Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: COc1ccc(CNc2nc(C)nc(Cl)n2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-N-(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 g, 604 mmol) in DMF (800 mL) at 0° C., was added sodium hydride (18.86 g, 786 mmol) slowly over min. 1-(Chloromethyl)-4-methoxybenzene (91 mL, 665 mmol) was slowly added over 15 min. The reaction mixture was stirred at 0-5° C. for 30 min and allowed to warm to room temp 25° C. After 1 h, cold water (2.5 L) was added and the mixture was stirred overnight. The resulting slurry was filtered, washed with water (150 mL, ×2) and dried to afford 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a solid (215.3 g, 559 mmol, 93% yield). LCMS (ES, pos.): Cacld for C20H21ClN4O2: 384.1. found: 385.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=8.12 Hz, 4H); 6.81-6.95 (m, 4H); 4.74 (s, 2H); 4.69 (s, 2H); 3.81 (s, 6H); 2.45 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:39]1([CH2:45][CH2:46][CH2:47][C:48]#[N:49])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:43][CH2:44][N:39]([CH2:45][CH2:46][CH2:47][C:48]#[N:49])[CH2:40][CH2:41]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:37])[CH3:38])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: N#CCCCN1CCNCC1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCC#N)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-piperazin-1-yl-butyronitrile (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H48N5O2Cl2 [(M+H)+] 688.3180, observed 688.3186.
Reaction SMILES: [CH:1]1([C:6]2([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([O:19]C)[CH:12]=3)[S:10][CH2:9][CH2:8][S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:6]2([C:11]3[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([OH:17])[CH:16]=3)[S:7][CH2:8][CH2:9][S:10]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(OC)cc(C2(C3CCCC3)SCCS2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1cc(O)cc(C2(C3CCCC3)SCCS2)c1

Procedure:
Compound 17 was prepared from Compound 10 using the same procedure as described above for Compound 16. Yield 0.67 g (74.1%) as a waxy solid. Rf=0.28 (hexane:ethyl acetate 8:2); 1H NMR δ 6.89 (d, J=2.4 Hz, 2H), 6.23 (t, J=2.1 Hz, 1H), 5.68 (br s, 2H), 3.34–3.07 (m, 4H), 2.78–2.67 (m, 1H), 1.71–1.38 (m, 8H); 13C NMR δ 156.26, 150.31, 108.13, 101.59, 79.28, 52.27, 39.02, 31.39, 25.94; MS: (ESI, Pos.) m/z 305 ([M+23]+).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48][OH:49].Cl.NCC(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:42])[NH:46][C:47]([CH2:50][OH:51])([CH3:52])[CH2:48][OH:49])=[CH:35][CH:36]=3)=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(N)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]([CH2:63][CH2:64][CH2:65]O)[Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:65][CH2:64][CH2:63][O:55][Si:56]([C:59]([CH3:60])([CH3:62])[CH3:61])([CH3:57])[CH3:58])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 64 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (65.7 mg, 0.136 mmol) was dissolved in THF (3.5 mL), and the solution was treated with triphenylphosphine (178 mg, 0.680 mmol), 3-(tert-butyldimethylsiloxy)-1-propanol (0.145 mL, 0.680 mmol) and 40% DEAD-toluene solution (0.310 mL, 0.680 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (58.2 mg, yield 64%).
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>CCO.COCCOC>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cccc(B(O)O)c1F
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 2b (1.0 g, 1.79 mmol) in bezene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 2c (348 mg, 32.3%). MS (CI) m/z 502.20 (MH+-Boc).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](OCC)=[O:5].[NH2:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:28])=[CH:12][CH:11]=1.C(OCl)(C)(C)C.C(N(CC)CC)C.Cl>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[CH2:18][O:17][C:16](=[O:28])[N:15]([CH2:14][C:13]3[CH:29]=[C:30]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:4](=[O:5])[CH:3]4[S:2][CH3:1])[N:20]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)CSC
Reactant: Nc1ccc(CN2N=C(c3ccc(Cl)cc3)COC2=O)cc1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2ccc(CN3N=C(c4ccc(Cl)cc4)COC3=O)cc21
Temperature: -60 °C
Reaction time: 3 h

Procedure:
Ethyl (methylsulphanyl)acetate (27.31 mmoles) is added dropwise to a solution of the compound obtained in Step E (23.75 mmoles) in THF (200 ml) at −60° C. under a nitrogen atmosphere. tBuOCl− (27.31 mmoles) is added dropwise to the reaction mixture over 20 minutes, keeping the temperature between −60° C. and −55° C. After stirring for 3 hours at −60° C., triethylamine (29.68 mmoles) is added dropwise. The reaction mixture is brought to ambient temperature; aqueous 3M HCl solution (340 ml) is then added and stirring is carried out for a further 2 hours. The organic phase is evaporated and the aqueous suspension is extracted with DCM. The organic phases are combined, then washed with 2M HCl solution and then with saturated NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue is triturated in ethyl ether, filtered and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(O[C@H]3CCOC3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 36.3 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.8 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.6 g, 22.8 mmol) and K2CO3 (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum The residue was purified by flash chromatography (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield). MS (ESI) m/z: Calc. 290.2 (M+). Found: 291.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30](O)=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:33][OH:34]>>[OH:34][NH:33][C:30]([C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])=[O:31]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 16 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 186.8 mg (0.4 mmol) of trans-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid with hydroxylamine provided 31.8 mg of trans-N-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxamide in 16% yield. MS: 470.1 (M+H)+
Reaction SMILES: [NH4+].[Cl-].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=1.C1COCC1>CO.[Zn]>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1cccnc1S(=O)(=O)Nc1cccc2cccnc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccnc1S(=O)(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
Sat. NH4Cl (0.49 g, 9.09 mmol) was added to a solution of 3-nitro-pyridine-2-sulfonic acid quinolin-8-ylamide (Intermediate 259) (0.3 g, 0.91 mmol) in MeOH:THF(10 ml, 1:1) followed by zinc powder (0.48 g, 7.27 mmol) and the mixture was stirred at room temperature for 18 h. The mixture was filtered through celite and washed with THF. The filtrate was concentrated in vacuo and the residue was diluted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH as the eluent to give the title compound (0.26 g, 95%)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)=O.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>CO.O>[CH2:22]([O:29]/[N:30]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(/C=N/OCc2ccccc2)cc1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 8 mL sealed vial was mixed N-(4-formylphenyl)isoindoline-2-carboxamide (50 mg, 0.188 mmol) in methanol (1 ml). A solution of O-benzylhydroxylamine hydrochloride (45.0 mg, 0.282 mmol) and sodium acetate (46.0 mg, 0.338 mmol) in water (1.000 ml) was then added and the reaction was stirred overnight at room temperature. The reaction was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with brine, dried with sodium sulfate, decanted, and concentrated. Purification by chromatography provided the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 8.21 (s, 1H), 7.65 (m, 2H), 7.50 (m, 2H), 7.44-7.28 (m, 9H), 5.14 (s, 2H), 4.78 (bs, 4H); MS (ESI(+)) m/e 372 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3ccccc3n2)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
4-Hydroxy-4-quinolin-2-yl-piperidine-1-carboxylic acid tert-butyl ester (3.16 g, 9.61 mmol) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (5.00 g, 20.98 mmol) in benzene (60 mL) under N2 were refluxed for 3 hours. The solution was cooled to ambient temperature, diluted with water (50 mL) and the resulting mixture was stirred at ambient temperature for 10 minutes. The benzene layer was separated, washed with brine, dried over magnesium sulfate and concentrated onto silica gel; flash chromatography using an ethyl acetate/hexanes gradient gave 4-quinolin-2-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.65 g, 55%) as a yellow oil. 1H NMR CDCl3 δ 8.09 (d, J=9 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.70-7.63 (m, 1H), 7.56 (d, J=9 Hz, 1H), 7.51-7.44 (m, 1H), 6.69-6.63 (m, 1H), 4.21-4.14 (m, 2H), 3.68 (t, J=6 Hz, 1H), 2.87-2.80 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH:7]=[CH2:8])[CH3:2].B1C2CCCC1CCC2.C([O-])(O)=[O:27].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH2:7][CH2:8][OH:27])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CC(CC(=O)OCC)c1cnc(C)nc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(CCO)c1cnc(C)nc1
Reaction time: 18 h

Procedure:
To a stirred solution of 4-4 (422 mg, 1.92 mmol) in THF was added 5.75 mL of 9-BBN (0.5 M/THF). After 18 hours, a slurry of NaBO3 (2.35 g) and NaHCO3 (2.42 g) in H20 (10 mL) was added and the mixture stirred vigorously for 1 hour. The mixture was extracted with CHCl3, washed with brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 3% EtOH/EtOAc) to give 4-5 as a clear oil.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:17])[CH2:15][CH3:16].CS(C)=O>O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:17][CH2:14][CH2:15][CH3:16])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCN
Solvent: CS(C)=O
Solvent: O
Product: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 7.1 parts of 4-fluoro-3-nitrobenzoic acid, 9.1 parts of 1-propanamine and 25 parts of dimethyl sulfoxide is stirred for 3 hours at 60° C. The reaction mixture is poured onto 150 parts of water. The precipitated product is filtered off, washed with water and dried, yielding 8.8 parts of 3-nitro-4-(propylamino)benzoic acid; mp. 208° C.
Reaction SMILES: C[N:2]1[CH2:6]CC[C:3]1=[O:7].[CH3:8]/[C:9](/[S:12][CH3:13])=[N:10]/[OH:11].CN=C=O>C(N(CC)CC)C>[CH3:8]/[C:9](/[S:12][CH3:13])=[N:10]\[O:11][C:3]([NH:2][CH3:6])=[O:7]
Reactant: CN1CCCC1=O
Reactant: CS/C(C)=N\O
Agent: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)O/N=C(\C)SC
Reaction time: 1 h
Yield: 96 %

Procedure:
A 256 g portion of an N-methyl pyrrolidone solution of methomyl oxime (containing 0.4 mole MMO) and 0.5 g triethylamine was charged to a 500 ml 5-necked flask. To this was added 28.7 g (0.5 mole) methyl isocyanate rapidly. The temperature rose to 40° C. for 1.0 hour. The reaction mixture was then transferred to a Kugelrohr apparatus, and the solvent removed at reduced pressure. A yield of 96% Methomyl, assaying >99% was realized.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:40][CH2:39][C:9]2[N:10](S(C3C=CC=CC=3)(=O)=O)[C:11]3[CH:12]=[CH:13][C:14]([C:17](=[O:29])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:19]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC2N(S(C3C=CC=CC=3)(=O)=O)C3C=C(C(=O)C4C=CC(Cl)=C(S(=O)(=O)N)C=4)C=CC=3C=2C1)=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1CO.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:40][CH2:39][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17](=[O:29])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:19]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(c3cc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)ccc3n2S(=O)(=O)c2ccccc2)C1
Agent: CCOC(=O)N1CCc2c(c3ccc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)cc3n2S(=O)(=O)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCC1CCCO1
Product: CCOC(=O)N1CCc2[nH]c3ccc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)cc3c2C1
Temperature: 140 °C

Procedure:
A mixture of 5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester (1 g) is dissolved in 5 mL of tetrahydrofuran-methanol-water (10:10:1) and treated with 0.344 g of potassium carbonate. The reaction mixture is heated at 140° C. for 15 min (microwave irradiation), filtered and concentrated. The residue is purified on reverse phase HPLC to give pure 8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); and 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); both as yellow syrups. Both isomers are separated by HPLC (Chiracel OD-H 250-4.6 mm, flow 1 ml/Min, UV 235 nM, gradient hexane-ethanol 70-30). The retention times are 6.91 min for 8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 10.20 min for 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Si:14]([O:21][CH2:22][C:23]1[CH:49]=[CH:48][C:26]([C:27]([NH:29][NH:30][C:31](=[O:47])[C@H:32]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([Cl:45])[C:38]=2[CH3:46])[C@@H:33]([OH:35])[CH3:34])=[O:28])=[CH:25][CH:24]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[Si:10]([O:35][C@@H:33]([CH3:34])[C@@H:32]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([Cl:45])[C:38]=1[CH3:46])[C:31]([NH:30][NH:29][C:27](=[O:28])[C:26]1[CH:48]=[CH:49][C:23]([CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[CH:24][CH:25]=1)=[O:47])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 135 %

Procedure:
Imidazole (3.99 g, 58.55 mol) and TBDMS-Cl (5.29 g, 35 mmol) were added sequentially to a pre-cooled (0° C.) solution of 4-((tert-butyldimethylsilyloxy)methyl)-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (6.22 g, 11.71 mmol) in DMF (300 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 h, whereupon the solution was poured into H2O (120 mL). The white precipitate was filtered, washed with H2O (30 mL) and taken up in CH2Cl2 (200 mL). This organic layer was washed with brine (1×100 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (10.2 g). This crude product was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][C:21]1[C:26]([OH:27])=[C:25]([CH:28]=O)[CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[OH:27][C:26]1[C:21]([O:20][CH3:19])=[CH:22][CH:23]=[CH:24][C:25]=1/[CH:28]=[CH:1]/[C:2]1[N:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc2ccncc2c(=O)n1-c1ccccc1
Reactant: COc1cccc(C=O)c1O
Solvent: CC(=O)O
Product: COc1cccc(/C=C/c2nc3ccncc3c(=O)n2-c2ccccc2)c1O
Yield: 9.5 %

Procedure:
The crude compound 18 (0.436 mg, 1.84 mmol) was mixed with o-vaniline (0.60 g, 4.0 mmol) in 5 mL of glacial acetic acid. The reaction mixture was heated in a microwave for 2 h keeping temperature constant at 150° C. The reaction mixture was concentrated in vacuo, co-evaporated several times with toluene and purified by flash chromatography (CH2Cl2/EtOAc) to give 65 mg of the target compound 19 (8% yield for two last steps). MS: m/z+372.2 [M+H]+.