Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[O:27]1[CH2:32][CH2:31][CH:30]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:25]6[CH:24]=[CH:23][N:22]=[CH:21][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(OC5CCOCC5)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A mixture of (1R)-1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (10 mg, 0.00003 mol), tetrahydro-4H-pyran-4-ol (6.5 μL, 0.000068 mol), diisopropyl azodicarboxylate (13 μL, 0.000068 mol), and triphenylphosphine (18 mg, 0.000068 mol) in tetrahydrofuran (200 μL, 0.002 mol) was stirred at room temperature overnight. It was purified with prep-HPLC to afford 2.3 mg of product. LCMS: m/z 435.1 (M+H)+,
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(OCC)C>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)N1CCC(C(=O)O)CC1
Reaction time: 8 h

Procedure:
A mixture of 300 g (2.32 mol) of isonipecotic acid and 1,200 ml of acetic anhydride is heated under reflux for 2 hours in a 4 liter reactor equipped with a mechanical stirrer, a condenser and a thermometer, and the mixture is left to stand overnight. 1 liter of diethyl ether is added to the mixture, which is starting to crystallise, the solid is filtered off and the cake is washed with diethyl ether (4×500 ml), drained and recrystallised from a 40/60 mixture of diisopropyl ether/isopropyl alcohol. 153 g are isolated in a first crop and 141 g in a second crop. The N-acetylisonipecotic acid obtained melts at 148° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9](=[O:25])[C:8]=2[C:26]#[N:27])[CH2:3]1.[Cl:28][CH2:29][C:30](Cl)=[O:31].CCN(C(C)C)C(C)C>ClCCl>[Cl:28][CH2:29][C:30]([N:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:9](=[O:25])[C:8]=2[C:26]#[N:27])[CH2:3]1)=[O:31]
Reactant: N#Cc1c(NC2CNC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1c(NC2CN(C(=O)CCl)C2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(Azetidin-3-ylamino)-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (1 eq, 0.150 g, 0.43 mmole) in dichloromethane at −10° C. was added chloroacetyl chloride (1.1 eq, 0.054 g, 0.474 mmole) followed by the addition of N,N′-diisopropylethylamine (1.5 eq, 0.083 g, 0.646 mmole, 0.110 mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-[1-(2-Chloro-acetyl)-azetidin-3-ylamino]-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.027 g, 15% calc M+H 425, obs M+H 425).
Reaction SMILES: [CH:1]1([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]C=C[CH2:2]1.C[N+]1([O-])CCOCC1.[O:26]1[CH2:31][CH2:30][O:29]CC1.O>O=[Os](=O)(=O)=O>[OH:26][C@H:31]1[C@@H:30]([OH:29])[CH2:2][CH:1]([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1C[C@@H](O)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (736 mg, 3.2 mmol) in dioxane —H2O (5.0 mL, 4:1) was added NMO (421 mg, 3.60 mmol) and OsO4 (1.0 mL mg, 0.32 mmol, 2.5 wt % in H2O) and the reaction mixture was stirred for 24 h at rt. Quenched with 10% aqueous Na2S2O3 solution and extracted with ethyl acetate. The combined organic layers washed with brine and dried over anhydrous Na2SO4. Filtered and concentrated to provide yellow oil, which was purified by flash chromatography (80% EtOAc-hexane) to yield 2-((3R,45)-3,4-dihydroxycyclopentyloxy)isoindoline-1,3-dione (650 mg, 77%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.94-2.12 (m, 2H) 2.14-2.35 (m, 2H) 4.22-4.88 (m, 2H) 4.75-5.11 (m, 1H) 7.67-7.78 (m, 2H) 7.79-7.86 (m, 2H). MS (ES) [M+H] calculated for C13H14NO5, 264.08; found 264.20.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:26]1([CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]1[CH2:32][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCN(CC2CCCCN2)CC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(piperidin-1-ylmethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.09 minutes; C28H33Cl2N5O2 (542.51); mass spectrum: (M−H)−=542/544/546 (chlorine isotope).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:29].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:26][O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:25])[NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)=[CH:14][N:15]=3)[CH2:20][CH2:21]2)=[O:37])[CH2:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide (100 mg, 0.29 mmol) in CH2Cl2 (10 mL) was treated with trans-1,4-cyclohexane dicarboxylic acid monomethyl ester. (110 mg, 0.59 mmol) and EDCI (230 mg, 1.18 mmol) at room temperature. After stirring overnight the reaction mixture was partitioned between EtOAc and water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column with 20-100% EtOAc in hexanes gradient to afford the product (120 mg, Yield: 80%). HRMS m/z calcd for C29H38N4O4 [M+H]+: 507.2966. Found: 507.2968.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2([C:34]([C:36]2([CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]2[C:42]2[CH:47]=[CH:46][C:45]([NH:48][CH3:49])=[C:44]([NH2:50])[CH:43]=2)=[O:35])[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:18]=[CH:19][C:20]=1[NH:21][CH3:22]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]([NH:50][C:44]2[CH:43]=[C:42]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][C:36]3([C:34]([C:24]3([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]3[C:17]3[CH:18]=[CH:19][C:20]([NH:21][CH3:22])=[C:15]([NH:14][C:11](=[O:13])[CH2:10][O:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:16]=3)=[O:35])[CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH:47]=[CH:46][C:45]=2[NH:48][CH3:49])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CNc1ccc(C2CCCCC2(CC(=O)OC)C(=O)C2(CC(=O)OC)CCCCC2c2ccc(NC)c(N)c2)cc1N
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Solvent: C1CCOC1
Product: CNc1ccc(C2CCCCC2(CC(=O)OC)C(=O)C2(CC(=O)OC)CCCCC2c2ccc(NC)c(NC(=O)COc3ccc(C#N)cc3)c2)cc1NC(=O)COc1ccc(C#N)cc1
Reaction time: 4 h

Procedure:
620 mg (3.5 mmol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mmol) of 1,1′-carbonylduimidazole were refluxed in 50 mL of tetrahydrofuran for 15 minutes. Then 1.0 g (3.28 mmol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylmethylcyclohex-1-yl) ketone were added and the mixture was boiled for a further 4 hours. Then the solvent was evaporated off and the crude product thus obtained was purified by column chromatography (150 g silica gel; eluant: dichloromethane with 0 to 2% ethanol). Yield: 1.4 g (93% of theory), C26H29N3O5 (463.5); Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[F:17].C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
A mixture of 3-methyl-1H-1,2,4-triazole (15.0 g, 181 mmol), 1,2-difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80° C. for 48 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford two regioisomeric products. Pure fractions of the less polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (7.2 g, 30.8 mmol, 17% yield) as an off-white solid. Pure fractions of the more polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (6.23 g, 28.0 mmol, 15% yield) as an off-white solid. Data for 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole: LC-MS (M+H)+=223.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.18-8.24 (m, 2H) 8.04 (s, 1H) 7.69-7.78 (m, 1H) 2.47-2.53 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)(C)(C)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[NH2:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2cccs2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Tert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.35 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate solution (5 ml.) The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduce pressure, and the residue was crystallized from ethyl acetate-diisopropyl ether to give 3-(aminomethyl)-6-hydroxy-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone hydrochloride (0.10 g, 83.3%) as crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[O:3]1.CN1CCOCC1.CN(C)C=O.C(OC(Cl)=O)C(C)C.Cl.[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:40][CH2:39]1>>[C:49]([C:48]1[CH:47]=[CH:46][C:45]([CH2:44][CH:41]2[CH2:42][CH2:43][N:38]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[O:3][C:4]=4[CH:10]=3)=[O:16])[CH2:39][CH2:40]2)=[CH:52][CH:51]=1)#[N:50]
Reactant: N#Cc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To a mixture of 0.3g (1.5 mmol) of N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid, 0.165 ml (1.5 mmol) of N-methyl-morpholine in 8 ml of dimethylformamid 0.2 ml (1.5 mmol) of isobutyl-chloroformate is added dropwise at 0° C. and the mixture is stirred at 0° C. for 1 hour. Then 0.333 g (1.4 mmol) of 4-piperidin-4-ylmethyl-benzonitrile hydrochloride and 0.165 ml (1.5 mmol) of N-methyl-morpholine are added and the reaction mixture is stirred at 0° C. for 1 hour, at room temperature for 16 hours. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.045 g (8.0%) of the title compound. Rf.: 0.4. Melting Point: 259-260° C. (isopropanol).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][S:15]([O:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:7]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(-n2cccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(-n2cccc2)c1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
170 mg of the resulting alcohol compound was dissolved in 10 ml of methylene chloride, and 120 mg of methanesulfonyl chloride and 150 mg of triethylamine were added. The mixture was stirred for 1 hour under ice cooling. The reaction mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 230 mg (yield 92%) of the captioned compound as a pale yellow oil.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][C:15]1[C:16](=[O:23])[C@@H:17]2[O:22][CH2:21][C@H:19]([CH:20]=1)[O:18]2>CO>[CH3:2][O:13][CH2:14][C:15]1[C:16](=[O:23])[C@@H:17]2[O:22][CH2:21][C@H:19]([CH:20]=1)[O:18]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1C(CO)=C[C@H]2CO[C@@H]1O2
Solvent: CO
Solvent: O
Product: COCC1=C[C@H]2CO[C@H](O2)C1=O
Yield: 44.7 %

Procedure:
2 g of p-toluene sulfonic acid monohydrate was added to 150 ml of a methanol solution containing 2.8 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-β-D-glycero-hex-3-enopyranos-2-ulose obtained in the above step (1), and the mixture was refluxed under heating for one hour. Disappearance of the starting material was confirmed by TLC, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane =1:2) to obtain 0.8 g of the desired product (Intermediate No. 48). The NMR analytical data of this product are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:16][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(O)cnc2ccccc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(OC)cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-hydroxycinchoninate, (J. Org. Chem. 1953, 18, 552) (1.53 g, 7.54 mmol), potassium carbonate (1.15 g, 8.29 mmol) in acetone (11 ml) was treated with methyl iodide (470 uL, 7.54 mmol) was stirred at RT under nitrogen overnight. The mixture diluted with water and extracted into DCM and washed with satd. sodium thiosulfate solution. The organics were dried over Na2SO4 and concentrated. Material purified by SGC (Combi flash, 10-50% EtOAc-hexanes over 40 minutes) gave methyl 3-methoxycinchoninate. 1H NMR (CDCl3) δ 8.85 (s, 1H), 8.07 (d, 1H), 7.72 (d, 1H), 7.61 (m, 2H), 4.08 (s, 3H), 4.03 (s, 1H). MS (ESI+) for m/z 218 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([OH:11])=O.[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:9]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:13])[F:12])=[O:11])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cnccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4-trifluoromethylpyridine-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (69% yield). 1H NMR (300 MHz, CDCl3) δ 8.87, 8.69, 8.05, 7.82, 7.62, 7.00, 4.10-3.69, 3.51-3.44, 3.38-3.35, 1.75-1.61, 1.52-1.45, 0.90. MS (ES+) m/z 451.3 (M+1).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>ClCCl>[CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH2:12][Br:34])[N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCc1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCOCc1cccc(CBr)n1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of 6-allyloxymethylpyridine-2-methanol (1.56 g, 8.72 mmol) and triphenylphosphine (2.74 g, 10.5 mmol) in dichloromethane (40 mL) at 0° C. was treated portionwise with CBr4 (4.34 g, 13.1 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1)] to give the title compound (1.99 g, 94%) as a colourless oil: NMR δH (400 MHz, CDCl3) 7.71 (1H, t, J 7.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 6.03-5.93 (1H, m), 5.37-5.32 (1H, m), 5.26-5.22 (1H, m), 4.64 (2H, s), 4.54 (2H, s) and 4.14-4.12 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1F.[O-:11][CH2:12][CH3:13].[Na+].[H-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[O:11][CH2:12][CH3:13]
Reactant: Fc1ncc(Cl)c(F)c1Cl
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1c(Cl)cnc(F)c1Cl
Reaction time: 8 h

Procedure:
To a solution of 70.2 g (0.38 mol) of 3,5-dichloro-2,4-difluoropyridine in 600 mL of ethanol was slowly added with stirring a solution of sodium ethoxide in ethanol prepared from 16 g (0.40 mol) of sodium hydride (60 percent in mineral oil, hexane washed) in 200 mL of ethanol. The mixture was allowed to stir overnight and the brown solution obtained was filtered through powdered cellulose and concentrated by evaporation under reduced pressure. The residue was partitioned between 500 mL of ether and 400 mL of water. The organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was distilled to obtain 62 g (84 percent of theory) of the title compound as a colorless oil having a boiling point of 175°-180° C. at 0.4 mm Hg (53 Pascals).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=CC(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>C1(C)C=CC=CC=1.Cl.CCOCC>[N:24]([CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[N+:25]=[N-:26]
Reactant: OCc1cccnc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccnc1Cl
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a solution of the above (2-chloro-pyridin-3-yl)-methanol (2.2 g, 15.1 mmol) and DPPA (3.9 mL, 18.2 mmol) in toluene (30 mL) was added DBU (2.9 mL, 18.2 mmol) at room temperature and stirred for 3 h. The reaction was diluted with 3M HCl (30 mL) and Et2O (75 mL). The layers were separated and the aqueous layer was extracted with Et2O (75 mL). The combined organic layers were washed with water (50 mL), brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to yield a yellow oil. Silica gel column chromatography using 95:5 hexanes:EtOAc afforded 2.0 g (77%) of 3-azidomethyl-2-chloro-pyridine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10]1)=[O:26])([CH3:21])[CH3:20]
Reactant: COc1cc2c(c(-c3ccccc3)c1)CCNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1cc2c(c(-c3ccccc3)c1)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 7-methoxy-5-phenyl-1,2,3,4-tetrahydro-isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].CO>O1CCOCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:18][CH3:17])=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a stirred solution of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (73.1 g, 286.6 mmol) in 1,4-dioxane (700 mL) was added 25 wt. % solution of NaOMe in MeOH (72.0 mL, 315 mmol) at RT under argon over 15 min. The resultant dark reaction mixture was stirred at RT for 1.5 h. The solvent was evaporated and to the resultant residue was added water (500 mL). The aqueous mixture was extracted with methylene chloride (4×120 mL). The combined organic layers were washed with water (2×300 mL) and then by saturated aqueous NaCl (2×150 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography eluting with 30% EtOAc/hexanes to give the title compound, 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (56.0 g, 78%) as pale yellow oil. HPLC: 3.19 min; MS, M+H=251. 1H NMR (DMSO-d6, 500 MHz): δ 8.05 (1H, s), 7.26-7.34 (5H, m), 5.24 (2H, s), 4.15 (3H, s).