Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[N:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:20])=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1cccc2ncc(I)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(I)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a solution of 7-iodo-1,5-naphthyridine 1-oxide (D-15) (1.570 g, 5.77 mmol, 1.0 eq) in chloroform (30 mL), p-toluenesulfonyl chloride (1.210 g, 6.35 mmol, 1.1 eq), potassium carbonate (2.711 g, 19.5 mmol, 3.4 eq) and water (10 mL) were added. After stirring at RT for 16 h, the reaction mixture was diluted with water (50 mL), filtered to obtain the desired product 7-iodo-1,5-naphthyridin-2(1H)-one (D-16) (740 mg, 47.1%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 8.60 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.85 (d, J=9.9 Hz, 1H), 6.72 (d, J=9.9 Hz, 1H); ESI-MS m/z: 272.97 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][NH2:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][NH:31][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2S(C)(=O)=O)n(C)c(=O)c1O
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cn1c(-c2ccc(F)cc2S(C)(=O)=O)nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (69 mg, 92% yield). 1HNMR (500 MHz, CDCl3) δ: 12.00 (1H, s), 7.87 (1H, dd, J=7.63, 2.45 Hz), 7.60 (1H, t, J=7.60 Hz), 7.50–7.42 (2H, m), 7.39 (1H, d, J=7.93 Hz), 7.32 (1H, s), 7.11 (1H, d, J=7.32 Hz), 4.55 (1H, dd, J=15.26, 6.41 Hz), 4.49 (1H, dd, J=15.26, 6.10 Hz), 3.26 (3H, s), 3.06 (3H, s). HRMS (ESI) calcd for C20H17Cl2FN3O5S (M+H): 500.0250; found: 500.0259.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([OH:16])=O)[N:7]=3.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([NH:32][C:33](=[NH:36])[S:34][CH3:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O.O>[C:25]([O:29][C:30](=[O:31])[NH:32]/[C:33](=[N:36]\[C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:16])/[S:34][CH3:35])([CH3:28])([CH3:26])[CH3:27]
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS/C(=N/C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (0.839 g, 0.00271 mol) and oxalyl chloride (2M in DCM, 1.36 mL, 0.002714 mol), in methylene chloride (16.70 mL) under nitrogen atmosphere was added 1 drop of N,N-dimethylformamide. The solution was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the acid chloride was redissolved in methylene chloride (9.0 mL). The solution was added dropwise to a solution of N-tertbutoxycarbonyl-S-methylpseudothiourea (0.5164 g, 0.002714 mol) and triethylamine (1.173 mL, 0.008414 mol) in methylene chloride (9.0 mL). The reaction was stirred at room temperature for 1.5 h. Methylene chloride and water were added and the mixture was extracted 3× with methylene chloride. Saturated sodium carbonate was then added and the mixture was extracted with chloroform. The organic layers were combined and concentrated. The product was redissolved in methylene chloride and methanol and filtered. The filtrate was collected, concentrated and dry loaded onto silica gel and purified by flash chromatography (0-15% MeOH in DCM) to give {[(E)-8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonylimino]-methylthiomethyl}-carbamic acid tert-butyl ester (658 mg) as an off-white solid. MS(ESI+) 481.0/483.0
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH:22][C:32](=[O:34])[CH3:33])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(-c2nnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of Example 24G (0.044 g, 0.122 mmol) in CH2Cl2 (2 mL) was treated with triethyl amine (0.051 mL, 0.366 mmol) followed by acetyl chloride (0.0173 mL, 0.244 mmol). The reaction was stirred at 25° C. for 1 hour and was concentrated under reduced pressure on a rotary evaporator. The residual white solids (0.075 g) were purified by flash chromatography on silica gel eluting with a solvent gradient of 30% to 50% ethyl acetate in hexanes to provide 0.035 g (71%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (d, J=8.09 Hz, 1H) 7.49 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.99 (dd, J=3.68, 0.74 Hz, 1H) 5.09-5.20 (m, 1 H) 4.63 (heptet, J=5.88 Hz, 1H) 1.85 (s, 3H) 1.45 (d, J=6.99 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:14](Br)[CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10][C:9]=2[CH:20]=1)=[O:4].S1(CCCC1)(=O)=O.[BH4-].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10][C:9]=2[CH:20]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2
Reaction time: 0.5 h

Procedure:
13.6 G. methyl-11-bromo-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylate is suspended in 150 cc. sulfolane and to the mechanically stirred mixture 7.18 g. sodium borohydride is added in portions over one hour. The foamy mixture is stirred an additional half hour. The mixture is diluted with 1.5 l. of water and extracted with ether. The organic layer is washed with water, dried, evaporated, and the residual oil is chromatographed on silica gel. Elution with benzene affords 8.1 g. of the pure oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[Cl:14][C:15]1[CH:16]=[C:17]([F:25])[C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=O.C(O)(=O)C.[F-].[NH4+]>C1(C)C=CC=CC=1.O1CCOCC1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([F:25])[C:18]([O:23][CH3:24])=[C:19]([CH:20]=[N:1][C:2]2[CH:11]=[C:10]([F:12])[CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:13])[NH:7]3)[CH:22]=1
Reactant: COc1c(F)cc(Cl)cc1C=O
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Agent: [Ti]
Agent: [F-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COc1c(F)cc(Cl)cc1C=Nc1cc(F)cc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To 0.54 g (3 mmol) 5-amino-7-fluoro-1H-quinolin-2-one and 0.57 g (3 mmol) 5-chloro-3-fluoro-2-methoxybenzaldehyde in 9 ml toluene and 2.6 ml 1,4-dioxane are added 0.65 ml acetic acid and 2.4 ml tetrabutyl orthotitanate. The mixture is heated over 17 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 1 hour. Phases are separated and addition of ethylacetate is repeated two times while stirring is done under reflux and phases are separated while they are still hot. The combined organic phases are concentrated and the residue is purified by flash chromatography on silica gel (ethyl acetate, then methanol in dichloromethane 10% to 20%) to yield 0.63 g of 5-{[1-(5-chloro-3-fluoro-2-methoxyphenyl)methylidene]-amino}-7-fluoro-1H-quinolin-2-one. 57 mg NaH (55% in mineraloil, 1.4 mmol) were washed with dry THF and suspended together with 0.63 g (1.8 mmol) of 5-{[1-(5-chloro-3-fluoro-2-methoxyphenyl)methylidene]amino}-7-fluoro-1H-quinolin-2-one in 22 ml THF. t-Butyldimethylsilyl chloride is added as solid and the mixture is stirred for 2.5 hours while it becomes a clear solution. In parallel 0.24 ml 1,1,1-trifluoro-2,3-epoxypropane in 6 ml THF and 2 ml hexane are cooled to −100° C. and 1.1 ml of a 2.5 M n-butyl lithium solution in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition the previously prepared 1-{t-butyldimethylsilyl}-5-{[1-(5-chloro-3-fluoro-2-methoxyphenyl)methylidene]amino}-7-fluoroquinolin-2-one solution in THF is added over 20 minutes while the temperature does not exceed −95° C. After 3.5 hours at −100° C. 2 ml diethyl ether are added and the reaction mixture is warmed to room temperature over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. After stirring for 30 minutes the phases are separated and the aqueous layer is extracted with dichloromethan, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (ethyl acetate in hexane 0 to 100%) yields 152 mg of 5-{[(5-chloro-3-fluoro-2-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]-amino}-7-fluoro-1H-quinolin-2-one
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][C:8]=1[F:17])[OH:6])[CH3:2].I[CH3:20]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][C:8]=1[F:17])[O:6][CH3:20])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(F)cc(OCC)cc1F
Reactant: CI
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OC)c1c(F)cc(OCC)cc1F
Temperature: 60 °C
Yield: 97.3 %

Procedure:
To a solution of (4-ethoxy-2,6-difluoro-phenyl)-hydroxy-acetic acid ethyl ester (4.0 g, 15.37 mmol, 1.0 equiv) in toluene (50 mL) was added iodo-methane (21.82 g, 9.78 mL, 153.70 mmol, 10.0 equiv) and silver(I) oxide (7.12 g, 30.74 mmol, 2.0 equiv) and the reaction mixture heated to 60° C. for 18 h. The reaction mixture was filtered, the filtrate poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 4.1 g (97%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.25 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.43 (s, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.26 (q, J=7.5 Hz, 2H), 5.05 (s, 1H), 6.43-6.48 (m, 2H). MS (ISP): 292.3 [M+NH4]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Cl:8].CN(C)C1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23].O>C(Cl)(Cl)Cl>[Cl:10][C:3]1[C:2]([NH:1][C:22](=[O:23])[CH2:21][Br:20])=[C:7]([Cl:8])[CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: O=C(Br)CBr
Reactant: Cc1cc(Cl)c(N)c(Cl)n1
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(NC(=O)CBr)c(Cl)n1
Yield: 72.8 %

Procedure:
3-Amino-2,4-dichloro-6-methylpyridine (48.0 g, 271.1 mmol) was dissolved in chloroform (384 mL), and N,N-dimethylaniline (39.4 g, 325.1 mmol) was added to the solution. A solution of bromoacetyl bromide (65.7 g, 325.5 mmol) in chloroform (96 mL) was added dropwise to the mixture under stirring and under cooling with ice. The resultant mixture was stirred for 1 hour at the same temperature and for 1 hour at room temperature. Subsequently, under cooling with ice, a solution of bromoacetyl bromide (27.4 g, 135.7 mmol) in chloroform (48 mL) was further added to the resultant mixture, followed by stirring for 1 hour at room temperature. Water (288 mL) was added to the reaction mixture, and the resultant mixture was stirred for 12 hours at room temperature. The reaction mixture was stirred for 2 hours under cooling with ice, and the precipitated crystals were collected through filtration. The crystals were washed with cold ethanol (96 mL) and dried at 50° C. by use of a blower, to thereby yield 58.81 g of N-(2,4-dichloro-6-methylpyridin-3-yl)-2-bromoacetamide (yield: 73%) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:6]=2[C:5](=[O:25])[NH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:9]2[N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:6]3[C:5](=[O:25])[NH:4][CH:3]=[CH:2][C:7]=3[N:8]=2)[CH2:29][CH2:28]1
Reactant: CSc1nc(Nc2cccc(C(F)(F)F)c2)c2c(=O)[nH]cc(Br)c2n1
Reactant: OC1CCNCC1
Product: O=c1[nH]ccc2nc(N3CCC(O)CC3)nc(Nc3cccc(C(F)(F)F)c3)c12
Yield: 60 %

Procedure:
The title compound was prepared as described in Example 1g by starting from 8-bromo-2-(methylthio)-4-(3-(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (60 mg, 0.26 mmol) and 4-hydroxypiperidine and continuing until the reaction yielded the title compound (40 mg, 60%)) as grey solid. MS m/z: 484 and 486 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH:36]1(O)[CH2:40][CH2:39][CH2:38][CH:37]1[OH:41]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:41][C@H:37]3[CH2:38][CH2:39][CH2:40][C@H:36]3[O:35]2)[CH2:33][CH2:34]1
Reactant: OC1CCCC1O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2CCC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 135.5 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.75 g), cyclopentane-1,2-diol (0.42 g), p-toluenesulfonic acid monohydrate (0.018 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 100%).
Reaction SMILES: FC1C=C(C2N(C3C=CC(F)=CC=3)N=C(C(O)=O)C=2)C=CC=1.Cl[C:24]1[CH:25]=[C:26]([N:31]2[C:35]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38](Cl)[CH:37]=3)=[CH:34][C:33]([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:45])=[N:32]2)[CH:27]=[CH:28][C:29]=1[F:30]>>[F:42][C:40]1[CH:41]=[C:36]([C:35]2[N:31]([C:26]3[CH:25]=[CH:24][C:29]([F:30])=[CH:28][CH:27]=3)[N:32]=[C:33]([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:45])[CH:34]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: O=C(O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)cc2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(F)c3)n(-c3ccc(F)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 90A in analogy to the synthesis of the compound of Example 1. 18 mg (47% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25]O>C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:25])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C#N)ccc1OCc1ccccc1
Yield: 100.3 %

Procedure:
4-benzyloxy-3-methoxybenzaldehyde (4.84 g, 20 mmol) in acetic acid (25 ml) and sodium acetate (3.3 g, 40 mmol) was reacted with hydroxylamine hydrochloride (2.8 g, 40 mmol) at reflux for 6 hours. The mixture was cooled, diluted with water, extracted with methylene chloride, dried over MgSO4, concentrated to give title compound (4.8 g, 100%).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:10]=1[CH3:24])=[O:8])C.Cl>O1CCCC1.O>[C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:10]=1[CH3:24])([OH:8])=[O:6]
Reactant: CCOC(=O)c1ccn(-c2ccc3ccccc3n2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)ccn1-c1ccc2ccccc2n1
Yield: 111.1 %

Procedure:
3.9 g (93 mmol) of lithium hydroxide monohydrate, portionwise every 24 hours, are added at 20° C. to 1.9 g (6.78 mmol) of 3-ethoxycarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring at reflux for 72 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue that is taken up in 75 mL of water. The pH of the aqueous phase is adjusted to 2 by addition of concentrated hydrochloric acid. After stirring for 1 hour, the aqueous phase is filtered and the solid residue is dried under reduced pressure (2.7 kPa) at 40° C. to give 1.9 g of 3-carboxy-2-methyl-1-(quinol-2-yl)-1H-pyrrole in the form of a beige-coloured solid.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3](=[O:38])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:30]CC3C=CC=CC=3)[CH2:19][CH2:18][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.FC(F)(F)C(O)=O>CO.[OH-].[OH-].[Pd+2]>[CH3:39][N:2]([CH3:1])[C:3](=[O:38])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([OH:30])[CH2:19][CH2:18][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c2ncnc(N3CCC(O)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Reaction time: 24 h
Yield: 14.5 %

Procedure:
Crude 3-(4-(benzyloxy)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)phenyl dimethylcarbamate from example 24, step F (85% pure, approximately 80 mg) was taken up in methanol (2 mL), and a catalytic amount of Pearlman's catalyst was added. The system was hydrogenated at 60 psi for 24 hours, after which a small amount of product was observed. Trifluoroacetic acid (0.1 mL) was added, and the hydrogenation was continued at 60 psi H2 for 3 days, after which the reaction was approximately one third of the way completed. The reaction was filtered, and the product was isolated by prep HPLC (30×100 mm C18 column, 10-100% acetonitrile:water (10 mM ammonium acetate), 15 min, 45 mL/min) to afford the title compound (9.6 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[CH2:14][CH2:15][OH:16].C(N(CC)CC)C.O>C(#N)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH:13]([NH:12][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])[CH2:14][CH2:15][OH:16])=[CH:22][CH:21]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(C(N)CCO)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(C(CCO)NC(=O)c2c(F)cccc2F)cc1
Reaction time: 7 h
Yield: 86.4 %

Procedure:
2,6-Difluorobenzoyl chloride (2.65 g, 0.015 mol) is added in portions to a solution of 3-amino-3- (4-t-butylphenyl)-1-propanol (3.1 g, 0.015 mol) and triethylamine (3.03 g, 0.04 mol) in 30 ml of acetonitrile at room temperature (20° C.) in the course of 10 minutes. The reaction mixture is further stirred for 7 hours, water is added and the mixture is extracted with ethyl acetate. 4.5 g of N-[1-(4-t-butylphenyl)-3-hydroxy-propyl]-2,6-difluorobenzamide are isolated from the ethyl acetate phase as a crude product having a content of 28% according to GC/MS analysis, which is employed as such in the next reaction step.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([NH2:19])[CH3:18].O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:19][CH2:17][CH3:18]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 20 ml of methanol was dissolved 24.5 g of 3,5-bistrifluoromethylbenzaldehyde, and under ice-cooling, added thereto was 60 ml of ethylamine (a 2M tetrahydrofuran solution). Subsequently, 4.38 g of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added distilled water and concentrated under reduced pressure. The residue was extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→chloroform:methanol=9:1), to give 6.35 g of N-(3,5-bistrifluoromethylbenzyl)-N-ethylamine as shown in Table 135 below.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)=[O:12]>>[CH3:1][S:2][C:3]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[CH3:10])[CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC(=O)c1cccc(N)c1
Product: CSC(=C[N+](=O)[O-])Nc1cccc(C(C)=O)c1
Temperature: 140 °C
Yield: 64.9 %

Procedure:
A neat mixture of 1,1-bismethylthio-2-nitroethylene (6.5 g, 38.5 mmol, 10 eq) and 3-aminoacetophenone (0.5 g, 3.85 mmol, 1 eq) was melted together and heated at 140° C. for four hours. The mixture was cooled to room temperature, then subjected to flash chromatography, eluting with 50% ethyl acetate/hexanes, to yield 0.63 g of a yellow powder as product. Yield=65%. NMR (300 MHz, CDCl3) δ 11.82 (bs, 1H), 7.95-7.91 (m, 2H), 7.59-7.48 (m, 2H), 6.73 (s, 1H), 2.65 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (193.6 mg, 0.56 mmol, 1.00 equiv) in methanol (15 mL). A solution of sodium hydroxide (111.6 mg, 2.79 mmol, 5.00 equiv) in water (1.5 mL) was added. The resulting solution was stirred overnight at 50° C. in an oil bath and concentrated to dryness. The residue was diluted by 10 mL of water and adjusted to PH=3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration. This resulted in 130 mg (69%) of (S)-3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.