Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(O)C>CO>[C:1]1([NH:7][N:8]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CO
Product: CC(C)(C)c1ccc(C=NNc2ccccc2)cc1
Yield: 93.1 %

Procedure:
In 20 ml of methanol was dissolved 2.18 g of phenylhydrazine. While metering, 3.24 g of 4-tert-butylbenzaldehyde was added dropwise to the solution. Reaction quickly took place. With heat release, the entire solution solidified. 5 ml of ethanol was added to the mass and the crystals were washed and collected by suction filtration. The crystals were washed with a small amount of methanol and dried in vacuum for 1.5 hours, obtaining 4.69 g (yield 93%) of pale yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][N:10]=[C:11]=[S:12].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[CH3:7][O:8][CH2:9][NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:15]2[C:16]([Cl:24])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[Cl:13])=[N:27]1)=[S:12]
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: COCN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCNC(=S)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Potassium carbonate (0.23 g, 1.7 mmol) and methoxymethyl isothiocyanate (0.16 g, 1.5 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.47 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methoxymethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carbothioamide (0.29 g, yield: 46.7%). mp: 95-96° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.82 (d, J=0.6 Hz, 3H), 3.41 (s, 3H), 5.10 (d, J=6.3 Hz, 2H), 5.91 (q, J=0.6 Hz, 1H), 7.68 (s, 2H), 8.80-9.20 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]3[C:22]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:21][N:20]=[C:13]3[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.Cl.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]3[C:22]([C:23]([CH3:28])([CH3:29])[C:24]([F:25])([F:27])[F:26])=[CH:21][N:20]=[C:13]3[C@H:14]([CH2:16][C:17]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]4=[O:47])[CH2:36][CH2:37]3)=[O:18])[CH2:15][C:4]=2[CH:3]=1
Reactant: CC(C)(c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)C[C@H]2CC(=O)O)C(F)(F)F
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)C[C@H]2CC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(7S)-4-chloro-10-(2,2,2-trifluoro-1,1-dimethylethyl)-3,6,7,12-tetrahydroimidazo[1′,2′:1,7]azepino[3,4-e]indazol-7-yl]acetic acid (100 mg, 0.275 mmol), 1-Piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride [Bergey et al. WO 2006/044504], HOBT (43 mg, 0.28 mmol), EDC (54 mg, 0.28 mmol) and N,N-diisopropylethylamine (48 uL, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:35][C:36]1[CH:47]=[CH:46][C:39]([C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:38][CH:37]=1.[C:48]([OH:51])(=[S:50])[CH3:49]>C1COCC1.O>[C:48]([S:50][CH2:35][C:36]1[CH:47]=[CH:46][C:39]([C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:38][CH:37]=1)(=[O:51])[CH3:49]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(CSC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
25.7 g (98 mmol) of triphenylphosphine and 100 ml of THF are introduced into a round-bottomed flask and 19.8 g (98 mmol) of diisopropyl azodicarboxylate, dissolved in 150 ml of THF, are added dropwise at 0° C. The mixture is stirred for one hour at 0° C. and a mixture of 9.4 g (49 mmol) of allyl 4-hydroxymethylbenzoate and 7 ml (98 mmol) of thioacetic acid is then added. The mixture is stirred at room temperature for four hours, the reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (60:40). 12.2 g (100%) of the expected product are obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: NC(=O)c1cccc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: NC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-benzamide was prepared from 2-Amino-3-fluoro-benzamide and 2,4,5 Trichloropyrimidine in an analogous manner to Example 1230a. Product was isolated as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:18]2([CH3:21])[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[N:8]=1.C([O-])(O)=O.[Na+].C1COCC1.Cl[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.O>[Br:1][C:2]1[N:3]=[C:4]([C:18]2([CH3:21])[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: COC(=O)Cl
Reactant: C[C@H](N)CNc1nccc(-c2[nH]c(C3(C)CC3)nc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3(C)CC3)nc2Br)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (S)—N1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (2.02 g, 5.8 mmol) in THF-water (1:1, 60 mL) was cooled to 0° C. and then solid NaHCO3 (2.5 g, 30 mmol) was added with concomitant frothing. After 5 minutes a THF solution of methyl chloroformate (0.35 mL, 0.44 g, 4.60 mmol, freshly prepared 1.0 M solution) was added dropwise to the mixture. After 20 minutes, LCMS indicated only ˜70% conversion. Additional methylchloroformate solution (0.3 M in THF, 5 mL, 1.5 mmol) was added over 5 minutes. The reaction was maintained overnight, allowing the cooling bath to expire. LCMS indicated ˜90% conversion and additional methylchloroformate solution (0.3 M in THF, 5 mL, 1.5 mmol) at 0° C. over 5 minutes. After stirring at room temperature for 1 hour, LCMS indicated complete reaction. The reaction mixture was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4), and concentrated to give (S)-methyl 1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate as a yellow solid (1.65 g): LCMS (m/z) 409.1 (MH+), tR=0.62 minute.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:13]([CH3:12])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: CN(CCC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1F

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyano-2-fluorobenzyl bromide (Fluorochem, 2.0 g, 9.3 mmol) and tert-butyl N-methyl-beta-alaninate (1.8 g, 11.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a yellow oil (2.4 g, 87%). 1H NMR (CDCl3, 300 MHz) δ 7.82 (dd, J=10.0, 1.6 Hz, 1H), 7.69 (dd, J=7.8, 1.6 Hz, 1H), 7.60 (m, 1H), 3.58 (s, 2H), 2.61 (t, J=6.9 Hz, 2H), 2.38 (t, J=6.9 Hz, 2H), 2.14 (s, 3H), 1.38 (s, 9H). LC/MS (Method B): 293.0 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 88.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH:33]1[C:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([NH2:44])[C:37]=2[CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:44][CH:43]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:38]=2[CH2:39][CH2:40][CH2:41][CH2:42]1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: NC1CCCCc2ccccc21
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCCCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylamine
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[C:11]([O:26][CH2:27][C:28]2[N:29]([CH2:33][CH3:34])[N:30]=[CH:31][N:32]=2)=[N:12][N:13]2[C:18]=1[CH:17]=[N:16][N:15]=[C:14]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>>[CH2:33]([N:29]1[C:28]([CH2:27][O:26][C:11]2[C:10]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[C:18]3[N:13]([C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[N:15][N:16]=[CH:17]3)[N:12]=2)=[N:32][CH:31]=[N:30]1)[CH3:34]
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Reactant: OB(O)c1ccsc1
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccsc1
Yield: 86 %

Procedure:
This was prepared in 86% yield using a similar procedure to that described in Example 18 except using thiophene-3-boronic acid instead of 3-trifluoromethylbenzeneboronic acid and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=187-193° C. (CH2Cl2-EtOAc); 1H NMR (400 MHz, CDCl3) δ 1.35 (3H, t, J=7.3 Hz), 4.14 (2H, q, J=7.3 Hz), 5.59 (2H, s), 7.29 (1H, m), 7.40 (1H, td, J=7.6 and 0.8 Hz), 7.48 (1H, s), 7.49 (1H, s), 7.64-7.66 (2H, m), 7.81 (1H, m), 7.90 (1H, s), 9.46 (1H, s); MS (ES+) m/e 422 [MH]+; Anal. Found C, 56.14; H, 3.84; N, 22.75%. C20H16FN7OS.0.3H2O requires C, 56.28; H, 3.92; N, 22.97%.
Reaction SMILES: Cl.[CH:2]12[CH2:7][CH:6]1[CH2:5][NH:4][CH2:3]2.CC(C)=O.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21]CC[CH2:18]1>O>[CH:2]12[CH2:7][CH:6]1[CH2:5][N:4]([C:17]([CH3:21])([CH3:18])[C:22]#[N:23])[CH2:3]2
Reactant: CN(C)C1(C#N)CCCC1
Reactant: C1NCC2CC12
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)N1CC2CC2C1
Yield: 84 %

Procedure:
The title compound (583 mg, 84%) was prepared from 3-azabicyclo[3.1.0]hexane hydrochloride (550 mg, 4.6 mmol) [Pestic. Chem: Hum. Welfar Environ., Proc, Int, Congr. Pestic. Che., 5th, 1982, 1,159-64, 1983], acetone (267 mg, 4.6 mmol) and potassium cyanide (300 mg, 4.6 mmol) in water (2.5 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 0.40 (1H, m), 0.58 (1H, m), 1.43 (8H, m), 2.64 (2H, m), 3.10 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:8][CH2:9][CH2:10][O:11]C1CCCCO1>C(O)(=O)C.C1COCC1.O>[OH:11][CH2:10][CH2:9][CH2:8][S:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1SCCCOC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1SCCCO
Yield: 96.8 %

Procedure:
A solution of 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)imidazole (2.0 g, 7.8 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 2-(3-hydroxypropylthio)-1-methylimidazole (1.3 g, 100%) as an off-white solid. 1H NMR Spectrum: (DMSOd6) 1.68(m, 2H); 2.98(t, 2H); 3.42(t, 2H); 3.57(s, 3H); 4.10(s, 1H); 6.90(d, 1H); 7.20(d, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=O.[O-:15][C:16]#[N:17].[K+].[OH-].[Na+].C(O)(C)C>C(O)(=O)C.O>[CH3:14][O:13][C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[NH:17][C:16](=[O:15])[NH:1]2
Reactant: COc1ccc(N)c(C(=O)O)c1OC
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2[nH]c(=O)[nH]c(=O)c2c1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
2-Amino-5,6-dimethoxybenzoic acid (10.5 g, 53.2 mM) was dissolved in glacial acetic acid (100 ml) and potassium cyanate (10.8 g, 133.0 mM) in 120 ml H2O was added gradually and stirred for 2 hours at 60° C. After cooling the reaction mixture to 20° C., sodium hydroxide pellets (78.2 g, 196 mole) were added while maintaining the temperature below 60° C. The reaction mixture was then heated at 90° C. for 45 minutes. Upon cooling in an ice bath, the sodium salt of the product precipitated, was filtered resuspended in H2O (120 ml), acidified (pH 3) with concentrated HCl, cooled, and filtered to give the crude product. Trituration with warm isopropanol afforded (60.8%) of a white solid, mp 266°-268° C.
Reaction SMILES: CO[C:3](=[O:14])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[NH2:5].[CH3:15][N:16]=[C:17]=[S:18]>>[C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:17](=[S:18])[N:16]([CH3:15])[C:3]1=[O:14])(=[O:13])[CH3:12]
Reactant: COC(=O)[C@@H](N)CCCCNC(C)=O
Reactant: CN=C=S
Product: CC(=O)NCCCCC1NC(=S)N(C)C1=O

Procedure:
Using an analogous procedure to Example 1 Nε-acetyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4ccccn4)c3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCCCN4)c3)oc12
Yield: 33.3 %

Procedure:
2-(3-(Pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (90 mg, 0.28 mmol) and platinum (IV) oxide monohydrate (45 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (petroleum ether/ethyl acetate=1:1). 30 mg of 2-(3-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 33%. 1H-NMR (400 MHz, DMSO-d6) δ 1.35-1.38 (m, 1H), 1.45-1.47 (m, 2H), 1.58-1.60 (m, 1H), 1.75-1.82 (m, 2H); 2.68-2.69 (m, 1H); 3.08-3.10 (d, J=9.6 Hz, 1H); 3.66-3.69 (m, 1H); 7.48-7.50 (t, J=6.0 Hz, 1H), 7.55-7.58 (d, J=6.4 Hz, 1H), 7.63-7.64 (d, J=5.6 Hz, 1H); 7.79-7.81 (m, 1H); 7.86 (brs, 1H); 7.94 (brs, 1H); 7.95-7.97 (m, 1H); 8.16-8.18 (m, 1H); 8.302 (s, 1H); LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:5]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=2)=[O:9])[CH:7]=1.[CH3:22][O-:23].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:5]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:23][CH3:22])[CH:11]=2)=[O:9])[CH:7]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(=O)c2ccnc(Cl)c2)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)c2cc(Br)cc(NS(C)(=O)=O)c2)ccn1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
To a mixture of 0.080 g (0.21 mmol) of N-[3-bromo-5-(2-chloro-pyridine-4-carbonyl)-phenyl]-methanesulfonamide in 10.0 mL of anhydrous methanol in a pressure tube was added 0.007 g (0.21 mmol) of sodium methoxide. The tube was sealed and the reaction was heated at 80° C. for 18 hours. The methanol was removed under vacuum and water was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give 0.035 g of N-[3-bromo-5-(2-methoxy-pyridine-4-carbonyl)-phenyl]-methanesulfonamide. The Suzuki reaction and removal of the triisopropylsilyl protecting group were carried out as described in Example 35. 1H NMR (400 MHz, CD3COCD3): δ 10.49 (s, 1H), 8.96 (s, 1H), 8.38 (d, J=5.1 Hz, 1H), 8.07 (t, J=1.9 Hz, 1H), 7.90 (t, J=1.6 Hz, 1H), 7.83 (t, J=1.9 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.30 (dd, J=5.1, 1.3 Hz, 1H), 7.26-7.18 (m, 2H), 7.10 (s, 1H), 6.75-6.72 (m, 1H), 3.96 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].C([O:13][CH2:14][CH3:15])(=O)C>>[C:14]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])(=[O:13])[C:15]1[CH:7]=[CH:6][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: C#CCC(O)CCCC
Product: C#CCC(CCCC)OC(=O)c1ccccc1

Procedure:
From fractions 13-20 is obtained 75 mg of colorless oil, identical to 4-hydroxy-1-octyne, [α]D25 =-17±1.0° (C=0.77, ethyl acetate). This compound has the (R)-configuration.
Reaction SMILES: [CH2:1]([N:8]([C:22](=[O:26])[CH2:23][C:24]#[N:25])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl>[NH2:25][C:24]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:22](=[O:26])[CH:23]=1
Reactant: COC(=O)c1cccc(NC(=O)N(Cc2ccccc2)C(=O)CC#N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(-n2c(N)cc(=O)n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyl-1-(cyanoacetyl)-3-[3-(methoxycarbonyl)phenyl]urea (3.51 g) was dissolved in dichloromethane (50 ml) and triethylamine (1.52 g) added. The mixture was stirred for one hour at room temperature and the product filtered off and washed with dichloromethane. Yield=3.16 g.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36](O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C.C(OCC)(=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:19][C:18]2[C:13]3[C:12]4[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]=4[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[C:14]=3[CH:15]=[N:16][C:17]=2[C:20]#[N:21])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (200 mg, 0.46 mmol), 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (670 mg, 3.56 mmol) and triphenylphosphine (724 mg, 2.76 mmol) in anhydrous DMF (2 mL) was treated dropwise with diethyl azodicarboxylate (0.53 mL, 3.40 mmol) and the mixture stirred at ambient temperature for 3 h then left to stand overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (3×15 mL), dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 20 g column, Si-SPE, 0-20% methanol in DCM). Collecting appropriate fractions afforded the title compound (160 mg, 57%). 1H NMR (CDCl3, 400 MHz): 9.57 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.46 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 1H), 8.23-8.21 (m, 1H), 7.71-7.61 (m, 1H), 7.58-7.45 (m, 2H), 5.88-5.83 (m, 1H), 4.36-4.11 (m, 1H), 3.87-3.36 (m, 2H), 2.48-2.26 (m, 2H), 2.13-2.05 (m, 1H), 1.46 (s, 9H). LCMS (Method B): RT=4.51 min, M+H+=598/600.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH2:13])C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:13]2[C:7]3[C:6](=[CH:11][C:10]([Cl:12])=[CH:9][CH:8]=3)[CH2:5][C:4]2=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)Cc1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3cc(Cl)ccc32)CC1
Yield: 138.8 %

Procedure:
(2-Amino-5-chloro-phenyl)-acetic acid ethyl ester (3.3 g, 15.4 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.6 g, 23 mmol) were set stirring in CH2Cl2 (50 mL) and sodium triacetoxyborohydride (4.9 g, 23.1 mmol) was added followed by acetic acid (3 mL). After 5 days saturated NaHCO3 was added and the organics separated. The organics were dried (MgSO4) and evaporated to give 7.5 g of a clear golden oil. The oil was purified (silica, 50% EtOAc/hexanes) to give 3.4 g (63%) of a white solid. TLC (silica, 25% EtOAc/hexanes): Rf=0.18. MS (electrospray): exact mass calculated for C18H23ClN2O3, 350.14. m/z found, 373.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.40-7.30 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.40 (m, 2H), 3.63 (s, 2H), 2.94 (m, 2H), 2.45-2.30 (m, 2H), 1.82 (m, 2H), 1.62 (s, 9H).