Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:35])[CH3:34])[C:25]4[CH:26]=N[C:28](OC)=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:37]1(C2N3C(CC(=O)NC4C=CC=CC=43)=NN=2)CCCCC1.BrCC(N(C(C)C)C1C=CC=CC=1)=O>>[CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:34])[CH3:35])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:37][CH:26]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=C1Cc2nnc(C3CCCCC3)n2-c2ccccc2N1
Agent: CC(C)N(C(=O)CBr)c1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(C3CCCCC3)n2-c2ccccc21)c1ccccc1

Procedure:
Following the procedure described for Preparation 8(A), 1-cyclohexyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(B) (640 mg, 0.226 mmol) was alkylated with 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1(A)) (580 mg, 0.226 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 4% MeOH in CH2Cl2) provided 668 mg of 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide. 1H NMR (CDCl3) δ 7.62-7.31 (m, 9), 4.93 (m, 1), 4.10 (d, 1), 3.91 (d, 1), 3.76 (d, 1), 3.45 (d, 1), 2.85 (m, 1), 2.19 (br. d., 1), 1.91 (m, 2), 1.69-1.11 (m, 7), 1.06 (m, 6): MS 458.4 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].ClC(Cl)(Cl)[C:47]([N:49]=C=O)=[O:48].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:47]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])(=[O:48])[NH2:49]
Reactant: O=C(Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
8 g of raw product of Step A were added with stirring at room temperature to a solution of 8 g of trichloroacetyl isocyanate in 160 ml of dry methylene chloride and after stirring for 15 minutes, 1.6 liters of a solution of aqueous 6% sodium bicarbonate were added thereto. The mixture was stirred at room temperature overnight and was then extracted with ethyl acetate. The organic phase was removed and the aqueous phase was acidified with 6 N hydrochloric acid to a pH of 2 in the presence of ethyl acetate. The organic phase was washed with water, dried and concentrated under reduced pressure to 30 ml. The product was precipitated by addition of isopropyl ether and the mixture was filtered and dried to obtain 2.7 g of 3-carbamoyloxymethyl-7β-[2-(2-tritylamino-4-thiazolyl)-acetamido]-ceph-3-eme-4-carboxylic acid melting at about 200° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]O>O1CCOCC1>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(O)c1

Procedure:
3-Hydroxyphenylacetic acid (5 g, 32.9 mmol) in MeOH was treated with 4N HCl in 1,4-dioxane (3 mL) at 80° C. for 3 hours. The solution was concentrated to dryness to give the desired product as a yellow oil (5 g).
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.C1C2C(=CC=CC=2)C=C(OS(C(F)(F)F)(=O)=O)N=1>>[ClH:4].[ClH:1].[ClH:4].[CH:10]1[C:11]2[C:6](=[CH:5][CH:14]=[CH:13][CH:12]=2)[CH:7]=[C:8]([C:16]2[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH:26]=3)[CH:21]=2)[N:9]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Agent: O=S(=O)(Oc1cc2ccccc2cn1)C(F)(F)F
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccccc2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid isoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.39 (br. s., 4H), 3.22-3.31 (m, 2H), 3.57-3.66 (m, 2H), 4.61-4.74 (m, 1H), 7.95 (t, J=7.5 Hz, 1H), 8.04-8.11 (m, 2H), 8.26 (d, J=8.1 Hz, 1H), 8.33 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.41-8.46 (m, 1H), 8.73 (s, 1H), 8.80-8.86 (m, 1H), 9.64 (s, 1H). MS (ES+): m/z=370.94 [MH+]. HPLC: tR=2.21 min (ZQ2, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#CC=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To a solution of 3-(4-(4-fluorophenoxy)phenyl)acrylonitrile (5 g, 20.90 mmol) in ethanol (80 mL) was added NaBH4 (5.44 g, 144 mmol). The mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water (50 mL), and ethanol was removed under reduced pressure. The residue was partitioned between EA (100 mL) and water (50 mL). The organic phase was washed with saturated NaHCO3 solution (80 mL), brine (50 mL), dried over sodium sulfate, concentrated, and purified via flash chromatography to afford the title compound (4.7 g, 16.48 mmol, 79% yield) as a white solid. LCMS: rt=1.55 min, [M+H+]=242
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[C:3]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])=[N:4][CH:5]=1
Reactant: C[C@@H](CO)Nc1ncc(Br)cc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Br)cnc2N[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
A solution of crude (S)-2-(3-amino-5-bromopyridin-2-ylamino)propane-1-ol (5.85 g, 23.77 mmol) dissolved in pyridine (58 mL) was cooled to 0° C. and treated with p-toluenesulfonyl chloride (4.53 g, 23.77 mmol) in one portion. The reaction mixture was stirred at 0° C. After 45 min, the solution was concentrated under reduced pressure. The residue was partitioned between water (60 mL) and ethyl acetate. The ethyl acetate layer was separated and washed with 5% aqueous sodium chloride solution (2×50 mL) and concentrated under reduced pressure. The resulting syrup was dissolved in toluene (100 mL), which was then removed under reduced pressure in an effort to remove residual pyridine. The crude product (10.4 g) was purified by column chromatography on silica gel (eluting with 3:1 dichloromethane-ethyl acetate followed by 2:1 dichloromethane-ethyl acetate and finally 3:2 dichloromethane-ethyl acetate). The product-containing fractions were combined and concentrated. The resulting syrup was dissolved in dichloromethane and the solution diluted with heptane. The mixture was concentrated under reduced pressure to yield (S)-N-(5-bromo-2-(1-hydroxypropan-2-ylamino)pyridin-3-yl)-4-methylbenzenesulfonamide (8.6 g, 21.5 mmol, 90%) as a nearly colorless foam/solid. MS (ESI, pos. ion) m/z 400, 402 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17](=[O:19])[CH3:18])=[C:10]2[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[F:23][C:20]([F:21])([F:22])[C:14]1[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[C:16]([C:17](=[O:19])[CH3:18])[N:15]=1
Reactant: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1nc(C(F)(F)F)n2c1CNCC2

Procedure:
1-Acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27f (0.24 g, 0.72 mmol) was dissolved in a little ethyl acetate. A solution of 2.7 N hydrochloric acid in 5 mL of ethyl acetate was then added. The reaction mixture was reacted at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound 1-(3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-ethanone 27g, which was directly used in the next step.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:7][N:6]=1.[Br:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].O>CN(C)C=O>[Br:26][C:27]1[CH:34]=[C:33]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:13]3[C:5]([C:4]([F:24])([F:3])[F:25])=[N:6]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1Br
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Sodium hydride (0.183 g, a 55% dispersion in paraffin liquid) was added to a solution of compound (1d) (0.940 g) in N,N-dimethylformamide (hereinafter referred to as DMF, 6 mL) at room temperature, followed by stirring for 30 min. Subsequently, 2-bromo-4-fluorobenzonitrile (0.838 g) was added to the reaction solution, followed by stirring at 60° C. for 1 hr. After cooling, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order and was dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1e) (0.56 g, 38%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N+:11]([O-])([OH:13])=[O:12]>O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 10.0 g of 4-n-propylphenol in 50 ml of water was added dropwise 11.0 ml of 61% nitric acid while cooling with ice, the temperature of mixture was raised to room temperature and the reaction was carried out for 2 hours. The reaction mixture was extracted with 300 ml of ethyl acetate, washed with a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform]to give 8.69 g of 4-n-propyl-2-nitrophenol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][C@@H:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C@H:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
(S)-4-(t-Butoxycarbonylamino)-5-(biphenyl-4-yl)-pentenoic acid ethyl ester (1.6 g), is dissolved in ethanol and hydrogenated under 48 psi for 2 hours with Pd/C catalyst. The mixture is filtered through Celite and the filtrate is concentrated in vacuo to yield (S)-4-(t-butoxycarbonylamino)-5-(biphenyl-4-yl)-pentanoic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[N:17]1.[I-].[K+].[OH-].[Na+]>CC(O)(CC)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[N:17]3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nc(CCl)co2)cc1
Reactant: c1c[nH]nn1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COc1ccc(-c2nc(Cn3ccnn3)co2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
A suspension of 5.59 g (25 mmol) 4-chloromethyl-2-(4-methoxy-phenyl)-oxazole, 2.59 g (37.5 mmol) 1H-[1,2,3]triazole, 0.41 g (2.5 mmol) potassium iodide and 1.5 g (37.5 mmol) sodium hydroxide (NaOH) in 50 ml 2-methyl-2-butanol was stirred at 120° C. for 5 h. After evaporation, the residue was quenched with water and extracted with ethyl acetate. The extract was dried, concentrated and purified on silica. Elution with ethyl acetate yielded 4.1 g (64%) 1-[2-(4-methoxy-phenyl)-oxazol-4-ylmethyl]-1H-[1,2,3]triazole as white crystals, melting at 126-127° C.
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH:25]=O>>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][CH:7]3[CH:4]4[CH2:5][CH2:6][CH:1]3[N:2]([CH2:25][C:24]3[CH:27]=[CH:28][C:29]([CH3:30])=[C:22]([CH:23]=3)[O:21][CH2:20][CH2:19][OH:18])[CH2:3]4)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(C=O)cc1OCCO
Reactant: c1cc2[nH]ncc2cc1NC1C2CCC1NC2
Product: Cc1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1OCCO

Procedure:
Reaction of Intermediate 23 with 3-(2-hydroxyethoxy)-4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4].[Cl:21][C:22]([Cl:28])([S:26]Cl)[CH:23]([Cl:25])[Cl:24].ClCCl>O>[C:3]([C:5]1[C:6](=[O:20])[N:7]([S:26][C:22]([Cl:28])([Cl:21])[CH:23]([Cl:25])[Cl:24])[C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Cl)C(Cl)Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 1.60 g (0.04 mol) of NaOH in 45 ml of water is added 9.64 g (0.04 mol) of 5-cyano-1-(2,6-dimethylphenyl)uracil, obtained as in Example 1. After dissolution, 50 ml of ice cold dichloromethane is added, followed by a solution of 9.36 g (0.04 mol) of 1,1,2,2-tetrachloroethanesulphenyl chloride (prepared by the method of U.S. Pat. No. 3,395,180) in 15 ml. of dichloromethane. The mixture is stirred for 30 min at 4°. The aqueous layer is separated and discarded. The dichloromethane solution is dried and stripped at aspirator pressure. The unreacted sulphenyl chloride is then removed by trituration with pentane/dichloromethane (4:1). The resultant crude product is purified by slurrying at 30° in 60 ml of ethanol-free chloroform, allowed to cool to RT and filtered. To the filtrate is added hexane to the cloud point, and the mixture is then filtered to yield 5-cyano-1-(2,6-dimethylphenyl)-3-(1,1,2,2-tetrachloroethanesulphenyl)uracil, m.p. 180°-183°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:7])=O.FS(OC)(=O)=O.C(Cl)Cl.[NH3:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:23])=[NH:7]
Reactant: N
Reactant: COc1cccc(OC)c1C(N)=O
Agent: COS(=O)(=O)F
Solvent: ClCCl
Solvent: CCO
Product: COc1cccc(OC)c1C(=N)N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2,6-dimethoxybenzamide (68 g.; prepared as described by P. Grammaticakis, Compt. rend., 1968, 267C,152), methyl fluorosulphonate (45 g.) and anhydrous methylene dichloride (1 l.) was stirred at room temperature for 3 hours. The solution was evaporated in vacuo, and the residue treated with anhydrous diethyl ether to give crude methyl 2,6-dimethoxybenzimidate fluorosulphonate as a white solid, m.p. 115°-137° C. This was dissolved in anhydrous ethanol (1 l.) and the solution was cooled to 0° C. Anhydrous ethanolic ammonia (350 ml.; prepared by saturation of anhydrous ethanol with anhydrous ammonia at 0° C.) was added, and the mixture kept at room temperature for 4 days. The solution was filtered, the filtrate was evaporated in vacuo, the residue was treated with an excess of 2N sodium hydroxide solution, and the precipitated solid was filtered off, washed with water and recrystallised from isopropanol to give 2,6-dimethoxybenzamidine (15 g.), m.p. 170°-174° C.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[C:24](Cl)(=[O:26])[CH3:25].[OH-].[Na+]>O1CCCC1>[C:24]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:12][CH2:13]1)(=[O:26])[CH3:25]
Reactant: c1cc2[nH]ncc2cc1NC1CCNCC1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Nc2ccc3[nH]ncc3c2)CC1
Yield: 60.2 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol) was added to a solution of the N-(4-piperidinyl)-1H-indazol-5-amine (0.301 g, 1.39 mmol) obtained in Example 15, (a) in tetrahydrofuran (5 ml) at room temperature, followed by adding thereto a solution of acetyl chloride (0.12 g, 1.53 mmol) in tetrahydrofuran (2 ml) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was suspended in acetone and stirred. Thereafter, the solid was collected by filtration and dried under reduced pressure to obtain N-(1-acetyl-4-piperidinyl)-1H-indazol-5-amine (0.216 g, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.F[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:20][C:16]1[N:15]=[C:14]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(F)n1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Oc2ccc3c(c2)CCCC3=O)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A suspension of 6-hydroxy-1-tetralone (3.0 g, 18 mmol), 2-fluoro-6-methylpyridine (2.06 g, 18.5 mmol) and Cs2CO3 (12.1 g, 37.0 mmol) in DMF (150 mL) was stirred at 150° C. in a sealed vessel overnight under N2. The reaction was poured into water (300 mL) and extracted with EtOAc (3×50 mL). Organics were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (PE:EA=5:1) gave 1.2 g (26%) of the title compound as a red oil. [M+H] calc'd for C16H15NO2, 254. found 254.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:22]=[CH:21][CH:20]=[N:19][C:9]=2[N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:11]=1)=[O:5])C.[OH-].[K+].Cl>CO>[Br:18][C:14]1[CH:13]=[C:12]([N:10]2[C:9]3[N:19]=[CH:20][CH:21]=[CH:22][C:8]=3[C:7](=[O:23])[C:6]([C:4]([OH:5])=[O:3])=[N:11]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 65 °C
Yield: 97.8 %

Procedure:
To 1-(3-Bromophenyl)-4-oxo-1,4-dihydropyridino[2,3-c]pyridazine-3-carboxylic acid ethyl ester (3.6 g, 9.6 mmol) in methanol(50 mL) was added potassium hydroxide (5.3 g, 94.6 mmol), heated to 65° C. and reacted for 3 h. Dilute hydrochloric acid was added to regulate pH to 5-6, solvent was removed by distillation, 50 mL water was added, filtrated to obtain product 3.25 g.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C=O.C(O)(=O)C>CO>[CH3:1][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:26]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1cnc(C2CCNCC2)nc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(C2CCN(C)CC2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.8 %

Procedure:
Sodium triacetoxyborohydride (532 mg, 2.51 mmol) was added to methyl 2-(piperidin-4-yl)pyrimidine-5-carboxylate (222 mg, 1.00 mmol), formaldehyde (37% aqueous solution, 1.50 ml, 20.07 mmol) and acetic acid (0.115 ml, 2.01 mmol) in methanol (4.994 ml) at 25° C. The resulting solution was stirred at ambient temperature for 3 days. The reaction mixture was diluted with methanol (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxylate (223 mg, 94%) as a cream waxy solid. This was used directly with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])=[C:11]([C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a mixture of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 100 mg, 0.330 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 106 mg, 0.346 mmol) and bromotripyrrolidinophosphonium hexafluoro-phosphate (PyBroP) (154 mg, 0.330 mmol) in 3 mL of DMF was added N,N-diisopropylethylamine (DIEA) (0.172 mL, 0.990 mmol). After stirring at RT for 16 h, the mixture was treated with 50 mL of EtOAc and washed with H2O (2×15 mL), brine (15 mL) and dried (Na2SO4). The organic solvent was evaporated and the residue was purified by flash chromatography on silica gel (5-10% EtOAc-hexane) to give 118 mg (85%) of the title compound as a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C28H36N4O6Si, 553.2 (M+H). found 552.6.