Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:22])=[C:13]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:14]=2)=[N:6][CH:7]=1.[S-:23][C:24]#[N:25].[K+].BrBr>C(O)(=O)C>[NH2:25][C:24]1[S:23][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:22])=[C:13]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH:14]=1)[N:6]=2
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccc(Cl)c(NC(=O)C(F)(F)F)c2)nc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
N-{5-[(5-Aminopyridin-2-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (12 g, 36.2 mmol) and potassium thiocyanate (14.1 g, 145 mmol) were suspended in acetic acid (145 mL), bromine (8.67 g, 54.3 mmol) was added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residual oily substance was dissolved in ethyl acetate (100 mL), and aqueous sodium hydrogen carbonate solution (150 mL) was gradually added to partition the solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was collected by filtration with diisopropyl ether (100 mL), and dried to give the title compound (10.1 g, 72%) as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18](F)=[C:19]([F:34])[CH:20]=[C:21]2[C:26]=1[N:25]([CH:27]1[CH2:29][CH2:28]1)[CH:24]=[C:23]([C:30]([OH:32])=[O:31])[C:22]2=[O:33].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:18]1[C:17]([Cl:16])=[C:26]3[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]3[CH:27]3[CH2:29][CH2:28]3)=[CH:20][C:19]=1[F:34])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CCC1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC12CCC1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1Cl)C2
Yield: 60.9 %

Procedure:
1.22 g of 1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]heptane, 0.96 g of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.58 g of 1,8-diazabicyclo[5.4.0]-7-undecene were added to 20 ml of acetonitrile, followed by heating under reflux for 3.5 hours. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (using a 100:1 mixture of chloroform and methanol as the eluent) and recrystallization (from ethyl acetate-diisopropyl ether) to obtain 0.96 g of 7-[1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]hept-3-yl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (m.p. 200-202° C.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[NH:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][Mg]Br>C1(C)C=CC=CC=1.C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([NH2:12])[CH3:13])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N=Cc1cccc2c1OCCO2
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(N)c1cccc2c1OCCO2
Temperature: 60 °C
Reaction time: 24 h

Procedure:
The dried resin to which the C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine (1 eq) was bound was suspended in dry toluene. Under a nitrogen atmosphere methyl magnesium bromide (150 eq) in a 3 M solution in ethyl ether was added. This mixture was shaken for 24 hours at 60° C. then filtered and washed with toluene, water, then methanol and dichloromethane alternately three times. The final wash was with methanol. The solid was dried under vacuum.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[CH2:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][CH2:18][C:19]=3[CH:24]=2)[CH:8]=1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 2,3-dihydro-benzofuran-5-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at refulx over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 4H), 7.07 (m, 2H), 6.73 (d, 1H), 4.54 (t, 2H), 3.77 (s, 2H), 3.71 (s, 2H), 3.66 (s, 3H), 3.18 (t, 2H), 2.94 (t, 2H), 2.63 (t, 2H); MS 326 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:7]=1.[BH4-].[Na+]>CO.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:6]([CH:8]([OH:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CCC(=O)O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid (0.10 g, 0.20 mmol) in methanol (4 mL) was added sodium borohydride (0.012 g, 0.32 mmol). The reaction was stirred at ambient temperature for 3 hours. The reaction was then diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration in diethyl ether/methylene chloride/hexanes gave the title compound (0.095 g, LRMS: 493.2, 495.3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:22]1[CH2:21][CH2:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[C:15]=2[CH2:23]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (560 mg, 1.364 mmol) in 2 mL of CH2Cl2 was added TFA (1.576 mL, 20.46 mmol). The reaction mixture was stirred at rt for 1 h, concentrated and then eluted through an Isolute SCX-2 cartridge (10 g) to remove excess TFA with (i) MeOH (ii) NH3/MeOH and the basic fraction evaporated in vacuum to give 6-benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (420 mg, quantitative yield) as a yellow gum. LCMS: [M+H]+=311.2, Rt(3)=0.11.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C1C=CC(C[N:18]2[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[CH:19]2)=CC=1F)#N>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][N:18]1[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[CH:19]1)#[N:2]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Product: N#Cc1cc(Cn2cncc2C=O)ccc1F

Procedure:
The titled product was prepared from 3-cyano-4-fluorotoluene using the same procedures as those described in Example 1, Steps D through G for the preparation of 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, except that 3-cyano-4-fluorotoluene was used in place of 4-cyano-3-fluorotoluene in Step D.
Reaction SMILES: [ClH:1].[CH:2](=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]([CH3:23])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:24][C:25]([F:30])([F:29])[CH2:26][NH:27][NH2:28]>CO>[ClH:1].[CH3:23][N:11]1[CH2:10][C:9](=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:14]2=[N:28][N:27]([CH2:26][C:25]([F:30])([F:29])[F:24])[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]2[CH2:12]1
Reactant: CN1CC(=Cc2ccccc2)C(=O)C(=Cc2ccccc2)C1
Reactant: NNCC(F)(F)F
Agent: Cl
Solvent: CO
Product: CN1CC(=Cc2ccccc2)C2=NN(CC(F)(F)F)C(c3ccccc3)C2C1
Yield: 59.9 %

Procedure:
A stirred suspension of 12.5 g of 3,5-dibenzylidene-1-methyl-4-piperidone, hydrochloride in 225 ml of methanol is treated with 6.9 g of 70% aqueous 2,2,2-trifluoroethylhydrazine, heated, and the resulting solution refluxed for four hours. The solvent is removed on a rotary evaporator and the light yellow foamy residue (18 g) is dissolved in 90 ml of acetonitrile and treated with 7.5 ml of 5.1 N alcoholic hydrogen chloride; the solid salt rapidly separates after a few seconds. Following cooling for about 16 hours, the material is filtered under nitrogen, washed with cold acetonitrile and ether, and dried in vacuo yielding 9.7 g of material, melting point 185°-187° C (foaming); sintering at 181° C. Crystallization from 50 ml of methanol and 50 ml of ether yields 7.9 g of product, melting point 185°-187° C (foaming).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20]C=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.[NH4+].[Cl-]>CN(C=O)C.[Zn]>[CH2:16]([CH:12]1[NH:11][C:10](=[O:24])/[C:9](=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=2)/[NH:14][C:13]1=[O:15])[C:17]1[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: O=C1NC(Cc2ccccc2)C(=O)N/C1=C\c1ccc(O)cn1
Reaction time: 2 h
Yield: 78 %

Procedure:
Compound C in Example 1 was added to a solution of NH4Cl (10 eq, 0.3 M) in DMF with zinc powder (10 eq). The reaction was stirred in an ice bath for 2 hr. After the reaction was complete, the reaction mixture was filtered. The filtrate was collected and water (2× to DMF) was added. The solid precipitate was collected. The collected solids were combined, washed with water, and dried to give a white powder (yield: 78%). mp. 251-252° C. 1H-NMR (400 MHz, DMSO-d6) δ 3.04 (dd, J=4.0, 11.2 Hz, 1H), 3.13 (dd, J=3.6, 11.2 Hz, 1H), 4.32 (dd, J=4.0, 6.0 Hz, 1H), 6.41 (s, 1H), 7.01 (d, J=1.2 Hz, 2H, ArH), 7.24-7.36 (m, 5H, ArH), 7.92 (s, 1H, ArH), 8.26 (d, J=1.6 Hz, 1H, NH), 9.60 (s, 1H, OH), 9.71 (s, 1H, NH)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC=C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[OH:15])[CH:19]=[CH2:20]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(OCc2ccccc2)cc1
Product: C=CCc1cc(OCc2ccccc2)ccc1O
Temperature: 165 °C
Yield: 85 %

Procedure:
1-Benzyloxy-4-allyloxy-benzene (20.4 g, 84.9 mmol) dissolved in mesitylene (150 ml) was heated at 165° C. for 48 hr under an argon atmosphere. After cooling to ambient temperature the resulting brown oil was chromatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-nHexane (1:9) to afford 2-allyl-4-benzyloxy-phenol (17.45 g, 72.6 mmol, 85%) as a pale yellow oil MS m/e=240.1 (M+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:10](=[O:12])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:16]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)COCc1ccccc1
Reactant: CC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A solution of 2 g of (benzyloxy)acetic acid in 30 ml of DMF was cooled to 0° C., and 2.44 g of 1-(4-aminophenyl)ethanone, 294 mg of DMAP, and 3.73 g of WSC/hydrochloride were added thereto, followed by stirring at room temperature for 3 hours. Liquid separation was carried out with ethyl acetate-1 M hydrochloric acid. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3.12 g of N-(4-acetylphenyl)-2-(benzyloxy)acetamide.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([N:17]1[CH2:22][C@@H:21]2[CH2:23][C@H:18]1[CH2:19][NH:20]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:9][O:8][C:7]1[C:2]([N:20]2[CH2:19][C@@H:18]3[CH2:23][C@H:21]2[CH2:22][N:17]3[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccnc1Br
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Solvent: ClCCl
Product: COc1cccnc1N1C[C@@H]2C[C@H]1CN2Cc1ccccc1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 2-bromo-3-methoxy pyridine (9.9 g) and (1S,4S)-N-benzyl-2,5-diazabicyclo[2.2.1]heptane (10.9 g) was heated at 100° C. in a Parr bomb for 67 h. The reaction mixture was cooled to 23° C., dissolved in CH2Cl2, extracted with 5% NaHCO3, and finally wit:h H2O. The organic layer was dried over K2CO3, filtered, and concentrated under reduced pressure. The crude oil was purified by silica gel chromatography (CH2Cl2 :MeOH; 96:4) to give the desired product (7.93 g, 51%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:74])(=O)=O)=CC=1>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([F:74])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2F)CCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the intermediate 17 (1.01 g, 1.2 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5M in hexane, 0.77 mL, 1.92 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 20 min at the same temperature. Then a solution of N-fluorobenzenesulfonimide (0.68 g, 2.16 mmol) in THF (3.0 mL) was added dropwise, and the mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated NaCl solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 19, which was used without further purification (0.95 g, 1.21 mmol, 101%).
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C>CCO.N.O.[Ni]>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[N:9]=[C:8]([NH:7][C:6](=[O:5])[OH:22])[CH:13]=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: NCc1ccc(-c2cccc(NC(=O)O)n2)cc1
Reaction time: 6 h

Procedure:
A suspension of [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under H2 (50 psi.) at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid ten-butyl ester, which was used directly in next step. 1H NMR (300 MHz, CDCl3) δ 7.83-7.92 (m, 3H), 7.70 (t, J=7.8 Hz, 1H), 7.33-7.40 (m, 4H), 3.92 (brs, 2H), 1.53 (s, 9H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)C=C.[CH2:13]1[C:22]2C(=CC=CC=2)CC[CH2:14]1.B(F)(F)F.CCOCC>>[CH2:22]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][CH2:5][CH2:6]2)[CH:13]=[CH2:14]
Reactant: c1ccc2c(c1)CCCC2
Reactant: C=CCN1CCc2ccccc21
Agent: FB(F)F
Solvent: CCOCC
Product: C=CCc1cccc2c1NCC2
Temperature: 200 °C
Yield: 77 %

Procedure:
A mixture of 2,3-dihydro-1-(2-propenyl)-1H-indole (1.59 g), tetralin (25 ml) and borontrifluoride etherate (1.3 ml) was heated at 200° C. for 1.5 hours. The reaction mixture was cooled to room temperature then quenched with 10% sodium carbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried and evaporated. The residue was chromatographed over silica (ethyl acetate-hexane 15:85) affording 1.23 g of the desired product (77% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29]>CN(C)C=O>[O:6]([CH2:5][CH2:4][CH2:3][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCCCOc1ccccc1
Temperature: 100 °C
Yield: 183.3 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. The solution was heated at 100° C. for 1.5 hours. The reaction solution was carefully poured onto 500 ml of ice water. The precipated oily substance was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted by chlorform:methanol (96:4 v/v). The obtained crude crystals were recrystallized form ethanol to give 1.2 g of dimethyl 4-[2-[4-(3-phenoxypropylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. This compound has the following physicochemical properties.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.O.[C:17](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)nc1
Yield: 90.5 %

Procedure:
A solution of 6-hydroxynicotinic acid (1.00 g, 7.19 mmol) and concentrated sulfuric acid (0.47 ml) in methanol (80 ml) was refluxed for 10 hours then poured into water and sodium bicarbonate (1.45 g) was added. The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel (eluting with 10% -20% methanol in dichloromethane) to give 6-hydroxynicotinic acid, methyl ester as a colourless solid (996 mg, 90%). The product was dissolved in concentrated aqueous ammonia solution and heated at 60° C. for 10 hours. Evaporation of the solvent in vacuo left a solid which was recrystallized from water to give 371 mg, 61% of the title compound as colourless needles.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(=O)C.[BH4-].[Na+]>CS(C)=O>[N+:1]([CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of 2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (21.0 g, 81.9 mmol) described in Manufacturing Example 2-1-3, acetic acid (21 mL) in dimethyl sulfoxide (200 mL) was added sodium borohydride (4.96 g, 131 mmol) at room temperature while cooling appropriately. After addition of sodium borohydride, the cooling bath was removed, followed by stirring for 15 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water twice and with saturated aqueous sodium chloride once, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (16.3 g, 77.1%).
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([OH:5])=[O:4].[H][H]>[Pt]=O.CO>[CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: CC(=Cc1cccc(F)c1)C(=O)O
Agent: O=[Pt]
Solvent: CO
Product: CC(Cc1cccc(F)c1)C(=O)O

Procedure:
15.6 G. of the above product from Example 4 was hydrogenated at 40 pounds per square inch in 800 ml. of methanol with 3 g. of platinum oxide catalyst. After the theoretical uptake of hydrogen, the hydrogenation was stopped. The catalyst was removed by filtration and the solvent removed in vacuo giving a theoretical yield of the desired product, α-methyl-3-fluorohydrocinnamic acid.
Reaction SMILES: Br[CH2:2][C:3]#[CH:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=2)=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:4][C:3]#[CH:2])=[N:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
2 mL (80% in toluene, 18.5 mmol) 3-bromo-propyne are added to a suspension of 3.8 g (18.5 mmol) 5-(4-chloro-phenyl)-pyridin-2-ol and 5.1 g (37 mmol) K2CO3 in 50 mL DMF and the reaction mixture is stirred for 64 h at RT. The mixture is evaporated down i. vac., the residue is combined with 80 mL water, extracted with 150 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 2:1).