Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:16][CH2:17][CH2:18][OH:19]>C(O)C>[OH:19][CH2:18][CH2:17][CH2:16][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCCCCl
Reactant: Oc1ccc(S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCSc1ccc(O)cc1
Reaction time: 8 h

Procedure:
4-Hydroxythiophenol (6.31 g, 50 mmol) was dissolved in ethanol (100 mL) and potassium tert.-butoxide (6.72 g, 60 mmol) was added. The mixture was stirred stirred until a clear, yellow solution was obtained. Then 3-chloro-1-propanol (4.20 mL, 50 mmol) was added with a syringe. The reaction mixture was stirred overnight at room temperature, the potassium chloride precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and the organic layer was extracted with water (2×100 mL) and brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (50 mL) and hexane (100 mL) and left standing open overnight. The solid product was filtered off and dried under high vacuum. Yield: 5.34 g (58%) pale yellow solid.
Reaction SMILES: Cl[C:2]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)=[O:3].N1C=CC=CC=1.[CH3:15][OH:16]>C(Cl)Cl>[NH:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:2]([O:16][CH3:15])=[O:3]
Reactant: CO
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc[nH]1

Procedure:
40 ml of a solution of 45 (mmoles) of 2-chlorocarbonyl-1H-pyrrole in methylene chloride were added dropwise to a cold mixture of 4.3 ml of pyridine and 3.5 ml of methanol and the mixture was washed with water, then with 6 ml of N sodium hydroxide, and was extracted with methylene chloride. The organic phases were dried and concentrated to dryness and the residue was chromatographed over silica. Elution with a mixture of hexane and ethyl acetate (8-2) yielded 4.014 g of methyl 1H-pyrrole-2-carboxylate melting at ≈74° C.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[Br:21][CH:22]([CH3:26])[C:23](Br)=[O:24]>C1(C)C=CC=CC=1>[Br:21][CH:22]([CH3:26])[C:23]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:24]
Reactant: CCCCCCCCCCCCO
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a stirred solution of 1-decanol 2 (10 g, 53.7 mmol) in toluene (100 mL) was added triethylamine (7.5 mL, 53.7 mmol)) followed by 2-bromo propionyl bromide 58 (12.7 g, 59.1 mmol) at 5-10° C. The reaction mixture was stirred for 3 hours at 55-60° C.; the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated, the organic layer was washed with brine, and the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 59 (16.2 g, yield: 94%) as a liquid.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:19])([CH3:18])[O:15][C:16](=[O:17])[C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH3:19][C:14]1([CH3:18])[O:13][C:12]2[CH:20]=[CH:21][C:9]([CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:35](=[O:37])[C:34]3[CH:33]=[CH:32][C:31]([C:30]#[C:29][C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=4)=[CH:39][CH:38]=3)=[CH:10][C:11]=2[C:16](=[O:17])[O:15]1
Reactant: CCCCCCNCc1ccc2c(c1)C(=O)OC(C)(C)O2
Reactant: O=C(O)c1ccc(C#Cc2ccc(F)cc2)cc1
Product: CCCCCCN(Cc1ccc2c(c1)C(=O)OC(C)(C)O2)C(=O)c1ccc(C#Cc2ccc(F)cc2)cc1
Yield: 98.5 %

Procedure:
The title compound was prepared following procedure described in example 20, step e) from 6-[(hexylamino)methyl]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (490 mg, 1.68 mmol) and 4-[(4-fluorophenyl)ethynyl]benzoic acid (484 mg, 2.02 mmol). Purification of the crude product by flash chromatography on silicagel (EtOAc/c-Hex (20/80) gave 850 mg (98%) of the title compound. HPLC, Rt: 5.54 min (purity: 99.9%). LC/MS, M+(ESI): 514.1. 1H NMR (CDCl3) δ: 7.45-7.90 (m, 6H), 7.37 (d, J=8.1 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 6.94 (d, J=8.5 Hz, 1H), 4.69 (s, 1.5H), 4.45 (s, 0.5H), 3.39 (s, 0.5H), 3.14 (s, 1.5H), 1.07-1.77 (m, 14H), 0.80 (m, 3H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]#[C:23][NH2:24].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(NC2CCCCC2)=S)CCCCC1>C(#N)C.C(N(CC)CC)C>[C:23]([NH:24][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:22]
Reactant: S=C(NCCCCOc1ccccc1)Nc1cccnc1
Reactant: N#CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: S=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CNC(=Nc1cccnc1)NCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-Phenoxybutyl)-N'-3-pyridylthiourea (1.41 g) was dissolved in acetonitrile (10 ml), and cyanamide (400 mg), N,N'dicyclohexylcarbodiimide (1.95 g) and triethylamine (0.08 ml) were added. The mixture was stirred for 3 days at room temperature, when it was filtered, washed with acetonitrile, and ether to yield a solid mixture of the crude product and N,N'-dicyclohexylthiourea. The pure compound was obtained by extracting the mixture with 0.5N hydrochloric acid (16 ml), filtering and re-precipitation by addition of 9N sodium hydroxide to the filtrate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23](O)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 53.7 %

Procedure:
N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-fluoro benzohydrazide was prepared using 4-fluorobenzoic hydrazide (4.4 mmol, 1.1 equiv.) and (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (4.0 mmol, 1.0 equiv.) as described previously in the preparation of intermediate 5a. The crude golden yellow solid was recrystallized using hot methylene chloride to provide the desired product as a light yellow solid (870 mg, 54% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.85 (br. s., 1H), 9.5 (br. s., 1H), 8.02 (dd, J=5.4, 8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.5 Hz, 1H), 5.59 (br. d, J=6.8 Hz, 1H), 4.70 (br. s., 1H), 4.24 (m, 1H), 4.12 (dd, J=4.9, 7.3 Hz, 1H), 2.35 (s, 3H), 1.38 (d, J=6.3 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H18ClFN4O3 [M]+ 404.82, found 405.4; TLC Rf=0.38, 100% EtOAc, vanillin stain.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:22]4[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:4][CH2:3][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@@H:22]5[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]5)[CH2:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:7][CH2:6]2)=[O:28])[CH2:26][CH2:25]1
Reactant: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of (3aR,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-indol-2-one (70 mg, 0.22 mmol) in DMF (3 mL) was added with cyclopropane carboxylic acid (18.86 mg, 0.22 mmol) and diisopropylethyl amine (0.046 mL, 0.26 mmol) at room temperature. After 5-10 minutes HATU (83 mg, 0.22 mmol) was added and the mixture stirred at room temperature over night. The solvent was removed in vacuo, the residue dissolved in dichloromethane (60 mL) and washed with 1N NaOH (7 mL) and brine and concentrated in vacuo. The residue was purified by preparative LC/MS (high pH) to provide the title compound (58 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.54-0.74 (m, 2H), 0.77-0.95 (m, 2H), 0.84 (s, 3H), 1.01-1.44 (m, 6H), 1.45-1.84 (m, 11H), 2.01-2.15 (m, 2H), 2.19-2.40 (m, 2H), 2.73-3.06 (m, 3H), 3.17-3.32 (m, 1H), 3.37 (s, 1H), 3.44-3.68 (m, 2H), 3.69-3.80 (m, 1H), 3.81-3.97 (m, 1H). MS (M+1): 388.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(OCCBr)cc1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-4-fluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.5, 1.5 Hz, 1H), 7.10-6.98 (m, 2H), 6.84-6.76 (m, 2H), 4.63 (t, J=5.0 Hz, 2H), 4.22 (t, J=5.0 Hz, 2H), 2.49 (s, 3H); MS (ES) m/z 329 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH2:31])(=[O:30])=[O:29])=[CH:18][CH:17]=1)[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:6]#[N:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39]([N:42]=[C:43]=[O:44])[CH2:40][CH3:41].Cl>CC(C)=O.ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:6]#[N:7])[N:8]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:31][C:43]([NH:42][CH2:39][CH2:40][CH3:41])=[O:44])(=[O:29])=[O:30])=[CH:20][CH:21]=1)[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(C#N)C(=O)OCC
Reactant: CCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C#N)C(=O)OCC

Procedure:
7.2 g of the product of Stage A, 6.5 g of anhydrous potassium carbonate and 1.48 ml of n-propyl isocyanate were stirred in 180 ml of acetone at reflux for 2 hours 30 minutes. After cooling, the solution was treated with 2N hydrochloric acid and the residue obtained was dissolved in an aqueous mixture of dichloromethane. After extraction with methylene chloride, the extracts were dried and the solvents were eliminated under reduced pressure and the product was crystallized from ethyl acetate to obtain 6.5 g of the expected product as a white solid with a Rf (SiO2, ethyl acetate)=0.48 and melting at 131°-133° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:15]2[N:14]=[C:13]3[CH:18]=[N:19][N:20]([CH3:21])[C:12]3=[C:11](Cl)[C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:25])C>>[CH2:1]([C:8]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[CH:18]=[N:19][N:20]([CH3:21])[C:12]=3[C:11](=[O:25])[C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cn1ncc2nc3ccc(Cc4ccccc4)cc3c(Cl)c21
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4)cc3c(=O)c21
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 7-benzyl-9-chloro-1-methyl-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 11, step 2, 1.00 g, 3.25 mmol) in 50% aqueous acetic acid (20 ml) was refluxed for 6 h. After cooling to room temperature, the formed solid was collected by filtration to give 905 mg (96%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[NH:23][CH2:22][CH2:21][CH2:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].Cl>O1CCCC1.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[NH:23][CH2:22][CH2:21][CH2:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(Cc2n[nH]c(=O)c3c2NCCC3)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cc2n[nH]c(=O)c3c2NCCC3)ccc1F
Temperature: 25 °C

Procedure:
A solution of EXAMPLE 506E (2.8 g, 8.8 mmol) in tetrahydrofuran (150 mL) was treated with LiOH (253 mg, 10.6 mmol) in water (20 mL) at 50° C. overnight. After cooling to room temperature, the mixture was acidified with dilute HCl to pH 4, and concentrated to about 10 mL. The solid material was collected by filtration, washed with water and dried to provide the title compound. MS (DCI/NH3) m/z 305 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:25][O:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[O:26][CH3:25])[CH2:32]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1nc(-c2cccc(C(F)(F)F)c2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cccc(C(F)(F)F)c3)nc3ccccc13)C2
Yield: 12 %

Procedure:
Reaction of 2-(3-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 54 (12% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.74 and 2.99 (2t, 2H), 3.52 and 4.04 (2t, 2H), 3.68-3.82 (4s, 6H), 4.43 and 4.95 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.75-7.88 (m, 2H), 7.93-8.04 (m, 2H), 8.11-8.17 (m, 1H), 8.21-8.26 (m, 1H), 8.74-8.85 (m, 2H); MS (ESI) m/z 494 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:8]=2)[N:3]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.N1C(C)=CC=CC=1C>O1CCOCC1>[CH:13]1([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH:8]=3)[N:3]=[C:2]([NH:29][C:26]3[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=3)[N:11]=2)[CH2:15][CH2:14]1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NC4CC4)c3c2)cc1
Reactant: Cn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2nc(NC3CC3)c3cc(-c4ccc(F)cc4)ccc3n2)n1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To a solution of [2-Chloro-6-(4-fluoro-phenyl)-quinazolin-4-yl]-cyclopropylamine (150 mg, 0.48 mmol) and 1-Methyl-1H-pyrazol-3-ylamine (70 mg, 0.72 mmol) in 1,4-dioxane (5 ml) was added 2,6-lutidine (2 equiv.; 102 mg, 0.96 mmol). The solution was heated to 100° C. for 3 hours, then cooled and purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product (140 mg, 0.287 mmol, 60% yield). The product was characterized as follows: MS (m/z): 375 ([M+H]+, 100); HPLC Rt=1.60 minutes (Method B).
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19]O)[N:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19][Cl:5])[N:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
Methanesulfonyl chloride (570 μL, 7.35 mmol) was added to a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.9 g, 6.12 mmol) containing TEA (2.6 mL, 18.4 mmol) in DCM (30 mL) at 0° C. The solution was stirred at room temperature for 18 h. The reaction was partitioned between aqueous NH4Cl and DCM. The organic phase was collected, dried over MgSO4, filtered and concentrated in vacuo. Chromatography (30% EtOAc in petrol) gave the title compound (1.6 g) as a white solid. MS: [M+H]+=339.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: C1OCOCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To 153 ml of fuming sulfuric acid, containing about 27% of SO3, 50 g (0.3 m) of terephthalic acid are added, under stirring, at room temperature, then 23 g (0.25 m) of 1,3,5-trioxane are added thereinto in two portions, by cooling to a temperature of 15-18° C. after any addition. At the end of the addition, the mixture is left 30 minutes under stirring at room temperature, then it is heated at 135-145° C. and let under stirring for 2-2.5 hours at this temperature until the end of the reaction. The reaction mixture is cooled to a temperature lower than 3° C., then 100 ml of glacial acetic are added thereto by keeping the temperature at about 25° C. At the end of the addition, the mixture is let to stand 60 minutes under stirring at 20-25° C. and filtered. The wet product is suspended in 1900 ml of water. The suspension is heated up to 25-30° C. under stirring, its pH is adjusted to about 8 by gradual addition of 175 g of sodium bicarbonate. The solid is filtered off on Celite® by washing with hot water (40-45° C.). The pH of the mother liquors is brought to 1.5 by addition of about 125 ml of 37% hydrochloric acid and the obtained precipitate is filtered at 20-25° C. by washing with water until the filtrate reaches a neutral pH. Thus, 32 g of 5-carboxyphthalide with a titer (HPLC)>93% are obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([OH:33])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34]I.O>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([O:33][CH3:34])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reactant: CI
Solvent: O
Solvent: C1CCOC1
Product: CO[C@]12CC[C@H](c3ccoc3)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]21C
Temperature: 70 °C

Procedure:
To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377)in 80 ml of dimethylformamide, 18 g of imidazole and 20.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and 15 g of crude 3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol were obtained. A suspension of this protected alcohol and 1.3 g of KH in 75 ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g of methyl iodide were added. After 30' the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 12 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5](C#N)=[CH:4][N:3]=1.[C:31]([O-:34])(O)=[O:32].[Na+]>O1CCOCC1.S(=O)(=O)(O)O.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5]([C:31]([OH:34])=[O:32])=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)ncc1C(=O)O)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 90 °C
Reaction time: 60 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile (53) (495 mg, 1.19 mmol) in anhydrous 1,4-dioxane (20 mL), sulfuric acid/water (1:1, 7 mL) was added dropwise. The reaction mixture was stirred at 90° C. for 60 h. The mixture was allowed to cool to RT and basified with NaHCO3. The precipitate was collected by filtration and then dissolved in water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 117, (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxylic acid. The material was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:30])[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:39])C=1.[K+].[Br-]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:30])[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:24][C:18]=3[N:17]=2)=[O:39])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(-n3ccnc3)c(F)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2cc(-n3ccnc3)c(F)cc2[nH]1
Yield: 46.4 %

Procedure:
The title compound (0.24 g, 45%) was prepared by the above general procedure using 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(imidazol-1-yl)-1H-benzimidazole (0.5 g, 1.14 mmol) (obtained in example 2), m-chloroperbenzoic acid (50%, 0.47 g, 1.4 mmol) and dichloromethane (10 mL). mp 234-235° C.; IR (KBr) 3449, 1049 cm- 1; 1H NMR (CD3OD+CDCl3) δ 2.28 (s, 3H, CH3), 4.42 (q,J=6.3 Hz, 2H, OCH2CF3), 4.74 (ABq, J=9.6 Hz, Δv=6.2 Hz, 2H, SOCH2), 6.74 (d,J=5.6 Hz, 1H), 7.20 (m, 2H), 7.52 (d,J=10.8 Hz, 1H), 7.70 (d,J=7.6 Hz, 1H), 7.86 (s, 1H), 8.30 (d,J=5.6 Hz, 1H); Mass (m/z) 453 (M+).