Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7](Cl)[CH:6]=1)=[O:4].[F-:16].[K+]>CS(C)(=O)=O.ClCCl.O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([F:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)nc2ccccc12
Reactant: [F-]
Agent: CS(C)(=O)=O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(F)nc2ccccc12
Temperature: 180 °C
Yield: 66.3 %

Procedure:
2-Chloroquinoline-4-carboxylic acid methyl ester (1.14 g) in dimethylsulfone (4.0 g) was treated with potassium fluoride (2.5 g) and heated at 180° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane:water (1:1, 200 ml), the organic phase separated, solvent removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane eluant) to give 2-fluoroquinoline-4-carboxylic acid methyl ester (0.7 g). 1H NMR (CDCl3) δ: 3.99 (3H, s), 7.57 (2H, m), 7.72 (1H, m), 7.95 (1H, d, J=8.5 Hz), 8.67 (1H, d, J=8.4 Hz). m/z (API+): 205 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:22][C:23]1[S:24][C:25]([CH3:29])=[C:26]([CH3:28])[N:27]=1>C1(C)C(C)=CC=CC=1>[CH3:28][C:26]1[N:27]=[C:23]([NH:22][C:3]([C:5]2[NH:6][S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[S:24][C:25]=1[CH3:29]
Reactant: Cc1nc(N)sc1C
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Solvent: Cc1ccccc1C
Product: Cc1nc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2)sc1C
Yield: 35 %

Procedure:
N-(4,5-Dimethyl-2-thiazolyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 37 from 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 2-amino-4,5-dimethyl-thiazole. Yield: 35% of theory;m.p. 253° C (decomp.; from xylene).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:27]=[C:28]([OH:30])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:28]2[CH:27]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:25]=[C:24]([F:23])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: COC(=O)CCc1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCc1cc(F)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 76.9 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (350 mg) in acetonitrile (25 mL) were added methyl 3-(3-fluoro-5-hydroxyphenyl)propanoate (208 mg) and cesium carbonate (1.41 g), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (390 mg) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:36][CH2:37][S:38][C:39]2[N:40]=[N:41][NH:42][CH:43]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:50](Cl)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl.P(Cl)(Cl)(Cl)(Cl)Cl.C(O)CC(O)C>ClCCl.O>[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:36][CH:37]([C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[S:38][C:39]2[N:40]=[N:41][NH:42][CH:43]=2)=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12
Agent: CC(O)CCO
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 7β-phenylacetamido-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (10.0 g: 15.9 mMol.) in dichloromethane (100 ml) under ice cooling are added pyridine (1.54 ml: 19.1 mMol.) and trityl chloride (5.32 g: 19.1 mMol.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is mixed with 10% hydrochloric acid (2 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated. To a solution of the residue in dichloromethane (50 ml) under ice cooling are added pyridine (2.57 ml: 31.8 mMol.) and phosphorus pentachloride (5.96 g: 28.6 mMol.), and the mixture is stirred for 30 minutes. The reaction mixture is added dropwise to a solution of 1.3-butanediol (8.6 ml: 95.9 mMol.) in dichloromethane (25 ml) at -30° C., and the mixture is stirred at - 20° to -30° C. for 10 minutes and under ice cooling for 40 minutes. The reaction mixture is mixed with water, diluted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. The residue is pulverized with ether, washed with ether, dissolved in dichloromethane, washed with 5% aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (6.70 g: pale yellow foam, Yield: 56%,
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]2[OH:32])=[C:14]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:13]=1.[N:48]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=2)[CH2:53][CH2:52][CH:51]([NH:54][C:55](N2C=CN=C2)=[O:56])[CH2:50][CH2:49]1>CC(O)C.C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:42]1([CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][NH:33][C:14]2[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:55]([NH:54][CH:51]3[CH2:50][CH2:49][N:48]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=4)[CH2:53][CH2:52]3)=[O:56])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]2[OH:32])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of N-{(1S,2R,3S,4R)-4-[2-(2-amino-ethylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide trifluoroacetate (Example 100) (27 mg, 37 μmol) in IPA (0.5 ml) is treated with imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate C) (1.1 ml of a 10 mg/ml solution in DCM, 40 μmol). After stirring at room temperature for 7 days, the solvent is removed in vacuo and purification of the residue by C-18 reverse phase column chromatography eluting with acetonitrile:water:TFA (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 748.6)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:46]1[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]2[CH:58]=[N:57][CH:56]=[C:55]([C:59]3[CH:60]=[N:61][N:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=34)[N:54]=2)[CH2:47]1>CN(C=O)C>[O:12]=[C:10]([N:46]1[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]2[CH:58]=[N:57][CH:56]=[C:55]([C:59]3[CH:60]=[N:61][N:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=34)[N:54]=2)[CH2:47]1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccn2ncc(-c3cncc(N[C@@H]4CCCNC4)n3)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
[(Tert-Butoxycarbonyl)amino]acetic acid (65 mg, 0.37 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (142 mg, 0.37 mmol) and diisopropylethylamine (65 mL, 0.37 mmol) were added to a solution of (R)—N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-amine (Preparation 28b, 100 mg, 0.34 mmol) in N,N′-dimethylformamide (2 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water and the organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to yield the title compound (88 mg, 57%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][O:27][Si](C)(C)C(C)(C)C)[CH:20]=[CH:19]3)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=CC(/C=C/C(O)=O)=CC=1)(C)(C)C.C[Si](C)(OCCN1C2C(=CC(N)=CC=2)C=C1)C(C)(C)C>>[C:1]([C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][OH:27])[CH:20]=[CH:19]3)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3c(ccn3CCO[Si](C)(C)C(C)(C)C)c2)cn1
Agent: CC(C)(C)[Si](C)(C)OCCn1ccc2cc(N)ccc21
Agent: CC(C)(C)c1ccc(/C=C/C(=O)O)cn1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3c(ccn3CCO)c2)cn1

Procedure:
(2E)-3-[6-(tert-butyl)(3-pyridyl)]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-5-yl}prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enoic acid, Example 44(b), (41 mg, 0.20 mmol) and 1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indole-5-ylamine, Example 73(a), (60 mg, 0.20 mmol) provided the title product. MS (ESI, pos. ion) m/z: 478 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Product: Clc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
A 269 g. portion of 6-(p-chlorophenyl)-3(2H)-pyridazinone and 1500 ml. of phosphorus oxychloride are heated on a steam bath for 5 hours. The excess phosphorus oxychloride is removed under vacuum. The solid concentrate is diluted with ice water and the resulting solid is recovered by filtration, washed with water and dried. This product is recrystallized twice from dimethylformamide-water yielding 6-(p-chlorophenyl)-3-chloropyridazine as an off-white solid, m.p. 202°-204° C.
Reaction SMILES: [CH3:1]S(O)(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=[CH:10]2>CO.C(OCC)(=O)C>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:1])=[O:18])=[CH:12][CH:11]=[CH:10]2
Reactant: CS(=O)(=O)O
Reactant: O=C(O)c1cccc2cc(O)ccc12
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2cc(O)ccc12
Temperature: 25 °C
Yield: 478.6 %

Procedure:
Methanesulfonic acid (18 mL, 0.28 mol) was added to a stirred solution of 6-hydroxy-1-naphthoic acid (262 g, 1.39 mol) in methanol (1 L) under N2 and the reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and concentrated to give a purple solid. The solid was dissolved in ethyl acetate (1 L), washed with water (3×300 mL), saturated sodium bicarbonate solution (2×300 mL), water (500 mL), brine (300 mL) and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated to give 271 g of the product as a pink solid. 1H NMR (400 MHz, d6-DMSO): δ 9.94 (s, 1H), 8.58 (m, 1H), 7.93 (d, J=8 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.22-7.19 (m, 2H), 3.88 (s, 3H). ESI-LCMS m/z 203 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.S(Cl)(Cl)=O>O>[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1cnc2ccccc2c1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1cnc2c(S(=O)(=O)Cl)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
The title compound was prepared according to the procedure of U.S. Pat. No. 5,332,822. To 9 mL (135 mmol) of chlorosulfonic acid at 0° C. was added slowly 3-methylquinoline (5.2 g, 36 mmol). The bath was removed and stirring was continued at 100° C. overnight. The reaction mixture was cooled to ambient temperature and then treated with 3.3 mL (45 mmol) of thionyl chloride. The reaction mixture was heated at 70° C. for 1 h, cooled to 0° C. and carefully quenched with ice (very vigorous reaction). The reaction mixture was diluted with 100 mL of water and extracted into dichloromethane (100 mL). The organic phase was washed with water, dried (MgSO4) and concentrated. The residue was triturated with dichloromethane/diethyl ether to provide 1.58 g (18%) of the title compound as a tan solid. 1H-NMR (300 MHz, DMSO-d6) δ9.17-9.29 (m, 2H), 8.32-8.38 (m, 2H), 7.96 (dd, 1H, J=7 Hz), and 2.51 (t, 3H, J=2 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)N2CCOCC2)c1
Temperature: 55 °C
Reaction time: 32 h
Yield: 22 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(morpholine-4-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (437 mg, 1 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 55° C. for 32 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(morpholine-4-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 22%) as a white solid: LC/MS m/e calcd for C23H27N3O4 (M+H)+: 410.49, observed: 410.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11]Br>C(O)(=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:11][CH2:9][C:8]([C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: CC(=O)c1cccnc1Br
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1cccnc1Br
Temperature: 90 °C
Yield: 73.4 %

Procedure:
A solution of 1-(2-bromopyridin-3-yl)ethanone (2.10 g, 10.5 mmol) in acetic acid (28.0 mL) was treated with bromine (595 μL, 11.5 mmol) and heated at 90° C. for 1 h. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and further extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) gave the desired product (2.15 g, 73%). LCMS calculated for C7H6Br2NO (M+H)+: m/z=277.9, 279.9, 281.9. found: 277.7, 279.7, 281.8.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:40])[C@@H:10]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1)[C:11]([NH:13][NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:40])[C@@H:10]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([C:36]([F:37])([F:39])[F:38])[CH:29]=1)[C:11]1[O:26][C:15]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-(methylsulfonyl)benzohydrazide (5.29 g, 8.80 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (4.64 g, 17.7 mmol), iodine (4.48 g, 17.6 mmol) and Et3N (4.9 mL, 35.2 mmol). The reaction mixture was warmed to room temperature, stirred for 20 minutes and quenched with 10% sodium thiosulfate (100 mL). The organic extract was washed with 10% sodium thiosulfate (100 mL), H2O (100 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a pink foam, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes) to provide the title compound (4.81 g, 94%), which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][NH:10][C:9](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.S(Cl)([Cl:21])=O>ClC1C=CC=CC=1>[Cl:21][C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[S:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]sc2c([N+](=O)[O-])cccc12
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c(Cl)nsc12
Reaction time: 1 h
Yield: 86 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 98.1 g (0.5 mol) of 7-nitro-1,2-benzisothiazol-3-one, 146.2 g (2 mol) of N,N-dimethylformamide and 500.0 g of chlorobenzene. While stirring, 119.0 g (1.0 mol) of thionyl chloride was added dropwise thereto at 80° to 90° C. over 1 hour, and the mixture was reacted at the same temperature for 3 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was recrystallized from toluene to give 91.2 g (0.43 mol) of 3-chloro-7-nitro-1,2-benzisothiazole. The yield based on 7-nitro-1,2-benzisothiazol-3-one was 85%.
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH2:9][N:10]2[CH2:25][CH2:24][C:13]3([O:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14]3(O)[CH3:22])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]1([C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][CH2:9][N:10]2[CH2:25][CH2:24][C:13]3([O:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[CH2:22])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN1C(=O)OC2(CCN(CC=C(c3ccccc3)c3ccccc3)CC2)C1(C)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C1N(CCC)C(=O)OC12CCN(CC=C(c1ccccc1)c1ccccc1)CC2
Reaction time: 4.5 h
Yield: 85.7 %

Procedure:
12.6 g of 8-(3,3-diphenyl-2-propenyl)-4-hydroxy-4-methyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4,5]decane are refluxed in a mixture of 126 ml of acetic acid and 5.7 ml of acetic anhydride under nitrogen while stirring for 4 to 5 hours, then the solvent is distilled off under reduced pressure. The residue is made alkaline by adding 5% by weight aqueous sodium hydroxide solution and extracted with benzene. After washing the benzene phase with water to neutral and drying over anhydrous sodium sulfate, benzene is evaporated under reduced pressure and the remaining crude product is recrystallized from ethanol to give the title compound in 85.7% yield, m.p.: 126°-127° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:23][CH:22]=1)=O.[OH2:34]>>[NH2:17][C:18]1[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])=[CH:23][CH:22]=2)=[N:8][C:9]2[C:5]([C:6]=1[C:7]([OH:34])=[O:12])=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:11][CH:10]=2
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C1=O
Reactant: NCC(=O)c1ccc(-c2ccccc2F)cc1
Reactant: O
Agent: Cl
Product: Nc1c(-c2ccc(-c3ccccc3F)cc2)nc2ccc(C(F)(F)F)cc2c1C(=O)O

Procedure:
A solution of 6.45 g of 5-triflouromethylisatin in water was reacted with 7.97 g of 2-amino-1-(2'-fluoro[1,1'-biphenyl]-4-yl)-ethanone hydrochloride (example 17) by the procedure described in example 18, giving 9.0 g of the desired compound as a yellow solid, mp 255°-260° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH2:13]([OH:16])[C:14]#[CH:15].Cl>O1CCCC1>[CH2:13]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]#[CH:15]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: C#CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)CC(=O)OCC
Yield: 95.3 %

Procedure:
A solution of ethyl 4-chloroacetoacetate (294 g) in tetrahydrofuran (200 ml) was added over 3 hours to a stirred, ice-cooled suspension of sodium hydride (150 g of a 80% dispersion in mineral oil) in tetrahydrofuran (500 ml) at such a rate than the reaction temperature remained ≤20°. A solution of prop-2-ynol (100 g) in tetrahydrofuran (200 ml) was then added over 2 hours to the above mixture with stirring and ice-cooling at such a rate that the reaction temperature never exceeded +25°. The mixture was then stirred at room temperature for 16 hours, poured into 2M HCl (900 ml) and the layers separated. The organic layer was evaporated and the resulting red oil was separated in a separating funnel from the mineral oil. The red oil was taken up in dichloromethane and the resulting solution was washed several times with water, dried over Na2SO4 and evaporated to give the title compound (313 g) as a dark oil which was used directly in Preparation 3.