Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13]CC=C)=[CH:12][C:7]=2[O:6][CH:5]=1.Cl[C:20]1[CH:25]=CC=C[C:21]=1Cl>>[CH3:18][C:2]([CH3:1])([CH3:17])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[C:12]([CH2:25][CH:20]=[CH2:21])[C:7]=2[O:6][CH:5]=1
Reactant: C=CCOc1ccc2c(CC(C)(C)C)coc2c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2c(CC(C)(C)C)coc12
Temperature: 50 °C

Procedure:
A solution prepared from 1,2-dichlorobenzene (65 mL) and the product of Step F (3.226 grams) was refluxed for 8 hours. The reaction, cooled to approx. 50° C., was subjected to high vacuum, removing the solvent by distillation. The remaining solid was digested in refluxing cyclohexane, cooled to ambient and filtered. The mother liquor was evaporated and chromatographed over silica gel (2.5:1 hex/ethyl acetate), producing more solid which was added to the previous, providing all the available title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH2:25])[CH2:22][CH2:21]2>>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:22][CH2:21]2
Reactant: Cc1cccc2c1C(N)CC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: Cc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-7-methyl-indan-1-ylamine (CAS no: 168902-78-1); MS: m/e=290.4 (M+H+).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:22][NH2:23])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:23][N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCNc1nc[nH]c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(-c2ccccc2)n[nH]1
Temperature: 170 °C
Reaction time: 14 h
Yield: 15.1 %

Procedure:
The mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (200 mg, 1.12 mmol), benzohydrazide (229 mg, 1.68 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 1-butanol (6 ml) in a sealed tube was stirred at 170° C. for 14 hours. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS (method A) to yield the desired product (50 mg, 17% yield). LCMS calculated for C16H21N6 (M+H): 297.2; found 297.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][NH:27][CH2:25][CH3:26])[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CCNC/C=C/[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with ethylamine in N,N-dimethylacetamide at room temperature to yield trans-{2-[4-(3-ethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 379 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH:24][CH2:25][CH2:26][P:27](=[O:34])([O:31]CC)[O:28]CC)(=[O:23])=[O:22])=[CH:16][CH:15]=1.Br[Si](C)(C)C.[OH-].[Na+]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH:24][CH2:25][CH2:26][P:27](=[O:28])([OH:31])[OH:34])(=[O:23])=[O:22])=[CH:16][CH:15]=1
Reactant: CCOP(=O)(CCNS(=O)(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)OCC
Agent: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NS(=O)(=O)NCCP(=O)(O)O)cc2)C1
Temperature: 39 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl 2-(N-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfamoylamino)ethylphosphonate (100 mg, 0.18 mmol, 1.00 equiv) in dichloromethane (5 mL) and bromotrimethylsilane (275 mg, 1.80 mmol, 9.89 equiv). The resulting solution was stirred overnight at 39° C. The resulting mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (5 mL). This was followed by the addition of a solution of sodium hydroxide (14.5 mg, 0.36 mmol, 2.00 equiv) in methanol (0.2 mL) dropwise with stirring. The solids were collected by filtration and dried under reduced pressure. This gave 40 mg (40%) of a sodium salt of the title compound as a white solid. 1H-NMR (300 MHz, d6-DMSO, ppm): δ 9.78 (1H, brs), 7.54 (1H, s), 7.47 (1H, brs), 7.09-7.17 (4H, m), 6.82 (1H, s), 4.31 (1H, brs), 3.88 (2H, brs), 3.13 (1H, brs), 3.04 (2H, brs), 2.90 (1H, brs), 2.58 (3H, s), 1.65-1.77 (2H, m). MS (m/z): 494 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3]([CH:8]([F:10])[F:9])=[N:4][N:5]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[C:6]=1[CH3:7]
Reactant: C1=COCCC1
Reactant: Cc1[nH]nc(C(F)F)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Br)c(C(F)F)nn1C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-(difluoromethyl)-5-methyl-1H-pyrazole (1.40 g, 6.63 mmol) in chloroform (30.0 mL, 0.375 mol) was added p-toluenesulfonic acid monohydrate (0.13 g, 0.66 mol) at 0° C. Dihydropyran (0.91 mL, 0.010 mol) was added and stirred at 25° C. for 2 h. The reaction was extracted with ethyl acetate and the organic extracts were washed with NaHCO3, water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The compound was chromatographed on silica gel using 10% EtOAc/hexanes to give the desired product. 1H NMR (CDCl3): δ 6.51-6.78 (t, 1H), 5.31 (dd, 1H), 4.01 (m, 1H), 3.65 (m, 1H), 2.40 (m, 1H), 2.35 (s, 3H), 2.21 (m, 1H), 1.95 (m, 1H), 1.50-1.70 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Yield: 96 %

Procedure:
Compound 17.2 was prepared as described for example 6.2, by reacting compound 1.1 with 2-bromo-5-trifluoromethylbenzyl bromide. 4-[3-(2-Bromo-5-trifluoromethylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 96%. (Molecular weight 533.01 (C21H14BrF6N3O2); retention time Rt=2.21 min. [B]; MS (ESI): 534.14 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[N:6]=[CH:5]2.[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:20][C@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ncc3cc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)ccc32)cc1
Temperature: 80 °C
Yield: 83.3 %

Procedure:
To a solution of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (870 mg, 2.75 mmol) in toluene (10 mL) was added in succession (S)-tert-butyl 3-aminopiperidine-1-carboxylate (660 mg, 3.3 mmol), sodium tert-butoxide (475 mg, 5 mmol), and rac-(±)-BINAP (180 mg, 0.29 mmol). The flask was evacuated and refilled with nitrogen three times, after which Pd2 dba3 (83 mg, 1.5 mol %) was added. The flask was again purged with nitrogen three times, and was then heated to 80° C. overnight. The solution was cooled to room temperature and then filtered through a pad of celite, washing with additional toluene. The toluene solution was then loaded directly onto a silica gel column that had been packed with heptane. The column was flushed with 2 column volumes of heptane, and then eluted with 40/60—EtOAc/heptane to afford the title compound (1.00 g 82%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[NH2:38][C@H:39]1[CH2:45][CH2:44][S:43][C@H:42]2[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([O:52][CH3:53])=[O:51])[N:41]2[C:40]1=[O:54]>>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8]([NH:38][C@H:39]2[CH2:45][CH2:44][S:43][C@H:42]3[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([O:52][CH3:53])=[O:51])[N:41]3[C:40]2=[O:54])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Reactant: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O
Product: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5S)-2-(4-fluorobenzyl)-5-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-ylcarbamoyl)octanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 76 (10 mg, 0.020 mmol) and (4S,7S,10aS)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (5.5 mg, 0.021 mmol) to give a white solid (10 mg, 70% yield). Anal. Calcd. for C40H53FN4O7S m/z 752.7. found: 753.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.43 (1H, m), 7.31 (1H, t, J=8.0 Hz), 7.28-7.18 (1H, m), 7.14-7.04 (3H, m), 7.01-6.95 (2H, m), 6.88 (2H, t, J=8.8 Hz), 5.35-5.27 (1H, m), 5.15-5.09 (1H, m), 5.04-4.95 (1H, m), 4.94-4.85 (1H, m), 4.05-3.90 (1H, m), 3.82 (3H, s), 3.69 (3H, s), 3.53-3.36 (1H, m), 3.22-3.06 (1H, m), 2.86-2.65 (3H, m), 2.45-2.32 (2H, m), 2.25-2.14 (1H, m), 2.12-1.87 (5H, m), 1.87-1.30 (14H, m), 1.30-1.20 (2H, m), 0.87 (3H, t, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32](C3C=CC(Br)=CN=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][N:3]=3)=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Reactant: FC(F)(F)c1ccc(Nc2cnc(Br)cn2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 130 °C

Procedure:
A solution of (5-Bromopyrazin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (0.072 g) and {4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.087 g) in 2 Ml DME was charged with 2 M sodium carbonate (1 Ml) and Pd(PPh3)4 (0.027 g, 0.1 equiv). The biphasic mixture was sparged with nitrogen for 3 min, then stirred at 130° C. under microwave heating for 30 min. The reaction was partitioned between EtOAc and water, and the organic extracts were dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography (33% EtOAc in hexanes) afforded the title compound: (M+H)+471.2.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]([OH:18])=[O:17])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[N+](=[CH2:21])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]([O:18][CH3:21])=[O:17])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c2ccccc2nc2ccc(Cl)cc12
Solvent: ClCCl
Product: COC(=O)c1c2ccccc2nc2ccc(Cl)cc12
Reaction time: 1.5 h

Procedure:
4.9 gm of 2-chloro-9-carboxy-acridine were suspended in 5 cc of methylene chloride at room temperature and then 60 cc of a methylene chloride solution of diazomethane titrating 17.9 gm per liter was added thereto. The reaction mixture was then stirred for 90 minutes while bubbling nitrogen therethrough to eliminate excess diazomethane. The methylene chloride solution was washed with an aqueous solution of 10% sodium carbonate, then with water, dried over magnesium sulfate, treated with charcoal, filtered and then evaporated to dryness. The residue was recrystallized from boiling methanol to obtain 3.2 gm of 2-chloro-9 -methoxycarbonylacridine melting at 130°C. The product occurred as a pale yellow solid soluble in chloroform, slightly soluble in ether and alcohol and insoluble in water.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.O1CCCC1.[CH3:22][C:23]([CH3:25])=[O:24].[Cl-].[NH4+]>O1CCCC1.O>[CH3:22][C:23]([OH:24])([CH3:25])[CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)Cc1ccc2ccccc2c1
Temperature: -69 °C
Reaction time: 12 h

Procedure:
2-Methylnaphthalene (7.11 g) was dissolved in tetrahydrofuran (100 ml) and the solution was cooled to −69° C. To the solution was added dropwise a 1.6M n-butyllithium-tetrahydrofuran solution (34 ml), and then a solution of acetone (4.41 ml) in tetrahydrofuran (4.41 ml). The reaction mixture was stirred for 12 hr while allowing to warm to room temperature. To the reaction mixture was added dropwise saturated ammonium chloride solution (6 ml), and the resulting mixture was poured into water (200 ml) and extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15) to give the title compound (3.80 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]([CH3:9])=[CH2:8])[S:5][CH:6]=1.[F:10][C:11]([F:50])([F:49])[C:12]1[CH:13]=[C:14]([C@H:22]2[O:26][C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=3B3OC(C)(C)C(C)(C)O3)[C@H:23]2[CH3:48])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:50][C:11]([F:10])([F:49])[C:12]1[CH:13]=[C:14]([C@H:22]2[O:26][C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=3[C:2]3[N:3]=[C:4]([C:7]([CH3:9])=[CH2:8])[S:5][CH:6]=3)[C@H:23]2[CH3:48])[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: C=C(C)c1nc(Br)cs1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1nc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)cs1
Temperature: 100 °C

Procedure:
In a tube were placed 4-bromo-2-isopropenyl-1,3-thiazole (20 mg, 0.097 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (29.4 mg, 0.0492 mmol), THF (340 μL), 1M aqueous K2CO3 (340 μL), and 1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (3.2 mg, 4.9×10−3 mmol). The mixture was degassed with N2. The tube was sealed and heated at 100° C. for 1.5 hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) and then by PTLC (90% CH2Cl2/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.16 (15% EtOAc/hexanes). LCMS=595.1 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.90 (s, 1H), 7.64-7.76 (m, 5H), 7.38 (s, 1H), 5.89 (s, 1H), 5.60 (d, J=8.1 Hz, 1H), 5.37 (d, J=1.2 Hz, 1H), 4.99 (d, J=16.0 Hz, 1H), 4.66 (d, J=16.0 Hz, 1H), 3.94 (m, 1H), 2.25 (s, 3H), 0.59 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1>>[NH2:21][CH2:20][CH2:19][C@H:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[CH2:13][CH2:14]1)[CH3:22]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(NC2CCN([C@H](C)CCN)CC2)cc1
Yield: 71.8 %

Procedure:
Using general procedure A with p-phenetidine (137 mg, 1.20 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (166 mg, 1.20 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-ethoxy-phenyl)-amine (251 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[C:3]=1[O:10][CH:11]([F:13])[F:12].C(OC(=O)C)(=[O:16])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][OH:16])[C:3]=1[O:10][CH:11]([F:13])[F:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OC(F)F)c(Cl)cc[n+]1[O-]
Product: OCc1nccc(Cl)c1OC(F)F
Temperature: 110 °C

Procedure:
70 ml of acetic anhydride was added to 7.61 g of 4-chloro-3-difluoromethyl-2-methylpyridine N-oxide (VI), which was heated at 110° C. for 1 hour. The solvent was distilled off under reduced pressure, and thereafter, saturated aqueous sodium bicarbonate solution was added thereto and the resulting mixture was extracted with ether. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 90% ethanol and 2.36 g of sodium hydroxide was added thereto and the resulting mixture was heated at 80° C. for 2 hours. The solvent was distilled off under reduced pressure, and thereafter, water was added thereto and the resulting mixture was extracted with chloroform. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chlorohorm) to obtain 1.55 g of 4-chloro-3-difluoromethyl-2-hydroxymethylpyridine (VII).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[N:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1.CO>CC#N>[F:40][C:37]([F:38])([F:39])[C:34]1[N:33]=[N:32][C:31]([CH2:30][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[N:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:4][CH2:3]2)=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccc(CBr)nn1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=c1ccc2ncc(=O)n3c2n1CC3CN1CCC(NCc2ccc(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a synthesis see Example 2(j)) (56.3 mg, 0.187 mmol), K2CO3 (34.4 mg, 0.249 mmol) and 3-(bromomethyl)-6-(trifluoromethyl)pyridazine (for a synthesis see Preparation 1 below) (30 mg, 0.124 mmol) in CH3CN (1 ml) and MeOH (0.1 ml) was stirred at room temperature overnight. LCMS showed amine derivative remaining. An excess of 3-(bromomethyl)-6-(trifluoromethyl)pyridazine (25 mg) was added. The mixture was stirred at room temperature for 1 h. The solid was filtered off and the solvent evaporated. Purification by flash chromatography using Flashmaster II and mixtures of DCM and MeOH as eluent afforded 2-{[4-({[6-(trifluoromethyl)-3-pyridazinyl]methyl}amino)-1-piperidinyl]methyl}-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (17 mg, 30%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10](=[O:12])[NH2:11])=[N:5]1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>COCCO>[F:14][C:2]([F:1])([F:13])[CH2:3][N:4]1[C:8](=[O:9])[C:7](=[CH:20][C:19]2[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=2)[C:6]([C:10](=[O:12])[NH2:11])=[N:5]1
Reactant: NC(=O)C1=NN(CC(F)(F)F)C(=O)C1
Reactant: O=Cc1ccc(O)cc1
Solvent: COCCO
Product: NC(=O)C1=NN(CC(F)(F)F)C(=O)C1=Cc1ccc(O)cc1

Procedure:
0.1 mole of 1-trifluoroethyl-3-carbamoyl-2-pyrazolin-5-one and 0.1 mole of p-hydroxybenzaldehyde were stirred for 1 hour in 150 ml of boiling ethylene glycol monomethyl ether. The solvent was distilled off under reduced pressure and the yellow dye was crystallized from methanol.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Ni].C(O)C>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Agent: [Ni]
Solvent: CCO
Product: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Yield: 100 %

Procedure:
A mixture of 31 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine and 240 parts of ethanol was hydrogenated at 0.5.105Pa in a Parr apparatus and at room temperature with 30 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated, yielding 27.4 parts (100%) of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine as a residue (interm. 117).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH3:30])[CH2:24][CH2:23]1>>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C@@H:29]([CH3:30])[CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:27][CH2:26]2)[CH2:36][CH2:35]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(C[C@H](C)N4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 1 from 4-isobutoxy-1H-indole-2-carboxylic acid, 80 (see example 8) and amine 50.