Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:24]2[CH:25]=[CH:26][C:27]([S:29]([O-:32])(=[O:31])=[O:30])=[CH:28][C:23]=2[S:22]/[C:4]/1=[N:5]\[N:6]=[C:7]1/[S:8][C:9]2[CH:17]=[C:16]([S:18]([O-:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:10]=2[N:11]/1[CH2:12][CH3:13].[NH4+].[NH4+].OO>>[N:5](=[C:4]1[N:3]([CH2:2][CH3:1])[C:24]2[CH:25]=[CH:26][C:27]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:28][C:23]=2[S:22]1)[N:6]=[C:7]1[N:11]([CH2:12][CH3:13])[C:10]2[CH:14]=[CH:15][C:16]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:17][C:9]=2[S:8]1
Reactant: CCn1/c(=N/N=c2\sc3cc(S(=O)(=O)[O-])ccc3n2CC)sc2cc(S(=O)(=O)[O-])ccc21
Agent: OO
Agent: [NH4+]
Product: CCn1c(=NN=c2sc3cc(S(=O)(=O)O)ccc3n2CC)sc2cc(S(=O)(=O)O)ccc21

Procedure:
The reaction mixture (0.2 ml) contained 1.0 mM ABTS, 20 μl peroxygenase fermentation supernatant (see Example 1), 0.5 mM hydrogen peroxide, and 50 mM Britton-Robinson buffer pH 4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:4][N:3]=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].CC[O-].[Na+]>CCO>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=1)[CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH:13]=[CH2:14])[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCC(=O)C=Cc1cnc(C)nc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCC(=O)CC(c1cnc(C)nc1)C(C(=O)OCC)C(=O)OCC
Reaction time: 1.5 h

Procedure:
The enone 15-3 (5.73 g, 28.4 mmol) was dissolved in TBF (200 mL) and EtOH (80 mL) at room temperature. To this was added diethyl malonate (6.46 mL, 42.5 mmol) and NaOEt (1 mL, 2.8 mmol) and the mixture stirred for 1.5 hours. The solution was partitioned between saturated NaHCO3 solution and EtOAc, washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with EtOAc) to give the diester 15-4 as an oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:30]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C1N(C2C=CC=C(NC(=O)C)C=2)N=C(C)C=1)=O.[OH-].[Li+].C(NC1C=C(N2C(N3C[C@H](S(C4C=CC=CC=4C(F)(F)F)(=O)=O)C[C@@H]3C(O)=O)=CC(C)=N2)C=CC=1)(=O)C>>[C:36]([NH:35][C:31]1[CH:30]=[C:29]([N:24]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:20])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]2)[CH:34]=[CH:33][CH:32]=1)(=[O:38])[CH3:37]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(NC(C)=O)c1
Agent: CC(=O)Nc1cccc(-n2nc(C)cc2N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2C(=O)O)c1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(NC(C)=O)c1
Agent: [Li+]
Product: CC(=O)Nc1cccc(-n2nc(C)cc2N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)c1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-[2-(3-acetylamino-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-[2-(3-acetylamino-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give a mixture of the title compound and (2R,4R)-1-[2-(3-acetylamino-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid as orange solid which was used in the next step without further purification. MS (ESI): m/z=537.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41](O)[CH2:42][CH2:43][CH2:44]C>O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH2:41][CH2:42][CH2:43][CH3:44])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCCCO
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.30 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.06 g of sodium carbonate, and 3.0 ml of n-pentanol was stirred at 100° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of pentyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-20).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:31]1>C(Cl)Cl>[CH2:36]([N:32]1[CH2:33][CH2:34][CH2:35][C@H:30]([NH:29][C:2]2[CH:3]=[C:4]([N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:31]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: N[C@H]1CCCN(Cc2ccccc2)C1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Solvent: ClCCl
Product: COc1ccc(CN(c2ccccc2)c2cc(N[C@H]3CCCN(Cc4ccccc4)C3)nn3c(C#N)cnc23)cc1
Temperature: 160 °C
Yield: 39.4 %

Procedure:
6-Chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile (100 mg, 0.257 mmol) from example XXXI, step (1b) and (S)-3-amino-1-benzylpiperidine (195 mg, 1.026 mmol) were combined in a 1-dram vial and heated at 160° C. for 6 h. The reaction was cooled to room temperature, dissolved in DCM (2 mL) and loaded onto to a 12 g silica gel column and eluted with 5%-100% EtOAc/heptane to give (S)-6-(1-benzylpiperidin-3-ylamino)-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile (55 mg, 40%). LCMS m/z (544, M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:6]OC)[C:3]([NH2:5])=[O:4].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N.N.[OH-].[Na+]>>[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH:5][C:3](=[O:4])[C:2]([CH3:6])=[CH2:1]
Reactant: CN(C)CCCN
Reactant: COCC(C)C(N)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)C(=O)NCCCN(C)C

Procedure:
117.2 g (1.0 mole) of 2-methyl-3-methoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 20 hours in a temperature range of 145°-175° C. until the evolution of ammonia is complete. The mixture is allowed to cool, 1.5 g of sodium hydroxide is added and the mixture is heated in a high vacuum at 90° to 110° C. The methanol is split off within about 30 minutes, vigorous foaming occurring. The temperature is increased and 122 g (0.72 mole=72% of the theoretical yield) of colorless oil having a Bp0.1 of 106°-110° C. are distilled off.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:22]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[I-].[Na+]>CN(C=O)C>[CH2:22]([O:29][C:30]([NH:31][CH2:32][CH2:33][N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]1[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:4])=[O:21])=[O:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cccc(F)c1NC(=O)OC(C)(C)C
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCNC(=O)OCc1ccccc1)c1c(F)cccc1C(=O)O
Temperature: 25 °C

Procedure:
Sodium hydride (60%, 120 mg, 3.0 mmol) was added to a solution of 2-tert-butoxycarbonylamino-3-fluorobenzoic acid methyl ester from Example 20A (750 mg, 2.8 mmol) in DMF (8.0 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 30 min. (2-bromoethyl)carbamic acid benzyl ester (360 mg, 2.8 mmol) and sodium iodide (420 mg, 2.8 mmol) were added and the mixture was heated at 65° C. for 18 h. The mixture was cooled and evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (EtOAc:pet. ether 30:70) to give a colourless gum; yield 340 mg, 27%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[Cl:18])[CH3:9].Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>CCOC(C)=O>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:20]=[O:22])=[CH:13][C:12]=1[Cl:18])[CH3:9]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1ccc(N)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccc(N=C=O)cc1Cl

Procedure:
1-Ethoxy-2-chloro-4-isocyanato-benzene is prepared by addition of triethylamine to a solution of 4-ethoxy-3-chlorophenylamine in EtOAc at 0-5° C. Triphosgene is added and the reaction mixture is slowly heated to reflux over 2 h. The solvent is removed in vacuo and the crude product is filtered through silica to afford the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1.O>CN(C)C=O>[N:41]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:33][CH3:34])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: c1c[nH]cn1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCCl)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCn3ccnc3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Propyl 3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (317 mg) and imidazole (78 mg) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (97 mg, yield 82%).
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.N(OC(C)(C)C)=O.O.C(Cl)[Cl:19]>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:19])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)(C)ON=O
Solvent: O
Product: Clc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (234 g, 932 mmol) in DCM (700 mL) and titanium (IV) chloride (174 g, 926 mmol), tert-butyl nitrite (572 g, 5.55 mol) was slowly added. The resulting mixture was stirred for 2 h at room temperature and treated with water (500 mL). The resulting mixture was extracted with DCM (3×500 mL). The combined organic layers were concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:50 v/v)) to obtain compound 90d as colorless oil (210 g, 83% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C4HBr2ClN2: 272.8 (M+H). found 272.6.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].C[OH:15]>O>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2](=[O:15])[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Br
Reactant: CO
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1=O
Yield: 88 %

Procedure:
3,3-Dibromo-6-chloro-1,3-dihydro-indol-2-one (21.34 g, 59.7 mmol) was suspended in a 4:1 (v:v) mixture of MeOH (172 mL): water (43 mL) and heated at reflux for 19 hr. The reaction was cooled in an ice bath and filtered. The red solid was washed once with cold CH3OH and dried to give the title compound as a red solid (10.49 g, 88% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 182/184 [M+H], 1 chlorine pattern observed.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCCCCC>C(Cl)Cl>[Br:8][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[P:19](=[O:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)cc(P(=O)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cc(OC)c(Br)c(P(=O)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NBS (6.7 g, 37.6 mmol) was added to a solution of (3,5-dimethoxyphenyl)diphenylphosphine oxide (12.3 g, 36.4 mmol) in CH2Cl2 (140 ml) at 0° C. The resulting suspension was stirred at 0° C. for 1 h. Na2CO3 (saturated, 40 ml) was added to quench the reactions. It was stirred at RT for 30 min, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (40 ml×2). The combined organic layer washed with brine and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow solid (14.3 g, 94% yield). It was sufficiently pure for the next step. The pure sample was obtained by crystallization from CH2Cl2/Hexane (1/15). 1H NMR (300 MHz, CD2Cl2) δ: 7.73-7.67 (m, 4H), 7.62-7.56 (m, 2H), 7.53-7.46 (m, 4H), 6.69 (d, J=3 Hz, 1H), 6.57 (dd, J1=3 Hz, J2=14.1 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H). 31P NMR (121.5 MHz, CD2Cl2) δ: 30.72.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A suspension of 0.46 g of 3-(4-ethoxycarbonylbutyl)-N-(3-pyridyl)-indole in 85 ml of aqueous 1N sodium hydroxide solution is heated at 95° for 8 hours. The resulting solution is neutralized with hydrochloric acid to pH of about 5.5. The resulting precipitate is filtered off, and triturated with acetonitrile to yield 3-(4-carboxybutyl)-N-(3-pyridyl)-indole (European Patent Application No. 126,401). 3-(4-Carboxybutyl)-N-(3-pyridyl)-indole has melting point of 122°-124°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.C[Si]([C:18]#[N:19])(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>[Zn+2].[I-].[I-].C1C=CC=CC=1>[C:18]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH:8]=1)#[N:19]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC=C2C#N
Reaction time: 1 h
Yield: 94 %

Procedure:
To a refluxing benzene solution (60 ml) of 6-methoxy-1-tetralone was added trimethylsilyl cyanide (TMSCN) (67.5 g) and a trace of AlCl3 or ZnI2. Refluxing was continued for 1 hr., then the solvent removed under vacuum. Isopropyl alcohol saturated with HCl(g) was added and the solution refluxed for 1 hr. Precipitation began to occur and the reaction was cooled, then evaporated to dryness. Water was added, followed by an ethyl acetate (EtOAc) extraction. The organic layer was washed in sequence with 1 N NaOH, IN HCl, and brine, separated, dried (MgSO4), filtered and evaporated. The dark oil was chromatographed on silica gel and eluted with CH2Cl2, affording 98.5 g, 94% yield of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([C:19]3[O:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C@@H:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([C:19]3[O:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C@@H:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:31])=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1ccc([C@H]2[C@H]3CCc4cc(C(=O)O)ccc4C3=NN2c2ccc(C#N)c(Cl)c2)o1
Reactant: CS(=O)(=O)CCN
Agent: Cl
Product: Cc1ccc([C@H]2[C@H]3CCc4cc(C(=O)NCCS(C)(=O)=O)ccc4C3=NN2c2ccc(C#N)c(Cl)c2)o1
Yield: 70 %

Procedure:
The title compound was prepared from (3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 40, and 2-(methylsulfonyl)ethanamine hydrochloride according to Method F (35 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6) water_suppression, δ ppm 1.19-1.21 (m, 1H), 1.91 (d, J=9.88 Hz, 1H), 2.07 (s, 3H), 2.96 (d, J=16.84 Hz, 2H), 3.01 (s, 3H), 3.63-3.66 (m, 2H), 3.86 (br. s., 1H), 5.92 (d, J=16.47 Hz, 1H), 5.95 (br. s., 1H), 6.27 (d, J=2.93 Hz, 1H), 7.06 (br. s., 1H), 7.33 (br. s., 1H), 7.65-7.74 (m, 3H), 8.08 (d, J=8.05 Hz, 1H), 8.77 (t, J=5.49 Hz, 1H); ES-MS m/z 537 (M+H).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(Cl)Cl.[Cl:29][C:30]1[CH:31]=[C:32]([C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:37]C(O)=O)[CH:33]=[CH:34][CH:35]=1>C(N(CC)CC)C>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:37][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH:33]=[CH:34][CH:35]=1
Reactant: O=CN1CCNCC1
Reactant: O=C(O)C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5.51 ml of diphenylphosphoryl azide and 1.93 ml of N-formylpiperazine were added, in that order, to 100 ml of a methylene chloride solution containing 5.00 g of 3,3-bis(3-chlorophenyl)acrylic acid (prepared as described in Preparation 110) and 4.75 ml of triethylamine. The reaction mixture was then stirred at room temperature for 18 hours, after which it was washed with a saturated aqueous solution of sodium bicarbonate and then with water. It was then dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixture of 100 ml of ethanol and 50 ml of tetrahydrofuran, and 50 ml of a 10% w/v aqueous solution of sodium hydroxide were added. The resulting mixture was stirred for 8 hours at room temperature, after which it was poured into water. The solution was extracted twice, each time with methylene chloride, and the combined extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 150 g of silica gel, using mixtures of methylene chloride and methanol ranging from 49:1 to 9:1 by volume as eluent, to give 5.23 g of the title compound as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)=[O:30])=[CH:19][CH:20]=1
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
A mixture of ethyl (4-aminophenyl)acetate (0.88 g), (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (1.0 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.81 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.02 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give ethyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetate as colorless crystals (1.49 g, yield 89%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OC)=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:3]=1.[OH-].[Na+].Cl.C([N:27](CC)CC)C.[Cl-].[NH4+].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CO.O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:27])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NCc1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Product: NC(=O)c1sc(Br)cc1NCc1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To a solution of methyl 5-bromo-3-[(3-nitrobenzyl)amino]thiophene-2-carboxylate (495 mg, 1.33 mmol) in MeOH (4 mL) was added a solution of sodium hydroxide (160 mg, 3.99 mmol) in water (2 mL). After stirring at 60° C. for 4 h, 6 M aqueous HCl (0.42 mL) was added to the mixture to adjust the pH to 10. After removal of the solvent at reduced pressure, the residue was diluted with DMF (6 mL). Then, triethylamine (3.7 mL, 27 mmol) and ammonium chloride (1.4 g, 27 mmol) were added. After stirring at room temperature for 5 min, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g, 8.0 mmol) and 1-hydroxybenzotriazole (1.1 g, 8.0 mmol) were added to the mixture, and stirring was continued for 17 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 50:50 hexane/EtOAc) to give the title compound (269 mg, 57%) as a yellow solid: