Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C@H:8]([NH:9][C@@H](C2C=CC=CC=2)C)[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)[CH3:2].[C:25]([OH:28])(=[O:27])[CH3:26]>[OH-].[OH-].[Pd+2]>[NH2:9][C@@H:8]1[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:4][C@H:3]1[CH2:1][CH3:2].[CH3:26][C:25]([OH:28])=[O:27]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A flask was flushed with nitrogen and charged with 20% palladium hydroxide on carbon (91 mg, 0.647 mmol). A solution of (3R,4R)-tert-butyl 3-ethyl-4-(((R)-1-phenylethyl)amino)piperidine-1-carboxylate (430.5 mg, 1.295 mmol) in acetic acid (8.6 ml) was added. The flask was flushed with nitrogen, sealed, evacuated briefly, and charged with hydrogen. The mixture was stirred at room temperature for 14 hrs. The flask was evacuated, backfilled with nitrogen, and opened. The reaction mixture is filtered through celite. The filtrate was concentrated by azeotropical distillation with toluene (3×25 ml) under reduced pressure to remove the residual acetic acid, yielding (3R,4R)-tert-butyl 4-amino-3-ethylpiperidine-1-carboxylate, HOAc salt (351 mg, 1.217 mmol, 94.0% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 4.16 (d, J=11.2 Hz, 1H), 4.07 (d, J=13.9 Hz, 1H), 3.03-2.85 (m, 2H), 2.56 (br. s., 1H), 2.02-1.94 (m, 1H), 1.92 (s, 3H), 1.77-1.66 (m, 1H), 1.53-1.36 (m, 10H), 1.32-1.16 (m, 1H), 1.00 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:37]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH2:38]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][CH2:37][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: C=CS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCS(C)(=O)=O)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added methyl vinyl sulfone (38 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:20](I)([CH3:22])[CH3:21]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH:20]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])=[CH:18][CH:17]=1)([CH3:22])[CH3:21]
Reactant: O=C(O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: CC(C)I
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Yield: 43.1 %

Procedure:
To a solution of 4-[2-(4-fluorophenyl)-2-oxoethyl]benzoic acid (Example 3, Step 1) (0.600 g, 2.32 mmol) in toluene(25 ml) was added silver carbonate (1.06 g) and isopropyl iodide (0.70 g).The reaction was refluxed for 2 hour. The reaction mixture was filtered on a pad of silica gel and washed with hexane/ethyl acetate 20%. to give (0.3 g) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([N:16]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)[CH2:17][CH3:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ClCCl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH2:14][N:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=1)[CH2:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)C(=O)c2sccc2OCc2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N(CC)Cc2sccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
Borane-tetrahydrofuran complex (2.7 mL of a 1.0M solution in THF) was added over 5 minutes to a solution of ethyl 4-[N-(3-benzyloxy-2-thienoyl)-N-(ethyl)amino]benzoate (1.0 g) in THF (10 mL). The reaction mixture was stirred at ambient temperature for 15 minutes and then heated under reflux for 1 hour. An excess of aqueous 2N HCl was added to the cooled reaction mixture which was evaporated to dryness. The residue was made basic by the addition of aqueous potassium carbonate solution and this was extracted with diethyl ether (50 mL). The ether extract was washed with brine and dried over MgSO4. The oil obtained on removal of the solvent was subjected to chromatography on silica eluting with dichloromethane to give ethyl 4-[N-(3-benzyloxy-2-thienylmethyl)-N-(ethyl)amino]benzoate as an oil in 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:26])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: COC(=O)CNc1ccc(Cl)cc1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: COC(=O)CN(C(=O)NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Three grams (15 mmol) of methyl 4-chlorophenylaminoacetate were dissolved in 40 ml of benzene, and 2.2 ml (15 mmol) of 4-chlorobenzenesulfonyl isocyanate were added to the resultant solution, followed by stirring for 1 hour. Crystals formed were collected by filtration to obtain N-(4-chlorobenzenesulfonyl)-N'-(4-chlorophenyl)-N'-methoxycarbonylmethylurea (6.1 g) as white crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>CCOCC>[C:18]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:19])[CH2:17][C:16]([CH3:15])=[O:20]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: CCOCC
Product: CC(=O)CC(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of benzyl N-(2-aminoethyl)carbamate (54 g, 0.276 mole) in ether (250 ml) and a solution of diketene (25.2 g, 0.30 mole) in ether (250 ml) were added simultaneously, dropwise, to ether (600 ml) while stirring and cooling over a 30 minute period. A white precipitate appeared. The solution was stirred 30 minutes longer, and then filtered. One recrystallization from water gave pure benzyl N-(2-acetoacetamidoethyl)carbamate (m.p.=116°-118° C.) at a yield of 90%.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:4]=[N:3]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:33])=[CH:10][CH:9]=2)[CH:4]=[N:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-n2cnn(C)c2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1ncn(-c2ccc(CBr)cc2)c1=O
Yield: 74.6 %

Procedure:
To a stirred solution of 2.6 grams (0.013 mole) of 4,5-dihydro-1-methyl-5-oxo-4-(4-methylphenyl)-1H-1,2,4-triazole in 150 mL of carbon tetrachloride were added 0.3 gram (catalyst) of benzoyl peroxide and 2.5 grams (0.014 mole) of N-bromosuccinimide. The reaction mixture was heated at reflux for three hours, after which it was cooled and concentrated under reduced pressure, yielding 2.6 grams of 4,5-dihydro-1-methyl-5-oxo-4-(4-bromomethylphenyl)-1H-1,2,4-triazole, which was used in the next reaction without further characterization.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][CH2:12][C:13]([C:15]2[CH:26]=[CH:25][C:18]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)=[O:14])=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].Cl>O>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[O:14])=[O:10])=[CH:27][CH:28]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)CCc1ccc(C(=O)CNC(=O)c2ccc(C(=N)N)cc2)cc1
Agent: Cl
Solvent: O
Product: N=C(N)c1ccc(C(=O)NCC(=O)c2ccc(CCC(=O)O)cc2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
100 mg of methyl p-(p-amidinobenzamidoacetyl)hydrocinnamate hydrochloride were heated with 4 ml of 2N hydrochloric acid at 100° C. for 60 minutes. The reaction mixture was cooled, 4 ml of water were added, and the mixture was stirred at 5° C. for 2 hours. The crystals which precipitated was filtered off with suction and dried over KOH in vacuo. 70 mg of pure p-(p-amidinobenzamidoacetyl)hydrocinnamic acid hydrochloride, melting point 273°-274° C. (decomposition), were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 3-nitrobenzoyl chloride (4.5 g, 24.25 mmol) in THF (30 ml) was added 1-methylpiperazine (8.50 g, 85 mmol). The reaction was stirred for 20 min at room temperature. The reaction mixture was diluted with 50 mL water and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine (50 mL). The brine was back extracted with ethyl acetate (2×50 mL) and all the organic layers were combined, dried over magnesium sulphate, filtered, and concentrated under vacuum give the title product (5.2 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[O:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=O)[O:30]C3C=CC([N+]([O-])=O)=CC=3)[CH:25]=[CH:26][CH:27]=2)=[N:20][CH:19]=[N:18]1>C(#N)C.CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]4[O:17][N:18]=[CH:19][N:20]=4)[CH:23]=3)=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(Nc1cccc(-c2ncno2)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(-c3ncno3)c2)[C@@H]1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 0.0030 mol, from example 1, part B) and [3-(1,2,4-oxadiazol-5-yl)]phenylcarbamic acid, 4-nitrophenyl ester (1.08 g, 0.0033 mol) in acetonitrile (25 mL) and dimethylformamide (20 mL) was stirred at 80° C. for one hour. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 10% citric acid and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (Sorbisol C 60 flash silica gel, 400 mL) and eluted with Hexane/EtOAc (2:1) and Hexane/EtOAc (1:1). The solvent was removed in vacuo, to give a solid that was triturated with anhydrous ether and dried in vacuo to yield 1.08 g of the title compound, m.p. 168°-170° C. TLC, silica gel, EtOAc/Hexane(2:l), Rf =0.42. 1H-NMR (DMSO-d6) δ9.1 (s, 1H), 9.0 (s, 1H), 8.5 (s, 1H), 7.5 (m, 4H), 7.0 (d, J=8.8 Hz 1H), 6.8 (d, J=8.8 Hz, 1H), 5.7 (d, J=5.9 Hz, 1H), 4.7 (t, J=8.8 Hz, 1H), 3.7 (dd, J=5.9 & 3.5 Hz, 1H), 3.4 (s, 1H), 1.5 (s, 3H), 1.2 (s, 3H); 13C-NMR (DMSO-d6) δ174.8, 158.6, 156.3, 155.7, 141.4, 132.6, 132.5, 130.0, 125.9, 123.7, 122.3, 120.6, 119.1, 117.9, 116.7, 102.7,l 80.4, 71.3, 49.5, 26.6, 18.9; IR (KBr) 2228, 1667, 1574, 1551, 1489 cm-1.M.S. (M+H)+ at 406, M.W. 405; [α]D =-55.20° (c=0.86 DMSO).
Reaction SMILES: C(OC(=O)[NH:7]/[C:8](=[N:34]\C(OC(C)(C)C)=O)/[CH:9]1[NH:21][CH2:20][C:18]2=[C:19]3[C:14](=[C:15]([C:30]([F:33])([F:32])[F:31])[C:16]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17]2)[CH:13]=[CH:12][N:11]3[CH2:10]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH2:22]([C:16]1[C:15]([C:30]([F:33])([F:32])[F:31])=[C:14]2[C:19]3=[C:18]([CH2:20][NH:21][CH:9]([C:8](=[NH:7])[NH2:34])[CH2:10][N:11]3[CH:12]=[CH:13]2)[CH:17]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N=C(N)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A solution of Z-tert-butyl(((tert-butoxycarbonyl)imino)(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)methyl)carbamate (74 mg, 0.13 mmol) in CH2Cl2 (5 mL) was treated with 4M HCl in 1,4-dioxane (12 mL) and the resulting mixture was stirred at room temperature overnight. Evaporation of the solvent and trituration with diethyl ether yielded 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboximidamide (26 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH3:26][O-:27].[Na+]>>[CH3:26][O:27][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 36 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.50 g) and sodium methoxide solution (from sodium, 0.16 g, and methanol, 20 ml) yielded the title compound, 0.29 g, m.p. 231°-2°° C. (recrystallised from methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20](Cl)=[O:21]>O1CCCC1>[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)C1CC1(Cl)Cl
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CC2(Cl)Cl)cc1
Temperature: 60 °C
Yield: 59.7 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 100 ml of absolute tetrahydrofuran by stirring and heating to 60° C. The solution is allowed to cool to room temperature, 5.15 g (29.7 millimoles) of 2,2-dichlorocyclopropanecarboxylic acid chloride, dissolved in 10 ml of absolute tetrahydrofuran, are added dropwise and the mixture is then stirred for 6 hours under reflux. Thereafter it is concentrated to about 50 ml and the product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 5.0 g (60% of theory) of 6-[p-(2,2-dichlorocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 252°-253° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.Cl[CH2:19][CH2:20][CH2:21][C:22]1([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30][CH3:31])=[O:29])[CH2:23]1>C1COCC1>[C:24]12([C:28]([O:30][CH3:31])=[O:29])[CH2:23][C:22]([C:32]([O:34][CH3:35])=[O:33])([CH2:27][CH2:26][CH2:25]1)[CH2:21][CH2:20][CH2:19]2
Reactant: COC(=O)C1CCCC(CCCCl)(C(=O)OC)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C12CCCC(C(=O)OC)(CCC1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a pre-cooled (−78° C.) solution of lithium diisopropylamide (27 mL, 54 mmol) in THF (80 mL) was added DMPU (30.2 g, 236 mol) dropwise, followed by an addition of dimethyl 1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate (11.7 g, 44.7 mmol) in THF (50 mL) within 20 min. The reaction mixture was stirred for 30 min at −78° C. and then allowed to warm up to room temperature over a period of 1.5 h. After quenched with saturated ammonium chloride (100 mL), the mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and extracted with dichloromethane (4×100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate: 20/1) to afford 8.32 g (82%) of dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate as a light yellow oil. ESI-MS m/z: 227 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][C:32](=[O:37])[C:33]([NH2:36])([CH3:35])[CH3:34]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:36][C:33]([CH3:35])([C:32]([O:31][CH3:30])=[O:37])[CH3:34])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Product: COC(=O)C(C)(C)NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and 2-aminoisobutyric acid methyl ester hydrochloride (Sigma), the title compound was obtained as a colorless oil after purcation by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[C:4]([Cl:11])[N:3]=1.C(O)C>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]([CH3:10])=[C:4]([Cl:11])[N:3]=1
Reactant: Cc1c(Cl)nc(Cl)nc1C=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(Cl)nc(Cl)nc1CO
Reaction time: 0.17 h

Procedure:
To a solution of 2,6-dichloro-5-methylpyrimidine-4-carbaldehyde (0.325 g, 1.70 mmol) in ethanol (10 mL) sodium borohydride (0.032 g, 0.85 mmol) was added at 0° C. The mixture was stirred for 10 minutes. Acetic acid (4 drops) was added and the volatiles were removed in vacuum. The residue was treated with 10% solution of methanol in chloroform (10 mL). The slurry was filtered through a pad of silica gel. The filtrate was concentrated and purified by column chromatography on silica using a gradient 0-4% of methanol in dichloromethane as eluent to yield the title product, 0.23 g (71%).
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:20]#[N:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O.C1(C)C=CC=CC=1>[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([C:20]#[N:21])=[N:3][OH:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCON=O
Reactant: N#CCc1ccccc1Oc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(=NO)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78002.1 %

Procedure:
854 Potassium hydroxide (3.96 g, 0.06 mol), toluene (100 ml) and butyl nitrite (6.19 g, 0.06 mmol) were added to 2-phenoxybenzyl cyanide (10.46 g, 0.05 mol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with hydrochloric acid, extracted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-phenoxy-α-hydroxyiminobenzyl cyanide (11.15 g, Yield: 93.6%, E/Z=11/89).
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28]Cl)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.[I-].[Na+].[Na].[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1>CC#N.CN(C=O)C>[CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28][N:38]3[CH:42]=[N:41][CH:40]=[N:39]3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: c1nc[nH]n1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCn4cncn4)cc3n2C2CCC2)cc1)C1CC1

Procedure:
To a solution of {4-[6-(2-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in CH3CN (10 mL) is added sodium iodide (1.84 g, 12.22 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (20 mL) and then used without further purification. To 1 mL of the DMF solution containing the iodoethyl intermediate (0.153 mmol) is added the sodium salt of 1,2,4-triazole (0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with 0.5 mL DMF and the desired product is purified by preparative LC to give {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).
Reaction SMILES: [C:1]([C:4]1[C:12](=[O:13])[N:11]2[C:7]([S:8][C:9]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=32)=[N:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>CN(C)C=O>[NH:33]1[C:32]([NH:31][C:1]([C:4]2[C:12](=[O:13])[N:11]3[C:7]([S:8][C:9]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=43)=[N:6][CH:5]=2)=[O:3])=[N:36][N:35]=[N:34]1
Reactant: O=C(O)c1cnc2sc3ccc(Cl)cc3n2c1=O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cnc2sc3ccc(Cl)cc3n2c1=O

Procedure:
In a manner similar to Example 4, 1.4 g. of 3-carboxy-7-chloro-4-oxo-4H-pyrimido[2,1-b]benzothiazole is reacted with 892 mg. of 1,1'-carbonyldiimidazole in 60 ml. of dimethylformamide at steam bath temperatures for 15 min. 5-Aminotetrazole (468 mg.) is added and the reaction mixture is heated for 30 min. The resulting suspension is cooled and filtered, 1.5 g., m.p. > 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].ClC1C(C(OO)=[O:32])=CC=CC=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([S:22]([CH3:23])=[O:32])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: CSc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: O=C(OO)c1ccccc1Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 48 h
Yield: 110 %

Procedure:
A solution of amide from Example 38 (0.2 g) in chloroform (5 ml) was treated with 70% m chloroperbenzoic acid (0.14 g). The reaction mixture was stirred for two days. calcium hydroxide (0.09 g) added and after stirring for a further 0.5 h the mixture was filtered. The filtrate was concentrated under reduced pressure to yield the sub-title product as a white solid (0.23 g).