Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[C:28](=[O:37])[C:29](=[O:36])[C:30]=5[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=4)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[C:28](=[O:37])[C:29](=[O:36])[C:30]=5[NH:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH:25]=4)[NH:20][CH:19]=3)[CH2:13][CH2:14]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ccc(-c4c(NC(C)(C)C)c(=O)c4=O)cc23)CC1
Solvent: CC#N
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(-c4c(NC(C)(C)C)c(=O)c4=O)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-t-butylamino-3-cyclobuten-3-yl)-1-triisopropylsilylindole (0.294 g, 0.45 mmol) in 10 mL of acetonitrile was added 48% HF (32 μL, 0.90 mmol) and the mixture was stirred at room temperature for 2 h. The resulting mixture was evaporated and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic phase was separated and the aqueous phase was back-extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated to give the title compound (0.213 g, 94%) as a yellow foam which could not be crystallized. This material was suspended in excess 1N HCl, a small amount of ethanol was added and the mixture was gently warmed to effect dissolution. Storage of this solution at -20° C. led to crystallization. The crystals were filtered, washed (acetone, ether) and dried in vacuo to give the hydrochloride (0.252 g, 89%) as a light yellow solid, mp 180° C. (softens), 215°-218° C. (foams): IR (KBr) 3400 (br), 1775, 1715, 1635, 1575 (br) cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 11.58 (br s, 1H), 11.32 (br s, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 4.93 (m, 2H), 3.91 (s, 3H), 3.79-3.62 (m, 4H), 3.17 (br s, 4H), 2.84 (t, J=7.0 Hz, 2H), 2.17 (m, 2H), 1.51 (s, 9H). Anal. Calcd for C28H34N6O3. 3 HCl. H2O: C, 53.38; H, 6.24; N, 13.34. Found: C, 53.24; H, 6.35; N, 13.24.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]#[C:19][CH3:20])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C(N(CC)CC)C.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C@@:3]([OH:5])([CH3:4])[C:2]([F:1])([F:21])[F:22])=[CH:11][CH:10]=3)[CH:13]([C:18]#[C:19][CH3:20])[CH2:14]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: CC#CC1CNCCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of (2S)-1,1,1-trifluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (0.190 g, 0.608 mmol) in DCM (5.0 mL) was added triethylamine (0.254 mL, 1.83 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was cooled to 0° C. and 6-chloropyridine-3-sulfonyl chloride (0.155 g, 0.730 mmol, Organic Process Research & Development 2009, 13, 875) was added in one portion. After the addition, the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was concentrated and the crude product was purified by column chromatography (40 g of silica, 10 to 30% acetone in hexanes) to afford (2S)-2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.240 g) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Br)ccc23)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Temperature: 0 °C

Procedure:
3(6-Bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (1.13 g, 3.0 mmol) was dissolved in DMF and cooled to 0° C. then sodium hydride (60% dispersion in mineral oil, 0.156 g, 3.9 mmol) was added. After 5 minutes benzyl bromide (0.500 mL, 4.2 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hour the reaction was re-cooled to 0° C. then quenched with aqueous HCl (5 mL, 1N). After extraction the crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:26])[C:16]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]([CH3:26])[C:16]([CH2:19][N:20]5[CH2:24][CH2:23][CH2:22][C:21]5=[O:25])=[CH:17][N:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: Cn1c(CN2CCCC2=O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Cn1c(CN2CCCC2=O)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a solution of 135 (125 mg, 0.267 mmol) in MeOH (10 mL) was added zinc powder (140 mg, 2.14 mmol) and ammonium chloride (42.9 mg, 0.80 mmol) in water (1 mL) and the reaction mixture was heated to reflux for 4 hours. The mixture was cooled to RT, filtered and concentrated. The residue was partitioned between water and DCM/MeOH and the organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 136 (77 mg, 66% yield) that was used crude in the next step with no additional purification. MS (m/z)=438.50 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)OCc2ccccc2)cc(N2CCCC2)c1Oc1ccccc1

Procedure:
In a similar manner to Example 3, piretanide can be reacted with benzyl chloride in DMF to yield benzyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[OH:27][C:7]1[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[N:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:9]2[S:18][N:19]=[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:8]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccccn2)c2snc(-c3ccccc3)c2c1O
Product: O=C(O)CNC(=O)c1nc(-c2ccccn2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-Hydroxy-3-phenyl-7-pyridin-2-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 407.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].N12CCCN=C1CCCCC2.[I-].[Na+].[SH:40][CH2:41][CH2:42][CH2:43][OH:44]>C(O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][S:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCCl)ccc1Cl
Reactant: OCCCS
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCSCCCO)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-5-[3-chloropropoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.06 g, Example 3a) and 1,8-diazabicyclo(5.4.0)undec-7-ene (0.07 ml) in 1-butanol (5 ml) was added sodium iodide (0.023 g) and 3-mecaptopropan-1-ol (0.04 ml). The reaction vessel was sealed and the mixture heated at 100° C. for 24 h. The reaction mixture was diluted with ethyl acetate and washed twice with 2M hydrochloric acid, twice with sodium hydrogencarbonate solution and once with brine. The organics were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by NPHPLC (eluting with 0-2% ethanol in dichloromethane) to leave the title compound as a white solid (0.05 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]([NH:42][C@H:43]([C:57](O)=[O:58])[CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C>[CH3:38][O:39][C:40](=[O:41])[NH:42][C@@H:43]([CH:44]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:57]([NH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][CH2:28][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:37])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:58]
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 81.8 %

Procedure:
A mixture of tert-butyl[(2S)-4-(2-aminophenyl)-1-{[tert-butyl(diphenyl)silyl]oxy}butan-2-yl]carbamate (5, 242 mg, 0.466 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (6, 225 mg, 0.752 mmol) (or any other suitable carboxylic acid), HATU (318 mg, 0.836 mmol) and DMAP (50 mg, 0.409 mmol) was dissolved in dry Py (2 ml) and the mixture was stirred at room temperature under N2 for 13 h. Quenched with water (0.5 mL), then diluted (DCM), washed with 5% KHSO4 in water, then saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purified through a chromatographic cartridge of silicagel (12 g) eluted with 10% to 30% EtOAc in hexane to give 305 mg (82% yield) of title compound as white foam, MS: m/z=822.2 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>CC#N>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][C:7]=1[Br:21]
Reactant: COC(=O)CCc1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)CCc1cnc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(5-aminopyrazin-2-yl)propanoate (25 mg, 0.138 mmol) in CH3CN (690 μL) was added NBS (24.56 mg, 0.138 mmol). The reaction mixture was stirred for 1 h at room temperature. After quenched with Na2S2O3 solution, the reaction mixture was stirred with NaHCO3 solution for 20 min and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude methyl 3-(5-amino-6-bromopyrazin-2-yl)propanoate was obtained (28%). LCMS (m/z): 260.2/262.2 (MH+), 0.54 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C([Li])CCC.[Br:18]CCBr.[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:18])[N:6]2[N:5]=1
Reactant: COCc1cc2ccccn2n1
Reactant: BrCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(methoxymethyl)pyrazolo[1,5-a]pyridine (3.5 g) dissolved in tetrahydrofuran (350 mL) was added n-butyllithium (2.66M hexane solution; 10.5 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. 1,2-Dibromoethane (2.05 mL) was added dropwise to the obtained reaction mixture and stirring was continued for 30 minutes. After adding saturated aqueous ammonium chloride to the reaction mixture, the temperature was raised to room temperature, water was added and extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (2.75 g) was obtained as a light yellow oil from the n-hexane:ethyl acetate (10:1) fraction.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]([F:19])([F:18])[C@@H:15]([OH:17])[CH3:16]>>[F:13][C:14]([F:19])([F:18])[C@H:15]([CH3:16])[O:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1
Reactant: OC1(c2cnccc2Cl)CCC1
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1ccncc1C1(O)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 108b, using 1-(4-Chloro-pyridin-3-yl)-cyclobutanol (Example 108a) and (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7) as starting materials and isolated (3.22 g, 57%) as yellow oil; MS (ESI, m/z): 262.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([C:20]([O:22]CC)=O)=[C:15]2[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([C:20]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=1)=[O:22])=[C:15]2[OH:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Temperature: 200 °C

Procedure:
A mixture of ethyl 8-((benzylamino)methyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 28, 513 mg) and 4-chlorobenzylamine (2.5 mL) is heated at 200° C. for 20 min. The mixture is concentrated, and the remaining oil is taken up in chloroform and applied to a silica gel column. The column is eluted with 1% methanol/chloroform followed by 2-4% methanol/chloroform to afford 483 mg of the title compound after crystallization from ethyl acetate/ether. Physical characteristics: M.p. 214-216° C.; 1H NMR (CDCl3) δ2.46, 3.59, 3.71, 3.86, 4.28, 4.67, 7.28-7.43, 7.53, 8.25, 8.84, 10.5. Anal. Found: C, 67.68; H, 5.89; N, 10.52; Cl, 6.64.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:27])[CH:18]=2)[C:6]1=[O:28]>O1CCOCC1.O>[CH:29]1([C@@H:4]([N:5]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH3:26])[N:19]([CH3:27])[CH:18]=3)[C:6]2=[O:28])[C:3]([OH:35])=[O:2])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)[C@@H](C1CCCCC1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1c(Cn1c(=O)n([C@@H](C(=O)O)C3CCCCC3)c(=O)c3ccccc31)cn2C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-cyclohexyl-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid methyl ester (124 mg, 0.26 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and is concentrated. The resulting residue is purified by flash chromatography with 3.5% MeOH in dichloromethane as the eluent to afford the title compound. LCMS (ESMS): m/z 460.86 (M+H+)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O[C:21](=[O:33])[CH2:22][C:23]1[N:27]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1COCC1.CO>[Br:32][C:29]1[CH:30]=[CH:31][C:26]2[N:27]([C:23]([CH2:22][C:21]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:24][N:25]=2)[CH:28]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1cnc2ccc(Br)cn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1cnc2ccc(Br)cn12)N1CCOCC1
Yield: 32 %

Procedure:
Add 0.5M diisobutylaluminum hydride in toluene (4.6 mL, 2.29 mmol) to a solution of (6-bromo-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester (0.65 g, 2.29 mmol) and morpholine (5 mL) in THF (40 mL) at −78° C. Gently warm the reaction to room temperature and dilute carefully with methanol. Filter and concentrate the filtrate. Flash chromatography gives the subtitled compound (0.24 g, 32%) as a white solid. MS ES+ m/e 324.0, 326.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([O:12][CH2:13][CH2:14][CH3:15])[C:4](=[O:16])[C:3]=1[C:17]([O:19]CC)=O.C(N1C2C(=CC=CN=2)C(O)=C(C(OCC)=O)C1=O)C1C=CC=CC=1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50](Br)=[CH:49][C:48]=1[S:54]([NH2:57])(=[O:56])=[O:55]>>[NH2:57][S:54]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[NH:46][C:17]([C:3]1[C:4](=[O:16])[N:5]([O:12][CH2:13][CH2:14][CH3:15])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19])(=[O:55])=[O:56]
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Reactant: CCCOn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Agent: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: CCCOn1c(=O)c(C(=O)Nc2ccccc2S(N)(=O)=O)c(O)c2ccccc21

Procedure:
The title compound is prepared according to the procedure of Example 84C substituting the product of Example 172D for the product of Example 84B and substituting 2-aminosulfonamide for the product of Example 84A.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=O)=[CH:4][CH:3]=1.[OH:16][NH2:17]>CO>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=[N:17][OH:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Reactant: NO
Solvent: CO
Product: CCOC(=O)c1c(Cl)ccc(C=NO)c1F
Temperature: 60 °C

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-formylbenzoate (1.1 g, 4.0 mmol) in MeOH (5 mL) was added (aq. solution) hydroxyl amine (4 mL) and the reaction mixture was heated at 60° C. for 2-3 h. The reaction mass was concentrated and extracted with EtOAC. The organic layer was washed with brine and concentrated to afford 0.900 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.31 (t, J=6.9 Hz, 3H), 4.40 (q, J=6.6 Hz, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 8.20 (s, 1H), 11.89 (br s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:8]=[C:9]([CH3:18])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+]>CO.O>[CH3:18][C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)c(C)cn1Cc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Cn2cc(C)c(-c3ccc(C)cc3)c2C(=O)O)cc1

Procedure:
A reaction mixture of 4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (550 mg, 1.58 mmol) and NaOH (1.26 g, 32 mmol) in MeOH (45 mL) and H2O (15 mL) was refluxed for 1 h. After removal of the solvent, aqueous 1N NaOH (100 mL) was added and extraction performed with EtOAc (2×20 mL). After drying of the combined organic phases over Na2SO4, filtration and removal of the solvent, the desired product 4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid was obtained, which was used without further purification.
Reaction SMILES: N[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[Br:16]Br>CC(O)=O>[Br:16][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[CH:2]=[N:3][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1c(N)nc(-c2ccccc2)cc1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cnc(-c2ccccc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.2 %

Procedure:
To 1.8 g (8.95 mM) of 2-amino-3-N-methyl-6-phenyl-4-pyrimidinone was added 40 ml CH3COOH and 0.535 ml Br2 (1.64 g≈10.3 mM). The reaction mixture was allowed to stir at ambient temperature for 18 hours. The solution was evaporated to dryness and the residual solid azeotroped from EtOH (2X). The solids were heated to reflux with 100 ml of H2O, cooled to 5° and filtered. This procedure was repeated, filtered hot, and allowed to crystallize at room temperature for 18 hours. The crystals were filtered and washed well with H2O to yield 1.0 g (40%) of title compound. Cooling of mother liquors gave an additional 0.6 g (24%) of title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16]=2[OH:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:25][C:16]1[C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CCN(Cc3ccccc3)CC2)c(O)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CN2CCNCC2)c(O)c1OC
Yield: 74.9 %

Procedure:
##STR7## 6.8 g (0.02 mol) of N-benzyl-N'-(2-hydroxy-3,4-dimethoxy-benzyl)-piperazine are dissolved in 200 ml of ethanol at 60° C. 1.1 g of 5% palladium on carbon are added thereto and the whole is hydrogenated under a pressure of 5,500 hPa, after which the alcoholic solution is filtered and the solvent is distilled off. The oil obtained is chromatographed on 150 g of silica. A first elution with dichloromethane removes the lower polarity impurities from the mixture. The silica is then washed with a CH2C2 /CH3OH mixture (90/10). 3.78 g of N-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine are obtained (60% yield), and the compound is then converted into its dihydrochloride (m.p. >190° C.) by adding twice the stoichiometric amount of HCl.