Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([S:7]([NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23](=[O:32])[N:24]([CH2:26][C:27]([O:29]CC)=[O:28])[N:25]=3)[CH:17]=2)[CH2:12]1)(=[O:9])=[O:8])[CH2:4][CH2:5][CH3:6]>CO>[CH2:3]([S:7]([NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23](=[O:32])[N:24]([CH2:26][C:27]([OH:29])=[O:28])[N:25]=3)[CH:17]=2)[CH2:12]1)(=[O:8])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)n(CC(=O)OCC)n3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)n(CC(=O)O)n3)cc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
11.3 ml of a 1N sodium hydroxide aqueous solution was added dropwise under ice cooling to 3.25 g of 2-n-butylsulfonylamino-5-[2-ethoxycarbonylmethylpyridazin-3(2H)-on-6-yl]indane suspended in 50 ml of methanol, and the mixture was stirred at room temperature for 5 hours. Methanol was removed, water was added to the residue, and the mixture was made acidic with 10% hydrochloric acid. Crystals precipitated were collected by filtration, washed with water and then recrystallized from ethanol-water to obtain 2.50 g of 2-n-butylsulfonylamino-5-[2-carboxymethylpyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][C:10](=O)[NH:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1>O1CCCC1>[O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][NH:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1
Reactant: O=C1CCc2cc3c(cc2N1)OCO3
Solvent: C1CCOC1
Product: c1c2c(cc3c1OCO3)NCCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-6-one (250 mg, crude) in tetrahydrofuran (50 ml) was dropwise BH3 in THF (1 N, 26 ml). The reaction was stirred at 60° C. overnight. Then the reaction mixture was quenched with hydrogen chloride (3 N), adjusted to pH 8 with sodium bicarbonate, extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]quinoline as a solid (180 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>C(O)CCC.O.CCN(CC)CC.C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2ccncc2)CC1
Temperature: 25 °C

Procedure:
A solution of 3 g Piperidin-4-yl-carbamic acid tert-butyl ester and 2.5 g 4-Chloropyridine in 9 ml n-butanol/water/NEt3 1:1:1 was heated at 100° C. for 48 h. Then the solution was cooled to RT diluted with DCM and washed with NaHCO3 solution and water. The organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Chromatographic purification of the residue on silica with DCM as eluent gave after evaporation of the fractions containing the product a white foam. Yield 1.7 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH3:12][C:13]([CH3:17])=[CH:14][Mg]Br>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[C:13]([CH3:17])[CH3:14])=[N:3][CH:4]=1
Reactant: COCOc1ccc(Cl)nc1
Reactant: CC(C)=C[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: COCOc1ccc(C=C(C)C)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-chloro-5-(methoxymethoxy)pyridine (0.620 g, 3.6 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.13 g, 0.18 mmol) in THF (7 mL) was cooled to 0° C. 2-methyl-1-propenylmagnesium bromide, (0.5 M in THF) (9.3 ml, 4.6 mmol) was added slowly and the reaction was allowed to stir 12 hrs at RT. The reaction was quenched by the addition of a 10:1 aqueous sat ammonium chloride/ammonium hydroxide solution and extracted into ethyl acetate. The combined organic layers were washed with 10:1 aqueous sat. ammonium chloride/ammonium hydroxide solution, water, brine, dried over sodium sulfate and concentrated. The crude product was purified by filtration through a plug of silica gel (2:1 Hexanes/EtOAc) to afford the title product. MS m/z: 194.1 (100%, M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[C:42]([NH:43]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:44]=[CH:45][CH:46]=1)=[O:37])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-tert.butoxycarbonylaminomethylcarbonylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.[NH2:11][C:12]1[C:13]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[Br:27]Br>>[NH2:11][C:12]1[C:13]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:14][C:15]([Br:27])=[C:16]([CH3:18])[N:17]=1
Reactant: BrBr
Reactant: Cc1cnc(C(=O)c2ccccc2)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1nc(N)c(C(=O)c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium carbonate (0.23 g, 1.64 mmol) is dissolved in glacial acetic acid (5 ml, 1.64 mmol) and (3-amino-5-methyl-pyrazin-2-yl)-phenyl-methanone (0.17 g, 0.82 mmol) and bromine (0.055 ml, 1.07 mmol) are added. The resulting yellow solution is stirred at room temperature for 1.5 hours. The solvent is removed in vacuo, and the residue is suspended in DCM, filtered and washed with DCM. The filtrated is concentrated and dried in vacuo to yield the title compound as a yellow solid. [M+H]+ 292.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (37.7 mmol, 8.86 g) in methanol (89 mL) at 0° C., was added sodium borohydride (39.6, 1.50 g). The mixture was stirred for 1 h. HCl 10% (100 mL) was added and the mixture was stirred for 0.25 h. The mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude alcohol was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])=O.[NH4+:14].Cl>CO.O.C[C]1[C](C)[C](C)[C](C)[C]1C.C[C]1[C](C)[C](C)[C](C)[C]1C.Cl[Rh]Cl.Cl[Rh]Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: [NH4+]
Agent: Cl[Rh]Cl
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(N)c1cccc(Br)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A mixture of 3′-bromoacetophenone (2.66 mL, 20 mmol), ammonium formate (6.31 g, 100 mmol) and dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (124 mg, 0.2 mmol) in anhydrous methanol (20 mL) under an atmosphere of nitrogen was heated at reflux for 5 hours then allowed to cool to room temperature overnight. The mixture was diluted with water (20 mL), acidified to pH 2 with dilute aqueous hydrochloric acid (2M) and washed with dichloromethane (2×60 mL). The aqueous solution was basified to pH 12 with solid potassium hydroxide, extracted with dichloromethane (3×50 mL) and the extracts washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to give 1-(3-bromophenyl)ethanamine (3.4 mg, 85%) as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
As described for Reference Example 26, 5.0 g of 2-chloro-5-nitrobenzoic acid is reacted with 50 ml of thionyl chloride to give 5.6 g of the product as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[C:20]=2[OH:29])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)CC.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:29][C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: COC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Yield: 42.4 %

Procedure:
A mixture of benzyl-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (400 mg, 0.61 mmol) in propionic acid (5 mL) was heated to reflux for 4 days. The mixture was diluted with water (50 mL), neutralized with sodium bicarbonate, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by pre-HPLC to afford methyl 2-(1-(benzyloxycarbonyl)piperidin-4-yl)benzo[d]oxazole-7-carboxylate (102 mg) as a yellow oil. LC-MS (ESI) m/z: 395 (M+1)+.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.ClC(N(C)C)=C(C)C.[NH2:30][C:31]1[N:35](C(OC(C)(C)C)=O)[N:34]=[C:33]([CH2:43][CH2:44][C:45]2[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([O:53][CH3:54])[CH:46]=2)[CH:32]=1.Cl.O1CCOCC1>C1COCC1.N1C=CC=CC=1>[CH3:52][O:51][C:49]1[CH:50]=[C:45]([CH2:44][CH2:43][C:33]2[NH:34][N:35]=[C:31]([NH:30][C:19]([C:17]3[S:18][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)=[O:21])[CH:32]=2)[CH:46]=[C:47]([O:53][CH3:54])[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)s2)CC1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCNCC4)s3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 13.5 %

Procedure:
5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylic acid (150 mg, mmol) was dissolved in dry THF (10 ml) under nitrogen, 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (177 μl, mmol) was added and the mixture was stirred at room temperature for 3.5 h. Tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (167 mg, mmol) and pyridine (47 μl, mmol) were added and the reaction was heated to 65° C. for 18 h. The reaction mixture was then cooled to room temperature and 4M HCl in dioxane (2.0 ml, 2.0 mmol) added. The mixture was stirred overnight at room temperature, evaporated and the residue was purified by acidic prep. HPLC, eluting with a gradient of 24-32% MeCN in 0.1% TFA in water. The clean fractions were taken and evaporated to give the title compound as a pale green solid (28.7 mg, 11%); 1H NMR (399.902 MHz, DMSO) δ 2.79 (s, 4H), 3.21 (s, 4H), 3.34 (s, 4H), 3.64 (s, 6H), 6.29 (m, 5H), 7.77 (m, 1H), 8.71 (s, 1H), 10.37 (s, 1H) MS: m/z=442 (MH+)
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[N:4][C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH2:62][C@H:63]1[CH2:66][CH2:65][N:64]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68].CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[N:4][C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([NH:61][CH2:62][C@H:63]1[CH2:66][CH2:65][N:64]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CN
Reactant: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)O)cc2F)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)NC[C@H]3CCN3C(=O)OC(C)(C)C)cc2F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinic acid (14.3 g, 40 mmol) and DMF (300 mL) was added of HBTU (18.2 g, 48 mmol) and HOBT (6.49 g, 48 mmol). The mixture was cooled down to 0° C., 8.93 g (48 mmol) of (R)-tert-butyl 2-(aminomethyl)azetidine-1-carboxylate was added, followed by 13.9 ml of DIEA (80 mmol). The mixture was stirred at r.t for 1 hour and extracted with 300 mL EtOAc. The organic layer was washed with 500 mL brine, dried over MgSO4 and then concentrated. The residue was purified by Biotage silica gel chromatography using EtOAc:Hex (1:1) as eluant. (R)-tert-butyl 2-((5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)methyl)azetidine-1-carboxylate was obtained as a yellow solid (16.5 g, yield 80%). LRMS (M+H+) m/z 527.1.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][N:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5](=[O:8])[NH:6][N:7]=1.Cl.Cl.N[N:16]1CC(C)=NN[C:17]1=O>CO>[NH2:9][N:4]1[CH2:3][C:2]([CH3:1])=[N:7][NH:6][C:5]1=[O:8].[N:16]1[CH:17]=[CH:11][C:10](=[O:12])[NH:9][N:4]=1
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: CC1=NNC(=O)N(N)C1
Agent: Cl
Solvent: CO
Product: O=c1ccnn[nH]1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A suspension is prepared of 39.9 g (0.234 mol) 6-methyl-4-acetylamino-4,5-dihydro-1,2,4-triazin-3-(2H)-one in 99 g 95% methanol. The suspension is heated to 45° C. and becomes a clear colourless solution. At between 45° and 50° C. a total of 15.4 g (0.421 mol) HCl are bubbled through this solution over a 2 to 3 hour period. After about 30% of the HCl has been added the reaction mixture is seeded with 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine hydrochloride. Thereafter 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine precipitates out continuously as the hydrochloride salt. After about 2 hours stirring, the maximum conversion of over 99% is reached. The reaction mixture is brought to pH 5 by the addition of 50% NaOH solution. The free aminotriazone triazinone 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine is formed in an amount of 29.7 g representing 14.3% by weight of the solution. This represents a yield of 99.2% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.[CH:26]([NH2:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28].CS(O)(=O)=O>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:35][CH:26]([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: NC(C(F)(F)F)C(F)(F)F
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CON(C)S(=O)(=O)c1c(Cl)ccc(Nc2c(NC(C(F)(F)F)C(F)(F)F)c(=O)c2=O)c1O

Procedure:
6-Chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide (Intermediate A) (50 mg, 0.102 mmol) and 1,1,1,3,3,3-hexafluoroisopropylamine (34.0 mg, 0.203 mmol) were dissolved THF (1 ml). To the solution was added methanesulfonic acid (7 μl, 0.108 mmol) and the resultant mixture was heated at 50° C. overnight (˜18 hr). The solution was concentrated in vacuo and the residue was re-dissolved in DMSO (900 μl). The solution was transferred to a HPLC vial and purified using mass-directed prep system using 50-98% acetonitrile in water (0.1% TFA). The solvent was removed from the purified fraction in vacuo. The residue was re-dissolved in MeOH the solvent was removed in vacuo to afford the title compound as an orange solid;
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20](Cl)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:26])=[N:9][CH:10]=1)=[O:4].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:27][C:3]([C:5]2[N:6]=[CH:7][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:18]=[N:19][C:20]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[C:21]([CH3:24])[C:22]=4[CH3:23])[CH2:13][C@H:12]3[CH3:26])=[N:9][CH:10]=2)=[O:4])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)cn1
Reactant: Nc1ccccc1
Product: Cc1c(Nc2ccccc2)nnc(N2CCN(c3cnc(C(=O)Nc4ccccc4)cn3)[C@H](C)C2)c1C
Temperature: 190 °C

Procedure:
To (R)-4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (compound 54, 250 mg, 0.663 mmol) is added aniline (2.4 mL, 26.5 mmol) in a microwave tube. The reaction mixture is heated at 190° C. for 30 min in a microwave reactor. The reaction mixture is loaded on silica gel and purified by flash chromatography, eluting with 50%-100% EtOAc:heptane for six column volumes, followed with 3%-10% MeOH in DCM. Both example 3 and 4 are collected and concentrated to afford white solids.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]#[N:11])[CH:8]=1.Br[CH2:13][CH2:14]Br.[Cl-].[NH4+]>CS(C)=O>[F:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:8]=1
Reactant: BrCCBr
Reactant: N#CCn1cc(F)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: N#CC1(n2cc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.6 %

Procedure:
Sodium hydride (1.26 g, 52.75 mmol, 60% oil dispersion) was washed with petroleum ether under a nitrogen atmosphere. The supernatant was removed after the solids settled. Then a solution of 2-(4-fluoro-1H-pyrazol-1-yl)acetonitrile (1.1 g, 8.79 mmol) and 1,2-dibromoethane (2.28 mL, 26.37 mmol) in dimethylsulfoxide (90 mL) was added at 0° C. over a period of 40 min. The reaction mixture was stirred at room temperature for 6 h. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 5-12% ethyl acetate in petroleum ether) to afford 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (300 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:21][C:22]#[CH:23])[C:10]([OH:20])([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:11](=[O:13])[CH3:12].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:21][C:22]#[CH:23])[C:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)([OH:20])[CH:11]([OH:13])[CH3:12]
Reactant: C#CCC(c1ccc(Cl)cc1Cl)C(O)(C(C)=O)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C#CCC(c1ccc(Cl)cc1Cl)C(O)(c1cccnc1)C(C)O
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A solution of 5.8 g of 4-(2,4-dichlorophenyl)-3-hydroxy-3-(3-pyridyl)-6-heptyn-2-one (see Example 4, 1st end product) in 100 ml of ethanol is treated at room temperature with 0.8 g of sodium borohydride and the mixture is stirred for 30 minutes. Thereafter, the excess sodium borohydride is destroyed by adjusting the yellowish reaction solution to pH 1 with 2N sulphuric acid and the mixture is again neutralized with saturated aqueous sodium bicarbonate solution. The mixture is evaporated under reduced pressure in order to remove the solvent, the residue is partitioned between ethyl acetate and water and the organic phase is washed with saturated aqueous sodium chloride solution and evaporated under reduced pressure in order to remove the solvent. The residue is purified by chromatography on silica gel with methylene chloride/ethyl acetate (3:7). In this manner there are obtained 5.7 g of 4-(2,4-dichlorophenyl)-3-(3-pyridyl)-6-heptyne-2,3-diol as a colorless solid foam. In an analogous manner, starting from
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH3:17])=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12>>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:12]([C:11]3[CH:15]=[CH:16][C:8]([C:7]4[C:2]([CH3:1])([CH3:18])[CH2:3][CH2:4][CH2:5][CH:6]=4)=[C:9]([CH3:17])[CH:10]=3)=[O:14])[CH2:24][C:23]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C1=CCCCC1(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1(C)C
Yield: 51.2 %

Procedure:
4-(6,6-Dimethyl-cyclohex-1-en-1-yl)-3-methyl-benzoic acid of Step B (0.078 g, 0.319 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.065 g, 0.351 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.0670 g) as white crystals, m.p. 131° C.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[S:8][C:7]([NH:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)=[N:6][C:5]1=[O:20])[CH3:3].C1C(=O)N(Br)[C:23](=[O:24])C1>C(Cl)(Cl)(Cl)Cl>[CH:2]([C:4]1([O:24][CH3:23])[S:8][C:7]([NH:9][C:10]23[CH2:19][CH:14]4[CH2:13][CH:12]([CH2:18][CH:16]([CH2:15]4)[CH2:17]2)[CH2:11]3)=[N:6][C:5]1=[O:20])([CH3:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)C1SC(NC23CC4CC(CC(C4)C2)C3)=NC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC1(C(C)C)SC(NC23CC4CC(CC(C4)C2)C3)=NC1=O
Temperature: 0 °C

Procedure:
A mixture of 5-(1-methylethyl)-2-(tricyclo[3.3.1.13,7]dec-1-ylamino)-1,3-thiazol-4(5H)-one (146 mg, 0.5 mmol) and NBS (107 mg, 0.6 mmol) in CCl4 (60 mL) was stirred at reflux for 30 min. The resulting mixture was cooled to 0° C., and filtered to remove the solid. The residue was then concentrated in vacuo and diluted with CH2Cl2 (20 mL). To this mixture was added MeOH (200 uL) and DIEA (200 uL). The mixture was stirred for 30 min, then was concentrated in vacuo and purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as white solid. MS (ES+): 323 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=1>CO.[OH-].[Na+]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cccs2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cccs2)nc1

Procedure:
A solution of 2.0 g of methyl 6-(2-thienyl)pyridine-3-carboxylate in 100 ml of methyl alcohol and 50 ml of 5N sodium hydroxide is stirred at room temperature for 16 hours under nitrogen. The reaction mixture is evaporated in vacuo to about one quarter of the volume and then diluted with 150 ml of cold water. The pH is adjusted to 4 with acetic acid and the desired white product collected, washed with 400 ml of cold water until neutral. The solid is washed with 50 ml of petroleum ether and dried under vacuum to 40° C. to give the desired product.