Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1>[Pd].CO>[CH3:33][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1(c2ccc(F)cc2)CCC(CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Reaction time: 23 h
Yield: 64 %

Procedure:
Palladium on carbon (5%, 60 mg) was added to a solution of 2-[4-dimethylamino-4-(4-fluorophenyl)cyclohexylidene]-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone (605 mg, 1.36 mmole) in abs. methanol (100 ml). The reaction mixture was hydrogenated for 23 hours at RT under a pressure of 3 bar. The catalyst was separated using Celite and the filtrate was concentrated by evaporation. After chromatographic separation of the residue (579 mg) on silica gel (50 g) with EE/methanol (2:1) the non-polar diastereoisomer of 2-[4-dimethylamino-4-(4-fluorophenyl)cyclohexyl]-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone was isolated in a yield of 31% (190 mg), and the polar diastereoisomer of 2-[4-dimethylamino-4-(4-fluorophenyl)cyclohexyl]-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone was isolated in a yield of 64% (386 mg). Both compounds were colourless oils.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:48]1[CH:60]=[CH:59][C:51]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[C:50]([NH:61][C:62]([C:64]2[CH:65]=[N:66][CH:67]=[C:68]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[CH:69]=2)=[O:63])[CH:49]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:10]1[CH2:11][CH2:12][N:7]([C:48]2[CH:60]=[CH:59][C:51]([C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])=[C:50]([NH:61][C:62]([C:64]3[CH:65]=[N:66][CH:67]=[C:68]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH:69]=3)=[O:63])[CH:49]=2)[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(N2CCOCC2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Cesium carbonate (0.14 g), morpholine (0.029 mL), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg), tris(dibenzylideneacetone)dipalladium(0) (2 mg), and palladium(II) acetate (1 mg) were added to a toluene (3.0 mL) solution of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and then morpholine (0.029 mL) was added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then cesium carbonate (72 mg), morpholine (0.029 mL), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg), tris(dibenzylideneacetone)dipalladium(0) (2 mg), and palladium(II) acetate (1 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-70% hexane/ethyl acetate] to obtain tert-butyl 4-morpholino-2-(5-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: [ClH:1].Cl.Cl.Cl.C(OC([N:12]1[CH2:16][C@@H:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31]CC)=[O:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)[CH2:14][C@H:13]1[C:34]([N:36]1[CH2:40][CH2:39][S:38][CH2:37]1)=[O:35])=O)(C)(C)C.Cl.Cl.Cl.C(OC(C1C=CC(N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)=NC=1)=O)C>>[ClH:1].[ClH:1].[ClH:1].[C:29]([C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:19][CH2:18][N:17]([C@@H:15]3[CH2:16][NH:12][C@H:13]([C:34]([N:36]4[CH2:40][CH2:39][S:38][CH2:37]4)=[O:35])[CH2:14]3)[CH2:22][CH2:21]2)=[N:24][CH:25]=1)([OH:31])=[O:30]
Reactant: CCOC(=O)c1ccc(N2CCN([C@H]3C[C@@H](C(=O)N4CCSC4)N(C(=O)OC(C)(C)C)C3)CC2)nc1
Agent: CCOC(=O)c1ccc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)nc1
Agent: Cl
Product: O=C(O)c1ccc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)nc1

Procedure:
6 mol/L Hydrochloric acid was added to 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride [product of Example 211 (2), 1.00 g] and the mixture was refluxed for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC. This was converted to hydrochloride with 4 mol/L hydrochloric acid-1,4-dioxane to give the title compound (158 mg) as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15](O)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O1CCOCC1.CCOC(C)=O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[O:24])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C

Procedure:
(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.70 g, 8.5 mmol) was mixed with p-anisic acid (1.42 g, 9.35 mmol) in 5 mL DMF and 25 mL dioxane. The mixture was stirred at RT, and to it were added DIEA (2.07 mL, 11.9 mmol) and then PyBOP (4.86 g, 9.35 mmol). The mixture was stirred at RT for 3 hours, diluted with 150 mL EtOAc, washed with water 60 mL×3, dried, concentrated, subjected to silica flash column using 0 to 20% EtOAc in DCM to isolate (R)-tert-butyl 3-(4-methoxybenzamido)piperidine-1-carboxylate (488) in quantitative yield. Compound 488 (1.86 g, 5.56 mmol) was treated with 30 mL commercial 4N HCl in dioxane at RT for 15 min, giving (R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) in quantitative yield as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:5]([N:8]([CH2:19][C:20](=O)[CH3:21])[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([CH3:7])[CH3:6].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:5]([N:8]1[CH2:19][C:20]([CH3:21])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:9]1=[O:18])([CH3:7])[CH3:6]
Reactant: CC(=O)CN(C(=O)Cc1ccccc1F)C(C)(C)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)C1
Yield: 48.2 %

Procedure:
6.8 g (17 mmol) of N-(3,5-dichloro-α,α-dimethylbenzyl)-N-(2-oxopropyl)-2-fluorophenylacetamide (having a melting point of from 167° to 170° C.) prepared in accordance with the method of Reference Example 8, was dissolved in 30 ml of ethanol, and 0.7 g (11 mmol) of sodium hydroxide powder was added thereto. The mixture was refluxed under heating for 10 minutes. The reaction solution was cooled, and then ethanol was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The crude crystals thereby obtained was recrystallized from methanol to obtain 3.1 g (yield: 49%) of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.245 g; 0.667 mmol), LHMDS 1N in THF (0.733 mL; 0.733 mmol), 1-iodopropane (0.098 mL; 1.000 mmol) in DMF (2.6 mL) for 18 h.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]([OH:27])([C:14]#[C:15][CH:16]([OH:26])[CH2:17][CH:18]([CH3:25])[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH3:24])[CH3:13]>C(O)C.[Pd]>[CH3:11][C:12]([OH:27])(/[CH:14]=[CH:15]\[CH:16]([OH:26])[CH2:17][CH:18]([CH3:25])[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH3:24])[CH3:13]
Reactant: CCC/C=C\CC(C)CC(O)C#CC(C)(C)O
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCC/C=C\CC(C)CC(O)/C=C\C(C)(C)O
Reaction time: 1.5 h
Yield: 55.1 %

Procedure:
At room temp., 520 mg (0.488 mmol) of 10% palladium on barium sulphate and 190 mg (1.47 mmol) of quinoline were added to a stirred solution of 7.70 g (32.3 mmol) of this (9Z)-2,7-dimethyltridec-9-en-3-yne-2,5-diol in 170 mL of ethanol. The flask was evacuated and flushed with nitrogen three times, and three times evacuated and flushed with hydrogen. The resulting reaction mixture was then stirred for 1.5 h under an atmosphere of hydrogen at ambient pressure and temperature, prior to evacuation and ventilation with nitrogen. The reaction flask was opened to air, and the catalyst filtered off by suction over a pad of Celite. After removal of the solvent in a rotary evaporator under reduced pressure, the resulting crude product (8.07 g) was purified by flash chromatography (100 g of silica gel, pentane/ether, 1:1, Rf=0.28) to afford 4.28 g (55%) of (3Z,9Z)-2,7-dimethyltrideca-3,9-diene-2,5-diol as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2=[CH:12][N:13]([CH2:14][C:15]([O:17]CC)=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[OH-].[Li+:21].Cl>C(O)C.O>[O:1]=[C:2]1[CH2:11][C:10]2=[CH:12][N:13]([CH2:14][C:15]([O-:17])=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[Li+:21]
Reactant: CCOC(=O)Cn1cc2c3c(cccc31)NC(=O)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])Cn1cc2c3c(cccc31)NC(=O)C2
Reaction time: 0.08 h

Procedure:
To a solution of ethyl (4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetate from Step G (79 mg, 0.306 mmol) in ethanol (3 mL) and water (0.5 mL) was added dropwise 1.0 N aqueous lithium hydroxide (0.34 mL, 0.34 mmol). After 5 min, 1 N aqueous HCl was added to adjust the mixture to pH 7 and the solution was concentrated in vacuo to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(OCC)C.[CH3:15][NH2:16]>O>[CH3:15][NH:16][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: N#Cc1cnccc1Cl
Solvent: CCOCC
Solvent: O
Product: CNc1ccncc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
4-Chloronicotinonitrile (45.0 g, 324 mmol) was suspended in water (250 mL) and 41% aqueous methylamine solution (250 mL). The resultant mixture was heated, with stirring, at 90° C. for 1 hour before the mixture was cooled to room temperature and extracted with ethyl acetate (×2). The combined organic layers were washed with water, followed by brine then dried (MgSO4) and evaporated to provide a residue. Trituration of the residue with diethyl ether gave the title compound (40.4 g, 93%) as a white solid. 1H NMR (CDCl3) 2.98 (3H, d, J=5.1 Hz), 5.20 (1H, br s), 6.53 (1H, d, J=6.13 Hz), 8.35 (1H, d, J=6.13 Hz), 8.43 (1H, s).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](Br)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.[F-].[Cs+]>COCCOC.CO.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>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:47]3[CH:48]=[CH:49][C:44]([CH2:43][OH:42])=[CH:45][CH:46]=3)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Temperature: 110 °C
Yield: 60.6 %

Procedure:
A mixture of compound 34C (0.135 g, 0.2 mmol), 4-(hydroxymethyl)phenylboronic acid (0.033 g, 0.22 mmol), Pd(PPh3)4 (0.012 g, 0.01 mmol) and CsF (0.091 g, 0.6 mmol) in the DME (2 mL) and MeOH (1 mL) were heated under microwave conditions (110° C., 20 minutes). The reaction mixture was concentrated, and partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 1:1/hexanes:EtOAc to provide 0.085 g of the desired product 34D, which was also a mixture of two regioisomers. MS (ESI(+)): m/z 701 (M+H).
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>O>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH:20]=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cc(CO)cc(OCc2ccccc2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of a sulfur trioxide-pyridine complex (2.113 g) and dimethyl sulfoxide (10 mL) was added dropwise to a mixture of (3-(benzyloxy)-5-methylphenyl)methanol (1.01 g), triethylamine (3.08 mL), and dimethyl sulfoxide (5 mL) at room temperature, and the obtained mixture was stirred overnight at room temperature. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with 1 M hydrochloric acid and brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (0.948 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:10]=2)[C:5](=[O:18])[N:4]([CH3:19])[CH:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:25][C:24]1[CH:23]=[CH:22][C:21]([F:20])=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[CH:10]=3)[C:5](=[O:18])[N:4]([CH3:19])[CH:3]=2)[CH:26]=1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1
Reactant: CC1(C)OB(c2cc(N)ccc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4cc(N)ccc4F)c3c2)cn1
Yield: 63.6 %

Procedure:
4-Bromo-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (35 mg, 0.11 mmol), 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (29 mg, 0.12 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and aqueous 1 M K3PO4 (0.3 mL) in dioxane (1.2 mL) were microwaved at 120° C. for 1.25 h. Work up was similar to that described for Example 18, step 3. Silica gel chromatography, eluting with 100% EA followed by 10% methanol in EA, gave the title compound (25 mg, 0.07 mmol) as a cream solid in 64% yield. LCMS (M+H)+ 349.
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 75%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].CI.O.[C:19](OCC)(=O)C>O1CCCC1>[CH3:19][N:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reactant: CCOC(C)=O
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2c(c1)CCCC2=O
Temperature: 40 °C
Reaction time: 15 h

Procedure:
6-Acetamido-1-tetralone (13.7 g, 67.4 mmol) was dissolved in tetrahydrofuran (40 ml). Sodium hydride(oil)(2.40 g, 101 mmol) was added to the solution, which was refluxed with heating for 2.5 hours. After cooling, methyl iodide(20 ml)was added to the reaction mixture, which was stirred at 40° C. for 15 hours. The reaction mixture was poured into a cold water, and extraction was conducted using ethyl acetate. The extract was washed with 1N hydrochloric acid and 1 N aqueous sodium hydroxide solution. The ethyl acetate layer was concentrated. The residue was purified by alumina column chromatography (development solvent; ethyl acetate:n-hexane=50:50 ˜100:0). The eluent was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-diisopropyl ether, to give the titled compound(8.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[C:9]=2[F:33])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][NH:24][CH3:25])[C:9]=2[F:33])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2Cl)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.6 %

Procedure:
To a solution of tert-butyl ({5-(2-chloropyridin-3-yl)-4-fluoro-1-[(3-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (476 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 240 mg, 63%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>CCOCC>[Br:12][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(CO)c(C)c1
Solvent: CCOCC
Product: Cc1ccc(CBr)c(C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5 g of (2,4-dimethylphenyl)methanol are dissolved in 100 ml of ether. The reaction mixture is cooled to 0° C. It is admixed dropwise with 5.2 ml of phosphorus tribromide. It is stirred at ambient temperature overnight. The reaction mixture is poured onto ice and extracted with AcOEt. The organic phase is washed with saturated NaCl solution. The organic phase is dried over MgSO4, filtered and evaporated to dryness. This gives 7.3 g of the expected compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1.C(N(CC)C(C)C)(C)C.CC#N.O>CCCCO.O>[Br:15][C:16]1[C:17]([N:1]2[CH2:5][CH2:4][C@H:3]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCNC1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CC#N
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@H](CNC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Yield: 60.7 %

Procedure:
(S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25CV) to give (R)-tert-butyl (1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes.