Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:52])([F:51])[C:10]1[CH:11]=[C:12]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:13][N:14]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[C:17]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:16]1=2.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:51][C:9]([F:8])([F:52])[C:10]1[CH:11]=[C:12]([CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=1)[CH2:13][N:14]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]2[CH:29]=[C:30]([C:34]([F:35])([F:36])[F:37])[C:31]([CH3:33])=[CH:32][C:16]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add trifluoroacetic acid (10 mL) to a solution of (S)-tert-butyl 5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.04 g, 3.13 mmol) in methylene chloride (50 mL) at 0° C. under nitrogen. Warm the mixture to room temperature, stir for 8 h and pour the mixture into saturated aqueous sodium bicarbonate solution (200 mL). Extract the mixture with methylene chloride (200 mL) and wash the combined organic extracts with brine (50 mL), dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure to provide the title compound as a colorless oil (1.73 g, >99%), which is used in the next step without purification. APCI MS m/z 553 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:20]1([CH2:26][S:27](Cl)(=[O:29])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:27]([CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:29])=[O:28])=[C:4]([F:10])[CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of (4-bromo-2-fluoro-phenyl)methanamine (3 g, 14.7 mmol) in dichloromethane (50 mL) was added N,N-diisopropylethylamine (3.3 mL, 19.1 mmol), followed by phenylmethanesulfonyl chloride (3.3 g, 17.6 mmol) and the reaction was stirred at ambient temperature for 3 hours. The reaction was diluted with dichloromethane and washed with water and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (20-100% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-methanesulfonamide (4.22 g, 80% yield). LCMS (m/z) ES+ 358 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:19].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]([F:19])=[O:11])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)C(C)(C)C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24h (170.3 mg, 0.74 mmol) was added 2.0 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (335 μL, 3.7 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (60 μL, 0.74 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 112.6 mg of a mixture of 24h and 25h as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:33][C@H:34]([CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[C:35]([NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12](=[O:14])[NH:33][C@@H:34]([C:35](=[O:36])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To the solution of (2S)-4-(benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}-4-oxobutanoic acid VIII (430 mg, 1.33 mmol) in DCM (10 mL) was added DIPEA (0.65 mL, 3.75 mmol), (2R)-2-amino-N-(quinolin-6-yl)-4-[4-(trifluoromethyl)phenyl]butanamide VII (540 mg 1.21 mmol) and TBTU (428 mg, 1.33 mmol). The mixture was stirred at r.t. overnight. The reaction mixture was then washed with 1 M K2CO3, 1 M HCl, brine and dried over MgSO4. The residue was then purified on a silica gel column (50:1 CHCl3/methanol) to yield benzyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoate IX (680 mg, 1.00 mmol, 75% yield). 1H NMR (CDCl3) 1.46 (s, 9H), 1.88-2.20 (m, 2H), 2.40-2.64 (m, 1H), 2.66-2.88 (m, 1H), 2.92 (d, J=6 Hz, 1H), 3.27 (dd, J=5 Hz, J=17 Hz, 1H), 4.49-4.70 (m, 2H), 5.12 (d, J=5 Hz, 2H), 5.59 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 7.22-7.42 (m, 8H), 7.53 (s, 1H), 7.57 (s, 1H), 7.72 (dd, J=2 Hz, J=9 Hz, 1H), 8.00 (d, J=9 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 8.41 (d, J=2 Hz, 1H), 8.82 (d, J=4 Hz, 1H), 8.89 (s, 1H); 19F NMR (DMSO-d6) −61.73 (s, 3F); ESIMS found for C36H37F3N4O6 m/z 679 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(OC)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-methoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (18.6 mg) with purity >90%. LCMS (pos) m/z 357.0.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([NH2:32])[CH2:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:27])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([NH:32][CH2:29][CH2:30][CH3:31])=[O:20])[C:14]1([CH3:22])[CH3:23])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Reactant: CCCN
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)NCCC)C1(C)C

Procedure:
The product from Example 205 and propylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.50 (s, 3H), 0.80 (t, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.14 (s, 3H), 1.24 (s, 3H), 1.28-1.43 (m, 5H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.72-1.82 (m, 1H), 2.25-2.47 (m, 2H), 2.61-2.67 (m, 2H), 2.96-3.03 (m, 3H), 7.25-7.29 (m, 1H), 8.50 (s, 1H). (ESI+) m/z 436 (M+H)+. Anal. calcd. for C24H41N3O2S: C, 66.16; H, 9.49; N, 9.65. Found: C, 65.94; H, 9.63; N, 9.44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][NH:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[N:56]([CH3:60])[CH:57]=[CH:58][N:59]=2)=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]([CH3:46])[CH2:48][C:49]3[CH:50]=[CH:51][C:52]([C:55]4[N:56]([CH3:60])[CH:57]=[CH:58][N:59]=4)=[CH:53][CH:54]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(-c2nccn2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-c4nccn4C)cc3)co2)c(C)c1
Reaction time: 1 h

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.14 mmol) was dissolved in DMF (3 mL) and EDCI (32 mg, 0.17 mmol) and HOBt (23 mg, 0.17 mmol) were added. The resulting solution was stirred for 60 min prior to the addition of N-methyl-1-[4-(1-methyl-1H-imidazol-2-yl)phenyl]methanamine (31 mg, 0.17 mmol) dissolved in DMF (2 mL) and stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc (20 mL) and washed with water, saturated aqueous NaHCO3, saturated brine, dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified using prep method C.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:41]=[N+:42]=[N-:43])[CH2:10][C@@H:11]([CH:38]([CH3:40])[CH3:39])[CH:12]([OH:37])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:44])([CH3:3])[CH3:2].[C:45](OC(=O)C)(=[O:47])[CH3:46]>N1C=CC=CC=1>[CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:41]=[N+:42]=[N-:43])[CH2:10][C@@H:11]([CH:38]([CH3:39])[CH3:40])[CH:12]([O:37][C:45](=[O:47])[CH3:46])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:44])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COCCCOc1cc(C(OC(C)=O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1

Procedure:
A solution of 144 mg of 3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-hydroxy-4-[4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one in 1.8 ml of acetic anhydride and 0.057 ml of pyridine is stirred for 30 hours at room temperature and is then concentrated to dryness by evaporation at room temperature and under reduced pressure. The residue is partitioned between dichloromethane (3x) and water/saturated sodium chloride solution (3x). The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (hexane/ethyl acetate=4:1), yielding the title compound: Rf (hexane/ethyl acetate=2:1)=0.38 and 0.33; HPLC Rt =21.76 and 21.82 minutes (diastereoisomeric mixture); FAB-MS M+ =653, (M+Na)+ =676.
Reaction SMILES: CN(C1C=CC=CN=1)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.C(Cl)Cl.[F:20][C:21]1[CH:47]=[CH:46][C:24]([O:25][C:26]2[C:40]([CH:41]3[CH2:45][CH2:44][CH2:43][NH:42]3)=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:23][CH:22]=1>O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[C:40]([CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:15]([NH2:14])=[O:16])=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:46][CH:47]=1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: NC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 mg of dimethylaminopyridine and 0.059 ml of trimethylsilyl isocyanate were added in order to a methylene chloride (1 ml) solution of 31.2 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with ethyl acetate, and then washed with saturated saline. After dried and concentrated, the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] to obtain the entitled compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](C(C)(C)C)[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)(Cl)Cl.[Fe].C(C1C=CC=C(O)C=1O)(C)(C)C>[Br:19][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=1
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: BrBr
Agent: [Fe]
Agent: CC(C)(C)c1cccc(O)c1O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
1,3,5-Tri-t-butylbenzene (150 g, 0.6 mol) was dissolved in carbon tetrachloride (300 mL) in a three-necked flask which had been painted black to avoid light and equipped with an overhead stirrer, thermometer and addition funnel under argon. Iron pellets (36 g, 0.64 mol) were added and the slurry was cooled to 5° C. t-Butylcatechol (1.0 g) was added and a solution of bromine (201.6 g, 1.26 mol) in carbon tetrachloride (75 mL) was added over a one hour period. The slurry was stirred for an additional 4 hours at 5° C. and quenched by pouring into ice water. The layers were separated and the organics washed with 10% sodium hydroxide solution. The solution was then washed with salt brine and dried over magnesium sulfate. The solvent was evaporated and the product was distilled under vacuum twice to give 75 g of product which was then recrystallized from heptane to give 47 g of pure product (29%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=3[CH:3]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2ccc(OC(=O)Cc3ccc(Cl)cc3)cc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (1.15 g., 0.005 mole) triethylamine (0.7 ml, 0.005 mole) and 4-dimethylaminopyridine (5 mg, catalyst) in dimethylformamide (10 ml) is added 2-(4-chlorophenyl)acetyl chloride (0.8 ml). The reaction mixture is stirred for 2 hours, poured into ice water, acidified with hydrochloric acid and extracted with ether. The organic extract is washed with water and dried over magnesium sulfate. The ether is distilled at reduced pressure and the residue chromatographed on silica gel as eluant (130 g, 70-230 mesh) using ethylacetatehexane (1:1) to give 2-sulfamoyl-6-benzothiazolyl 2-(4-chlorophenyl)acetate which melts at 206°-208° C. after recrystallization from benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][N:11]=[C:10]([C:19]([NH:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=3)=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)cn1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(cyclopropylmethyloxy)-pyridine-2-carboxylic acid (example H) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 453.0924 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5]2[CH:10]=[CH:11][N:12]=[CH:13][C:4]=2[S:3]1(=[O:15])=[O:14].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>O1CCOCC1>[CH2:16]([NH:23][C:7]1[N:2]([CH3:1])[S:3](=[O:15])(=[O:14])[C:4]2[CH:13]=[N:12][CH:11]=[CH:10][C:5]=2[N:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CSC1=Nc2ccncc2S(=O)(=O)N1C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1C(NCc2ccccc2)=Nc2ccncc2S1(=O)=O

Procedure:
A solution of 2-methyl-3-methylsulfanyl-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g) and benzylamine (0.5 mL) in dioxane (2.5 mL) was refluxed until completion of the reaction (t.l.c.). After cooling, the addition of ether gave rise to the precipitation of the title compound. The precipitate was collected by filtration, washed with ether and recrystallized from methanol-ether (yield: 0.4 g); m.p. 142°-146° C. (Compound 20).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[C:17]1([CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Li].IC1C=CC=CC=1C>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:24])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: [Li]c1ccccc1C
Agent: Cc1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2C)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (from Example 1) and a solution of 2-tolyllithium (˜3 equiv, freshly prepared from 2-iodotoluene, as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-o-tolyl-methanone as a white solid. MS (M+H)+: 274.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[NH2:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1>O1CCCC1>[CH3:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:3](=[CH:2][NH:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1)[C:4](=[O:13])[NH:5]2
Reactant: Cc1cccc2c1/C(=C/O)C(=O)N2
Reactant: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=CNc1cc[nH]n1)C(=O)N2

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one (0.110 gms.) is reacted with 0.18 mL of 3-aminopyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]1)=[CH:11][C:10]2=[O:22])[CH3:4].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CC(N(C)C)=O>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][CH:3]([C:5]2[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][C:10]3=[O:22])[CH3:4])=[CH:31][CH:30]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Agent: Br
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Yield: 58.8 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.30 mmol) and 4-fluoroaniline (0.113 mL, 1.19 mmol) in DMA (1 mL) were stirred at RT for 4 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. A further purification was done by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford a oil which was triturated with pentane to give 8-(1-(4-fluorophenylamino)ethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (80 mg, 59%) as a white solid. NMR Spectrum (DMSOd6): 1.16 (d, 3H), 1.50 (d, 3H), 2.66 (bs, 3H), 2.81 (ddd, 1H), 2.93 (bs, 3H), 3.14 (ddd, 1H), 3.57-3.70 (m, 2H), 3.87-4.03 (m, 3H), 4.93-5.01 (m, 1H), 5.62 (s, 1H), 6.24-6.29 (m, 1H), 6.43-6.50 (m, 2H), 6.85 (t, 2H), 7.55 (d, 0.5H), 7.56 (d, 0.5H), 7.77 (d, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1C=CC=CC=1.[ClH:33]>O>[ClH:33].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O

Procedure:
A mixture of 2.83 g (0.01 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (II), 4.4 g (0.051 mol) of anhydrous piperazine and 30 ml of dry pyridine is refluxed for 6 hours. The solvent is stripped off in vacuo, the residue is taken up in 25 ml of water, the pH is adjusted to 1 with concentrated hydrochloric acid, while cooling with ice and, when the mixture is cold, the precipitate is filtered off under suction and washed with cold 10% strength hydrochloric acid and ethanol. After drying in vacuo at 100° C., 3.05 g of 1-cyclopropyl-6,8-difluoro-7-(piperazin-1-yl)-1,4-di- hydro-4-oxoquinoline-3-carboxylic acid hydrochloride having a decomposition temperature of 354°-355° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][NH:20][C:18]=3[N:19]=2)=[N:6]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.ClC(Cl)(Cl)S(O[CH2:52][C:53]([F:56])([F:55])[F:54])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][N:20]([CH2:52][C:53]([F:56])([F:55])[F:54])[C:18]=3[N:19]=2)=[N:6]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1nnn2CC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
150 mg (0.415 mmol) of the compound from example 53 and 113 mg (0.0415 mmol) of BEMP were initially charged in 7 ml of dimethylformamide, and a solution of 117 mg (0.415 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate in 2.5 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at RT for 16 h. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water with 0.05% trifluoroacetic acid, gradient 10:90→90:10). 22 mg of the title compound were obtained (11% of theory).