Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:19])[C:9]2=[O:20])(=[O:5])=[O:4].[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:14][CH:13]=2)[C:9](=[O:20])[C:10]1=[O:19]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A mixture of crude 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetic acid (0.178 g, 0.57 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.274 g, 1.428 mmol) and DMAP (0.029 g, 0.238 mmol) in dry DCM (10 ml) was stirred at room temperature overnight. The mixture was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude was purified by silica gel flash chromatography (DCM:MeOH from 99.5:0.5 to 98:2) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.128 g, 0.179 mmol, 37% yield). This product was further purified by crystallization from ethyl acetate/hexane 1/1 to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N,N-dimethyl sulfamoyl)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.052 g, 0.179 mmol, 15% yield). MS/ESI+ 714.11 [MH]+; [αD]=−37.09, c=0.488; MeOH; 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.15 (s, 2H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.19 (d, 1H), 6.83-7.01 (m, 2H), 6.74 (d, 1H), 6.67 (t, 1H), 6.13 (dd, 1H), 4.53 (d, 2H), 3.91 (d, 2H), 3.58 (dd, 1H), 3.28 (dd, 1H), 2.79 (s, 6H), 1.09-1.43 (m, 1H), 0.55-0.84 (m, 2H), 0.18-0.52 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([OH:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CCCC2O
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.3 %

Procedure:
6-Methoxytetralone (10 g, 0.057 mol) was mixed with 150 ml of dry ethanol and sodium borohydride (1.2 eq) was added by portions to the stirred mixture. The reaction mixture was left to stir at ambient temperature for 15 h. The reaction mixture was then concentrated by rotary evaporation, mixed with 100 ml of water and heated for 1 h at 45° C. The resulting mixture was extracted into diethyl ether (3×80 ml). Combined organic extract was dried over Na2SO4 and concentrated by rotary evaporation to give 10.39 g of yellow oil which was used in the next step without additional purification.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[C:16]([CH2:21]Cl)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1.O>CS(C)=O>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:21][C:1]#[N:2])[C:15]=3[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(-c2nccc3c(CCl)cccc23)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2nccc3c(CC#N)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Sodium cyanide (1.89 g) was dissolved in 100 ml of dimethylsulfoxide, and 8.6 g of 1-(4-methylphenyl)-5-chloromethylisoquinoline was added. At room temperature, the mixture was stirred for 1 hour. After the reaction, the reaction mixture was poured into water, extracted with ether, washed in water, and dried. The solvent was distilled off. The residue was recrystallized from ether to afford 7 g of 1-(4-methylphenyl)isoquinoline-5-acetonitrile as prisms having a melting point of 101.7° to 102.1° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][N:12]([S:13]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)(=[O:15])=[O:14])[CH3:17]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NCc1csc2cncn12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NCc1csc2cncn12
Reaction time: 2.5 h

Procedure:
A 210 mg potion of 3-aminomethylimidazo[5,1-b]thiazole was dissolved in 4 ml of dichloromethane, and 202 mg of 4-dimethylaminopyridine and 0.179 ml of N,N-dimethylsulfamoyl chloride were further added, followed by stirring for 2.5 hours. Then, to the reaction solution, an aqueous semi-saturated sodium hydrogencarbonate solution were added, and extraction was then carried out three times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was then evaporated under reduced pressure. Afterward, the resulting residue was purified by a silica gel column chromatograph to obtain 177 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH:19]=[CH2:20])=[O:17]>ClCCCl>[CH:19]([O:18][C:16](=[O:17])[O:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[CH2:20]
Reactant: OCC1CCN(Cc2ccccc2)C1
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)OCC1CCN(Cc2ccccc2)C1
Yield: 70.7 %

Procedure:
A solution of (1-benzyl-pyrrolidin-3-yl)-methanol (prepared as described by Y.-H. Wu and R. F. Feldkamp, Pyrrolidines I, 1961, 26, 1519-1524) (455 mg, 2.38 mmol) and vinyl chloroformate (0.40 mL, 4.7 mmol) in 1,2-dichloroethane (10 mL) was heated to reflux for 2 h then concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (5% MeOH/CH2Cl2) gave a yellow oil (440 mg, 71%). 1H NMR (CDCl3) δ 1.84 (m, 1H), 2.26 (m, 1H), 3.03 (m, 5H), 4.01 (br s, 2H), 4.23 (m, 2H), 4.61 (dd, 1H, J=6.2, 2.3 Hz), 4.93 (dd, 1H, J=14, 2.1 Hz), 7.06 (dd, 1H, J=14, 6.3 Hz), 7.41 (m, 3H), 7.53 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([O:32][Si](C)(C)C)=[CH:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:28]([CH2:29][CH2:30][CH3:31])[C:27]([O:26][CH3:25])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCC=C(OC)O[Si](C)(C)C
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (158 mg, 0.5 mmol) and (1-methoxypent-1-enyloxy)trimethylsilane (16 mmol) which was prepared using General Silyl Ketene Acetal Method A in 10 mL of dry DCM was added TiCl4 (0.5 mL of 1.0 M DCM solution, 0.5 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated and purified on SiO2 by MPLC using a EtOAc/hexane gradient to give 160 mg (77% yield) of methyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)pentanoate. MS found: (M+H)+=417.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH3:30])=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.C(Cl)Cl.CO.[OH-].[NH4+:44]>>[CH3:30][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:5]4[CH:10]=[CH:9][N:44]=[C:7]([CH3:8])[CH:6]=4)=[CH:3][NH:4]3)=[CH:9][CH:8]=2)=[O:12])=[CH:18][C:17]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: Cc1ccc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)cc1S(=O)(=O)N[Si](C)(C)C(C)(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2c[nH]c3cc(C(=O)c4ccc(C)c(S(N)(=O)=O)c4)ccc23)ccn1

Procedure:
2-Methyl-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide is prepared from 0.25 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-2-methyl-benzenesulfonamide according to the procedure described in Example 6 (microwave irradiation at 150° C. for 5 min). MS (m/z): 404 (M−1); Rf 0.19 (90:10:1 methylene chloride/methanol/ammonium hydroxide).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([C:22]([OH:24])=O)[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O=S(Cl)[Cl:27]>>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([C:22]([Cl:27])=[O:24])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)Cl)c1

Procedure:
20 ml of SOCl2 was added to 4.0 g (1.23×10-2 mol) of 4-octyloxybiphenylcarboxylic acid, and the mixture was refluxed under heating for 5 hours to obtain 4-octyloxybiphenylcarboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Oc1cccc(Cl)c1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of 3-chlorophenol (9.26 g) in DMF (25 ml) was added dropwise to a stirred suspension of sodium hydride (1.44 g) in DMF (50 ml) (effervescence) and the resulting mixture was stirred at room temperature for 1 hour. A solution of 2-(bromomethyl)benzonitrile (11.76 g) in DMF (25 ml) was then added to the stirred reaction mixture and after a further hour at room temperature the mixture was poured into water and extracted with ether. The extracts were washed successively with water, dilute aqueous sodium hydroxide and brine, then dried and concentrated to give crude 2-(3-chlorophenoxymethyl)benzonitrile (13.95 g) as an orange-brown oil which crystallised on standing. An analytical sample, recrystallised from petrol, had m.p. 56° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=O)(C)(C)C.[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21](O)=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1>>[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[C:15]([NH2:14])=[N:16][CH:17]=[CH:18]3)[CH2:9]1
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: Nc1nccc2cc(O[C@H]3CCNC3)ccc12

Procedure:
This compound was prepared from (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (195 mg, 1.04 mmol) and 1-amino-6-hydroxyisoquinoline (200 mg, 1.25 mmol) by the Mitsunobu procedure described in 3C, subsequent Boc deprotection according to procedure described in 3D gave (S)-6-(pyrrolidin-3-yloxy)-isoquinolin-1-ylamine, El-MS: m/z=230.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[S:18]([O-:21])([O-:20])=[O:19].[Na+].[Na+].C(O)C>O>[OH:21][S:18]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)(=[O:20])=[O:19]
Reactant: O=S([O-])[O-]
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1ccc2cc(OCCCCS(=O)(=O)O)ccc2[nH]1
Reaction time: 72 h
Yield: 75.4 %

Procedure:
A solution of 53.3 g of 6-(4-chlorobutoxy)carbostyril and 32 g of sodium sulfite dissolved in 500 ml of water and 200 ml of ethanol was refluxed for 1 day. The solution was allowed to cool and stand for 3 days and then filtered. The filtrate was made acidic with diluted hydrochloric acid. The solvent was removed by distillation. To the resulting residue was-added water, and the precipitate was collected by filtration to obtain 47.5 g of 6-(4-hydroxysulfonylbutoxy)carbostyril as a white powder.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14])[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)CO)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (1.26 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.96 g, 77%) as an off-white solid. MS (ISP) 272.2 [(M+H)+], mp 101° C.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH:16][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: Nc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(F)cc2F)C1
Yield: 18.1 %

Procedure:
The title compound (D31) (90 mg) was prepared according to the experimental procedure described in Description 30 starting from 1-Boc-3-azetidinone (300 mg, 1.75 mmol) and 2,4-difluoroaniline (0.178 ml, 1.75 mmol). Reaction time: 1 week.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([NH:20][CH3:21])=[N:17][CH:16]=2)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2].[OH-].[Na+].[CH3:24]O>S(=O)(=O)(O)O.O>[CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([NH:20][CH3:21])=[N:17][CH:16]=2)=[CH:13][CH:14]=1)[C:5]([O:7][CH3:24])=[O:6])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)OC
Yield: 67 %

Procedure:
0.5 g (1.6 mmol) of 2(S)-ethoxy-3-[4-(2-methylaminothiazol-5-yl)phenyl]propanoic acid in 10 ml of methanol and a few drops of sulfuric acid is heated at 60° C. for 2 hours. The reaction medium is cooled, diluted with water, neutralized to pH 7 with aqueous 1M sodium hydroxide solution and then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 50/50 heptane/ethyl acetate mixture. 0.34 g (67%) of methyl 2(S)-ethoxy-3-[4-(2-methylaminothiazol-5-yl)phenyl]propanoate is obtained in the form of a yellow solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Product: COc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Reaction time: 0.25 h

Procedure:
The product of Step 1a (21.7 g, 86.4 mmole) was suspended in POCl3 (240 mL). The suspension was refluxed for 2 hours. After removal of the POCl3 in vacuo, the residue was partitioned between EtOAc (IL), and cold aqueous NaOH (generated from 1.0N 200 mL NaOH and 20 mL 10.0 N NaOH) and stirred for 15 min. The organic layer was washed with water (2×200 mL), brine (200 mL), dried (MgSO4), and concentrated in vacuo to supply 4-chloro-2-phenyl-7-methoxyquinoline (21.0 g, 90%) as a light brown solid. 1H NMR (DMSO-d6) δ: 3.97 (s, 3H), 7.36 (dd, J=9.2, 2.6 Hz, 1H), 7.49-7.59 (m, 4H), 8.08 (d, J=9.2 Hz, 1H), 8.19 (s, 1H), 8.26-8.30 (m, 2H); 13C NMR (DMSO-d6) δ: 55.72, 108.00, 116.51, 119.52, 120.48, 124.74, 127.26, 128.81, 130.00, 137.58, 141.98, 150.20, 156.65, 161.30. LC-MS (retention time: 1.547, Method D), MS m/z 270 (M++1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[Br:11]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)c1ccccc1O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-isopropylphenol (1.39 mL, 10 mmol, 1 eq.) in DCM (8 mL), bromine (0.52 mL, 10 mmol, 1 eq.) was added at r.t. over a period of 10 min. The reaction mixture was stirred at r.t. for 18 hours. The mixture was poured into a mixture of sat. aq. NaHCO3 soln. (25 mL) and ice. The resulting mixture was extracted with AcOEt (2×25 mL). The comb. org. layers were washed successively with water (25 mL) and sat. aq. NaCl soln. (25 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield 4-bromo-2-isopropyl-phenol as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]([NH:23]C(=O)OC(C)(C)C)=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1>>[NH2:23][C:17]1[N:18]([CH3:22])[C:19](=[O:21])[CH2:20][C@:15]2([C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([C:39]2[C:34]([F:33])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:7][CH:6]=3)[N:16]=1
Reactant: OB(O)c1cccnc1F
Reactant: CN1C(=O)C[C@]2(N=C1NC(=O)OC(C)(C)C)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Product: CN1C(=O)C[C@]2(N=C1N)c1cc(-c3cccnc3F)ccc1Oc1c2cc(Cl)nc1F

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 12 above, but using (S)-tert-butyl 7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate (Example 1-B) and 2-fluoropyridin-3-ylboronic acid.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[N:13][CH:12]=[C:11]2O.C(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[N:13][CH:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1cc2nncc(O)c2cc1OC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2nncc(Br)c2cc1OC
Temperature: 65 °C
Reaction time: 18 h

Procedure:
Phosphorus oxybromide (125 g, 0.436 mol) was added to a suspension of 6,7-dimethoxycinnolin-4-ol (65 g, 0.32 mol) in chloroform (550 mL, 6.9 mol). The reaction mixture was stirred at 65° C. for 18 hours. Formation of a fine yellow solid was observed. The reaction mixture was poured onto crushed ice (200 g), and the pH was adjusted to 6-7 with sodium acetate (285 g) and sat. NaHCO3. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide a light tan oil. DCM (40 mL) and hexanes (250 mL) were added, and the resulting solid was filtered to provide 4-bromo-6,7-dimethoxycinnoline as an off-white solid.
Reaction SMILES: [CH:1]1[C:2](=[O:16])[CH:3]=[CH:4][C:5]2=[N:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]=12.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:16]
Reactant: O=c1ccc2nc3ccccc3ccc-2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1ccc2c(c1)C=Cc1ccccc1N2
Reaction time: 3 h
Yield: 64.1 %

Procedure:
Title compound 374 (170 mg, 0.82 mmol) was solubilized in CHCl3 (5 mL) and a saturated solution of Na2S2O4 in water was added (20 mL). The mixture was stirred for 3 hours. The 2 layers were split and the organic layer was dried over sodium sulfate, filtered and evaporated to afford title compound 375 (110 mg, 65%). MS (m/z): 209.9 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[OH-].[K+].O>CS(C)=O>[C:23]([O:22][C:20](=[O:21])[NH:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 93.1 %

Procedure:
A mixture of N-(4-fluoro-3-nitrophenyl)benzamide (1.00 g, 3.8 mmol), N-Boc-4-hydroxyaniline (0.83 g, 3.8 mmol) and 85% KOH (0.51 g, 7.7 mmol) in DMSO (20 mL) was heated at 80° C. for 1 hour, and then poured into H2O (100 ml) under stirring. The resulting oily crystal was extracted with EtOAc. The extract was washed with H2O (3 times) and brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound, which was purified by washing with i-Pr2O to give the desired compound as yellow crystals (1.59 g, 92%).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].Br[CH2:14][C:15]1[C:16]([CH2:21]Br)=[CH:17][CH:18]=[CH:19][CH:20]=1>C(O)C.C(OCC)C>[CH2:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C:3]1([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9]
Reactant: BrCc1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C1(C(=O)O)Cc2ccccc2C1

Procedure:
Sodium (3.7 g) was dissolved in 80 ml of ethyl alcohol, followed by the addition of 150 ml of diethyl ether. Diethyl malonate (12.5 ml) was added followed by 20 g of α,α'-dibromo-o-xylene in 150 ml of diethyl ether with overhead stirring. The reaction was heated to reflux for 5 hours. The reaction was cooled, filtered, and the solvent was removed under vacuum. The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) and heated to reflux for 15 hours. The reaction was then cooled and rinsed with 200 ml of diethyl ether. The aqueous phase was acidified with 30% hydrochloric acid. The precipitate was collected and dried under vacuum over Drieruite for 5 hours to yield 8.86 g of indan-2,2-dicarboxylic acid.