Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br)=[CH:5][O:6][CH2:7][F:8].[C:18]1([CH3:25])[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:1][O:2][C:3](=[O:17])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:25])=[CH:5][O:6][CH2:7][F:8]
Reactant: COC(=O)C(=COCF)c1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(=COCF)c1ccccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.66 g of 2-(2-bromomethylphenyl)-3-fluoromethoxyacrylic acid methyl ester, 0.65 g of o-cresol, 1.38 g of pulverized potash and 0.07 g of 18-crown-6 in 15 ml of acetonitrile is stirred at room temperature for 24 hours. Water is then added, the reaction mixture is acidified with 1N hydrochloric acid and extraction is carried out with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate yields pure 3-fluoromethoxy-2-[2-(2-methylphenoxymethyl)phenyl]-acrylic acid methyl ester in the form of a viscous oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:25]1([N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=3[N+:19]([O-:21])=[O:20])[CH2:2]2)[CH2:27][CH2:26]1
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NS(=O)(=O)c1ccc(NCC2CN(C3CC3)CCO2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 415B (0.633 g) and (1-ethoxycyclopropoxy)trimethylsilane (1.601 ml) in anhydrous methanol (15 mL) and acetic acid (1.7 ml) was refluxed for 30 minutes and allowed to cool to room temperature. Sodium cyanoborohydride (0.377 g) was then added and the mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to dryness. The residue was mixed with 5% aqueous Na2CO3 solution (25 mL) and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 5% and 10% methanol in dichloromethane to provide the title compound.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[N:15]=[C:16]4[N:21]([C:13]=3[C:12]([CH3:23])=[C:11]([CH3:24])[N:10]=2)[C@@H:20]([CH3:22])[CH2:19][O:18][CH2:17]4)=CC=1.[OH-].[Na+].C(Cl)(Cl)Cl>FC(F)(F)C(O)=O>[CH3:22][C@H:20]1[CH2:19][O:18][CH2:17][C:16]2=[N:15][C:14]3[C:9]([NH2:8])=[N:10][C:11]([CH3:24])=[C:12]([CH3:23])[C:13]=3[N:21]12
Reactant: COc1ccc(CNc2nc(C)c(C)c3c2nc2n3[C@@H](C)COC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)c2nc3n(c2c1C)[C@@H](C)COC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
(4S)—N-(4-Methoxybenzyl)-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazin-9-amine (350 mg, 0.99 mmol) was dissolved in 15 mL of trifluoroacetic acid and stirred at ambient temperature overnight. The solvent was removed under reduced pressure to give an orange residue which was then treated with 30 mL of aqueous 10% NaOH solution and the mixture was stirred for 2 hours. The solution was then extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give an orange solid. Chromatography (SiO2, 10-30% CMA/CHCl3) gave an off-white solid. Crystallization from acetonitrile gave (4S)-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazin-9-amine (115 mg) as a white powder, mp 264-267° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:14]1[CH2:22][CH2:23][O:24][CH:13]1[C:12]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=2)=[C:10]([O:17][CH3:18])[CH:11]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C2OCCO2)ccc1Oc1ccc(N)c([N+](=O)[O-])c1

Procedure:
4-[(4-amino-3-nitrophenyl)oxy]-3-(methyloxy)benzaldehyde (2.42 g, 8.4 mmol), ethyleneglycol (4 ml) and p-toluenesulfonic acid (50 mg) in 50 mL of toluene was heated at 125 degrees Centigrade with a Dean-Stark trap for approximately 18 hours. The reaction mixture was diluted with ethyl acetate and washed twice with saturated NaHCO3. The aqueous layers were extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated to give 4-{[4-(1,3-dioxolan-2-yl)-2-(methyloxy) phenyl]oxy}-2-nitroaniline. (M+1) 332.9, 2.13 min (LC/MS method B)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].C[Si](C)(C)Cl.C(N(CC)CC)C.[O:20]1CCOC[CH2:21]1>>[CH:21]([N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])=[O:20]
Reactant: C1COCCO1
Reactant: O=C1NCCCN1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: O=CN1CCCNC1=O
Reaction time: 72 h

Procedure:
The mixture of 10 parts by weight of 1,3-diaza-cyclohexane-2-one, 49 parts by weight of trimethylchlorosilane, 25 parts by weight of triethylamine and 150 parts by volume of dioxane were boiled for 3 days with stirring and exclusion of moisture, then filtered, evaporated to 50 parts by volume in vacuo and stirred overnight with 11.5 parts by volume of formic acid-acetic acid anhydride. The mixture was evaporated to dryness in vacuo, and the residue was recrystallized from ethanol/ether.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[CH:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])(=[O:7])=[O:6].[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[CH:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)OCCOC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])C(OCc1ccccc1)C(=O)OCCOC(=O)c1ccccc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, benzoyloxyethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (39a) (3.2 g max.) dissolved in 30 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.51 g (8.0 mmol) of sodium azide (NaN3). After work-up, the crude title compound (39b) was obtained and used in the next step without further purification. MS (ESI) m/z 555.83 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](OC)=O)=[CH:26][CH:25]=1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21
Yield: 32.1 %

Procedure:
10 mg (0.032 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.087 mmol) of methyl 4-bromophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 5 mg (53%) of a solid, Rf=0.69 (dichloromethane/methanol=15:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]3[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[C:30]1([NH:36][C:37]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:22]=[CH:21][C:11]4[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4ccccc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A suspension of 1-(6-(3-aminophenyl)-2-benzothiazolyl)-3-ethylurea (0.062 g, 0.20 mmol), triethylamine (0.083 mL, 0.60 mmol, 3.0 eq), and phenyl isocyanate (0.055 mL, 0.50 mmol, 2.5 eq) in 2 mL toluene was stirred at room temperature for about 1 hour. The white precipitation was filtered off, washed with Et2O and MeOH, and dried under vacuum to give the desired compound 0.038 g (44%). LC/MS 431.8 (M+1); LC retention time 3.49 min.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.[OH-].[Na+]>>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([Cl:25])[CH:22]=1)[O:18][CH2:17][CH2:16][N:11]([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared from 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid ethyl ester using the procedure described in Step B of Example 1 with 2N NaOH. Purification by flash chromatography (1% MeOH in CH2Cl2) provided the title acid. 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t, 4H), 1.33 (m, 4H); MS 411 (M−1). Example numbers 112-122 are not used in this specification
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[S:6])[NH:4][NH:5][C:17]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:18]
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
To a stirred room temperature solution of 4-methylthiosemicarbazide (5.91 g, 5.62×10-2 mole) and pyridine (150 ml) was added 2-naphthoyl chloride (10.7 g, 5.61×10-2 mole). After stirring overnight, the pyridine was evaporated at reduced pressure. The concentrate was treated with water and the undissolved product was collected by filtration and dried by suction. Crystallization from acetone/ethanol afforded off-white needles, Mp 211° C. (decomp).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]4)[C:6]=2[CH:24]=1.[ClH:26].Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[ClH:26].[ClH:26].[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[C:2]([CH3:1])[C:3]([CH3:25])=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c2cc1C
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 127 (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH4-].[Na+]>CO>[O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:19][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCC1
Reactant: O=Cc1cccc(OCC2CO2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cc(CNC2CCCC2)cc(OCC2CO2)c1
Reaction time: 4 h
Yield: 79 %

Procedure:
To a solution of 3-(oxiran-2-ylmethoxy)benzaldehyde (1.0 g, 5.61 mmol) in MeOH (15 mL) was added cyclopentanamine (502 mg, 5.89 mmol) at room temperature. After 4 h, sodium borohydride (318 mg, 8.42 mmol) was added in portions and the mixture was stirred for another 1 h. The reaction mixture was quenched by adding aqueous 1 N HCl until the pH was adjusted to 4-5. The resulting solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification. (1.1 g, yield 79%) MS (ESI+) e/z: 248.2 [M+1]+.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2].[Br:10][C:11]1[N:12]=[C:13](Br)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:10][C:11]1[N:12]=[C:13]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: CC(C)n1cc(N)cn1
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1cc(Nc2nc(Br)cn3ccnc23)cn1
Temperature: 25 °C
Yield: 144.8 %

Procedure:
A mixture of impure 1-isopropyl-1H-pyrazole-4-amine (2) (1.00 g), from above, 6,8-dibromoimidazo[1,2-a]pyrazine (3) (750 mg, 2.71 mmol), and N,N-diisopropylethylamine (526 mg, 4.16 mmol) in DMF (20 mL) was stirred at 100° C. for 3 h. After this time, the reaction was cooled to room temperature and poured into ice water (200 mL). The resulting suspension was filtered and the filter cake dried to a constant weight under vacuum to afford impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (1.26 g) as an off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 4.49 (m, 1H), 1.40 (d, 6H); ESI MS m/z 323.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CN(C=O)C>[CH:62]1([C@@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1
Reactant: CCOP(C)(=O)c1ccc([C@H](N)C2CCCCC2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (1.187 g, 5.76 mmol) and Et3N (1.75 mg, 17.3 mmol) in DMF (15 mL) was added HATU (2.62 mg, 6.9 mmol). The mixture was stirred for 5 min at room temperature and then compound 26-e (1.7 g, 5.76 mmol) was added. The resulting mixture was stirred at room temperature for 15 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (ethyl acetate:MeOH=5/1) to provide the product, 26-f, (1.05 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[C:5]#[N:6].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH2:14][CH2:13]1)[C:5]#[N:6]
Reactant: Cc1cc(C#N)ccc1/C=C/N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C#N)ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-4-((E)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}vinyl)benzonitrile (100 mg, 0.24 mmol) in 15 mL of methanol and 10 mL of DCM was added NaBH4 (508 mg, 2.4 mmol), then stirred at room temperature overnight. The crude product was purified via prepare TLC (methanol/DCM 1:10) to give 3-methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.12 (d, J=8.6 Hz, 2H), 7.23˜7.40 (m, 5H), 3.01˜3.21 (m, 2H), 2.80˜2.92 (m, 4H), 2.50˜2.65 (m, 10H), 2.33 (s, 3H). MS m/z: 379 (M+1)+. (0.062 μM)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[O:21]1[CH:28]2[CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:25][CH:24]4[CH2:23][CH2:22][O:21][CH:28]4[CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1CC2CNCC2O1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2CCOC2C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with hexahydro-2H-furo[3,2-c]pyrrole (1214875-23-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:17])([CH3:16])[CH2:14][OH:15]>>[Cl:1][C:2]1[C:3]([O:15][CH2:14][C:13]([F:17])([F:12])[CH3:16])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(F)(F)CO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: CC(F)(F)COc1ncc(C(=O)O)cc1Cl
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (1.12 g, colorless oil) from 5,6-dichloronicotinic acid (1.00 g, 5.21 mmol) and 2,2-difluoropropan-1-ol (0.50 g, 5.21 mmol) in a similar manner to Step-1 of Intermediate-A3.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[CH:25]=[CH2:26].[OH-].[K+]>CN1C(=O)CCC1>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:26][CH2:25][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[C:18]([F:28])([F:17])[F:27])[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnccc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 8-ethyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH2:20]>C(O)C>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH:20][S:10]([C:8]1[S:9][C:5]([S:1]([NH2:2])(=[O:4])=[O:3])=[CH:6][CH:7]=1)(=[O:11])=[O:12]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)s1
Reactant: NCc1cccs1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(S(=O)(=O)NCc2cccs2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
To a solution of 5-sulfamoyl-thiophene-2-sulfonyl chloride (0.80 g, 3.1 mmol) in ethanol (10 mL) at 0° C. was added 2-thiophenemethylamine (0.67 mL, 6.51 mmol) and this mixture stirred at room temperature for 18 hr. After evaporation of solvent the residue was dissolved in ethyl acetate (200 mL) and this solution was washed with saturated aqueous sodium bicarbonate (2×50 mL), dried (MgSO4), and evaporated to a crude material which was purified by column chromatography (silica, 5% methanol/methylene chloride) and recrystallization [methanol/methylene chloride (1:50)] to give the desired product (450 mg, 45%): mp 146°-148° C. Analysis: Calculated for C9H10 N2O4S4 : C, 31.94; H, 2.98; N, 8.28. Found: C, 32.00; H, 2.96; N, 8.29.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[N:10]=[CH:11][N:12]=[C:13](O)[C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:13]1[C:14]2[N:15]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: Oc1ncnc2oc(-c3ccccc3)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 67 %

Procedure:
2-Phenyl-oxazolo[5,4-d]pyrimidin-7-ol (0.10 g, 0.43 mmol) was dissolved in 3 mL POCl3, and the mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to room temperature and poured onto ice water. The resulting mixture was extracted by CH2Cl2. The combined organic layers were concentrated and the residue was purified by column chromatography (EtOAc:hexanes=1:10) to afford the title compound as a white solid (73 mg, 67%). 1H NMR 400 MHz (CDCl3) δ 8.82 (s, 1H), 7.35-7.32 (m, 2H), 7.68-7.57 (m, 3H). LC-MS (ESI) m/z 232.0 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[N+:14]([C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]=1[OH:13])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(-c2ccccc2)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1O

Procedure:
A solution of 3-phenyl phenol(2 g, 11 mmol) in acetic acid was treated with concentrated nitric acid drop-wise until all starting material was consumed. The solution was partitioned between water and methylene chloride. The organic phase was separated and the aqueous phase was extracted once more with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography(ethyl acetate/hexanes) to afford desired (1.2 g, 50%). 1H NMR (CDCl3): δ 10.65(s, 1H), 8.18 (d, 1H, J=10.0 Hz), 7.65 (d, 2H, J=6.0 Hz), 7.49 (m, 3H), 7.34 (s, 1H), 7.10 (d, 1H, J=10.0 Hz).