Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[N:9](C(OCC(C)C)=O)[C:8]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:30][CH2:29][CH2:28][N:27]([C:31](OC(C)(C)C)=[O:32])[CH2:26][C:25]=4[CH:38]=3)=[CH:20][C:7]=2[N:6]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[F:55][C:56]1[CH:57]=[C:58]([CH:62]2[CH2:67][C:66](=[O:68])[CH2:65][CH2:64][N:63]2C(Cl)=O)[CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:1][CH2:2][CH2:3][NH:4][C:5]1[NH:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:30][CH2:29][CH2:28][N:27]([C:31]([N:63]5[CH2:64][CH2:65][C:66](=[O:68])[CH2:67][CH:62]5[C:58]5[CH:59]=[CH:60][CH:61]=[C:56]([F:55])[CH:57]=5)=[O:32])[CH2:26][C:25]=4[CH:38]=3)=[CH:20][C:7]=2[N:6]=1
Reactant: O=C1CCN(C(=O)Cl)C(c2cccc(F)c2)C1
Reactant: CC(C)COC(=O)n1c(NCCF)nc2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4ccc5[nH]c(NCCF)nc5c4)cc3C2)C(c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
1,1-Dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4 (5H)-carboxylate (59.4 mg, 0.11 mmol) was taken into neat TFA (1 mL) and allowed to stand for 1 h at room temperature then concentrated and dried. The residue was taken into THF (5 mL) followed by addition of DIPEA (0.2 mL, 1.1 mmol) followed by addition of 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (29 mg, 0.11 mmol) in a minimum of THF and the resulting solution was stirred at room temperature for 30 minutes. The mixture was then concentrated and taken up into methanol (5 mL) followed by addition of solid potassium carbonate (80 mg, 0.56 mmol) and stirring was continued for 30 minutes. The mixture was then concentrated and partitioned with ethyl acetate and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was triturated with ethyl ether and the solid collected by filtration and dried to afford 1-{[7-{2-[(2-fluoroethyl)amino]-1H-benzimidazol-5-yl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-2-(3-fluorophenyl)piperidin-4-one (46.4 mg, 75% yield). 1H NMR (400 MHz, d6-DMSO): 7.51 (s, 1H), 7.42 (d, 1H), 7.36 (s, 1H), 7.31 (q, 1H), 7.18 (d, 1H), 7.12-7.03 (m, 4H), 6.99 (d, 1H), 5.20 (tr, 1H), 4.66 (tr, 1H), 4.57 (dd AB, 2H), 4.54 (tr, 1H), 4.20 (br m, 2H), 3.75-3.56 (br m, 6H), 2.86 (m, 2H), 2.60 (m, 1H), 2.33 (br d, 1H). MS (EI) for C30H29F2N5O3: 547 (MH+).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(F)c2)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine-2HCl (70.6 mg, 0.209 mmol), (3-fluorophenyl)acetic acid (32.2 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base (0.146 mL, 0.836 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The solid was filtered and dried to afford a white solid as the product. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (t, J=8.46 Hz, 2H), 3.73 (s, 3H), 3.92 (s, 2H), 4.19-4.26 (m, 2H), 7.08-7.11 (m, 1H), 7.12-7.17 (m, 2H), 7.23 (d, J=8.34 Hz, 1H), 7.25 (s, 1H), 7.31 (s, 1H), 7.36 (s, 1H), 7.39 (d, J=6.82 Hz, 1H), 8.10-8.17 (m, 2H).
Reaction SMILES: BrC1C=CC(F)=C2C=1CC[C@H:6]2[O:12]C1C=CC2[C@H](CC(O)=O)COC=2C=1.FC1[CH:28]=[CH:29][C:30]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[C:31]2[C:35]=1[C@H:34]([O:36][C:37]1[CH:49]=[CH:48][C:40]3[C@H](CC(O)=O)COC=3C=1)[CH2:33][CH2:32]2.B(O)O>>[CH3:32][C:31]1[CH:35]=[C:34]([CH:33]=[C:29]([CH3:28])[C:30]=1[B:50]1[O:51][C:52]([CH3:57])([CH3:58])[C:53]([CH3:55])([CH3:56])[O:54]1)[O:36][CH2:37][CH2:49][CH:48]([CH3:40])[CH2:6][OH:12]
Reactant: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: CC1(C)OB(c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)OC1(C)C
Agent: OBO
Product: Cc1cc(OCCC(C)CO)cc(C)c1B1OC(C)(C)C(C)(C)O1

Procedure:
Examples 53, 54, and 55 are also obtained via coupling {(S)-6-[(R)-4-bromo-7-fluoroindan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid (Example 63) or {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid with the corresponding coupling partner bearing a metal or pseudo-metal group, e.g., boronic acid or ester, or a leaving group, e.g., Cl or Br, at the carbon to be coupled. Accordingly, Example 53 is obtained from, e.g., 4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methylbutanol or the corresponding boronic acid (Intermediate 23) and [(S)-6-((R)-4-bromo-7-fluoroindan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid (e.g., as acid or the piperazinium or morpholinium salt) or from, e.g., 4-(4-bromo-3,5-dimethylphenoxy)-2-methylbutanol and {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid (e.g., as acid or the piperazinium or morpholinium salt), as described below.
Reaction SMILES: C([O:4][C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=CC=1.[Sn](Cl)(Cl)(Cl)Cl>ClCCl>[S:41]1[CH:35]=[CH:40][CH:39]=[C:38]1[C@:5]1([O:18][C@H:17]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29])[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Sc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@](O)(c2cccs2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 99 %

Procedure:
Compound [2] (0.31-8.02 g, 0.68-17.7 mmol) is dissolved in 3.2-100 ml of dry dichloromethane, and thiophenol (0.15-3.9 g, 1.36-35.4 mmol) and tin tetrachloride (0.35-9.22 g, 1.36-35.4 mmol) are added and the mixture is stirred until reaction is complete. The reaction mixture is diluted and then washed with saturated sodium bicarbonate solution. The crude product compound [3] obtained in this way is purified by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.27-7.14 g, 0.54-14.2 mmol, about 80%) and is dissolved in anhydrous methanol (3-90 ml) and catalytic amounts of sodium methylate (prepared from 0.002-0.05 g of sodium in 0.1-2 ml of methanol) are added. After the reaction is complete, the mixture is neutralized with an acidic ion exchanger (0.2-5 g Amberlite IR-120, H+ -form) (4: 0.21-5.31 g, 0.54-14.1 mmol, about 99% yield). FAB-MS: M+H+ =378. NMR data consistent with Nicolaou et al., J. Am. Chem. Soc. 112:3695 (1990)) and T. J. Caulfield, Ph. D. Dissertation, The University of Pennsylvania (1991).
Reaction SMILES: CC1C=C(C=CN=1)C(O)=O.C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[F:53][C:54]1[CH:59]=[CH:58][C:57]([S:60][C:61]2[CH:62]=[C:63]3C4(CCN(C(OCC5C=CC=CC=5)=O)CC4)C[NH:67][C:64]3=[CH:65][CH:66]=2)=[CH:56][CH:55]=1>ClCCl>[F:53][C:54]1[CH:59]=[CH:58][C:57]([S:60][C:61]2[CH:62]=[CH:63][C:64]([NH2:67])=[CH:65][CH:66]=2)=[CH:56][CH:55]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CNc1ccc(Sc3ccc(F)cc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cc1cc(C(=O)O)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a suspension of 2-methylisonicotinic acid (596 mg, 4.35 mmol) in dichloromethane (100 mL) are added N,N-diisopropylethylamine (1.15 mL, 6.72 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.91 g, 5.02 mmol). The mixture was stirred at room temperature for 1 h, after which benzyl 5-(4-fluorophenylthio)spiro[indoline-3,4′-piperidine]-1′-carboxylate (1.51 g, 3.37 mmol) is added. The reaction mixture is stirred at room temperature. After 18 h, additional 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.75 equiv) is added. After 2 days reaction time, the mixture is diluted with dichloromethane (300 mL), washed with saturated aqueous sodium hydrogen carbonate (100 mL) and brine (100 mL). The organic layer is dried over sodium sulphate, filtered and is concentrated under reduced pressure to give a brown oil. Purification of the crude by column chromatography on silica gel (heptane/ethyl acetate 40 to 100% as eluent) affords the desired product (1.09 g, 1.92 mmol, 57% yield) (HPLC-MS Method 2: retention time: 2.284 min, m/z 568.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:30](B1OC(C)(C)C(C)(C)O1)=[CH2:31].C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:30]=[CH2:31])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 46.3 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g), bis(tricyclohexylphosphine)palladium (II) dichloride (332 mg), tripotassium phosphate (11 g) and vinylboronic acid pinacol ester (3 g) were added toluene (27 mL) and water (1.4 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g). 4-(3-Methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g) was dissolved in ethanol (20 mL), 5% palladium carbon-ethylenediamine complex (600 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 8 hr at room temperature. After celite filtration, the solvent in the filtrate was evaporated to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg). 4-(5-Ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg) was dissolved in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. 1N Aqueous sodium hydroxide solution (7 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (441 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42]N(C)C)=[O:39])=[CH:36][C:35]=1[O:48][CH3:49]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][CH2:6][N:7]([CH3:16])[CH3:8])=[O:39])=[CH:36][C:35]=4[O:48][CH3:49])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 66.5 %

Procedure:
A mixture of 0.0638 g (0.211 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0601 g (0.32 mmole) of toluenesulfonic acid monohydrate, 0.053 g (0.211 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 20 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) and then recrystallization from acetonitrile to give 0.0363 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-9) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([C:35](O)=[O:36])[N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[CH2:38]([NH:45][C:35](=[O:36])[C@@H:10]([N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCc1ccccc1
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3-[(tert-Butoxycarbonyl)amino]-N-({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)-N-(2-methylpropyl)-L-alanine (27 mg), benzylamine (200 μl) and diisopropylethylamine (300 μl) were dissolved in 1,2-dichloroethane (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (100 mg) was added, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and fractions eluted with water-acetonitrile (9:1) to acetonitrile were collected. The mixture was basified (pH 10) with saturated aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (19 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][CH:12]([F:15])[CH2:13][OH:14]>>[F:11][CH:12]([F:15])[CH2:13][O:14][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: OCC(F)F
Product: CC(=O)c1ccc(OCC(F)F)nc1
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (1.34 g, a white solid) from 1-(6-chloropyridin-3-yl)ethanone (1.5 g, 9.64 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-2.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: Clc1ccccn1
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccccn4)CC3)cc2)C1
Temperature: 160 °C

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide (30 mg) and 2-chloropyridine (90 mg) were heated at 160° C. for 2 hours. 2-Chloropyridine (0.2 ml) was added and the mixture was again heated at 160° C. for 4 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 393.54 (C23H31N5O); MS (ESI): 394 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9](=[O:13])(=[O:12])[CH2:10][CH2:11][N:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:2]1[C:7]2=[N:8][S:9](=[O:13])(=[O:12])[CH2:10][CH2:11][N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Cl)cc3Cl)C2=N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (26 mg) were added a solution of 2,4-dichlorophenylboronic acid (38 mg) in ethanol (0.5 mL), toluene (0.5 mL), tetrakis(triphenylphosphine)palladium(0) (11 mg) and cesium carbonate (98 mg), and the mixture was stirred at 100° C. overnight. To the reaction solution were added saturated aqueous sodium hydrogen carbonate solution (1 mL) and ethyl acetate (3 mL) and the mixture was stirred. The organic layer was passed through a phase separation filter, and the solvent was evaporated from the separated solution by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase:acetonitrile/10 mM aqueous ammonium acetate solution) to give the title compound (20.7 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25](OCC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[BH4-].[Li+].O1CCCC1.Cl>CO>[OH:26][CH2:25][CH2:24][CH:21]1[S:20][C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[N:23][CH2:22]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc2cc(C3=NCC(CCO)S3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.8 %

Procedure:
To a mixture of ethyl (2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.27 g), lithium borohydride (70 mg) and tetrahydrofuran (10 mL) was added methanol (2 mL), and the mixture was stirred at room temperature for 5 hr. Diluted hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (46 mg, yield: 19%) as colorless plate crystals.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:30][C:31](=[O:33])[CH3:32].[I-].[Na+]>CC(C)=O>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([NH:17][CH2:30][C:31](=[O:33])[CH3:32])=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(=O)N1c2ccc(N)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CNc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-amino-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 112) (1.46 g, 4.78 mmol) in acetone (15 mL) at 60° C. was added potassium carbonate (0.991 g, 7.17 mmol) and the resulting mixture was stirred at this temperature for 15 min. 1-Chloro-2-propanone (0.457 ml, 5.74 mmol) was added as well as sodium iodide (0.860 g, 5.74 mmol) and resulting mixture was stirred at 60° C. for 1 h then cooled to room temperature, filtered through celite and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 10 to 100% AcOEt in Hexanes) gave 1-methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[(2-oxopropyl)amino]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (1.11 g, 3.07 mmol, 64%) as an orange foamy solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[C:24]([OH:30])(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:28][CH2:27][CH2:26][CH2:25][C:24]([OH:30])=[O:29])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:23])[NH:19][S:20]1(=[O:21])=[O:22]
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CCCC(=O)O
Product: O=C(O)CCCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and pent-4-enoic acid analogous to Example 44: (M−1)−=327.
Reaction SMILES: CC1C=C(S(N2C3C=C(C(O)=O)C=CC=3SCC2)(=O)=O)C=C(C)C=1.NC1C=CC(C(OC(C)(C)C)=O)=CC=1.C([O:43][C:44](=[O:75])[C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([C:54]2[CH:55]=[CH:56][C:57]3[S:62][CH2:61][CH2:60][N:59]([S:63]([C:66]4[CH:71]=[C:70]([CH3:72])[CH:69]=[C:68]([CH3:73])[CH:67]=4)(=[O:65])=[O:64])[C:58]=3[CH:74]=2)=[O:53])=[CH:47][CH:46]=1)(C)(C)C>>[CH3:73][C:68]1[CH:67]=[C:66]([S:63]([N:59]2[C:58]3[CH:74]=[C:54]([C:52]([NH:51][C:48]4[CH:47]=[CH:46][C:45]([C:44]([OH:75])=[O:43])=[CH:50][CH:49]=4)=[O:53])[CH:55]=[CH:56][C:57]=3[S:62][CH2:61][CH2:60]2)(=[O:65])=[O:64])[CH:71]=[C:70]([CH3:72])[CH:69]=1
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCSc3ccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)cc32)c1
Agent: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: Cc1cc(C)cc(S(=O)(=O)N2CCSc3ccc(C(=O)O)cc32)c1
Product: Cc1cc(C)cc(S(=O)(=O)N2CCSc3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc32)c1

Procedure:
Reaction of 4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid with tert-butyl 4-aminobenzoate in accordance with the general method of example 30, step 4 produced 4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic acid tert-butyl ester. White solid, MS (ISP)=539.3 (M+H)+.