Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:23]C(=O)C(C)(C)C)=[C:8]2[C:14]([Cl:15])=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.C[O-].[Na+].CO.[NH2:35][CH2:36][C:37]([OH:39])=[O:38]>>[CH2:16]([N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:35][CH2:36][C:37]([OH:39])=[O:38])=[O:5])[C:7]([OH:23])=[C:8]2[C:14]([Cl:15])=[CH:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ncc2c(c(Cl)cn2Cc2ccccc2)c1OC(=O)C(C)(C)C
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(c(Cl)cn2Cc2ccccc2)c1O
Yield: 47.9 %

Procedure:
A mixture of 1-benzyl-3-chloro-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (65 mg) and NaOMe/HOMe (0.94 mL, 0.5 M) was refluxed for 1 h; then cooled, partitioned between EtOAc and diluted HCl solution, organic phase was washed with sat. NaCl solution, dried over sodium sulfate and then filtered, concentrated to give a residue, which was refluxed with glycine (236 mg) and NaOMe/HOMe (4.71 mL) overnight; the solvent was subsequently removed, the residue was partitioned between MTBE (methyl tert-butyl ether) and water, the aqueous phase was then acidified with 2 M HCl to pH=1-2, the solids were collected with filtration after cooled in an ice/water bath, the solids were then freeze dried to give the title compound (27 mg). ESI (m/z): 360 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)=[CH:5][N:4]=1)#[CH:2].I[C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>C(N(CC)CC)C>[F:9][C:8]1[C:3]([C:1]#[C:2][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]3)=[CH:32][CH:33]=2)=[N:4][CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)[CH:7]=1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ncc(C2=CCC(C)CC2)cc1F
Solvent: CCN(CC)CC
Product: CC1CC=C(c2cnc(C#Cc3ccc(OCCN4CCC(C)CC4)cc3)c(F)c2)CC1

Procedure:
The product was prepared analogously to Example 48.1c from 130 mg (0.60 mmol) of 2-ethynyl-3-fluoro-5-(4-methylcyclohex-1-enyl)pyridine and 207 mg (0.60 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine (Example 19.1 a) (24 at RT, triethylamine as base). Yield: 15 mg (6% of theoretical); C28H33FN2O (M=432.573); calc.: molpeak (M+H)+:433; found: molpeak (M+H)+:433; HPLC-MS: 5.60 minutes (method H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:20](Cl)=[O:21].C(N(C(C)C)CC)(C)C>ClCCl>[N+:26]([C:25]1[CH:24]=[CH:23][C:19]([C:20]([N:6]2[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])=[CH:18][C:17]=1[CH3:16])([O-:28])=[O:27]
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
A mixture of 1.17 g of 6,11-dihydro-5H-dibenz[b,e]azepine, 1.20 g of 3-methyl-4-nitrobenzoyl chloride, 0.80 ml of diisopropylethylamine in 25 ml of dichloromethane is stirred 18 hours at room temperature. The mixture is washed with water and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and diluted while hot with hexane to give 1.40 g of crystals. Recrystallization from dichloromethane-hexane gives 1.26 g of crystals, m.p. 179°-180° C.
Reaction SMILES: [C:1]([CH:4]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:26]O>>[C:1]([CH:4]([NH:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:26])=[O:10])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)C(CCCCC(=O)O)NC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCC(NC(=O)c1ccccc1)C(C)=O

Procedure:
6-Acetyl-6-benzoylaminohexanoic acid (4.35 g) was dissolved in 100 ml of methanol, and 0.5 ml of conc. sulfuric acid was added. The mixture was heated to reflux for 2.5 hours. The reaction solution was cooled, poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to provide 4.4 g of the objective compound as yellowish crystals. M.p. 59-60° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](Cl)=[O:37])(=[O:28])[CH3:27]>>[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:37])(=[O:28])[CH3:27]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC(C)=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-(chlorocarbonyl)phenyl acetate as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:38]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[C:16]2[Br:38])=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1ccc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2cc3ccc(O)c(Br)c3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To a mixture of 7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (100 mg, 0.201 mmol) in DMF (1 mL) was added N-bromosuccinimide (39.4 mg, 0.221 mmol) at 0° C. The reaction mixture was stirred at RT for 1.5 h, then loaded onto a 2 g SCX column, washed with MeOH, and eluted with 2M NH3 in MeOH. The product-containing fractions were concentrated and the crude material was purified via silica gel flash column chromatography to give the desired product as a brown solid (33.6 mg, 29% yield). MS (M+1)=577.3.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:29]([CH:31]=[CH2:32])=[O:30]>O1CCCC1>[OH:30][CH:29]1[NH:2][C:1](=[O:3])[C:4]2([C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:32][CH2:31]1
Reactant: C=CC=O
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Temperature: 50 °C
Yield: 112.7 %

Procedure:
Following the general procedure of Example 1, 20.9 g (0.1 mole) of 9-carbamoylfluorene were added to 300 ml of tetrahydrofuran. The solution was heated to 50° C. and stirred while 6 ml of benzyltrimethylammonium hydroxide were added in one portion. After stirring the reaction mixture at 50° C. for thirty minutes, 6.2 g (0.11 mole) of acrolein were added and the mixture was then heated at reflux for four hours. The reaction mixture was cooled to 25° C. and the solvent was removed by evaporation under reduced pressure to provide 29.9 g of 6'-hydroxyspiro(9H-fluorene-9,3'-piperidine)-2'-one and its tautomeric isomer 9-carbamoyl-9-(3-oxopropyl)fluorene. m.p. 199°-201° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: COc1cc(-c2nc(CCl)c(C)o2)cc(OC)c1OC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(OC)c(OC)c(OC)c3)oc2C)c1)C(=O)O
Yield: 3 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazole, the title compound was obtained in 3% yield as a white solid. MS: (M+H)+ 495.2.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:23]3[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=3)([CH3:22])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:23]3[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[CH:31][CH:32]=3)([CH3:22])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(C)(CO)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
To a solution of 35 mg of methyl 4-{2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-1-hydroxypropan-2-yl}benzoate in 1.4 ml of THF were added dropwise 0.17 ml of a 1 M diisobutylaluminum hydride/toluene solution at −78° C., followed by stirring at 0° C. for 3 hours. To the reaction mixture was added 0.14 ml of a 1 M diisobutylaluminum hydride/toluene solution at 0° C., followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous Rochelle salt solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography to obtain 20 mg of 8-[(2,6-difluorobenzyl)oxy]-N-{1-hydroxy-2-[4-(hydroxymethyl)phenyl]propan-2-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:10]=3[NH:11][C:12](=[O:26])[CH:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)=O.CO>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:10]=3[NH:11][C:12](=[O:26])[C@@H:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1NC(=O)C(NC(=O)OCc1ccccc1)N=C2c1cccc(F)c1
Agent: O=C=O
Solvent: CO
Product: Cc1cccc2c1NC(=O)[C@@H](NC(=O)OCc1ccccc1)N=C2c1cccc(F)c1
Yield: 45.7 %

Procedure:
Racemic benzyl (5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (5.9 g, 14.3 mmol) was resolved under the Chiral SFC conditions. Berger SFC MGIII, Column: CHIRALPAK® IC 25×3 cm ID, 5 μm, Mobile Phase: 45/55 CO2/MeOH; Flow rate: 160 mL/min; Detector wavelength: 220 nM. The desired stereoisomer was collected as the second peak in the elution order. After evaporation of solvent, (S)-benzyl (5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (2.73 g, 46% yield) was obtained as a white solid. HPLC: RT=3.075 min Purity=99%. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm). Chiral HPLC RT: 8.661 min(AD, 60% (EtOH/MeOH)/heptane)>99% ee. (on AD chiral column desired is the first peak, which is the second peak on the IC SFC).
Reaction SMILES: C(O[CH:5]([CH3:7])[CH3:6])(C)C.C(O[C:12](=O)[CH3:13])(=O)C.S(=O)(=O)(O)O.S(=O)(=O)=O>O1CCOCC1.C1C=CC=CC=1.C1(C)C=CC=CC=1.ClC(Cl)Cl.C(OCC)(=O)C.C(Cl)Cl>[CH:7]1[C:5]2[C:6](=[CH:12][CH:13]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(C)C
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1ccc2ccccc2c1

Procedure:
Methylene chloride, diisopropylether, ethyl acetate, trichloromethane, toluene, benzene, or 1,4-dioxane may be used instead of acetic acid anhydride, while fuming sulfuric acid, sulfur trioxide, chlorine sulfates or combinations thereof may be used as an alternative to concentrated sulfuric acid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[N+:22]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>CO.[Fe]>[O:2]=[C:3]1[NH:22][C:13]2[C:12](=[CH:21][CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[NH:11][CH:4]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(NC(C(=O)OC)c2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccccc1)N2
Yield: 56.3 %

Procedure:
Iron (34.89 g, 623.04 mmol, 5.00 equiv) was added portionwise to a stirred solution of methyl 4-(2-methoxy-2-oxo-1-phenylethylamino)-3-nitrobenzoate (42.87 g, 124.62 mmol, 1.00 equiv) and aqueous NH4Cl (32.1 g, 600.00 mmol, 5.00 equiv, 80 mL) in methanol (300 mL). The resulting solution was heated under reflux for 5 h. Upon cooling, the solids were filtered out. The resulting filtrate was concentrated under vacuum, affording 19.81 g (56%) of methyl 3-oxo-2-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a yellow solid. LC-MS (ES, m/z): 283 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].O[C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=3[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3cccc(C(F)(F)F)c3)nc2c1

Procedure:
3-Trifluoromethylbenzoyl chloride (9.03 g, 0.043 mol) and 2-hydroxy-5-nitroaniline (6.58 g, 0.041 mol) in toluene (200 ml) are refluxed for 48 hours. POCl3 (20 ml) is added, the mixture is refluxed for a further 2 hours and concentrated, and the solid is recrystallized from NaOH (pH=10). The product is filtered off and recrystallized from water and finally from isopropyl ether. Yield: 10.3 g (78%); Rf (8/2 petroleum ether/ethyl acetate): 0.58; IR (KBr): 3085, 1620, 1531, 1425, 1340 cm−1.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([C:5]3[S:6][C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)=[CH:3][CH:4]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(-c3cnc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example E.87) (0.25 g, 0.626 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.152 g, 0.689 mmol) according to the general procedure VI. Obtained as a yellow solid (0.060 g, 23%). MS (ISP) 413.1 [(M+H)+], 415.2 [(M+2+H)+] and 417 [(M+4+H)+]; mp 237° C.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CS(=O)(=O)NCCN
Product: CS(=O)(=O)NCCNc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and N-[2-aminoethyl]-methanesulfonamide,
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:22])[C:16]#[C:17][C:18]([F:21])([F:20])[F:19])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([C:16]1[N:1]([C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])[N:2]=[N:3][C:17]=1[C:18]([F:19])([F:20])[F:21])=[O:22])[CH3:13]
Reactant: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(F)(F)F)nnn1-c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 59.5 %

Procedure:
A mixture of 2-azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/z 353.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:26][C:27]1[C:28]([CH3:35])=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.O>[F:33][C:32]1[C:27]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]([CH3:19])[C:11]=2[O:17][CH3:18])=[C:28]([CH3:35])[C:29]([OH:34])=[CH:30][CH:31]=1
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Reactant: Cc1c(O)ccc(F)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (intermediate III(k)) (500 mg, 1.92 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added (COCl)2 (731.6 mg, 5.76 mmol, 3.3 eq) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was concentrated under reduced pressure and the residue that remained dissolved in THF (6 mL) and added to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (246.5 mg, 1.75 mmol, 1.0 eq) and NaHCO3 (733.5 mg, 8.73 mmol, 5.0 eq) in THF (8 mL). After the addition, the reaction mixture was stirred for a further 2 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with 5% Na2CO3, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 10:1 to 5:1 then CH2Cl2:MeOH, 20:1) to give the title compound as a white solid (540 mg, 80%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)CS3(=O)=O)cc2)CC1
Yield: 40 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (240 mg) described in Preparation Example 4 and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (650 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 1, the title compound (264 mg) was obtained.
Reaction SMILES: [CH:1]([C:4]1[C:13]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])[CH3:2].[OH-].[K+].O1CCOCC1>O>[CH:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc3ccccc3nc2C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nc2ccccc2cc1O
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-isopropyl-quinolin-3-yl ester (1.31 g, 3.8 mmol), 0.64 g (11.4 mmol) of KOH in 10 mL of water, and 50 mL of p-dioxane was heated to refluxe for 1.5 hours until completion. The p-dioxane was removed under reduced pressure and the residue was diluted with water and acidified with 1N HCl to pH=6. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford quantitatively 0.71 g of 2-isopropyl-quinolin-3-ol
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[CH3:18][C:19]1[C:23]([CH3:24])=[C:22]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([O:30]C)=[O:29])[NH:21][N:20]=1.CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[CH3:18][C:19]1[C:23]([CH3:24])=[C:22]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([OH:30])=[O:29])[NH:21][N:20]=1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]nc(C)c2C)c1
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]nc(C)c1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate (compound 59.2) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 231 (M+H)+.