Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH2:24][CH2:25][CH3:26].N12CCCN=C1CCCCC2.C(OC(C)C)(C)C>CN(C)C=O>[C:23]([N:28]1[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:35])[CH2:32][CH2:33]1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCC(=O)N1CCC(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)OC(C)C
Product: CCCC(=O)N1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 40.6 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1-butyryl-4-piperidinecarboxylic acid (6 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 250 g) contained in a column 4.2 cm in diameter [eluant: a mixture of methylene chloride and methanol (99:1 by volume)], collecting 70-cc fractions. Fractions 82 to 110 are combined and concentrated to dryness under reduced pressure (b 2.7 kPa). The solid obtained is taken up with stirring with isopropyl ether, then separated by filtration and dried. 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 1-butyryl-4-piperidinecarboxylate (6 g), m.p. 165° C., is thereby obtained.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[C:11]([C:15]([C:18]([O:21][C:22]([C:28](Cl)=[O:29])([C:24]([F:27])([F:26])[F:25])[F:23])([F:20])[F:19])([F:17])[F:16])([F:14])([F:13])[F:12]>[Pd]>[C:11]([C:15]([C:18]([O:21][C:22]([CH:28]=[O:29])([C:24]([F:26])([F:27])[F:25])[F:23])([F:20])[F:19])([F:17])[F:16])([F:14])([F:13])[F:12]
Reactant: O=C(Cl)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Product: O=CC(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 75 h
Yield: 53.5 %

Procedure:
A 3-necked round bottom flask equipped with a dropping funnel and reflux condenser was charged with 10% Pd/C(0.35 g) and cooled to 0° C. Triisopropylsilane (6.0 g) was added. CF3CF2CF2OCF(CF3)COCl (10.9 g) was added, and the mixture was stirred at 25° C. for 75 hr. During this period, a total of 0.5 g of additional catalyst was added in ca. 0.1 g increments. Vacuum transfer and separation of the lower layer after chilling at -25° C. provided 5.26 g of liquid. 1H NMR (THF-d8 /F11): 9.9 (m). 19F NMR: -79.4 (m), -81.1 (s), -81.4 (t, J=7.2), -129.5 (s), -138.8 (m). 1H-decoupling experiment showed JHCCFCa. 2.5 Hz.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]1.[CH2:28]([O:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH3:29]>>[CH2:28]([O:30][CH2:31][CH2:32][C:33]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([OH:24])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:27])[C:9](=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]2)[C@@H:10]([CH3:25])[CH2:11]3)[CH2:14][CH2:15]1)=[O:34])[CH3:29]
Reactant: CCOCCC(=O)Cl
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Product: CCOCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
15.0 g of 11β,17,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted analogously to Example 4(a) with 3-ethoxypropionic acid chloride, worked up, and purified, thus isolating 13.6 g of 21-(3-ethoxypropionyloxy)-11β,17-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 186° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]=[O:11])[CH3:2].[OH-:12].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])[CH3:2]
Reactant: [OH-]
Reactant: CCc1ccccc1CC=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1ccccc1CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the crude (2-ethylphenyl)acetaldehyde in 20 ml of EtOH was added a solution of 2.29 g (13.52 mmol) of AgNO3 in 7.5 ml of water and a solution of 2.08 g (37.2 mmol) of KOH in 13 ml of water at 0° C. The reaction mixture was stirred at 0° C. for 2 h and was filtered to remove the solid. The filtrate was extracted with CH2Cl2 (20 ml×3) to remove impurity. The aqueous was acidified with 6N HCl to PH=1 and was extracted with CH2Cl2 (50 ml×3). The combined organic layers were dried MgSO4 and concentrated to give 2-ethylphenylacetic acid.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:17][C:18]([OH:20])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.ClC(OCC)=O.[CH3:27][NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[CH3:27][N:28]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[C:18](=[O:20])[CH2:17][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: O=C(O)Cn1ccc2ccccc21
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Cn1ccc2ccccc21)[C@@H]1CCCC[C@H]1N1CCCC1
Reaction time: 0.08 h
Yield: 29.5 %

Procedure:
Triethylamine (139 μl, 1 mmol) was added to a solution of 1H-indole-1-acetic acid (175 mg, 1 mmol) in tetrahydrofuran (10 ml) at -15° C. with vigorous stirring. Ethyl chloroformate (96 μl, 1 mmol) was added, and the mixture stirred for five minutes. A solution of trans-(±)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine (182 mg, 1 mmol) in tetrahydrofuran (2 ml) was added, and stirring continued for 30 minutes at -15° C., then 30 minutes at room temperature. The reaction was evaporated to small volume, the residue dissolved in ethyl acetate (50 ml), and washed with saturated sodium biocarbonate solution (3×50 ml). The organic extract was drige (MgSO4), evaporated under reduced pressure, and recrystallized from diethyl ether/methylene chloride to yield the amide (100 mg, 32%); Vmax C=0 1635 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([NH2:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:22](COCC[Si](C)(C)C)[N:23]=[C:24]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH2:28][CH2:27]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([NH2:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:22][N:23]=[C:24]([NH:25][CH:26]3[CH2:27][CH2:28][N:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH2:30][CH2:31]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2nc(-c3c(F)cccc3F)c3cc(C(N)=O)ccc3c21
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)n[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A 50 ml round-bottom flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 300 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide in 8 ml of DCM. 3 ml of TFA are added and the mixture is stirred at RT for 2 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of water and 2 ml of 0.75M aqueous ammonia solution. The product is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. Chromatography on silica gel (15-40 μm), eluting with AcOEt, gives 30 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (pale yellow solid). MS (E/I): m/z=554 (M+); 1H NMR: 1.69 (m, 2H); 2.17 (m, 2H); 3.38 (m, 2H); 3.83 (m, 2H); 3.93 (m, 1H); 6.24 (m, 1H); 7.33 (t, J=8.0 Hz, 2H); 7.58 (broad s, 1H); 7.69 (m, 1H); 8.17 (broad s, 1H); 8.23 (broad s, 1H); 8.36 (broad d, J=8.5 Hz, 1H); 8.44 (d, J=8.5 Hz, 1H); 12.9 (broad s, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[NH:19]1[CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>C(O)C>[N:19]1([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[N:3]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: C1CNC1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(N2CCC2)nc2ccccc21
Temperature: 50 °C

Procedure:
2-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (0.5 g) was placed in a flask with azetidine (0.48 mL), Hunig's base (iPr2Net, 1.5 mL) in 1 mL of ethanol. The reaction was heated to 50° C. overnight and then concentrated to dryness to get 0.55 g of crude 2-(azetidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:15])=[CH:4][N:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(Br)nc1
Reactant: O
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: O=C(O)c1ccc(Br)nc1
Temperature: 110 °C
Yield: 44 %

Procedure:
After dissolving 2-bromo-5-picoline (100 g, 0.291 mol) in 1000 ml of water, Aliquat336 (2 ml) was added, and then potassium permanganate (251 g, 0.797 mol) was gradually added over a period of 1 hour and 30 minutes while stirring at 110° C. This mixture was further stirred for an hour, the reaction mixture was filtered through celite without cooling and washed with water, and the filtrate was concentrated to approximately half volume under reduced pressure. After adding 48% hydrobromic acid (˜300 ml), the precipitated crystals were filtered, washed with water and dried to yield the title compound (white crystals 52 g, 44%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[C:11]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][N:13]1[C:14]2[C:10](=[CH:9][C:8]([NH2:7])=[CH:16][CH:15]=2)[C:11]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:12]1
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NC(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of [1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yl]-carbamic acid tert-butyl ester [0.2 g, Reference Example 30] in dichloromethane was treated with trifluoroacetic acid (2 mL). After stirring at ambient temperature for 16 hours the reaction mixture was evaporated. The residue was suspended in saturated sodium bicarbonate solution (10 mL) and the resulting solid was filtered then dried to give the title compound as a yellow solid, m.p. 247-248° C. MS: 263 (MH+).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14](CC([O-])=O)=[CH:13][CH:12]=1.Cl>O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:1])=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: O=C([O-])Cc1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A 30 liter resin pot is fitted with stirrer, thermometer and reflux condenser, and charged with 2.62 kg of 50% aqueous sodium hydroxide and 11.34 liters of water. 4-(2',4'-Difluorophenyl)phenylacetate (1.876 kg., 7.55 m) is added and the batch is heated to reflux over 2.5 hours. The batch is refluxed for 2 hours (in solution at 75°), then cooled to 100° and added to a solution of 3.27 liters of concentrated hydrochloric acid in 9.8 liters of water in a 50 liter resin pot over a 30 minute period.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13](Cl)Cl.Cl.[NH2:17]O.C([O-])=O.[Na+]>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]#[N:17]
Reactant: Clc1cnc2c(C(Cl)Cl)c(Cl)ccc2c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Yield: 78.5 %

Procedure:
28.1 parts by weight of the 3,7-dichloro-8-dichloromethylquinoline thus obtained, 6.95 parts by weight of hydroxylamine hydrochloride and 13.6 parts by weight of sodium formate in 200 ml of formic acid and 60 ml of water were stirred for 12 hours at 100° C., the reaction solution was poured onto ice, the precipitated solid was filtered off under suction, washed neutral with water and dried. 19 parts by weight of 3,7-dichloro-8-cyanoquinoline of melting point 222° C. were obtained. Yield: 78.5% of theory.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[N:24]([CH3:50])[C:25]([C:27]1[S:49][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([C:40](=[O:48])[NH:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=1)=[O:26]>CCOC(C)=O>[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[N:24]([CH3:50])[C:25]([C:27]1[S:49][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([C:40]([NH:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:45])=[O:46])=[O:48])=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=1)=[O:26]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)NCCS(C)(=O)=O)cc1OCC2)c1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)NCCS(C)(=O)=O)cc1OCC2)c1cc(C(=O)N2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of HCl in EtOAc (4M, 20 mL) was slowly added into a solution of tert-butyl 4-(4-chloro-3-(N-methyl-8-(2-(methylsulfonyl)ethylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate (350 mg, 0.48 mmol) in EtOAc (5 mL) at 0° C. The mixture was stirred at room temperature for overnight. The solids were filtered and washed with EtOAc, dried to give 334 (176.6 mg, yield: 55%). 1H NMR (MeOD, 400 MHz): δ7.77-7.44 (m, 7H, ArH, NH), 6.93 (s, 1H, ═CH), 4.24-3.04 (m, 23H). LC-MS: (ESI, m/z)=631 [M+H]1
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]O>CCOCC.CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Reactant: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.071 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL) and the solution was treated with methyl alcohol (0.075 mol, 3 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer acidified with 5N HCl to pH 1. The precipitated oil was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with water (50 mL×4) and dried over anhydrous MgSO4. The oily product crystallized on standing.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)[CH2:3][OH:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:22])=[O:23])[CH:19]=[CH:20][C:12]1=2)[CH2:3][OH:4]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(O)CO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccccc1C(O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.5 %

Procedure:
To a solution of 4-(2-(1,2-dihydroxyethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 0.585 mmol) in DCM (5 mL) was added TFA (0.7 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by prep HPLC to obtain 4-(2-(1,2-dihydroxyethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (14 mg, 5.9%) as a white solid. m/z (ESI) 434.0 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.48 (s, 1H), 7.61 (d, J=5.0 Hz, 1H), 7.37 (d, J=4.5 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.16 (d, J=4.3 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.71 (d, J=4.2 Hz, 1H), 6.05 (d, J=8.5 Hz, 1H), 5.16 (s, 1H), 4.66 (d, J=25.7 Hz, 2H), 4.34 (q, J=10.8, 10.3 Hz, 2H), 3.77 (t, J=8.3 Hz, 1H), 3.68-3.45 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](F)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:21](#[N:25])[CH:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:22]([CH3:24])([CH3:23])[C:21]#[N:25])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(F)c1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1cccc(C(C)(C)C#N)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
2-(3-Ethoxy-phenyl)-2-methyl-propionitrile was prepared using a procedure adapted from literature (Organic Syntheses, Vol. 79, pp. 209-215). To a solution of 1-ethoxy-3-fluoro benzene (3.0 g, 19.4 mmol) in 25 mL of toluene was added solid potassium bis(trimethylsilyl)amide (5.84 g, 29.2 mmol, 1.5 eq) followed by isobutyronitrile (7.08 mL, 77.8 mmol, 4 eq). The reaction mixture was stirred at 100° C. for 12 hr. It was diluted with 75 mL of ethyl acetate and 75 mL of 1N aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (1×50 mL), brine (1×50 mL), and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in 5 mL of methylene chloride and applied to a 40 g silica gel cartridge. The product was eluted using a gradient of ethyl acetate in hexanes to yield 2.96 g (15.6 mmol, 80%) of pure 2-(3-ethoxy-phenyl)-2-methyl-propionitrile. LR-MS: 190.12 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[CH3:8][N:9]=[C:10]=[O:11]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:10](=[O:11])[NH:9][CH3:8])=[N:3][O:2][CH3:1]
Reactant: CN=C=O
Reactant: CONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CNC(=O)OC(CCl)=NOC

Procedure:
N-Methoxychloroacetamide (3.5 grams), benzene (60 ml) and dibutyltin dilaurate (1 drop) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methyl isocyanate (2.0 grams) dissolved in benzene (15 ml) was added dropwise to the reaction mixture at room temperature and with stirring. After the addition was completed the reaction mixture was heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture was distilled to remove benzene and unreacted isocyanate leaving an oily residue. The residue was subjected to vacuum (0.1 mm Hg) whereupon it solidified. The solid was recrystallized from a carbon tetrachloride-hexane mixture to yield a white crystalline solid. The solid was washed with hexane and dried to yield the desired product 1-chloro-2-(N-methylcarbamoyloxy)-2-methoxyiminoethane having a melting point of 80°-82°C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[S:16][CH:17]=[C:18]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:29].Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].[CH:43]1([CH2:46][NH2:47])[CH2:45][CH2:44]1>ClCCl.O>[C:23]([NH:22][C:20]([C:18]1[N:19]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:31]([NH:47][CH2:46][CH:43]4[CH2:45][CH2:44]4)=[O:32])=[C:3]([F:29])[CH:4]=3)[CH2:9][CH2:10]2)[S:16][CH:17]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1csc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)n1
Reactant: NCC1CC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1csc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)c(F)c3)CC2)n1
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
2-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylthiazole-4-carboxamide (100 mg, 0.238 mmol) and 4-nitrophenol chloroformate (48 mg, 0.238 mmol) were combined and stirred in dichloromethane for 1 hour at room temperature. Cyclopropylmethylamine (50.9 mg, 0.715 mmol, 62 μl) was added and the reaction was stirred for 30 minutes. The reaction mixture was diluted with water and flushed through a hydrophobic frit. The organic phase was concentrated under vacuum and purified by acidic reverse phase HPLC to afford the title compound (5 mg). MS (ESI) m/z 517.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36].C[O-].[Na+:40]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O-:37])=[O:36].[Na+:40]
Reactant: O=C(NCCc1ccc(SC(F)(F)F)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(SC(F)(F)F)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
6-Chloro-7-(4-(4-(trifluoromethylthio) phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (58.7 mg, 0.106 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (213 μL, 0.106 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (60.0 mg, 0.105 mmol, 98.3% yield) as a solid. MS (apci) m/z=552.0 (M+2H—Na).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Ic1cccs1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2cccs2)cc1

Procedure:
2-Iodothiophene and 4-fluorophenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(4-fluorophenyl)thiophene as colorless powder.