Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[CH2:6].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>C1COCC1.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([OH:20])([CH2:6][CH2:5][CH:4]=[CH2:3])[C:16]([F:19])([F:17])[F:18]
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: C=CCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a 300 mL oven dried 3 necked, round bottomed flask with a stirring bar, argon inlet, addition funnel and a reflux condenser was added magnesium (turnings, 3.03 g, 125 mmol) and dry THF (75 mL). To this well stirred mixture was added 4-bromo-1-butene (12.0 mL, 118.21 mmol) at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was aged 30 min then cooled to 0° C. in an ice bath. To this well stirred solution was added a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (5.00 g, 22.36 mmol) in THF (35 mL), dropwise over 30 min. The cooling bath was allowed to expire and the mixture was stirred 20 h at ambient temperature. The reaction was diluted with EtOAc and 10% aqueous citric acid. This mixture was stirred for 4 h. The layers were separated and the organic phase was washed with aqueous NaHCO3 and brine. Drying (MgSO4), filtration, removal of the solvent in vacuo, and chromatography on 300 g of silica gel using 15% EtOAc in hexane as eluant gave 4.80 g of (+/-) 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-5-hexen-2-ol as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1>C(OCC)(=O)C.ClCCl.O=[Mn]=O>[OH:12][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[4-(Hydroxymethyl)phenyl]propan-2-ol (1.0 g, 6 mmol) was dissolved in the mixture of ethyl acetate (10 mL) and dichloromethane (5 mL). To the solution, MnO2 (2.6 g, 30 mmol) was added, and the mixture was stirred overnight at room temperature. The solid was filtered off and washed with ethyl acetate. The combined organic phases were concentrated to afford the title compound. 1H NMR (400 MHz CDCl3): δ 10.00 (s, 1H), 7.80 (d, 2H), 7.60 (d, 2H), 1.60 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[CH2:34]([OH:36])[CH3:35]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:32])[C:29]([O:36][CH2:34][CH3:35])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: FC(F)(F)Oc1cccc(-c2ccc3c(ccn3Cc3ccccc3)c2)c1
Reactant: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Yield: 84 %

Procedure:
Ethyl {1-benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate was prepared from 1-benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indole (1.06 g, 2.89 mmol), oxalyl chloride (1.04 mL, 13.0 mmol), and ethanol (1.5 mL), following the procedure described in Step 3 of Example 1. Purification by flash chromatography using 5-10% ethyl acetate in hexane as an eluant yielded the title compound as a light brown gum (1.14 g, 84%). Mass spectrum (+ESI, [M+H]+) m/z 468; 1HNMR (500 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.45 (d, 1H, J=1.4 Hz), 7.7 (m, 2H), 7.6-7.65 (m, 3H), 7.25-7.4 (m, 6H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.1 Hz), and 1.35 ppm (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC3C=CC(OC)=CC=3)[C:7]=2[C:22]2[CH:31]=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)[C:29]3[CH:28]=[CH:27][C:26](=[O:45])[NH:25][C:24]=3[N:23]=2)[CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1.C(OCC)(=O)C>[ClH:46].[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:7]=2[C:22]2[N:23]=[C:24]3[C:29]([CH:28]=[CH:27][C:26](=[O:45])[NH:25]3)=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]3)[CH:31]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3ccc(=O)[nH]c3n2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1ccc2c(C3CCCNC3)cc(-c3c(O)cccc3OCC3CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a stirred solution of tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate (0.260 g, 0.425 mmol) in 1,4-dioxane (2 mL) was added 4 N HCl in dioxane (2 mL). The mixture was stirred at room temperature overnight, and diluted with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,8-naphthyridin-2(1H)-one hydrochloride as a yellow solid (0.146 g, 80%).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][CH:18]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:28][CH:29]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2cnccc2CCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2cnccc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
tert-Butyl 4-[2-(4-(phenethyl)pyrid-3-yl)ethyl]benzoate (0.36 g, 0.95 mmol) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (0.5 ml). The reaction was stirred at ambient temperature for 5 hours, then partitioned between ethyl acetate and buffer (pH 6). The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to give the title product (0.168 g) as a salt with THF.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][S:15]2)[S:10][C:9]1=[S:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:38])[CH:32]=[CH:31][C:30]([S:33]([O:36]C)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[C:27]1([CH3:38])[CH:28]=[CH:29][C:30]([S:33]([O-:36])(=[O:34])=[O:35])=[CH:31][CH:32]=1.[CH2:1]([N+:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][S:15]2)[S:10][C:9]=1[S:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1C(c2ccccc2)=CSC1=C1SC(=S)N(Cc2ccccc2)C1=O
Product: CSC1=[N+](Cc2ccccc2)C(=O)C(=C2SC=C(c3ccccc3)N2C)S1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
The title compound was prepared from 3′-benzyl-3-methyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one and methyl p-toluenesulfonate in a manner similar to that described in Example 1. 1H-NMR (CDCl3): δ 7.72 (2H, d), 7.49-7.56 (3H, m), 7.42-7.47 (2H, m), 7.36-7.41 (5H, m), 7.05 (2H, d), 6.99 (1H, s), 5.29 (2H, s), 4.26 (3H, s), 3.14 (3H, s), 2.29 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCO)OCc1ccccc1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Product: O=CCCNC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A solution of (3-hydroxy-propyl)-carbamic acid benzyl ester (100 g, 478 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO; 7.5 g, 48 mmol) in DCM (1 L) was treated with (diacetoxyiodo)benzene, PhI(OAc)2, (170 g, 528 mmol) in three portions. After 18 h at rt, the mixture was slowly quenched with saturated aqueous (satd. aq.) NaHCO3. The organic layer was separated, washed with satd. aq. NaCl (500 mL), dried (Na2SO4), and concentrated. The residue was purified by FCC to give a solid, which was stirred in 1:1 Et2O/hexanes for 2 h. The solid was collected by filtration. Successive iterations were combined to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 7.36-7.31 (m, 5H), 5.14 (br s, 1H), 5.08 (s, 2H), 3.49 (q, J=6.0, 2H), 2.75 (t, J=5.7, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([O:14]C)=O)[C:8]([S:16][CH3:17])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:19]1[CH:24]=[CH:23][C:22]([C:25](N)=[NH:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)=[N:26][C:12](=[O:14])[C:9]3=[C:8]([S:16][CH3:17])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)c1ccncc1
Reactant: COC(=O)c1c(SC)nn(C2CCCC2)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1[nH]n(C2CCCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 0 °C
Yield: 12.2 %

Procedure:
A mixture of methyl 1-cyclopentyl-3-methylthio-5-amino-1H-pyrazole-4-carboxylate (3.0 g, 0.012 mol), 4-pyridine carboxamidine hydrochloride (1.9 g, 0.012 mol), potassium carbonate (1.6 g, 0.012 mol) and DMF (25 ml) were refluxed for 4 hours. Additional 4-pyridinecarboxamidine hydrochloride (1.9 g) and potassium carbonate (1.6 g) were added and the reaction mixture was refluxed for 24 hours. The solution was poured into ice-water, neutralized with acetic acid and the resulting precipitate was collected by filtration and washed with water. Recrystallization of the solid from DMF afforded 0.48 g (12%) of 1-cyclopentyl-3-methylthio-6-(4-pyridyl )-pyrazolo [3,4-d]-pyrimidin-4-one as a white powder, m.p. 272°-274° C. when dried at 110° C. for 16 hours in high vacuum.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].CCOCC>C(O)(=O)C>[NH2:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([I:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: ClI
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(I)cc(C(=O)O)c1N

Procedure:
Iodine monochloride (28.9 g) was added over 0.5 hours to a stirred solution of 2-amino-3-methylbenzoic acid (24.5 g) (Aldrich Chemical Co. Ltd.) in acetic acid (250 cm3). After 24 hours ether (250 cm3) was added and the mixture was filtered. The solid material was dried in vacuo to afford the title compound, m.p. 214° (38.6 g).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-])=O>CO.CCOC(C)=O.CCO.[Pd]>[CH3:13][O:12][C:9]1[CH:8]=[C:7]2[C:6]([CH2:5][CH2:4][C:3](=[O:2])[NH:14]2)=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)NC(=O)CC2
Reaction time: 12 h
Yield: 43.4 %

Procedure:
A solution of 3-(4-methoxy-2-nitro-phenyl)-acrylic acid methyl ester (4.00 g, 16.9 mmol) in MeOH (100 mL) and EtOAc (20 mL) is added a slurry of Pd/C (200 mg) in EtOH (20 mL). The suspension is hydrogenated under a pressure of 60 psi for 12 hours. The mixture is then filter through a pad of celite and the filtrate is concentrated and purified on silica gel chromatography column with 30-40-50% EtOAc/Hexanes to obtain the title product (1.30 g, 43%) and an uncyclized by-product (0.60 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:8].[Na+].Cl[CH2:11][C:12]([CH2:14]Cl)=[CH2:13]>O1CCOCC1>[O:7]([CH2:11][C:12]([CH2:14][O:8][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C=C(CCl)CCl
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(COc1ccccc1)COc1ccccc1
Yield: 66.3 %

Procedure:
A solution of 2.0 ml (22.7 mmol) of phenol in 40 ml of dioxane was heated to reflux and treated with 0.96 g (23.8 mmol) of sodium hydroxide. After the solid had dissolved, the solution was treated dropwise over a period of 15 min with 1.25 ml (10.8 mmol) of 2-chloromethyl-3-chloro-1-propene. The resulting solution was heated at reflux for 6 h, allowed to cool, and concentrated in vacuo. The residue was taken up in ether, washed with several portions of water, dried over MgSO4, and concentrated to a yellow liquid. Flash chromatography using 10% ethyl acetate in hexane gave 1.72 g (65%) of the desired compound as a colorless oil. 1H NMR (CDCl3) δ 4.63 (m, 4H), 5.35-5.45 (m, 2H), 6.9-7.0 (m, 6H), 7.25-7.35 (m, 4H). Mass spectrum (M +NH4)+ =258.
Reaction SMILES: C[Zn]C.I[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:14]([O-:16])=[O:15])[NH:7][N:6]=1.[CH3:17]O.Cl>O1CCOCC1.C(Cl)Cl>[CH3:17][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:14]([O-:16])=[O:15])[NH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: CO
Agent: C[Zn]C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1n[nH]c2cccc([N+](=O)[O-])c12
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of dimethyl zinc (1.73 ml, 3.46 mmol) was added dropwise to a mixture of 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (0.427 g, 0.519 mmol) in dioxane (0.2M, 9 mL) under argon. The mixture was heated under reflux for 2 hours. After cooling, MeOH (<1 mL) was added, followed by 2N HCl (1 mL) and DCM (5 mL). After stirring mixture for 30 minutes, the organic layer was separated, washed with saturated aqueous sodium bicarbonate, water, and brine. The combined organic extracts were dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (1-10% EtOAc in DCM to provide 3-methyl-4-nitro-1H-indazole (0.082 g, 27% yield) as a brown residue.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccc(Cl)nn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(N)nn2)CC1
Temperature: 165 °C
Yield: 24.5 %

Procedure:
6-Chloro-pyridazin-3-ylamine (2.0 g, 15.4 mmol, Eq: 1.00) was dissolved in 1-methylpiperazine (15.5 g, 154 mmol, Eq: 10.0) and heated in a sand bath at 165° C. for 4 hours. The reaction mixture was then heated at 200° C. for 2 hours in a microwave reactor. The crude product was purified by chromatography using 10% methanol (with approximately 2% ammonium hydroxide) in DCM. To the still impure product was added aqueous sodium bicarbonate and DCM and the layers were separated. The aqueous layer was back extracted twice with DCM. The combined organic layers were concentrated, triturated with isopropyl acetate, filtered and dried to give 730 mg (24.5%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[Cl:15].[CH2:16]([N:23]([CH2:29]OC)[CH2:24][Si](C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:16]([N:23]1[CH2:29][CH2:9][C:8]([C:6]2[CH:5]=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[CH:7]=2)([C:10]([F:13])([F:12])[F:11])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 55.1 %

Procedure:
To a stirred solution of 1,2,3-trichloro-5-(1-trifluoromethyl-vinyl)benzene (5 g, 18.21 mmol) in dry DCM (50 mL) was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (Preparation 29, 18.64 mL, 72.86 mmol). Resulting reaction mixture was cooled to 0° C. and TFA (0.14 mL, 1.825 mmol) was added slowly. Reaction mixture was stirred at room temperature for 5 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford yellow thick oil, which was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (3×50 mL). Organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to afford crude compound which was purified by column chromatography using 230-400 mesh silica to afford product as oily liquid (4.1 g, 55.11%). 1H-NMR (400 MHz, CDCl3) δ: 2.28-2.32 (m, 1H), 2.53-2.62 (m, 1H), 2.67-2.73 (m, 1H), 2.79-2.84 (m, 1H), 3.05 (s, 2H), 3.61-3.70 (m, 2H), 7.26-7.35 (m, 5H), 7.42 (s, 2H). (m/z): 407.9 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9](C(O)=O)=[CH:8][C:7]=1[O:15][CH3:16].S(Cl)(Cl)=[O:18].Cl[CH2:22][Cl:23]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:15][CH3:16])=[CH:8][CH:9]=[CH:13][C:14]=1[C:22]([Cl:23])=[O:18]
Reactant: ClCCl
Reactant: COc1cc(C(=O)O)ccc1OCCCCl
Reactant: O=S(Cl)Cl
Product: COc1cccc(C(=O)Cl)c1OCCCCl

Procedure:
To a mixture of 4-(3chloropropoxy)-3methoxybenzoic acid (2.4 g, 10 mmol) in dichloromethane (5 ml) was added thionyl chloride (0.9 ml, 12 mmol) dissolved in dichloromethane (5 ml). The reaction was stirred and refluxed for 1 hour, and then the dichloromethane was removed in vacuo to leave a dark oil. The oil was triturated with hexane and the solid that formed while scratching with a glass rod was collected to afford 1.6 g of (3chloropropoxy)-3-methoxybenzoyl chloride, m.p.=60-63° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH:34]([C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2/[CH:12]=[CH:34]/[C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Reactant: O=Cc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (340 mg) obtained in Example 321b) in THF (5 ml) was added sodium hydride (50% oil dispersion, 55 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. A solution of 2-formylthiazole (86 mg) in THF (1 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 2 hr. The resultant precipitate was collected by filtration to give the title compound as a white solid (149 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([O:14][C:15](Cl)=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:6])[C:2]#[CH:3].[CH2:18]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C.O>[CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([O:14][C:15](=[O:16])[N:22]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6])[C:2]#[CH:3]
Reactant: Cc1ccc(NCC(C)C)cc1
Reactant: C#CCOC(=O)Nc1cccc(OC(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCOC(=O)Nc1cccc(OC(=O)N(CC(C)C)c2ccc(C)cc2)c1
Temperature: 15 °C

Procedure:
A solution of 25.4 g (0.1 mol) of chloroformic acid-3-(2-propinyl-oxycarbonylamino)-phenylester in 100 ml acetic acid ethylester is added within a period of 20 minutes to a solution of 16.3 g (0.1 mol) of N-isobutyl-p-toluidine in 50 ml acetic acid ethylester. Simultaneously a solution of 13.8 g (0.1 mol) of potassium carbonate in 50 ml water is added dropwise while stirring and cooling to 15° C. temperature. Thereafter, the solution is further stirred at 15° C. for 30 minutes. The organic phase is then separated and washed at 0° C. with dilute sodium hydroxide, dilute hydrochloric acid and water. After drying on magnesium sulfate the mass is concentrated at a reduced pressure. It is then recrystallized from acetic acid ethylester/pentane.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]1[CH:9]([OH:10])[CH2:8][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:6]1[CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)C>[OH:4][CH:5]1[CH:9]([OH:10])[CH2:8][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:3])=[O:18])[CH:6]1[CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)CCC1C(CCCCCCC(=O)O)CC(O)C1O
Solvent: CCOCC
Product: CCCCCC(O)CCC1C(CCCCCCC(=O)OC)CC(O)C1O
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A solution of diazomethane (60 mg.) in diethyl ether (10 ml.) was added to 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoic acid (0.3 g.; prepared as described in Example 1(q)) and the reaction mixture was left to stand for one day at room temperature. The polymethylenes formed as by-products of the reaction were removed by filtration and the filtrate was washed with dilute aqueous sodium carbonate solution. Evaporation of the ethereal solution gave crude methyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate (0.26 g.), νmax 3450 cm-1, 1730 cm-1.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=O.CCOCC.C([O-])(=O)C.[Na+]>C1COCC1.O>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]2[O:1][N:2]=[C:3]([CH:4]([OH:6])[CH3:5])[N:7]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(O)C(N)=NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
The title compound from Example 1 (6.45 g) was cooled on an ice-bath with 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g 3-chlorobenzoyl chloride was added. The mixture was warmed to r.t. and stirred for 2 h. Addition of Et2O (200 mL), washing with sat. aq. NH4Cl and re-extraction of the aq. layer gave after combining and concentration of the org. layers followed by drying in vacuo 27.24 g, which was directly used in the next step. The material was dissolved in ethanol (250 mL) and refluxed for 1 h, followed by addition of 14.0 g (170 mmol) sodium acetate in water (40 mL). After refluxing over night, cooling to RT and addition of water (250 mL) the mixture was concentrated in vacuo to about half of its volume, resulting in a precipitate which was filtered off and recrystallized from EtOAc/heptane to yield 6.45 g (25%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2([Cl:19])C=O)=[CH:5][CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+].[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:29].O>C(O)C>[C:28]([C:30](=[CH:22][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]=1[Cl:19])[C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:29]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(CN2c3ccccc3CC2(Cl)C=O)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccc(OC)cc2)c2ccccc12

Procedure:
To 600 mg of 1-(4-methoxybenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (12a). Yield 620 mg of (12a). M.p. 153°-4° C. (sample recryst. from EtOH).