Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O.N1C=CC=CC=1.Cl.[NH2:26][OH:27].C(OCC)(=O)C>CCCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[N:26][OH:27]
Reactant: COc1cccc(C(=O)c2ccc(F)cc2F)c1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: c1ccncc1
Product: COc1cccc(C(=NO)c2ccc(F)cc2F)c1
Yield: 99 %

Procedure:
Combine (2,4-difluoro-phenyl)-(3-methoxy-phenyl)-methanone (51.2 g, 0.206 mol) and pyridine (293.4 g, 300 mL). Add hydroxylamine hydrochloride (21.7 g, 0.312 mol) and heat to 100° C., under a nitrogen atmosphere, for 4 hours. TLC (20% ethyl acetate in heptane) shows that the reaction is complete. Concentrate the reaction mixture and dry (vacuum at 50° C.). Distribute the material between ethyl acetate and water. Wash the organic layer with 10% HCl, saturated sodium chloride, dry (MgSO4) and concentrated to obtain the title compound as a white solid (53.66 g, 99% Yield). Use compound in a crude form or recrystallize from heptane and dry (P2O5). NMR and MS are consistent with the final, desired compound, which is a mixture of the Z-isomer (81%) and the E-isomer (19%). mp=122° C.-127° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](C1C=CC(B(O)O)=CC=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: CC(C)(C)c1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a like manner as described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-tert-butylphenylboronic acid (302 mg, 1.70 mmol) were coupled to yield 2-(4-tert-butyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 150 mg (42%), as a white solid. mp 243-244° C.; 1H NMR (300 MHz, d6-DMSO) δ 1.33 (s, 9H), 3.05 (m, 2H), 3.38 (m, 2H), 7.20 (app t, 1H, J=7.8 Hz), 7.57 (m, 5H), 7.67 (dd, 1H, J=7.2, 0.6 Hz), 8.07 (br t, 1H), 11.51 (br s, 1H); HRMS (FAB, MH+) Calcd for C21H23N2O: 319.1810, Found: 319.1813; Anal. (C21H22N2O.0.3 H2O) C, H, N.
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>CO>[OH:17][CH2:16][CH2:18][NH:19][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1
Reactant: NCCO
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)cc1NCCO
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) in methanol (20 mL) was added ethanolamine (0.36 g). The mixture was heated to reflux until a precipitate formed. The reaction mixture was cooled to room temperature, filtered, and the resulting solid was recrystallized from ethanol to give the title compound (0.72 g); mp 207° C.; NMR: 5.91 (s,1); MS(EI): m/z=232(M). Analysis for C12H12N2O3 ·0.2 H2O: Calculated: C, 61.11; H, 5.30; N, 11.88; Found: C, 61.13; H, 5.20; N, 11.72.
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)C1(Cc2ccccc2)CCC(NCc2ccccc2)CC1

Procedure:
2.00 g 4-benzyl-4-dimethylamino-cyclohexanone were dissolved in 30 ml analytical grade tetrahydrofuran, and 926 mg benzylamine followed by 746 μl glacial acetic acid were added, while stirring in an ice-bath. 2.56 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 15 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 25 ml diethyl ether each time. The combined organic phases were then washed twice with 20 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with diethyl ether with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 774 mg of the nonpolar diastereoisomer of 1,N′-dibenzyl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained, and were converted into 731 mg of the corresponding hydrochloride by dissolving in 6.2 ml 2-butanone and addition of 23.8 μl water followed by 334 μl chlorotrimethylsilane and stirring overnight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C([Sn](CCCC)(CCCC)/[CH:59]=[CH:60]\[O:61][CH2:62][CH3:63])CCC.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:62]([O:61]/[CH:60]=[CH:59]\[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:63]
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 84.5 %

Procedure:
A flask was charged with 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Steps A-B; 100 mg, 0.21 mmol), tri-O-tolylphosphine (12.8 mg, 0.042 mmol) and tris(dibenzylideneacetone)dipalladium (19.3 mg, 0.021 mmol). To the flask was added DMF (3 mL), followed by (Z)-tributyl(2-ethoxyvinyl)stannane (114 mg, 0.316 mmol) and triethylamine (0.04 mL, 0.30 mmol). The reaction mixture was degassed under nitrogen, and stirred at 100° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH/DCM as eluent to afford 82.8 mg of product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5]O.ClCCCS([NH:37]CC(OC)CSCCCCCCCCCCCCCCCC)(=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>>[CH3:1][O:2][CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][NH2:37]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)COC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)COC

Procedure:
2-Methoxymethyl-3-octadecylcarbamoyloxypropanol Vk2 is allowed to react and worked up by the same procedure as described in (4). The phthalimide compound: m.p. 84°-85° C. The summary of the experimental condition and the physical data of the product are listed in Table 6.
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][O:7][P:6]1Cl)([CH3:4])([CH3:3])[CH3:2].[OH:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([CH3:30])([CH3:29])[CH2:13]1.C(N(CC)CC)C.CCCCCC>O1CCCC1>[C:1]([N:5]1[CH2:9][CH2:8][O:7][P:6]1[O:11][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[N:15]([O:20][CH:21]([CH3:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]([CH3:29])([CH3:30])[CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(ON1C(C)(C)CC(O)CC1(C)C)c1ccccc1
Reactant: CC(C)(C)N1CCOP1Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(ON1C(C)(C)CC(OP2OCCN2C(C)(C)C)CC1(C)C)c1ccccc1
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A solution of 9.8 grams (54 mmol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 40 ml of tetrahydrofuran is added dropwise over 30 minutes to a solution of 15.0 grams (54 mmol) of 4-hydroxy-1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidine, prepared in Example 2A, 6.0 grams (159 mmol) of triethylamine and 80 ml of tetrahydrofuran. The reaction temperature increases from 20° C. to 32° C. during the addition. The reaction mixture is stirred for three hours after the addition is complete. Triethylamine hydrochloride is removed by filtration, and the filtrate is concentrated under reduced pressure to yield an oil. Trituration of the crude product with hexane affords 9.3 grams (41% yield) of the title compound as a white solid melting at 110-113° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.C1(N)CC1>CN(C=O)C>[CH:18]1([NH:19][C:8](=[O:10])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:16][CH2:17]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(O)cc1

Procedure:
4-Hydroxybenzenecarboxylic acid was stirred with WSC hydrochloride, HOBt hydrate and cyclopropylamine in DMF at room temperature to obtain N-cyclopropyl-4-hydroxybenzamide.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>CO>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 30 °C
Reaction time: 21 h

Procedure:
A solution of (4-{1-[(1Z)-3-amino-1-cyclopentyl-3-oxoprop-1-en-1-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate, (10, 500 mg) in methanol (MeOH, 8.0 mL) in a pressure glass tube was treated with the catalyst Ru(COD)(SL-A153-1)(CF3CO2)2 (6.6 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 50 bar pressure. The reaction mixture was stirred at 30° C. under this hydrogen pressure for 21 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 98% ee (99% of the second peak, (R)-11; 1% of the first peak, (S)-11) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with methanol (5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (470 mg) was analyzed by chiral HPLC analysis and result showed a 98.0% of enantiomeric excess favoring the second peak (99.0% of the second peak, (R)-11; 1.0% of the first peak, (S)-11).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[CH:14]1([CH:20]=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[OH:21])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=CC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(Br)cc1)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-dibromobenzene (42.4 mmol, 10 g) in THF (100 mL) at −78° C. was added dropwise n-BuLi (42.4 mmol, 2 M in hexane). The mixture was stirred at −78° C. for 0.5 h., cyclohexanecarboxaldehyde (42.4 mmol, 4.8 g) was added. The mixture was stirred at −78° C. for 0.5 h and then warmed to r.t. The reaction mixture was diluted with EtOAc, washed with NaHCO3 and brine. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography gave the title compound.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[S:12][C:11]([C:13]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[N:35]=[C:34](S(C)(=O)=O)N=1.O>CN(C)C=O>[Cl:7][C:8]1[S:12][C:11]([C:13]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH:24]([C:34]3[CH:1]=[C:32]([O:31][CH3:30])[CH:37]=[C:36]([O:38][CH3:39])[N:35]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Cc1nccc(-c2ccc(Cl)s2)c1C(=O)OCC
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(Cl)s2)ccnc1C(C(=O)OCC)c1cc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
Next, 2.9 g of potassium t-butoxide was added to 50 ml of N,N-dimethylformamide. To the resulting mixture, 8.9 g of ethyl 4-(5-chlorothiophen-2-yl)-2-(α-ethoxycarbonylmethyl)nicotinate dissolved in N,N-dimethylformamide was added dropwise at -10° C., and the resulting reaction solution was stirred at room temperature for 1 hour. 5.6 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added thereto, and the reaction solution was stirred at a temperature of from 60° C. to 80° C. for 8 hours. After completion of the reaction, the reaction solution was poured into water and brought to pH 4-5 and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 2.7 g (yield 23%) of the desired compound. m.p.: 127°-132° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C(O)(C)C.C(Cl)(Cl)Cl>[F:20][C:18]([F:19])([F:21])[C:15]1[CH:14]=[CH:13][C:12]([S:9]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)(=[O:10])=[O:11])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To a solution of 2.99 g (9.29 mmol) of 1-(4-trifluoromethyl-benzenesulfonyl)-cyclopropanecarboxylic acid ethyl ester in THF/water (1/1, 50 mL) were added 0.82 g (19.5 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The organic solvent was removed under reduced pressure and the aqueous layer washed with diethyl ether (2×50 mL). The basic aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 2.19 g of 1-(4-trifluoromethyl-benzenesulfonyl)-cyclopropanecarboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]1[C:25]([CH3:26])=[C:24]([CH:27]=O)[CH:23]=[N:22]1)[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:47]CCCl>>[ClH:47].[CH2:19]([N:21]1[C:25]([CH3:26])=[C:24]([CH2:27][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:12][CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH:23]=[N:22]1)[CH3:20]
Reactant: ClCCCl
Reactant: c1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CCn1ncc(C=O)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1ncc(CN2CCN(c3nccnc3-c3ccccc3)CC2)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Dissolve 3′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.28 g, 1.18 mmol) in DCE (5 mL). Add 1-ethyl-5-methyl-1H-pyrazole-4-carbaldehyde (0.24 g, 1.76 mmol) and stir at room temperature for 20 min. Add sodium triacetoxyborohydride (0.5 g, 2.36 mmol) followed by acetic acid (0.07 mL, 1.24 mmol). Stir at room temperature for 16 hr. Purify via SCX chromatography, followed by silica gel chromatography, eluting with 3:97 to 7:93 7 N ammonia in methanol:ethyl acetate, to give the free base of the title compound (0.22 g, 52%). MS (ES): m/z=363.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:4][PH:5](Cl)=[O:6])[CH:2]=[CH2:3].[O-:8][C:9]#[N:10].[Na+]>C(#N)C>[CH2:1]([CH2:4][PH:5]([N:10]=[C:9]=[O:8])=[O:6])[CH:2]=[CH2:3]
Reactant: N#C[O-]
Reactant: C=CCC[PH](=O)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=CCC[PH](=O)N=C=O
Reaction time: 5.5 h
Yield: 70.6 %

Procedure:
166 g (1.2 mol) of allylmethylphosphinic acid chloride were dissolved in 300 ml of acetonitrile and heated with 78 g (1.2 mol) of sodium cyanate to 50°-55° C. while stirring. After 5.5 hours, the precipitate was filtered off by suction and washed with acetonitrile. The filtrate was then concentrated and the residue distilled at a temperature of 78°-80° C. and at a pressure of 25 Pa. 123 g of allylmethylphosphinic acid isocyanate (71% of theory) were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].Br[CH2:18][CH2:19][F:20]>>[F:20][CH2:19][CH2:18][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=1[CH3:9]
Reactant: FCCBr
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Product: Cc1nc(NC(=O)C(C)(C)C)ccc1COCCF

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.556 g, product of example 112 step B]) and 1-bromo-2-fluoro-ethane (0.475 g) as a light yellow gum (0.115 g). MS (ESI): 269.3 (MH+).
Reaction SMILES: [OH-].[Na+].[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([O-:6])([O-:5])=[O:4].[Na+].[Na+].[N+]([O-])(O)=O>O>[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([OH:5])([OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O

Procedure:
To 22.5 ml of a 0.67 M aqueous solution of cis-[Pt(NH3)2 -(H2O)](NO3)2, the pH of which had been adjusted to 4 with sodium hydroxide, there was added 4.23 grams disodium D-glucose-6-phosphate dissolved in 30 ml of water. The pH of the reaction mixture was then adjusted to 5.0 using 2 M nitric acid. The solution was stoppered, and stirred for 42 days as in the previous examples. The above-identified, water-soluble blue complex was isolated by the method described in Example 1 in a yield of 2.69 grams.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1.[ClH:21]>C1COCC1>[Cl:21][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(OCCBr)c(-c2ccnn2C)c1
Reactant: Cl
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(N)ccc1OCCCl
Temperature: 150 °C

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (450 mg, 1.33 mmol), concentrated HCl (0.9 mL) in THF (4 mL) was heated with microwave irradiation at 150° C. for 30 minutes. The crude was concentrated in vacuo to give the title compound as a brown oil. Exact mass calculated for C12H14ClN2O 251.1. found 252.0 (MH+). This was used without purification in next step.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: COc1cc(C(C)=O)cnc1OCC(F)F
Product: COc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)F
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (1.05 g, a white solid) from 1-(6-(2,2-difluoroethoxy)-5-methoxypyridin-3-yl)ethanone (0.94 g, 4.04 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=O)[CH2:3][CH2:2]1.N1CCCC1.O.C1(C)C=CC([S:22](O)(=O)=O)=CC=1.[S].[N:28]#[C:29][NH2:30]>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:22][C:29]([NH2:30])=[N:28][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=CCC1CCOCC1
Reactant: N#CN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [S]
Solvent: O
Solvent: C1CCNC1
Product: Nc1ncc(C2CCOCC2)s1

Procedure:
A mixture of (tetrahydro-pyran-4-yl)-acetaldehyde (Pharmacore), pyrrolidine, p-toluenesulfonic acid monohydrate, sulfur and cyanamide were processed using the method described in Example 136A to obtain the title compound. MS (ESI+) m/z 185 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:21]([O:25][C:26](=[O:37])[C@H:27]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:28])([CH3:24])([CH3:23])[CH3:22].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[C:21]([O:25][C:26](=[O:37])[C@H:27]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:28][C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To N-benzyloxycarbonyl-N-methyl-L-valine (0.50 g, 1.9 mmol), L-aspartic acid di-tert-butyl ester hydrochloride (0.53 g, 1.9 mmol), WSC hydrochloride (0.43 g, 2.3 mmol), and 1-hydroxybenzotriazole monohydrate (0.35 g, 2.3 mmol) were added tetrahydrofuran (10 ml) and triethylamine (0.39 mL, 2.8 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give the title compound (0.91 g, 1.8 mmol, 98%).