Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[N:6][C:5]2=[N:9][S:10][N:11]=[C:4]2[N:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[C:12]1(=[O:22])[N:16]([C:2]2[C:7]([N:16]3[C:15](=[O:17])[C:14]4=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]4[C:12]3=[O:22])=[N:6][C:5]3=[N:9][S:10][N:11]=[C:4]3[N:3]=2)[C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: Clc1nc2nsnc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1nc2nsnc2nc1N1C(=O)c2ccccc2C1=O

Procedure:
The cyclization reaction of o-diaminobenzene (compound II) in an aqueous solution of glyoxal and sodium hydrogen sulfite gives quinoxaline (compound III; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). Quinoxaline is in turn oxidized by an aqueous solution of potassium permanganate to produce 2,3-pyrazinedicarboxylic acid (compound IV; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). 2,3-pyrazinedicarboxylic acid is then chlorinated with phosphorus pentachloride at 300° C. to produce 2,3,5,6-tetrachloropyrazine (compound V; See C. G. Allison et al., J. Chem. Soc. (C), 1970, page 1023). The reaction of 2,3,5,6-tetrachloropyrazine with ammonium chloride at a temperature of 120° C. gives 2,3-diamino-5,6-dichloropyrazine (compound VI; See Palamidess et al., Ed. Sc. XXI-fasc, 11, 1966, page 810). The cyclization reaction of 2,3-diamino-5,6-dichloropyrazine with thionyl chloride in the presence of pyridine in xylene produces 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VII; See Y. C. Tong, J. Heterocyclic Chem., 12, 1975, page 451 ). The 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine is reacted with potassium phthalimide in the presence of dimethyl formamide (DMF) at a temperature of 60° C. to produce 5,6-diphthalimido[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VIII; See Example 1). The 5,6-diphthalimido-[1,2,5]thiadiazolo[3,4-b]pyrazine is then reacted with an aqueous solution of hydrazine at 0° C. to produce 5,6-diamino-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound IX; See Example 2). Finally the cyclization reaction of 5,6-diamino[1,2,5]thiadiazolo[3,4-b]pyrazine with thionyl chloride in the presence of pyridine in methylene chloride gives bis[1,2,5]thiadiazolo[3,4-b:3',4'-e]pyrazine (compound I; See Example 3).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[F:20][CH:21]([F:31])[O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.CO>C(COC)OC.ClCCl.O>[F:20][CH:21]([F:31])[O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][C:10]#[N:11]
Reactant: O=Cc1ccccc1OC(F)F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: N#CCc1ccccc1OC(F)F
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
A solution of p-toluenesulfonylmethyl isocyanide (2.4 g) in dimethoxyethane (10 mL) was added to a solution of potassium tert-butoxide (2.68 g) in dimethoxyethane (30 mL) at −35° C., and the reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was cooled to −55° C. A solution of difluoromethoxybenzaldehyde (2 g) in dimethoxyethane (5 mL) was added dropwise, and the reaction solution was stirred at the same temperature for two hours. 10 mL of methanol was added to the reaction solution, and the reaction solution was heated under reflux for 15 minutes. The reaction solution was left to cool to room temperature. Then, water and dichloromethane were added and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.45 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COB(OC)OC
Reactant: CCCCCCc1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCCCc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of 4-bromo-1-hexylbenzene (500 mg, 1.7 mmol) in THF (15 mL) at −78° C. was added t-butyllithium (1.7 M in pentane, 2.0 mL) slowly dropwise. After stirring at −78° C. for 1 h, trimethyl borate (0.39 mL, 3.46 mmol) was added. The reaction mixture was warmed at RT over 2 h. After stirring at RT for 15 min, the reaction mixture was quenched with saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with HCl (10% solution), brine, and dried (MgSO4), filtered, and concentrated under reduce pressure to give 415 mg (4-hexylphenyl)boronic acid as a colorless solid.
Reaction SMILES: C1(S[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)([CH3:12])[C:9]([OH:11])=[O:10])C=CC=CC=1>C(O)(=O)C.[Zn]>[O:19]([C:15]1[CH:14]=[C:13]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:18]=[CH:17][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(Sc1ccccc1)(C(=O)O)c1cccc(Oc2ccccc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 95.1 %

Procedure:
1.11 g (3.17 mmols) of 2-phenylthio-2-(3-phenoxyphenyl)propionic acid obtained in Example 6 was dissolved in 10 ml of acetic acid and the solution was heated while refluxing for 1 hour with stirring in the presence of 1.0 g of zinc powder. The solid substance present in the reaction mixture was removed by filtration and washed with methylene chloride. The combined filtrate and washing was concentrated to obtain 0.86 g of a crude product which was then purified by silica gel column chromatography eluting with diethyl etherhexane (1:5 by volume) to obtain 0.73 g (95% yield) of 2-(3-phenoxyphenyl)propionic acid. nD26 1.5780.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:21][N:22](C)[CH:23]=O>>[CH3:21][N:22]([CH3:23])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([O:18][CH2:19][CH3:20])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CCOc1nsc(NC(=O)Oc2ccccc2)c1C#N
Reactant: CN(C)C=O
Product: CCOc1nsc(NC(=O)N(C)C)c1C#N
Temperature: 25 °C

Procedure:
A solution of 9.5 g of phenyl (4-cyano-3-ethoxy-5-isothiazolyl)carbamate in 45 ml of dimethylformamide was placed in a pressure bottle; and while being stirred, was cooled below 0°. A total of 3.7 g of dimethylamine was collected in a dropping funnel by condensing the gas in a dry-ice trap. The liquified amine was added to the pressure bottle, and the bottle sealed. The contents of the bottle were allowed to warm to ambient temperature, then heated at 80° while being stirred overnight. The bottle was cooled to 5° and opened. The reaction mixture was evaporated to dryness under reduced pressure to give a brown solid. This solid was recrystallized from ethanol to give 5.9 g of 1,1-dimethyl-3-(4-cyano-3-ethoxy-5-isothiazolyl)urea, m.p. 204°-205°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[CH:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C(O)=O)C=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:9]=[CH:13][C:14]=1/[C:15](/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:9]/[CH:5]=[CH:4]/[C:3]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)=[O:2]
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(C(=CC=Cc2ccccc2)C(=O)O)c1
Solvent: C1CCOC1
Product: COc1ccccc1/C(=C/C=C/C(=O)NCCCCc1cccnc1)c1ccccc1
Yield: 114.8 %

Procedure:
As in Example 134, a solution of (2E,4E)-5-(3-methoxyphenyl-5-phenyl-2,4-pentadienoic acid 4(2.96 g) and 3-pyridinebutanamine (1.107 g) in tetrahydrofuran (15 mL) was stirred for 1 hour at room temperature. After the usual work up, the crude amide was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to provide 2.5 g of (2E,4E)-5-(methoxyphenyl)-5-phenyl- N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 66°-68° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC)=[O:39])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH:12]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[C:11]2=[O:43])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccc(C)o3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccc(C)o1)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
1-[1-(5-Methylfuran-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (0.80 g) was dissolved in the mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml), aqueous lithium hydroxide monohydrate (0.29 g) solution (10 ml) was added, the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the residue was weakly acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 442 mg of the title compound as a light yellow crystal.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[C:15](Cl)=[N:16][C:17]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:17]2[N:16]=[CH:15][C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[N:18]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(Cc2nc(Cl)c3c(n2)CCN(Cc2ccccc2)CC3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(Cc2ncc3c(n2)CCNCC3)cc1
Temperature: 75 °C
Yield: 85 %

Procedure:
Under nitrogen, a mixture of 7-benzyl-4-chloro-2-(4-methylbenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Preparation 35, Step B, (150 mg, 0.40 mmol), ammonium formate (250 mg, 4.0 mmol) and 20% palladium on charcoal (15 mg) in ethanol (5 ml) was heated at 75° C. for 1 h. After returning to room temperature, the mixture was filtered through a pad of Arbocel, washing the pad with ethanol. The combined eluates were concentrated in vacuo and the residue purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.880NH3, 95:5:0.5 then 90:10:1, to afford the title compound as an oil in 85% yield, 85 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21]O)[O:10][C:9]2=[O:23])=[CH:4][CH:3]=1.[C:24]1([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21][N:32]3[N:33]=[N:34][C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:31]3)[O:10][C:9]2=[O:23])=[CH:6][CH:7]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: COc1cccc([C@H]2[C@H](CO)OC(=O)N2c2ccc(Cl)cc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc([C@H]2[C@H](Cn3nnc(-c4ccccc4)n3)OC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(4S,5R)-3-(4-Chlorophenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one (40 mg, 0.12 mmol) and phenyltetrazole (17 mg, 0.12 mmol) are dissolved in DCM (1 mL), cooled to 0° C. and are then subsequently treated with triphenylphosphine (29 mg, 0.11 mmol) and diisopropylazodicarboxylate (0.024 mL, 0.12 mmol). The mixture is allowed to stir to room temperature overnight and is then purified by flash chromatography (4 g Redisep cartridge, 10-30% Ethyl acetate-hexanes) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 8.05-8.03 (m, 2H), 7.54-7.50 (m, 3H), 7.47-7.43 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.30-7.24 (m, 2H), 7.09 (t, J=2.08 Hz, 1H), 7.05-7.03 (app d, J=7.8 Hz, 1H), 6.90 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 5.72 (d, J=5.1 Hz, 1H), 5.50 (dd, J=14.7, 8.7 Hz, 1H), 5.43 (dd, J=14.7, 10.6 Hz, 1H), 5.12-5.08 (m, 1H), 3.76 (s, 3H); HPLC-MS calculated C24H20ClN5O3 (M+H+) 462.1, found 462.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([NH:12][C:13]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])[CH2:23]4)[N:14]=3)=O)[CH2:9][CH2:8]2)[CH:6]=1.C(O)(=O)C.O.[OH-].[NH4+]>[Zn].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]3[NH:12][C:13]4=[N:14][C:15]([N:22]5[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]6[CH2:34][CH2:33][CH2:32][CH2:31]6)=[O:29])[CH2:23]5)=[CH:16][CH:17]=[C:18]4[N:19]=3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C([C@@H]1CCCN(c2ccc([N+](=O)[O-])c(NC(=O)C3(n4cc(Cl)cn4)CC3)n2)C1)N1CCCC1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 103.7 %

Procedure:
Into a flask was added (R)-1-(4-chloro-1H-pyrazol-1-yl)-N-(3-nitro-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (107 g, 219.29 mmol) and acetic acid (750 mL, 6.74 mol). The mixture was stirred for 5 min. Zinc powder (71.70 g, 1.10 mol) was added. An exotherm to 79° C. was observed over a period of 30 sec. The reaction mixture was warmed to 100° C. and stirred for 2 h. The mixture was cooled to 50° C. and water (750 mL) was added. The mixture was stirred for 10 min and cooled to 10° C. Ethyl acetate (500 mL) was added and the mixture was stirred for 20 min and filtered through Celite rinsing with ethyl acetate (300 mL). The filtrate was cooled to 10° C. and aqueous ammonium hydroxide (936.92 mL, 6.74 mol) was added dropwise over a period of 20 min. The layers were separated and the organics were washed with a mixture of water:brine (1:1, 500 mL), and concentrated under reduced pressure. Ethyl acetate (200 mL) was added and the mixture was concentrated under reduced pressure followed by the addition of acetonitrile (500 mL). The mixture was concentrated to dryness at 45° C. to afford (R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (100 g) as an amorphous material. 1H NMR (500 MHz, CDCl3) δ 1.55-1.70 (m, 1H), 1.72-2.05 (m, 11H), 2.60-2.70 (m, 1H), 2.90-2.95 (m, 1H), 3.03-3.10 (m, 1H), 3.42-3.50 (m, 3H), 3.56-3.62 (m, 1H), 4.20-4.25 (m, 1H), 4.38-4.44 (m, 1H), 6.62-6.68 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 1H); MS (ES+) (M+H) 440; HPLC retention time: 4.450 min (Method: Same as for Step 1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([N+:16]([O-:18])=[O:17])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C1COCC1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([NH:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
To a solution of 2-(benzylthio)-4,6-dichloro-5-nitropyrimidine (WO 01/58906 A1) (9 g, 28.5 mmol) in THF (60 mL) and DIEA (9.9 mL, 7.36 g, 57 mmol, 2 equiv.) was added drop wise a solution of 4-aminotetrahydropyran (2.77 g, 27.4 mmol, 0.96 equiv.) in THF (20 mL) over 15 min. The reaction mixture was stirred at room temperature for 18 h. The solvent was then removed in vacuo and the residue purified by column chromatography (silica gel, elution with 4/1 hexanes/ethyl acetate) to afford, after evaporation and drying, the desired product as a yellow solid (7.59 g, 70% yield). 1H NMR (300 MHz, CDCl3) δ, ppm: 7.86 (br d, J=6.8 Hz, 1H), 7.42-7.36 (m, 2H), 7.36-7.27 (m, 3H), 4.38 (s, 2H), 4.31-4.20 (m, 1H), 3.96 (dt, J=11.7, 3.5 Hz, 2H), 3.47 (ddd, J=11.7, 11.3, 2.2 Hz, 2H), 1.92 (br dd, J=12.4, 2.2 Hz, 2H), 1.66-1.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](C(OC(C)(C)C)=O)[C:13](=[O:22])[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:22])[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one-1-carboxylate from Step D (1.22 g, 3.32 mmol) in CH2Cl2 (7 mL) at ambient temperature was added TFA (3 mL). After stirring for 1.5 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between CH2Cl2 (30 mL) and saturated NaHCO3 (30 mL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×30 mL). The combined organics were dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=268 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]([F:43])([F:42])[C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:23]>>[F:20][C:21]([F:42])([F:43])[C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1)=[O:23]
Reactant: CC1(C)OB(c2ccc(CCNC(=O)C(F)(F)F)cc2)OC1(C)C
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCNC(=O)C(F)(F)F)cc2)cc1
Yield: 39.8 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (100 mg, 0.25 mmol, prepared in example 2) and 2,2,2-Trifluoro-N-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-acetamide (105 mg, 0.31 mmol) were treated as described in example 6. The reaction was purified by radial chromatography eluting with 70:30 hexanes:ethyl acetate to afford 48 mg (39%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12](O)([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[CH:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][CH:5]3[C:4]=2[C:3]=1[Cl:26].[OH-].[K+]>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[C:3]=1[Cl:26]
Reactant: CN1CCC2C(C1)c1c(ccc(Cl)c1Cl)N2CC(C)(O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3c(Cl)c(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8,9-Dichloro-5-(2-hydroxy-2-(pyridin-4-yl)propyl)-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (500 mg, 1.2 mmol) was dissolved in thionylchloride (5 mL) and stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (5 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (482 mg, 8.5 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, formate salt) δ (ppm): 8.60 (d, 2H), 7.70 (d, 2H), 7.30 (m, 2H), 7.18 (d, 1H), 4.60 (m, 2H), 3.40 (m, 2H), 3.10 (m, 2H), 2.90 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([C:33](O)=[O:34])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:11][N:12]=3)[CH2:2][CH2:3]2)=[O:34])[CH:22]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)nc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)cn3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2-Piperazin-1-yl-5-trifluoromethyl-pyrimidine (Example AE) and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 431.1 MH+.
Reaction SMILES: Cl.[C:2]1([CH:8]2[NH:13][C:12]([NH2:14])=[N:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]3[C:23](=[O:24])[CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[N:14]=[C:12]3[NH:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1=NCCC(c2ccccc2)N1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCC(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A suspension containing 4 g (16.12 mmoles) of 6-phenyl-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2), 3.11 g (16.12 mmoles) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 6.68 g (48.36 mmoles) of anhydrous potassium carbonate in 50 ml of ethanol were refluxed for 18 h. The cooled solution was evaporated and the residue was treated with water and allowed to stir at 0° C. during 2 h. The precipitate which formed was recovered by filtration and dried at 90° C. during 18 h. 4.80 g (98%) of product was thus obtained.