Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.[CH3:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][C:20]([CH:1]([C:3]2[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:4]=2)[C:3]2[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C=O)c(C(=O)O)c1
Reactant: CN(C)c1ccccc1
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
In another known process for the preparation of CVL there are three steps. The first step comprises the interaction of the methyl ester of 2-formyl-5-dimethylaminobenzoic acid with two equivalents of N,N-dimethylaniline to obtain the methyl ester of 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. After isolation, this benzoic acid is oxidized in the second step and finally in the third step the oxidized product is saponified and the lactone ring is closed to obtain the 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide (CVL).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][S:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:25])=[O:24])=[CH:19][CH:20]=1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)CCc2ccc(Cl)cc2)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a solution of 2-amino-5-methoxy-benzenesulfonamide (4.0 g, 19.80 mmol) in pyridine (60 mL), 2-(4-chloro-phenyl)-ethanesulfonyl chloride (4.73 g, 19.79 mmol) was added slowly at 0° C. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure at 35° C. The residue was then partitioned between ethyl acetate and 1N HCl. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) to give the title compound (7.1 g, 88%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH3:24])[CH:2]([CH3:4])[CH3:3].N1([CH2:35][C:36]([NH2:38])=[O:37])C2C=CC=CC=2N=N1.[OH-].[Na+]>CCO>[CH3:24][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([C:14]3[CH:13]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[NH:38][C:36](=[O:37])[CH:35]=3)[CH:16]=2)[NH:20][N:19]=1
Reactant: Cc1n[nH]c2ccc(/C=C/C(=O)c3ccccc3OCC(C)C)cc12
Reactant: NC(=O)Cn1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1n[nH]c2ccc(-c3cc(-c4ccccc4OCC(C)C)[nH]c(=O)c3)cc12
Temperature: 90 °C
Yield: 21.4 %

Procedure:
To a mixture of (E)-1-(2-isobutoxyphenyl)-3-(3-methyl-1H-indazol-5-yl)prop-2-en-1-one (50 mg, 0.15 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetamide (Aldrich) (50 mg, 2.84 mmol), and 20 mg of NaOH in 10 mL of EtOH was heated to 90° C. for 4 h. The reaction mixture was concentrated down and purified by preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate) to afford 4-(3-methyl-1H-indazol-5-yl)-6-{2-[(2-methylpropyl)oxy]phenyl}pyridin-2(1H)-one (12 mg, 21.4%). 1H NMR (400 MHz, d6-DMSO): δ 12.78 (s, 1H), 8.15 (s, 1H), 7.71 (d, 1H), 7.53 (m, 2H), 7.45 (t, 1H), 7.15 (d, 1H), 7.07 (t, 1H), 6.77 (br s, 1H), 6.61 (s, 1H), 3.84 (d, 2H), 2.02 (m, 1H), 0.95 (d, 6H); MS (EI) for C23H23N3O2: 374 (MH+).
Reaction SMILES: O[C:2]1([CH2:26][I:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:34])CC>ClCCl>[F:34][C:2]1([CH2:26][I:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CI)CC3)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CI)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-hydroxy-4-iodomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.01 mmol) with DAST (1.32 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[N:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:22][O:23][C:24]([NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:25])[NH:26][CH:27]([C:28]([N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[C:15]1[NH:16][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)=[CH:13][N:14]=1)=[O:29])[CH:31]([CH3:33])[CH3:32]
Reactant: Brc1ccc2cc(-c3cnc(C4CCCN4)[nH]3)ccc2c1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
5-(6-Bromo-naphthalen-2-yl)-2-pyrrolidin-2-yl-1H-imidazole (3.80 g), 2-methoxycarbonylamino-3-methyl-butyric acid (2.21 g), and HATU (5.06 g) were dissolved in anhydrous DMF (75 mL), and N-methylmorpholine (2.68 mL) was added. The reaction mixture was stirred at ambient temperature for 16 hours and evaporated under vacuum. The oil was dissolved in dichloromethane, purified by chromatography (0-100% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(6-bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.814 g, 72%) as an off-white solid.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:17][C:18]1[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[S:21][C:22]=1[CH3:23].C(OC)(C)(C)C>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24](=[O:26])[CH2:25][C:11]([C:6]2[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=2)([OH:16])[C:12]([F:13])([F:14])[F:15])[S:21][C:22]=1[CH3:23]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1cc(Br)c(C)s1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1sc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 5 h
Yield: 127.2 %

Procedure:
LiH (3.2 g) is added to a solution of 1-(3,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (56 g) and 1-(4-bromo-5-methyl-thiophen-2-yl)-ethanone (41 g) in dry THF (500 ml). After 5 h at 60° C. under nitrogen atmosphere, tert-butylmethylether (500 ml) is added to the reaction mixture. The reaction is slowly quenched with water (500 ml) at 5° C. and further extracted twice with tert-butylmethylether (500 ml). The organic phases are combined, washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo to yield 1-(4-bromo-5-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butan-1-one (110 g, 77% purity) as a brown oil. The crude product is used without further purification.
Reaction SMILES: [N:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[NH:12][C:11]=2[C:27]([NH2:29])=[O:28])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO>[N:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[NH:12][C:11]=2[C:27]([NH2:29])=[O:28])(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1[nH]c2ccc(C#Cc3ccccc3)cc2c1S(=O)(=O)N1CCOCC1
Solvent: CO
Product: NC(=O)c1[nH]c2ccc(CCc3ccccc3)cc2c1S(=O)(=O)N1CCOCC1
Reaction time: 1 h

Procedure:
3-(Morpholin-4-ylsulfonyl)-5-(phenylethynyl)-1H-indole-2-carboxamide (50 mg, 0.12 mmol, 1.0 equiv) was dissolved in 10 mL of methanol. The vessel was degassed and charged with 10% palladium on carbon (5 mg, 10 weight percent). The vessel was then charged with 1 atm. H2 and stirred vigorously for 1 hour. The reaction was filtered through a pad of Celite, the pad was washed with methanol and the filtrate was concentrated in vacuo to provide the title compound. Proton NMR was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H24N3O4S (M+H+): 414.1482. Found 414.1479.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([O:19]C)=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH:33]=[CH:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].B>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:31][CH:32]=[CH:33][CH2:34]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:36][CH:37]=1
Reactant: COc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccc(O)cc32)cc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
79 mg (0.15 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-8-methoxy-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 10 ml of dichloromethane. 1.0 ml of borane tribromide was added to the obtained solution, and they were stirred at room temperature for 6 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])([OH:3])=[O:2].[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:17]=[CH:18][CH:19]=[CH:20]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])([OH:3])=[O:2]
Reactant: COC(=O)c1cc(/C=C/C(=O)O)cc(-n2cccc2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CCC(=O)O)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 89.9 %

Procedure:
To a mixture of methyl 3-((E)-2-carboxyethenyl)-5-(pyrrol-1-yl)benzoate (1.9 g) and nickel(II) chloride in methanol (40 ml) was added portionwise sodium borohydride (1.24 g). After stirring for 7 hours at room temperature, the reaction mixture was filtered and poured into water, followed by acidification of the solution to pH 2. The resulting precipitate was collected by filtration and washed with water to give methyl 3-(2-carboxyethyl)-5-(pyrrol-1-yl)benzoate (1.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH:24][NH2:25])=O)=[C:9]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].S(O)(O)(=O)=O.CS[C:38](=[NH:40])[NH2:39].N12CCCC1=NCCC2>C(O)CCC>[NH2:40][C:38]1[N:39]=[C:22]([CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:24][N:25]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)C1=C(COCC(=O)NN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: C1CN=C2CCCN2C1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCOC(=O)C1=C(COCc2nc(N)n[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 15.3 %

Procedure:
A solution of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-acetylhydrazine (0.87 g), 2-methylisothiourea sulphate (0.68 g) and 1,5-diazabicyclo[4.3.0]non-5-ene (0.74 g) in n-butanol (30 ml) was heated under reflux for 16 hours and then evaporated. The residue was partitioned between dichloromethane and water and the organic layer dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on silica (t.l.c. grade, 10 g) using dichloromethane plus 0-100% v/v ethyl acetate as eluant. Appropriate fractions were combined and evaporated and the residual oil triturated with ethyl acetate. The resulting solid was collected, washed with ethyl acetate and dried to give the title compound (0.14 g), m.p. 199°-202° C. decomp.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cccc(OCCCCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methyl 3-(3-chloro-propoxy)-phenylacetate (12.7 g, 52.3 mmol) was dissolved in dioxane (25 mL) and 1N NaOH (53 mL) was added. The mixture was stirred at room temperature for 45 minutes then acidified by addition of 1N hydrochloric acid (60 mL). A white precipitate formed which was filtered, washed with 1N HCl, water and dried. 3-(3-Chloro-propoxy)-phenylacetic acid (11.7 g, 98%). 1H NMR (CDCl3) δ 7.25 (1H, dd), 6.93-6.85 (3H, m), 4.11 (2H, t), 3.79 (2H, t), 3.70 (2H, s), 2.25 (2H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[CH2:25])[C:21]3[C:20](=[O:26])[N:19]([CH3:27])[C:18](=[O:28])[N:17]([CH3:29])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:23]([N:22]1[C:21]2[C:20](=[O:26])[N:19]([CH3:27])[C:18](=[O:28])[N:17]([CH3:29])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:24]=[CH2:25]
Reactant: C=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCn1c(N2CCNCC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
A mixture of 4-(7-allyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (1.5 g), trifluoroacetic acid (3 ml), and dichloromethane (10 ml) was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Water (10 ml) and 5 M potassium carbonate aqueous solution (5 ml) were added to the residue, extracted with dichloromethane, then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 750 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCCC1CCC(C2CCC(/C=C/C(=O)OCC)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CCC(=O)OCC)CC2)CC1

Procedure:
(E)-3-(4′-Propyl-bicyclohexyl-4-yl)acrylic acid ethyl ester is hydrogenated in THF in the presence of palladium on charcoal. After 1 eq. of hydrogen has been consumed the catalyst is filtered off, the solvent is evaporated and the residue is filtered through silica yielding 3-(4′-propyl-bicyclohexyl-4-yl)-propionic acid ethyl ester as a colourless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:4][Si:3]([CH3:6])([CH3:5])[C:1]1[O:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: Oc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cc2ncccc2o1
Temperature: 500 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Ethynyltrimethylsilane (32.5 ml, 0.2298 mol), copper(I)iodide (2.2 g, 0.0114 mol) and bis(triphenylphospine)palladium(II)chloride (4.1 g, 0.0057 mol) are added to a degassed solution of 2-Bromopyridine-3-ol (20 g, 0.1149 mol) in dioxane (20 ml). The mixture is stirred for 5 min under nitrogen and then triethyl amine (80 ml, 0.574 7 mol) is added. The mixture is heated to 500° C. for 18 h, cooled to RT, filtered through celite and the filtrate is concentrated under reduced pressure. The crude material is purified by column chromatography by using petrolether and ethyl acetate (90:10) as an eluent to afford (22 g, 56%) of the title compound as a brown liquid. TLC: hexane/ethyl acetate: (9/1): Rf=0.50; LCMS (method B): 4.875 min (purity 98.4%); M+H+ 192.1; 1H NMR (DMSO-d6, 400 MHz) δ [ppm] 8.50-8.48 (1H, dd, J1=1 Hz, J2=4.6 Hz), 8.015-7.9923 (1H, dd, J1=1 Hz, J2=8.32 Hz), 7.352-7.350 (1H, d, J1=0.8 Hz), 7.314-7.280 (1H, m), 0.372-0.355 (9H, s).
Reaction SMILES: [F:1][C:2]1[C:31]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][N:11](C4CCCCO4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[C:31]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)N(C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCN(C)CC3)cc2[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCN(C)CC3)cc2[nH]1)C(C)C
Yield: 40.2 %

Procedure:
A solution of 364 mg of 3-[3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropylurea in solution in 6.9 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 4 hours. After evaporation, the reaction crude is purified by preparative HPLC with, as eluent, a gradient of water/acetonitrile containing respectively 0.07% of trifluoroacetic acid. 123 mg of 3-{3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-1,1-diisopropylurea in the form of a trifluoroacetate salt are obtained in the form of a pink solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.32 (d, J=7.0 Hz, 12H); 2.91 (s, 3H); 3.04 (m, 2H); 3.28 (m, 2H); 3.53 (m, 4H); 4.01 (m, 2H); 7.18 (d, J=8.0 Hz, 1H); 7.41 (d, J=11.5 Hz, 1H); 8.03 (s, 1H). ES m/z=443: MH+ (base peak)—m/z=342: (M+H—C6H15N)+.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].[ClH:36].O1CCOCC1>COCCOC.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>[ClH:20].[ClH:36].[Cl:20][C:21]1[CH:26]=[C:25]([C:2]2[N:6]=[C:5]([N:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3)[S:4][N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)ns2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: COCCOC
Product: Clc1cccc(-c2nsc(N3CCNCC3)n2)c1
Temperature: 100 °C
Yield: 90 %

Procedure:
A mixture of tert-butyl 4-(3-bromo-1,2,4-thiadiazol-5-yl)piperazine-1-carboxylate (1 g, 2.86 mmol), 3-chlorophenylboronic acid (537 mg, 3.44 mmol), Na2CO3 (364 mg, 3.44 mmol) and tetrakis(triphenylphosphine) palladium (0) (66.2 mg, 57.3 μmol) in 36 mL DME/12 mL water was heated to 100° C. over night. The mixture was extracted with EtOAc (80 mL)/water (80 mL). The organic layer was dried over Na2SO4, filtered off and concentrated in vacuo to give amber oil which was dissolved in 25 mL dioxane, 7.16 mL 4N HCl/dioxane was added and stirred over night at RO. Et2O was added and the mixture was filtered and washed with Et2O. The filter cake was dried in vacuo at 50° C. to yield 926 mg (90%) of the intermediate compound as light yellow solid. MS (m/e): 281.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][O:13][C:5]2([CH2:9][C@@H:8]([C:10]([OH:12])=O)[CH2:7][CH2:6]2)[O:4][CH2:3]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[CH2:39][CH2:38][C:35]2([CH2:37][CH2:36]2)[CH2:34][C:33]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[CH3:15][C:2]1([CH3:1])[CH2:3][O:4][C:5]2([CH2:9][C@@H:8]([C:10]([NH:31][C:32]3[CH2:39][CH2:38][C:35]4([CH2:37][CH2:36]4)[CH2:34][C:33]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:12])[CH2:7][CH2:6]2)[O:13][CH2:14]1
Reactant: CCOC(=O)C1=C(N)CCC2(CC2)C1
Reactant: CC1(C)COC2(CC[C@H](C(=O)O)C2)OC1
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)C1=C(NC(=O)[C@H]2CCC3(C2)OCC(C)(C)CO3)CCC2(CC2)C1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of (S)-8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxylic acid (1.5 g, 7.0 mmol) and NMM (1.15 ml, 10.50 mmol) in acetonitrile (35 ml), isobutyl chloroformate (1 ml, 7.70 mmol) was added drop wise at −5 to −10° C. After 1 h, a solution of ethyl 6-aminospiro[2.5]oct-5-ene-5-carboxylate (3.42 g, 17.50 mmol) in acetonitrile (15 ml) was added and the reaction was allowed to stir at 0° C. to −5° C. for 1 h followed by stirring overnight at 25-30° C. Upon completion, the reaction mixture was quenched by addition of water (10 ml). Organic solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (50 ml) and 10% sodium bicarbonate (25 ml). The organic mass was extracted using ethyl acetate (3×50 ml). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a crude solid, which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain the title compound (1.55 g, 56.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([S:9][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:8][C:4]=2[CH:3]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: CCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCSc1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.1 %

Procedure:
To a solution of 5-chloro-2-mercaptobenzimidazole (1.84 c, 10 mmol) (Varima, R. S., J. Indian Chem. Soc. 62, 73 (1985)) in methanol (10 mL) and 2N sodium hydroxide (13 mmol) was added octyl bromide (2.17 g, 10 mmol). The solution was stirred at ambient temperature for 72 hours, evaporated, dissolved in CH2Cl2, washed with brine and dried over Na2SO4. Evaporation of the solvent and flash chromatography (Merck Kieselgel, 5% Et2O/CH2Cl2) gave a residue which solidified on standing. A pentane wash gave the title compound as a beige solid (2.23 g), m.p. 66°-67° C. NMR (CDCl3)δ7.3(m, 3H), 5.33(t, J=6 Hz, 2H), 1.20(br, 15H).