Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[C:17]1([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:24]([CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:26])=[O:25])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)Cc3ccccc3)c2)cc1Cl
Yield: 42.8 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added alpha-toluenesulfonyl chloride (18.3 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-phenyl-methanesulfonamide (14.3 mg, >95% purity, yield: 42.8%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 384 [M+H]+, retention time=2.22 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 4.65 (s, 2H) 7.29-7.32 (m, 5H) 7.63 (t, J=2.21 Hz, 1H) 7.76 (dd, J=8.15, 1.71 Hz, 1H) 8.00 (d, J=1.64 Hz, 1H) 8.09 (d, J=8.21 Hz, 1H) 8.35 (d, J=2.53 Hz, 1H) 8.61 (d, J=2.02 Hz, 1H) 10.24 (br. s., 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16]>[Pd].C(OCC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: OCCCC#Cc1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCOCC
Product: OCCCCCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(2-napthyl)-4-pentyn-1-ol (520 mg, 247 mmol) and 10% palladium on activated carbon in ethyl ether (50 ml) was stirred at room temperature under a hydrogen atmosphere for 2 days. Solvent removal, after filtration through celite, gave the titled compound as a light yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:28]=[O:29]>>[C:30]1([NH:27][C:28]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:29])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Product: O=C(Nc1ccccc1)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 7.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 221 using 218 (50 mg, 0.14 mmol) and isocyanato benzene (26 mg, 0.22 mmol) to provide 223 (5 mg, 7% yield) as a tan solid. LC-MS (M+H=465, obsd.=465).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15].Cl>C(=S)=S>[CH3:2][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]([CH3:15])=[O:16])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of isopropylbenzene (50 g) in carbon disulfide (250 mL) is treated with aluminum chloride (170 g), and the resulting mixture is cooled to 0° C. Acetyl chloride (33 g) is added at the rate of 1 mL/min, and the resulting mixture is stirred overnight. The mixture is poured into aq. HCl (2N, 400 mL), and the layers are separated. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined, washed with brine, dried over Na2SO4, filtered and concentrated to afford the product, 4-isopropylacetophenone, as an oil (66 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16]C)=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.[NH2:18][NH2:19].CO>O>[NH2:1][C:2]1[C:3]([C:14]([NH:18][NH2:19])=[O:16])=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: NN
Reactant: COC(=O)c1nc(-c2cccnc2)cnc1N
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(-c2cccnc2)cnc1N
Yield: 58.5 %

Procedure:
A mixture of methyl 3-amino-6-(3-pyridyl)pyrazine-2-carboxylate (2 g, 8.687 mmol) was heated in Hydrazine (1.392 g, 1.363 mL, 43.43 mmol) with a minimal amount of MeOH (5 mL) added at 80° C. for 2 hours. Water was added and the product collected by filtration, washed with methanol and dried to furnish the product as a brown solid (1.17 g, 58% Yield). 1H NMR (400.0 MHz, DMSO) d 4.52 (br s, 2H), 7.43 (m, 1H), 7.71 (s, 2H), 8.54 (2H, m), 8.90 (1H, s), 9.39 (1H, s), 10.16 (1H, s) ppm; MS (ES+) 231
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][N:5]2[C:6]3[C:11](=[C:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH2:3][CH:2]([CH3:19])[CH3:1])[CH2:24][CH2:23]1
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCC1CC1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=9.2 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 6.56 (d, J=1.7 Hz, 1H), 4.05 (d, J=6.6 Hz, 2H), 2.67 (t, J=7.1 Hz, 2H), 2.07 (m, 1H), 1.15 (m, 1H), 1.03 (d, J=6.6 Hz, 6H), 0.58 (m, 2H), 0.35 (m, 2H); MS (ES) m/z 321 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1>C(O)C.[Pt]>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([NH2:12])[CH:3]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Agent: [Pt]
Solvent: CCO
Product: CC(=O)c1cc(C)cc(N)c1O
Reaction time: 0.73 h
Yield: 67.9 %

Procedure:
A solution of 2-hydroxy-5-methyl-3-nitroacetophenone [4.0 g; Joshi et al., J. Amer. Chem. Soc., (1954), 76, 4993] in ethanol (150 ml) was hydrogenated at 25° C. and 3.5 kg/cm2 for 44 minutes using a catalyst of platinum on charcoal. The solution was filtered and the filtrate was evaporated at 30° C. under diminished pressure to give a dark red oil, which set to a semi-solid on standing overnight. This material was purified by chromatography on a column of silica gel using diethyl ether as eluant. The fastest running band (yellow) was collected to give 3-amino-2-hydroxy-5-methylacetophenone (2.3 g), m.p. 56°-58° C., in the form of a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:15])[CH3:14].[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1>>[ClH:1].[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[N:19]([C:2]2[N:11]=[C:10]([NH:15][CH2:13][CH3:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:18]=1
Reactant: CCN
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Product: CCNc1nc(-n2nc(C)cc2C)nc2ccccc12
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, ethylamine and 3,5-dimethylpyrazole. Mp. 286° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.C1(=O)O[CH:21]=[CH:20]O1>O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:20]=[CH:21][N:16]=2)[CH2:10][CH2:9]1
Reactant: O=c1occo1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Solvent: O
Product: Clc1cncc(Cl)c1N1CCC(c2ncco2)CC1
Temperature: 170 °C
Yield: 11.2 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (0.10 g, 0.36 mmol) in polyphosphoric acid (5 mL) at 80° C. was added vinylene carbonate (35 mg, 0.40 mmol). The mixture was heated at 170° C. for 4 hours, cooled to r.t. and poured into water (200 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic extracts were washed with water (100 mL), a saturated solution of sodium hydrogen carbonate (50 mL), water (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to furnish a colourless oil (12 mg). The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1 then hexane, EtOAc, 1:1) to furnish the title compound as a white solid (13 mg, 12%), LC-MS (ESI) Rt 2.66 min, m/z 298 (100%, W); m/z (ESI) C13H14Cl2N3O requires 298.0508 found [M+H]+ 298.0507.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH:28](/[C:17](=[C:6]1\[C:5](=[O:27])[NH:4][C:12]2[C:7]\1=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)/[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc2c(cc1OC)N(C(C)=O)C(=O)C2=C(Cl)c1cccc(C#N)c1
Reactant: Nc1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(C#N)c1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-chloro-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-indolinone and aniline
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+].ClCCl>O.CCOCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: BrCCCCCCOCCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 2-quinolineethanol (1.00 g), 1,6-dibromohexane (4 ml), TAB (100 mg), 50% aqueous sodium hydroxide (4 ml) and dichloromethane (3 ml) was stirred at room temperature for 40 h, then diluted with water (40 ml) and ether (25 ml). The organic phase was washed with water (20 ml), dried and evaporated in vacuo. The residual oil was purified by FCC eluting with hexane followed by hexane-ether (9:1) and ether, to give the title compound (1.18 g) as a pale yellow oil, t.l.c. (diethyl ether) Rf 0.44.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[N:25]1([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:34]([C:31]2([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:32][CH2:33]2)=[O:35])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=C(O)C1(N2CCCCC2)CC1
Reactant: Cc1ccc(S(=O)(=O)[C@H]2CN[C@H](C(=O)NC3(C#N)CC3)C2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(N4CCCCC4)CC3)C2)cc1
Yield: 40 %

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-tosylpyrrolidine-2-carboxamide 7G with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)-4-tosylpyrrolidine-2-carboxamide as a light yellow solid (40%). MS ISP (m/e): 485.4 (100) [(M+H)]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)=[O:9])[CH2:3][CH2:2]2)=[O:37])[CH2:33][CH2:34]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Reactant: O=C(O)CN1CCN(Cc2ccccc2)CC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)CN2CCN(Cc3ccccc3)CC2)CC1

Procedure:
Intermediate 42 (303 mg, 1 mmol) was reacted with carboxylic acid 46 by Method E. Flash chromatography eluted with 9:1 DCM:MeOH afforded compound 50 (379 mg, 73%) as a white solid: Mp 178-183° C. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.34-7.26 (m, 4H), 7.26-7.19 (m, 3H), 6.25 (d, J=7.5 Hz, 1H), 4.14 (d, J=13.4 Hz, 1H), 3.95 (d, J=12.5 Hz, 1H), 3.75-3.66 (m, 1H), 3.45 (s, 2H), 3.23 (d, J=13.2 Hz, 1H), 3.12 (t, J=11.9 Hz, 1H), 3.00 (d, J=13.1 Hz, 1H), 2.78 (t, J=11.6 Hz, 1H), 2.47-2.30 (m, 8H), 1.89-1.76 (m, 2H), 1.40-1.31 (m, 1H), 1.23-1.13 (m, 1H). Purity 90%. HRMS calculated for C20H21F3N4O3−H+ 518.2379. found (ESI(−), [M−H]) 518.2365.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:14])([N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:5].[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[CH2:23][CH:22]([NH:28][CH:29]([CH3:33])[C:30](O)=[O:31])[CH2:21][CH2:20]2>>[CH3:1][O:2][C:3](=[O:15])[C:4]([N:6]1[CH:10]=[C:9]([NH:11][C:30](=[O:31])[CH:29]([NH:28][CH:22]2[CH2:21][CH2:20][C:19]3[C:24](=[C:25]([F:27])[CH:26]=[C:17]([F:16])[CH:18]=3)[CH2:23]2)[CH3:33])[N:8]=[CH:7]1)([CH3:14])[CH3:5]
Reactant: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: CC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: COC(=O)C(C)(C)n1cnc(NC(=O)C(C)NC2CCc3cc(F)cc(F)c3C2)c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionic acid to afford the title compound; MS 421.5 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[N:15]=C(C#N)[CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-:23].[Na+].Cl.[CH2:26]([OH:28])[CH3:27]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[N:15]=[C:27]([C:26]([OH:23])=[O:28])[CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCO
Reactant: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C#N)nc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a stirred mixture solution of 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonitrile (630.0 mg, 2.0 mmol) in ethanol (10.0 mL) was added 50% sodium hydroxide in water (8.5 mL). The reaction mixture was stirred at 90° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (635.9 mg, 95%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=335.1.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccc(Br)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-bromophenyl)ethanol (Chen, L.; et al., US 20060004045) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.58 g, 98%): 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.41-8.05 (m, 3H), 8.03-7.68 (m, 2H), 7.68-6.95 (m, 10H), 5.88-5.44 (m, 1H), 4.25-3.80 (m, 2H); ESIMS m/z 578 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH:12]([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[O:22][C:21]([C:23]([Cl:25])=[O:24])=[CH:20][CH:19]=1>C1C=CC=CC=1>[ClH:25].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:23]([C:21]3[O:22][C:18]([CH3:17])=[CH:19][CH:20]=3)=[O:24])[CH:12]([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CN(CCCc2ccccc2)CCN1
Reactant: Cc1ccc(C(=O)Cl)o1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)N2CCN(CCCc3ccccc3)CC2C)o1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of 1-(3-phenylpropyl)-3-methylpiperazine, 5-methyl-2-furoyl chloride and benzene.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.[N+:12]([O-:15])([OH:14])=[O:13]>O>[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([O-:14])=[O:13].[N+:12]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([O-:15])=[O:13]
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClCCCl
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccccc1O
Temperature: 110 °C
Reaction time: 8 h
Yield: 46.5 %
Yield: 46.5 %

Procedure:
A 100 mL three-necked round bottom flask fitted with reverse dean-stark apparatus was charged with 9.411 g (0.1 mol) phenol, 60 mL 1,2 dichloro ethane and 1.882 g of catalyst as prepared in example 5. The reaction flask was flushed with nitrogen. The reaction mixture was refluxed at 110° C. for 1 h followed by dropwise addition of 8.6 mL (0.133 mol) of 70% HNO3. The water formed during the reaction was removed using reverse dean-stark apparatus. The reaction was carried out for 8 h. The reaction was monitored by GC analysis. In this case, 100% phenol conversion was obtained with 46.5% 2-nitro phenol and 46.5% 4-nitro phenol. Other unidentified products were 7%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([S:31][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: SCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, benzylmercaptan and DBU in DME. ES-MS m/e (%): 329 (M+H+, 100).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH:11]=[CH:10][C@H:9]([N:12]=[N+]=[N-])[C:6]21[CH2:8][CH2:7]2)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]([O:4][C@@H:5]1[CH:11]=[CH:10][C@H:9]([NH2:12])[C:6]21[CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C=C[C@H](N=[N+]=[N-])C12CC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C=C[C@H](N)C12CC2

Procedure:
A solution of the product of step b) (0.85 g) and triphenylphosphine (1.46 g) in tetrahydrofuran (5 ml) and water (1 ml) was stirred at ambient temperature under nitrogen for 64 hours. The reaction mixture was concentrated to dryness under reduced pressure azeotroping with toluene (2×50 ml) and purified by chromatography (SiO2; 97:2:1 ethyl acetate:methanol:ammonia) to afford the subtitle compound (0.67 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](O[C:13](=O)[CH3:14])(=O)[CH3:10].[CH2:16]([N:19]1[C@H:24]([CH3:25])[CH2:23][N:22]([C@H:26]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=2)[C:44](Cl)=[O:45])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si](C(C)(C)C)(C)C)[CH:28]=2)[C@@H:21]([CH3:50])[CH2:20]1)[CH:17]=[CH2:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH2:9][CH3:10].[CH2:16]([N:19]1[C@H:24]([CH3:25])[CH2:23][N:22]([C@H:26]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=2)[C:44]([N:5]([CH2:13][CH3:14])[C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)=[O:45])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C@@H:21]([CH3:50])[CH2:20]1)[CH:17]=[CH2:18]
Reactant: Nc1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC)c3cccc(F)c3)c2)C[C@H]1C
Product: CCNc1cccc(F)c1

Procedure:
3-Fluoro-N-ethylaniline [NMR (DMSO-d6, 200 MHz): δ1.18 (t, J=7.2 Hz, 3H); 3.02 (dq, J1 =7.2 Hz, J2 =7.2 Hz, 2H); 5.86 (br m, 1H); 6.24-6.42 (m, 3H); 7.07 (q, J=7.8 Hz, 1H)] was prepared from 3-fluoroaniline and acetic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(3-fluorophenyl)benzamide as a white solid. NMR (DMSO-d6, 200 MHz): δ0.92 (d, J=6 Hz, 3H); 0.96 (d, J=6 Hz, 3H); 1.05 (t, J=7 Hz, 3H); 1.7 (m, 1H); 2.05 (m, 1H); 2.3 (m, 1H); 2.5 (m, 2H); 2.7 (m, 1H); 2.9 (m, 1H); 3.2 (m, 1H); 3.9 (q, J=7 Hz, 2H); 4.8 (s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=16 Hz, 1H); 5.8 (m, 1H); 6.45 (d, J=8 Hz, 1H); 6.6 (s, 1H); 6.65 (d, J=8 Hz, 1H); 6.9 (d, J=8 Hz, 1H); 7.0-7.2 (m, 3H); 7.2-7.4 (m, 5H); 9.35 (s, 1H). [α]D20 =+4.3° (abs EtOH, c=3.9). Calc. for C31H36FN3O2HCl 0.5 H2O: C, 68.06; H, 7.00: N, 7.68; Cl, 6.48. Found C, 68.10;H, 7.04; N, 7.63; Cl, 6.42. Mass spectrum (CI--CH4) m/e: 502 (M+1, 39%), 501 (M, 9%), 348 (29%), 153 (100%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[CH:12]=[C:13]([NH2:25])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22].[Cl:26][C:27]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:28]=1[O:29][CH:30]([CH3:34])[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[ClH:10].[Cl:10][C:11]1[CH:12]=[C:13]([NH:25][C:31](=[O:32])[CH:30]([O:29][C:28]2[CH:35]=[CH:36][C:37]([C:39]([F:41])([F:40])[F:42])=[CH:38][C:27]=2[Cl:26])[CH3:34])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCOc1ccc(NC(=O)C(C)Oc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Product: Cl

Procedure:
0.342 mL (2.000 mmol) of ethyl-diisopropylamine was added to a solution of 0.364 g (1.500 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (intermediate product Z1b), 0.403 g (1.500 mmol) of 2-(2-chloro-4-trifluoromethyl-phenoxy)-propionic acid and 0.562 g (1.750 mmol) of TBTU in 10 mL abs. THF and the mixture was stirred for 1 hour at RT. The reaction mixture was evaporated down i. vac. and the residue combined with dichloromethane and water. The org. phase was separated off, washed with sat. aqueous sodium bicarbonate solution and water and evaporated down i. vac. The residue was purified by column chromatography (silica gel, gradient dichloromethane/10% conc. aqueous ammonia in MeOH 100:0→5:95).