Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].Cl.[C:35](=[NH:40])(OCC)[CH3:36].C(N(CC)CC)C.Cl>C(O)C.O1CCOCC1.CO>[ClH:1].[ClH:1].[C:35]([N:31]1[CH2:32][CH2:33][CH:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([N:15]([CH2:14]/[CH:13]=[CH:12]/[C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[NH:4])[NH2:5])[CH:7]=3)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)(=[NH:40])[CH3:36]
Reactant: CCOC(C)=N
Reactant: CCS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 144.7 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]ethanesulfonamide dihydrochloride (311 mg) in ethanol (10 ml) were added ethyl acetimidate hydrochloride (260 mg) and triethylamine (0.500 ml). The resulting mixture was stirred at room temperature for 12 hours. After addition of a 4M solution of hydrogen chloride in dioxane (1 ml), the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 20% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. The resulting amorphous solid was dissolved in water (10 ml) and the solution was lyophilized to give the title compound (243 mg, yield 62%) as a colorless amorphous solid.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1
Yield: 0 %

Procedure:
A solution of 1.25 g (5 mol) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole and 20 mL of 1M BBr3/CH2Cl2 in 50 mL of methylene chloride was stirred at room temperature for 5 hours and concentrated at reduced pressure. The residue was dissolved in ethyl acetate, washed with brine and dried (MgSO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 577 mg (49% yield) of 4-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole, 125-127° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O)#[N:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[N:1]=[C:2]3[CH:3]([C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]3)[CH:16]([C:15]3[CH:18]=[CH:19][C:20]([F:21])=[C:13]([CH:14]=3)[C:11]#[N:12])[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: N#Cc1cc(C=O)ccc1F
Product: CC1(C)CC(=O)C2C(=NC3=C(C(=O)CC(C)(C)C3)C2c2ccc(F)c(C#N)c2)C1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-cyano-4-fluorobenzaldehyde in an analogous manner to that described in Example 1 gave 5-(2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-1,8-dioxo-1H-acridin-9-yl)-2-fluorobenzonitrile. Crystallization from ethanol gave a pale yellow-green crystalline solid of melting point 274-275° C.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5]Br)[CH3:2].[I-:19].[Na+]>CC(C)=O>[CH2:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5][I:19])[CH3:2]
Reactant: [I-]
Reactant: CCC(=CC=Cc1ccc2c(c1)OCO2)CCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(=CC=Cc1ccc2c(c1)OCO2)CCI

Procedure:
D11. 3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl iodide [IX; Ar is 3,4-methylenedioxyphenyl, R is C2H5 ] was prepared from 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl bromide (Preparation C10) and 6 g. of sodium iodide in 120 ml. of acetone, to give 10.5 g. of product as an oil.
Reaction SMILES: C([NH:4][C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=O)C>Cl>[NH2:4][C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)CC1
Agent: Cl
Product: CC1(N)CCN(Cc2ccccc2)CC1

Procedure:
39.4 g of 4-acetylamino-1-benzyl-4-methylpiperidine are heated to boiling in 400 ml of concentrated hydrochloric acid for 3 days. After evaporation to half the volume in a rotary evaporator, the pH is adjusted to 12 with 50% strength sodium hydroxide solution while cooling. The mixture is extracted three times with methylene chloride. The combined organic phases are then dried over sodium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is employed without further purification in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[C:4]([CH3:15])[CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.BrC1C=CC(NC(=O)CC(N(C2CCCCC2)C(NC2CCCCC2)=O)=O)=C(C)C=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Br)ccc1NC(=O)CC(=O)O
Reactant: Sc1ccccc1
Agent: Cc1cc(Br)ccc1NC(=O)CC(=O)N(C(=O)NC1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1NC(=O)CC(=O)Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred mixture of 5.44 grams (0.02 mole) of 3-[(4-bromo-2-emthylphenyl)amino)-3oxopropanoic acid prepared in Example V (Compound No. 97) and 2.31 grams (0.02 mole) of thiophenol in approximately 100 milliliters of dry tetrahydrofuran in an oven-dried reaction flask was fed a solution of 4.13 grams (0.02 mole) of 1,3-dicyclohexylcarbodiimlde in about 25 milliliters of dry tetrahydrofuran, while cooling the reaction mixture in an ice-water bath. On completing the feed the ice bath was removed and the mixture stirred for about one hour following which the precipitated 1,3-dicyclohexylurea by-product (2.5 grams) was removed by filtration. Vacuum stripping the filtrate gave a solid which was recrystallized from acetone to give a compound, melting point 184° C.-187° C., which proved to be 1-(3-[(4-bromo2-methylphenyl)amino]-3-oxopropanoyl)-1,3-dicyclohexylurea. The filtrate from this was concentrated and flash chromatographed (7:3 hexane:ethylacetate, silica column) to give 2.83 grams (0.008 mole) of S-phenyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanethioate having a melting point of 133° C.-135° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][C:15]=1[NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:26][C:15]1[CH:16]=[CH:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:19][C:14]=1[CH3:13])=[O:7]
Reactant: Cc1cc(N2CCOCC2)ccc1N
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2C)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methoxy-benzoic acid (247 mg), 2-methyl-4-morpholin-4-yl-phenylamine (205 mg), EDAC (410 mg), HOBT (289 mg) and N-methylmorpholine (353 μl) in DMF (5 ml) was stirred at room temperature for 18 h. The mixture was then diluted with water (30 ml) and the resulting solid collected by filtration and dried (464 mg)
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[C:19](Br)=[N:18][C:17]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].C(N(CC)CC)C>[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.CN(C)C=O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[C:19]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])=[N:18][C:17]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(Br)n3C3CC3)cc21
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(C#C[Si](C)(C)C)n3C3CC3)cc21
Temperature: 25 °C
Yield: 86 %

Procedure:
Combine 1-isopropylsulfonyl-2-amino-6-(1-(cyclopropyl)-2-(bromo)-4-(2-fluorophenyl)-imidazol-5-yl)-benzimidazole (0.332 g, 0.64 mmol), trimethylsilylacetylene (0.36 mL, 2.56 mmol), tetrakis(triphenylphosphine)-palladium (0.150 g, 0.128 mmol), triethylamine (2 mL) and dimethylformamide (4 mL) and heat to 70° C. for 18 hours. Cool to ambient temperature and remove solvents under reduced pressure. Purify the residue on silica gel eluting with acetonitrile/dichloromethane mixtures to provide the title compound (0.295 g). MS(ES+): m/z=536.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Reaction time: 17 h
Yield: 60.4 %

Procedure:
To a solution of (2-benzyloxyphenyl)acetic acid (36 g) in dimethylformamide (360 ml) were added potassium carbonate (61.2 g) and methyl iodide (31.6 g) successively. After being stirred for 17 hours, the mixture was filtered and the filtrate was poured into aqueous 1N hydrochloric acid solution (1.8 l). The separated oil was extracted with diethyl ether and the organic layer was washed with brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [eluting with ethyl acetate - n-hexane (1:1)] to afford methyl (2-benzyloxyphenyl)acetate (23 g).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:7](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3cccc(C)c3)nc12

Procedure:
From meta-toluic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+17.7° (c=0.79, CHCl3), ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [NH:1]([CH:3]([CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]([OH:6])[CH3:5])[NH2:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](OC)=[C:26]([C:29]#[N:30])[C:27]#[N:28]>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[NH2:30][C:29]1[N:1]([CH:3]([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:4]([OH:6])[CH3:5])[N:2]=[C:25]([O:24][CH3:23])[C:26]=1[C:27]#[N:28]
Reactant: CC(O)C(CCCc1ccccc1)NN
Reactant: COC(OC)=C(C#N)C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C#N
Temperature: 20 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
4.2 g of 3-hydrazino-2-hydroxy-6-phenylhexane are are dissolved in 20 ml of methanol, and 1.38 ml of triethylamine are added. Then, 1.38 g of 1,1-dimethoxy-2,2-dicyano-ethylene are added. The reaction solution is stirred for 2 hours at approx. 20° C. For work-up, the mixture is diluted with citric acid solution and ethyl acetate and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried with magnesium sulphate and evaporated in vacuo. The evaporation residue is chromatographed on silica gel (Merck Si 60 0.04-0.063 mm) with a cyclohexane/ethyl acetate mixture in a ratio of 4:1 to 1:1. This gives a fraction which, after evaporation in vacuo, affords 0.959 g (=30.5% of theory) of 5-amino-4-cyano-3-methoxy-1-[2-hydroxy-6-phenyl-hex-3-yl]-pyrazole as diastereomer mixture.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[Cl:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]([C:22](Cl)=[O:23])[CH:17]=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[Cl:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]([C:22]([N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][C:2]([F:11])([F:12])[F:1])=[O:23])[CH:17]=1
Reactant: FC(F)(F)CNc1ccccc1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N(CC(F)(F)F)c1ccccc1
Reaction time: 2 h

Procedure:
200 mg (1.14 mmol) N-(2,2,2-trifluoroethyl)aniline and 1.14 mL (1.14 mmol) of a 1M sodium hydroxide solution were added dropwise to 212 mg (1.2 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane while cooling with a bath of ice and ethanol. The mixture was first stirred for 2 h with cooling and then stirred for 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water and 1M hydrochloric acid, dried on sodium sulphate, filtered and concentrated by rotary evaporation i.vac.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:9]([C:18]([O:20]CC)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.[C:23](#[N:25])[CH3:24].O>C1(C)C=CC=CC=1>[CH3:7][C:8]1[C:9]([C:18](=[O:20])[CH2:24][C:23]#[N:25])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CC#N
Reactant: CCOC(=O)c1nc2ccccc2nc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2ccccc2nc1C(=O)CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of potassium tert-butoxide (72.7 g, 647 mmol) in toluene (810 mL) was added a solution of ethyl 3-methylquinoxaline-2-carboxylate (70.0 g, 324 mmol) and acetonitrile (38.3 mL, 809 mmol) in toluene (270 mL) dropwise over 50 min at 5° C. After being stirred for 5 min at 0° C., water (585 mL) was added. The organic layer was extracted with water (100 mL) and the aqueous layer was combined and acidified to pH 3-4 with 10% aqueous hydrochloric acid. The resulting precipitate was collected and dissolved to tetrahydrofuran. And then the organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude solid was purified by silica gel column chromatography (silica gel 2.2 kg, chloroform to chloroform:ethyl acetate=19:1) to give 3-(3-methylquinoxalin-2-yl)-3-oxopropanenitrile. MS (APCI): m/z 212 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:15][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[CH3:11])=[O:9]
Reactant: Cc1ccccc1CN
Reactant: O=C(O)c1cncc(Br)c1
Product: Cc1ccccc1CNC(=O)c1cncc(Br)c1

Procedure:
Prepared from 5-bromonicotinic acid and 2-methylbenzylamine using procedures as described in Example 1H. MS (APCI) m/z 305, 307 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH2:21])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Solvent: ClCCl
Product: O=C(COCc1ccccc1)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)—C-(7-Benzenesulfonyl-chroman-2-yl)-methylamine (130 mg, 0.43 mmol) triethylamine (0.3 mL) and benzyloxy acetyl chloride 77 uL) were added to 3 mL methylene chloride at 0° C. The reaction mixture was stirred at room temperature for three hours and then quenched by addition of water. The mixture was extracted with methylene chloride and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography gave 4.34 mg of (R)—N-(7-benzenesulfonyl-chroman-2-ylmethyl)-2-benzyloxy-acetamide.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C>CO.O1CCOCC1>[CH:8]1([C:7]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)([O:20][CH3:21])[CH:2]([OH:1])[C:3]([O:5][CH3:6])=[O:4])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(O)C(OC)(C1CCCCC1)C1CCCCC1
Reaction time: 30 h
Yield: 97 %

Procedure:
10 g (34.9 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml each of methanol and glacial acetic acid, 1 ml of RuO(OH)2 in dioxane was added, and hydrogenation was carried out with H2 in an autoclave at 100° C. under 100 bar for 30 h. The catalyst was filtered off, the mixture was concentrated, mixed with ether and washed with NaCl solution, and the organic phase was dried and concentrated. 10,1 g of methyl 3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate were obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=1.CI.[OH-].[Na+].[C:20](O)(=O)C>O.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:20])=[N:12][CH:13]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1ccccn1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CI
Product: CSc1ncc(Cc2ccccn2)c(=O)[nH]1

Procedure:
A solution of 5-(2-pyridylmethyl)-2-thiouracil (6.6 g), methyl iodide (4.3 g) and sodium hydroxide (2.5 g) in water (100 ml) and ethanol (100 ml) was stirred at 70° for 30 minutes, allowed to cool and glacial acetic acid added to pH5. The solution was partially evaporated and cooled in an ice-bath. The precipitate was filtered off and recrystalled from ethanol to give 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 195°-197.5°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2].C(N(C(C)C)CC)(C)C.[ClH:41].[N:42]1([C:47](N)=[NH:48])C=CC=N1>CN(C)C=O>[ClH:41].[ClH:41].[CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:47](=[NH:42])[NH2:48])[CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2]
Reactant: N=C(N)n1cccn1
Reactant: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=N)N)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
To a solution of 3-[4-[4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester (70 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.032 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (27 mg), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether and the supernatant was removed. This procedure was repeated twice and hydrogen chloride-ethanol solution was added to the obtained residue and insoluble material was removed. The solution was concentrated and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Nc4ccc(C(=O)NC5CCN(C)CC5)cc4OC)nc32)cc1
Yield: 99.2 %

Procedure:
A mixture of 0.11 g (0.30 mmole) of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-291), 0.088 g (0.22 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.13 g of 4-[7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-291) as a white solid.