Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[C:25]([CH2:24][CH2:23][CH2:22][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]1[CH3:1])#[N:26]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1CCCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To the stirred solution of tert-butyl 3-methylpiperazine-1-carboxylate (prepared according to procedure reported in US200876758A1, 2008, 5 g, 24.97 mmol) in N,N-dimethylformamide (50 ml) were added potassium carbonate (17.25 g, 125 mmol) and 4-bromobutanenitrile (2.98 ml, 30.0 mmol) at 25° C. The resulting solution was stirred at 25° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction water (100 ml) was added and extracted with dichloromethane (3×60 ml). The combined extract was washed with brine (25 ml) and dried over sodium sulphate, filtered and concentrated to give crude compound. The crude compound was purified by column chromatography over silica gel (100-200) using 15% ethyl acetate in hexane to obtain the title compound (5 g, 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)=O>C(OCC)C>[Br:20][C:16]1[CH:15]=[C:14]([C:12]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH2:11])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: C=C(c1ccc(OC)cc1)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
4-Bromoanisole (2.2 mL, 0.017 mol) in diethyl ether (10 mL) was added to a mixture of magnesium turnings (0.5 g, 0.02 mol) in diethyl ether (5 mL), at room temperature. The resulting mixture was heated to reflux for 1 h. The mixture was then cooled to room temperature. A solution of 3-bromoacetophenone (3.4 g, 0.017 mol) in diethyl ether was then added dropwise causing a gentle reflux. After 3 h heating to reflux the reaction mixture was examined by LC-MS which showed complete conversion to the desired product. The mixture was quenched with 1 N HCL solution (20 mL). Ethyl acetate (20 mL) was added and the aqueous phase was separated. The aqueous phase was then extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The crude was then dissolved in toluene (10 mL) and a catalytic amount of p-toluene sulfonic acid (30 mg) was added and refluxed for 3 h. The solvent was removed and the crude residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (3.7 g, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)C(F)(F)F)=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1F.[C:19](=O)([O-])[O-:20].[Cs+].[Cs+].CI.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[O:20][CH3:19]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(Br)c(F)c1[N+](=O)[O-])C(F)(F)F
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CNc1ccc(Br)c(OC)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A solution of N-(4-bromo-3-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (1.27 g, 3.84 mmol) in N,N-dimethylformamide (43.4 mL) was treated with cesium carbonate (2.50 g, 7.67 mmol) followed by the addition of methyl iodide (1.19 mL, 19.2 mmol). The reaction mixture was stirred at 20° C. for 1 h, then warmed to 50° C. and stirred at that temperature for 16 h, after which time additional methyl iodide (0.5 eq) was added to the reaction mixture and the reaction mixture was heated at 50° C. for 4 h. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with water (3×) and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude methylated amide which was used without further purification. The crude intermediate methylated amide was dissolved in methanol (43.4 mL) and water (8.68 mL, 482 mmol), treated with potassium carbonate (2.65 g, 19.2 mmol), and the resultant mixture was stirred at 60° C. for 15 h, after which time the reaction mixture was concentrated to remove most of the methanol and the aqueous residue was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (906 mg, 90%) as a yellow solid. LCMS calculated for C8H10BrN2O3 (M+H)+: m/z=261.0, 263.0. found: 260.9, 262.8.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:2].CSC.B>C1COCC1>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CC#N)cc2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4′-cyanomethyl-biphenyl-4-yl)-cyclopentyl]-amide (210 mg, 0.55 mmol, prepared in example 8) was dissolved in 20 mL dry THF. To this solution was added 0.83 mL (1.65 mmol) of a 2.0 M solution of borane dimethyl sulfide in THF. The reaction was heated to reflux for 4 hours then concentrated in vacuo. To this solid was added 30 mL of diethyl ether, 15 mL of concentrated HCl, 10 mL of water, and 5 mL of methanol and stirred at room temperature for 30 minutes. The aqueous layer was separated, and the organic phase washed 1× with water. The combined aqueous phases were made basic with sodium hydroxide at 0° C. and extracted into diethyl ether (2×50 mL) followed by ethyl acetate (1×50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to a crude oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9]([NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)=[CH:10][C:11]2[C:12]([CH3:20])=[CH:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:33](=O)[CH2:34][CH3:35]>>[CH2:1]([O:7][C:8]1[C:9]([N:21]([CH2:33][CH2:34][CH3:35])[C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=2)=[CH:10][C:11]2[C:12]([CH3:20])=[CH:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC=O
Reactant: CCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Product: CCCCCCOc1cc2c(cc1N(CCC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure P, (Compound 112, 0.030 g, 0.07 mmol) was reacted with propionaldehyde to afford 0.032 g (100%) of the title compound as a yellow oil.
Reaction SMILES: CNC(C1C2C=C(C3C(Cl)=CN=C([NH:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]4[CH3:31])N=3)SC=2C=CC=1)=O.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49](Cl)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1.C(OC(N1CCN(CCCN)[C@@H](C)C1)=O)(C)(C)C>>[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:21][CH2:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]5[CH3:31])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Agent: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1CCCN
Product: Cc1cnc(NCCCN2CCNC[C@@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, the title compound is synthesized from 2-(2-chloro-5-methyl-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and (S)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 465 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(N[S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:11]=[C:10]([O:12][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])=[O:21]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OS(=O)(=O)C(F)(F)F
Yield: 88.8 %

Procedure:
A solution of methyl 2,4-dihydroxybenzoate 46 (0.5 g, 2.97 mmol), N-phenyltrifluoro-methanesulfonamide (2.125 g, 5.95 mmol) and DIPEA (1.039 mL, 5.95 mmol) in DCM (15 mL) was stirred at room temperature for 2 days then washed with saturated NaHCO3, brine, dried over MgSO4, filtered and solvent evaporated to provide methyl 2,4-bis(trifluoromethylsulfonyloxy)benzoate 47 (1.14 g, 89% yield) after purification by Biotage (0 to 10% EtOAc in Hexane). LRMS (ESI): (calc.) 431.94 (found) 455.0 (MNa)+
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([S:11](Cl)(=[O:13])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([OH:26])[CH2:23][NH:24][CH3:25])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([OH:26])[CH2:23][N:24]([CH3:25])[S:11]([C:10]2[C:6]3[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=3[S:8][CH:9]=2)(=[O:13])=[O:12])=[CH:20][CH:21]=1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: CNC[C@@H](O)c1ccc(F)cc1
Product: CN(C[C@@H](O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (285 mg) and (1S)-1-(4-fluorophenyl)-2-(methylamino)ethanol (the compound of Preparation Example 38) (230 mg), the title compound (370 mg) was obtained as a light brown solid, in the same way as Preparation Example 41. The NMR data matched the racemic mixture described in Preparation Example 48. The optical purity as measured by high performance liquid chromatography (ChiralPak AD-H, hexane:2-propanol=8:2) was >99% e.e.
Reaction SMILES: C1(N)CCCC1.BrC1C(Cl)=NC(Cl)=NC=1.[Cl:16][C:17]1[N:18]=[CH:19][C:20]2[CH:25]=[CH:24][N:23]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:21]=2[N:22]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]2[CH:25]=[CH:24][N:23]([CH:26]3[CH2:29][CH2:30][CH2:28][CH2:27]3)[C:21]=2[N:22]=1
Reactant: CCC(CC)n1ccc2cnc(Cl)nc21
Agent: Clc1ncc(Br)c(Cl)n1
Agent: NC1CCCC1
Product: Clc1ncc2ccn(C3CCCC3)c2n1

Procedure:
2-chloro-7-(cyclopentyl)-7H-pyrrolo[2,3-d]pyrimidine is prepared from cyclopentyl amine and 5-bromo-2,4-dichloropyrimidine using a method similar to that for the preparation of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine given in example 1.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=O)[CH:5]=1)(=[O:3])[NH2:2].CO.[NH3:33]>>[NH2:33][C:26](=[O:28])[C@@H:25]([NH:24][C:6]1[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=1)[CH3:30]
Reactant: N
Reactant: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: CO
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Yield: 66 %

Procedure:
A solution of (S)-methyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoate (4.128 g, 10.05 mmol) in 7M ammonia in methanol (100 mL, 700 mmol) was heated in a sealed tube for 3 days at 50° C. After cooling, the reaction mixture was evaporated in vacuo. The residue was triturated with 150 mL methanol and filtered to obtain the first batch of product. The filtrate was evaporated and chromatographed over silica gel with 50-100% acetone in hexanes. The product fractions were isolated and evaporated in vacuo. This residue was triturated with 40 mL methanol and filtered to give the second batch of product. The first and second batches of product were combined and triturated once more with 10 mL methanol, filtered and dried under vacuum at 50° C. to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (Example 1) as a pale tan-gray powder (2.620 g, 6.63 mmol, 66% yield). LC/MS: m/z=396.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): 8.54 (2H, d, J=8.8 Hz), 8.27 (1H, s), 7.95 (1H, d, J=6.4 Hz), 7.74 (1H, s), 7.53 (1H, s), 7.31-7.24 (2H, m), 7.19-7.13 (2H, m), 7.08 (1H, s), 7.04-6.97 (3H, m), 4.60-4.51 (1H, m), 1.36 (3H, d, J=7.0 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:17][CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.C(O)(=O)C>ClCCl>[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:17][CH2:16]1
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)cccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1nc2c(C(=O)NCC3CCNCC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (56.0 mL, 10 eq) was added to a flask containing a ˜5° C. solution of 4-{[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidine-1-carboxylic acid tert-butyl ester (30.0 g, 1.0 eq) in dichloromethane (300 mL) while maintaining the temperature below 10° C. The resulting mixture was stirred at 20-30° C. for 2 h. When the reaction was complete, triethylamine (73.2 mL, 7.0 eq) and acetic acid (4.3 mL, 1.0 eq) were added to provide a solution of the title intermediate with an apparent pH of approximately 4 that was used directly in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([CH3:29])[CH:21]=2)=[N:2]1.Cl.[Sn](Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:30])=[CH:21][C:22]=1[CH3:29]
Reactant: Cc1cc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)ccc1N
Temperature: 40 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
Compound 157 (0.10 g, 0.25 mmol) was dissolved in acetic acid (1.0 mL) and hydrochloric acid (1.0 mL) and the solution was added with tin(II) chloride (0.10 g, 0.5 mmol), followed by stirring at 40° C. for 2 hours. Then, the reaction mixture was neutralized by adding 6 mol/L sodium hydroxide and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 158 (46 mg, 50%).
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)=[O:31])[CH:26]=1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(c1cccnc1)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1

Procedure:
From 1,3-dihydro-1-{trans-4-[1-piperazinyl]-1-cyclohexyl}-2H-benzimidazol-2-one and nicotinoylchloride hydrochloride using the procedure described for Example 11, Step 3 there was obtained 1,3-dihydro-1-{trans-4-[4-(3-pyridinecarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.51 (s, 1H), 8.68 (s, 2H), 7.77 (m, 1H), 7.38 (m, 1H), 7.12-7.04 (m, 4H), 4.26 (m, 1H), 3.83 (s, 2H), 3.47 (s, 2H), 2.71 (s, 2H), 2.58 (s, 2H), 2.53 (m, 2H), 2.30 (q, 2H), 2.0 (q, 4H), 1.53 (m, 2H), 1.26 (m, 2H). The hydrochloride salt was precipitated from chloroform/toluene: Analysis calculated for C23H27N5O2.HCl.0.20 CHCl3.0.45 CH3C6H5C: 57.99, H: 6.43, N: 12.83 found C: 58.04, H: 6.36, N: 12.75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1Oc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-2-phenoxy-phenylamine (75 mg, 0.34 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (95 mg, 0.341 mmol) in pyridine (0.5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J =2.0 Hz, 1 H), 7.80 (dd, J=8.4, 2.0 Hz, 1 H), 7.70 (d, J=2.4 Hz, 1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.27-7.23 (m, 2 H), 7.14-7.10 (m, 1 H), 7.05-7.02 (m, 2 H), 6.66 (d, J=8.4 Hz, 1 H), 6.60-6.56 (m, 2 H). MS m/z:484.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: COc1nc(Cl)ncc1I
Product: COc1nc(Cl)ncc1-c1cccs1
Yield: 54 %

Procedure:
Preparation according to procedure 3 with the use of 2-chloro-5-iodo-4-methoxy-pyrimidine and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane for 36 hrs at 95° C. In this way, a yield of 54% is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:42])([CH3:41])[CH2:29][C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[C:34]([F:40])[CH:33]=1)=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([C:30](=[O:31])[CH2:29][C:28]([CH3:42])([CH3:41])[CH3:27])=[CH:33][C:34]=1[F:40]
Reactant: CC(C)(C)CC(=O)c1ccc(CN)c(F)c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)c(F)c1
Yield: 48.1 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (127 mg, 0.3 mmol) with 4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamine (120 mg, 0.54 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol), BINAP (40 mg, 0.06 mmol) and cesium carbonate (137 mg, 0.42 mmol) in anhydrous toluene (20 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 and 9:1) followed by reverse phase HPLC [Zorbax Bonus RP, 5 □M 21.2×100 mm, eluting with water/acetonitrile (0.05% TFA in each) (35:65 to 15:85 gradient over 5 min), flow rate 25 mL/min, UV detector (230 nm)] to give 7-chloro-6-[4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (72 mg, 49%). MS (ES+) m/z: 499 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][CH:16]([OH:18])[CH3:17])[CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:18][CH:16]([CH2:15][CH2:14][C:4]1[CH:3]=[C:2]([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=1)[CH3:17])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cc(CCC(C)O)cc(F)c2c1
Solvent: c1ccncc1
Product: COc1ccc2cc(CCC(C)OC(C)=O)cc(F)c2c1
Temperature: 0 °C
Yield: 85 %

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)-butan-2-ol (2.8 g) was dissolved in pyridine (22 ml) and cooled in an ice-bath. Acetyl chloride (2.9 ml) was added dropwise with stirring. The solution was then stirred for 30 minutes at 0° and 1 hour at room temperature. The suspension produced was poured into ice-water (250 ml) and the product was extracted into ether. The ether was washed with dilute hydrochloric acid and sodium hydrogen carbonate solution. After drying over anhydrous sodium sulphate and solvent was removed under reduced pressure to give the title compound as a pale yellow oil (2.8 g., 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:29]([NH:33][C:34]#[N:35])[CH2:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1>[CH2:29]([N:33]([C:34]#[N:35])[C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:19]=[CH:20][C:9]([O:8][C:5]2[C:4]([F:21])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:10][CH:11]=1)[CH3:18])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCNC#N
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C#N)C(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 5 h

Procedure:
While cooling with ice, a solution of 9.9 g (0.030 mole) of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionyl chloride in 30 ml of toluene is added dropwise to a solution of 3.5 g (0.035 mole) of triethylamine and 3.2 g (0.033 mole) of n-butylcyanamine in 40 m of toluene. After 5 hours, the precipitate is removed by filtration and the filtrate is purified by chromatography through silica gel. The eluate is concentrated by evaporation, affording 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid N-n-butyl-N-cyanamide as a yellowish oil. nD25 : 1.5482.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH2:5]C.[CH3:21][O:22]N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)CC>>[CH3:21][O:22][C:19]1[CH:20]=[C:15]([C:2](=[O:1])[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:4][CH3:5])[CH:16]=[CH:17][CH:18]=1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)c1cccc(OC)c1

Procedure:
was synthesised in the same way as 91c from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxobutan-2-ylcarbamate (95d, 250 mg, 1.02 mmol).