentrated to dryness and the residue recrystallized from ethyl acetate to give the product as a yellow solid 0.8 g (48% yield). Recrystallization from methanol/ethyl acetate gave an analytical sample, mp: 161°-163° C.