Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:10]2[CH:9]=[C:8]([CH3:22])[CH:13]=[CH:12][CH:11]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: Cc1cccc(Nc2ncccc2N)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Nc2ncccc2NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (1.7 mL, 12.0 mmol) was added to a mixture of N2-m-tolylpyridine-2,3-diamine (600 mg, 3.01 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.03 g, 5.42 mmol), HOAt (740 mg, 5.42 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.04 g, 5.42 mmol) in anhydrous DCM (25 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 16 h. After re-cooling the mixture to 0° C., additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (220 mg, 1.20 mmol), HOAt (160 mg, 1.20 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol) and triethylamine (0.41 mL, 3.01 mmol) were added. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 72 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an off-white foam. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method C): RT 2.70 min [M+H]+ 371.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18](Cl)=[O:19]>C1(C)C(C)=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18]([C:6]1[N:2]([CH3:1])[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]=1[CH3:7])=[O:19]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)c(Cl)c2)n1C
Yield: 79.6 %

Procedure:
A solution of 3.6 g of ethyl 1,4-dimethylpyrrole-2-acetate and 8.3 g of 3,4-dichlorobenzoyl chloride in 20 ml of xylene is refluxed for 40 min and then chilled. The separated solid is collected by filtration and dried to give 5.6 g (80%) of ethyl 5-(3,4-dichlorobenzoyl)-1,4-dimethylpyrrole-2-acetate as white crystals, m.p. 92°-93.5° C.
Reaction SMILES: COC1C=CC([C@@H]2O[C@H]2C(N)=O)=CC=1.NC1C=CC=CC=1S.N[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][C@@H:31]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C@@H:32]([OH:36])[C:33]([NH2:35])=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClC1C=CC=CC=1>[OH:36][C@H:32]1[C:33](=[O:34])[NH:35][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C@H:31]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1ccccc1S
Solvent: Clc1ccccc1
Solvent: CO
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (9.66 g) and chlorobenzene (193 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (6.89 g) and ferric chloride hexahydrate (1.35 mg) in methanol (0.1 ml) is added immediately into the reaction mixture, and the mixture is stirred at the same temperature for 5 minutes. The reaction mixture containing (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide is refluxed for 15 hours during which p-toluenesulfonic acid monohydrate (2.88 g) is added thereto in 6 portions (0.48 g×6) at intervals of 2.5 hours to remove the chlorobenzene. The remaining chlorobenzene is evaporated, and methanol (50 ml) is added to the residue. The mixture is refluxed for one hour, allowed to cool to room temperature, and further cooled at 3° C. overnight. The precipitated crystals are collected by filtration, washed with chilled methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (11.73 g).
Reaction SMILES: [CH:1]([C:3]([OH:20])=[C:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1)=[CH2:2].[C:21]([O:24][CH:25]=[CH2:26])(=[O:23])[CH3:22].OC1C=CC(C=O)=CC=1>CN(C)C=O>[CH:1]([C:3]([OH:20])=[C:4]=[CH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[CH2:2].[C:21]([O:24][CH:25]=[CH2:26])(=[O:23])[CH3:22]
Reactant: C=CC(O)=C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Agent: O=Cc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: C=COC(C)=O
Product: C=CC(O)=C=Cc1ccc(O)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To prepare a novel vinyl 4-t-butoxycarbonyloxybenzal-vinyl alcohol-vinyl acetate copolymer, poly(vinyl alcohol) with an average molecular weight of about 8,000-200,000 is dissolved in dimethylformamide to give a 5-20 wt % solution. This solution is then added to an acid and stirred at 50-140° C. for 1-5 hrs. 4-hydroxybenzaldehyde is added, followed by stirring under the same conditions as above. Precipitation occurs in distilled water. The precipitate is dissolved in dimethylformamide again and re-precipitated in distilled water. The procedure of dissolving in dimethylformamide and precipitating in distilled water is repeated two or three times. Then, the final precipitates are dried in vacuo to obtain pure vinyl-4-hydroxybenzal-vinyl alcohol-vinyl acetate copolymer. The acid, hydrochloric acid, sulfuric acid, or phosphoric acid is used at an amount of 1-20 weight parts based on 100 weight parts of the total reaction. Instead of dimethylformamide, distilled water may be employed. In this case, as the polymerizing reaction progresses, the copolymer is produced as precipitates. A desired product can be obtained by filtering and washing the precipitates.
Reaction SMILES: [CH2:1]([C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][OH:17])[O:5][CH2:4]1)[CH3:2].CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:31])C>C(Cl)Cl>[CH3:14][C:12]([O:11][C:9]([N:8]1[C@H:3]([CH2:1][CH3:2])[CH2:4][O:5][C@H:6]([C:16]([OH:31])=[O:17])[CH2:7]1)=[O:10])([CH3:13])[CH3:15]
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: CC[C@@H]1CO[C@H](CO)CN1C(=O)OC(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Product: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a vigorously stirred solution of 1,1-dimethylethyl(2S,5R)-5-ethyl-2-(hydroxymethyl)-4-morpholinecarboxylate (2.52 g, 10.27 mmol) in CH2Cl2 (50 mL) that was cooled to 0° C. were added TEMPO (0.321 g, 2.054 mmol) and (diacetoxyiodo)benzene (7.28 g, 22.60 mmol). The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with CH3OH and then concentrated to afford the title compound (0.711 g) as a yellow oil. LC-MS (ES) m/z=260 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22](=[O:23])[CH2:21][CH:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[O:23]=[C:22]1[N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:13]=2)[CH2:19][CH:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]1
Reactant: COC(=O)C1CC(=O)N(c2cccc(N)c2)C1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1
Temperature: 23 °C
Reaction time: 27 h

Procedure:
Benzyl isocyanate (2.3 mL, 18.6 mmol, 1.2 equiv) was added to a solution of methyl 1-(3-aminophenyl)-5-oxopyrrolidine-3-carboxylate (3.6169 g, 15.4 mmol, 1 equiv) in dichloromethane (77 mL). The resulting solution was stirred at 23° C. for 27 hr, during which time a white precipitate formed. The reaction was filtered, and the solid was collected to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 7.76 (t, 1H, J=1.8 Hz), 7.13-7.36 (m, 8H), 6.59 (t, 1H, J=5.9 Hz), 4.30 (d, 2H, J=5.9 Hz), 4.03 (dd, 1H, J=9.7 Hz, 8.7 Hz), 3.94 (dd, 1H, J=9.5 Hz, 6.1 Hz), 3.68 (s, 3H), 3.41-3.50 (m, 1H), 2.80 (dd, 1H, J=17.0 Hz, 9.5 Hz), 2.71 (dd, 1H, J=17.0 Hz, 7.0 Hz). MS: (+) 368.0 (M+H), 385.5, 390.0, 735.5; (−) 366.0 (M−H), 426.0, 733.5, 793.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[N:7][CH:8]=1)#N.[OH2:20]>C(O)=O.[Ni]>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[N:7][CH:8]=1)=[O:20]
Reactant: O
Reactant: N#Cc1ccc(Oc2cccc3c2CCC3=O)nc1
Agent: [Ni]
Solvent: O=CO
Product: O=Cc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
To a solution prepared by suspending 4.6 g of 4-[(5-cyano-2-pyridinyl)oxy]-1-indanone obtained in Reference Example 59 in 4.4 ml of water and 11 ml of formic acid, 2.6 g of raney nickel was added at 60° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][O:10][C:11](=[O:42])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]2[CH2:24][NH:23][CH2:22][CH2:21][N:20]2[C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)=[CH:14][C:13]=1[OH:41].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:9][O:10][C:11](=[O:42])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]2[CH2:24][NH:23][CH2:22][CH2:21][N:20]2[C:25](=[O:40])[C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=2)=[CH:14][C:13]=1[O:41][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.5 %

Procedure:
tert-Butyldimethylsilyl chloride (2.34 g) was added to a solution of 4-[[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-piperazin-2-yl]methyl]-2-hydroxybenzoic acid methyl ester (2.56 g), 4-(dimethylamino)pyridine (126 mg) and triethylamine (2.51 ml) in dichloromethane (50 ml) at room temperature. After stirring at room temperature for 15 hours, additional triethylamine (2.51 ml) and tert-butyldimethylsilyl chloride (2.34 g) were added and the whole mixture was stirred for further 1 day. Water (200 ml) was added to the mixture, and the resulting mixture was extracted with dichloromethane. The organic extracts were washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol to give 4-[[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]piperazin-2-yl]-methyl]-2-(tert-butyldimethylsilyloxy)benzoic acid methyl ester (1.72 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=2)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:23][CH:22]=1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccc(Cl)cc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(Cl)cc2)c1)c1ccccc1
Yield: 49 %

Procedure:
In a manner similar to that describe in Example 425 a mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-chloro-1-ethynylbenzene were reacted to give the title compound as white needles (60 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15](=[NH:17])[NH2:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][C:26](=O)[CH3:27]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:15]2[NH:16][CH:25]=[C:26]([CH3:27])[N:17]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1
Reactant: N=C(N)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1c[nH]c(-c2sc(Br)nc2-c2ccc(Cl)cc2Cl)n1
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carboximidamide (70 mg, 0.2 mmol) in DCM (4 mL) was added potassium carbonate (82.7 mg, 0.598 mmol) followed by solution of chloroacetone (50 uL, 0.6 mmol) in DCM (0.4 mL). The mixture was heated to reflux for 3 hours, at which time LCMS indicated ˜50% conversion. Additional cloroacetone (11 ul) and K2CO3 (19 mg) were added and heating was continued for additional 4 hours. LCMS showed complete conversion. Solvent was removed under reduced pressure and the residue was purified using ISCO chromatography, 20%-60% ethyl acetate in hexane to afford the title compound (56 mg, 70%). LCMS: (FA) ES+, 388, 390, 392. 1H NMR (400 MHz, d1-chloroform) δ: 7.60 (dd, J=5.37, 1.71 Hz, 1H), 7.45-7.40 (m, 3H), 2.23 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([CH3:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH3:43])=[C:28]([O:27][CH:24]([CH3:25])[CH3:26])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(C)C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 84.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=443 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.17-8.16 (m, 1H), 8.13-8.09 (m, 2H), 8.00-7.96 (m, 1H), 7.59-7.57 (m, 1H), 7.31-7.29 (m, 1H), 4.74 (hp, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.36 (s, 3H), 1.97 (s, 3H), 1.35 (t, 6H))
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([CH3:9])[NH:7][O:8][C:4]=2[C:3]=1[NH:12]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O>[NH2:12][C:3]1[C:4]2[O:8][NH:7][CH:6]([CH3:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[F:1]
Reactant: CC1NOc2c1ccc(F)c2NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1NOc2c1ccc(F)c2N
Reaction time: 1 h
Yield: 111.7 %

Procedure:
Trifluoroacetic acid (50 mL) was stirred and cooled in an ice-water bath. To this was added t-butyl N-(6-fluoro-3-methyl-1,2(2H)-benzisoxazol-7-yl)carbamate (3.0 g). Upon completion of addition, the reaction mixture was stirred for one hour and then concentrated to a residue. The residue was taken up in water and made basic to pH 8 with sodium bicarbonate. The mixture was then extracted thoroughly with methylene chloride. The combined extracts were washed with water, dried with magnesium sulfate, and concentrated, yielding 2.1 grams of 7-amino-6-fluoro-3-methyl-1,2(2H)-benzisoxazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:11][N:12]([CH2:14][C:15]1[C:19]([F:20])=[C:18]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)[N:17]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:16]=1)C.C(Cl)(=O)OC(Cl)C.C(N(CC)CC)C.O>O1CCCC1>[F:20][C:19]1[C:15]([CH2:14][NH:12][CH3:11])=[CH:16][N:17]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:18]=1[C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CN(C)Cc2cn(S(=O)(=O)c3ccccc3)c(-c3cccnc3F)c2F)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of 1-(2,4-dimethoxyphenyl)-N-{[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}-N-methylmethanamine (2.75 g) in tetrahydrofuran (10 mL) was added a solution of 1-chloroethyl chlorocarbonate (781 mg) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred for 15 min. Triethylamine (2.3 mL) was added and the obtained mixture was refluxed for 16 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (12 mL) was added to the residue, and the mixture was refluxed for 1.5 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate:methanol=9:1→1:1) to give the title compound as a yellow solid (yield 1.46 g, 75%).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C=O)C>[CH:2]1([NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)N(C)C)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (Example 149) (115 mg, 0.279 mmol) and NEt3 (43 μL, 0.307 mmol) in DMF (2 ml) was added dimethylcarbamoyl chloride (35 μL, 0.307 mmol). Reaction mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (75 mg, 56%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]1)[CH3:2].Br[C:33]1[N:37]=[C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[C:40]([Cl:48])[CH:39]=2)[S:35][N:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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>[Cl:48][C:40]1[CH:39]=[C:38]([C:36]2[S:35][N:34]=[C:33]([C:8]3[C:3]([CH2:1][CH3:2])=[C:4]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]4)[CH:5]=[CH:6][CH:7]=3)[N:37]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH:45]([CH3:46])[CH3:47]
Reactant: CCOC(=O)CCN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Temperature: 120 °C
Yield: 37.4 %

Procedure:
To a solution of ethyl 3-(4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinyl)propanoate (D140) (1.3 g, 3.03 mmol) in N,N-Dimethylformamide (DMF) (6 mL) and Water (1.500 mL) was added 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (1.010 g, 3.03 mmol), tripotassium phosphate (1.928 g, 9.08 mmol) and Pd(Ph3P)4 (0.350 g, 0.303 mmol). The reaction mixture was heated by Biotage Initiator to 120° C. for 20 min. The reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated and purified by ISCO column chromatography to afford ethyl 3-(4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)propanoate (D141) (0.63 g). MS (ES): C30H38ClN3O3S requires 555.2. found 556.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(Cl)ccc2c1N
Reactant: OB(O)c1ccccc1
Product: CCCNC(=O)c1nnc2c(-c3ccccc3)c(Cl)ccc2c1N
Yield: 56.2 %

Procedure:
Using Method F, 4-amino-7-chloro-8-iodo-N-propyl-cinnoline-3-carboxamide (184 mg, 0.47 mmol) and phenylboronic acid (229 mg, 1.89 mmol) were reacted (refluxed 40 hours) to afford the title compound (90 mg, 56% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (bs, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.42-7.55 (m, 5H), 3.43 (apparent q, J=6.6 Hz, 2H), 1.63 (apparent sextet, J=7.2 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS APCI, m/z=341 (M+H) HPLC 2.04 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH2:21][CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH2:21]([C:3]1[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])=[N:5][C:6]2[C:11]([C:2]=1[NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:22]
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-3-ethyl-5,7-difluoroquinolin-2-yl)piperidin-2-one (40.0 mg, 0.120 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(3-ethyl-5,7-difluoro-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-2-piperidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.84 (2H, dd, J=7.2, 2.3 Hz), 7.46 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.08 (1H, d, J=11.7 Hz), 6.97 (1H, ddd, J=13.5, 8.6, 2.5 Hz), 6.65 (1H, t, J=2.3 Hz), 4.24-4.39 (1H, m), 3.80 (4H, t, J=4.8 Hz), 3.50-3.60 (1H, m), 3.10-3.30 (4H, m), 2.38-2.64 (4H, m), 1.88-2.17 (4H, m), 1.01 (3H, t, J=7.4 Hz). Mass Spectrum (ESI) m/e=468.2 (M+1).