Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C([C:15]2[C:20]([C:21](N)=[O:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)C(C2C=CC(N)=CC=2)=CC=1.[N+:24]([C:27]1[CH:28]=[C:29]([NH2:42])[C:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)([O-:26])=[O:25].C(Cl)(=O)C1C=CC=CC=1>CN(C1C=CN=CC=1)C.CN1CCCC1=O>[C:21]([N:42]=[C:29]1[CH2:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=[C:30]1[C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)(=[O:22])[C:20]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC(=O)c1ccccc1-c1cc(N)ccc1-c1ccc(N)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O=C(Cl)c1ccccc1
Product: O=C(N=C1CC([N+](=O)[O-])=CC=C1c1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
A method for preparing 4,4'-diaminobiphenyl-2-benzamide which consists essentially of the steps of reacting 4,4'-dinitro-2-biphenylamine with benzoyl chloride in the presence of 4-dimethylamine pyridine in N-methyl-2-pyrrolidinone (NMP) to give 2-(N-benzoylimino)-4,4'-dinitrobiphenyl, and hydrogenating said 2-(N-benzoylimino)-4,4:dinitrobiphenyl.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23].[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23]
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Solvent: CN(C)C=O
Product: O=C1c2c(ccc(F)c2Cl)-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Yield: 26.2 %

Procedure:
6.24 g (18.2 mmol) of (S)-8-chloro-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were stirred with 3.43 g (20 mmol) of chloroacetic anhydride and 40 ml of N,N-dimethylformamide at room temperature for 60 hours and at 105° for 2.5 hours. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.88 g (26%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 214°-217°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[C:24](=O)[C:23]([CH3:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:21]3[CH2:20][CH2:19][CH2:24][C:23]([CH3:32])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Reactant: CC1(c2ccccc2)CCCC(Br)C1=O
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4(C)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (90 mg, 0.36 mmol) and crude 6-bromo-2-methyl-2-phenyl-cyclohexanone (0.29 g, ca. 1.1 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (65 mg, 43%). MS (ISP) 419.3 [(M+H)+]. mp 160-164° C.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])=O.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH2:1][C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:4]=1[CH3:30])[CH3:33]
Reactant: CNC
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(CN(C)C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 37 %

Procedure:
Using N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 20 and dimethylamine, the title compound was synthesized in the same manner as in Example 26. Yield: 37%. Amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 17, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino4methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 56% yield; NMR Spectrum: (DMSOd6): 2.21 (s, 3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.25 (d, 2H), 7.56 (d, 1H) 7.69 (d, 1H), 7.82 (d, 1H), 8.26 (d, 1H), 8.37 (d, 1H), 8.96 (d, 1H); Mass Spectrum M+H+ 452 and 454 .
Reaction SMILES: C([Li])CCC.[Si:6]([O:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([F:31])[CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:32][C:33]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:34]=1[CH:35]=[O:36].C(=O)(O)[O-].[Na+]>CCCCCC.O.C(OCC)C>[Si:6]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([CH:35]([C:34]2[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:33]=2[F:32])[OH:36])=[N:27][CH:26]=1)([C:19]([CH3:21])([CH3:22])[CH3:20])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](OCc1cncc(F)c1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)ccc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1cnc(C(O)c2cc(F)ccc2F)c(F)c1)(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
At −78° C., a hexane solution (30.0 ml, 46.8 mmol) of n-butyl lithium and N,N,N′N′-tetramethylethylenediamine (7.06 ml, 46.8 mmol) were added sequentially to diethyl ether (250 ml). After stirring at −20° C. for 30 minutes, the reaction mixture was cooled to −78° C., and a diethyl ether (50 ml) solution of 3-(t-butyldiphenylsilyloxymethyl)-5-fluoropyridine (15.5 g, 42.5 mmol) was added thereto. The resulting mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 2,5-difluorobenzaldehyde (6.04 g, 42.5 mmol). The resulting mixture was stirred for 2 hours. Water and then, a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture. The resulting mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then, filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure to give the title compound (17.0 g, 33.5 mmol, 79%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:17])[CH:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[H][H]>O1CCOCC1.P([O-])([O-])([O-])=O.[Pt]=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:17])[CH:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([OH:20])=[O:19]
Reactant: [H][H]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ncccn3)CC12
Agent: O=[Pt]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)O)=C(Sc3ncccn3)CC12
Reaction time: 4 h
Yield: 38.8 %

Procedure:
63.4 mg of p-nitrobenzyl 3-(2-pyrimidinylthio)6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate obtained in Example 26 was dissolved in a mixture of 3.2 ml of dioxane and 1.2 ml of a 0.1 M phosphate buffer (pH 6.86). Then, 70 mg of platinum oxide was added, and the reaction was performed at room temperature for 4 hours in a Paar reducing apparatus (hydrogen pressure 4 kg/cm2). The catalyst was removed by filtration. The filtrate and the wash liquid were combined, and after adjusting the pH of the mixture to 7.2, concentrated under reduced pressure to about 2/3 of the initial amount. Sodium chloride (2 g) was added to the concentrated solution, and water was added to adjust the total amount to 70 ml. The resulting solution was applied to a column of Diaion HP-20AG (1.1×20 cm), and eluted with 300 ml in total of an aqueous solution of acetone with the concentration of acetone varying gradually from 0 to 50% (v/v) by a concentration gradient method. The fractions were screened by high-speed liquid chromatography, and fractions having an ultraviolet absorption at λmax 300 nm were collected and lyophilized to afford 16.8 mg of the desired product (yield 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][Cl:18])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2cc(Cl)ccc2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(Cl)ccc2n1CCCCl
Reaction time: 3 h

Procedure:
To a stirred mixture of 6.5 parts of 5-chloro-2-methyl-1H-benzimidazole-1-propanol and 120 parts of trichloromethane are added dropwise 12 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. Water is added to the residue and the mixture is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 5-chloro-1-(3-chloropropyl)-2-methyl-1H-benzimidazole.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[CH3:2][CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:9][CH:10]=1)[CH3:3]
Reactant: CC(C)Oc1ccc(CN)cc1
Reactant: O=C(O)c1ccncc1F
Product: CC(C)Oc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 1-(4-isopropoxyphenyl)-methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.80 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 7.21 (d, 2H, J=8.0 Hz), 4.49 (s, 2H), 2.82-2.89 (m, 1H), 1.19 (d, 6H, J=4.5 Hz). [M+H] calc'd for C16H18N2O3, 287. found 287.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C1O[CH2:36][CH2:35]OCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[N:12]1[CH:36]=[CH:35][CH:9]=[CH:10][C:11]=1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: c1ccc(-n2c3ccccc3c3ccccc32)nc1
Yield: 93 %

Procedure:
In 40 ml of o-dichlorobenzene as solvent, 3.94 g of carbazole, 7.26 g of 2-iondopyridine, 13.10 g of potassium carbonate, 3 g of copper powder, and 0.62 g of 18-crown-6-ether were mixed and refluxed under a nitrogen atmosphere for 10 hours. Thereafter, copper and inorganic salts were removed, and the mixture was purified by column chromatography. Consequently, ligand Hpcz (9-(2-pyridyl)carbazole) was obtained (opal powder, the yield: 93%). The following is the synthesis scheme (b-1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:33][CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: Nc1nc(NCCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 3-phenylpropylamine in DME. ES-MS m/e (%): 340 (M+H+, 100).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH3:12])=[C:6]([Cl:24])[CH:5]=1.CC(C[AlH]CC(C)C)C.CCCCCC.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.CC(C)=O>[Cl:24][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])[CH3:12]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(C(=O)OC)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CO)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
The compound (526.4 mg) obtained in Example 77-3 was dissolved in THF (10 ml) and the whole was cooled to 0° C. Under a nitrogen atmosphere, a 0.94 mol/l DIBAL n-hexane solution (3 ml) was dropped to the reaction solution and the whole was stirred at room temperature for 1 hour. After having been cooled to 0° C., the reaction solution was added with ethyl acetate (10 ml) and acetone (10 ml) and the whole was stirred at room temperature for 1 hour. The reaction solution was added with a saturated aqueous sodium potassium tartrate solution (30 ml) and the whole was vigorously stirred at room temperature for 2 hours and then subjected to extraction with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the resultant was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (n-hexane/ethyl acetate), thereby obtaining the subject compound (290.8 mg) as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[O:16])[CH2:8][CH2:7]1)=[O:5]>CO.[Pd]>[NH2:34][C:31]1[CH:32]=[CH:33][C:2]([Br:1])=[C:3]([CH:30]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[O:16])[CH2:8][CH2:7]1)=[O:5]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])ccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(-c4ccccc4)cc3)CC2)c1
Reaction time: 8 h
Yield: 3.7 %

Procedure:
10% Pd/C (60 mg) was added to a stirred solution of biphenyl-4-carboxylic acid {2-[4-(2-bromo-5-nitro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide (120 mg, 2.4 mmol) in methanol (10 mL) and the mixture was stirred under an atmosphere of hydrogen with pressure overnight. The mixture was then filtered over celite and the filtrate concentrated to afford 46 mg (40.7%) of biphenyl-4-carboxylic acid {2-[4-(5-amino-2-bromo-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS: 95.6%, 1H NMR (CDCl3): δ 7.9 (m, 2H), 7.6 (m, 4H), 7.4 (m, 4H), 6.8 (m, 2H), 4.2 (m, 2H), 4.0 (m, 11H), 3.6 (m, 3H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:14]=1[NH2:15]>CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]([F:24])([F:23])[F:25])=[CH:16][C:14]=1[NH:15][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: COc1cc(OC)c(C(F)(F)F)cc1N
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(F)(F)F)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 89.9 %

Procedure:
p-Tolyl isocyanate (0.16 mL, 1.24 mmol) was added to a solution of 2,4-dimethoxy-5-(trifluoromethyl)aniline (0.25 g, 1.13 mmol) in EtOAc (3 mL) and the resulting mixture was stirred at room temp. for 18 h. The resulting precipitate was washed with Et2O to give the title compound as a white solid (0.36 g): 1H-NMR (CDCl3) δ 2.21 (s, 3H), 3.97 (s, 3H), 3.86 (s, 3H), 6.88 (s, 1H), 7.05 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 8.13 (s, 1H), 8.33 (s, 1H), 9.09 (s, 1H); FAB-MS m/z 355 ((M+1)+). B1e. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: O[CH2:2][C@@H:3]([N:10]1[C@H:23]2[C@H:13]([CH2:14][C:15]3([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=42)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:12][C:11]1=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[OH-].[Li+]>CS(C)=O>[C:4]1([C:3]([N:10]2[C@H:23]3[C@H:13]([CH2:14][C:15]4([C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=53)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH2:12][C:11]2=[O:28])=[CH2:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C[C@H]2CC3(CCNCC3)c3ccccc3[C@H]2N1[C@H](CO)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C(c1ccccc1)N1C(=O)C[C@H]2CC3(CCNCC3)c3ccccc3[C@H]21
Yield: 68.6 %

Procedure:
A solution of (3aR,9bS)-1-((S)-2-hydroxy-1-phenylethyl)-1,3a,4,9b-tetrahydrospiro[benzo[g]indole-5,4′-piperidin]-2(3H)-one (Step 4, 2.3 g, 6.1 mmol) and lithium hydroxide monohydrate (2.3 g, 55 mmol) in DMSO (15 ml) was heated at 170° C. for 4 h. The reaction mixture was evaporated. The residue was poured into water, extracted with EtOAc (3×). The extracts were concentrated to give the title compound as brown oil (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].C(O)C.C(O)(=O)C>[Fe].CCOC(C)=O>[NH2:21][C:17]1[CH:16]=[C:15]([C:10]2[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=[C:2]([F:1])[CH:3]=3)[CH:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Temperature: 92 °C

Procedure:
To 3-fluoro-N-(6-methyl-3′-nitrobiphenyl-3-yl)-5-(trifluoromethyl)benzamide (4.09 g, 9.78 mmol) was added ethanol (93.2 mL) followed by iron (3.0 g, 54 mmol) and acetic acid (9.32 mL, 164 mmol). The solution was heated at 92° C. for 2 h using the rotovap motor/heating bath. To the reaction mixture was added EtOAc and the mixture was then filtered and was concentrated in vacuo. The residue was used in the next reaction without purification. MS (EI) m/z=389 (M+H).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][N:8]([CH3:10])[C:6]([C:5]1[CH:4]=[N:3][C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:12][CH:11]=1)=[O:7]
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(N2CCNCC2)nc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
A solution of 6-chloro-N,N-dimethylnicotinamide (250 mg, 1.354 mmol), piperazine (584 mg, 6.77 mmol), sodium tert-butoxide (260 mg, 2.71 mmol) and BrettPhos (36 mg, 0.068 mmol) in anhydrous 1,4-dioxane (7 ml) was purged with argon. Next, Pd2(DBA)3 (62 mg, 0.068 mmol) was added and the mixture was heated in a closed vial to 70° C. for 2 hours, then heating was turned off and the mixture was stirred at room temperature for 3 days. The mixture was filtered through kieselguhr, the filter was washed with ethyl acetate, the combined filtrates were concentrated under reduced pressure and the residue was purified by repeated column chromatography (silica, gradient from 1 to 10% methanol containing 7N ammonia in DCM) to yield 158 mg of a solid (0.674 mmol, 50% yield) MS (multi-mode) m/z=235.2 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:10]1[CH:17]=[C:16]([Cl:18])[C:13]([C:14]#[N:15])=[C:12](Br)[C:11]=1[O:20][CH3:21])(=[O:9])[CH3:8].[CH3:22][N:23]([CH3:35])[C:24]([C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].N#N.ClCCl>O.C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:7]([C:10]1[C:11]([O:20][CH3:21])=[C:12]([C:29]2[CH:28]=[CH:27][C:26]([C:24]([N:23]([CH3:35])[CH3:22])=[O:25])=[N:31][CH:30]=2)[C:13]([C:14]#[N:15])=[C:16]([Cl:18])[CH:17]=1)(=[O:9])[CH3:8]
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
Reactant: COc1c(C(C)=O)cc(Cl)c(C#N)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
Sodium carbonate (3.0 g, 20 mmol) in water (20 mL) was added to a mixture 4-acetyl-2-bromo-6-chloro-3-methoxybenzonitrile (2.5 g, 8.7 mmol) and {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (1.9 g, 10.0 mmol, Example 301 Step 2) in acetonitrile (100 mL). The reaction was degassed with N2 and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (400 mg, 0.4 mmol) was added and the reaction mixture was degassed again with N2. The reaction was heated at 100° C. for 4 hrs and was complete by LC/MS. The reaction was allowed to cool to room temperature and was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated to give the crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to give 5-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)-N,N-dimethylpyridine-2-carboxamide as yellow oil (2.2 g, 71%). LCMS calculated for C18H17ClN3O3(M+H)+: m/z=358.1; found: 358.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(F)ccn1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn2ccc(F)cc2n1
Yield: 17.7 %

Procedure:
A mixture of 4-fluoropyridin-2-amine (1.0 g, 8.92 mmol) and ethyl 4-chloro-3-oxobutanoate (1.46 mL, 10.7 mmol) in THF (20 mL) was stirred at about reflux overnight. The residue was concentrated and was chromatographed on the C18 ISCO Combiflash system using the following gradient: A: Water (0.1% NH4HCO3); B: Methanol; 10% B to 60% B over 20 min to give 350 mg product as brown oil (350 mg, yield: 17.6%).