Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH2:7]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[S:27]([CH:26]=[CH2:25])(=[O:29])=[O:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N(Cc1ccccc1)CC(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzylamino-acetaldehyde diethyl acetal (14.6 ml, 61.3 mmol) and triethylamine (19.0 ml, 122.0 mmol) in dichloromethane (200 ml) at 0° C. under argon was added 2-chloro-1-ethanesulfonyl chloride (10.0 g, 61.3 mmol). After stirring at rt for 3 h, the reaction mixture was quenched with water (300 ml), extracted with dichloromethane (200 ml×2), washed with brine (150 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound which was used in next step without further purification; 1H NMR (CDCl3): 1.23 (t, 6H), 3.22(d, 2H), 353 (m, 2H), 3.72 (m, 2H), 4.52 (s, 12H), 4.63 (t, 1H), 5.88 (d, 1H), 6.23 (d, 1H), 6.50–6.43 (m, 1H), 7.35 (m, 5H); LCMS: 268 (MH+−46).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.Cl[Si](C)(C)C.O>CN(C=O)C>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[CH:20][CH:19]=4)=[C:3](/[CH:1]=[CH:31]/[C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of compound 5f (0.68 g, 1.7 mmol) and 2-methylquinoline (0.26 mL, 2.0 mmol) in DMF (5 mL) was added chlorotrimethylsilane (0.64 mL, 5.0 mmol) dropwise. The resulting mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled, and water (20 mL) was added. The precipitated solid was collected by filtration, washed with MeOH (2×5 mL), and dried under high vacuum. Compound 5g was obtained as an orange solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H31 N5O3: 534.2 (M+H). found: 534.4.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][C:6]=1[NH:13][C:14]([NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[O:15].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:7][C:6]=1[NH:13][C:14]([NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[O:15]
Reactant: COc1cccc(F)c1Oc1ccc(C=O)cc1NC(=O)Nc1nccs1
Reactant: C1COCCN1
Product: COc1cccc(F)c1Oc1ccc(CN2CCOCC2)cc1NC(=O)Nc1nccs1
Yield: 78 %

Procedure:
1-[2-(2-Fluoro-6-methoxy-phenoxy)-5-morpholin-4-ylmethyl-phenyl]-3-thiazol-2-yl-urea (35 mg, 78%) was prepared from 1-[2-(2-fluoro-6-methoxy-phenoxy)-5-formyl-phenyl]-3-thiazol-2-yl-urea (39 mg, 0.1 mmol) and morpholine following the general procedure O.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccn1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (75 mg, 0.18 mmol), methyl-pyridin-2-yl-amine (60 mg, 0.54 mmol), BOP (103 mg, 0.234 mmol), DIEA (193 L, 1.08 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-pyridin-2-yl-amide: MS m/z: (M+H) 505.1.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.C(OC(=O)C)C>CCCCCC>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][NH:5][C:4]2=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)NCCc1ccc(OC)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 145 °C
Reaction time: 0.75 h
Yield: 22.7 %

Procedure:
[2-(4-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-35a: 10 g, 44.84 mmol) was added to PPA (100 mg) at 145° C. The resulting mixture was stirred at 145° C. for 45 minutes. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was quenched with chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 1.8 g of the product (22.69% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:28]=[C:29]([OH:36])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34].O>CN(C)C=O>[CH3:26][C:27]1[CH:28]=[C:29]([O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 112.9 %

Procedure:
1-Bromooctadecane (43.54 g, 0.131 mol) and potassium carbonate (54.15 g, 0.392 mol) were added to a solution of 3-methyl-4-nitrophenol (20 g, 0.131 mol) in dimethylformamide (120 mL) The reaction mixture was heated to 110° C. and stirred at this temperature for 60 hours. The reaction mixture was cooled and poured into water (2 L), stirred for 0.5 hour and extracted with methylene chloride (1 L). The organic extract was washed with 5% aqueous solution sodium bicarbonate (0.5 L), water (2×0.6 L), dried over sodium sulfate and concentrated to give (60 g) of crude product. This product was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH:18][CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][N:18]([CH3:19])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: CNC
Product: CN(C)CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Yield: 87 %

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and dimethyl amine using General Procedure G1, followed by General Procedure E in 87% yield. LCMS Rt=8.69 min, m/z=272 (M+1). 1H NMR (CDCl3, δ): 7.40 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H), 2.43 (s, 2H), 20.1 (s, 6H), 2.0-1.6 (m, 8H). 13C NMR (CDCl3, δ, mult): 149.2(0), 129.5(0), 129.2(1), 126.7(1), 131.6(1), 69.3(2), 52.1(0), 48.0(3), 36.0(2), 23.2(2),
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15](=O)[NH:16]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:25].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.C(OCC)(=O)C>[Br:25][C:15]1[C:14]([C:20]([F:23])([F:22])[F:21])=[N:13][C:12]2[C:17]([N:16]=1)=[CH:18][C:9]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])=[CH:10][CH:11]=2
Reactant: BrP(Br)Br
Reactant: O=C(c1ccccc1)c1ccc2nc(C(F)(F)F)c(=O)[nH]c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc2nc(C(F)(F)F)c(Br)nc2c1
Temperature: 0 °C
Yield: 53 %

Procedure:
A mixture of 7-benzoyl-3-trifluoromethylquinoxalin-2(1H)-one (3.0 g, 9.4 mmol) [J. Org. Chem. 57(21), 5630,1992] and 40 ml of phosphorous tribromide was refluxed for 5 hours. The mixture was cooled and poured into ice water and the precipitate was isolated. The crude solid was dissolved in a mixture of diethylether and ethyl acetate (1:1), followed by addition of Norite A and anhydrous magnesium sulfate. The mixture was filtered and the solvent evaporated under reduced pressure. The residue was triturated with hexane, filtered off and dried to yield 1.9 g (53%) of the title compound as a pale yellow solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1)[CH2:8][CH2:9][NH:10][CH:11]([C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[N:14]=1)[CH3:12])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([CH2:25][NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)[N:14]=3)[CH3:12])=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: Cc1cc(C(C)NCCN(Cc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(C)NCCNCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Yield: 90.4 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-{2-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethylamino]-ethyl}-carbamic acid tert-butyl ester (155 mg, 0.320 mmol) in DCM/TFA (50%, 5 mL) was stirred for 0.5 h. The solvent was evaporated and sat. aqueous K2CO3 solution was added. The mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave 110 mg (90%) of N-benzo[1,3]dioxol-5-ylmethyl-N′-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethyl]-ethane-1,2-diamine as a red oil. [M+H]+ 380.96; 1H-NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.87 (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 6.79 (s, 1H), 6.71 (s, 2H), 5.90 (s, 2H), 3.74 (q, 1H), 3.66 (s, 2H), 2.70-2.50 (m, 6H), 2.2 (br s, 2H), 1.37 (d, 3H); 13C-NMR (100 MHz, CDCl3) δ 175.6, 170.0, 154.6, 147.9, 146.8, 136.4, 134.2, 130.5, 121.4, 116.8, 115.6, 108.8, 108.3, 101.1, 58.8, 53.8, 48.9, 47.4, 24.4, 22.4.
Reaction SMILES: C(OC(=O)[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:21]=2[CH2:33][CH:34]=[CH2:35])=[CH:11][CH:10]=1)[CH2:6][O:7][CH3:8])C.[C:37]([O:40]CC)(=[O:39])C>>[CH3:8][O:7][C@@H:6]([CH2:5][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:21]=2[CH2:33][CH2:34][CH3:35])=[CH:13][CH:14]=1)[C:37]([OH:40])=[O:39]
Reactant: CCOC(C)=O
Reactant: C=CCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(C(COC)C(=O)OCC)cc1
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-3-methoxy-propionic acid ethyl ester from Example 160, Step B which was treated in ethyl acetate with Pd(C) and H2 in balloon presure to give after filtration the corresponding reduced product which was hydrolyzed under Standard Procedure C to give the title compound.
Reaction SMILES: [H-].[Na+].[O:3]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][C:10]3[O:3][CH:4]=[CH:5][C:6]2=3)=[CH:18][CH:19]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COC(=O)c1cc2occc2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2occc2n1Cc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
To a mixture of sodium hydride (0.29 g, 55% dispersion in paraffin liquid) and DMF (10 mL) was added methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (0.5 g) under ice-cooling, followed by stirring for 10 minutes and further 1-(bromomethyl)-4-chlorobenzene (0.81 g) was added thereto, followed by stirring at room temperature for 4 hours. To the reaction mixture was added a 10% aqueous citric acid solution (10 mL), followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 5/1-3/1) to obtain 4-(4-chlorobenzyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.35 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:35]=[CH:34][C:19]2[O:20][C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=3[C@@H:23]3[C@H:28]([NH2:29])[CH2:27][CH2:26][CH2:25][N:24]3[C:18]=2[CH:17]=1.[CH:36](=O)[CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH3:36][CH:37]([CH3:39])[CH2:38][NH:29][C@H:28]1[C@@H:23]2[N:24]([C:18]3[CH:17]=[C:16]([Cl:15])[CH:35]=[CH:34][C:19]=3[O:20][C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=32)[CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)C=O
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 121.4 %

Procedure:
After 10 min. stirring sodium triacetoxyborohydride (11 mg, 0.05 mmol) was added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) and isobutyraldehyde (3.45 mg, 0.03 mmol) in 1 mL of CH2Cl2 (pH=4). The resulting mixture was stirred at room temperature for 18 h. The mixture was evaporated and chromatographed on silica. Elution with CH2Cl2/methanol 8:2 gave trans-N-(2-methylpropyl)-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (13 mg, 100%). Data: (m/z)=357 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[CH3:22][CH:23]([CH3:26])[CH:24]=O.[BH3-]C#N.[Na+]>CO.CCOC(C)=O>[CH3:1][N:2]([CH2:22][CH:23]([CH3:26])[CH3:24])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: CC(C)C=O
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CN(C)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (100 mg, 0.33 mmol, 1.00 equiv) in methanol (5 ml) was added 2-methylpropanal (50 mg, 0.69 mmol, 2.00 equiv) at room temperature and the reaction solution was stirred for 1 h. Then NaBH3CN (45 mg, 0.72 mmol, 2.00 equiv) was added and stirred overnight at ambient temperature. The resulting solution was diluted with EtOAc (100 mL), washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 54.0% in 13 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give 75 mg (63%) of the desired 1-N-methyl-1-N-(2-methylpropyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a white solid. MS: (ES, m/z): 359 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 4.07-4.09 (m, 1H), 3.02 (t, 2H), 2.99 (t, 2H), 2.54-2.59 (m, 3H), 2.37-2.39 (m, 5H), 2.18-2.21 (m, 2H), 1.95-1.99 (m, 2H), 1.81-1.85 (m, 1H), 1.45-1.61 (m, 4H), 1.01 (s, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.CC(C)([O-])C.[K+].[C:14]([O:18][C:19](=[O:22])[CH2:20]Br)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[CH:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])[CH:3]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
A mixture of 1H-pyrazole-4-carbaldehyde (0.5 g, 5.2 mmol), potassium tert-butoxide (0.7 g, 6.25 mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature for 5 minutes. Tert-butylbromoacetate (1.11 g, 5.72 mmol) was added and the resulting mixture was stirred for 2 hours at room temperature. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was collected, washed with water then brine, passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in iso-hexane, to afford the title compound (0.678 g, 62%) as colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH3:27])[CH2:5][C:6]1([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]1=[O:20].CO>O>[CH3:3][CH:4]([CH3:27])[CH2:5][C:6]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]1=[O:20]
Reactant: CCOC(=O)CC1(CC(C)C)CC(=O)N(CCc2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CC1(CC(=O)O)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Sodium hydroxide (283 mg, 7.08 mmol) is added to a mixture of ethyl 3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetate (611 mg, 1.77 mmol), methanol (10 mL), and water (5 mL), and the mixture is allowed to stir overnight at room temperature. The mixture is partitioned with 10 ml of water and 10 mL of Et2O. The layers are separated and the pH of the aqueous layer was adjusted to pH 2 (pH meter) with 1.2N HCl. The aqueous layer is extracted with EtOAc (2×10 mL) and CH2 Cl2 (2×10 mL), and the combined organic layers are dried (MgSO4), filtered and concentrated to give 500 mg (89%) of the title compound as a white foam which is carried on crude.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([O:27]CC)=[O:26])[C:4]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2].O.O.[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([OH:27])=[O:26])[C:4]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c(C2CCCCC2)n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
To a solution of ethyl 2-(3-cyano-2-cyclohexyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (485 mg, 0.975 mmol) in tetrahydrofuran (2.9 mL), and water (0.98 mL), was added solid lithium hydroxide monohydrate (40.9 mg, 0.975 mmol). The reaction was stirred at room temperature for 45 minutes, after which analysis by LCMS indicated that the reaction was not complete. After 20 more minutes, an additional equivalent of lithium hydroxide monohydrate (40.9 mg) was added, and the reaction was stirred at room temperature for an additional 20 minutes, after which it was determined to be complete by LCMS analysis. Concentration of the reaction mixture, followed by acidification with aqueous 3M hydrochloric acid solution (0.65 mL), extraction with dichloromethane (1×50 mL), then ethyl acetate (2×50 mL), drying (sodium sulfate), filtering and concentration afforded 2-(3-cyano-2-cyclohexyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (442 mg, 0.941 mmol, 97% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.96 (d, 1H), 7.43 (app. t, 1H), 7.32 (dd, 1H), 7.04 (d, 1H), 4.57 (s, 2H), 4.29 (s, 2H), 3.33-3.36 (m, 4H), 2.50 (m, 1H), 1.93-1.96 (m, 7H), 1.70-1.88 (m, 8H), 1.28-1.32 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:16][CH:15]=1.CN(C)C=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][C:17]4[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)=[O:7])=[CH:11][CH:12]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccc(F)cc1
Yield: 19 %

Procedure:
To 3.96 parts of 1-(4-fluorobenzoyl)aziridine, dissolved in 16 parts of benzene, are added 3.25 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 90 parts of benzene and 45 parts of N,N-dimethylformamide. The whole is stirred and refluxed for 5 hours. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with methylbenzene. The combined organic phases are dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1part (19%) of 4-fluoro-N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]benzamide; mp. 193.7° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (210 mg, 0.68 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (220 mg, 0.68 mmol) according to the general procedure M. Obtained as a white foam (260 mg, 68%).