Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH3:38][C:39]([CH3:41])=[O:40].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][S:16]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)[C:39]([OH:40])([CH3:41])[CH3:38])(=[O:18])=[O:17]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(OCc3ccccc3)cc2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)C(c2ccc(OCc3ccccc3)cc2)C(C)(C)O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under inert gas, 3.22 g of C-(4-benzyloxyphenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 70 ml of THF, and then, at a temperature of −78° C., 12.50 ml of a 1.8 N phenyllithium solution were added dropwise. The reaction mixture was allowed to come to 0° C. and stirred briefly, then cooled again to −78° C., and 4.00 ml of acetone were added dropwise. The mixture was allowed to come to −20° C. within 15 minutes, admixed with 1.29 ml of acetic acid and 100 ml of ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (3.65 g) with a molecular weight of 485.6 g/mol (C26H31NO6S).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH:14]=[CH:15][C:16]=1[S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[C:44]([N:48]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[N:43][CH:42]=[CH:41]2.O.[C:64]([OH:68])(=[O:67])[CH:65]=O>>[C:59]([O:58][C:56]([N:48]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C:44]1[C:45]2[C:40](=[CH:39][C:38]([NH:37][CH:65]([C:30]3[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][C:23]([NH:22][C:13]4[CH:14]=[CH:15][C:16]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[C:11]([CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])[CH:12]=4)=[O:36])=[CH:28][CH:29]=3)[C:64]([OH:68])=[O:67])=[CH:47][CH:46]=2)[CH:41]=[CH:42][N:43]=1)=[O:57])([CH3:62])([CH3:61])[CH3:60]
Reactant: O=CC(=O)O
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C

Procedure:
Using a procedure analogous to that used to prepare 2D, 17D (0.130 g, 0.25 mmol) was reacted with Intermediate 1 (0.090 g, 0.25 mmol) and glyoxylic acid monohydrate (0.027 g, 0.29 mmol) to give, after purification by reverse phase HPLC, 17E (109 mg, 49%). MS (ESI) m/z 890.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][C:26]([CH3:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH3:38][C:26]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH2:25][CH2:24][CH2:23][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC(C)(CCCBr)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccccc2)CC1)c1ccccc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A solution of 0.634 g (0.002 mol) of biphenyl-2-carboxylic acid-piperidin-4-ylamide, 0.5 g (1.75 mmol) of methyl 5-bromo-2-methyl-2-phenyl-pentanecarboxylate and 1 ml (0.007 mol) of triethylamine are dissolved in 3 ml dimethylformamide. The mixture is stirred for 14 hours at 80° C. Then the reaction mixture is poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate. After column chromatography on silica gel (eluant: dichloromethane/methanol=10:1) colourless crystals remain.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[CH:13][C:12]=2[CH:14]=1
Reactant: COc1ccc(-c2cc3cc(C(F)(F)F)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(C(F)(F)F)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
Compound 88 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, and the product was purified by column chromatography (eluant 25% EtOAc/hexanes) to give the product as a solid: (0.025 g, 4.8%); MS 277 [M−H]−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH:14]([OH:16])[CH3:15])=[N:10]2)=[C:5]2[NH:17][CH:18]=[CH:19][C:4]=12.C([Mg]Br)C.N1C=CC=CC=1.Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1>[OH:16][CH:14]([C:11]1[N:12]=[CH:13][N:9]([C:6]2[N:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[C:19]([C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:18][NH:17][C:5]=23)[N:10]=1)[CH3:15]
Reactant: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]ccc12
Reactant: CCOC(=O)C(=O)Cl
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(C(C)O)n3)ncc(OC)c12
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)ethanol (100 mg, 0.386 mmol) in THF (8 mL) was added ethylmagnesium bromide (1.736 mL, 1.736 mmol) at −40° C. After stirring at −5° C. for 1 h, pyridine (0.016 mL, 0.193 mmol) was added quickly. The mixture was cooled to −40° C. and ethyl 2-chloro-2-oxoacetate (0.176 mL, 1.543 mmol) was added. After stirring at −40° C. for 30 min, the reaction was quenched by adding i-PrOH and water. The mixture was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and concentrated under vacuum to give crude product ethyl 2-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (100 mg, 0.278 mmol, 72.2% yield). LCMS: m/z 360.1 (M+H)+, 1.53 min (method 8).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]([CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12])(=O)[CH3:8].C(O)C>CN(C)C=O>[OH:13][CH2:14][CH2:15][C:10]1[C:11](=[O:12])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[NH:1][C:7]=1[CH3:8]
Reactant: Nc1cc[nH]n1
Reactant: CC(=O)C1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1[nH]c2ccnn2c(=O)c1CCO
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of 49.86 g (0.6 mole) of 3-aminopyrazole and 84.56 g (0.66 mole) of α-acetyl-γ-butyrolactone dissolved in 60 ml of N,N-dimethylformamide was heated under reflux for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, after which 100 ml of ethanol was added to it and the precipitated crystals were collected by filtration. They were then washed with ethanol to afford 104.9 g (yield 90%) of the title compound as prisms, melting at 225°-226° C.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[C:4]([F:21])[C:5]([O:19][CH3:20])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].BrC1C(F)=C([F:43])C(OC)=C2C=1N(C1CC1)C=C(C(O)=O)C2=O.C1(N2C3C(=C(OC)C(F)=C(F)C=3C(F)(F)F)C(=O)C(C(O)=O)=C2)CC1.C1(N2C3C(=C(OC)C(F)=C(F)C=3)C(=O)C(C(O)=O)=C2)CC1>>[CH:12]1([N:10]2[C:11]3[C:6](=[C:5]([O:19][CH3:20])[C:4]([F:21])=[C:3]([F:22])[C:2]=3[F:43])[C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: COc1c(F)c(F)c(Br)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: COc1c(F)c(F)c(C(F)(F)F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: COc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Product: COc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In a similar manner, the following compounds were prepared: 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid; 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid; 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-5-methoxy-4-oxo-3-quinolinecarboxylic acid; and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([Br:14])=[CH:12][S:11][C:8]2=[CH:9][N:10]=1)=[O:4].CO.[OH-].[Na+]>O>[Br:14][C:13]1[C:7]2[C:8](=[CH:9][N:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[S:11][CH:12]=1
Reactant: COC(=O)c1cc2c(Br)csc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Br)csc2cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Methyl-3-bromothieno[2,3-c]pyridine-5-carboxylate (635 mg, 2.33 mmol) is combined with 25 ml MeOH. The mixture is treated with 2N NaOH (3 ml, 6 mmole) and 3 ml H2O and the reaction is stirred 4 h at rt. The volatiles are removed in vacuo and the residue is combined with 5 ml H2O. The pH of the mixture is adjusted to 3.5 with 10% aqueous HCl. The tan precipitate is collected, washed with water, and is dried in vacuo at 50° C. to afford 475 mg (79%) of 3-bromothieno[2,3-c]pyridine-5-carboxylic acid as a tan solid. MS (ESI): 257.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:40])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[NH2:40][N:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18]
Reactant: O=c1[nH]nc(-c2ccc(Br)cc2)c2ccccc12
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Reaction time: 0.75 h
Yield: 144.1 %

Procedure:
A mixture of 4-(4-bromophenyl)phthalazin-1(2H)-one (Aldrich) (0.200 g, 0.663 mmol) and KOtBu (1 M in THF, 1.0 mL, 1.0 mmol) in THF (2 mL) was stirred for 45 minutes, diluted with DMF (1 mL), and O-(diphenylphosphoryl)hydroxylamine (0.240 g, 1.03 mmol) was added and stirred for 90 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated to give 302 mg of crude material as a white solid, which was used without purification. LC/MS (APCI) M/Z 318.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:26][CH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[C:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17]3)[C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: OCc1cccc(B(O)O)c1
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: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3cccc(CO)c3)cc2)CC(C)(C)C1
Temperature: 160 °C
Yield: 65.6 %

Procedure:
A sealed tube containing 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.20 g, 0.50 mmol), 3-(hydroxymethyl)phenyl boronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), 2 M Na2CO3 (4 mL) and DME (4 mL) was heated at 160° C. for 25 minutes. Cooled to room temperature, the mixture was extracted with EtOAc. The EtOAc extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 30% EtOAc in hexanes to give 0.14 g (66%) of the title compound (247) as pale yellow solid. mp 197-198° C. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12H), 1.25 (s, 2H), 1.93 (s, 4H), 4.52 (d, J=5.9 Hz, 2H), 5.20 (t, J=5.9 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.52-7.58 (m, 3H), 9.27 (s, 1H). LCMS (ESI): m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:21]([O:22][CH3:23])=[C:20]3[C:15]([C:16](=[O:45])[C:17]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][C:34]=4[CH3:44])=[O:30])=[CH:18][N:19]3[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:14][C:13]=2[F:46])[CH2:7]1)C.O1CCOCC1.[Li+].[OH-].Cl>C(OCC)(=O)C>[F:46][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([O:22][CH3:23])[C:12]=1[N:8]1[CH2:9][CH2:10][CH2:11][C@H:6]([CH2:5][C:4]([OH:47])=[O:3])[CH2:7]1)[N:19]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH:18]=[C:17]([C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:35][C:34]=1[CH3:44])=[O:30])[C:16]2=[O:45]
Reactant: CCOC(=O)C[C@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CC(F)(F)F)c3c2OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1c(N2CCC[C@H](CC(=O)O)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Yield: 91.7 %

Procedure:
83 mg (0.123 mmol) of the compound of Example 21 are stirred with 3.0 ml of dioxane and 614 μl of LiOH (1M solution in water, 5 eq.) at RT overnight. The mixture is acidified with 1N HCl and diluted with ethyl acetate. It is extracted by shaking twice with water and once with a saturated NaCl solution. The organic phase is dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under HV. 73 mg of the title compound (90% of theory) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(N)cc1OC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)n2ccnc2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.8 %

Procedure:
To a mixture of 4-amino-2-methoxy-benzoic acid methyl ester (1.000 g, 5.246 mmol, Maybridge) in N,N-dimethyl formamide (20.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 919.8 mg, 5.502 mmol). After it was stirred at rt for 21 hrs under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-[(imidazole-1-carbonyl)-amino]-2-methoxy-benzoic acid methyl ester (1.34 g, 4.87 mmol, 92.8%) which was used without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([O:13]C)[CH:9]=[CH:10][C:11]=1[CH3:12].[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].Cl>ClC1C=CC=CC=1.C1(C)C=CC=CC=1.O1CCCC1>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([C:9]2[CH:10]=[C:11]([CH3:12])[C:6]([Cl:5])=[CH:7][C:8]=2[OH:13])=[O:20])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C)c(Cl)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: Cc1cc(C(=O)c2cccc(Br)c2)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Aluminum chloride (20.4 g) was added to a solution of 3-chloro-4-methylanisole (20 g) in chlorobenzene (56 ml) at 20-30° C., and then 3-bromobenzoyl chloride (28 g) was further added dropwise over about 30 minutes at 25 to 30° C. After completion of addition, the mixture was stirred at 25° C. for 1 hour, and then heated at 40° C. for 1 hour. After the reaction was completed, the mixture was cooled, and toluene/tetrahydrofuran (1:1, 200 ml) was added dropwise at 20 to 30° C. Then, 4N hydrochloric acid (80 ml) was added dropwise. The organic layer was separated, washed successively with 2N hydrochloric acid (60 ml) and a 10% aqueous sodium chloride solution. The organic layer was concentrated to 80 g. After methanol (100 ml) was added, the mixture was concentrated again to 90 g. Methanol (80 ml) was added to the residue, the mixture was stirred at room temperature for 30 minutes, and below 5° C. for 1 hour. Crystals were collected, washed with cooled methanol (40 ml) and dried under reduced pressure to obtain the title compound (35.4 g, yield 85.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=2[OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[CH3:32]>CN1C(=O)CCC1>[CH3:28][C:27]1[CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=[C:23]([CH3:32])[C:22]=1[O:17][C:15]1[CH:14]=[CH:13][C:12]([OH:18])=[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
The title B compound, 2-(4-fluorobenzenesulfonyl)benzene-1,4-diol (1.2 g, 4.48 mmol) is added to a suspension of NaH (60% dispersion in mineral oil; 0.39 g, 9.86 mmol) in 15 mL of NMP at 0° C. in one portion. The mixture is warmed to RT and after 30 min, 4-chloro-3,5-dimethylnitrobenzene (1 g, 5.38 mmol) is added and the reaction is heated at 120° C. for 1 h. The reaction is cooled to RT and quenched with aqueous 1N HCl. The mixture is partitioned between water and EtOAc, and the organic solution is washed with water and brine, dried over anhydrous Na2SO4 and concentrated. Chromatography on silica (eluant; EtOAc/hexane-1/2/1/1) affords 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluorobenzenesulfonyl)phenol: NMR (CDCl3) 2.11 (s, 6H), 6.85-6.96 (m, 3H), 7.00 (app t, 2H, J=9), 7.88 (dd, 2H, J=9, 5),7.98 (s,2H), 8.73 (s, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)[CH2:39][CH:40]=1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C=C2
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccc(F)cc34)CC1)C=C2
Temperature: 80 °C
Yield: 60.9 %

Procedure:
To a solution of [(2R)-8-methoxy-2H-chromen-2-yl]methyl 4-methyl-benzenesulfonate (0.350 g, 1.01 mmol) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.655 g, 3.03 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.240 g (61%, >97% ee) of 5-fluoro-3-(1-{[(2R)-8-methoxy-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow solid. [α]D25=−2.14 (c 10.27 in chloroform, >97% ee); Rf=0.49 (silica, methanol:ethyl acetate 1:9); mp 189-191° C. dec; Anal. Calcd. for C24H23FN2O2.0.3 H2O: C, 73.15; H, 5.99; N, 7.11. Found: C, 73.19; H, 6.03; N, 7.08.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
A solution of morpholine (0.50 g, 5.7 mmol) in CH2Cl2 (10 mL) was treated with Et3N and cooled to 0° C. The mixture was treated with chloroacetyl chloride (0.50 mL, 6.3 mmol) as a solution in CH2Cl2 (2 mL). The reaction was stirred at 0° C. for 15 min and then at room temperature for 30 min. The reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.72 g, 76%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 4.06 (s, 2H), 3.73-7.67 (m, 4H), 3.62 (app t, 2H, J=4.0 Hz), 3.52 (app t, 2H, J=4.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:44]C(=O)OC(C)(C)C)[C:11](=[O:43])[NH:12][C@H:13]2[CH2:34][O:33][C:32](=[O:35])[C@H:31]3[N:27]([CH2:28][CH2:29][CH2:30]3)[C:26](=[O:36])[C@H:25]([CH3:37])[NH:24][C:23](=[O:38])[C@H:22]([CH3:39])[N:21]([CH3:40])[C:20](=[O:41])[C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]2=[O:42])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>ClCCl>[F:53][C:54]([F:59])([F:58])[C:55]([O-:57])=[O:56].[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH3+:44])[C:11](=[O:43])[NH:12][C@H:13]2[CH2:34][O:33][C:32](=[O:35])[C@H:31]3[N:27]([CH2:28][CH2:29][CH2:30]3)[C:26](=[O:36])[C@H:25]([CH3:37])[NH:24][C:23](=[O:38])[C@H:22]([CH3:39])[N:21]([CH3:40])[C:20](=[O:41])[C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]2=[O:42])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H]1NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)COC(=O)[C@@H]2CCCN2C1=O
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)[C@@H]([NH3+])Cc2cc(F)cc(F)c2)COC(=O)[C@@H]2CCCN2C1=O
Product: O=C([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2.12 g (2.94 mmol) of the carbamate from example 12A are dissolved in dichloromethane (32 ml) and cooled to 0° C. Subsequently, a mixture of water and trifluoroacetic acid (1/9) (32 ml) is added, and the mixture is stirred at 0° C. for 45 min. and then evaporated. 2.83 g of crude product are obtained, which after taking up in toluene and dichloromethane and subsequent concentration is reacted further.