Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Br[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:15][CH:16]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[CH:33])=[CH:28][CH:27]=1)[CH3:24]>CCOC(C)=O.[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>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[C:33][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:15][CH:16]=2)=[CH:28][CH:27]=1)[CH3:24]
Reactant: C#Cc1ccc(OCC)cc1
Reactant: CC(=O)NCCc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#Cc2ccc(CCNC(C)=O)nc2)cc1
Temperature: 80 °C

Procedure:
0.55 mL (3.91 mmol) DIPEA is added to 190 mg (0.78 mmol) N-[2-(5-bromo-pyridin-2-yl)-ethyl]-acetamide (I48.1), 3.72 mg (0.02 mmol) CuI and 13.7 mg (0.02 mmol) bis(triphenylphosphin)palladium-(II)-chloride. 171 mg (1.17 mmol) 4-ethoxyphenylacetylene are added and the reaction mixture is heated for 10 min at 80° C. in a microwave oven. The mixture is diluted with EtOAc and washed with water (1×) and diluted aq. ammonia solution. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[CH:19][N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:21][CH:20]=[CH:19][N:7]3[C:8](=[O:18])[C:9]=2[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH3:3])[N:24]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.040 g, 0.13 mmol), 2-amino-6-bromopurine (0.056 g, 0.26 mmol), and N,N-diisopropylethylamine (0.045 mL, 0.26 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH), to give the desired product. LCMS calculated for C19H15F2N8OS (M+H)+: m/z=441.1. Found: 441.1.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:17]=[CH:16][C:9]3[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[O:13][C:8]=3[CH:7]=2)[CH2:2]1.[CH3:18][CH:19]([NH2:21])[CH3:20]>C(O)C>[CH3:14][C:12]1[O:13][C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:3]([OH:1])[CH2:2][NH:21][CH:19]([CH3:20])[CH3:18])[CH:17]=[CH:16][C:9]=2[C:10](=[O:15])[CH:11]=1
Reactant: CC(C)N
Reactant: Cc1cc(=O)c2ccc(OCC3CO3)cc2o1
Solvent: CCO
Product: Cc1cc(=O)c2ccc(OCC(O)CNC(C)C)cc2o1

Procedure:
3.7 g 1,2-epoxy-3-(2-methyl-4H-1-benzopyrane-4-one-7-yloxy)-propane and 2.5 cm3 2-propylamine were boiled in 40 cm3 ethanol for 2 hours; the process of example 9 (a) was followed. 4.3 g 1-(2-methyl-4H-1-benzopyrane-4-one-7-yloxy)-3-(1-methylethyl-amino)-2-propanol (m.p. 80°-82° C.) was obtained in the form of a base.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1[CH3:12].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C1(O)CCCCC1>O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]2[CH3:12])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: COC(=O)N1CCC(N)C(C)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: OC1CCCCC1
Product: COC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])C(C)C1

Procedure:
A mixture of 43 parts of methyl 4-amino-3-methyl-1-piperidinecarboxylate, 57.6 parts of 1,4-dichloro-2-nitrobenzene, 32 parts of sodium carbonate, 0.2 parts of potassium iodide and 160 parts of cyclohexanol is stirred and refluxed (160°-163° C) for 20 hours with water-separator. The reaction mixture is evaporated. Water is added and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. Methylbenzene is added to the oily residue and the whole is washed with a diluted hydrochloric acid solution. After filtration over hyflo, the layers are separated. The methylbenzene phase is treated with activated charcoal. The latter is filtered off and the filtrate is dried, filtered and evaporated, yielding methyl 4-(4-chloro-2-nitrophenylamino)-3-methyl-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(-c2ccc(C(F)(F)F)cc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A mixture of ethyl 2-[5-(4-trifluoromethylphenyl)-2-furyl]benzoate (1.80 g), 1 M aqueous sodium hydroxide solution (20 ml), tetrahydrofuran (35 ml) and ethanol (35 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water and 1 M hydrochloric acid (30 ml) was added. The mixture was extracted with ethyl acetate-tetrahydrofuran (1:1, volume ratio). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-ethanol to give 2-[5-(4-trifluoromethylphenyl)-2-furyl]benzoic acid (1.15, yield 53%) as colorless plate crystals. melting point: 182–183° C.
Reaction SMILES: [OH-].[Li+].[N:3]1([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[S:18]([NH:21][C:22]2[C:31]([C:32]([O:34]C)=[O:33])=[C:30]3[C:25]([C@H:26]4[CH2:38][CH2:37][O:36][C@H:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)=O>O1CCOCC1.O>[N:3]1([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[S:18]([NH:21][C:22]2[C:31]([C:32]([OH:34])=[O:33])=[C:30]3[C:25]([C@H:26]4[CH2:38][CH2:37][O:36][C@H:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CCCN2CCCC2)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2CCCN2CCCC2)ccc2c1OC[C@@H]1OCC[C@H]21
Temperature: 80 °C
Yield: 10.3 %

Procedure:
Lithium hydroxide (0.028 g) was added to a solution of methyl cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 14, 0.06 g) in dioxane (2 mL) and water (1 mL) and the mixture was stirred and heated at 80° C. for 8 hours. After cooling, the mixture was acidified by addition of aqueous formic acid solution (10%) and extracted with DCM. The organic layer was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ammonia in methanol (2M) and DCM with a gradient of 1-10%. The isolated solid was triturated with a mixture of ether and cyclohexane (50%) and the solid was collected by filtration. The solid was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 10-95%. The isolated product was triturated with ether and the solid was collected by filtration to give cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid (0.006 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:25]N(C)C=O.CI>O>[CH3:25][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:22])[O:19][CH2:20][CH3:21]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 1.5 g of [3-(3-methyl-1,2,4-triazolo[4,3-b]-pyridazin-6-yl)phenyl]carbamic acid, ethyl ester, 0.29 g of sodium hydride (50% in oil) and 150 ml of dimethylformamide was stirred under argon for 1 hour and then 0.38 ml methyl iodide was added. This mixture was stirred overnight then poured onto 500 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and concentrated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing product were combined, the solvent evaporated in vacuo and the solid recrystalized from dichloromethane-hexane, to give 1.25 g of an off-white powder, mp 146°-149° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:27]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1)(=[S:27])[NH2:2]
Reactant: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C#N)cc2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product of step (b) (10 g) in a mixture of pyridine (500 ml) and triethylamine (80 ml) was covered with a blanket of H2S gas and stirred at ambient temperature overnight. The dark green reaction mixture was evaporated to dryness and the residue was triturated with dry ether. The resultant solid was collected and washed thoroughly with ether to give methyl 4-[3-(4-thiocarbamoyl-benzoyl) carbazoyl]phenoxyacetate (10.5 g) as a yellow solid; NMR Spectrum (DMSO--d6) 3.72 (3H, s), 4.90 (2H, s), 7.06 (2H, d), 7.90 (2H, d), 7.95 (4H, m), 9.62 (1H, br s), 10.01 (1H, br s), 10.40 (1H, br s), 10.55 (1H, br s); Mass Spectrum m/Z 388 (M+H)+.
Reaction SMILES: C1([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[C:16](=[O:17])[C:15](OC)=[CH:14][N:13](C=C)[CH:12]=3)=[CH:7][CH:6]=2)CCC=1.[C:22]1(C)[C:23](S([O-])(=O)=O)=[CH:24][CH:25]=[CH:26][CH:27]=1>>[CH:9]1([C:15]2[C:16](=[O:17])[C:11]([C:8]3[CH:7]=[CH:6][CH:5]=[C:10]([CH:27]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[CH:9]=3)=[CH:12][N:13]([N:13]([CH3:14])[CH3:12])[CH:14]=2)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:10]1
Reactant: C=Cn1cc(OC)c(=O)c(-c2ccc(C3=CCC3)cc2)c1
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Product: CN(C)n1cc(-c2cccc(C3CCCCC3)c2)c(=O)c(C2CC=CCC2)c1

Procedure:
3-[4-(1-cyclobutenyl)phenyl]-5-methoxy-1-vinyl-4(1H)-pyridone, toluenesulfonate
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=CC=CC=1C=C.Cl[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O>>[CH3:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: C=Cc1ccccc1
Reactant: ClCCc1ccccc1
Agent: C=Cc1ccccc1Cl
Agent: O=P(O)(O)O
Solvent: O=[N+]([O-])O
Product: CC1CC(c2ccccc2)c2ccccc21
Reaction time: 2 h

Procedure:
A mixture of 90 parts of styrene, 183 parts of o-chlorostyrene and 117 parts of o-chloroethylbenzene is added to a mixture of 722 parts of 93 per cent strength by weight phosphoric acid and 7.5 parts of 65 per cent strength by weight nitric acid at 35° to 40° C over 5 hours. The emulsion is stirred for a further 2 hours at 35° to 40° C and the organic phase is then separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation at 10 mm Hg gives 26 parts of 1-methyl-3-phenylindan and 148.5 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].BrC[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: BrCCc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCn2cccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.1 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.45 mmol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powdered potassium hydroxide (0.224 g, 4 mmol) was added and heated at 100 deg C. for 3 h. 2-(2-Bromo-ethyl)pyridine (0.09 g, 0.51 mol) was added at the same temperature and stir for 3 h at RT Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.01 g, 7% yield). 8-Chloro-2-methyl-5-(2-pyrrol-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.010 g, 0.0319 mmol) was dissolved in THF (0.5 mL), A solution of oxalic acid dihydrate (0.004 g, 0.0319 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as white solid (0.01 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:22][CH3:23])[C:17]([O:19]CC)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:22][CH3:23])[C:17]([OH:19])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(CC)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
415 mg (0.97 mmol) of ethyl 2-{4-[5-Chloro-2-(difluormethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 348 mg (93% of theory)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A172) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH2:22][C:15]4=[CH:14][C:13]=3[C:12]=2C(OC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH2:22][C:15]4=[CH:14][C:13]=3[CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1cc1n2CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ccc2c(c1)cc1n2CCC1)c1ccccc1
Yield: 36.4 %

Procedure:
A mixture of methyl 7-benzenesulfonylamino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 26, 0.075 g) and lithium hydroxide mononhydrate (0.049 g) in dioxane (2 mL) and water (1 mL) was irradiated in the microwave at 110° C. for 20 minutes. After cooling, the mixture was diluted with water and acidified to pH4-5 with formic acid. The resultant solid was washed with water and ether, then dried to give a cream powder. The solid was dissolved in methanol and acetone and freeze-dried, then dried in a dessicator, in vacuo, at 40° C. overnight. The solid was triturated with DCM and filtered, washed with DCM (1 mL) and pentane (1 mL) then dried in a dessicator, in vacuo, at 40° C. overnight. The yellow solid was dissolved in hot ethyl acetate and pentane was added until the mixture went cloudy. On cooling, the solid was collected by filtration, washed with pentane and dried in a dessicator, in vacuo, at 40° C. overnight to give 7-benzenesulfonylamino-2,3-dihydro-1H-pyrrolo[1,2-a]indole (0.023 g) as a cream solid.
Reaction SMILES: C[C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=CC=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[CH2:24](N1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O)CCC>>[CH2:17]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[SH:5]([CH3:24])[C:6]([C:7]([OH:9])=[O:8])=[CH:2][N:3]=2)[C:13]1=[O:23])[CH2:22][CH2:21][CH3:20]
Reactant: CCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: CCCCN1CCN(C2=NC=C(C(=O)O)[SH]2C)C1=O
Yield: 94 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-butyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 94% yield: MS (ES+) m/z 284.2 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].C(O[C:7](=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH3:8])C.O>CCO>[NH2:11][C:10]1[NH:3][N:2]=[C:7]([CH3:8])[C:9]=1[C:12]#[N:13]
Reactant: NN
Reactant: CCOC(C)=C(C#N)C#N
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(N)c1C#N
Temperature: 95 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
Hydrazine monohydrate (6.8 ml, 0.14 mol) was dissolved in EtOH (10 ml) and cooled to 0° C. (1-Ethoxyethylidene)malononitrile (10 g, 0.073 mol) was added slowly and the mixture was heated at 95° C. for 2 h. After cooling to rt, water (20 ml) was added and the mixture was allowed to stand at rt overnight. The mixture was concentrated under reduced pressure and the resulting residue treated with EtOH (6 ml) and water (6 ml). After cooling in an ice/water bath for 10 min, the resulting precipitate was collected by filtration to give 6.34 g of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[S:4][N:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[S:4][N:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)sn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 29.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3-methylisothiazol-5-yl)carbamate (259 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 20 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (92.7 mg, 29.5%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:12])=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH3:13][N:14]=[C:15]=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[Cl:12][C:5]1[N:4]=[N:3][C:2]([NH:1][C:15]([NH:14][CH3:13])=[O:16])=[CH:7][C:6]=1[C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(N)nnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Nc1cc(C(C)(C)C)c(Cl)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1.3 g of (0.007 mole) of 3-amino-6-chloro-5-(1,1-dimethylethyl)pyridazine in 65 ml of methylene chloride was added one drop of triethylamine and 0.8 g (0.014 mole, 2.0 equivalents) of methyl isocyanate. The mixture was stirred at room temperature for about 18 hours. Additional methyl isocyanate (0.8 g, 0.140 mole, 2.0 equivalents) was added and about 3 hours later, the solution was diluted to 400 ml using methylene chloride. The solution was washed with four 40-ml portions of 1.0N hydrochloric acid and 50 ml of water, and was then dried with magnesium sulfate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][CH:17]3[CH2:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:6][CH:5]=1.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[N:26]=[CH:25]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C.O>[CH:17]1([N:16]([CH2:15][C:13]2[N:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[S:11][CH:12]=2)[C:29]([C:27]2[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=2)=[O:30])[CH2:20][CH2:19][CH2:18]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: FC(F)(F)Oc1ccc(-c2nc(CNC3CCC3)cs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cnc(C(=O)N(Cc2csc(-c3ccc(OC(F)(F)F)cc3)n2)C2CCC2)c1
Yield: 37.8 %

Procedure:
A solution of N-({2-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}methyl)cyclobutaneamine (430 mg), methyl-1H-imidazole-4-carboxylic acid (451 mg), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (598 mg) and diisopropylethylamine (0.69 mL) in acetonitrile (15 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) and PTLC (silica gel, chloroform:methanol=19:1). The resulting residue was re-crystalized with isopropyl ether to afford the title compound (216 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:12](=[O:13])[NH:23][N:24]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)C(CC(=O)O)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(=O)CC2c2ccccc2)cc1
Yield: 99 %

Procedure:
A solution of 4-(4-methoxy-phenyl)-4-oxo-3-phenyl-butyric acid (1.5 g, 5.28 mmol) and hydrazine hydrate (1.5 eq., 363 μL) in 20 mL of EtOH was stirred at 80° C. overnight. The solvent was reduced and the solid was filtered and then washed with cold EtOH to give 6-(4-methoxy-phenyl)-5-phenyl-4,5-dihydro-2H-pyridazin-3-one (1.46 g, 99%): mp 176-7° C.; MS m/z 281 (M+H).