Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I/[CH:2]=[CH:3]/[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[NH:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4]/[CH:3]=[CH:2]/[N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[CH:6][CH:7]=1
Reactant: c1cc[nH]c1
Reactant: I/C=C/Oc1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C(=C/n1cccc1)\Oc1ccc(-c2ccccc2)cc1
Yield: 86.4 %

Procedure:
The compound 10 was prepared following the procedure described for 5 with 4 (0.2 g, 0.62 mmol, 1 eq), pyrrole (0.062 g, 0.93 mmol, 1.5 eq), Cs2CO3 (0.40 g, 1.2 mmol, 2.5 eq), CuI (0.059 g, 0.31 mmol, 0.5 eq) and L2 (0.060 g, 0.31 mmol, 0.5 eq) at 70° C. for 12 h to give crude product which were purified by silica gel column chromatography using ethyl acetate-hexane (9:95) to afford compound 10 as white crystals (0.14 g, 85%): mp 102-105° C. Olefinic protons coupling on the named compound gave an AB-system with a typical roof effect with peaks centered at 7.04 and 6.99 ppm. 1H NMR (300 MHz, CDCl3): 7.62-7.53 (m, 4H, HAr), 7.48-7.40 (m, 2H, HAr), 7.38-7.31 (m, 1H, HAr), 7.17-7.09 (m, 2H, HAr), 7.04 (distorted d, 1H, J=11.1 Hz, (O)—CH═CH(N)), 6.99 (distorted d, 1H, J=11.1 Hz, (O)—CH═CH(N)), 6.82 (dd, 2H, J1=4.2 Hz, J2=2.2 Hz, CH═CH of pyrrole), 6.28 (dd, 2H, J1=4.2 Hz, J2=2.2 Hz, CH═CH); 13C NMR (75 MHz, CDCl3): 156.8, 140.4, 136.3, 135.0, 128.8, 128.4, 127.1, 126.9, 119.6, 118.3, 116.5, 110.0 ppm; IR (cm−1): 3086, 3034, 2715, 2682, 1659, 1607, 1587, 1517, 1485, 1360, 1326, 1300, 1239, 1229, 1185, 1173, 1119, 1094, 1072, 1056, 1007, 975, 907, 857, 838, 614; HRMS (ESI) Calculated for C18H15NO [M+H]+ 262.1232. Found 262.1233; Elemental analysis calculated for C18H15NO.0.17H2O: C, 81.77; H, 5.85; N, 5.29. found: C, 81.76; H, 5.91; N, 5.03.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:67]2[CH:72]=[CH:71][C:70]([F:73])=[CH:69][CH:68]=2)[N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)=[CH:56][CH:55]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:64]1[CH2:63][CH2:62][N:61]([CH:60]([C:67]2[CH:72]=[CH:71][C:70]([F:73])=[CH:69][CH:68]=2)[C:57]2[CH:56]=[CH:55][C:54]([F:53])=[CH:59][CH:58]=2)[CH2:66][CH2:65]1)=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 95.8 %

Procedure:
N-tert-Butoxycarbonyl-L-phenylalanine (4.60 g, 17.3 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (33 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (6.04 mL, 34.7 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.58 g, 17.4 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (5.00 g, 17.3 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 120 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×120 mL), brine (2×120 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (30% EtOAc in hexanes) to provide 8.88 g (95%) of the pure titled compound as a off-white foam: mp 54-74° C. APCI-MS m/z 536.4 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)#[N:18]
Reactant: Cc1cccc(N)c1
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)c1
Temperature: 95 °C

Procedure:
To a mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (75 mg, 0.28 mmol) in toluene (1.5 mL) and dioxane (0.5 mL) was added m-toluidine (45 mg, 0.42 mmol), Pd(dba)2 (16 mg, 0.028 mmoL), Q-Phos (30 mg, 0.042 mmol) and Cs2CO3 (274 mg, 0.84 mmol). After heating at 95° C. for 15 h, the mixture was filtered, the filtrate was concentrated and purified by column chromatography to give (R)-2-(5-cyano-6-(m-tolylamino)pyrazin-2-ylamino)-4-methylpentanamide.
Reaction SMILES: BrC1SC(Cl)=C(Cl)C=1C(=O)CCl.CC1C=CSC=1.ClCC(Cl)=O.ClCC([C:28]1[C:32]([CH3:33])=[C:31]([C:34](=[O:37])[CH2:35][Cl:36])[S:30][CH:29]=1)=O.ClCC(C1SC=C(C)C=1)=O>C(#N)C.O.CCCCCC.C(OCC)(=O)C>[Cl:36][CH2:35][C:34]([C:31]1[S:30][CH:29]=[CH:28][C:32]=1[CH3:33])=[O:37]
Reactant: Cc1c(C(=O)CCl)csc1C(=O)CCl
Agent: Cc1ccsc1
Agent: Cc1csc(C(=O)CCl)c1
Agent: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccsc1C(=O)CCl
Yield: 5 %

Procedure:
General procedure described for compounds 1 and 2 starting from 3-methylthiophene and chloroacetyl chloride. Three products were isolated by column chromatography column (hexane:ethyl acetate 3:1). Compound 16: yield 69%, m.p.: 155-156° C., 1H-NMR (CDCl3): δ8.2 (s, 1H, Ar), 4.54 (s, 2H, CH2), 4.52 (s, 2H, CH2), 2.8 (s , 3H, CH3); 13C-NMR (CDCl3): δ187.2 (CO), 185.1 (CO), 148.2 (C—CO), 139.1 (C—CO), 137.9 (CH), 48.1 (CH2), 47.3 (CH2), 16.0 (CH3); M/z (EI): 254, 252, 250 (M+, 1, 6, 9%), 203, 201 (M-CH2Cl, 47, 100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 99%, r.t.=4.73 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50. Compound 17: yield 8%, m.p.; 76-77° C., 1H-NMR (CDCl3): δ7.6 (s, 1H, Ar), 7.1 (s, 1H, Ar), 4.55 (s, 2H, CH2), 2.3 (s , 3H, CH3); 13C-NMR (CDCl3): δ188.1 (CO), 144.2 (C—CO), 143.2 (C—CH3), 138.9 (CH), 134.9 (CH), 49.4 (CH2), 19.5 (CH3); M/z (EI): 176, 174 (M+, 9, 23%), 125 (M-CH2Cl, 100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=4.56 min, Conditions Acetonitrile/H2O [(0.05% H3PO4+0.04% Et3N)] 50/50. Compound 18 yield 5%, yellow oil, 1H-NMR (CDCl3): δ7.44 (d, J=4.9 Hz, 1H, Ar), 7.0 (d, J=4.9 Hz, 1H, Ar), 4.55 (s, 2H, CH2), 2.3 (s ,3H, CH3); 13C-NMR (CDCl3): δ188.2 (CO), 151.3 (C—CH3), 136.8 (CH), 136.2 (C—CO), 135.0 (CH), 51.5 (CH2), 20.9 (CH3); M/z (EI): 176, 174 (M+, 6, 16%), 125 (M-CH2Cl, 100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 99%, r.t.=3.65 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2].Cl.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C.O>[C:1]([C:3]1[C:8]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: NC1CCOCC1
Reactant: N#Cc1ncc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ncc(F)cc1NC1CCOCC1
Temperature: 115 °C
Yield: 25.3 %

Procedure:
200 mg of 2-cyano-3,5-difluoropyridine, 236 mg of 4-aminotetrahydropyran hydrochloride, 395 mg of potassium carbonate and 173.4 mg of triethylamine in 3 ml of dimethyl sulphoxide are introduced into a 5 ml microwave tube reactor. The mixture is then heated in a microwave for 1 hour at 115° C. The reaction medium is run into 50 ml of water and 50 ml of ethyl acetate. The aqueous phase is re-extracted twice with 25 ml of ethyl acetate. The combined organic phases are washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. After purification by flash chromatography on 25 g of silica gel, elution being carried out with mixtures of ethyl acetate and heptane (40/60 then 60/40 by volume), and the first eluted product being recovered, 80 mg of 2-cyano-5-fluoro-3-(tetrahydropyran-4-yl)aminopyridine are thus obtained in the form of an ecru powder, the characteristics of which are the following:
Reaction SMILES: CS[C:3](=[N:12][CH2:13][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[CH2:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH2:31][C:26]([C:21]3[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=3)([C:27]([F:28])([F:30])[F:29])[CH2:13][N:12]=2)=[CH:5][C:6]=1[CH3:11]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 4-bromo-3-methyl-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (4.40 g, 13.3 mmol) in dry THF (60 mL) was added 2-(3,5-dichlorophenyl)-1,1,1-trifluoro-2-propene (4.35 g, 16.25 mmol) at −7° C. A solution of tetrabutyl ammoniumfluoride (5.32 mL, 1 M in THF, 5.33 mmol) was added at this temperature and the mixture was allowed to warm to room temperature over night. All volatiles were removed in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (4.50 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:15]#[N:16].[OH-].[Na+]>O>[NH2:16][C:15]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C(=O)O)c1ccc(O)c(N)c1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2oc(N)nc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of (2) (630 mg, 1 mmol) in H2O (33 ml) was added BrCN (383 mg, 1.04 mmol) at room temperature. The reaction mixture is stirred for 40 h at room temperature. The reaction mixture is neutralized to pH 6□7 with 40% aq. NaOH and filtered. The solid was recrystallized with 50% aq. MeOH and filtered. The solid is dried under vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[H][H]>O.[Ru]>[C:6]([CH:5]1[CH2:4][NH:3][C:2](=[O:1])[CH2:10][CH2:9]1)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)nc1
Reactant: [H][H]
Agent: [Ru]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1CCC(C(=O)O)CN1
Yield: 72.9 %

Procedure:
To a suspension of 10.0 g of 6-hydroxynicotinic acid in 200 ml water were added 6.5 g of sodium bicarbonate. The resulting solution was subjected to 500 psig hydrogen at 100° C. for 12 hours in the presence of 2.5 g ruthenium on alumina. The catalyst was removed by filtration. The filtrate was acidified to pH 4 with 6N HCl and evaporated to a colorless solid (~15 g ). The solid was treated with 40 ml methanol and filtered to remove most of the sodium chloride. The filtrate was evaporated to give 7.5 g of the title compound: MS m/z 143 (M+); 300-MHz 1H NMR (DMSO-d6) δ1.62-1.77 (m, 1 H), 1.83-1.97 (m, 1 H), 2.00-2.21 (m, 2 H), 2.23-2.35 (m, 1 H), 3.21 (d, J=8 Hz, 2 H), 7, 28 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
Carboxylic acid (76) (53 mg, 0.26 mmol) was coupled to aniline (64) (56 mg, 0.26 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH2:14]1[C:23](=[O:24])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1.O>C(O)(=O)C.C(OC(=O)C)C.CCCCCC.ClCCl>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:22]2/[C:23](=[O:24])[CH2:14][CH2:15][C:16]3[C:21]/2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C1CCc2ccccc2C1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C=C2/C(=O)CCc3ccccc32)cc1
Temperature: 7.5 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
4-methylsulfonylbenzaldehyde (1.0 g, 5.43 mmol) was dissolved in glacial acetic acid (20 ml) and con. Hydrochloric acid (10 ml) was added and cooled at 5-10° C. Then, beta-tetralone (0.72 ml, 5.45 mmol) was dropped slowly and stirred for 3 hours at the same temperature. At room temperature, water (200 ml) and dichloromethane (200 ml) were poured, separated with layers, washed with the saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by performing a silica gel column chromatography (an eluting agent: ethylacetate/n-hexane=2/3, v/v) and 1.32 g of the present compound (productive yield 78%) was obtained as a yellow crystal.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:31])([CH3:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[CH2:23][NH2:24])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:35][C:36](=O)[NH:37][C:38]1[N:39]([CH3:47])[N:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOCC>[Si:1]([O:8][C:9]([CH3:31])([CH3:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[CH2:23][NH:24][C:36]([NH:37][C:38]3[N:39]([CH3:47])[N:40]=[C:41]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:42]=3)=[O:35])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21)O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1cc(F)ccc1Oc1ccc2c(cnn2CC(C)(C)O[Si](C)(C)C(C)(C)C)c1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
A mixture of 2-{1-[2-(tert-butyldimethylsilanyloxy)-2-methyl-propyl]-1H-indazol-5-yloxy}-5-fluorobenzylamine (0.072 g, 0.162 mmol), (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloroethyl ester (0.080 g, 0.24 mmol) and DIEA (0.06 mL, 0.324 mmol) in DMA (3 mL) was heated to 80° C. for 16 hours. The mixture was diluted with ether (60 mL) and washed with water (3×5 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate/hexanes (3:1) to afford 0.084 g of product (83% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C(=O)O)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccnc(C(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 4-tert-butoxycarbonylamino-pyridine-2-carboxylic acid (43) (800 mg, 3.2 mmol) in CHCl3 was added morpholine (0.4 mL, 3.8 mmol), HOBT (857 mg, 6.3 mmol), EDC.HCl (1.2 g, 6.3 mmol) and DIPEA (0.8 mL, 4.8 mmol), and stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with 10% MeOH/CHCl3. The organic layer was washed with water, dried over Na2SO4 and evaporated to give compound 44 (920 mg, 92%) as a white solid; (m/z): 308 [MH]+; 1H NMR (400 MHz, CDCl3): δ 8.40 (1H, d, J=5.6 Hz), 7.57 (1H, d, J=2.0 Hz), 7.54 (1H, d, J=5.6 Hz), 6.98 (1H, br s), 3.79 (4H, m), 3.67-3.66 (4H, m), 1.53 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1CCCc2c(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cccc21
Yield: 72.1 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(4-chlorobenzyl)-piperazine; yield 72.1% of theory; m.p. of the dihydrochloride (recrystallized from 1N hydrochloric acid) 239°C (decomposed);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([NH:17][C:16]1[CH:15]=[C:14]([Cl:13])[CH:20]=[C:19]([Cl:21])[CH:18]=1)=[O:7]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc(Br)cc(Br)c1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Br)cc(Br)c1O
Yield: 44.2 %

Procedure:
Using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.O1CCCC1.[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N#Cc1ccc(N)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: -75 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
2,4,6-trichloro-1,3,5-triazine (0.07440 mol) and tetrahydrofuran (100 ml) were combined and cooled to −75° C. under Ar atmosphere. 4-aminobenzonitrile (0.07440 mol) was added and the solution was stirred for 4 hours at −75° C. Triethyl-amine (0.07440 mol) was added dropwise and the reaction mixture was allowed to warm up slowly to room temperature and stirred for 3 days. After adding 1,4-dioxane (100 ml), the resulting precipitate was collected by filtration, washed with tetrahydro-furan, and dried, yielding 12.74 g 4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]benzonitrile (interm. 1).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH:14]=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2].Cl.O>CO.O1CCOCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:27])([CH3:28])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2cc(CO[Si](C)(C)C(C)(C)C)ccc2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)C=C(n2cc(CO)ccc2=O)c2cc(C#N)ccc2O1
Yield: 94.5 %

Procedure:
In 11.5 ml of methanol, is dissolved 1.16 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 13. Then, 2.87 ml of 4N hydrochloric acid in dioxane is added to the solution at 0° C., and reacted at room temperature for 1.5 hours. After stopping the reaction by adding water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/20 mixture of methanol/methylene chloride as a developing solvent to obtain 0.80 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)c(Br)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
3-Bromo-4-fluorobenzonitrile (10.0 g, 50 mmol, 1 eq) and imidazole (5.1 g, 75 mmol, 1.5 eq) are dissolved in dimethylformamide (100 ml) and carefully admixed with sodium hydride (60% in mineral oil, 3.0 g, 75 mmol, 1.5 eq) under nitrogen at room temperature. The mixture is stirred at 100° C. for 4 hours. After cooling to room temperature, water (10 ml) is added and the mixture is evaporated to dryness. The residue is washed with water and petroleum ether and purified by column chromatography (silica gel, methyl tert-butyl ether/ethyl acetate gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C>[CH3:34][S:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:37])=[O:36]
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.40 mmol of methanesulfonyl chloride in 3 ml of DMF were added. The reaction solution was then stirred at room temperature for a further 6 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:35]3[CH2:36][CH2:37][N:32]([C:28]4[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=4)[CH2:33][CH2:34]3)=[O:16])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: Cc1ccnc(N2CCNCC2)c1
Product: Cc1ccnc(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)c1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(4-methyl-pyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 512.3 ([M+H]+)