Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.C([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])(OC(C)(C)C)=O>>[NH2:31][CH:32]([CH3:33])[C:34]([N:12]1[CH2:13][CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[CH2:9]2)[CH2:11]1)=[O:35]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: CC(N)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 19 and 20, with the exceptions that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that N-Boc alanine was used instead of N-Boc glycine.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7]1)(=O)=O.[CH:17]1([CH2:20][NH:21][C:22](=[O:42])[CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30](O)[CH:31]=3)[N:26]=[C:25]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH:17]1([CH2:20][NH:21][C:22](=[O:42])[CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:5][C@H:6]4[CH2:10][CH2:9][C@H:8]([N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[CH2:7]4)[CH:31]=3)[N:26]=[C:25]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:18][CH2:19]1
Reactant: O=C(Cn1c(-c2ccccc2)nc2ccc(O)cc2c1=O)NCC1CC1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](N2CCCCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cn1c(-c2ccccc2)nc2ccc(O[C@H]3CC[C@H](N4CCCCC4)C3)cc2c1=O)NCC1CC1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
A mixture of crude (1S,3R)-3-piperidin-1-ylcyclopentyl methanesulphonate (INTERMEDIATE XII.1) (90 mg, 0.4 mmol), N-cyclopropylmethyl-2-(6-hydroxy-4-oxo-2-phenyl-4H-quinazolin-3-yl)acetamide (INTERMEDIATE IV.6) (71 mg, 0.2 mmol) and Cs2CO3 (326 mg, 1.0 mmol) in DMSO (0.3 mL) was heated at 80° C. for 16 h. The mixture was then cooled and diluted with water. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with methanol:dichloromethane (1:9, v/v) as eluent to afford N-cyclopropylmethyl-2-[4-oxo-2-phenyl-6-((1S,3S)-3-piperidin-1-ylcyclopentyloxy)-4H-quinazolin-3-yl]acetamide (EXAMPLE 5a) (14 mg, 0.029 mmol, 14%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25]OS(C(F)(F)F)(=O)=O)[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(#N)C.O>[C:11]([O:15][C:16](=[O:17])[NH:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([CH2:25][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[N:4]2)[CH2:23][CH2:24]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1n[nH]c(C)c1C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(=O)(=O)C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1nn(C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3,4,5-trimethyl-1H-pyrazole (84 mg, 0.761 mmol) in dry acetonitrile (4 mL) at room temp is added sodium hydride (33 mg of a 60% dispersion on mineral oil, 0.83 mmol). The mixture is stirred at room temp for 10 minutes and then treated with a solution of trans-trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (step 1) (250 mg, 0.692 mmol) in dry acetonitrile (3 mL). The reaction mixture is stirred at room temp for 17 hours. The mixture is diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The EtOAc extracts are combined, washed with brine (20 mL), dried (MgSO4), filtered and evaporated to give the title compound as a colourless oil. This is used in the next step without further purification; MS m/z 322.4 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][CH2:10][N:11]3[C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[CH3:28])=[N:4][N:3]=[N:2]1.Br[CH2:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][CH2:17][C:16]([N:11]1[C:12]2[C:7](=[C:6]([C:5]3[N:4]=[N:3][N:2]([CH2:31][C:32]4[CH:33]=[C:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH:35]=[CH:36][CH:37]=4)[N:1]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn[nH]4)cccc32)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn(Cc5cccc(NC(=O)OC(C)(C)C)c5)n4)cccc32)c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
A mixture of 1-(5-(1H-tetrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one (0.16 g, 0.409 mmol), tert-butyl 3-(bromomethyl)phenylcarbamate (0.152 g, 0.531 mmol) and K2CO3 (0.113 g, 0.817 mmol) in DMF (1 mL) was stirred at 80° C. for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (96 mg, 40% yield). LCMS, [M+H]+=597.4.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH:38]2[CH2:40][CH2:39]2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH:38]1([NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH2:40][CH2:39]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 568.0 [(M-H−]; mp 232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]([CH2:12][C:13]([OH:15])=O)[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[Li].[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][C:22]([CH:25]([NH:32][CH3:33])[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>CC#N.O.CN(C=O)C>[C:19]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:24]=[CH:23][C:22]([CH:25]([N:32]([CH3:33])[C:13](=[O:15])[CH2:12][N:7]2[C:6]3[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)OCC(=O)N2CC(=O)O
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OCC(=O)N2CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
[7-(methyloxy)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetic acid, lithium salt (106 mg, 0.44 mmol), [1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (122 mg, 0.44 mmol), triethylamine (91 uL, 0.66 mmol), and (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP Reagent, 232 mg, 0.524 mmol) were added in that order to a 4 mL screw capped vial that contained 1 mL of anhydrous DMF. The reaction mixture was stirred for 20 hours at room temperature, after which time HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that the reaction was complete. The solvent was removed under vacuum and the residue was dissolved in 2 mL of DMSO, filtered through a 0.2 um PTFE Acrodisk, and purified by reverse-phase HPLC (Phenomenex C-18, 50×100 mm, 80 mL/min, A: acetonitrile (0.1% TFA) B: water (0.1% TFA), A: 15 to 98% over 20 min, UV detection at 214 nm) to give the title compound (123 mg, 0.246 mmol, 56%) as the TFA salt in the form of an off-white solid. MS (ES) m/e 501 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([CH:28]1[CH2:32][C:31](=[O:33])[O:30][C:29]1=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:21]([CH:28]([CH2:32][C:31]([NH:1][C:2]1[CH:3]=[C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)[CH:17]=[CH:18][C:19]=1[F:20])=[O:33])[C:29]([OH:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CC(Cc2ccccc2)C(=O)O1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: Cc1ccccc1
Product: O=C(CC(Cc1ccccc1)C(=O)O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.135 g, 0.5 mmol; prepared in a manner similar to that described in Example 23), 3-benzyldihydrofuran-2,5-dione (0.095 g, 0.5 mmol) and toluene (8 ml) was heated under reflux for 1 hour, allowed to stand at ambient overnight, then heated under reflux for a further 6.5 hours and allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with hexane (10 ml) and dried in vacuo to give 2-benzyl-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid (0.156 g) as an off white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 2.2–2.95 (m 5H) (—CH2CH(CO2H)CH2Ph), 4.2 (s, 2H) (ArCH2—), 6.9–7.25 (m, 7H) (7×ArH), 7.6–7.9 (m, 4H) (4×ArH), 8.15 (d, 1H) (ArH), 9.65 (s, 1H) (chain CONH), 12.2 (s, 1H) (—CO2H), 12.5 (s, 1H) (ring CONH).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:51]=[C:52]([S:57](Cl)(=[O:59])=[O:58])[CH:53]=[CH:54][C:55]=1[Cl:56]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([C:52]1[CH:53]=[CH:54][C:55]([Cl:56])=[C:50]([Cl:49])[CH:51]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 3,4-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:28])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:5])C.Cl>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[F:27][C:21]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][C:18]([C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([CH:7]3[CH2:8][CH:6]3[C:4]([OH:5])=[O:3])[CH:10]=2)[NH:15][CH:16]=1)=[O:28]
Reactant: CCOC(=O)C1CC1c1cnc2[nH]cc(C(=O)Cc3cccc(F)c3F)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(C3CC3C(=O)O)cc12

Procedure:
2-{3-[(2,3-Difluoro-phenyl)-acetyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-cyclopropanecarboxylic acid ethyl ester, (130 mg, 0.33 mmol, was dissolved in 1 mL ethanol and 1 mL 10% potassium carbonate solution. The mixture was heated to reflux for ˜16 hours. The reaction was then acidified with 6N HCl to a pH ˜4-5 and extracted with dichloromethane. The essentially pure 2-{3-[(2,3-Difluoro-phenyl)-acetyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-cyclopropanecarboxylic acid was used without further purification in the next step. MS ES+ 357.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[N:12][N:13](C(OC(C)(C)C)=O)[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[N:12][NH:13][C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc(CSc2ccc(Cl)cc2)cc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(CSc2ccc(Cl)cc2)cn[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of tert-butyl 4-((4-chlorophenylthio)methyl)-6-oxopyridazine-1(6H)-carboxylate Part C (137 mg, 0.34 mmol) in CH2Cl2 (5 mL) was added TFA (1.50 mL, 19.41 mmol). The mixture was stirred at RT for 15 min before being concentrated. The crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product) to afford 5-((4-chlorophenylthio)methyl)pyridazin-3(2H)-one 7D (81 mg, 81% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 7.76 (1H, d, J=2.01 Hz), 7.27 (4H, s), 6.56 (1H, s), 3.82 (2H, s).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[Cl-:14]>>[Cl:14][CH2:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Cc1nccc(C(F)(F)F)c1CO
Reactant: [Cl-]
Product: Cc1nccc(C(F)(F)F)c1CCl

Procedure:
3-Hydroxymethyl-2-methyl-4-trifluoromethylpyridine from step 1 above was converted to the chloride using the procedure given in step 2 of Example 3. The crude 3-chloromethyl-2-methyl-4-trifluoromethylpyridine was purified by pressurized silica gel column chromatography using 95:5 hexane:EtOAc as eluant. 3-Chloromethyl-2-methyl-4-trifluoromethylpyridine was obtained as a white solid (TLC Rf = 0.45 (9:1 hexane:EtOAc)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH2:20]>C(O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([NH2:19])=[O:20])[CH2:11][CH2:12][S:13](=[O:17])(=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Reactant: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1

Procedure:
A solution of 4-(4-nitro-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (as prepared in the previous step) in ethanol and water is treated with NaBO3 (Synthetic Communications, 20(4), 563-71, (1990)). The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:5]=1[CH3:12]>C(Cl)(Cl)(Cl)Cl.[W]>[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:5]=1[CH2:12][Br:1]
Reactant: Cc1c(F)ccc(F)c1Cl
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(F)c(CBr)c1Cl
Temperature: 0 °C
Yield: 81.9 %

Procedure:
A solution of bromine (24.4 g) in carbon tetrachloride (50 ml) was added slowly over a period of 2 hours 45 minutes to a vigorously stirred solution of 2-chloro-3,6-difluorotoluene (24.4 g) in carbon tetrachloride (150 ml) irradicated by a 200 watt tungsten lamp maintained at 0° C. The solvent was removed by evaporation under reduced pressure and the residual oil distilled to yield 2-chloro-3,6-difluorobenzyl bromide (29.7 g) b.p 96°-101°/0.7 cm Hg
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].O.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)ccc1Cl

Procedure:
4-Chloro-3-hydroxybenzoic acid (1.00 g, 5.80 mmol) was suspended in acetic anhydride (11 ml) and heated to reflux for 3 h. After cooling, water (11 ml) was added and the mixture was refluxed again for 1 h. After cooling, crystals formed overnight which were collected by suction filtration and dried in vacuo to yield the title compound (630 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:31][C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[O:24][CH2:23]4)=[CH:18][CH:17]=3)[CH2:14][C:9]2=[N:8][N:7]=1)=O)C.[NH3:32].CO>>[O:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[O:31][C@@H:22]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][N:13]3[CH2:12][CH2:11][N:10]4[C:6]([C:4]([NH2:32])=[O:3])=[N:7][N:8]=[C:9]4[CH2:14]3)=[CH:21][CH:20]=2)[CH2:23]1
Reactant: N
Reactant: CCOC(=O)c1nnc2n1CCN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)C2
Solvent: CO
Product: NC(=O)c1nnc2n1CCN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)C2
Temperature: 25 °C

Procedure:
A solution of compound 240 (6.98 g, 16.6 mmol) in a solution of ammonia in methanol (102 mL, 7 mmol) is stirred at 90° C. in a pressure tube for 22 h. The mixture is gradually cooled to rt. The mixture is filtered, and the solids are washed with chilled methanol then air dried to give the title product 241. (LC/MS method 16: ES+ m/z 393.3 [M+H]+, Rt=2.60 min)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18](O)=[O:19])=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:21][N:22](C=O)C.CCN(C(C)C)C(C)C.Cl.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2]1[C:3]([C:18]([NH:22][CH3:21])=[O:19])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)nc1C(=O)O
Reactant: CN(C)C=O
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1nc(C2CCC3(CC2)OCCO3)ccc1N
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A solution of 3-amino-6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-2-carboxylic acid (Compound 232D, 0.229 g, 0.823 mmol) in DMF (2.0 mL, 26 mmol) was cooled to 0° C. treated with DIPEA (2.87 mL, 16.4 mmol), methylamine hydrochloride (0.556 g, 8.23 mmol) and TBTU (0.396 g, 1.23 mmol). The flask was sealed and the mixture was allowed to come up to RT and stir overnight. The DMF and DIPEA were removed in vacuo and the residue was taken up in water and extracted multiple times with EtOAc and DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to a yellow oil. This was purified on an ISCO Combiflash unit using 0-4% MeOH/DCM to isolate 145 mg of an oil. 1H NMR (400 MHz, DMSO-d6) δ 1.51-1.87 (m, 8H), 2.54-2.64 (m, 1H), 2.79 (d, J=4.80 Hz, 3H), 3.88 (s, 4H), 6.62 (s, 2H), 7.05-7.10 (m, 1H), 7.11-7.16 (m, 1H), 8.29 (d, J=4.55 Hz, 1H). MS (ES+):m/z=292.01 (100) [M+1]. HPLC: tR=3.31 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[CH3:15][NH:16][CH3:17]>CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>[CH3:15][N:16]([CH3:17])[C:12](=[O:14])[CH2:11][C:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1ccc(CC(=O)O)cc1
Reaction time: 3 h
Yield: 8.5 %

Procedure:
N,N'-Carbonyldiimidazole (11.4 g) was added to a stirred solution of 1,4-phenylenediacetic acid (11.4 g) in dry dimethylformamide (300 ml) under an atmosphere of nitrogen. The mixture was stirred at 20° for 2 h as dimethylamine gas (about 10 g) was bubbled through. The reaction mixture was then stirred at 20° for 3 h and evaporated in vacuo to leave a brown oil which was diluted with saturated K2CO3 solution (50 ml). The resulting mixture was evaporated in vacuo to leave an off-white solid which was triturated with EA (2×200 ml). The organic phase was discarded and the aqueous phase was acidified (pH1) with 5M hydrochloric acid to precipitate an off-white solid which was triturated with absolute ethanol (25 ml) and filtered to give the title compound (1.1 g) as a fine white solid m.p. 163°-165° (softening at 160°).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Clc1ccccc1N1CCNCC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4Cl)CC3)nc2c1
Yield: 89 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 3.09-3.16 (m, 4H), 3.79-3.90 (m, 6H), 4.10-4.16 (m, 4H), 7.00-7.30 (m, 7H), 7.38-7.66 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19](O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].O1CCCCC1[O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[CH2:44][O:45][NH2:46].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:46][O:45][CH2:44][C:43]2[CH:47]=[CH:48][CH:49]=[C:41]([OH:40])[CH:42]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:31])=[O:32]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Reactant: NOCc1cccc(OC2CCCCO2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(O)c2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To 400 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-pyran-2-yl oxy)benzyl]hydroxylamine, 159 mg of HOBt, and 243 mg of WSC, followed by stirring at room temperature for 3 hours. The reaction solution was added with ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue was added methanol, and concentrated hydrochloric acid was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 1 hour. The precipitated crystal was collected by filtration to obtain 275 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.