Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C@H:20]1[CH2:24][C@@H:23]([CH2:25][OH:26])[C@H:22]([OH:27])[C@@H:21]1[OH:28]>CN(C)C=O.O>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:19][C@H:20]2[CH2:24][C@@H:23]([CH2:25][OH:26])[C@H:22]([OH:27])[C@@H:21]2[OH:28])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc(N[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 4-amino-6-chloro-5-nitropyrimidine (320 mg, 1.83 mmol) in N,N-dimethyl formamide (5 mL) and triethylamine (512 μL, 3.67 mmol) was added (1S,2R,3S,5S)-3-Amino-5-hydroxymethyl-cyclopentane-1,2-diol (293 mg, 2.02 mmol). The mixture was stirred at room temperature and monitored by thin layer chromatography until starting material was no longer detected. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (2×10 mL). The organic extract was washed with saturated aqueous sodium chloride (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was recrystallized from hot methanol/water to give a 315 mg of (1S,2R,3S,5S)-3-(6-amino-5-nitro-pyrimidin-4-ylamino)-5-hydroxymethyl-cyclopentane-1,2-diol as a yellow solid.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Br:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([OH:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1>C(O)C>[NH2:15][C:9]1[CH:8]=[C:7]([Br:6])[C:12]([F:13])=[CH:11][C:10]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)c(F)cc1O
Temperature: 85 °C

Procedure:
Tin(II) chloride dihydrate (16.83 g, 74.6 mmol) was added to a solution of 4-bromo-5-fluoro-2-nitrophenol (4.4 g, 18.64 mmol) in ethanol (180 mL). The mixture was flushed with nitrogen and heated to 85° C. (oil bath temperature) for 1 day. The mixture was diluted with ethyl acetate (500 mL), saturated aqueous sodium bicarbonate (200 mL) was added with vigorous stirring. The mixture was filtered through celite and the celite pad was repeatedly washed with ethyl acetate. The two phases were separated and the organic phase was washed with brine. The combined aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over MgSO4, filtered and concentrated to give 2-amino-4-bromo-5-fluorophenol. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.61 (br. s., 2H) 6.60 (d, J=10.11 Hz, 1H) 6.76 (d, J=7.33 Hz, 1H) 9.69 (br. s., 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[OH:10]O>Cl>[OH:10][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9]
Reactant: OO
Reactant: O=Cc1cnccc1Cl
Agent: Cl
Product: O=Cc1cnccc1O
Yield: 80 %

Procedure:
Following the procedure described in MARSAIS et al. (J. Het. Chem., vol. 25, p. 81-87, 1988), compound 2 is heated for 6 h in an aqueous solution of 3 N HCl containing several drops of 3% H2O2, in order to obtain 4-hydroxypyridine-3-carboxaldehyde 4 as a colorless solid (>80%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Product: CC(C)Nc1ccc(C#Cc2cc(-c3nc4ccc(CN5CCN(C)CC5)cc4[nH]3)ccc2Cl)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a khaki solid. Mp:127-128° C.; 1H NMR (300 MHz, CDCl3) δ: 8.11-8.13 (1 H, d, J=6.0 Hz), 7.82 (1 H, s), 7.64 (2 H, m), 7.53 (1 H, s), 7.35-7.38 (1 H, d, J=9.0 Hz), 7.29-7.32 (1 H, d, J=9.0 Hz), 6.66-6.69 (1 H, d, J=9.0 Hz), 5.22 (1 H, s), 4.12-4.14 (1 H, m), 3.62 (2 H, s), 2.51 (8 H, brs), 2.31 (3 H, s), 1.25-1.31 (6 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H31ClN7: 500.2324. found: 500.2313.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19](Cl)=[O:20])=[CH:16][C:15]=2[CH:22]=1.O>C1COCC1.C(OCC)(=O)C>[CH3:3][C:4]1[N:5]([C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([Br:10])=[CH:22][C:15]=3[CH:16]=2)=[O:20])[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1cc2cc(Br)ccc2o1
Reactant: Cc1ccc(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C)n1C(=O)c1cc2cc(Br)ccc2o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
0.3 g of sodium hydride (60% suspension in paraffin oil) is introduced into 10 ml of THF and 0.5 mL [sic] of 2,5-dimethylpyrrole in 10 ml of THF is added dropwise (5 minutes). After stirring at 50° C. for 1 hour, a reddish suspension is present. 1.3 g of 5-bromobenzofuran-2-carbonyl chloride in 10 ml of THF is [sic] added dropwise at 25° C. (5 minutes) and the mixture is subsequently stirred for 2 hours. The addition of 100 ml of completely deionized water and 100 ml of ethyl acetate follows. The separated organic phase was additionally washed 2× with 100 ml of water and concentrated in vacuo. After chromatography on silica gel (eluent heptane/ethyl acetate 4:1), the residual oil gives 700 mg of yellow crystals (yield 44%), m.p. 115-116°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16]([F:21])([F:20])[CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:22][S:23]([NH2:26])(=[O:25])=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16]([F:21])([F:20])[CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product from step 3, methanesulfonamide (32 mg), HBTU (86 mg), and DIPEA (0.18 mL) in dichloromethane (1.7 mL) was stirred at rt for 16 hr. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine, and dried (Na2SO4). The crude was purified with HPLC. LCMS (Method D): RT=5.35 min, m/z: 400.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.14 (d, J=12.3 Hz, 1H), 4.13-3.98 (m, 2H), 3.13 (s, 3H), 2.18 (s, 1H), 2.04 (s, 2H), 1.90-1.56 (m, 4H), 1.55-1.39 (m, 1H), 1.19 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[NH:15][C:14](=[O:20])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[F:29][C:30]([F:42])([F:41])[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CCOC(C)=O.O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[NH:15][C:14](=[O:20])[CH:13]=[C:12]3[NH:40][CH:37]2[CH2:38][CH2:39][N:34]([S:31]([C:30]([F:41])([F:42])[F:29])(=[O:33])=[O:32])[CH2:35][CH2:36]2)=[CH:23][CH:24]=1
Reactant: NC1CCN(S(=O)(=O)C(F)(F)F)CC1
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2[nH]1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=c1cc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2[nH]1
Temperature: 95 °C

Procedure:
A mixture of 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinolin-2(1H)-one (48 mg, 0.0892 mmol), 1-((trifluoromethyl)sulfonyl)piperidin-4-amine (26.4 mg, 0.0981 mmol), Pd2(dba)3 (8.2 mg, 0.00892 mmol), dppf (14.8 mg, 0.0268 mmol), Cs2CO3 (72.7 mg, 0.223 mmol) and 1,4-dioxane (0.9 mL) was heated under argon to 95° C. overnight. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (40-50% EtOAc/hexanes) chromatography to yield 6-(bis(4-chlorophenyl)methyl)-8-bromo-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[Cu][C:22]#[N:23].CN1CCCC1=O.C(O)(=O)C>C(OCC)(=O)C>[Cl:20][C:18]1[CH:19]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:17]=1)[C:22]#[N:23]
Reactant: N#C[Cu]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a round bottom flask charged with 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (3.00 g, 8.14 mmol) and copper (I) cyanide (7.29 g, 81.0 mmol) was added N-methylpyrrolidinone (25 mL). This suspension under N2 was placed in an oil bath at 175° C. After 5 hours the reaction mixture was allowed to cool to room temperature. Glacial acetic acid (30 mL) was added to the mixture and stirred for 10 minutes. The mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth and the pad was washed with ethyl acetate (100 mL). The filtrate was washed with water (3×100 mL) and brine (2×100 mL). The organic fraction was dried (Na2SO4), filtered and the solvent was removed under reduced pressure to yield a solid. This was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 120 gram column, eluting with 0-5% methanol in CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 12.70 (s, 1H), 7.76-7.72 (m, 1H), 7.62-7.56 (m, 2H), 7.54-7.52 (m, 1H), 6.48 (d, J=6.8 Hz, 1H). LRMS (M+1)=314.87.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[C:1]([C:3](=[CH:12][NH:22][C:21]1[CH:23]=[CH:24][C:18]([C:17]([F:25])([F:26])[F:16])=[CH:19][CH:20]=1)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(C(F)(F)F)cc1
Yield: 90.8 %

Procedure:
A mixture of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (10 g) and 45 ml of ethanol is heated to affect dissolution. Then 8.12 g of p-trifluoromethylaniline in 10 ml of ethanol is added and the mixture heated at reflux for 45 minutes. The mixture is cooled and filtered to give 14.01 g of α-cyano-β-(4-trifluoromethylanilino)-N-ethoxycarbonylacrylamide, which is added to about 60 ml of tetralin and heated at reflux for several hours. On formation of precipitate, the mixture is allowed to cool and then filtered, washed with ether, to yield 5-cyano-1-(4-trifluoromethylphenyl)uracil, m.p. 230.5°-231.5°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH3:9].[C:11]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:23][CH2:22]1)=[O:19].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:29](=[O:30])[CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:18](=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:22][CH2:23]1
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CNCCCC(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 127.4 %

Procedure:
To a stirred mixture of 4-methylaminobutyric acid methyl ester hydrochloride (546 mg, 3.26 mmol) and 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (1.20 g, 3.26 mmol) in DCM (15 mL) was added N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.36 g, 3.58 mmol) followed by N,N-diisopropylethylamine (1.42 mL, 8.15 mmol). LC-MS (Method 2-90) showed product was present (Rt 3.11 min; m/z 482.4 [M+H]+). Water and DCM were added and the layers were separated. The organic layer was washed with water (2×) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.0 g, 100% yield) as a light yellow oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-].[CH3:23][CH2:24][O:25][C:26]([CH3:28])=[O:27]>C1COCC1.CCCCCC.O>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]([CH2:28][C:26]([O:25][CH2:24][CH3:23])=[O:27])([OH:20])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of DIPA (3.1 mL) in THF (30 mL) was added dropwise a 2.6 M solution (8.6 mL) of n-butyl lithium in hexane at −70° C. After stirring at 0° C. for 40 minutes, EtOAc (2.3 mL) was added dropwise thereto at −70° C., followed by stirring for 5 minutes. A solution of 1-benzylazepan-4-one (3.6 g) in THF (10 mL) was added dropwise thereto, followed by stirring for 40 minutes. To the reaction mixture was added a saturated aqueous NH4Cl solution, followed by addition of water and extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH: aqueous ammonia) to obtain ethyl (1-benzyl-4-hydroxyazepan-4-yl)acetate (5.0 g) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:27][NH:28][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc2nc(Nc3nc4cc(C(=O)O)ccc4n3C)sc2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C)cc3s1)n2C
Yield: 73.8 %

Procedure:
2-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (26 mg) was prepared by following General Procedure F using 2-(6-methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 353. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (m, 1H), 8.00 (br, 1H), 7.66 (d, 1H), 7.55 (s, 2H), 7.38 (m, 2H), 7.14 (d, 1H), 3.63 (s, 3H), 2.87 (d, 3H), and 2.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11]([OH:14])(=[O:13])=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(NC2CCCCC2)c(S(=O)(=O)O)c1

Procedure:
To 4-chloro-3-sulphonitrobenzene (130 g) in water (2 liters) was added cyclohexylamine (75 ml) and sodium carbonate (26.5 g). The reaction mixture was heated at 90° for 10 hours, cooled and the solid so formed isolated by filtration to give 4-cyclohexylamino-3-sulphonitrobenzene (120 g).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([O:34]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:26]=2)=[CH:21][CH:20]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10].O.C(OCC)(=O)C>CN(C)C=O>[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:34])[CH:26]=2)=[CH:23][CH:24]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Reactant: CCCCCCCN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
0.31 mL (2.10 mmol) of heptylamine is added to a solution of 0.51 g (1.05 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate in 15 mL of dimethylformamide. The tube is sealed and rapidly placed in an oil bath preheated to 80° C. The reaction mixture is stirred at 80° C. for 1 hour 30 minutes. After cooling, the reaction is worked up by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 75/25 heptane/ethyl acetate mixture to give 0.38 g (77%) of ethyl (Z)-2-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:20])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])[C:3](O)=[O:4].[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.CCN(CC)CC.[NH4+].[Cl-]>O=S(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]([F:20])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])[C:3]([NH:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=1)=[O:4]
Reactant: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)O)ccc21
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)C(F)(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Difluoro-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetic acid 16 (306 mg, 1.08 mmol) was dissolved in SOCl2 and two drops of DMF were added at 0° C. The mixture was stirred at 0° C. for 30 min then evaporated and the product was dissolved in CH2Cl2 (7 mL). B) Methyl 4-(aminomethyl)benzoate SLA 07006 (179 mg, 1.08 mmol) and DMAP (14 mg, 0.11 mmol) were dissolved in CH2Cl2 (7 mL) and Et3N (1.5 mL) at 0° C. A) was added at 0° C. via syringe in B) and the resulting mixture was stirred at 0° C. for 10 min and abandoned at RT for 1 h. Aqueous NH4Cl 5% (100 mL) was added and the mixture extracted with EtOAc (3×50 mL). The organic layer was washed with NaHCO3 5% (3×100 mL) and brine (3×100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography using as eluent cyclohexane:EtOAc=9:1. Methyl 4-((2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)methyl)-benzoate 21 was obtained (0.27 g, 58% yield) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]([F:46])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:44][S:41]([C:38]3[CH:39]=[CH:40][C:35]([O:34][C:33]([F:32])([F:45])[F:46])=[CH:36][CH:37]=3)(=[O:42])=[O:43])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-[(trifluoromethyl)oxy]benzenesulfonamide: 1H-NMR (CDCl3) δ 7.98 (2H, d, J=9.1 Hz), 7.47-7.21 (11H, m), δ 12 (1H, br.s), 3.50-3.43 (2H, m), 2.85 (2H, t, J=6:5 Hz). 2.32 (3H, s), 2.23 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=3)=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NCc1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
50.0 mg (0.170 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 32.8 mg (0.187 mmol) of 3-trifluoromethylbenzylamine are placed in 2 ml dimethylformamide and treated with 27.6 mg (0.204 mmol) of HOBt. After 10 mins' stirring, 42.4 mg (0.221 mmol) of EDC hydrochloride are added and the mixture stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1) and thus yields 76 mg (99% of theory) of the target compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N:11]=[C:12]=[S:13])[CH2:4][CH2:3]1.C(Cl)Cl.[CH3:17][NH2:18]>C(O)C>[CH3:17][NH:18][C:12]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[S:13]
Reactant: CN
Reactant: O=C1CCC(N=C=S)c2ccsc21
Solvent: CCO
Solvent: ClCCl
Product: CNC(=S)NC1CCC(=O)c2sccc21

Procedure:
A mixture of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylisothiocyanate (5.0 g) and methylene chloride (100 ml) is stirred and a saturated solution of methylamine in ethanol (15 ml ethanol saturated with methylamine) added. The mixture is stirred for 15 hours then heated at reflux for 2 hours, cooled and evaporated to dryness in vacuo. The residue is triturated with water, the title thiourea collected and dried.