Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([OH:29])[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33](S(C)(=O)=O)[N:32]=1.O>C1COCC1>[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:29][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][C:7]3[N:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[N:8]=3)[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])[N:32]=1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2C(=O)OCC[Si](C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.4 g, purity: 60%) was suspended in 50 ml of THF. To this suspension, trimethylsilylethyl 6-(4,6-dimethoxypyrimidin-2-yl)oxysalicylate (3.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. To this mixture, 4-chloro-6-methoxy-2-methylsulfonylpyrimidine (1.8 g) was added, and the mixture was stirred at room temperature for further 12 hours. After completion of the reaction, water was added thereto, and the mixture was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The crude extract thus obtained was purified by silica gel column chromatography to obtain the above identified compound as a slightly yellow liquid (4.0 g).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:19]2[CH2:21][O:20]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C@H:19]3[CH2:21][O:20]3)=[CH:13][CH:12]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@H]1CO1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(COc2ccc(C[C@H](NC(=O)OC(C)(C)C)[C@H]3CO3)cc2)cs1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
0.6 g (3.26 mmol) 4-Chloromethyl-2-methyl-thiazole hydrochloride was added to a stirred solution of 0.76 g (2.71 mmol) tert-butyl (1S)-2-(4-hydroxyphenyl)-1-[(2S)-oxiranyl]ethylcarbamate in 15 ml N,N-dimethylformamide. 3.25 g (10 mmol) cesium carbonate and 550 mg (3.66 mmol) sodium iodide was added, and the mixture was stirred at 20° C. for 24 hours. 200 ml ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with water (5×50 ml), and the organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silicagel column using hexane-ethyl acetate (1:1) as solvent to yield 820 mg (Y=78%) title compound. 1H-NMR (CDCl3): δ 1.36 (9H,s), 2.71 (3H,s), 2.75-2.95 (4H,m), 3.61 (1H,s(br)), 4.39 (1H,s(br)), 5.11 (2H,s), 6.91 (2H,d), 7.11 (2H,d), 7.12 (1H,s).
Reaction SMILES: O=[C:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].Cl.[NH2:18][OH:19].[OH-].[Na+].C(=O)([O-])O.[Na+]>CO>[OH:19][N:18]=[C:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: NO
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(CCN1C(=O)c2ccccc2C1=O)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
1.08 g (5.00 mmol) of N-(3-oxobutyl)phthalimide was dissolved in 10 ml of methanol and to the solution was added 0.695 g (10.0 mmol) of hydroxylamine hydrochloride. To this suspension was added 2 ml of 5N aqueous sodium hydroxide solution, followed by being stirred at room temperature for 16 hours. The reaction mixture was poured into 100 ml of saturated aqueous sodium hydrogencarbonate and extracted with chloroform (30 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with hexane to give 0.98 g (yield 84%) of the titled compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[S:25]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3Cl)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine in 100 ml DCM and 4 ml pyridine, 11.6 g of 2,5-dichloro-benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 17.9 g.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[OH:24][CH2:23][C@@H:22]1[CH2:26][C@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
4.14 g (109.5 mmol) of sodium borohydride was suspended in 150 ml of THF at 0° C. and 17.6 ml (142.2 mmol) of borontrifluoride etherate was added dropwise over a period of 10 minutes. 15.6 g (54.7 mmol) of 1-(4-toluenesulfonyl)-4-hydroxy-D-proline was added in portions and the mixture was allowed to stir at room temperature for 16 hours. The reaction was then cooled to 0° C. and quenched with methanol; 10% aqueous HCl solution was then added and the mixture was gently heated to 60° C. for 1 hour. The pH of the reaction was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 10.2 g of the product as a white solid in 69% yield. M.P.=103°-105° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([NH2:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:12][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1cc(-c2ccccc2)on1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc(-c3ccccc3)on2)c1=O
Temperature: 92 °C
Yield: 122.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), 299a (640 mg, 4.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.1 g, 4.0 mmol), Pd2(dba)3 (366.8 mg, 0.40 mmol), XantPhos (462.4 mg, 0.80 mmol), and cesium carbonate (2.6 g, 8.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 92° C. for 3 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with acetonitrile to afford 299b (1.7 g, 87%). MS-ESI: [M+H]+ 346.0.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:23](CC)CC)C.ClC(OCC(C)C)=O.N>ClCCl.CCCCCC.C(OCC)(=O)C.O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
400 mg (1.44 mmol) of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dehydrated dichloromethane (14.4 mL), and 176 mg of triethylamine was added, followed by cooling to 0° C. 237 mg of isobutyl chloroformate was added to the mixture, followed by stirring at the same temperature for 20 minutes. 1.0 mL of concentrated aqueous ammonia was added to the reaction mixture, followed by stirring at room temperature for 1 hour. Subsequently, water (10 mL) was added and the organic layer was fractionated, followed by sequential washing with water and saturated brine and drying over anhydrous magnesium sulfate. The residue resulting from concentration of the solvent under reduced pressure was applied to silica gel column chromatography (hexane/ethyl acetate=1/3), and subsequently crystallized with chloroform/hexane=1:3 to afford 315 mg of the title compound as a colorless crystalline powder (yield 79%). Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=4/1, UV 210 nm, flow rate 1 mL/min., retention time 16.2 min.).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:29][OH:30])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1.C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:19]=[C:18]([CH2:29][O:30][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
Triethylamine (3.25 L, 23.3 mol) was added to a solution containing [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol (Example 516, 5.18 kg, 14.8 mol) in THF (25.2 L) and toluene (6.3 L) at rt under N2. The reaction mixture was heated to 35° C. and methanesulfonyl chloride (1.82 L, 23.5 mol) was added slowly maintaining the temperature between 35-45° C. The reaction mixture was stirred for an additional 2 h at 45° C. When HPLC analysis indicated the disappearance of the starting material, the reaction mixture was cooled to rt and quenched with 10% aq. NaCl (6.3 L). The organic layer was washed with brine (5.0 L) and the desired mesylate was used in solution in the next synthetic step without isolation. Data compared favorably with that obtained for Example 1, Step D.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[F:10])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[NH2:17][OH:18].Cl>CCO.O>[NH2:7][C:6]1[CH:8]=[CH:9][C:3]([C:1](=[NH:2])[NH:17][OH:18])=[C:4]([F:10])[CH:5]=1
Reactant: N#Cc1ccc(N)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(N)cc1F
Temperature: 60 °C
Yield: 60.3 %

Procedure:
4-cyano-3-fluoroaniline (10 g, 0.0735 mol) was dissolved in EtOH (36.7 ml) and water (7.3 ml), Na2CO3 (5.06 g, 0.65 eq) was added. The mixture was heated at 60° C. and a solution of NH2OH.HCl (5.615 g, 1.1 eq) in water (7.3 ml) was added slowly, the mixture was heated at 60° C. overnight. The mixture was cooled to 0° C., and the solid collected by filtration. Washed with water (7 ml), EtOH (7 ml), Et2O (20 ml) and dried to give 7.5 g of compound 139-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:15]
Reactant: [H][H]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. After reaction completion (the reaction being complete when 3 mole equivalents of hydrogen have been reacted), the mixture was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline as a white solid (120.6 g, 98%); NMR Spectrum (CDCl3): 2.11 (s, 3H), 2.50 (s, 3H), 6.51 (d, 1H), 6.58 (s, 1H), 6.75 (d, 1H), 6.98-7.03 (m, 2H), 8.18 (s, 1H); Mass spectrum: MH+ 215.
Reaction SMILES: Cl.[CH:2]1([C:5]([CH:7]([N:15]2[CH2:20][CH2:19][CH:18]([SH:21])[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[O:6])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32].O>ClCCl>[C:29]([S:21][CH:18]1[CH2:17][CH2:16][N:15]([CH:7]([C:5]([CH:2]2[CH2:4][CH2:3]2)=[O:6])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[CH2:20][CH2:19]1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)CC1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
In 5 ml of dichloromethane, 0.50 g (1.5 mmol) of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-mercaptopiperidine hydrochloride were dissolved, followed by the addition of 0.3 g (3 mmol) of triethylamine. To the resulting mixture, a solution of 0.16 g (1.5 mmol) of butyryl chloride in 1 ml of dichloromethane was added dropwise under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate. The solvent was concentrated by evaporation under reduced pressure and the residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=30/1), whereby 0.32 g (yield: 58%) of the title compound was obtained as white crystals.
Reaction SMILES: C1(S([N:10]2[C:18]3[CH:17]=[C:16]([Cl:19])[CH:15]=[C:14]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:46])[NH:25][C:26]5[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:28][C:27]=5[CH2:41][C:42]([O:44]C)=[O:43])[C:12]([C:13]=34)=[C:11]2[C:47]([O:49]C)=[O:48])(=O)=O)C=CC=CC=1.CO.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[Cl:19][C:16]1[CH:15]=[C:14]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:46])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:28][C:27]=3[CH2:41][C:42]([OH:44])=[O:43])[C:12]3=[C:11]([C:47]([OH:49])=[O:48])[NH:10][C:18]([CH:17]=1)=[C:13]23
Reactant: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)CC1CCc2cc(Cl)cc3c2c1c(C(=O)OC)n3S(=O)(=O)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CC2CCc3cc(Cl)cc4[nH]c(C(=O)O)c2c34)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65.2 %

Procedure:
A solution of methyl 1-benzenesulfonyl-7-chloro-3-[p-tert-butoxycarbonylaminomethyl-o-(methoxycarbonylmethyl)phenylcarbamoylmethyl]-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (300 mg, 0.414 mmol) in a mixture of THF (5 mL), MeOH (5 mL), and 1N LiOH (5 mL) was stirred for 19 h at room temperature, acidified to pH 3 with 5% KHSO4, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was rinsed with diethyl ether and dried in vacuo to give 150 mg of the title compound (quant): 1H NMR (DMSO-d6) δ12.54 (br, 2H), 11.42 (s, 1H), 9.33 (s, 1H), 7.37 (d, 1H, J=7.9 Hz), 7.35 (s, 1H), 7.13 (d, 1H, J=7.9 Hz), 7.10 (s, 2H), 6.83 (s, 1H), 4.08 (d, 2H, J=7.9 Hz), 3.88 (m, 1H), 3.59 (d, 1H, J=16.3 Hz), 3.55 (d, 1H, J=16.3 Hz), 3.09 (mr, 1H, J=14.0 Hz), 2.81 (md, 1H, J=16.8 Hz), 2.64 (dd, 1H, J=14.0, 3.5 Hz), 2.53 (m, 1 H), 2.09 (md, 1, H, J=12.2 Hz), 1.83 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.Br[C:22]1[C:37]([F:38])=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[C:24]([Cl:39])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:39][C:24]1[CH:23]=[C:22]([NH:1][C:2]2[N:12]=[C:11]3[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]3[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:4][N:3]=2)[C:37]([F:38])=[CH:36][C:25]=1[C:26]([NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:27]
Reactant: CN1CCC(NC(=O)c2cc(F)c(Br)cc2Cl)CC1
Reactant: CN1C(=O)CCN(C2CCCCC2)c2nc(N)ncc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCCC3)CCC(=O)N4C)cc2Cl)CC1
Temperature: 103 °C

Procedure:
2-amino-9-cyclohexyl-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (Intermediate 263; 100 mg, 0.36 mmol), 4-bromo-2-chloro-5-fluoro-N-(1-methylpiperidin-4-yl)benzamide (Intermediate 262; 133 mg, 0.38 mmol), xantphos (12.61 mg, 0.02 mmol), palladium(II) acetate (163 mg, 0.73 mmol) and caesium carbonate (14.20 mg, 0.04 mmol) were added to dioxane (10 mL) and heated at 103° C. overnight. The resulting solution was filtered and passed through a 5 g SCX-3 column. The obtained yellow foam was triturated with hot ethyl acetate to afford a yellow solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.Cl[CH:26](Cl)C>CN(C)C=O>[C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:26])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A mixture of 2-phenylsulphenyl-4-trifluoromethylbenzoic acid (11.5 g), thionyl chloride (1 1.4 g), dimethylformamide (0.2 ml) and dichloroethane was heated at reflux for 90 minutes. The solution was then concentrated under reduced pressure and the residue was dissolved in methanol and heated at reflux for one hour. The resulting solution was poured into aqueous sodium bicarbonate and extracted with ether. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. The resulting material was crystallised from hexane to give methyl 2-phenylsulphenyl-4-trifluoromethylbenzoate (10.5 g) as white crystals, m.p. 58° C.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>C(#N)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:8]2[CH2:7][CH2:6][NH:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9]2)=[CH:13][CH:12]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)C1CNCCN1
Solvent: CC#N
Product: CC(C)C1CN(Cc2ccc(Br)cc2)CCN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 g of 2-isopropyl-piperazine could be dissolved in acetonitrile and cooled to 0° C. A solution of 0.5 quiv. 4-bromobenzylbromide in acetonitrile could be added dropwise over 1 h. The reaction would be stirred at room temperature for 2 h. The reaction mixture could be concentrated and the residue could be purified by column chromatography (silica, eluent dichloromethane, 0-5% methanol, 0-0.5% dimethylethylamine) to afford 1-(4-bromo-benzyl)-3-isopropyl-piperazine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:26]=1)=[C:3]([CH3:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:5]2
Reactant: N#Cc1ncc(N2CCOCC2)cc1N
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (93 mg, 0.34 mmol), 3-amino-5-morpholinopicolinonitrile (70 mg, 0.34 mmol) and a 4.0M solution of HCl in dioxane (0.08 mL, 0.34 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 3-((5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)-2-pyridinecarbonitrile was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68 (1H, dt, J=3.1, 1.6 Hz), 8.00 (1H, d, J=8.6 Hz), 7.87-7.97 (3H, m), 7.64 (1H, td, J=8.2, 5.5 Hz), 7.39 (1H, ddd, J=7.0, 4.9, 1.8 Hz), 7.17-7.32 (2H, m), 6.23 (1H, d, J=2.3 Hz), 3.75-3.86 (4H, m), 3.17-3.31 (4H, m), 2.29 (3H, s). Mass Spectrum (ESI) m/e=441.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:9](I)([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:10][C:3]=12.N1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)N1c2nccc(Br)c2CC1(I)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccnc1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c(-c2cccnc2)cc2c(Br)ccnc21
Yield: 50 %

Procedure:
A solution of 4-bromo-2-iodo-1-(phenylsulfonyl)-2-(3-pyridinyl)-1H-pyrrolo[2,3-b]pyridine (0.44 mmol), 3-pyridinyl boronic acid (0.35 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.013 mmol) in a 4:1 solution of 1,4-dioxane (4 mL):saturated sodium carbonate (1 mL) was stirred for 18 h at 100° C. in a sealed tube. After concentrated in vacuo, the residue was partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer was washed with brine (1×5 mL), dried over magnesium sulfate, and concentrated. Purification by flash chromatography (0-20% ethyl acetate/dichloromethane) provided the title compound as a yellow oil (50%). ESMS [M+H]+: 414.8.