Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:33][C:34]([CH3:36])=[O:35]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:34]([CH3:36])([OH:35])[CH3:33])(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:2][CH2:3]1
Reactant: CC(C)=O
Reactant: CC(C)(C)Cc1nc2cc(S(C)(=O)=O)ccc2n1CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-(methylsulfonyl)-1H-benzimidazole (Step D, 8.22 g, 25.7 mmol) in tetrahydrofuran (200 mL) was added lithium bis(trimethylsilyl)amide (1.07 M in hexane, 28.8 mL, 30.8 mmol) at −40° C. under nitrogen atmosphere. After stirring for 10 min, acetone (20 mL) was added at −40° C. and the mixture was allowed to warm to room temperature. After stirring for 18 h, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (300 mL×3). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2 as eluent) to afford the title compound (4.68 g, 48%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH:10]([OH:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1C(O)c1ccc(O)cc1
Temperature: -10 °C

Procedure:
A solution containing commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (0.500 g, 17.0 mmol) and lithium aluminum hydride (34.0 mmol) in THF (84 mL) was refluxed for 3 h. The reaction was cooled to −10° C., and carefully quenched with 0.1N NaOH and H2O. The aqueous solution was extracted with ether and concentrated. Purification on silica gel gave the title compound as a white solid, mp 94-96° C. (DMSO-d6) δ0.90 (t, 3 H), 1.35 (sextet, 2 H), 1.64 (quintet, 2 H), 2.84 (t, 2 H), 5.6 (d, 1 H), 5.87 (d, 1 H), 6.69 (d, 2 H), 7.07 (t, 1 H), 7.15 (dt, 1 H), 7.22 (d, 2 H), 7.40-7.43 (m, 2 H), 9.24 (s, 1 H). IR (KBr) 3350, 2950, 1610, 1510 and 1450 cm−1. mass spectrum (EI) m/z 296 (M+). Anal. Calcd. for C19H20O3 C, 77.00; H, 6.80; N, 0.00. Found: C, 75.63; H, 6.86; N, 0.04.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH:12]1[C:23](OCC)=[O:24].Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][C:12]=3[C:23](=[O:24])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C1CC(c2ccccc2)CCC1=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: O=c1oc2cc(O)cc(O)c2c2c1CC(c1ccccc1)CC2

Procedure:
A solution of phloroglucinol (1.56 g) and ethyl 2-oxo-5-phenylcyclo-hexane-carboxylate (2.52 g) in ethanol (25 ml) was treated with dry HCl as described in example 1a. The precipitate was filtered and washed with water and EtOH. Yield 1.0 g (32%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH3:11])=[C:2]=[O:3].[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:13]([NH:12][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10][CH3:11])=[O:3])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: CSc1ccccc1N=C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CSc1ccccc1NC(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isocyanato-2-(methylsulfanyl)benzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 545.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:20]([O:22]CC)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:26]>N1CCOCC1>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:20]([N:26]2[CH2:10][CH2:9][O:8][CH2:1][CH2:2]2)=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reactant: [NH4+]
Agent: [Cl-]
Solvent: C1COCCN1
Product: O=C(Nc1ccc(OCc2ccccc2)c2c1OCCO2)N1CCOCC1

Procedure:
A mixture of 38 g of 5-benzyloxy-8-ethoxycarbonylamino-1,4-benzodioxane (XIg), code number 770 522, and 300 ml of morpholine was brought to reflux for 16 hours, in the presence of a pinch of ammonium chloride. Then the morpholine in excess was evaporated and the residue was recrystallized in 96° ethanol.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[NH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C>C(#N)C>[C:6]([C:5]([C:8]#[N:9])=[CH:4][NH:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:16])#[N:7]
Reactant: NCCNC(=O)c1ccc(F)cc1
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CC(C#N)=CNCCNC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
After adding acetonitrile (100 mL) and ethoxymethylenemalononitrile (4.5 g) to N-(2-aminoethyl)(4-fluorophenyl)carboxamide hydrochloride (8.3 g), a solution of triethylamine (4.5 g) in acetonitrile (20 mL) was added thereto. After stirring at room temperature for 15 minutes, the solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was stirred. The precipitated solid was filtered out to obtain the crude title compound (6.5 g) as a brown solid.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.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>[F:10][C:3]1[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: Nc1ccc(F)c(Br)c1F
Reactant: CCB(CC)c1cccnc1
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: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(F)c(-c2cccnc2)c1F
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture of 3-bromo-2,4-difluorophenylamine (from Example 2, step b) (12.5 g, 60 mmol), diethyl(3-pyridyl)borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) in tetrahydrofuran (150 ml) and water (50 ml) was degassed with nitrogen for 15 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and the reaction was heated at reflux for 4 days. The mixture was cooled to ambient temperature and the majority of the tetrahydrofuran removed on a rotary evaporator. The residue was diluted with water (250 ml), extracted with ethyl acetate (300 ml), the organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography [silica gel, 10–50% EtOAc/isohexane (containing 1% triethylamine)] afforded 5.8 g (47%) of the title compound as a cream-coloured solid: 1H NMR (400 MHz, CDCl3) δ 3.69 (2H, br s), 6.72–6.88 (2H, m), 7.39 (1H, dd, J 8, 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5, 1), 8.72 (1H, s).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1([C:12]2[N:16]([CH2:17][C:18]3[CH:26]=[CH:25]C(C(O)=O)=[CH:20][CH:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)(Cl)Cl>[N:7]1([C:12]2[N:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:1]([C:2]([Cl:4])=[O:3])=[CH:25][CH:26]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1

Procedure:
Oxalyl chloride (4 mL) was added to a suspension of 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoic acid (0.28 g, 0.872 mmol) in chloroform (50 mL). The mixture was heated at reflux for 1 hour and then concentrated under vacuum. The residue was diluted with toluene, concentrated under vacuum and then dried under vacuum at ambient temperature over the weekend to provide crude 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[N:3]1[CH2:23][CH2:22][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].O>O1CCCC1>[CH2:36]([O:35][C:33](=[O:34])[O:21][C:7]1[C:6]2([CH2:5][CH2:4][N:3]([N:2]([CH3:1])[CH3:24])[CH2:23][CH2:22]2)[NH:10][C:9](=[O:11])[C:8]=1[C:12]1[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])[CH3:37]
Reactant: Cc1cc(C)c(C2C(=O)NC3(CCN(N(C)C)CC3)C2=O)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)NC12CCN(N(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
97 mg 8-Dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (from Step 4) and 45 mg triethylamine are dissolved in 15 ml tetrahydrofuran, and the mixture cooled in an ice bath. Then, 33 mg ethyl chloroformate is added at 0° C. The mixture is allowed to warm to room temperature, and stirred for 2 hours. Then water is added and the mixture extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and the solvent evaporated. The crude product is purified by chromatography on silica gel, with ethyl acetate/methanol/triethylamine (90:5:5) as a solvent, yielding 79 mg Carbonic acid 8-dimethylamino-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester as a solid, mp 162-166° C. 1H-NMR (CDCl3): 7.20 ppm (s, broad, 1H), 6.83 ppm (s, 2H), 4.02 ppm (q, 2H), 3.05 ppm (m, 2H), 2.54 ppm (m, 2H), 2.40 ppm (s, 6H), 2.25 ppm (m, 5H), 2.17 ppm (s, 6H), 1.70 ppm (m, 2H), 1.10 ppm (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([C:32]([CH3:34])=[CH2:33])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:11]([O:13]C(C)(C)C)=[O:12])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([C:32]([CH3:34])=[CH2:33])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:11]([OH:13])=[O:12])=[O:6]
Reactant: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)O)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A cold (0° C.) solution of tert-butyl α-[2-[(3,4-difluorebenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (EXAMPLE 94, step 4; 505 mg, 0.959 mmol) in CH2Cl2 (2 mL) is treated with TFA (2 mL) and maintained at 0° C. for 30 min. The ice bath is removed, and after 1 h, the solution was diluted with CH2Cl2 and concentrated (3×). The residual oil is diluted with H2O (10 mL) and extracted into CH2Cl2 (3×25 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide 430 mg (95%) of the title compound as a slightly yellow, amorphous solid:
Reaction SMILES: Cl.[C:2](Cl)(=O)[CH3:3].[NH2:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:10]=[C:9]([C:21]([OH:23])=[O:22])[C:8]=1[Cl:24].C(OCC)(=O)C.CCCCCC>C(O)C>[CH2:2]([O:22][C:21]([C:9]1[C:8]([Cl:24])=[C:7]([NH2:6])[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:10]=1)=[O:23])[CH3:3]
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2ccc(Cl)cc2F)nc(C(=O)O)c1Cl
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1Cl
Temperature: 62 °C
Yield: 63.5 %

Procedure:
A 1N solution of HCl in ethanol was generated by adding 0.565 mL of acetyl chloride dropwise to 12 mL of ethanol cooled in an ice bath. This solution was added to 200 mg of 6-amino-5-chloro-2-(4-chloro-2-fluorophenyl)-pyrimidine-4-carboxylic acid and the resulting solution was heated at 62° C. overnight. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic phase was dried and concentrated, and the product was purified by column chromatography (dichloromethane/ethyl acetate gradient). A second chromatography utilizing an amine-functionalized silica gel column (Biotage KP-NH) and an ethyl acetate/hexane gradient solvent system yielded the title compound (139 mg, 63.5% yield): mp 131-132° C.: 1H NMR (CDCl3): δ 7.97 (m, 1H), 7.2 (m, 2H), 5.63 (br s, 2H), 4.48 (q, 2H), 1.44 (t, 3H).
Reaction SMILES: [OH:1][NH:2]Cl.C(=O)(O)[O-].[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]([OH:17])=[O:16]>O>[OH:1][N:2]=[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: ONCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NO)c1cccs1
Yield: 47.9 %

Procedure:
A cooled solution of hydroxylamino hydrochloride (0.884 g) and sodium bicarbonate (1.08 g) in water (20 ml.) was added to a cooled (0°) solution of thien-2-yl-glyoxylic acid (2.0 g) and sodium bicarbonate (1.08 g) in water (20 ml.). After two days at 20° the solution was extracted with ether, cooled and acidified with concentrated hydrochloric acid. The resulting white solid was filtered off (0.564 g) and the filtrate was then thoroughly extracted with ether. The combined extracts were washed with brine, dried and concentrated. The solid residue was triturated with benzene to give the oxime (syn-isomer) (1.05 g; 51%), m.p. 1320,λmax. (ethanol) 284 mm (ε9,500), νmax. (Nujol) 2590 and 1706 (CO2H) and 1655 cm-1 (C=N), (DMSO-d6), -2.5 to -9.5 (broad multiplet; N-OH and COOH), 2.36 (multiplet; thienyl C-5 H) and 2.82 (multiplet; thienyl C-3 H and C-4 H).
Reaction SMILES: C([BH3-])#N.[Na+].Cl.Cl.[N:7]1([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1.CCO>CO>[CH:26]1([CH2:29][N:10]2[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Reactant: O=CC1CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(CC3CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (20.0 mmol) sodium cyanoborohydride was added batchwise at RT to a stirred mixture of 1.71 g (5.0 mmol) tert-butyl 4-piperazin-1-yl-piperidine-1-carboxylate dihydrochloride, 0.75 mL (10.0 mmol) cyclopropanecarbaldehyde, 30 mL EtOH and 20 mL MeOH and stirred overnight at RT. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in saturated NaHCO3 solution and extracted erschöpfend with EtOAc. The combined organic phases were dried over Na2SO4, suction filtered, evaporated down under reduced pressure and purified by column chromatography over silica gel.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C=O)C.O>[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([CH2:43][CH2:44][CH2:45][N:46]6[CH2:51][CH2:50][O:49][CH2:48][CH2:47]6)[CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1)NC1CC1
Reactant: ClCCCN1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCN(CCCN5CCOCC5)CC4)sc23)c(F)c1)NC1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
To a stirred solution of compound 271 (150 mg, 0.302 mmol) and DIPEA (227 μl, 1.302 mmol) in DMF (10 mL) was added 4-(3-chloropropyl)morpholine (53.3 mg, 0.325 mmol). The reaction mixture was stirred at 50° C. for 2 h. More 4-(3-chloropropyl)morpholine (212 mg, 1.3 mmol) was added in 4 h and the reaction mixture was heated at 50° C. for an additional 19 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 15/85 over 20 CV) to produce a material that upon trituration with AcOEt afforded title compound 276 (40 mg, 0.07 mmol, 22% yield) as beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 7.71 (dd, J=2.4 and 13.6 Hz, 1H), 7.48 (s, 1H), 7.34 (t, J=9.2 Hz, 1H), 7.22-7.18 (m, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.55 (d, J=5.2 Hz, 1H), 6.37 (s, 1H), 3.56 (q, J=4.8 Hz, 4H), 3.12 (bs, 2H), 2.70-2.62 (m, 2H), 2.62-2.58 (m, 2H), 2.58-2.50 (m, 1H), 2.43 (t, J=7.2 Hz, 2H), 2.40-2.32 (m, 2H), 2.30 (t, J=7.2 Hz, 2H), 1.64 (quint, J=6.8 Hz, 2H), 0.66-0.62 (m, 2H), 0.44-0.41 (m, 2H). MS (m/z): 552.4. (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][C:5]2[CH:13]=[CH:14][S:15][C:4]=2[S:3]1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[CH3:1][N:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]2[CH:13]=[CH:14][S:15][C:4]=2[S:3]1
Reactant: CCOC(=O)C1=Cc2ccsc2SN1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CN1Sc2sccc2C=C1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
To a solution of the product from Step B (1.00 g, 3.66 mmol) in anhydrous THF (20 mL) at -70° C. was added DIBAL (1.0M, 7.69 mL, 7.69 mmol). The mixture was warmed to ambient temperature and stirred for 2 h, additional DIBAL (20 mmol) was added and the reaction was stirred for 18 h. Methanol (100 mL) was added and the reaction mixture was evaporated to a residue which was suspended in 2N HCl (50 mL) and extracted with ethyl acetate (2×80 ml). The combined extracts were dried (MgSO4) and evaporated to give a solid which was recrystallized from ethyl acetate/hexane to give the desired product (0.80 g, 95%): mp 128°-130° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:29]1[N:30]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[CH:31]=[C:32]([C:34](OCC)=O)[N:33]=1.O>C1COCC1>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([N:30]2[CH:31]=[C:32]([CH2:34][N:18]3[CH2:19][CH2:20][N:15]([C:12]4[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=4)[CH2:16][CH2:17]3)[N:33]=[C:29]2[C:23]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=2[Cl:21])=[CH:44][CH:43]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(Cc3cn(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)n3)CC2)cc1
Reaction time: 0.17 h
Yield: 2.7 %

Procedure:
To a suspension of lithium aluminum hydride (21 mg, 0.54 mmol) in THF (2 mL), 1-(4-methylphenyl)piperazine hydrochloride (32 mg, 0.13 mmol) was added. After 10 minutes, a solution of ethyl 2-(2,4-dichlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (39 mg, 0.1 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred for 10 minutes, and diluted by water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by HPLC (YMC-packed Pro C18 20×150 mm column, 10-90% CH3CN in H2O/TFA, 25 mL/min) to give the product 1-{[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-yl]methyl}-4-(4-methylphenyl)-piperazine (1.4 mg, 2% yield): LC-MS m/z 511.1 (MH+), retention time 2.94 min (method 1). 1H NMR (300 MHz, CDCl3) δ: 2.29 (3H, s), 3.42-3.49 (8H, br), 4.39 (2H, s), 6.85-7.41 (11H, m), 7.54 (1H, s).
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[CH2:3]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:29]([N:31](CC)CC)[CH3:30].C(N)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O>O1CCCC1>[CH2:29]([NH:31][CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[CH2:3]1)[CH3:30]
Reactant: CN1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: CCN(CC)CC
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Product: CCNC1CN(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 18 h
Yield: 73 %

Procedure:
Under nitrogen, a stirred solution of the compound from Step E (5.00 g, 16.8 mmol) and p-toluenesulfonyl chloride (1.1 eq, 18.5 mmol, 3.30 g) in tetrahydrofuran (100 mL) was treated with triethylamine (1.1 eq, 2.78 mL). After 18 h at room temperature, TLC. indicated that starting material was still present so additional p-toluenesulfonyl chloride (0.4 eq, 1.3 g) and triethylamine (0.4 eq, 1.0 mL) was added. Stirring was continued for another 18 h, at which point TLC. indicated the absence of starting material. Ethylamine (18 g) was added to the reaction mixture and the flask was stoppered. After 18 h at room temperature, TLC. indicated that the intermediate tosylate was absent. At this point, the reaction mixture was combined with another 1.55 g run for workup. The mixture was partitioned between 1 M aqueous hydrochloric acid (100 mL) and diethyl ether (250 mL) and the acidic aqueous phase was separated. The organic phase was further extracted with 1 M aqueous hydrochloric acid (3×100 mL), and the combined aqueous layers were then back washed with ether (3×100 mL), basified using solid sodium bicarbonate, and extracted with ethyl acetate (4×250 mL). The combined organic ethyl acetate extracts were dried over MgSO4, treated with decolorizing carbon (Norite A), filtered through celite, and concentrated under reduced pressure, to provide 5.2 g (73%) of the sulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][NH2:12]>C(O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1F
Reactant: CN
Solvent: CCO
Product: CNc1cccc(N)c1C#N

Procedure:
2-Amino-6-fluorobenzonitrile (200 mg) is heated in a sealed vessel in ethanol saturated with methylamine gas at 140° C. for 4 hrs. The solvent is evaporated, water is added and the product is extracted into methylene chloride. Evaporation of the solvent gives the title compound as an oil, (200 mg) which is converted to the crystalline hydrochloride with i-propanolic HCl-diethyl ether, m.p. 214°-216° C. (dec).