Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a stirred solution of 4-amino-3-fluorobenzoic acid (4.97 g, 32.04 mmol), tert-butyl piperazine-1-carboxylate (5.97 g, 32.04 mmol) and triethylamine (10 mL) in dichloromethane (100 mL) was added 1-propanephosphonic acid cyclic anhydride (20 mL, 50% solution in ethyl acetate, dropwise). The reaction mixture was stirred for 1 hour then was diluted with ethyl acetate, washed with potassium carbonate (aqueous), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (9.5 g). MS (ESI) m/z: 324.5 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N2CCC(CO)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2ccc(C#N)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 5.5 g of 1-(4-cyanophenyl)-4-hydroxymethyl-piperidine and 5.16 g of triethylamine in 150 ml of methylene chloride, 5.84 g of methanesulphonic acid chloride are slowly added dropwise at ambient temperature and with stirring. After it has all been added the mixture is left to stand overnight and the solvent is removed under reduced pressure. The residue is chromatographed with methylene chloride/methanol (50:1) over silica gel. Yield: 6.95 g (93% of theory), Mass spectrum: (M+H)+ =295
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2-].[Li+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1.O>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Reactant: Nc1ccncc1
Agent: [Li+]
Agent: [NH2-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 50 °C
Yield: 93.6 %

Procedure:
To a 100-mL, three-neck, round bottom flask were added 294.0 mg (3.124 mM) of 4-aminopyridine, 238.8 mg (10.40 mM) of lithium amide, and 15 mL of tetrahydrofuran. The reaction mixture was heated to 50° C. for 1 hour. A solution of 998 mg (2.792 mM) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one in 25 mL of tetrahydrofuran was added in one portion. The reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled to 50° C. and diluted by dropwise addition of 25 mL of water. The solid precipitate was collected by filtration and dried in a vacuum oven at 45° C. for 12 hours to provide 93.6% yield of the filtered compound, mp 305-307° C. Mass Spec (APCI) 403.9 m/z. HPLC established the product was 98.5% pure.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.O>C1COCC1.C1CCCCC1>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: BrCc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: O
Product: Brc1ccccc1CC(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,3′-methylenedipyridine (5.0 g, 29.4 mmol) in THF (300 mL) at 0° C. was treated with lithium diisopropylamide (39 mL of a 1.5 M solution of the mono-THF complex in cyclohexane, 58.7 mmol) dropwise over 10 min. After stirring at 0° C. for 30 min, 2-bromobenzylbromide (7.3 g as a solution in 100 mL THF, 29.4 mmol) was added dropwise via cannula. The reaction mixture was stirred for 1 h at 0° C. before being poured into H2O (300 mL) and extracted with CH2Cl2 (3×300 mL). The organic extracts were pooled, washed with saturated aqueous NaCl (2×200 mL), dried (Na2SO4), and concentrated under reduced pressure to provide 3,3′-[2-(2-bromophenyl)ethane-1,1-diyl]dipyridine. ESI+MS: 339.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[C:6]([CH:18]=1)[O:7][CH:8]1[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9]1.C([O-])([O-])=O.[K+].[K+].O>CO.C(Cl)Cl>[NH3:10].[CH3:6][OH:7].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])=[C:6]([CH:18]=1)[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1
Reactant: CC(Oc1ccc(Cl)cc1OC1CN(C(=O)C(F)(F)F)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(Oc1ccc(Cl)cc1OC1CNC1)c1ccccc1
Product: N
Reaction time: 15 h
Yield: 68 %

Procedure:
To the title compound of Step B in MeOH (4 mL) was added K2CO3 (0.10 g, 0.72 mmol). After 15 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were dried and concentrated. Silica gel chromatography (1-7 2M NH3/MeOH in CH2Cl2) gave 0.75 g (68% yield) of the title compound. MS (ESI): mass calcd. for C17H18ClNO2, 303.10; m/z found, 304.1 [M+H]+. 1H NMR (CDCl3): 7.38-7.31 (m, 4H), 7.28-7.24 (m, 1H), 6.72 (dd, J=8.6, 2.4 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.23 (q, J=6.4 Hz, 1H), 4.99-4.93 (m, 1H), 3.95-3.81 (m, 4H), 1.66 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH2:13]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N:30]2[CH2:35][CH2:34][NH:33][C@H:32]([CH3:36])[CH2:31]2)=[N:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:21][N:22]=3)[CH2:31][C@H:32]2[CH3:36])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Product: CCOC(=O)c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)C[C@H]2C)nc1
Yield: 71.1 %

Procedure:
Following the above procedure, 6-chloronicotinic acid ethyl ester (100 mg, 0.54 mmol, 1.7 eq) and 1-benzyl-4-((R)-3-methyl-piperazin-1-yl)-phthalazine (100 mg, 0.31 mmol, 1.0 eq) afford the title compound as a white solid (103 mg, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>O1CCCC1>[C:26]([N:19]1[CH2:20][CH2:21][CH:17]([NH:16][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:25])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:22]([O-:24])=[O:23])[CH:11]=2)=[O:15])[CH2:18]1)(=[O:28])[CH3:27]
Reactant: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(pyrrolidin-3-yl)thiophene-2-carboxamide (0.15 g, 0.36 mmol) and acetyl chloride (41.0 mg, 0.54 mmol) in tetrahydrofuran (5.0 mL), was added triethylamine (54.2 mg, 0.54 mmol). The resulting reaction mixture was stirred at ambient temperature for 4 hours. After this time, the reaction mixture was quenched with ice water and stirred at room temperature for 20 minutes and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo at 40° C. overnight to afford the title product as an solid (80 mg, 48% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.91 (1H, d), 8.51(1H, m), 3.68 (1H, m), 3.50 (2H, m), 3.23 (2H, m), 2.09 (1H, m), 1.94 (3H, m). MS m/z: 461.17, 363.17 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].O.CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][N:23]=[N+:24]=[N-:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2ccc(C(=O)CN=[N+]=[N-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
To a solution of {4-[4-(2-bromoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (166 mg, 0.451 mmol) in acetone/water (4:1, v/v, 5 mL) is added NaN3 (44 mg, 0.676 mmol) and the mixture is stirred at ambient temperature for 2 h. Water (10 mL) is added and EtOAc is used to extract. The organic phase is dried with MgSO4, concentrated, and dried under high vacuum to give the title compound (154 mg): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.16 (m, 2H) 1.20 (t, J=7.07 Hz, 3H) 1.40-1.49 (m, 2H) 1.84 (d, J=10.11 Hz, 4H) 1.76-1.87 (m, 1H) 2.17 (d, J=6.82 Hz, 2H) 2.48 (tt, J=112.25, 3.03 Hz, 1H) 4.08 (q, J=7.16 Hz, 2H) 4.45 (s, 2H) 7.25 (d, J=8.34 Hz, 2H) 7.76 (d, J=8.34 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C1COCC1>[F:27][C:25]1[CH:24]=[CH:23][C:22]([N+:28]([O-:30])=[O:29])=[C:21]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:26]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COc1cccc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(Nc2cc(F)ccc2[N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
A solution of 3-methoxyphenylamine (1.58 g, 12.82 mmol) in anhydrous THF (20 mL) was cooled to −70° C. To this was added dropwise 1M LiHMDS in THF (25.14 mL, 25.14 mmol), over 10 minutes. This was stirred at −70° C. for 15 minutes before a solution of 2,4-difluoronitrobenzene (2.00 g, 12.57 mmol) in anhydrous THF (10 mL) was added dropwise. The dark yellow solution was then allowed to reach RT and was quenched with saturated aqueous NH4Cl solution. This was extracted into EtOAc (3×) and the combined organic fractions were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a dark yellow gum, which solidified on standing (3.35 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 9.60 (1H, s), 8.25 (1H, dd, J=9.48, 5.99 Hz), 7.34 (1H, t, J=8.00 Hz), 6.90-6.77 (4H, m), 6.47 (1H, ddd, J=9.47, 7.11, 2.64 Hz), 3.83 (3H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)c3ccccc3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and benzoyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.29-1.39 (m, 2H) 2.26 (t, J=6.82 Hz, 2H) 6.80 (s, 1H) 7.55-7.67 (m, 4H) 7.76 (d, J=8.59 Hz, 2H) 7.85-7.94 (m, 2H) 7.98 (d, J=7.07 Hz, 2H) 8.11 (d, J=8.59 Hz, 2H) 8.17 (d, J=8.08 Hz, 1H) 10.62 (s, 1H); ESI-MS: m/z calc'd for C28H24N4O2S 480.58. found 481.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[C:15]([N+:35]([O-])=O)=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:18]=3[CH:34]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.CCOC(C)=O.[Fe]>[NH2:35][C:15]1[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=2)=[CH:34][C:18]2[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:21][C:17]=2[CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Iron (28 mg, 0.495 mmol) was added to a stirring solution of ethyl 5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (50 mg, 0.099 mmol) in EtOH (495 μL) and AcOH (495 μL) at 100° C. It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (45 mg, 96%). 1H NMR (400 MHz, DMSO-d6) d ppm 7.99-8.06 (2H, m), 7.89-7.96 (2H, m), 7.65-7.72 (1H, m), 7.61 (1H, t, J=7.65 Hz), 7.55 (1H, s), 7.31-7.40 (2H, m), 7.00 (1H, s), br. s.), 4.29 (2H, q, J=7.03 Hz), 1.56 (9H, s), 1.26 (3H, t, J=7.15 Hz). LC-MS retention time: 2.03 min; m/z (MH+): parent does not ionize. 420 (-tBu) was observed. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 40 °C

Procedure:
A mixture of 5-methyl-1H-pyrazol-3-amine (3.00 g, 30.9 mmol), 2,4,5-trichloropyrimidine (5.67 g, 30.9 mmol, 1 equiv.) and Na2CO3 (3.60 g, 34.0 mmol, 1.1 equiv.) in EtOH (100 mL) was heated at 40° C. for 24 h. The solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (350 mL) and water (100 mL). The EtOAc layer was washed with water (3×), saturated aqueous NaCl (1×) and dried over Na2SO4. The resulting EtOAc solution was concentrated in vacuo, providing the product 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 244.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[C:13](=[O:15])=[O:14]>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: COc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
2-(methyloxy)thiophene (1.01 g, 8.85 mmol) was added slowly over 15 min to a 100 mL round-bottomed flask containing 2.5M nBuLi in hexanes (3.8 mL, 9.50 mmol) in Tetrahydrofuran (THF) (40 mL) at −78° C. After warming to room temperature and stirring for 2 h, the mixture was cooled to −35° C. and crushed solid CO2 was added. The mixture warmed to room temperature over 3 hours and was cooled in an ice bath and quenched with NH4Cl(sat.). The cold reaction mixture was partitioned between CHCl3/H2O, the aqueous layer was made acidic with 6N HCl. The separated organic layer was dried with Na2SO4 and concentrated affording the title compound (1.3 g, 8.05 mmol, 91%) which was used without further purification: LC-MS (ES) m/z=159 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1N=CN([C:25]([N:27]2[CH:31]=N[CH:29]=[CH:28]2)=[O:26])C=1.CCN(C(C)C)C(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]([C@@H:56]2CCCN[CH2:57]2)[O:49][CH2:50][C:51]([NH:53][CH2:54][CH3:55])=[O:52])[CH:45]=[CH:46][CH:47]=1>C(Cl)Cl>[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]([O:49][CH2:50][C:51]([NH:53][CH2:54][CH3:55])=[O:52])[C@@H:56]2[CH2:57][CH2:29][CH2:28][N:27]([C:25]([NH:1][C@@H:2]([CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:26])[CH2:31]2)[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OC(C)(C)C
Reactant: CCNC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A solution of (S)-tert-butyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (34.7 mg, 0.129 mmol) in CH2Cl2 (2 mL) was cooled in an ice-bath and CDI (25 mg, 1.2 mmol) and DIEA (83.2 mg, 0.11 mL, 0.645 mmol) were added. The mixture was stirred at rt for 0.5 h and 2-((3-chlorophenyl)((R)-piperidin-3-yl)methoxy)-N-ethylacetamide (40 mg, 0.129 mmol) was added. The reaction mixture was stirred overnight, washed with brine, dried over Na2SO4 and concentrated to give crude tert-butyl (2S)-2-((3R)-3-((3-chlorophenyl)(2-(ethylamino)-2-oxoethoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (60 mg, yield: 75.6%). MS (E/Z): 607 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[F:13][C:14]1[CH:27]=[CH:26][C:17]2[S:18][C:19]([S:22](Cl)(=[O:24])=[O:23])=[C:20]([CH3:21])[C:16]=2[CH:15]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:22]([C:19]2[S:18][C:17]3[CH:26]=[CH:27][C:14]([F:13])=[CH:15][C:16]=3[C:20]=2[CH3:21])(=[O:24])=[O:23])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.4 %

Procedure:
To an ice cooled solution of 4-bromo-2-(trifluoromethyl)benzenamine (CAS 445-02-3, 18 g) in pyridine (25 ml) was added 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (CAS:404964-34-7, 2.0 g). The reaction mixture was stirred at rt for 72 h, concentrated under vacuum, and the residue was chromatographed over silica gel using heptane/chloroform as eluent to obtain 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (2.35 g) as a colorless solid. MS (ISN): 465.9, 468.0 (M−H)−
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[C:13]3[C:12]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO.CCOC(C)=O.[Cl-].[Na+].O>[CH2:19]([C:17]1[CH:18]=[C:13]2[C:12]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cc4ccccc4)cc23)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2c[nH]c3ncc(Cc4ccccc4)cc23)cn1
Temperature: 90 °C
Yield: 73.7 %

Procedure:
A mixture of benzyl derivative 38 (36 mg, 0.08 mmol) and 10% NaOH solution (0.80 mL) in EtOH (2.5 mL) was heated at 90° C. After 1 h the mixture was cooled to r.t., diluted with AcOEt and saturated brine and partitioned. The aqueous layer was extracted with AcOEt (3×). The combined organic extracts were dried (MgSO4), concentrated and the residue was purified by LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 39 (17 mg, 70%). 1H NMR (400 MHz; CDCl3) δ 3.97 (s, 3H), 4.12 (s, 2H), 7.19-7.36 (m, 6H), 7.58 (s, 1H), 7.71 (s, 1H), 7.86 (brs, 1H), 8.24 (m, 1H), 8.79 (brs, 1H). MS (CI) m/z 289 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][CH:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(N)CO
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(C)C(CO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 2-amino-3,3-dimethyl-1-butanol (CAN 3907-02-6, 74.8 mg, 0.64 mmol) as starting materials, and isolated (40 mg, 28.16%) as light yellow sticky solid; LC-MS (UV peak area, ESI) 89.43%, 334.2 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:7])[CH3:6].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:5]([C:8]1[CH:9]=[C:10]([N+:1]([O-:4])=[O:2])[C:11]([O:18][CH3:19])=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:7])[CH3:6]
Reactant: COc1ccc(C(C)=O)c2c1CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1c([N+](=O)[O-])cc(C(C)=O)c2c1CCCC2
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
A solution of 100% nitric acid (0.42 ml, 10 mmol) in 2 ml of acetic anhydride was added dropwise with stirring at -10° to -15° C. to a solution of 8-acetyl-1,2,3,4-tetrahydro-5-methoxynaphthalene (2.1 g, 10 mmol) in 25 ml of acetic anhydride containing one drop of conc. sulfuric acid. Stirring was continued for 20 min. at the same temperature, then the reaction mixture was poured into 100 ml of icewater. The precipitated crystals were collected by filtration and washed with water and a small amount of cold ethanol to give 1.48 g (59%) of the title compound. M.p. 76°-77° C.; 1H-NMR (CDCl1): 1.60-1.93 (m, 4H, 2CH2), 2.57 (s, 3H, COCH3), 2.67-3.13 (m, 4H, 2CH2), 3.88 (s, 3H, OCH3), 7.97 (s, 1H, H-7)