Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[CH2:18](OC1C=CC(C(C)CC(OCC)=O)=CC=1)C=C>>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(CCC(=O)OCC)ccc1O
Reactant: C=CCOc1ccc(C(C)CC(=O)OCC)cc1
Product: C=CCc1cc(C(C)CC(=O)OCC)ccc1O

Procedure:
Ethyl 3-(3-allyl-4-hydroxyphenyl)butanoate was prepared as for ethyl 3-(3-allyl-4-hydroxyphenyl)propionate as in Example 1 but using ethyl 3-(4-allyloxyphenyl)butanoate in place of ethyl 3-(4-allyloxyphenyl)propionate; microanalysis: found: C, 72.6; H, 7.80%; C15H20O3 requires C, 72.6; H, 8.12%; m/z 249(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(N(C(C)C)CC)(C)C.[Na+].[I-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]([CH3:16])([C:13]([O:12][CH2:10][CH3:11])=[O:18])[CH3:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
A 15-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4-dichloroaniline (1.63 g, 10.0 mmol) and treated with ethyl-2-bromoisobutyrate (1.6 mL, 11 mmol), diisopropylethylamine (1.9 mL, 11.0 mmol), and NaI (824 mg, 0.600 mmol). The vessel was sealed tightly, heated to 110° C. and maintained at that temperature for 48 h. After allowing the reaction mixture to cool to room temperature, the reaction was diluted with THF and the solids were filtered off. The filtrate was collected and concentrated under vacuum. The crude oil was purified by silica gel chromatography (35 g Redisep column, silica 40 um, 35 mL/min, A: CH2Cl2, B: MeOH, B: 0% for 20 min, 5% for 5 min, 10% for 5 min; detection at 214 nm) to give 1.71 g (55%) of ethyl N-(3,4-dichlorophenyl)-2-methylalaninate as a brown oil. MS (ES) m/z 276 [M+H]+
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1.N12CCCN=C1CCCCC2.C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:61]([CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1)=[N+:62]=[N-:63]
Reactant: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(Cc1cccc(CN=[N+]=[N-])c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 9-{2-[2-(3-hydroxymethyl-phenyl) -1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (230 mg, 0.49 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL, 0.88 mmol), and tetrahydrofuran (12 mL) at 0° C. under an atmosphere of nitrogen was added diphenylphosphoryl azide (0.19 mL, 0.88 mmol). Mixture stirred overnight warming to room temperature. Solvent removed under vacuum and product isolated as a white solid after purification on silica. M+1=494.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:25]([O:28][CH2:29][CH2:30]Br)(=[O:27])[CH3:26].[Cl-].[NH4+]>C(COC)OC.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:26][C:25]([O:28][CH2:29][CH3:30])=[O:27])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(=O)OCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57M hexane solution, 7.01 ml) was added to a dimethoxyethane solution (50 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (3.03 g, 10.0 mmol) obtained in Example 5. The temperature of the reaction mixture was raised to room temperature, at which stirring was conducted for 15 minutes. After cooling to −78° C., bromoethyl acetate (1.33 ml, 12.0 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated ammonium chloride solution, followed by extraction with diethyl ether. The extracts were combined, washed successively with water, a saturated aqueous solution of sodium thiosulfate, and brine, dried over MgSO41 and then distilled under reduced pressure to remove the solvent. The residue thus obtained was recrystallized from hexane, whereby the title compound (1.95 g, 50%) was obtained as colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[O:17]([CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:26]([CH2:25][CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:28])=[O:27])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)CCOc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)CCOc3ccccc3)c2)cc1Cl
Yield: 22.5 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 2-phenoxy-ethanesulfonyl chloride (21.14 mg, 96 μmol, 1.1 eq). The product was purified by preparative TLC, the plate was eluted with dichloromethane/methanol 95/5, to give N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-2-phenoxyethanesulfonamide (8.1 mg, >95% purity, yield: 22.5%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:27])[C@@H:8]([NH:13][C@@H:14]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:4]1)#[N:2].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1B(O)O>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]>[C:1]([C:3]1([NH:6][C:7](=[O:27])[C@@H:8]([NH:13][C@@H:14]([C:20]2[CH:25]=[CH:24][C:23]([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][C:33]=3[F:35])=[CH:22][CH:21]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)NC1(C#N)CC1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)c1nccs1)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared via the Suzuki cross-coupling of (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid (1-cyanocyclopropyl)-amide with 2,4-difluorobenzeneboronic acid, in the presence of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex. MS (−ESI): 479 [M−1]−
Reaction SMILES: O.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Br[CH:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:14]1([CH:13]=[CH:12][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrC(c1ccccc1)C(Br)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 98 %

Procedure:
Hexadecyltributyl phosphonium hectorite (0.050 mmol) was mixed with 2.0 ml of water containing dissolved sodium iodide (0.264 mmol) and sodium thiosulfate (32.0 mmol) and toluene (2.0 ml) containing dissolved 1,2-dibromo-1,2-diphenyl ethane (1.0 mml). After vigorous stirring for a reaction time of 7 hr at 90° C. the emulsion was broken by centrifugation, and 1,2-diphenylethylene was obtained in 98.0% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:21]2[C:20]3[C:15](=[CH:16][C:17]([C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68]O>O1CCOCC1.C1COCC1>[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][O:8][C:7]1[C:2]([F:1])=[C:3]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][C:17]([C:22]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)=[O:23])=[CH:18][CH:19]=4)[NH:14][C:13]=3[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc(O)c4F)c23)CC1
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN(C)CCOc1cccc(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)c1F
Temperature: 95 °C

Procedure:
A mixture of 4-(2-fluoro-3-hydroxyphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Intermediate 84-1, 20 mg, 0.045 mmol) and polymer-supported triphenylphosphine (2.63 mmol/g, 0.358 mmol) in 1,4-dioxane was treated at 0° C. with a solution of diethyl azodicarboxylate (19.5 mg, 0.157 mmol) in THF (0.5 mL), followed after 5 min by a solution of 2-(dimethylamino)ethanol (10 mg, 0.112 mmol) in THF (0.5 mL). The mixture was heated in a sealed tube by microwave irradiation at 90-100° C. for 30 min. The resulting mixture was filtered, the solids were washed with methanol, and the filtrates were concentrated and purified by preparative HPLC to provide 4-(3-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide. Mass spectrum m/z 518.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCC1Cc2cccc(-c3ccccc3F)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3F)c2O1)OCc1ccccc1
Yield: 84 %

Procedure:
Treatment of (±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.5 g, 5.36 mmol) with diisopropylethylamine (1.04 g, 8.04 mmol) and benzyl chloroformate (1.01 g, 5.89 mmol) generally according to the procedure described for Intermediate 12 afforded 1.7 g (84%) of (±)-benzyl[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil Rf=0.68 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C22H18FNO3: C, 72.72; H, 4.99; N, 3.85. Found: C, 72.65H, 5.41; N, 3.47. Chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=13.628 min, Chiralcel OJ, hexane:isopropanol 9:1); Fraction 2 (Rt=17.247 min, Chiralcel OJ, hexane:isopropanol 9:1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]2)=O)[CH2:14][CH2:13]1)=O)C.O>C(OC)(C)(C)C>[F:25][C:23]([F:24])([F:26])[C:20]1([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([CH2:10][OH:9])[CH2:17][CH2:16]2)[CH2:21][CH2:22]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C(F)(F)F)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: OCC1CCN(CC2(C(F)(F)F)CC2)CC1
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
Lithium aluminum hydride (208 g, 5.0 eq) is suspended in 3.9 L of methyl tert-butyl ether and the suspension is stirred for 10 min. A solution of 1-(1-trifluoromethyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (260 g, 0.93 mol) in 1.3 L of methyl tert-butyl ether is added dropwise at <30° C. The mixture is refluxed for 20 h and cooled to 0˜10° C. 500 mL of water are added at 0˜10° C. and the mixture is stirred for 30 min. The suspension is filtered and the cake is washed with 1.8 L of methyl tert-butyl ether. The filtrate is concentrated to ˜3 L of volume at <35° C. under vacuum. The solvent is displaced with tetrahydrofuran (1.0 L×2) and concentrated to provide 212 g of the title compound in 96.8% purity.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C(OCC)C>[Cl:14][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=S1(=O)N=C(Cl)c2ccccc21
Temperature: 25 °C
Yield: 33.7 %

Procedure:
Saccharin (10.0 g, 0.0546 mol) and phosphorus pentachloride (12.6 g, 0.060 mol) were heated at 170° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature and suspended in diethyl ether (200 mL). The precipitate was collected by filtration, thoroughly washed with diethyl ether and dried to yield 3-chloro-1H-1λ6-benzo[d]isothiazole-1,1-dione (3.7 g, 0.0184 mol) as a white solid which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:10][NH:11][C:12]([NH2:14])=[S:13]>CO>[CH3:10][NH:11][C:12]1[S:13][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:14]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: CNC(N)=S
Solvent: CO
Product: CNc1nc(CC(=O)OC)cs1
Temperature: 80 °C

Procedure:
A mixture of methyl 4-chloro-3-oxobutanoate (1 g, 11.1 mmol) and 1-methylthiourea (1.72 g, 11.43 mmol) in MeOH (5 mL) was heated to 80° C. for 3 hours. The mixture was cooled, ethanol evaporated, and diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and the reaction mixture purified by a standard method to provide methyl 2-(2-(methylamino)thiazol-4-yl)acetate. LC-MS: m/z (M+H)=187.2
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])O1>>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[N:7]=[C:2]([C:36]4[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=4[C:38]#[N:39])[CH:3]=[CH:4][CH:5]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(-c4ccccc4C#N)n3)cnc2n1

Procedure:
3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine was coupled to 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile following the procedure in Example 2 to give 2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile as an orange oil.
Reaction SMILES: C1(C[O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1OCCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1OCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To a solution of 8.2 g (27 mmol) of 2-[3-(phenylmethoxy)propoxy]isoindoline-1,3-dione, as prepared in the preceding step, in 120 mL anhydrous ethanol under nitrogen was added 1.5 g of 10 wt % Pd/C. Then the nitrogen in the reaction was replaced with hydrogen and the reaction was stirred at room temperature for 5 h. After the reaction was completed, the mixture was filtered through a pad of Celite (diatomaceous earth). The solvent of the filtrate was removed under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate/hexanes (1:1, v/v) as eluent to yield 4.4 g (75%) of white solid as product: 1H NMR (300 MHz, CDCl3) δ7.85-7.81 (m, 2H), 7.78-7.74 (m, 2H), 4.37 (t, J=5.88 Hz, 2H), 3.93 (t, J=5.80 Hz, 2H), 2.55 (br s, 1H), 1.99 (quintet, J=5.86, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[C:24]([F:39])=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[C:24]([F:39])=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[C:31](=[CH:20][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=2[CH3:1])[C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4F)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 62.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (54 mg, 62.1%) as a yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([OH:16])[CH2:14][F:15])(=O)=O)=CC=1.[N:17]1([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CO>[F:15][CH2:14][CH:13]([OH:16])[CH2:12][N:20]1[CH2:21][CH2:22][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:18][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CF)cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCN(CC(O)CF)CC1
Temperature: 25 °C
Yield: 18.7 %

Procedure:
To the crude 3-fluoro-2-hydroxypropyl 4-methylbenzenesulfonate (1.98 g, 7.98 mmol) in methanol (40 mL) was added benzyl piperazine-1-carboxylate (1.76 g, 7.98 mmol). The reaction was stirred at RT over the weekend. After being evaporated to dryness, the residue was purified on silica gel, eluting with 0 to 10% MeOH in DCM to yield the desired product (443 mg, 18.7%). LCMS calculated for C15H22FN2O3(M+H)+: m/z=297.2; Found: 297.4.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)O1.Cl[C:22]1[C:31]([N:32]([CH3:36])[CH:33]([CH3:35])[CH3:34])=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:37]([O:39][CH3:40])=[O:38])[CH:28]=2)[N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH3:36][N:32]([CH:33]([CH3:35])[CH3:34])[C:31]1[C:22]([C:9]2[O:10][C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][CH:13]=2)=[N:23][C:24]2[C:29]([N:30]=1)=[CH:28][C:27]([C:37]([O:39][CH3:40])=[O:38])=[CH:26][CH:25]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)o2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(-c4ccccc4)o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(5-phenylfuran-2-yl)-1,3,2-dioxaborolane (553 mg, 2.05 mmol) in dioxane (5.5 mL) and water (3 drops) was methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (200 mg, 0.68 mmol), K3PO4 (430 mg, 2.03 mmol) and Pd(PPh3)4 (39.3 mg, 0.03 mmol) with stirring for 1 h at 95° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylate as light yellow solid (150 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([OH:34])=O)=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:43]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([NH2:43])=[O:34])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(N)=O
Yield: 86.9 %

Procedure:
A solution of 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.44 g, 0.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxybenzotriazole ammonium salt (0.24 g, 1.6 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.38 g, 86.4%) as crystals.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1ccc2ccccc2n1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc3ccccc3n2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Quinoline-2-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=503.3.