Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:11][CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([N:14]1[C:22]2[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)[CH2:12][CH3:13])(=[O:38])=[O:37]
Reactant: CCC(CCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(CCOS(C)(=O)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-(1-(3-(4-chlorophenyl)-1-hydroxypentan-3-yl)-1H-indol-4-yl)methanesulfonamide (20 mg, 0.05 mmol), as described in Example 40 Step I, and NMM (10 mg, 0.1 mmol) in DCM (3 mL) was added methanesulfonyl chloride (7 mg, 0.06 mmol). Then the mixture was stirred at room temperature for 1 h, quenched with saturated ammonium chloride solution (5 mL), and extracted with ethyl acetate. The organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by Prep-TLC (PE/EA=4/1) to afford the title compound as colorless oil. LC/MS m/z=485.1[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CN(C)CCN
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NCCN(C)C)cc3)cc12

Procedure:
N1-(1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)-N2,N2-dimethylethane-1,2-diamine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and N1,N1-dimethylethane-1,2-diamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.85 (m, 2H), 8.43 (d, 1H), 7.52 (s, 1H), 7.48 (m, 2H), 7.40 (m, 2H), 6.69 (m, 1H), 4.39 (m, 1H), 3.42 (m, 2H), 3.18-3.25 (m, 6H), 2.87 (s, 6H), 2.56 (s, 3H), 1.69 (d, 3H). LRMS [M+H]=428.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]
Reactant: Oc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A solution of 2,4-difluorophenol (5.39 g, 41.4 mmol) in N,N-dimethylformamide (34.5 mL) was cooled to 10° C. and treated portionwise with sodium hydride (1.66 g, 41.4 mmol). After stirring 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (2.28 g, 10.36 mmol) was added portionwise. The reaction mixture was stirred at ambient temperature for 1.5 hours, diluted into ethyl acetate and quenched with 0.5 M HCl to pH 6. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the title compound (3.24 g, 95%).
Reaction SMILES: CO.[OH-].[Na+].C[O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:30])=[CH:24][CH:23]=1)=[O:8].Cl>O>[F:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:12]3[C:11]4[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=4)[N:15]=[CH:14][CH:13]=3)=[CH:23][CH:24]=2)=[O:30])=[CH:37][CH:36]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
After adding methanol (9 ml) and 2N aqueous sodium hydroxide (3 ml) to methyl-4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinoline carboxylate (300 mg, 0.65 mmol), the mixture was stirred at room temperature for 2 hours and then at 60° C. for 20 minutes. The reaction solution was cooled to room temperature and 1N hydrochloric acid was added for neutralization, after which methanol (6 ml) and water (6 ml) were added, the mixture was stirred overnight, and the precipitated light brown crystals were filtered out and dried under reduced pressure to obtain the title compound (227 mg, 0.51 mmol, 78.0%).
Reaction SMILES: [N:1]1([C:7]2[C:8]([C:15]([F:18])([F:17])[F:16])=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28].Cl>C(#N)C>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]([C:15]([F:16])([F:18])[F:17])=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: CCCI
Reactant: N#Cc1cccc(N2CCNCC2)c1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(C#N)c2C(F)(F)F)CC1

Procedure:
Preparation according to Example 1: 3-piperazin-1-yl-2-(trifluoromethyl)benzonitrile (0.83 g, 3.25 mmol), acetonitrile (40 ml), potassium carbonate (0.88 g, 8.1 mmol) and 1-iodopropane (0.255 ml, 3.25 mmol). Yield: 0.74 g (77%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 234-236° C. MS m/z (relative intensity, 70 eV) 297 (M+, 15), 269 (14), 268 (bp), 225 (26), 177 (8).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: COCCN
Reactant: Cc1ccc2nc(Nc3nc4cc(C(=O)O)ccc4n3C)sc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C)cc3s1)n2C

Procedure:
2-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (29 mg) was prepared by following General Procedure F using 2-(6-methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 397.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.[OH-].[Na+]>C(O)C>[CH3:10][C:9]1[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:5][CH:6]=[CH:7][C:8]=1[S:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(SCc2cccs2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2cccs2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 75 %

Procedure:
2-Chloromethyl-3-methyl-4-(2-thienylmethylthio)pyridine hydrochloride, 2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 25° C. for 20 h. After crystallization from toluene/methanol, the title compound is isolated. Yield: 75%, m.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:22]3[CH2:21][CH2:20][CH:19]([N:18]4[C:17]5[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=5[NH:15][C:14]4=[O:13])[CH2:24][CH2:23]3)[N:10]=2)[CH:7]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Temperature: 45 °C
Reaction time: 20 h
Yield: 34.8 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1: 0.186 g), 4-(2-keto-1-benzimidazolinyl)piperidine (Aldrich; 0.201 g), triethylamine (0.094 g), and dichloromethane (4 mL) is stirred at 45° C. for 20 h, after which time the mixture is cooled. Dichloromethane and aqueous sodium bicarbonate are added and the solids collected and dried. Additional material is obtained by concentration of the organic layer. Crystallization from methanol/dichloromethane/hexane gives 0.123 g of the title compound; mp 210-211 (decomp)°C; IR (mineral oil) 1695, 1486, 1338, 736, 1074 cm-1. 1H NMR (DMSOd6) δ1.63, 2.19, 2.38, 3.08, 3.66, 4.12, 6.96, 7.23, 7.54, 7.87, 8.80, 10.84.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[C:21]([C:22]([C:24]4([CH3:32])[CH2:29][O:28]C(C)(C)[O:26][CH2:25]4)=[O:23])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl>O1CCCC1.CO>[OH:26][CH2:25][C:24]([CH2:29][OH:28])([CH3:32])[C:22]([C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:14]=2)[NH:19][CH:20]=1)=[O:23]
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)COC(C)(C)OC4)c3n2)cc(OC)c1OC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(CO)CO)c3n2)cc(OC)c1OC
Reaction time: 1 h
Yield: 7.1 %

Procedure:
A suspension of [2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(2,2,5-trimethyl-[1,3]dioxan-5-yl)-methanone (30 mg, 0.7 mmol) in tetrahydrofuran (5 ml) and MeOH (4 ml) was heated using a heat gun until homogeneity was achieved. The reaction mixture was treated with 1M HCl (1.0 ml, 1.0 mmol) and stirred for 1 hour. The reaction mixture was concentrated to 3 ml of solvent and then partitioned between EtOAc/saturated aqueous NaHCO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated affording 20 mg (73%) of 3-hydroxy-2-hydroxymethyl-2-methyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a pale yellow solid. MP 222-223° C., M+H=402.
Reaction SMILES: CO.[N+:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12][CH:13]=1)([O-])=[O:4].C[O-].[Li+].C(Cl)[Cl:26]>[Ti](Cl)(Cl)(Cl)Cl.O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:11]1[N:12]=[CH:13][C:8]([CH2:7][C:6]([Cl:26])=[N:3][OH:4])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)nc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: ON=C(Cl)Cc1ccc(COc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a methanol (5 mL) solution of 5-(2-nitro-ethyl)-2-(pyridin-2-yloxymethyl)-pyridine (93 mg, 0.36 mmol) described in Manufacturing Example 154-1-7 was added lithium methoxide (27 mg, 0.72 mmol), which was stirred for 5 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (3 mL) and methylene chloride (3 mL) was added titanium (IV) tetrachloride (87 μL, 0.79 mmol) under nitrogen atmosphere at −78° C., which was stirred for 2 hours at 0° C. More titanium(IV) tetrachloride (50 μL, 0.46 mmol) was added at −78° C., which was stirred for 3 hours at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (24 mg). This compound was used in the following reaction without any further purification.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-acetylaniline (1 ml; 8.3 mmol) and acetic anhydride (10 ml) was stirred overnight at ambient temperature. Saturated aqueous sodium carbonate was added till basic reaction and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated under reduced pressure to leave N-(2-acetylphenyl)acetamide quantitatively. This product was dissolved in ethanol (40 ml) and hydroxylamine, hydrochloride (0.94 g; 13.6 mmol) was added. The mixture was heated to reflux for 7 hours and then left at ambient temperature overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and aqueous sodium carbonate. The organic phase was concentrated and subjected to chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1 v/v) as the eluent. Yield: 0.26 g (15%). Mp. 99-100° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=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>[CH:16]1([CH2:15][O:14][C@@H:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][CH3:19])[CH:22]=3)=[CH:3][CH:4]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:18][CH2:17]1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)OCC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cccc(-c2ccc(C[C@H](OCC3CC3)C(=O)OC)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
53 mg (0.046 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 145 mg (0.46 mmol) of methyl (S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propionate and 129 mg (0.55 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 3 ml of dimethylformamide. 0.3 ml of a 2M potassium phosphate solution is added and the reaction mixture is stirred at 90° C. for 2 hours. The reaction is halted by the addition of 10 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 70 mg of methyl (S)-2-cyclopropylmethoxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=45%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:27][CH3:30])[CH:24]([CH3:25])[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)C(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2-methylpropan-1-ol (73.6 mg, 0.173 mmol) in N,N-dimethylformamide (1.0 mL) was added sodium hydride (10.3 mg, 0.260 mmol) at 0° C. After 30 min, to the mixture was added methyl iodide (53.9 μL, 0.865 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hrs. The mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (43.7 mg, 0.0996 mmol, 58%).
Reaction SMILES: [Sn](Cl)Cl.[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C@@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2>CN(C=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]1)[C@@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc([N+](=O)[O-])cc2o1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Product: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc2c1
Reaction time: 8 h

Procedure:
15.0 ml (30 mmol) of a 2 M tin(II) chloride solution in DMF are added to N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzofuran-2-carboxamide (1550 mg, 4.92 mmol). The mixture is stirred overnight. The solvent is removed under reduced pressure using a rotary evaporator. The crude product is taken up in methanol and, together with acidic ion exchange resin (Dowex WX2-200), shaken for about 1 h. The loaded ion exchanger is washed with methanol, then with water, DMF, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator. The crude product is purified on silica gel 60 (mobile phase: dichloromethane/triethylamine 100:1→dichloro-methane/methanol/triethylamine 100:1:1→dichloromethane/methanol/triethylamine 90:10:1). 643 mg (46% of theory) of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36](Cl)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([C:23]#[C:22][C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (example B.14) according to general procedure II. Obtained as a yellow solid (44 mg, 30%). MS (ISP) 590.0 (M+H)+]; mp 220–223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][N:18]([CH3:19])[CH3:17])=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: Cc1ccccc1-c1ccc(Cl)cc1C#N
Reactant: CNC
Solvent: ClCCl
Product: CN(C)Cc1ccccc1-c1ccc(Cl)cc1C#N

Procedure:
The starting material is prepared as follows: 3.8 g of 3-chloro-6-o-tolyl-benzonitrile (described in Example 3) is brominated as described in Example 2, and the residue dissolved in 25 ml of methylene chloride. The solution is added slowly to that of 14 g of liquid dimethylamine in 100 ml of methylene chloride while stirring at 0°. The mixture is stirred at room temperature for 16 hours, evaporated and the residue stirred with diethyl ether and 1 N hydrochloric acid. The aqueous phase is separated, combined with methylene chloride and basified with cold 2 N aqueous sodium hydroxide. The organic layer is separated, dried and evaporated to yield the 3-chloro-6-(o-dimethylaminomethyl-phenyl)-benzonitrile.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH:30]([C:38](O)=[O:39])[CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([CH:30]5[CH2:31][C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[O:28][CH2:29]5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1COc2ccccc2C1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1COc2ccccc2C1

Procedure:
The title compound, white solid (26 mg, 64.9%), MS (ISP) m/z=492.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and chroman-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH:15](=[N:4]/[C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: Fc1ccccc1/N=C/c1ccccc1

Procedure:
Dissolved 2-fluoroaniline (2.0 mL, 20.8 mmol, 1.05 eq) in 40 mL of anhydrous ether. Added Magnesium Sulfate (7146 mg, 59.3 mmol, 4 eq), 7 g of powdered mol sieves, and benzaldehyde (2.0 mL μl, 19.8 mmol). To this mixture was added pTsOH (18.8 mg, 98.9 jμmol, 0.005 eq) and heated to reflux overnight. The reaction was cooled, filtered and concentrated to yield (E)-N-benzylidene-2-fluorobenzenamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 1H), 7.95 (m, 2H), 7.52 (m, 5H), 7.18 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18]3)[N:10]([C:31]([C:27]3[O:26][CH:30]=[CH:29][CH:28]=3)=[O:32])[CH2:9][CH2:8][C:7]2=1
Reactant: O=C(Cl)c1ccco1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1
Agent: Cl
Product: CCOC(=O)C1(C2c3[nH]c4ccc(OC)cc4c3CCN2C(=O)c2ccco2)CCC1

Procedure:
The procedure is as in Example 55, using as substrate the compound of Example 7 and as reagent 2-furoyl chloride.