Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:9][CH2:8][CH2:7][C:6]2[N:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]3=[CH:3][C:2]1=2.[CH2:14]([NH2:16])[CH3:15]>>[CH2:1]1[CH2:9][CH2:8][CH2:7][C:6]2[N:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]3=[C:3]([CH2:15][CH2:14][NH2:16])[C:2]1=2
Reactant: CCN
Reactant: c1ccn2c3c(cc2c1)CCCC3
Product: NCCc1c2c(n3ccccc13)CCCC2

Procedure:
2-Pyridylacetate (25 g, 150 mmol) and 2-chlorocyclohexanone were heated under reflux in dry benzene for 42 h. under a Dean Stark trap to remove water. Evaporation of the volatiles under reduced pressure gave a very thick red-brown oily residue. The residue was treated with toluene and filtered. The toluene filtrate was evaporated to give an orange-brown oil. The oil was purified on alumina eluting with 10% petroleum ether in toluene to give 2.7 g of 1,2,3,4-tetrahydropyrido[1,2-a]indol-10-carboxylic acid ethyl ester [modification of L. K. Dalton; T. Teitei Aust. J. Chem. 1969 22, 1525-1530]. The ethyl ester (1 g, 4 mmol) was dissolved in ethanol (40 mL) with warming. To the solution was added 2.5 N NaOH (30 mL). The reaction mixture was heated under reflux for 2 h, then allowed to cool and stir at room temperature for 2 days. The solution was acidified with 2N HCl and extracted into methylene chloride. Removal of the volatiles under reduced pressure gave a residue, which was purified by column chromatography on silica gel eluting with 5-15% ethyl acetate in hexane. The corresponding carboxylic acid was obtained. The carboxylic acid (210 mg, 0.98 mmol ) was dissolved in bromobenzene and heated at 170° C. for 15 min. The solvent was removed under reduced pressure to give a residue, which was purified on silica gel eluting with 100% hexane to remove bromobenzene followed by 5% ethyl acetate in hexane to isolate the product. Evaporation of the volatiles gave 1,2,3,4,-tetrahydropyrido[1,2-a]indole (140 mg), mp: 55-57° C. [M+H]+ 172 m/z. 1,2,3,4,-tetrahydropyrido[1,2-a]indole was formylated, converted to the nitroolefin and reduced to the corresponding ethylamine as described in Example 9 to give the title compound. The title compound was dissolved in ethanol and treated with an ethanolic solution of fumaric acid. After standing in a freezer overnight crystals formed. The solution was decanted from the crystals which were rinsed with ethyl ether and dried under reduced pressure to give the fumaric acid salt of the title compound, mp: 166-172° C. The filtrate was diluted with ethyl ether and a second crop of crystals was recovered, mp: 169-172° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:20]=[C:19]2[C:21]3[CH:15]([N:16]([CH3:22])[CH2:17][CH2:18]2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:24]C(C)C)[CH:12]=2)[C:7]=3[C:6]=1[O:30][CH3:31])([CH3:3])[CH3:2]>C(O)(=O)C.S(=O)(=O)(O)O>[OH:24][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:28][CH3:29])[C:7]1=[C:21]3[CH:15]([N:16]([CH3:22])[CH2:17][CH2:18][C:19]3=[CH:20][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]1[O:30][CH3:31])[C:14]2=[O:23]
Reactant: COc1cc2c(cc1OC(C)C)C(=O)C1c3c(cc(OC(C)C)c(OC)c3-2)CCN1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)C(=O)C1c3c(cc(OC(C)C)c(OC)c3-2)CCN1C
Temperature: 25 °C
Yield: 22.2 %

Procedure:
The solution of compound (3) (50 mg) in acetic acid-sulfuric acid solution (96:4, 5 ml) was refluxed for 1 hour under nitrogen. After cooling to room temperature, the solution was evaporated under vacuum. The residue was neutralized with ammonia water and extracted with chloroform (100 ml×2). The combined chloroform layers were washed with water (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue obtained was purified on a silica gel column and eluted with chloroform-methanol (99:3) to obtain a brown solid, 9-hydroxy-2-isopropyloxy-1,10-dimethoxy-7-oxoaporphine (4) (10 mg, 22% yield): m.p. 240-242° C.; IR(KBr) νmax 3422, 3008, 2977, 2932, 1728, 1651, 1593, 1513, 1461, 1417, 1380, 1351, 1280, 1247, 1213, 1149, 1116, 1059, 1013, 932, 894, 866, 822 cm−1; 1H NMR (200 MHz, CD3OD) δ 1.51 (6H, d, J=6.0 Hz, 2×CH3), 4.01 (3H, s, OCH3), 4.02 (3H, s, OCH3), 4.87 (1H, m, OCH), 7.25 (1H, s, H-3), 7.74 (1H, s, H-8), 7.83 (1H, d, J=4.8 Hz, H-4), 8.63 (1H, d, J=4.8 Hz, H-5), 8.68 (1H, s, H-11); ESI MS (positive): [M+H]+366.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:38]1([S:35]([C:31]2[CH:30]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)ccc1O
Temperature: 25 °C
Reaction time: 113 h

Procedure:
N-{5-[(1R)-2-Amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (33.2 mg) was added to a solution of 1-{4-[(6-bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 1v.) (50 mg) in DMF (5 ml). The reaction mixture was treated with N,N-diisopropylethylamine (29.3 μl) and stirred at room temperature for 113 h. The reaction mixture was partitioned between EtOAc and water and the organic extracts were washed with ammonium chloride, dried (MgSO4) and concentrated in vacuo. The residue was purified by column DCM) to afford the title compound. LCMS RT=2.73 min 610(M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[N:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ncc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1[C@@H](CC(=O)c1cnc(=O)[nH]c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
To a solution of (S)-3-(4-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-3-o-tolylpropan-1-one (700 mg, 1.53 mmol, Eq: 1.00) in dioxane (18 mL) was added 37% aq. hydrochloric acid solution (2.56 mL, 30.6 mmol) and the resulting solution was first stirred at ambient temperature for 45 min and then 2½ h at 60° C., then poured onto sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient dichloromethane to dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (592 mg, 97%). White solid, MS (ESI+): m/z=: 397.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]1([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17]1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(CN2CCOC(c3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
1.877 g of 3-Bromobenzyl bromide and 1 g of 2-Phenyl-morpholine in 15 mL of acetonitrile were stirred at room temperature and 2.076 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification by flash chromatography afforded 1.073 g of product. 65% yield ES MS m/z 332
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.OC[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:5][CH2:2][C@@H:12]1[CH2:13][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CBr)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tetrabromomethane (1.23 g) was added to a solution of 1,1-dimethylethyl (3R)-3-(hydroxymethyl)-1-piperidinecarboxylate (500 mg) in methylene chloride (2.7 mL). The reaction mixture was cooled to 0° C. and a solution of triphenylphosphine (731 mg) in methylene chloride (2.7 mL) was slowly added. After 1 hour at 0° C., the reaction mixture was concentrated and directly purified by chromatography on silica gel eluting with heptane/ethyl acetate 1:15 followed 1:10 to yield the title compound as a slightly yellow oil (627 mg).
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[C:21]3[C:24]([OH:26])=[O:25])=[N:16]2)=[CH:11][CH:10]=1)#[N:8].IC>CN(C=O)C.CCOC(C)=O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[C:21]3[C:24]([O:26][CH3:1])=[O:25])=[N:16]2)=[CH:11][CH:10]=1)#[N:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(-n2cc3c(C(=O)O)cccc3n2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nn(-c3ccc(C#N)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (1.2 eq.) was added to a solution of (C6) in dry DMF (0.2 M). The resulting white suspension was stirred at RT for 30 min. After cooling down to 0° C., iodomethane (7 eq.) was added, then, the reaction mixture was stirred at RT for 90 min. The solution was diluted with EtOAc and washed with brine (2×) and dried (Na2SO4). Evaporation of the solvent afforded the title compound that was used in the next step without further purification. 1H NMR (300 MHz, CDCl3, 300K) δ 9.02 (1H, s), 8.14 (2H, d, J=8.7 Hz), 8.01-7.95 (2H, m), 7.85 (2H, d, J=8.5 Hz), 7.42 (1H, t, J=7.4 Hz), 4.02 (3H, s). MS (ES+) C16H11N3O2 required: 277, found: 278 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O.[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH2:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1>>[C:22]([O:21][C:19]([N:6]1[C@H:5]([C:3](=[O:2])[NH:45][C@H:29]([C:28]([O:27][CH3:26])=[O:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: COC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Yield: 78.4 %

Procedure:
(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (5.1 mmol) was hydrolyzed and coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (5.85 mmol) according to general procedures B and A to provide (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.4 g). (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g) was dissolved in MeOH, Pd/C was added and the mixture stirred under balloon pressure of hydrogen for 1 h. Mixture was filtered through celite, washed with MeOH and EtOAc and concentrated to provide (S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.06 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (26%). mp 222° C.; LCMS: m/z=541.18 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.10 (s, 1H), 7.58 (s, 1H), 7.25 (m, 6H), 6.54 (m, 1H), 3.60 (m, 4H), 3.34 (s, 3H), 2.95 (d, 3H, J=4.8 Hz), 2.25 (m, 2H), 1.96 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].O1CCCC1.[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(N(CC)CC)C>[Cl:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)(=[O:26])=[O:25])[CH:3]=2)[NH:7][N:6]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc2[nH]nc(Cl)c2c1)c1cccc(F)c1
Yield: 37.2 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.18 g of 5-amino-3-chloro-1H-indazole, 20 ml of tetrahydrofuran, 0.25 ml of triethylamine and 0.23 g of 3-fluorobenzenesulfonyl chloride. 0.13 g of N-(3-chloro-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a yellow foam which decomposes at approximately 80° C. (analysis C13H9ClFN3O2S % calculated: 47.93; H, 2.78; Cl, 10.88; F, 5.83; N, 12.90; O, 9.82; S, 9.84. % found C, 48.11; H, 2.64; F, 5.14; N, 13.14; S, 8.22).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][CH:11]2[C:16]1[N:17]=[CH:18][N:19](C(OC(C)(C)C)=O)[CH:20]=1)(=[O:4])=[O:3].Cl>CO>[NH:19]1[CH:20]=[C:16]([C@@H:11]2[CH2:10][CH2:9][CH2:8][C:7]3[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:14]=[CH:13][C:12]2=3)[N:17]=[CH:18]1
Reactant: CC(C)(C)OC(=O)n1cnc(C2CCCc3c(NS(C)(=O)=O)cccc32)c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cccc2c1CCC[C@H]2c1c[nH]cn1
Reaction time: 1.5 h

Procedure:
A solution of Example 9B (130 mg, 0.33 mmol) in methanol (10 mL) was treated with 1N HCl (5 mL), stirred for 1.5 hours, concentrated at 45° C., and dried under vacuum for 30 minutes. The residue was dissolved in methanol, filtered through cotton, concentrated and dried under vacuum for 3 hours to provide the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCNCC(=O)OCC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of diester 58 (3.88 g, 20.2 mmol) in dry acetonitrile (40 mL) at 0° C., under Argon, was added slowly benzyl chloroformate (3.17 mL, 1.1 equiv.). The solution was stirred at 0° C. for 1 h after which it was poured into water (50 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). the combined organic extracts were washed with 5% HCl, water, brine and dried over anhydrous sodium sulfate. Evaporation of the solvents was followed by distillation to afford compound 70 as a colorless oil (5.4 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([NH:18]C(=O)C)=[N:15][C:14]=2[CH3:22])[CH:5]=[C:6]([Cl:12])[C:7]=1[S:8](=[O:11])(=[O:10])[NH2:9]>Cl.C(O)C>[NH2:18][C:16]1[S:17][C:13]([C:4]2[CH:5]=[C:6]([Cl:12])[C:7]([S:8]([NH2:9])(=[O:10])=[O:11])=[C:2]([Cl:1])[CH:3]=2)=[C:14]([CH3:22])[N:15]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(N)(=O)=O)c(Cl)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1cc(Cl)c(S(N)(=O)=O)c(Cl)c1

Procedure:
A solution of N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) (0.70 g, 1.84 mmol) in aqueous hydrochloric acid (5M, 10 ml) and ethanol (20 ml) is heated at reflux for 90 minutes. When cool, the mixture is concentrated to remove ethanol and the aqueous solution is brought to pH 9 by addition of aqueous sodium hydroxide (4M). The product is extracted with n-butanol (50 ml) and the organic extract is dried over MgSO4. Removal of the solvent followed by chromatography on silica (eluting with ethyl acetate—hexane, 2:1 increasing to 4:1) affords the title compd. MH+ (MS, AP+): 337.8, 339.5
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([Cl:12])[C:3]=1[CH:4]=[O:5].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:6]([Cl:12])[C:3]=1[CH:4]=[O:5])[CH2:10][O:11][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=Cc1c(Cl)cc(CO)cc1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A solution of 500 mg (2.4 mmol) A3 in 5 ml dry dimethyl formamide under nitrogen was cooled in an ice bath and 73 mg (3.0 mmol) sodium hydride was added and the mixture was stirred for 10 minutes. After addition of 410 mg (2.6 mmol) ethyl bromoacetate, the mixture was heated to 110° C. for 8 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulphate and evaporated to dryness. Purification of the residue by column chromatography on SiGel (heptane/ethyl acetate 4:1) yielded 40 mg (6%) A15.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][O:13][CH2:12][CH:11]([CH3:15])[NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][O:13][CH2:12][CH:11]([CH3:15])[N:10]([C:25](=[O:26])[C:24]3[CH:28]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]=3[N:29]3[N:33]=[CH:32][CH:31]=[N:30]3)[CH2:9]2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cc(OCC2CNC(C)COC2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC(COc3ccc(F)c(C)c3)COCC2C)c1

Procedure:
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-7, 13 mg, 0.051 mmol, 1 equiv), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (16 mg, 0.077 mmol, 1.5 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 15 mg, 0.077 mmol, 1.5 equiv), 1-hydroxybenzotriazole (12 g, 0.077 mmol, 1.50 equiv) and triethylamine (21 uL, 0.15 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 23° C. for 20 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (100% hexanes initially, grading to 40% hexanes in EtOAc) to provide 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-oxazepane (4-8) as a mixture of diastereomers. LRMS m/z (M+H) 439.0 found, 439.2 required.
Reaction SMILES: [C:1]1([C:7]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:1]1([C:7]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH:9][C:20](=[O:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(CN)(Cn1cncn1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(CNC(C)=O)(Cn1cncn1)c1ccccc1
Yield: 89.3 %

Procedure:
To a 100 mL flask stirring under nitrogen was charged 2.58 g (0.010 mole) of 2-phenyl-2-[(1,2,4-triazol-1-yl)methyl]-1-hexylamine and 15 mL of acetic anhydride. To the mixture was added 1.5 mL of pyridine and the reaction was stirred at room temperature for 3 hours. After GLC indicated the reaction was complete, it was quenched with 20 mL of water and 100 mL of ether after the acetic anhydride and pyridine were removed under vacuum. The residue was dissolved in ether and washed with 2×50 mL water and 2×50 mL of saturated sodium bicarbonate. The organic phase was dried, concentrated and gave 2.68 g (89.3% yield) of a solid, melting point 112°-115° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:30][CH2:31][CH3:32])[C:5]1[CH:6]=[C:7](C(OCC)=O)[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:2][CH3:3].[OH-].[K+]>C(O)C>[CH2:30]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:6]=[CH:7][C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:31][CH3:32]
Reactant: CCCN(CCC)c1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)c1ccc(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Temperature: 60 °C
Yield: 83.6 %

Procedure:
Ethyl 1-(dipropylamino)-6-mesityl-4-oxo-4H-quinolizine-3-carboxylate (0.0145 g, 0.033 mmol) was dissolved in ethanol (0.3 mL). Potassium hydroxide (6M in ethanol, 94 μL, 0.57 mmol) was added. The solution was heated at 60° C. for 1 h. The solution was extracted using ethyl acetate, dried over magnesium sulfate and concentrated to give 0.010 g (83% yield) of the title compound.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:13]=1)=[O:11])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:14]2[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH:17]=[CH:16][C:15]=2[OH:18])=[CH:25][CH:24]=1)[CH3:28]
Reactant: CCOc1ccc(Cc2cc(C(=O)CP(=O)(OCC)OCC)ccc2O)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(Cc2cc(C(=O)CP(=O)(O)O)ccc2O)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 83.5 %

Procedure:
To a solution of {2-[3-(4-ethoxybenzyl)-4-hydroxyphenyl]-2-oxoethyl}phosphonic acid diethylester (1.00 g) in dichloromethane (4.7 mL) was added bromotrimethylsilane (1.6 mL) at 0° C., and the reaction mixture was stirred for 9 hr at room temperature. Methanol (4.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. Evaporation and crystallization from ethyl acetate-n-hexane gave the title compound (0.72 g) as a pale brown crystal.