Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:18]>CC(O)C.CCOCC>[Cl:18][CH2:3][CH2:2][CH:1]=[C:4]([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
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Reactant: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: ClCCC=C(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 93 %

Procedure:
Cyclopropyldiphenylmethanol (500 mg, 2.23 mmol) was dissolved in 1M HCl in i-PrOH (4.0 mL). The reaction mixture was then heated at 60° C. for 1 h. The reaction was cooled 20° C. and diluted with Et2O (100 mL). The organic solution was successively washed with H2O NaHCO3 saturated aqueous solution and brine. It was then dried over MgSO4, filtered, concentrated in vacuo and chromatographed on a silica gel column by elution with Hexanes to give 4-Chloro-1,1-diphenyl-1-butene (506 mg, 93%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ2.59 (q, 2H, J=6.9 Hz), 3.58 (t, 2H, J=6.9 Hz), 6.12 (t, 1H, J=7.3 Hz), 7.16-7.42 (m, 10H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[C:13]([CH:25]=1)[C:14]([NH:16][CH2:17][C:18]1[NH:23][C:22](=[O:24])[CH:21]=[CH:20][CH:19]=1)=[O:15])C1C=CC=CC=1.C(O)C>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[C:13]([CH:25]=1)[C:14]([NH:16][CH2:17][C:18]1[NH:23][C:22](=[O:24])[CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(NCc1cccc(=O)[nH]1)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(NCc1cccc(=O)[nH]1)c1cc(O)ccc1OCC(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 6-[5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone, 60 ml of ethanol, 40 ml of methanol and 0.043 g of 10% palladium on charcoal was hydrogenated on a Parr apparatus at about 20° C. for about 16 hours. Filtration followed by evaporation of the filtrate provided a residue which was triturated with acetonitrile. The solid was separated by filtration and washed with acetonitrile to provide 6-[5-hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>CN(C=O)C.O>[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][N:71]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:19][N:18]=2)=[O:21])[CH2:70][CH2:69]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol), HOBt (0.065 g, 0.000482 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes 4-(2-chloro-phenylamino)-piperidine dihydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using basic alumina (50% ethyl acetate in hexane) afforded 0.142 g (78%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[CH:27]=1>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[O:13][C:12]([C:10]([N:8]3[CH2:9][CH:6]([O:5][C:26]4[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[CH:27]=4)[CH2:7]3)=[O:11])=[N:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Reactant: Cc1cc(O)ccc1C=O
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Yield: 67 %

Procedure:
Using a similar protocol as described in Example 71A employing 73B and 4-hydroxy-2-methylbenzaldehyde as starting materials afforded 9.4 g (67%) of 73C as a solid. 1H NMR (500 MHz, CDCl3): δ 2.67 (s, 3H), 3.89 (s, 3H), 4.37 (m, 1H), 4.70 (m, 1H), 4.78 (m, 1H), 5.15 (m, 2H), 6.65 (s, 1H), 6.74 (d, 1H), 7.02 (d, 2H), 7.78 (d, 1H), 8.11 (d, 2H), 10.2 (s, 1H).
Reaction SMILES: [C:1]1(CCCC([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C[O:15][C:16]([C:18]1C=CC(O)=[CH:20][CH:19]=1)=[O:17].C(OC(C1C=CC(O)=CC=1)=O)CC.[OH-].[Na+]>O>[C:1]1([O:17][C:16](=[O:15])[CH2:18][CH2:19][CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])CCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCOC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(=O)Oc1ccccc1
Temperature: 70 °C

Procedure:
Part II: 5.739 g of sodium 4-phenylbutyrate (Triple Crown America, Inc.), 0.125 g of methylparaben (Merck), 0.075 g of propylparaben (Merck), 232.035 g of deionized water, and 20 g of 10% NaOH were mixed in a beaker and heated at 70° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example C1) (2.76 g, 8.74 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an orange solid (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([NH:12][CH3:13])=[N:6][C:5]2=O.CN(C)C1C=CC=CC=1.[OH-].[Na+].P(Cl)(Cl)([Cl:28])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH3:13])[N:6]=[C:5]2[Cl:28]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNc1nc(=O)c2cc(Br)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Product: CNc1nc(Cl)c2cc(Br)ccc2n1
Yield: 46.6 %

Procedure:
To a solution of phosphorus oxychloride (50 mL) was added powdered 6-bromo-2-methylamino-1H-quinazolin-4-one (10.0 g, 39.4 mmol) followed by dimethyl-phenyl-amine (8 mL) and the mixture was heated to reflux under N2 atmosphere for half an hour. After cooling down, the mixture was poured onto ice and basified with aqueous NaOH solution (2 M). The precipitate was collected by filtration and purified by column to afford (6-bromo-4-chloro-quinazolin-2-yl)-methyl-amine (5 g, 18.3 mmol, 46.6%) as a yellow solid. 1H NMR (DMSO-d6): δ 8.03 (s, 1H), 7.86-7.84 (m, 2H), 7.47-7.45 (d, 1H), 2.86-2.84 (d, 3H).
Reaction SMILES: O.[C:2]([N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[P:14]([OH:17])([OH:16])[OH:15].S(=O)(=O)(O)O.C=O>O>[P:14]([CH2:2][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:16])=[O:15]
Reactant: OP(O)O
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 110 °C
Yield: 151.4 %

Procedure:
Cycle 1: A reactor was charged with N-acetyliminodiacetic acid monohydrate (1 7.0 g), water (5 g), phosphorous acid (11.39 g) and 98% sulfuric acid (15 g). The mixture was heated to 110° C. and 42.2% formaldehyde (5.6 mL) was added drop wise over a one hour period. After another 13/4 hour at 110° C. the mixture was cooled to 25° C. The mixture was filtered and the solid was washed with water to give 12.46 g of N-(phosphonomethyl)iminodiacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:3]2[C:11]([C:35]#[C:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: C#CCCCN1CCN(C)CC1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#CCCCN3CCN(C)CC3)c3c(Cl)nc(N)nc32)c1C

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidin-2-amine with 1-methyl-4-(pent-4-ynyl)piperazine, according to the general procedure A gave the title compound, as a solid. Mp=160.1-162.3° C. HPLC Rt=4.08 min.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.[CH3:11][O:12][CH:13]([O:22][CH3:23])[CH2:14][C@@H:15]1[C:17]([CH3:19])([CH3:18])[C@@H:16]1[CH:20]=O.[C:24](Cl)(Cl)([Cl:26])[Cl:25].O>CCCCC>[CH3:11][O:12][CH:13]([O:22][CH3:23])[CH2:14][C@H:15]1[C:17]([CH3:19])([CH3:18])[C@H:16]1[CH:20]=[C:24]([Cl:26])[Cl:25]
Reactant: COC(C[C@H]1[C@@H](C=O)C1(C)C)OC
Reactant: ClC(Cl)(Cl)Cl
Agent: CN(C)P(N(C)C)N(C)C
Solvent: O
Solvent: CCCCC
Product: COC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)OC
Temperature: 14 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Tri(dimethylamino)phosphine (163.2 mmol) was added with stirring at 0° C. to a solution of (1R,cis)-2-(2,2-dimethoxyethyl)-3,3-dimethylcyclopropanecarbaldehyde (65.5 mmol) and carbon tetrachloride (163.2 mmol) in n-pentane (350 ml) kept under nitrogen in a 1-l flask. After 15 minutes stirring, the mixture was warmed up to 14° C. and kept at this temperature for 15 minutes. Then, water (75 ml) was added at 14° C. and--after removal of the aqueous phase--the organic phase was washed with two 35-ml portions of water. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried solution to give a residue (15.7 g) containing 32.1 mmol of 2-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]ethanal dimethyl acetal (100% (1R,cis), purity 51.7%, yield 49%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:15]2[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1cc(-c2cnn(C)c2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-5-iodo-1,3-dimethylbenzene and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following a procedure analogous to that described in Step 1 of Intermediate 17. LC (method 9): tR=1.09 min; Mass spectrum (ESI+): m/z=265 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:28]1([C:31]([O:24][CH:23]([CH:25]2[CH2:27][CH2:26]2)[C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=5[Cl:22])[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(O)C1CC1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.8 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (200 mg, 0.473 mmol), cyclopropanecarboxylic acid (61 mg, 0.710 mmol), triethylamine (0.132 mL, 0.946 mmol) and 4-dimethylaminopyridine (87 mg, 0.710 mmol) in tetrahydrofuran (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (181 mg, 0.946 mmol) at room temperature. The mixture was stirred at room temperature for 15 hr. Saturated aqueous ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from ethanol to give the title compound (155 mg, 0.316 mmol, 67%) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[OH:20][C:21]1[C:22]([CH:31]=[O:32])=[CH:23][C:24]2[O:29][CH2:28][CH2:27][O:26][C:25]=2[CH:30]=1>C(OCC)(=O)C.O>[CH2:7]([O:20][C:21]1[C:22]([CH:31]=[O:32])=[CH:23][C:24]2[O:29][CH2:28][CH2:27][O:26][C:25]=2[CH:30]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cc2c(cc1O)OCCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc2c(cc1OCc1ccccc1)OCCO2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (0.27 g) and benzyl bromide (0.17 mL) were sequentially added to an N,N-dimethylformamide (2 mL) solution of 7-hydroxy-2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (0.23 g), followed by stirring at 65° C. for 2 hours. Benzyl bromide (0.077 mL) was added to the reaction mixture, followed by stirring at 65° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 75-60% hexane/ethyl acetate] to obtain 0.32 g of 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde as a light yellow solid.
Reaction SMILES: Cl.[NH:2]1[C:6]([CH2:7][CH:8]=[O:9])=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[S:23]([N:2]1[C:6]([CH2:7][CH:8]=[O:9])=[CH:5][N:4]=[CH:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=CCc1cnc[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cncc2CC=O)cc1

Procedure:
A solution of 1.46 g (10 mM) of 2-(5-imidazolyl)-acetaldehyde HCl in 20 ml of dichloromethane is treated with 2.01 g (20 mM) of triethylamine and 1.9 g of p-toluenesulfonyl chloride at 25° C for about 16 hours after which the solution is washed with 3 N hydrochloric acid, water, sodium bicarbonate and water then dried and evaporated to afford 2-(1-tosylimidazol-5-yl)acetaldehyde upon recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>C(O)C.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 9 h
Yield: 79.1 %

Procedure:
2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in ethanol (5 ml), and a catalytic amount of Raney nickel catalyst was added to stir the mixture at room temperature for 9 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2) to obtain the title compound (113 mg).
Reaction SMILES: F[C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[OH:11].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[F:23][C:21]1[CH:20]=[CH:19][C:3]2[CH2:4][N:5]3[CH:9]=[CH:8][CH:7]=[C:6]3[CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[O:11][C:2]=2[CH:22]=1
Reactant: CN1CCC(C(O)c2cccn2Cc2ccc(F)cc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C2Oc3cc(F)ccc3Cn3cccc32)CC1
Temperature: 50 °C

Procedure:
To a solution of [1-(2,4-difluorobenzyl)-2-pyrryl]-(1-methylpiperidin-4-yl)methanol(28.1 g; 0.088 mole) in 320 ml of tetrahydrofuran was added potassium tert-butoxide (11.3 g; 0.10 mole). The reaction mixture was warmed (50° C.) for 15 minutes, diluted with ethyl acetate and washed with water (2×). The organics were then dried (saturated NaCl solution, anhydrous MgSO4). This was concentrated to a solid, m.p. 115°-120° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=3)[S:23][C:24]=2[CH:30]=1
Reactant: BrBr
Reactant: CCCCCCCCCCCCOc1ccc(-c2nc3ccccc3s2)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOc1ccc(-c2nc3ccc(Br)cc3s2)cc1
Yield: 9.6 %

Procedure:
Bromine was added dropwise to a solution of 2-(4-dodecyloxy-phenyl)benzothiazole (20 g, 0.059 mol) and acetic acid (1,000 cm3). The reaction mixture was then heated for a further 6 h. The cooled reaction mixture was then added to aqueous sodium metabisulphite solution (1,000 cm3). The product was extracted using diethyl ether (3×100 cm3). The combined organic layers are washed with concentrated sodium carbonate solution (2×100 cm3) and then with water (1×100 cm3), dried (MgSO4), filtered and then evaporated down under partially reduced pressure The crude product was purified using column chromatography, using a 50:50 mixture of dichloromethane/hexane an eluent to yield 2.7 g (9.6%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CC(C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][OH:10])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: OCc1ccccc1Cc1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 16 h

Procedure:
In an inertized flask containing 2-(4-fluoro-benzyl)-benzoic acid (1 eq.), toluene (0.8 L/mol) is added and the vessel is cooled down to 0-5° C. Sodium dihydro-bis(2-methoxyethoxy)aluminate (“RedAl”) (1 M in toluene, 2.3 eq.) is added dropwise and the reaction mixture is stirred at 5° C. during 16 hours. Acetone (3 eq.) is added dropwise at 5° C. and the mixture is stirred during 15 minutes. The temperature is allowed to rise to 25° C. A sodium hydroxide solution (5 eq.) is added and the mixture is stirred vigorously during 20 minutes. The organic layer is separated and washed again with a slightly acidic aqueous solution. The organic layer is filtered over Dicalite and used further in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10]([C:12]([CH3:14])=O)=[CH2:11]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[CH:11][CH:10]=[C:12]2[CH3:14]
Reactant: COc1ccccc1N
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COc1cccc2c(C)ccnc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirred solution of 2-methoxyaniline (1 g. 8.1 mmol.) in acetic acid (10 ml), activated silferc (1.3 g. ferric chloride 8.1 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.62 g, 8.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.1 g. 8.1 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 60%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20]Cl>>[CH3:18][O:19][CH2:20][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 2-bromophenol (0.67 ml, 5.8 mmol) and diisopropylethylamine (1.1 ml, 6.4 mmol) was added chloromethyl methyl ether (0.49 ml, 6.4 mmol). The reaction mixture was stirred at ambient temperature for 2 h, quenched with sat'd NaHCO3 and diluted with CH2Cl2. The organic phase was washed with water and dried over Na2SO4 to afford 700 mg (58%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([NH:15][NH:16][C:17]([C@H:19]2[CH2:25][CH2:24][C@@H:23]3[CH2:26][N:20]2[C:21](=[O:35])[N:22]3[O:27]CC2C=CC=CC=2)=[O:18])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([NH:15][NH:16][C:17]([C@H:19]2[CH2:25][CH2:24][C@@H:23]3[CH2:26][N:20]2[C:21](=[O:35])[N:22]3[OH:27])=[O:18])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3O)C1

Procedure:
By using the procedure described in Step-2 of Example-1, and by using trans-3-[N′-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-pyrrolidin-1-carboxylic acid tert-butyl ester (11.5 gm, 0.024 mol), methanol (115 ml) and 10% palladium on carbon (3.0 gm) to provide the title compound in 9.5 gm quantity as a pale brown solid and it was used for the next reaction immediately.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Na+]>Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(O)CCCCl
Reactant: C1=COCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(CCCCl)OC1CCCCO1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-chloro-4-hydroxynonane (Example A, Step 2) (11.0 g., 0.062 mole) and dihydropyrane (5.2 g., 0.062 mole), cooled in an ice bath is added 5 drops of hydrochloric acid (conc.). A slight exothermic reaction is noted and when this is complete the reaction is allowed to come to room temperature then stand at this temperature for 2 hours. At the end of this period, several pellets of sodium hydroxide are added and the reaction is distilled in vacuo. The yield of 1-chloro-4-(2-tetrahydropyranyloxy)nonane is 12.5 g. (77%), boiling 96°-102°C./0.1 mm. Upon redistillation, a boiling point of 90°-92°C./0.1 mm. is obtained.