Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[CH:4][CH:3]=1.[OH:44]OS([O-])=O.[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[O:44])=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(SCc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(S(=O)Cc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.108 mmol, example 129, step 2) in THF (4 mL) and water (2 mL) was added Oxone (73 mg, 0.119 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with aqueous sodium thiosulfate, partitioned between DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified by silica gel chromatography eluting with petroleum/ethyl acetate (1:0 to 1:1) to give 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylsulfinyl)-1H-purine-2,6(3H,7H)-dione (60 mg, 97.6%) as yellow oil. LCMS retention time 1.499 min; LCMS MH+-THP 571.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:49])[CH2:30][CH2:31][N:32]([C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1)[C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:49][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:42]1[CH:43]=[CH:44][C:45]([NH:46]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:47][CH:48]=1)[C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN(C)CCN(C(=O)Cc1ccccc1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(phenyl-acetyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C35H34N4O4
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:42]3[S:43][C:39]4[C:38]([CH3:57])=[N:37][N:36]([CH3:35])[C:40]=4[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(s1)c(C)nn2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2cc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)sc12
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (119 mg, 0.238 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (210 mg, 0.476 mmol) and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.119 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 15-65% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (101 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (d, J=9.60 Hz, 1H), 2.02-2.22 (m, 1H), 2.33 (br s, 3H), 3.55-3.71 (m, 1H), 3.82 (d, J=11.62 Hz, 1H), 3.90 (br s, 3H), 3.97-4.13 (m, 2H), 4.27-4.40 (m, 1H), 4.41-4.53 (m, 2H), 7.24-7.44 (m, 1H), 7.84-8.04 (m, 3H), 8.63 (br s, 1H), 9.22 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6O2S, 417. found, 417.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH:31](O)=O>C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([CH:17]3[CH2:18][CH2:19][N:20]([CH3:31])[CH2:21][CH2:22]3)[C:9]=2[C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c(-c3ccncc3)c(-c3ccc(F)cc3)nc3[nH]ncc23)CC1
Temperature: 75 °C
Yield: 19 %

Procedure:
To a suspension of 6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.24 g, 0.6 mmol, obtained in example 170) in formic acid (0.64 mL), 35-40% aqueous formaldehyde (0.96 mL) was added. It was heated to 70-80° C. for 24 h. It was allowed to cool and 1 N NaOH was added. It was extracted with CHCl3 and the combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using CHCl3-MeOH—NH3 mixtures of increasing polarity as eluent, to afford 47 mg of the desired compound (yield: 19%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:20]#[N:21])[C:15](=[O:19])[NH:16][C:17]=3[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N.S(=O)(=O)(O)[OH:24]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:20]([NH2:21])=[O:24])[C:15](=[O:19])[NH:16][C:17]=3[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(O)O
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(-n2ccnc2)cc1
Agent: N
Product: Cc1[nH]c(=O)c(C(N)=O)cc1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A solution of 1,2-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3-pyridinecarbonitrile (5.0 g) in 25 ml of concentrated sulfuric acid is heated on a steam bath for 40 minutes, cooled to room temperature and poured into 150 ml of ice. The mixture is adjusted to pH 8 with concentrated ammonia. The solid is collected and recrystallized successively from 10:1 water/acetic acid, dimethylformamide, and 2-methoxyethanol to give 2.06 g of 1,2-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3-pyridinecarboxamide, mp 311°-315° C. (dec).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:27]O>O>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH3:27])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Yield: 72 %

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (1.42 g) and conc. sulfuric acid (0.2 ml) were dded to methanol (30 ml) and the mixture was refluxed for 3 hours. Then, water was added. The mixture was extracted with ethyl acetate and the extracted layer was washed and dried. Ethyl acetate was distilled off under reduced pressure and the residue was recrystallized from hexane-ethyl acetate to obtain the title compound, m.p. 137°-138° C., yield 72%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[O:27]1[CH2:30][C:29]([CH2:33][NH2:34])([CH2:31][NH2:32])[CH2:28]1>>[NH2:32][CH2:31][C:29]1([CH2:33][NH:34][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=3)[N:5]=[C:4]([N:14]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]3)[CH:3]=2)[CH2:30][O:27][CH2:28]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Reactant: NCC1(CN)COC1
Product: NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(CO)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using [4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, 1 H), 7.83 (m, 1 H), 7.75 (s, 1 H), 7.59 (m, 1 H), 7.42 (m, 1 H), 7.34 (s, 2 H), 7.25 (t, 1 H), 6.13 (s, 1 H), 5.10 (t, 1 H), 5.04 (s, 2 H), 4.47 (d, 2 H), 4.34 (m, 6 H), 3.58 (d, 2 H), 3.52 (d, 2 H), 2.96 (t, 2 H), 1.79 (m, 2 H).
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:6]2[C:5]1=[O:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][CH:2]([F:1])[CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)F)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(CC(F)F)CC2CNCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (compound 105-C-1) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. After the reaction mixture was stirred at rt for 1 hour, the solvent was removed in vacuum to give the crude product 105-C, which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccccc2B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: CCOC(=O)C1(c2ccccc2-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and 1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]=O)=O)=[CH:8][CH:7]=1.[OH-].[K+]>C(O)C>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:14]=[N:4][CH:1]=[CH:2][N:3]=2)=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: Cc1ccc(C(=O)C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2cnccn2)cc1
Yield: 29.9 %

Procedure:
The procedure of Example 1 was repeated, using 16 g (0.267 mol) of ethylenediamine, 32.0 g (0.216 mol) of 4-methylphenylglyoxal, 450 ml of ethanol and 13.2 g of potassium hydroxide, with the result that 11.0 g of the titled compound was obtained (yield: 30%).
Reaction SMILES: ClCCCl.[CH:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1)=O.[Cl:29][C:30]1[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:31]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][CH2:5][C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[CH:33]=[CH:32][C:31]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cc1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
Solid NaBH(Oac)3 (113 mg, 0.54 mmol) was added to a DCE solution (4 mL) of methyl 2′-formyl-3′-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (121 mg, 0.36 mmol) and 2,4′-dichloro-[1,1′-biphenyl]-4-amine (93 mg, 0.39 mmol), and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and water, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(O)(=O)C.[Cl:15][CH2:16][C:17](Cl)=[O:18].O.O.O.C([O-])(=O)C.[Na+]>O>[Cl:15][CH2:16][C:17]([NH:4][C:3]1[C:5]([CH3:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C)c(N)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C)c(NC(=O)CCl)c1C
Reaction time: 0.5 h

Procedure:
A mixture of 7.8 g of 2,3,6-trimethylaniline R. A. Scherrer and H. R. Beatty, J. Org. Chem. 37, 1681 (1972), and 50 ml glacial acetic acid was cooled to 10° C. in a glass stoppered bottle, 7.23 g chloroacetyl chloride was added, mixed quickly and followed immediately by a cooled solution of 19.3 g sodium acetate trihydrate in 80 ml water. The mixture was shaked for 30 min. and the solid material was filtered off and washed carefully with water. After drying, a yield of 9.94 g (81%) was obtained. It melted at 145°-146° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1[CH:30]=[CH:31][C:26]([C:24]2[CH2:23][C:22](=[O:38])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=3[N:7]=2)=[CH:27][C:28]=1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from [2-(3-[2,3′]bipyridinyl-4-yl-3-oxo-propionylamino)-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M295) (288 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (195 mg, 86%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:13])[C:9]([F:10])([F:11])[F:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1CCC[C@H]1CO)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CCCN1C(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of the product of step A (1.002 g, 5.08 mmol) and triethylamine (0.78 ml, 5.60 mmol) in CH2Cl2 (50 ml) at -25° C. was added methane sulfonyl chloride (0.40 ml, 5.17 mmol) over a period of 5 min and stirring was continued for 1 hr. The solvent was evaporated in vacuo and the residue purified by chromatography(SiO2, 33% EtOAc in hexanes, elution). The title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]1([C:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH2:10][CH:11]=[CH2:12])[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(OCC)(=[O:40])C.Cl>C(OCC)C>[C:1]1([C:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH2:10][CH:11]=[CH2:12])[CH:8]=[O:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(C#N)(COCC[Si](C)(C)C)c1ccccc1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCC(C=O)(COCC[Si](C)(C)C)c1ccccc1
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A solution of 2-phenyl-2-(2-(trimethylsilyl)ethoxymethyl)-pent-4-enenitrile (354 mg, 1.23 mmol) in ethyl ether (1.0 mL) was cooled in an ice bath and a 1.5 M solution of diisobutylaluminum hydride in toluene (1.25 mL, 1.88 mmol) was added. After 2.5 h, ethyl acetate (0.30 mL, 270 mg, 3.1 mmol) was added and the mixture was transferred to a stirred mixture of 30 mL of ethyl ether and 10 mL of 2 N aqueous HCl at 0° C. After 10 min, the layers were separated and the aqueous layer was stirred for 0.5 h with another 30 mL of ethyl ether. The two organic layers were washed in succession with 10 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The combined organic layers were dried over sodium sulfate and evaporated. The residue was dissolved in 5.0 mL of THF and 0.7 mL of water was added followed by 1.0 g of silica gel. After stirring for 40 min at RT, the mixture was filtered and the silica gel was washed with additional THF. The filtrate was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with 2% ethyl ether in hexane, to give 140 mg of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H), 7.35 (t, 2H, J=7 Hz), 7.26 (t, 1H, J=7 Hz), 7.16 (d, 2H, J=7 Hz), 5.47 (ddt, 1H, J=17, 10, 7 Hz), 5.06-4.96 (m, 2H), 3.98 (d, 1H, J=9 Hz), 3.80 (d, 1H, J=9 Hz), 3.58-3.47 (m, 2H), 2.73 (d, 2H, J=7 Hz), 0.88 (t, 2H, J=8 Hz), -0.03 (s, 9 H). Mass spectrum (CI): m/z=263 (M-27, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[O:9][CH:10]=[C:11]([CH3:13])[N:12]=1.C(N(CC)CC)C>CCOCC>[CH3:13][C:11]1[N:12]=[C:8]([NH:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])[O:9][CH:10]=1
Reactant: Cc1coc(N)n1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc(C)co1
Reaction time: 2 h

Procedure:
Ethyl chloroformate (1.05 ml, 0.011 mol) was added dropwise to a stirred solution of 2-amino-4-methyloxazole (1.0 g, 0.010 mol) and triethylamine (1.5 ml, 0.011 mol) in dry ether (50 ml) at 5°-10° C. The mixture was stirred for 2 hours at 0°-5° C. then the white solid was filtered off and washed well with water to remove triethylamine hydrochloride. Residue (0.5 g) was recrystallised from chloroform-petroleum spirit, m.p. 126° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.[C:16](#[N:19])[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:15][C:8]1[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:11](/[CH:18]=[CH:17]/[C:16]#[N:19])=[C:10]([S:13][CH3:14])[N:9]=1
Reactant: C=CC#N
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CSc1nc(N)nc(-c2ccco2)c1/C=C/C#N

Procedure:
From 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine, acrylonitrile, bis(triphenylphosphine)palladium(II) chloride and cesium carbonate in dioxane. EI-MS m/e (%): 258 (M+, 76), 241 ([M—NH3]+, 100), 150 (56), 114 (32).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>CC(O)=O>[Br:15][CH:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:11]1=[O:13]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)CC(=O)C1Br

Procedure:
To a stirred solution of 5-phenylcyclohexane-1,3-dione (1.88 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid, which was used without further purification. LCMS (ES+) 266.8 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[CH2:17][CH:18]([CH3:19])[N:14]4[C:15]=3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13]4)=[C:9]([NH2:24])[C:8]=2[F:25])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:27](I)(F)F.CI>CN(C)C=O>[CH3:27][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:16]3[CH2:17][CH:18]([CH3:19])[N:14]4[C:15]=3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13]4)=[C:9]([NH2:24])[C:8]=2[F:25])[CH2:2][CH2:3]1
Reactant: FC(F)(F)I
Reactant: CC1Cc2c(N3CCNCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CI
Solvent: CN(C)C=O
Product: CC1Cc2c(N3CCN(C)CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23

Procedure:
To a mixture of 9-(1-piperazinyl)-8-fluoro-7-amino-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (3.45 g) and dimethylformamide (20 ml) is added a dimethylformamide solution (20 ml) of trifluoromethyl iodide containing methyl iodide (7.7 g), and the mixture is reacted in a stainless steel autoclave on an oil bath at 110°-120° C. for 5 hours. After completion of reaction, dimethylformamide is distilled off under reduced pressure, and to the residue is added a 10% aqueous sodium hydroxide solution. Insoluble materials are removed by filtration. The filtrate is regulated to pH 8 with acetic acid, and the precipitated crystal is separated by filtration, washed with water, and dried to give 9-(4-methyl-1-piperazinyl)-8-fluoro-7-amino-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (1.82 g) as yellow cubic crystals. m.p. 240°-243° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19](O)=[O:20])[C:13]1=[O:22].B>C1COCC1.ClCCl.[OH-].[Na+]>[CH3:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:22]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CC(=O)O)c1=O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Temperature: 27 °C
Reaction time: 1 h

Procedure:
26.5 g (87.7 mmol) of [1-(2,6-dimethyl-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]acetic acid were introduced as initial charge in 265 ml of THF at RT. 132 ml of 1M borane solution in THF (132 mmol) were added dropwise. During this addition, the temperature increased to 27° C. The reaction mixture was stirred for 1 h at RT and then the same amount of borane solution was added. The reaction mixture was stirred overnight at RT. It was diluted with 500 ml of dichloromethane, and 500 ml of 1N sodium hydroxide solution were added with cooling. The reaction mixture was stirred for 30 min, the phases were separated and the organic phase was washed with water, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. This gave 12.6 g (48%) of the desired product as crystalline solid.