Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[C:24]([OH:30])=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1>CN(C=O)C>[Cl:29][C:26]1[N:25]=[C:24]([OH:30])[C:23]([NH:22][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[CH:28][N:27]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cnc(Cl)nc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(Cl)nc1O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5.88 g (47.7 mmol) isonicotinic acid and 7.74 g (47.7 mmol) 1,1′-carbonyldiimidazole in 30 mL DMF are stirred for 30 min at 45° C. prior to addition of 8.0 g (47.7 mmol) of 5-amino-2-chloro-pyrimidin-4-ol. The mixture is stirred for 12 h at rt, concentrated and purified by HPLC (reversed phase, water (+0.1% TFA)/MeOH) to yield N-(2-chloro-4-hydroxy-pyrimidin-5-yl)-isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH3:24][C:25]1[NH:29][N:28]=[C:27]([CH2:30][N:31]2[C:35](=[O:36])[CH2:34][S:33][C:32]2=[O:37])[N:26]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:34]4/[C:35](=[O:36])[N:31]([CH2:30][C:27]5[N:26]=[C:25]([CH3:24])[NH:29][N:28]=5)[C:32](=[O:37])[S:33]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: Cc1nc(CN2C(=O)CSC2=O)n[nH]1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Product: Cc1nc(CN2C(=O)S/C(=C\c3ccc4c(c3)nnn4Cc3ccc(Cl)cc3C(F)(F)F)C2=O)n[nH]1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-[(5-methyl-1H-1,2,4-triazol-3-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 86) following General Procedure F.
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2[NH:7][C:8]([C:10]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:11]=3[N:12]=[C:13]([NH:21][C:22]3([CH3:25])[CH2:24][CH2:23]3)[C:14]([CH3:20])=[N:15]4)=[CH:9][C:5]=2[C:4](=[O:26])[NH:3]1.C(Cl)(Cl)[Cl:28]>>[Cl:28][C:9]1[C:5]2[C:4](=[O:26])[NH:3][C@H:2]([CH3:1])[C:6]=2[NH:7][C:8]=1[C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([NH:21][C:22]1([CH3:25])[CH2:23][CH2:24]1)[C:14]([CH3:20])=[N:15]2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1NC1(C)CC1
Reactant: ClC(Cl)Cl
Product: Cc1nc2cccc(-c3[nH]c4c(c3Cl)C(=O)N[C@@H]4C)c2nc1NC1(C)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a suspension of (R)-6-methyl-2-(2-methyl-3-((1-methylcyclopropyl)-amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (333) (160 mg, 0.46 mmol) in 5 mL of CHCl3 at RT was added n-chlorosuccinimide (73.8 mg, 0.55 mmol) and the mixture was stirred in an oil bath at 50° C. for 1.5 h. LCMS indicated 80% conversion. Additional n-chlorosuccinimide (21 mg, 1.55 mmol) was added and heating at 50° C. was continued for another 30 min. It was cooled to RT, treated with 5 mL of ice cold 0.5 N NaOH, and extracted with 25 mL of DCM followed by 25 mL of EtOAc. The combined organic extracts were concentrated and the residue was purified on a silica gel column (50% EtOAc in DCM followed by 5% MeOH in EtOAc) to give (R)-3-chloro-6-methyl-2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (454) (145 mg, 82% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.97 (1H, br.), 8.26 (1H, dd, J=7.6, 1.2 Hz), 7.84 (1H, s), 7.72 (1H, dd, J=8.0, 1.2 Hz), 7.64 (1H, s), 7.43 (1H, t, J=7.8 Hz), 4.61 (1H, q, J=6.7 Hz), 2.45 (3H, s), 1.45 (3H, s), 1.37 (3H, d, J=6.7 Hz), 0.89 (2H, m), 0.75 (2H, m). m/z (ESI, +ve) 382.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(I)c23)CC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reaction time: 2 h
Yield: 69.1 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (1 mL, 7.36 mmol) was slowly added to a stirring mixture of tert-butyl 4-(3-iodo-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (3.1 g, 6.134 mmol) and K2CO3 (1.27 g, 9.2 mmol) in DMF (30 mL) at room temperature. After 2 hours, EtOAc (200 mL) and water (100 mL) were added to the mixture, and the phases were separated with warming. The resulting organic suspension was washed with water (3×50 mL) with warming. Final organic phase was concentrated in vacuo without drying over MgSO4 to prevent the loss of the product. The residue was triturated with CH3CN, and the solid formed was filtered, washed with CH3CN (2×10 mL) and dried under high vacuum to provide tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (2.65 g, 69% yield) as a solid. LCMS (APCI+) m/z 626.1 (M+H)+, Retention time=4.96 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16](C=O)=[CH:15][CH:14]=1.[OH:21]OS([O-])=O.[K+].CCOC(C)=O>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1.[OH:21][C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: O=S([O-])OO
Reactant: O=Cc1ccc(O)cc1
Agent: COC(=O)c1ccc(O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To prepare methyl 4-hydroxybenzoate, 4-hydroxybenzaldehyde (100 mg) was dissolved in MeOH (10 mL), and OXONE (0.503 g) was added and stirred at room temperature for 18 hours with the reaction having a final volume (11 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain methyl 4-hydroxybenzoate in 4% yield and 4-hydroxyphenol in 77% yield after purification by silica gel column chromatography.
Reaction SMILES: C1COCC1.[NH2:6][C@@H:7]1[C:19](=[O:20])[N:9]2[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH2:14][OH:15])[CH2:12][S:13][C@H:8]12.C(=O)([O-])O.[Na+].Cl.ClCC([NH:31][C:32]1[S:33][CH:34]=[C:35](/[C:37](=[N:41]/[O:42][CH3:43])/[C:38](Cl)=[O:39])[N:36]=1)=O>O.O1CCCC1.C(OCC)(=O)C.O>[NH2:31][C:32]1[S:33][CH:34]=[C:35](/[C:37](=[N:41]/[O:42][CH3:43])/[C:38]([NH:6][C@@H:7]2[C:19](=[O:20])[N:9]3[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH2:14][OH:15])[CH2:12][S:13][C@H:8]23)=[O:39])[N:36]=1
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Yield: 63.6 %

Procedure:
In 800 ml of water-tetrahydrofuran (briefly, THF) (1:1) is suspended 16.9 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid, and with ice-cooling and stirring, 27.72 g of sodium hydrogen carbonate is added. Then, 29.4 g of 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride is added gradually thereto and the mixture is stirred for 30 minutes. To this reaction mixture are added 150 ml of water and 200 ml of ethyl acetate and the water layer is separated. Under ice-cooling and stirring, this water layer is adjusted to pH 7.0 with 1N-hydrochloric acid. Under stirring at room temperature, 18.9 g of sodium N-methyldithiocarbamate is added gradually to thereby eliminate the aminoprotective group (This is confirmed by TLC). To the reaction mixture is added 300 ml of ethyl acetate and the water layer is separated and concentrated under reduced pressure to 70 ml. The residue is chromatographed on a column of XAD-II (1 l) and eluted with water. The fractions rich in the desired compound are pooled and concentrated to 100 ml, and with ice-cooling and stirring, the residue is adjusted to pH 2.5 with 4N-hydrochloric acid. The resulting crystals are collected by filtration, washed with 100 ml of water, 50 ml of ethyl acetate and 50 ml of THF, and dried under reduced pressure. The above procedure yields 19.3 g of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].NN>C(O)C.[Pd]>[Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1Cc2ccccc2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Yield: 46.5 %

Procedure:
A mixture of 1.40 g of 5-(2-chloro-4-nitrobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.20 g of 10% palladium-on-carbon, 0.25 g of anhydrous hydrazine in 25 ml of absolute ethanol is heated at reflux for 1 hour. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo to a residue which is dissolved in methylene chloride and hexane added at the boil to give 0.60 g of the desired product as a crystalline solid, m.p. 158°-161° C.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C@@H:14]4[CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16][C@@H:15]4[N:7]([C:8]=23)[CH2:6][CH2:5]1>C(O)CCC>[CH3:3][N:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C@@H:14]4[CH2:19][NH:18][CH2:17][CH2:16][C@@H:15]4[N:7]([C:8]=23)[CH2:6][CH2:5]1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3C
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12
Yield: 95.1 %

Procedure:
Powdered potassium hydroxide (10.0 g) was added to a stirred solution of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (4.52 g, 15.0 mmol) in warm 1-butanol (50 mL) and the resulting mixture was heated under reflux for 5 h. It was then evaporated under reduced pressure and the residue treated with water and extracted with dichloromethane (2×). The extract was washed with water, dried over magnesium sulfate and concentrated to yield 3.27 g (95%) of the title compound as a viscous liquid. 1H NMR (CDCl3, 300 MHz) δ 1.74–1.93 (m, 4H), 2.57–2.71 (m, 1H), 2.80–2.95 (m, 3H), 2.87 (s, 3H), 2.95–3.12 (m, 2H), 3.26–3.38 (m, 3H), 3.55–3.64 (m, 1H), 6.41 (d, J=7.3 Hz, 1H), 6.51 (d, J=7.3 Hz, 1H), 6.65 (t, J=7.3 Hz, 1H) ppm. MS (CI): 230 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][CH2:27][C:28]2C=C[CH:31]=[CH:30][CH:29]=2)[CH:5]=[CH:6][CH:7]=1.[C:34](O)(=[O:36])[CH3:35]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:26][CH2:27][CH2:28][CH:29]3[CH2:30][CH2:31][O:36][CH2:34][CH2:35]3)=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCc2ccccc2)c1-c1cccc(N)c1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCCC2CCOCC2)c1-c1cccc(N)c1

Procedure:
5-(3′-Amino-2-benzyloxy-6-ethoxy-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (17.51 g; 39.7 mmol) is hydrogenated in ethanol (66 ml) and acetic acid conc. (198 ml) over Pd/C 10% (8.1 g) for 20 hours. The catalyst is filtered off and the mother liquor is concentrated. The residue is taken up in water and the pH is adjusted to 10 by addition of NH4OH conc. The suspension is filtered with suction and the crystals are washed thoroughly with water and dried under a high vacuum.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O.Cl[Sn]Cl>CCO>[C:15]1([NH:14][C:5]2[C:4]([NH2:1])=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[N:12]3)=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1c(Nc2ccccc2)ccc2cccnc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(Nc2ccccc2)ccc2cccnc12
Yield: 64.3 %

Procedure:
In a similar fashion using route 19 general procedure 29, (8-nitro-quinolin-7-yl)-phenyl-amine 574 (100 mg, 0.37 mmol), SnCl2 (425 mg, 1.8 mmol) and EtOH (10 ml) gave the title compound (56 mg, 62%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1>C1CCCCC1.[Rh].[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH3:1][C:2]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:15])[CH3:16])[N:4]=[CH:3]1
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Agent: [Rh]
Agent: [Al+3]
Agent: [O-2]
Solvent: C1CCCCC1
Product: CC(C)C1CCCCCCCCC(C)(C)C=N1
Yield: 89.5 %

Procedure:
466.8 g (2 mols) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene is dissolved in 4 liters of cyclohexane, and the solution is hydrogenated at 20°-25° C. under an initial pressure of 100 bars, in the presence of 50 g of rhodium/aluminium oxide, for 4 hours in a steel autoclave. The solvent is then distilled off to obtain, as the main fraction, 425 g (1.79 mols) of 3,3-dimethyl-12-isopropyl-1-aza-cyclododecene; b.p. 92°-94° C./4 Pa; nD20 =1.4706.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[Na].[BH4-]>C(O)C>[OH:22][CH:1]1[C:2]2[C:3](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4](=[O:17])[N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Agent: [BH4-]
Agent: [Na]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0 %

Procedure:
To a solution of 6.25 g (20.0 mol) of 4-(4-phthalimidobutylthio)pyridine in 300 ml of ethanol, 1.51 g (40 mmol) of sodium-borohydride was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.73 g of the desired compound (27.5% yield, colorless crystals), mp. 144°-145° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyl-1,3-oxazole (2.10 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-benzyl-3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate as colorless crystals (3.04 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 99-100° C.
Reaction SMILES: [H-].[Na+].[C:3]([N:5]=[C:6]1[NH:10][CH2:9][CH2:8][S:7]1)#[N:4].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([N:10]1[CH2:9][CH2:8][S:7][C:6]1=[N:5][C:3]#[N:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: N#CN=C1NCCS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=C1SCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a suspension of 0.24 g of sodium hydride in 40 ml of N,N-dimethylformamide was added dropwise a solution of 1.27 g of 2-cyanoiminothiazolidine in 10 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. After stirring, 1.27 g of benzyl chloride was added, and the mixture was stirred at temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure, water was added to the residue, and the resulting crystals were then collected by filtration to give 1.84 g of 3-benzyl-2-cyanoiminothiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:38])[CH:3]=1.Cl.[NH2:40][OH:41].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:40]\[OH:41])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:38])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-tert-butyl 4-(4-(1-(4-chloro-2-methylphenyl)-3-(2-methylpyridin-4-yl)-3-oxopropyl)phenyl)piperidine-1-carboxylate and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=548.0 ([M+H]+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH2:38][CH:35]4[CH2:36][CH2:37][N:33]([CH3:32])[CH2:34]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCC(CN)C1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCN(C)C3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-methylpyrrolidin-3-yl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.97 (m, 1H) 1.98-2.29 (m, 1 H) 2.40-2.47 (m, 3 H) 2.54-2.65 (m, 1 H) 2.73-2.91 (m, 4 H) 2.97-3.25 (m, 1 H) 3.40 (dt, J=18.51, 6.28 Hz, 2 H) 3.50-3.78 (m, 2 H) 7.67 (d, J=7.33 Hz, 1 H) 7.70-7.89 (m, 2 H) 8.12-8.32 (m, 1 H) 8.33-8.74 (m, 2 H) 8.77-8.98 (m, 2 H) 9.66-9.94 (m, 1 H) 12.62-13.68 (m, 1 H). MS m/z [M+H]+ 417.2.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17](=O)[C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([C:18]([CH2:19][CH3:20])([CH3:22])[CH3:21])[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C(C)(C)CC)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C(C)(C)CC)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 211 mg (0.66 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-2,2-dimethylbutanamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Cl-].[K+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:33]2.COC1C=CC(C=O)=CC=1>C(O)C>[OH:39][C@@H:35]1[C:36]2[C:32](=[CH:31][C:30]([O:29][CH3:28])=[CH:38][CH:37]=2)[CH2:33][C@@H:34]1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C1Cc2cc(OC)ccc2C1=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1Cc2cc(OC)ccc2[C@H]1O
Reaction time: 48 h
Yield: 84.3 %

Procedure:
Colletotrichum gloeosporioides is cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H2O (0.5 gram), NaNO3 (2 grams), FeSO4.7H2O (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of 5-methoxy-2-carboethoxy-1-indanone is dissolved in 2 ml of 95% ethanol, the resulting solution is added to the culture, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.7 grams of (1S,2S)-1-hydroxy-2-carboethoxy-5-methoxyindane as a yellow oil. The chiral purity of the product is greater than 98% as judged by chiral chromatography.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)CC2.[C-]#N.[Na+].ClC1[N:18]=[C:17]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH:16]=C(C)N=1>CS(C)=O>[F:25][C:23]1[CH:24]=[C:19]([C:17]2[CH:16]=[C:6]([CH3:5])[N:1]=[C:8]([C:7]#[N:4])[N:18]=2)[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: C1CN2CCN1CC2
Reactant: Cc1cc(-c2cc(F)cc(F)c2)nc(Cl)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(-c2cc(F)cc(F)c2)nc(C#N)n1
Temperature: 32.5 °C
Reaction time: 3 h
Yield: 530 %

Procedure:
To a solution and 13 mg of 1,4-Diazabicyclo[2.2.2]octane (DABCO) in 5 ml of DMSO and 60 mg (1.22 mmol) of sodium cyanide were added 280 mg (1.16 mmol) of 2-Chloro-4-(3,5-difluoro-phenyl)-6-methyl-pyrimidine. After stirring for 3 h at 30-35° C., the mixture was worked according to standard procedures to yield the title compound (142 mg, 53%) as a light yellow crystalline solid, negative-ion MS (ISP): m/e=230.4 [M−H]−.