Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.Cl.[NH2:24][OH:25]>N1C=CC=CC=1.C(Cl)Cl>[NH2:9][CH2:10][C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:8](=[N:24][OH:25])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:22]
Reactant: NO
Reactant: O=C1CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: NCC(=O)Nc1ccc([N+](=O)[O-])cc1C(=NO)c1ccccc1F

Procedure:
A solution of 50 g (0.167 mol) of 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one and 17.4 g (0.25 mol) of hydroxylamine hydrochloride in 200 ml of pyridine is heated to reflux overnight under argon. The mixture is concentrated in a rotary evaporator and the residue is taken up in methylene chloride. The organic phase is washed with water, dried and evaporated. The aqueous phase is extracted with chloroform overnight in a perforator. After drying and removing the solvent, the residue is combined with the crude product obtained above, suspended in 200 ml of methylene chloride and filtered off. There is obtained 2-amino-2'-[o-fluoro-α-(hydroxylimino)benzyl]-4'-nitro-acetanilide of melting point 198°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]=[C:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].Cl>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][C@@H:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2]
Reactant: CCCCC1=CC(=O)CCC1C(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCC[C@H]1CC(=O)CC[C@H]1C(=O)OCC
Yield: 92.8 %

Procedure:
2-Butyl-4-oxocyclohex-2-ene carboxylic acid ethyl ester [Tetrahedron 37 1033 (1981)] (4.48 g; 20 mmole) dissolved in absolute ethanol (15 ml) containing 2N hydrochloric acid (1 ml) was reduced at room temperature over 5% palladium on carbon (150 mg) at 50 p.s.i. (3.45 bar). After one hour the mixture was filtered through avicel and the solvent was evaporated under reduced pressure. The residue was taken up in diethyl ether and washed successively with water, saturated aqueous sodium bicarbonate and water. Drying over MgSO4 and evaporation gave an oil (4.2 g) which was chromatographed on silica. Elution with diethyl ether:hexane (2:8) gave the pure title ester (3.6 g, 80%) as a clear liquid. Found: C,68.86; H,9.84. C13H22O3 requires C,68.99; H,9.80%.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH3:17])[CH2:15][CH3:16])[CH:3]([CH3:5])[CH3:4].[NH2:25][CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH:27]([CH3:29])[CH3:28].[H][H].[OH-].[Na+]>Cl>[NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:17])[CH2:15][CH3:16])[CH:3]([CH3:5])[CH3:4].[NH2:25][CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([CH:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)([CH3:41])[CH3:40])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C(N)CCCCCCCCCC(C)(C)c1ccc(N)cc1
Reactant: [H][H]
Reactant: CCC(C)(CCCCCCCCC(N)C(C)C)c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C(N)CCCCCCCCCC(C)(C)C1CCC(N)CC1
Product: CCC(C)(CCCCCCCCC(N)C(C)C)C1CCC(N)CC1
Temperature: 25 °C

Procedure:
5.0 parts of a mixture of 3-amino-12-(4-aminophenyl)-2,12-dimethyl-tetradecane and 3-amino-13-(4-aminophenyl)-2,13-dimethyltetradecane in 60 ml 1N aqueous hydrochloric acid, were shaken at room temperature and atmospheric pressure in the presence of 1.0 parts of Nishimura catalyst. After the hydrogen uptaken had ceased at 118% of the theory, the solution was made alkaline with caustic soda. The work up was completed after an ether extraction, filtration, and short path distillation, giving 3.4 parts of 3-amino-12-(4-aminocyclohexyl)-2,12-dimethyltetradecane and 3-amino-13-(4-aminocyclohexyl)-2,13-dimethyltetradecane, b0.3 190°.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:26][CH2:27][OH:28])[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:35][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1)[CH2:25][CH2:26][CH2:27][OH:28])=[O:34]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCO)C2CCCC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCO)C1CCCC1
Reaction time: 1 h

Procedure:
A solution of (2-{3-chloro-5-[cyclopentyl-(3-hydroxy-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tertbutyl ester (0.07 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.011 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][C:24]([OH:26])=[O:25])=[C:9]2[CH3:27])=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:24](=[O:26])[CH2:23][C:10]1[CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:27]
Reactant: Cc1c(CC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: OCCCCO
Product: Cc1c(CC(=O)OCCCCO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 66 %

Procedure:
Prepared from 6g and 1,4-butanediol similarly to example 1-II, yield 66%, m.p. 149-151° C., 1H NMR 200 MHz (CDCl3) δ (ppm): 1.57-1.65 (m, 2H), 1.68-1.75 (m, 2H), 2.02 (s, 3H), 2.97 (s, 3H), 3.46 (s, 2H), 3.62 (t, 2H, J=6.0), 4.15 (t, 2H, J=6.3), 6.45 (s, 1H), 7.11-7.15 (m, 6H), 7.60 (d, 2H, J=8.6). MS-ESI: m/z 482 (M+Na+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1[CH:25]=[CH:24][C:23]2[CH2:26][CH2:27][CH2:28][N:21]3[C:22]=2[C:14]=1[C:15]1[C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]=13.[CH3:30][C:31]1[N:35](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=[N:33][C:32]=1[CH:55]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(O)(=O)C>[CH3:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1/[CH:55]=[C:17]1\[CH2:18][CH2:19][C:20]2[N:21]3[CH2:28][CH2:27][CH2:26][C:23]4[CH:24]=[CH:25][CH:13]=[C:14]([C:15]=2[C:16]\1=[O:29])[C:22]3=4
Reactant: O=C1CCCc2c1c1cccc3c1n2CCC3
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1/C=C1\CCc2c(c3cccc4c3n2CCC4)C1=O
Reaction time: 0.5 h
Yield: 220.1 %

Procedure:
n-Butyllithium (1.73M in hexane; 4.14 ml) was added dropwise to a cold (-70°) stirred solution of diisopropylamine (1 ml) in dry THF (10 ml) under nitrogen. The resulting solution was stirred at 0° for 30 min, cooled to -70° and added dropwise to a cold (-70°) stirred suspension of 5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (645 mg) in dry THF (20 ml) under nitrogen. The solution was allowed to reach 0° over 1 h, cooled to -70° and a solution of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (1.01 g) in dry THF (10 ml) was added dropwise. The stirred mixture was allowed to reach room temperature over 2 h, and then stirred for a further 3 h. The solution was cooled to -70° and treated with acetic acid (8 ml) and p-toluenesulphonic acid (5.44 g) and heated at reflux for 16 h. The solvent was removed in vacuo, the residue was treated with 8% sodium bicarbonate solution (150 ml) and extracted with dichloromethane (4×50 ml). The combined, dried organic extracts were evaporated to give a gum (ca. 2 g) which was purified by FCC eluting with System A to give the title compound (145 mg) as a solid, m.p. 260°-264°.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(CC)CC)C.[CH:65]1([C:68](Cl)=[O:69])[CH2:67][CH2:66]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:68]([CH:65]3[CH2:67][CH2:66]3)=[O:69])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 32 mg of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]([N:13]([CH:36]3[CH2:38][CH2:37]3)[C:14]([C@H:16]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)=[O:15])[CH3:12])=[CH:8][CH:9]=2)[N:4]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:3]=1.N1C(C)=CC=CC=1C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)([O-])O.[Na+]>ClCCl.CO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]([N:13]([CH:36]3[CH2:38][CH2:37]3)[C:14]([C@H:16]3[CH2:21][NH:20][CH2:19][CH2:18][NH:17]3)=[O:15])[CH3:12])=[CH:8][CH:9]=2)[N:4]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:3]=1
Reactant: COCCCn1cc(Cl)c2ccc([C@@H](C)N(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OC(C)(C)C)C3CC3)cc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: COCCCn1cc(Cl)c2ccc([C@@H](C)N(C(=O)[C@H]3CNCCN3)C3CC3)cc21
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of di-tert-butyl (2R)-2-{[{(1R)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}(cyclopropyl)amino]carbonyl}piperazine-1,4-dicarboxylate (44.0 mg) and 2,6-lutidine (0.050 mL) in dichloromethane (1.0 mL) was added trimethylsilyltriflate (0.051 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto were added aqueous saturated sodium hydrogen carbonate solution and methanol (2.0 mL) under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate→ethyl acetate/methanol=5/1) to give (2R)-N-{(1R)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}-N-cyclopropylpiperazine-2-carboxamide [Ex(2-1)] (25.4 mg) and as a colorless oil.
Reaction SMILES: [C:1]1(=O)[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[C:13](Cl)(=O)[CH2:14][CH2:15][CH2:16]C.[OH-].[NH4+:21]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:13]([C:1]1[NH:21][C:5](=[O:7])[C:4]2[C:3]([CH:2]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH2:15][CH3:16]
Reactant: [NH4+]
Reactant: CCCCC(=O)Cl
Reactant: O=C1Cc2ccccc2C(=O)O1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCc1cc2ccccc2c(=O)[nH]1
Reaction time: 1 h

Procedure:
To a solution of 4 g (24 mmol) of homophthalic anhydride in 12 ml of dry pyridine in a 250 L 3 neck flask fitted with a reflux condenser and addition funnel at 0° C. was added 5.4 g (45 mmol) of valeryl chloride in 16 ml of dry chloroform over 45 minutes. The reaction mixture was stirred for a further 1 hour and then was treated with 100 ml of conc. ammonium hydroxide dropwise. The mixture was refluxed for 2 hours and then allowed to stand overnight at room temperature. The two phases were separated and the organic phase was washed with water (1×20 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from hot MeOH/water to give a pale purple solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 116. (400 MHz, CDCl3): 1.28 (6H, d (J=6.85), CH3), 2.54-2.56 (4H, m, CH2), 3.12 (1H, m, CH), 3.34-3.37 (4H, m, CH2), 3.79 (2H, s, CH2), 3.80-3.82 (4H, m, CH2), 3.94-3.97 (4H, m, CH2), 5.13 (2H, b, NH2), 7.21 (1H, s, ar), 9.21 (2H, s, ar). (M+H)+ 519.27
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][NH:6][C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:22]=[N:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CO>>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][NH:6][C:7]([C:8]1[CH2:22][N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)c(F)c2)O1
Reactant: C=NCCN1CCOCC1
Solvent: CO
Product: O=C(NCc1ccc(F)c(F)c1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of N-(3,4-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (58 mg, 0.195 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.1 mL, 0.22 mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a hydroscopic yellow powder (30 mg, 31% yield). 1H NMR (500 MHz, DMSO) δ: 11.95 (1H, br s), 9.56 (1H, br s), 8.03 (1H, t, J=6.1 Hz), 7.41–7.30 (2H, m), 7.15–7.12 (1H, m), 4.41 (2H, d, J=6.1 Hz), 4.04 (2H, s), 4.02–3.93 (2H, m), 3.82–3.77 (2H, m), 3.65–3.51 (4H, m), 3.45–3.41 (2H, m), 3.15–3.06 (2H, m). HRMS calcd for C18H20F2N3O4 (M+H): 380.1422. found: 380.1424.
Reaction SMILES: B(O)(O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20](Cl)[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[CH:17]=[N:16][C:15]=2[CH:26]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[C:17]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)=[N:16][C:15]=2[CH:26]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Product: Clc1ccc2c(c1)N=C(c1ccncc1)c1ccccc1N2
Yield: 30.4 %

Procedure:
4 pyridyl-4-boronic acid (14 mg, 0.12 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (26 mg, 0.1 mmol) were reacted according GP11 to give 9.3 mg of the title compound (160FE69A). MS (ESI) 306 (MH+). Purity for MH+ (UV/MS) 98/95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([CH:14]([F:16])[F:15])=[CH:12][N:11]([CH:17]([CH3:21])[C:18]([OH:20])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([CH:14]([F:15])[F:16])=[CH:12][N:11]([CH:17]([CH3:21])[C:18]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:20])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (purity 88%, 0.16 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 65 mg (76% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[OH:12]O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N+:9]([O-:12])[CH:8]=[CH:7]2
Reactant: OO
Reactant: Brc1cccc2ccncc12
Solvent: CC(=O)O
Product: [O-][n+]1ccc2cccc(Br)c2c1
Temperature: 75 °C

Procedure:
A solution of 8-bromo-isoquinoline (prepared by the method of F. T. Tyson, J.A.C.S., 1939, 61, 183) (1.25 g, 6 mmol) in acetic acid (5 ml) was treated with 27% aqueous hydrogen peroxide solution (1.8 ml) and heated at 75° C. overnight. The mixture was evaporated and the residue partitioned between aqueous sodium carbonate solution and dichloromethane, re-extracting with dichloromethane twice more. The combined organic extracts were dried and evaporated. The residue was triturated with ether/petrol and isolated by filtration (1.14 g, 85%).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].Br[CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[C:13](=[O:17])[CH2:12]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCN1CCN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 1 h

Procedure:
Amine preparation: to 4-CBZ-piperazin-2-one (1.95 g) in DMF (5 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 660 mg) in several aliquots. After stirring for 1 h, 2-bromoethylacetate (1.38 ml) was added. The reaction mixture was stirred at room temperature overnight; it was then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The resulting residue was purified using flash chromatography to yield 4-(2-acetoxy-ethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (925 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.ClCCl.C(O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (240 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (20 mL), water (2×20 mL), aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 45-50% ethyl acetate/petroleum ether, to give an oil. The oil was co-evaporated with ethanol, and the residue was held under high vacuum to give (4S,7R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (128 mg, 73%) as a white solid. APCI(+)-MS (M+H) 531.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:5][S:4][N:3]=1.C(N(CC)CC)C.[CH:22]([CH:24]=[CH2:25])=[O:23]>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH2:25][CH2:24][CH:22]=[O:23])[CH:12]=2)=[CH:5][S:4][N:3]=1
Reactant: Cc1nscc1-c1c[nH]c(=O)[nH]c1=O
Reactant: C=CC=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nscc1-c1cn(CCC=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-(3-methyl-4-isothiazolyl)-2,4(1H,3H)-pyrimidinedione (Pre 47, 0.126 mmol) was dissolved in N,N-Dimethylformamide (DMF) (1 ml). TRIETHYLAMINE (0.021 ml, 0.151 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Acrolein (8.42 μl, 0.126 mmol) was added and the mixture was stirred at room temperature monitoring the reaction progression by LCMS. After 7 hrs Acrolein (3 μl) was added and the mixture was stirred at rt overnight.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19](OCCC(C)C)=[O:20].Cl>CCOCC>[OH:20][N:19]=[C:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]1=[O:18]
Reactant: O=C1CCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCOCC
Product: O=C1C(=NO)Cc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
To an ice-cooled solution of 1.91 g (0.008 m) of 4-(phenylmethoxy)-1-indanone in 75 ml of anhydrous ether is added dropwise with stirring 1.2 ml (0.088 m) of isoamyl nitrite while hydrogen chloride is simultaneously bubbled in. After stirring at room temperature for twenty minutes, the reaction mixture is partially concentrated and the solid which separates is filtered to yield 1.83 g (86%) of material sufficiently pure to be used in the next step.