Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH2:11]=O>C1COCC1>[C:5]1([CH:3]2[O:4][CH2:11][NH:1][CH2:2]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCC(O)c1ccccc1
Reactant: C=O
Solvent: C1CCOC1
Product: c1ccc(C2CNCO2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 2-amino-1-phenylethanol (1.000 g, 0.007 mmol) and formaldehyde (37%, 0.92 mL, 0.012 mmol) in THF (10 mL) was heated to reflux for 3 h and allowed to cool to ambient temperature with stirring over night. The mixture was concentrated and the residue was dissolved in dichloromethane. The resulting solution was washed with water. The organic phase was dried over anhydrous sodium sulphate, concentrated in vacuo. The yellowish residue was purified by column chromatography to obtain the title compound in 91% yield (0.990 g). MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OC1C=CC=CC=1[N+]([O-])=O)=O.Cl.Cl.CC1C=CC(N2CCNCC2)=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCN(C(=O)OC[C@@H]3CCCN(C)C3)CC2)cc1
Agent: Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C(Cl)Oc1ccccc1[N+](=O)[O-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)OC[C@H]3CCCN(C)C3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
(S)-(1-Methylpiperidin-3-yl)methanol (1.50 g, 11.6 mmol; prepared according to Example 1 but starting from (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (1.30 mL, 12.2 mmol) and nitrophenyl chloroformate (2.46 g, 12.2 mmol) were added. The reaction mixture was stirred at 0° C. for 2 hours and then a solution of 4-(4-methylphenyl)piperazine dihydrochloride (1.88 g, 7.5 mmol) and DIPEA (3.70 mL, 22.1 mmol) in DMF (40 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 85:15 mixture of DCM:MeOH) followed by reverse phase HPLC (Advanced Chromatography Technologies ACE-122-1030 RP silica 100×30 mm column, packed with Ace 5 C8 (5 μm), Pore Size 100 Å, 30 mL/min, gradient of CH3CN in water, with 0.1% TFA in each solvent, 8-38%). The residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 min, filtered and concentrated in vacuo to give a yellow oil which was recrystallised from heptane/EtOAc to give [(3S)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate (521 mg, 13.5%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)=[CH:35][C:36]#[N:37])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C(=O)c2cccc(OCc3ccccc3)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(OCc3ccccc3)c2)c1
Yield: 86.4 %

Procedure:
(3-Benzyloxyphenyl)-(3,5-dimethoxyphenyl)methanone (10.66 g, 30.60 mmol), cyanomethylphosphonic acid diethyl ester (9.63 ml, 61.19 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 61.20 ml, 61.19 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give 3-(3-benzyloxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as a white solid (9.82 g, 86%): 1HNMR (DMSO-d6) 7.47-7.31 (m, 6H, Ar), 7.20-6.88 (m, 3H, Ar), 6.66-6.62 (2ts, 1H, Ar), 6.46 (d, J=2 Hz, 2H, Ar), 6.40 (s, 0.5H, double bond proton of one isomer), 6.38 (s, 0.5H, double bond proton of the other isomer), 5.12 (s, 1H, half CH2), 5.11 (s, 1H, half CH2), 3.76 (s, 3H, OCH3), 3.73 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 161.2, 160.4, 158.4, 158.2, 139.6, 138.9, 138.8, 138.3, 136.7, 129.8, 128.4, 127.9, 127.8, 121.5, 120.8, 117.9, 117.9, 116.8, 116.0, 115.5, 114.4, 107.1, 106.5, 101.9, 101.1, 96.8, 96.5, 69.4, 55.4, 53.6; Anal. Calcd. For C24H21NO3: C, 77.61; H, 5.70; N, 3.77. Found: C, 77.39; H, 5.70; N, 3.69.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.CN(C=O)C.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CCOC(C)=O>[N:22]1([C:2]2[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.397 mmol) in pyrrolidine (1.0 ml) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 91%).
Reaction SMILES: Cl.CNC.CCC(=O)CC.[C-]#N.[K+].[CH3:14][N:15]([CH3:23])[C:16]1([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>O>[CH3:14][N:15]([CH3:23])[C:16]([CH2:20][CH3:19])([CH2:17][CH3:18])[C:21]#[N:22]
Reactant: CN(C)C1(C#N)CCCC1
Agent: CNC
Agent: Cl
Agent: [C-]#N
Solvent: CCC(=O)CC
Solvent: O
Product: CCC(C#N)(CC)N(C)C
Yield: 57.5 %

Procedure:
The title compound (8.05 g, 57.5%) was prepared from dimethylamine hydrochloride (8.154 g, 0.1 mol), 3-pentanone (8.61 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 0.96 (6H, t, J=7.6 Hz), 1.67-1.90 (4H, m), 2.33 (6H, s).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>C(#N)C>[CH3:15][O:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1)=[O:13].[CH2:24]([N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH3:23]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(C(Br)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(C(Nc2ccccc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
2-Bromo-2-(4-(methoxycarbonyl)phenyl)acetic acid (700 mg, 2.56 mmol), aniline (0.23 mL, 2.56 mmol), and DIPEA (0.94 mL, 5.38 mmol) are dissolved in acetonitrile (5 mL). The reaction is stirred at 100° C. under microwave irradiation for 15 minutes. Acetonitrile is evaporated and the residue is dissolved in DCM and washed with water and brine. The organic layer is dried (Na2SO4), filtered and evaporated. The crude compound is purified by flash chromatography (DCM/MeOH=9/1) to obtain intermediate I142 as a white solid (381 mg, 37% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:27][OH:28]>>[OH:28][NH:27][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:5])=[O:4]
Reactant: NO
Reactant: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)c(C)c1
Product: Cc1cc(/C=C/CN(C)S(=O)(=O)CC(=O)NO)ccc1-c1ccccc1

Procedure:
In a manner similar to Example 1 (b), methyl 2-({methyl-[3-(2-methylbiphen-4-yl)-trans-prop-2-enyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the titled compound as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:35][CH2:34][O:33][CH3:32])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: COCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 4-chloroquinazolin-6-ol (1.00 g, 5.54 mmol), triphenyl phosphine (1.45 g, 5.54 mmol) and 2-methoxyethanol (0.421 g, 5.54 mmol) in dichloromethane (83 mL) was added diisopropyl azodicarboxylate (1.18 g, 5.54 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (1.15 g, 87%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)[C:3]=1[S:24]C#N.[BH4-].[Na+].[OH2:29]>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[N:23]=[CH:22][O:29][N:20]=2)[C:3]=1[S:24][S:24][C:3]1[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)=[N:5][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[C:2]=1[NH2:1]
Reactant: O
Reactant: N#CSc1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(SSc2c(-c3ncon3)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 55 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,2,4-oxadiazol-3-yl)-4-thiocyanatopyrazole 1.00 g (2.37 mmol) was dissolved in 20 ml of dry methanol, and then 210 mg (5.00 mmol) of 90% sodium borohydride was added at 0° C. After the mixture was was stirred at 0° C. for 3.5 hrs, the reaction mixture was poured into 80 ml iced water, and then the precipitate was collected by filtration. After drying in vacuo, the resulting yellow crystal was recrystalized from ethyl acetate-n-hexane mixed solvent to obtain 512 mg (0.65 mmol) of the title compound as a yellow crystal. Yield 55%.
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]2[O:19][CH2:20][O:21][C:3]=12.C([Li])CCC.CN([CH:35]=[O:36])C1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[CH:35]([C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]2[O:19][CH2:20][O:21][C:3]=12)=[O:36]
Reactant: CN(C=O)c1ccccc1
Reactant: Brc1c2c(cc3c1OCO3)C(c1ccccc1)CNCC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=Cc1c2c(cc3c1OCO3)C(c1ccccc1)CNCC2
Reaction time: 1 h

Procedure:
A mixture of 7.8 g (0.0225 mole) of 6-bromo-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in toluene was added to a mixture of 2.2 ml (6.07 mole) of butyl lithium diluted with 100 ml of ethyl ether at -78°. Then, 10 ml of N-methylformanilide was added. After stirring for 1 hour at -78°, the cooling bath was removed and 100 ml of 10% hydrochloric acid was added. After stirring for 15 minutes, the layers were separated. The ether layer was dried and evaporated. The residue was dissolved in ethyl acetate then extracted by aqueous sodium bisulfite. The aqueous layer was removed, washed with ether and made basic with solid carbonate. After extraction with ethyl ether the extracts were evaporated. The residue was heated in 6 N hydrochloric acid for 1 hour. The solution was made basic and the product extracted into chloroform. After purification over silica with 5% methanol-chloroform, 6-formyl-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine was obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.[NH2:15]C1C(C)=CC(C(OC)=O)=NC=1.N([O-])=O.[Na+].O>C1COCC1.[Pd].CC(O)=O>[NH:8]1[C:7]2=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=[C:2]2[CH:1]=[N:15]1
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(=O)c1cc(C)c(N)cn1
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2cn[nH]c2cn1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a stirring solution of methyl 4-methyl-5-nitro-pyridine-2-carboxylate (3.00 g) in THF (40 mL) was added Pd/C catalyst (300 mg). The flask was evacuated and back-filled with hydrogen from a balloon three times and then stirred under hydrogen overnight. The mixture was filtered through Celite, and the filter cake was extracted several times with ethyl acetate. The combined organic extracts were concentrated and the resulting white powder (2.58 g, 100%) consisting of methyl 5-amino-4-methyl-pyridine-2-carboxylate was used in the next step without further purification and characterization. To a stirring solution of methyl 5-amino-4-methyl-pyridine-2-carboxylate (2.58 g, 15.53 mmol) in AcOH (60 mL), was added 2.0 M sodium nitrite in water (9.3 mL, 18.63 mmol) and the mixture was stirred for 4 h at room temperature. The acetic acid and other volatiles were removed at high vacuum, the resulting solid was suspended in water and filtered to give the title compound as a yellowish solid (2.18 g, 79% yield). 1HNMR (DMSO-d6): δ ppm 13.98 (bs, 1H), 9.10 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 3.88 (s, 3H). LCMS (API-ES M+Na+) 200.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CCI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)CCn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 80 °C
Yield: 16.9 %

Procedure:
A mixture of (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 43; 150 mg, 0.47 mmol), tetrabutylammonium iodide (174 mg, 0.47 mmol) and 1-iodo-3-methylbutane (230 μL, 1.75 mmol) in dimethylformamide (3 mL) was heated at 80° C. for 4 days. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 60-80% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1-(3-methyl-butyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (31 mg, 17%) as a tacky oil. APCI(+)-MS (M+H) 391.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([OH:17])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.[OH-].[Na+]>C1COCC1>[NH2:16][CH2:15][CH:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=1)[OH:17]
Reactant: N#CC(O)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of LAH (2.36 g, 59 mmol) in dry THF (70 mL) was added a solution of (3-chloro-phenyl)-hydroxy-acetonitrile (4.0 g, 24 mmol) in dry THF (55 mL) dropwise at 0° C. under nitrogen atmosphere. The mixture was warmed to 25° C. and then heated at 60° C. for 2 hours. After cooling to 0° C., a saturated solution of sodium hydroxide was added dropwise and extracted with dichloromethane (200 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (methanol:dichloromethane, 1:10) to afford 2-amino-1-(3-chloro-phenyl)-ethanol. (Yield 2.86 g, 70%). LC-MS: [M+H]+ 172.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>[Cl-].[Zn+2].[Cl-].O>[CH:1]1([C:9](=[O:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: C1=CCCCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(=O)C1CC=CCCCC1
Temperature: 92.5 °C
Reaction time: 7.5 h
Yield: 26.5 %

Procedure:
To cyclooctene (300 g, 2.73 mol) were added acetic anhydride (556 g, 5.45 mol) and zinc chloride (30 g, 0.22 mol). The reaction mixture was warmed to 90-95° C. within 30 min., stirred at that temperature during 7.5 hours, cooled to 60° C., and treated with caution, within 10 min., with water (400 ml). The resulting mixture was heated at 100° C. during 3 h., cooled to 25° C., and extracted with hexane (3×300 ml). The combined organic phases were washed with aq. sat. NaCl soln. (800 ml), aq. sat. NaHCO3 soln. (800 ml), aq. sat. NaCl soln. (400 ml), and dried (Na2SO4). Evaporation of the solvent led to 375 g of crude material which was distilled under vacuum with a short-path Vigreux column. After collecting the unreacted cyclooctene (65 g, 21.7%) at 40-50° C./100 mbar, the fractions distilling at 110° C./24 mbar were collected (144 g) and redistilled using a microdistillation column (20×1.5 cm, filled with 3×3 mm rolled wire netting) to give 110 g of 1-cyclooct-3-enylethanone (34% based on the reacted cyclooctene, 109° C./20 mbar) as colourless oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[C:8]([N+:21]([O-])=O)[CH:7]=2)[CH2:3][CH2:2]1.P(OCC)(OCC)OCC>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]3=[N:12][N:13]([C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=4)[N:21]=[C:8]3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(OCC2CC2)ccc1N=Nc1ccc(O)cc1
Agent: CCOP(OCC)OCC
Product: Oc1ccc(-n2nc3ccc(OCC4CC4)cc3n2)cc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 4-{[4-(cyclopropylmethoxy)-2-nitrophenyl]diazenyl}phenol and triethyl phosphite (4 mL) was stirred at 140° C. overnight. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid (103 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[O:5][CH2:6][C:7]#[N:8].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:11]=1)[O:5][CH2:6][C:7]#[N:8]
Reactant: N#CCOc1cc(Cl)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCOc1cc(N)cc(Cl)c1
Temperature: 70 °C
Yield: 62.5 %

Procedure:
A warm solution of 8.23 g of (3-chloro-5-nitro-phenoxy)-acetonitrile in 150 ml of ethyl acetate was treated with 34.9 g of tin (II) chloride dihydrate and the solution was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, basified with saturated sodium bicarbonate solution, extracted twice with ethyl acetate, dried (MgSO4), and evaporated to dryness. The residue was purified by silica gel chromatography using ethyl acetate/hexane (35:65) as solvent and obtained 4.42 g of (3-amino-5-chloro-phenoxy)-acetonitrile as a cream solid.
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:24](O)=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1CCC([N:40]=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.CN(C)C=O>[NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C@H:2]([C:24]([NH2:40])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of Boc-Cys(Trt)-OH (100 gm) in methylene chloride (1000 ml) at −10 to 0° C., was charged sequentially, a solution of DCC (57.9 g) in methylene chloride (125 ml) and HOBT (34.8 gm) in dimethyl formamide (70 ml). Stirred the solution for 30 minutes at the same temperature and then charged ammonia solution (120 ml). After completion of the reaction the resultant precipitate was filtered and the filtrate was taken and washed with 10% sodium bicarbonate solution. The separated organic layer was concentrated and crystallized the product Boc-Cys(Trt)-NH2 from ethyl acetate and hexane (Yield: 100 g, HPLC Purity 98%, Chiral purity: 99.9% and D-Cys: 0.1%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1.C(OCC)(=O)C>[C:32]([N:22]1[CH2:23][CH2:24][CH:19]([N:14]2[CH:15]=[CH:16][C:17](=[O:18])[C:12]([C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[CH:9][CH:10]=3)=[N:13]2)[CH2:20][CH2:21]1)(=[O:34])[CH3:33]
Reactant: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1-Phenyl-1H-pyrazol-5-yl)-1-piperidin-4-ylpyridazin-4(1H)-one (0.30 g) and triethylamine (0.26 mL) were dissolved in THF (20 mL), acetylchloride (0.066 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from 2-propanol/diethylether to give the title compound (0.15 g).