Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30](=[O:55])[NH:31][C:32]5[N:36]([C:37]6[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=6)[O:40][CH2:41][CH2:42]OS(C)(=O)=O)[N:35]=[C:34]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:33]=5)[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:2]1.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>C1COCC1>[CH:30]([OH:55])=[O:59].[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30]([NH:31][C:32]5[N:36]([C:37]6[CH:50]=[CH:49][CH:48]=[C:39]([O:40][CH2:41][CH2:42][N:56]7[CH2:61][CH2:60][O:59][CH2:58][CH2:57]7)[CH:38]=6)[N:35]=[C:34]([C:51]([CH3:54])([CH3:52])[CH3:53])[CH:33]=5)=[O:55])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:1]1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCOS(C)(=O)=O)c2)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCN3CCOCC3)c2)n1
Product: O=CO
Yield: 110.3 %

Procedure:
A brown solution of Intermediate 148g (0.099 mmol) and morpholine (43 mg, 0.50 mmol) in THF (1 mL) was stirred in a sealed vial at 60° C. for 18 h. The solution was decanted and concentrated. MDAP (Method 7) gave the title compound as an off-white solid (44 mg, 54%). LCMS (Method 5): Rt 3.64 min, m/z 760.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.41-0.54 (4H, m), 1.27 (9H, s), 1.52-1.62 (2H, m), 1.72-1.81 (3H, m), 1.83-1.96 (3H, m), 1.99-2.15 (2H, m), 2.42 (4H, t, J=4.4 Hz), 2.66 (2H, t, J=5.7 Hz), 3.22-3.29 (2H, m), 3.52 (4H, t, J=4.58 Hz), 4.11 (2H, t, J=5.7 Hz), 4.81 (1H, td, J=8.6, 5.5 Hz), 5.48 (1H, t, J=4.3 Hz), 6.33 (1H, s), 6.95-6.98 (1H, m), 7.06-7.12 (3H, m), 7.14 (1H, dd, J=9.9, 2.2 Hz), 7.25-7.42 (5H, m), 7.57 (1H, dd, J=2.1, 0.9 Hz), 7.61 (1H, dd, J=9.8, 0.8 Hz), 8.11 (1H, s), 8.16 (1.3H, s).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]1([PH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(=O)C=C>>[C:1]([CH2:2][CH2:3][P:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CC(=O)OC
Agent: C=CC(=O)[O-]
Product: COC(=O)CCP(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 8.6 g (0.1 mole) methyl acrylate and 19.5 g (0.105 mole, 5% excess) of diphenyl phosphine was reacted at 15° C. in the routine manner of Example 1. U.V. irradiation resulted in a rapid reaction. After 1 hour, there was no acrylate left unconverted. The expected mono- and diadducts were formed in a weight ratio of about 95 to 5. (A sample of the reaction misture which was not irradiated also showed a complete conversion after 22 hours but not after 1 hour. ) On distillation of the reaction mixture in vacuo, the monoadduct, i.e. 2-carbomethoxyethyl diphenyl phosphine, was obtained as an almost colorless, liquid distillate having a slight yellow tint (Table 4).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:26][C:25]4([CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[O:24][CH2:23][CH2:22]3)=[O:20])[N:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[C:8]1([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:26][C:25]4([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[O:24][CH2:23][CH2:22]3)=[O:20])[N:18]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1csc(-c3ccccc3)n1)CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3.8 mL) was added to a solution of tert-butyl 4-(2-phenylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 112, step a) (0.85 mg) in DCM (15.2 mL). The resulting mixture was stirred at RT for 1 h. Toluene (30 mL) was added and the mixture was evaporated in vacuo. The yellow residue was dissolved in MeOH and applied to a SCX cartridge pre-wetted with MeOH. The cartridge was washed with MeOH and eluted with 2M ammonia in MeOH. The eluent was evaporated in vacuo to give the subtitled compound as a brown oil. Yield 0.629 g.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:18](=O)[O:17][CH:16]3O)=[CH:7][CH:6]=1>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:18](=[O:17])[NH:2][N:1]=[CH:16]3)=[CH:7][CH:6]=1
Reactant: NN
Reactant: COc1ccc(C=Cc2ccc3c(c2)C(O)OC3=O)cc1
Solvent: CCO
Product: COc1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1
Reaction time: 5 h

Procedure:
Nine and one-half ml of hydrazine was added to a solution of 8.0 gm 5-(p-methoxyphenyl)ethenyl-3-hydroxyphthalide in 100 ml ethanol and the mixture was refluxed with stirring for 5 hours. The reaction mixture was cooled and the product filtered off and washed with isopropanol and dried. Wt=4.0 gm, m.p.=280°-289°.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.COC(OC)[N:12]([CH3:14])C.O.[NH2:18]N>C(O)C>[CH3:5][C:3]1[C:2]([C:1]([O:7][CH3:8])=[O:6])=[CH:14][NH:12][N:18]=1
Reactant: NN
Reactant: COC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: O
Product: COC(=O)c1c[nH]nc1C
Temperature: 100 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of methyl acetoacetate (30.0 g) and dimethylformamide dimethylacetal (34.7 mL) was stirred at 100° C. for 12 hr, and the mixture was allowed to cool. Ethanol (500 mL) and hydrazine monohydrate (12.6 mL) were added to the reaction mixture at room temperature, and the mixture was heated under reflux for 12 hr. The mixture was allowed to cool, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give the title object compound (22.3 g, 61%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 3-benzyloxyestra-1,3,5(10)-trien-17-one (40, 2.70 g, 7.5 mmol) in THF (5.0 mL) and MeOH (30 mL) was added sodium borohydride (284 mg, 7.5 mmol) at 0° C. The reaction mixture was stirred for 30 min, then quenched with saturated aqueous NH4Cl, and H2O added. The precipitate was collected by filtration and washed with H2O to afford 2.73 g of 41 (100% yield) mp: 118-119° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH:36]=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCOC(C)=O>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:2]=2[NH:1][CH:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:34][CH2:33]2)[CH3:36])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 61.5 %

Procedure:
Using a similar procedure to that described in Example 47-C, 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.7 g, 8.8 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-acetaldehyde (3.0 g, 13 mmol) afforded, after trituration with EtOAc:methylene chloride, 2.8 g (61%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:14](NC3CCCCC3)=[O:15])=[C:11]3[CH2:29][CH2:30][CH2:31][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=[O:33].[K+].[K+].ClC1C=CC([N:45]2[C:49]([CH:50]([CH:57]3[CH2:62][CH2:61]CCC3)[CH2:51][O:52]S(C)(=O)=O)=C3CCCC3=N2)=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[CH3:32][O:33][C:51](=[O:52])[C:50]1[CH:57]=[CH:62][C:61]([O:15][CH2:14][CH:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[CH2:31][CH2:30][CH2:29][C:11]=23)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:45][CH:49]=1
Reactant: O=C(NC1CCCCC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of methyl 6-hydroxynicotinate 4 (80 mg, 0.19 mmol; CAS Reg. No. 10128-91-3) in dry DMF (3 ml) was added dry K2CO3 (29 mg, 0.226 mmol) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. Methanesulfonic acid 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethyl ester (35 mg, 0.227 mmol) dissolved in dry DMF (1 ml) was added at 0° C. The reaction mixture was heated to 100° C. in a sealed tube for 12 h. 10% Aqueous citric acid solution (10 ml) and EtOAc (5 ml) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted one more time with EtOAc (5 ml). The combined organic layers were washed with brine (5 ml) and dried over Na2SO4. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography over silica gel (20% EtOAc/hexane) to give the title compound (60.2 mg, 0.12 mmol; 67%) as off-white solid.
Reaction SMILES: CI.[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1C[O:13][CH2:12][CH2:11]1.C(C1C=CC=CC=1)C>C1COCC1>[O:13]1[C:12]2[C:6](=[CH:7][CH:8]=[CH:9][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CCOC1
Reactant: CCCCCCC
Solvent: CCc1ccccc1
Solvent: CI
Product: c1ccc2c(c1)CCCO2
Reaction time: 0.25 h

Procedure:
To 0.9 g (4 mmole) of sulfone ketone in 40 ml of THF is added 2.5 ml (5 mmole, 1.25 eq.) of 2 M of Lithium diisopropylamine(LDA) in heptane/THF/ethylbenzene at −60° C. The mixture is stirred for about 15 minutes, and then 1.24 ml (20 mmole, 5 eq.) of methyl iodide is added. The reaction mixture is stirred for 1 hour at −60° C., and then the cold bath is removed. After stirring overnight, the reaction mixture is partitioned between EtOAc and water, washed with 0.5N HCl, aqueous sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to afford 0.68 g of the desired product as an oil, which solidified upon standing. TLC (30% EtOAc/Hexane, Rf=0.39). Mass spec. m/e=239.1.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH2:8][C:9]([NH2:11])=[S:10].Cl[C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>C(Cl)Cl.O>[CH3:16][O:15][C:13]([NH:8][C:9](=[NH:11])[S:10][CH3:5])=[O:14]
Reactant: NC(N)=S
Reactant: COC(=O)Cl
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)NC(=N)SC
Temperature: 20 °C
Reaction time: 0.05 h

Procedure:
5 ml. of water and 1.9 ml. of dimethyl sulfate were added to 1.52 g. of thiourea (20 mmol). The mixture was stirred for about 3 mins. (until the initial heat evolution had subsided). The clear solution was then heated on a steam bath for 1 hour with stirring. The solution was cooled to about 20° C. and surrounded by a water bath (18° -22° C.). Freshly distilled methyl chloroformate (3.1 ml., 40 mmol) was added all at once followed by dropwise addition of 25 ml. of 10% aqueous sodium hydroxide over a period of 30 mins. The resulting product was isolated by extraction with methylene chloride and concentrated in vacuo to give an oily yellow solid which crystallized from ether as white prisms, mp. 97° -100° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[OH:15]>CC#N>[C:13]([C:11]1[CH:10]=[CH:9][C:8]([OH:15])=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:12]=1)#[N:14]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: CCN=C=O
Solvent: CC#N
Product: CCNC(=O)Nc1cc(C#N)ccc1O
Yield: 70 %

Procedure:
Ethyl isocyanate (7.1 g; 100 mmol) was added to a stirred solution of 2-amino-4-cyanophenol (13.4 g; 100 mmol) in MeCN (250 mL), and the resultant solution was stirred for 12 h. The precipitate was filtered off and dried (vacuum) to give the sub-title compound in a 70% yield.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C(N([CH2:27][CH3:28])CC)C.[OH:29][C:30]1[CH:49]=[CH:48][C:33]([CH:34]=[CH:35][C:36]([O:38][C@@H:39]2[CH:43]3[O:44][CH2:45][C@@H:46]([OH:47])[CH:42]3[O:41][CH2:40]2)=[O:37])=[CH:32][CH:31]=1>ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:29][C:30]2[CH:31]=[CH:32][C:33]([CH:34]=[CH:35][C:36]([O:38][C@@H:39]3[CH:43]4[O:44][CH2:45][C@@H:46]([O:47][C:17](=[O:18])[C:16]5[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:27]=[CH2:28])=[CH:21][CH:20]=5)[CH:42]4[O:41][CH2:40]3)=[O:37])=[CH:48][CH:49]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CCN(CC)CC
Reactant: O=C(C=Cc1ccc(O)cc1)O[C@H]1COC2C1OC[C@H]2O
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)O[C@H]3COC4C3OC[C@H]4OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
3.3 g of 4-(6-acryloyloxyhexyloxy)benzoyl chloride dissolved in 40 ml of dichloromethane was added dropwise to a solution of 2.4 ml of triethylamine, 0.3 g of 4-N,N′-dimethylaminopyridine and 1.8 g of 3-(R)-hydroxy-hexahydro-furo[3,2-b]furan-6-(S)-yl 4-hydroxycinnamate (26) in 40 ml of dichloromethane. The reaction was stirred overnight at room temperature. The solution was extracted with 80 ml of 2.5 N HCl. The organic layer was washed with water, dried over MgSO4 and passed through a silica pad. The solvent was evaporated. The crude producty was recrystallised twice from ethyl acetate. 2.8 g of white crystals were obtained (yield: 61%). The melting point of the compound was 142° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:8]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:8]=3)[N:3]=[C:2]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[N:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CN(C)CC#Cc1ccc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)CC#Cc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
In a 50 mL round-bottomed flask was added 2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine, (61 mg, 0.16 mmol), 3-pyridineboronic acid (25 mg, 0.20 mmol), K2CO3 (0.11 mg, 0.78 mmol) and PdCl2(PPh3)2, (5.5 mg, 7.8 mM) in dioxane (2 mL) to give a yellow suspension. The mixture was heated at reflux for 3 h under argon. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL) were added to the mixture to form a precipitate. The resulting precipitate was filtered through Celite. The filtrate was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (1×15 mL) and brine (1×15 mL) and then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with AcOEt/MeOH 1:0 to 9:1). The desired product was washed with CH2Cl2 to give 25 mg of N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amine as a light brown solid in 37% yield. LCMS m/z=432 (M+1) (Method C) (retention time=1.86 ruin). 1H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.51 (s, 1H), 8.77-8.56 (m, 3H), 8.26 (dd, J=6.9, 2.5 Hz, 1H), 8.02-7.78 (m, 3H), 7.64-7.47 (m, 2H), 3.54 (s, 2H), 2.30 (s, 6H).
Reaction SMILES: Cl.[CH3:2][C:3]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13].C([N:21](CC)CC)C.[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32](Cl)=O>C(Cl)Cl>[CH3:2][C:3]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]2[C:6](=[CH:7][C:8]3[NH:12][C:32]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][N:26]=4)=[N:21][C:9]=3[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cnccn1
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(N)ccc21
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1(C)C(=O)Nc2cc3[nH]c(-c4cnccn4)nc3cc21
Reaction time: 3 h

Procedure:
5.0 g. (18.5 mmol) 3-methyl-3-ethoxycarbonyl-6-aminoindolin-2-one hydrochloride are suspended in 60 ml. methylene chloride and mixed with 12.5 ml. (90.4 mmol) triethylamine. 6.4 g. (45.2 mmol) pyrazine-2-carboxylic acid chloride are then added portionwise, while cooling with ice, and the reaction mixture is further stirred for 3 hours. The reaction mixture is evaporated, worked up with water, filtered off with suction and purified by column chromatography elution agent: methylene chloride/methanol 99:1 v/v). There are obtained 4.0 g. (65% of theory) of the title compound; m.p.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:9]2[C:10]3[N:11]=[C:2]([C:27]4[CH:28]=[C:29]([NH:33][S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:30]=[N:31][CH:32]=4)[CH:3]=[CH:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:14]=1
Reactant: Clc1ccc2ncnc(Oc3cccnc3)c2n1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(Oc4cccnc4)c3n2)c1)c1ccccc1
Temperature: 25 °C
Yield: 125.9 %

Procedure:
A mixture of 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 0.348 mmol) (Intermediate 8), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.150 g, 0.418 mmol) (Intermediate 2), PdCl2(dppf)-CH2Cl2Adduct (0.057 g, 0.070 mmol) and 1N aq. sodium bicarbonate (0.70 ml, 0.70 mmol) in dioxane (1.74 ml) was subjected to microwave irradiation for 30 min at 120° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was diluted water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc only) to give N-(5-(4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.20 g, 13%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.45-7.49 (2H, m), 7.51-7.56 (1H, m), 7.61 (1H, dd, J=8.4 and 4.8 Hz), 7.84-7.87 (2H, m), 7.92-7.95 (1H, m), 8.38 (1H, d, J=2.8 Hz), 8.45 (1H, s), 8.49-8.51 (2H, m), 8.53 (1H, dd, J=4.8 and 1.2 Hz), 8.66 (1H, d, J=2.4 Hz), 8.73 (1H, s), 9.06 (1H, d, J=2.0 Hz). m/z=457 [M+1]+.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH2:5][CH3:6].[Cl:7][SiH:8]([Cl:10])[Cl:9].[I-].C([P+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][CH:2]1[Si:8]([Cl:9])([Cl:7])[CH:5]([CH3:6])[CH:4]=[CH:3]1.[Cl:7][Si:8]([Cl:10])([Cl:9])[CH:2]([CH:3]=[CH:4][CH:5]([Si:8]([Cl:10])([Cl:9])[Cl:7])[CH3:6])[CH3:1]
Reactant: C=CC=CCC
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CC(C=CC(C)[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Product: CC1C=CC(C)[Si]1(Cl)Cl
Temperature: 180 °C
Yield: 60 %
Yield: 10 %

Procedure:
As in Example 1, 1,3-hexadiene (0.99 g, 12.06 mmol), trichlorosilane (6.60 g, 48.73 mmol) and tetrabutylphosphonium iodide (0.47 g, 1.22 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180 ° C. for 10 hours. The resulting mixture was distilled to yield 1.32 g (yield: 60%) of 1,1-dichloro-2,5-dimethyl-silacyclo-3-pentene and 0.43 g (yield: 10%) of 2,5-bis(trichlorosilyl)-3-hexene main products.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[C:34](N1C=CN=C1)([N:36]1[CH:40]=[CH:39]N=C1)=[O:35].[CH3:46][S:47](CCN)(=[O:49])=[O:48].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:34]([NH:36][CH2:40][CH2:39][S:47]([CH3:46])(=[O:49])=[O:48])=[O:35])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)CCN
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCNC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (54.1 mg) and triethylamine (0.7 mL) were dissolved in dichloromethane (10 mL), 1,1′-carbonylbis(1H-imidazole) was added, and the mixture was stirred at room temperature. After 1 hr, 2-(methylsulfonyl)ethanamine (1.0 mL) was added, and the mixture was further stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=90:10). crystallized from diethyl ether/ethyl acetate/hexane to give the title compound (37.6 mg).