Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 84.6 %

Procedure:
A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethyl sulphoxide is heated at 135°-140° C. for 2 h. The solvent is removed by distillation under high vacuum, and the residue is suspended in H2O, filtered off with suction and washed with water. For further purification, the moist crude product is boiled with 100 ml of water, filtered with suction at room temperature, washed with H2O and dried to constant weight in a vacuum drying oven over CaCl2 at 100° C. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid of decomposition point 255°-257° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:10]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:30].S([O-])([O-])=O.[Na+].[Na+].[OH-:42].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:10]2)(=[O:30])=[O:42])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(Sc3ccc(F)cc3)C2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCCC(S(=O)(=O)c3ccc(F)cc3)C2)cc1
Reaction time: 2 h

Procedure:
A solution of 3-[(4-fluorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine and excess meta-chloroperoxybenzoic acid in methylene chloride was stirred at room temperature overnight. An excess of sodium sulfite and water was added and the mixture was stirred for 2 hr. An excess of sodium hydroxide was added. The methylene chloride phase was extracted with several portions of dilute aqueous sodium hydroxide, dried over magnesium sulfate and the solvent removed in vacuo to give an oil. The oil was crystallized from a mixture of methylene chloride-diethylether-hexane to give white crystals,
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[O:30][N:29]=1.CC#N>CCOC(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:4]([CH2:27][C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=3)[O:30][N:29]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(C(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 75 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
A mixture of 2,4-bis(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.18 mmol), Cs2CO3 (0.064 g, 0.20 mmoL), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.052 g, 0.20 mmoL) and CH3CN (4 mL) was stirred at 75° C. for 18 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.056 g, 62%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=8.8 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H) 8.23 (s, 1H), 8.09-8.06 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.48 (s, 1H), 6.03 (s, 2H); MS m/z 527 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH3:28]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[O:17][CH2:26][CH2:27][CH3:28])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(I)c(O)c(OCc2ccccc2)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(I)cc(C=O)cc1OCc1ccccc1
Temperature: 77.5 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
To a mixture of 3-benzyloxy-4-hydroxy-5-iodo benzaldehyde (23.1 g, 0.065 mol) and potassium carbonate (11.70 g, 0.084 mol) in DMF (55 ml) was added 1-bromo propane (12.03 g, 0.09 mol). The reaction mixture was stirred at 75-80° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether (480 ml). The ether layer was dried Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using (1:18) EtOAc: light petroleum as eluent to give the 3-benzyloxy-4-propoxy-5-Iodo benzaldehyde (21.4 g, 83%). TLC: Ethyl acetate:light petroleum (1:9), Rf=0.5; 1H NMR (CDCl3, 200 MHz): δ 1.03 (t, J=7.21 Hz, 3H), 1.75 (m, 2H), 4.05 (t, J=6.66 Hz, 2H), 5.15 (s, 2H), 7.3-7.45 (m, 6H), 7.83 (d, J=1.54 Hz, 1H), 9.79 (s, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:18])([Cl:17])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14](O)=[O:15])[N:12]=1)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>ClCCl>[ClH:1].[Cl:1][C:2]([Cl:18])([Cl:17])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([Cl:20])=[O:15])[N:12]=1)=[O:6]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
In 20 ml of dichloromethane was suspended 6.67 g. of 2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-ylacetic acid and, while the suspension was stirred under cooling with ice, 4.15 g. of finely crushed phosphorus pentachloride was added, whereupon the suspended acid was completely dissolved. Then, after an elapse of about 5 minutes, fresh crystalline substance separated. The mixture was stirred at room temperature for 1 hour, after which time the precipitates were collected by filtration and rinsed with petroleum ether. The procedure provided 6.59 g. (yield 84.8%) of 2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-ylacetyl chloride.hydrochloride, melting point: 109.7° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH:19]([C:23](O)=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]=[CH:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[CH:61]=[C:62]([CH:72]=[C:73]([C:75]([F:78])([F:77])[F:76])[CH:74]=1)[CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C.O>[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH:19]([C:23]([NH:59][C:60]5[CH:61]=[C:62]([CH:72]=[C:73]([C:75]([F:76])([F:77])[F:78])[CH:74]=5)[CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)C1CCc2ccc(Oc3ccnc4[nH]c(=O)ccc34)cc2C1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc5[nH]c(=O)ccc45)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 7-[(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.18 g, 0.00053 mol) in DMF (5.3 mL) was added diisopropylethylamine (0.11 mL, 0.00063 mol) and HATU (0.24 g, 0.00063 mol). The reaction mixture was allowed to stir at rt for 1 hr. tert-Butyl [3-amino-5-(trifluoromethyl)benzyl]-carbamate (0.15 g, 0.00053 mol) was added and the reaction mixture was allowed to stir for an additional 15 hr. Water was added to the reaction mixture and a solid precipitated. This solid was collected by filtration and purified by column chromatography to give tert-butyl [3-[({7-[(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate as a white solid (0.24 g, 75%). LCMS: (FA) ES+ 609.4.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=O.[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]>>[C:7]([C:9](=[C:2]([CH:4]1[CH2:6][CH2:5]1)[CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=C(C)C1CC1
Yield: 27.9 %

Procedure:
A solution of 118 g (1.4 mol) of cyclopropyl methyl ketone and 113 g (1 mol) of ethyl cyanoacetate was reacted by a method similar to Example 3a) to give 50 g (yield 29%) of ethyl 2-cyano-3-cyclopropylbut-2-enoate (b.p. 105° C./6 mbar).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>CC(O)C>[CH3:9][S:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:11][NH2:12])[CH:7]=1
Reactant: NN
Reactant: CSc1cc(Cl)ncn1
Solvent: O
Solvent: CC(C)O
Product: CSc1cc(NN)ncn1
Temperature: 90 °C

Procedure:
A mixture of 4-Chloro-6-methylsulfanyl-pyrimidine (1.1 g, 6.85 mmol), hydrazine monohydrate (1.2 g, 23.5 mmol), and 2-propanol (10 mL) is heated to 90° C. for 4 hours. The reaction mixture is then cooled to room temperature, concentrated, triturated with water, and filtered. The undissolved solid is washed with water, air-dried to give (6-Methylsulfanyl-pyrimidin-4-yl)-hydrazine as light yellow solid: 1H NMR 400 MHz (d6-DMSO) δ 8.29 (s, 1H), 8.16 (s, 1H), 6.55 (s, 1H), 4.34 (s, 2H), 2.43 (s, 3H); MS m/z 157.05 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)CCc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.54 g), lithium hydroxide monohydrate (0.0743 g), tetrahydrofuran (6 mL), water (4 mL) and methanol (4 mL) was stirred at room temperature for 1.5 hrs. 1N Hydrochloric acid (1.8 mL) was added to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals (0.49 g, 94%). melting point: 98-99° C.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[N:18]O)[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.C(O)(=O)C.O.[Pd]>[NH2:18][CH2:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:7]2[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C=NO)cc2C1C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CN)cc2C1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Tert-butyl 1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (995 mg) was dissolved in EtOH-acetic acid-water (8:1:1, 20 mL). To the reaction mixture was added 10% palladium-supported carbon (480 mg), followed by stirring under a hydrogen atmosphere, at room temperature and normal pressure, for 4 hours. Then, the reaction mixture was filtered through celite and the solvent was evaporated to obtain tert-butyl 7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (956 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.I[C:23]1[CH:24]=[C:25]([CH:29]([N:31]([O:43][CH3:44])[C:32]([C:34]2[C:35]([CH:40]([F:42])[F:41])=[N:36][N:37]([CH3:39])[CH:38]=2)=[O:33])[CH3:30])[CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:23]2[CH:24]=[C:25]([CH:29]([N:31]([O:43][CH3:44])[C:32]([C:34]3[C:35]([CH:40]([F:41])[F:42])=[N:36][N:37]([CH3:39])[CH:38]=3)=[O:33])[CH3:30])[CH:26]=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(I)c1
Reactant: Oc1ccc(Cl)cc1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(Oc2ccc(Cl)cc2)c1
Yield: 22.9 %

Procedure:
A mixture of 4-chlorophenol (0.2 g, 0.86 mmol) in DMF (2 ml), cesium carbonate (0.7 g, 1.14 mmol), N,N-dimethylglycine (0.01 g, 0.057 mmol), 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(3-iodo-phenyl)-ethyl]methoxy-amide (0.25 g, 0.57 mmol), prepared as described in example P2, and Cul (0.09 g, 0.024 mmol) was subjected to microwave irradiation at 90° C. for 20 minutes. Reaction mass was diluted with water and extracted with ethyl acetate (3×60 ml), washed with water, brine and dried over anhydrous sodium sulfate. The crude mass was purified by chromatography to yield 0.057 g (28% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[3-(4-chloro-phenoxy)-phenyl]-ethyl}-methoxy-amide in form of a resin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([Br:9])=[CH:4][C:3]=1I.[Br-:11].[Br:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[Zn+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:14]2[S:15][CH:16]=[CH:17][C:13]=2[Br:12])[C:5]([Br:9])=[CH:4][C:3]=1[C:14]1[S:15][CH:16]=[CH:17][C:13]=1[Br:11]
Reactant: [Br-]
Reactant: Brc1cc(I)c(Br)cc1I
Reactant: [Zn+]c1sccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Brc1cc(-c2sccc2Br)c(Br)cc1-c1sccc1Br
Temperature: 85 °C
Yield: 55 %

Procedure:
A oven dried 2000 cm3 flask is charged with 1,4-dibromo-2,5-diiodobenzene (61.00 g, 125.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (2.195 g, 3.127 mmol) and anhydrous tetrahydrofuran (300 cm3). Once the starting materials are dissolved, a solution of 0.5 M of 3-bromo-2-thienylzinc bromide in tetrahydrofuran (500 cm3, 250.2 mmol) is transfered using a canula and the reaction heated to 85° C. for 3 hours. The reaction is cooled down overnight and the white precipitate filtered off. This precipitate is washed with water (750 cm3) and methanol (250 cm3) to obtain 25.77 g of the title product. Further product is recovered from the initial filtrate. The filtrate is reduced to ca. 90 cm3 in vacuo and then 500 cm3 of methanol is added. The precipitate is filtered off, washed with water (750 cm3) and methanol (250 cm3) and finally triturated three times in hot propan-2-ol to obtain an additional 12.72 g of the title product. (38.49 g, Yield: 55%). NMR (1H, 300 MHz, CDCl3): δ 7.71 (s, 2H); 7.42 (d, J=5.3 Hz, 2H); 7.09 (d, J=5.3 Hz, 2H). NMR (13C, 75 MHz, CDCl3): δ 136.62; 136.10; 135.16; 130.50; 126.97; 123.52; 111.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COc1ccc(S(=O)(=O)Nc2ccccc2Nc2ccccc2)cc1OC

Procedure:
The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfonyl chloride (0.01 mol) and o-phenylene diamine by general Method C. It was purified by recrystallization from EtOH (0.65 g, 21%). EI-MS m/z 309 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][Si](C)(C)C)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: COC(C)(C)C
Product: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 45.7 %

Procedure:
To a solution of 5-(4-Chloro-phenyl)-7-trifluoromethyl-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (13.3 g, 34 mmol) in THF (60 mL) and MeOH (150 mL) at 0° C. was added K2CO3 (467 mg, 10 mol %) and the mixture was stirred at 0° C. for 6 h, diluted with TBME and ice water, separated, washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (heptane/EtOAc 100:0-90:10), triturated in heptane, filtered and dried to give the title compound(5.0 g, 45%) as an orange crystalline solid. MS (ISP) 322.2 [(M+H)+] and 324.2 [(M+2+H)+]; mp 102-103° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7]N=C[C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[C-:12]#[N:13].[Na+].[CH3:15][OH:16]>[O-2].[O-2].[Mn+4]>[CH3:15][O:16][C:10]([C:2]1[NH:1][C:9]2[CH:8]=[CH:7][N:13]=[CH:12][C:4]=2[CH:3]=1)=[O:11]
Reactant: [C-]#N
Reactant: O=Cc1cc2cnccc2[nH]1
Reactant: CO
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Product: COC(=O)c1cc2cnccc2[nH]1
Reaction time: 5 h

Procedure:
Add to a 0° C. solution of 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde (9b-1, 3.24 g, 22.19 mmol) in methanol under argon, sodium cyanide (5.44 g, 111 mmol) and manganese dioxide (9.65 g, 111 mmol). Stir the reaction mixture for 5 h, filter through Celite® and dilute with 500 ml EtOAc. Wash the organic layer with water (2×) and brine, dry over sodium carbonate, filter, and concentrate to provide the title compound (3.27 g) as a pure tan solid. Prepare 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid amide 6b-1 from 5b-1 by any of the above described procedures for the synthesis compound 6a-1 from ethyl ester 4a-1.
Reaction SMILES: ClCC[S:4](Cl)(=[O:6])=[O:5].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C(N)C=C.C(N(C(C)C)CC)(C)C.[CH3:28][CH:29]([OH:31])[CH3:30]>>[CH:29]([O:31][S:4](=[O:5])(=[O:6])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=[CH2:11])([CH3:30])[CH3:28]
Reactant: c1ccncc1
Reactant: CC(C)O
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: C=CCN
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNCCS(=O)(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
2-Chloroethylsulfonyl chloride (2 g, 12.3 mmol) was is dissolved in 2-propanol (20 mL), pyridine (2.7 mL) was added, and the mixture was stirred at room temperature for 3 hours. Allylamine hydrochloride (1.15 g, 12.3 mmol) and diisopropylethylamine (6.4 mL) was added, and stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure, 5% sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (0.5 g, 2.4 mmol, 20%).
Reaction SMILES: C(N[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.[NH:31]1[CH2:36]CCC[CH2:32]1.C[NH:38]C>>[ClH:11].[NH2:38][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:31]([CH3:36])[CH3:32])=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1
Reactant: CNC
Reactant: C1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN(C)C)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing l-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with dimethylamine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-dimethylaminopentan-1-one hydrochloride, m.p. 221°-224° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]\[CH:22]=O)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]\[CH2:22][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(/C=C\C=O)ccc1OCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(/C=C\CN2CCOCC2)ccc1OCc1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-[(1Z)-3-oxo-1-propen-1-yl]benzoate (may be prepared as described in Description 122; 163 mg, 0.52 mmol) in 1,2-dichloroethane (10 ml) was added morpholine (0.05 ml, 0.52 mmol) and acetic acid (0.03 ml, 0.52 mmol). The solution was stirred for 3 hours then sodium triacetoxyborohydride (165 mg, 0.78 mmol) was added and stirred for one hour. Saturated NaHCO3 solution (10 ml) was added and the mixture was stirred for 15 minutes. Dichloromethane (10 ml) was added and the organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a yellow gum. 197 mg.
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][NH:7][CH3:8].[Mg](N(C)C)Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([OH:35])[C:23](=[O:34])[N:24]([CH3:33])[C:25]=2[C:29]([O:31]C)=O)[C:20]1=[O:36]>ClCCl.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([OH:35])[C:23](=[O:34])[N:24]([CH3:33])[C:25]=2[C:29]([N:7]([CH3:8])[CH3:6])=[O:31])[C:20]1=[O:36]
Reactant: COC(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: CNC
Agent: CC(C)[Mg]Cl
Agent: CN(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
To THF (80 mL) cooled to −10° C. was added iPrMgCl (2M in THF, 60 mL). Dimethylamine (2M in THF) was then added at −10 to 0° C., the mixture then stirred for 1 hour at −5 to −10° C. The resulting suspension of ClMgNMe2 at −10° C. was allowed to warm to 0° C., and a solution of methyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (10.0 g) in dichloromethane (100 mL) was added over 20 minutes at 0° C. The mixture was then stirred until reaction was complete by HPLC. The reaction mixture was quenched with 1N HCl (335 mL). The organic layer was collected and the aqueous layer extracted with CH2Cl2 (35 mL). The organic phases were then combined and washed with brine (35 mL). Volatiles were evaporated to give the title product as an amorphous solid.