Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:4]=1[CH:5]=[CH:6][CH:7]([S:21]([CH:24]([CH:38]=[CH:39][C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([NH:33][C:34](=[O:37])[CH2:35]Cl)[CH:26]=1)(=[O:23])=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:20])[CH2:18]Cl)[CH:9]=1.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:21]([CH:24](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([NH:33][C:34](=[O:37])[CH2:35][N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)[CH:26]=1)(=[O:23])=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:20])[CH2:18][N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)[CH:9]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(NC(=O)CCl)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CCl)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)CN3CCN(C)CC3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CN3CCN(C)CC3)c2)c(OC)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 2,4,6-trimethoxystyryl-3-(chloroacetamido)-4-methoxybenzyl sulfone (example 7) (10 mmol), N-methylpiperazine (10 mmol) and potassium carbonate (10 mmol) in dimethylformamide (20 mL) was refluxed for 5 h at 80° C. The reaction mixture was cooled to room temperature, and water was added. The solution was then extracted with ethyl acetate and organic layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent in a rotary evaporator gave (E)-2,4,6-trimethoxystyryl-3-[(4-methylpiperazinyl)acetamido]-4-methoxy-benzylsulfone in 87% yield. m.p. 176-178° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][C:23]1[CH:24]=[C:25](OB(O)O)[CH:26]=[CH:27][CH:28]=1)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][CH:24]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOc1cccc(OB(O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Reaction time: 17 h
Yield: 65 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-propoxyphenylboric acid (536 mg), cupric acetate (271 mg), MS 4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 17 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) as a light yellow, oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a well stirred solution of 5-(benzyloxy carbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine (17.0 g, 44.04 mmol) and 4-dimethylaminopyridine (6.99 g, 57.25 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature. The reaction mixture was stirred for 12 hours and then the solvent was removed in vacuo. The residue was purified by chromatography (SiO2, EtOAc/Hexane 10-30%) to get 5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a colorless viscous oil(12.6 g, 50%). 1H NMR (CDCl3): δ 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, δA =5.08, δB =5.20, J=12.3 Hz, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:19])C(Cl)(Cl)Cl)[C:9]([OH:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([C@H:8]1[C:9]([CH3:11])([CH3:10])[O:12][C:14](=[O:19])[NH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)[C@H](Cc1ccccc1)NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(C)OC(=O)N[C@H]1Cc1ccccc1
Yield: 77.3 %

Procedure:
To a solution of (9) (4.093 g, 12.63 mmol) in ethanol (280 ml) was added potassium carbonate (0.872 g, 6.32 mmol) and the solution was refluxed for 30 minutes. After concentration in vacuo, dichloromethane was added and the mixture was washed with saturated aqueous sodium chloride solution. Concentration in vacuo gave crude crystalline solid which was purified by recrystallisation in diethyl ether/40-60 petroleum ether to give the title compound (10) (2.003 g, 77%); mp 59° C.; νmax (CHCl3) 1753 cm-1 ; [α]D25 (c 0.6 in CHCl3)=-103.5; (Found: C, 70.52; H. 7.09; N, 6.52. C12H15NO2 requires C, 70.22; H, 7.37; N, 6.82%); δH (200 MHz; CDCl3) 1.45 (6H, s, C(CH3)2), 2.64-2.88 (2H, m, CH2Ph), 3.72 (1H, dd, J=4.5 and 10.9, CHCH2), 5.45 (1H, s, NH), 7.18-7.38 (5H1 m, ArCH); δC (125 MHz; CDCl3) 21.82 (CH3), 27.42 (CH3), 36.99 (CH2), 63.08 (CH), 83.28 (C), 127.32 (CH), 129.08 (CH), 129.22 (CH), 137.19 (C), 158.47 (CO); m/z (CI+, NH3) 206 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[F:12]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([NH2:9])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(F)c(Cl)cc1F

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (XXXVIII) (17.5 g) was dissolved in acetic acid (150 ml) in a 1L 3-neck round bottom flask equipped with cooling condenser. To it iron powder (35.0 g) was added slowly while the solution was stirred by an overhead stirrer. The reaction was exothermic which occurred in less than 30 min and generated much heat that was absorbed by a cooling bath. After that, ethyl acetate (300 ml) was added and the mixture filtered. The solution was washed with water and dried over sodium sulfate. The product was purified by column chromatography (silica gel, hexane:ethyl acetate, 4:1) (14.3 g). 1H NMR (CDCl3, 300 MHz) 3.89 (2H, br), 6.56 (1H, m), 7.02 (1H, m) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[S:5]1(=[O:20])=[O:19].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][N:4]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[S:5]2(=[O:20])=[O:19])[CH2:34][CH2:33]1
Reactant: O=S1(=O)c2ccccc2C(c2ccccc2)N1CCCl
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2C(c2ccccc2)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
The procedure is as in Example 1, starting with 2-(2-chloroethyl)-3-phenyl-1,2-benzisothiazole 1,1-dioxide (2.85 g), 4-[(5-fluoro-3-indolyl)methyl]-piperidine (2.15 g) and sodium bicarbonate (2.3 g) in a mixture of dimethylformamide (30 cc) and tetrahydrofuran (20 cc). The mixture is heated to boiling for 48 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with a mixture of ethyl acetate and cyclohexane (80:20 by volume) as eluent, 2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-3-phenyl-1,2-benzisothiazole 1,1-dioxide (2.6 g) is obtained, and is converted to a hydrochloride, m.p. 175° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61][C:62]3[N:63]=[C:6]([C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[O:8][N:65]=3)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc([C@@H]4CCCO4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(S)-Tetrahydrofuran-2-carboxylic acid (75.7 mg, 0.65 mmol), HATU (247 mg, 0.65 mmol), and DIPEA (0.11 mL, 0.65 mmol) were stirred in dry DMF (6 mL) for 1 h before 17 (200 mg, 0.59 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give (S)-1,7-dimethyl-3-(2-methyl-5-(5-(tetrahydrofuran-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A77) as a solid. 1H NMR (400 MHz, d4-MeOH) δ 9.07 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.45 (d, J=4 Hz, 1H), 7.36 (dd, J=8, 4 Hz, 1H), 7.25 (d, J=4 Hz, 1H), 5.10 (dd, J=8, 4 Hz, 1H), 4.03 (dd, J=12, 8 Hz, 1H), 3.96 (dd, J=12, 8 Hz, 1H), 3.83 (s, 3H), 2.85 (s, 3H), 2.41-2.34 (m, 1H), 2.28-2.20 (m, 1H), 2.16 (s, 3H), 2.12-2.03 (m, 2H). MS m/z 417.5, 418.5 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].C(=O)(O)[O-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[CH2:21][N:20]([CH3:26])[CH2:19][CH:18]2[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.Cl>O1CCCC1.O>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[CH2:21][N:20]([CH3:26])[CH2:19][CH:18]2[C:27]1[CH:28]=[C:29]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: NCCCS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCCS(=O)(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-aminopropane-1-sulfonic acid (180 mg, 1.29 mmol, 1.00 equiv) in tetrahydrofuran/water (10/10 mL) with sodium bicarbonate (430 mg, 5.12 mmol). This was followed by the addition of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (500 mg, 1.29 mmol, 0.99 equiv) in several batches. The resulting solution was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The pH value of the solution was adjusted to 6 with 1M hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (500 mg) was purified by preparative HPLC to give 26.7 mg of the title compound (4%) as a TFA salt. 1H-NMR (300 MHz, DMSO, ppm): 10.28 (s, 1H), 7.53˜7.79 (m, 6H), 6.83 (s, 1H), 4.74 (s, 2H), 4.51 (s, 1H), 3.90 (s, 1H), 3.06 (s, 3H), 2.86˜2.93 (m, 2H), 2.33˜2.44 (m, 2H), 1.58˜1.63 (m, 2H). MS (ES, m/z): 493 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2].C(O)(C)(C)C.N.[Li]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(N)c2c1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC1=CCc2cccc(N)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
The product of Example 1D (1.8 g, 9.63 mmol) and tert-butanol (2.13 g, 28.8 mmol) were dissolved in tetrahydrofuran (20 mL) in a 3-neck 1000 mL round-bottom flask, and the solution was cooled to −78° C. Ammonia (˜35 mL) was condensed into the flask, then lithium metal was added (wire, 225 mg, 32.4 mmol) in portions over 10 min. The reaction mixture was stirred at −78° C. for 1 h, quenched with methanol (50 mL) and H2O (50 mL). The reaction was allowed to stir overnight at room temperature to allow NH3 to evaporate, then it was diluted with ethyl acetate (300 mL), washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel, eluting with 15%-25% ethyl acetate-hexanes, to afford the title compound as a brown oil (999 mg, 55%). 1H NMR (DMSO-d6) δ 6.82 (t, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.1 Hz), 6.35 (d, 1H, J=7.5 Hz), 4.80 (s, 2H), 4.78 (t, 1H, J=3.8 Hz), 3.78 (q, 2H, J=7.1 Hz), 3.36 (q, 2H, 4.8 Hz), 3.00 (t, 2H, J=4.9 Hz), 1.26 (t, 3H, J=7.1 Hz); MS (DCI+) m/z 190 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:30]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][O:28][CH3:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(COC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 32 %

Procedure:
A solution of 4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.5 g), benzyl bromide (1.5 mL) and cesium carbonate (4.2 g) in N,N-dimethylacetamide (45 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.8 g, 32%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([O:24]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:23])=O)=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[S:36]1[CH:40]=[N:39][N:38]=[C:37]1[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:41][C:37]4[S:36][CH:40]=[N:39][N:38]=4)(=[O:24])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: COc1nc(Cl)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1nc(Cl)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A vial was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)isoquinoline-6-sulfonate (0.042 g, 0.076 mmol), 1,3,4-thiadiazol-2-amine (8.48 mg, 0.084 mmol), and cesium carbonate (0.074 g, 0.229 mmol). The vial was flushed with Ar (g), then acetonitrile (0.381 ml) was added. The reaction was stirred for four hours at room temperature. The mixture was diluted with EtOAc and 1 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford crude 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide as a yellow solid. (ESI) 470.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][CH2:13][C@H:14]([OH:26])[CH2:15][P:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]2)(=[O:18])[O-:17])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[Li+:27]>C(O)C.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][CH2:13][C@H:14]([OH:26])[CH2:15][P:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:17])[O-:18])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[Li+:27]
Reactant: C[C@@H](NC[C@H](O)CP(=O)([O-])CC1CC=CCC1)c1cccc(C(=O)O)c1
Agent: [Pd]
Agent: [Li+]
Solvent: CCO
Product: C[C@@H](NC[C@H](O)CP(=O)([O-])CC1CCCCC1)c1cccc(C(=O)O)c1
Reaction time: 0.25 h

Procedure:
20 mg of 5% palladium-on-carbon are added to a solution of 0.125 g of lithium 3-{N-[1(R)-(3-carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohex-3-enylmethyl)phosphinate in 5 ml of ethanol and the batch is hydrogenated at room temperature and normal pressure for 15 minutes. The catalyst is filtered off through Celite® and the filtrate is adjusted to a pH of 1 with ethanolic hydrochloric acid. Removal of the solvent and recrystallisation from isopropanol gives lithium 3-{N-[1(R)-(3-carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinate, which is identical with the compound of Example 5(f).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:37]([N:44]1[CH2:49][CH2:48][CH:47](N)[CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[CH2:37]([N:44]1[CH2:49][CH2:48][CH:47]([NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NC3CCN(Cc4ccccc4)CC3)cc21
Reaction time: 18 h
Yield: 97 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 1-benzyl-piperidin-4-yl-amine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-4 as an oil in 97% yield.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1)=[O:24]
Reactant: CSc1ccccc1-c1cc(C=O)c[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)c1ccccc1-c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (200 mg) in ethyl acetate (10 mL) was added 3-chloroperbenzoic acid (238 mg) under ice-cooling. After stirring at room temperature for 1 hr, a saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound as a pale-pink powder (yield 160 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)=[S:24])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccccn2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccccn3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenylthio)pyridine (6.0 mmoles, 1.2 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (6.0 mmoles, 1.4 g) were reacted according to procedure C to yield the title compound, 1.9 g, 72%. Mass spec (FD) 439. Calculated for C19H13ClF3N3 S2 : C, 51.88; H, 2.98, N, 9.55 Found: C, 51.99; H, 3.15; N, 9.63.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:13]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[O:23]=[C:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:24])=[O:2])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1

Procedure:
700 mg (2.15 mmol) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester is mixed in 15 ml of methanol with 2.7 ml of 1N sodium hydroxide solution and refluxed for 1 hour. After the methanol is distilled off in a vacuum, it is diluted with water and shaken once with ethyl acetate. The aqueous phase is mixed with 5 ml of 1 mol citric acid solution and stirred overnight. The solid precipitation is suctioned off and very quickly dried. 600 mg of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid, which is used as a crude product in the next stage, is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>>[C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: C=C1CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 2.5 h

Procedure:
L-aspartic acid, 13.3 parts, was added to 100 parts by volume of 2 N aqueous sodium hydroxide and the resulting solution was cooled to 0°-10° C. in an ice bath. Diketene, 8.4 parts, was added and the resulting two phase mixture was stirred for 2.5 hours at 0°-10° C. The homogeneous solution was washed twice with 100 parts by volume of ether and the aqueous layer was acidified with 16.6 parts by volume of concentrated hydrochloric acid. This solution was extracted three times with 100 parts by volume of ethyl acetate, the combined extracts were dried over sodium sulfate, filtered and the solvent evaporated under vacuum at 25°-30° C. to give 2.3 parts of N-acetoacetyl-L-aspartic acid, mp 127°-129.5° C.