Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[C:9]([C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)#[N:10].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(Cl)Cl.O>[NH2:10][C:9]([C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)=[C:3]([S:4]([CH3:6])=[O:5])[S:2][CH3:1]
Reactant: N#Cc1ccc2occc2c1
Reactant: CSCS(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CSC(=C(N)c1ccc2occc2c1)S(C)=O
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A solution of dry methyl methylthiomethyl sulphoxide (7.0 g., 0.056 mole) in dry tetrahydrofuran (25 ml.) was added dropwise to a stirred suspension of 50% sodium hydride in oil dispersion (3.0 g., 0.62 mole) in dry tetrahydrofuran (50 ml.) under nitrogen at ambient temperature. This mixture was stirred for 0.5 hours and a solution of 5-cyanobenzo(b)furan (8.0 g., 0.056 mole) in dry tetrahydrofuran (25 ml.) added dropwise. The now reddish suspension was stirred at 50°-60° C. overnight, and the resulting thick suspension cooled and treated dropwise with water (5 ml.). Methylene chloride (100 ml.) was next added, followed by magnesium sulphate, and the mixture filtered. Evaporation of the filtrate in vacuo furnished a brown solid (15 g.), which was triturated with ethyl acetate, collected, washed with ethyl acetate and then hexane and dried, in vacuo, to give 1-amino-1[5-benzo(b)furanyl]-2-methylsulphinyl-2-methylthio-ethylene (12.7 g.) as a cream solid, m.p. 157°- 159° C. (decomp.).
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:16]=2)[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH:30]=[CH:29]2>C1(O)C=CC=CC=1>[C:38]1([S:35]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([NH:25][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:16]=5)[N:11]=[CH:10][N:9]=4)=[CH:34][CH:33]=3)[CH:29]=[CH:30]2)(=[O:36])=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(=O)OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Reactant: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: Oc1ccccc1
Product: CC(=O)OCC=Cc1ccc2ncnc(Nc3ccc4c(ccn4S(=O)(=O)c4ccccc4)c3)c2c1
Temperature: 100 °C
Yield: 43 %

Procedure:
A mixture of ester 26 (630 mg, 1.97 mmol) and 5-amino-1-phenylsulfonylindole in phenol (3.0 g) was heated at 100° C. for 20 hours. Excess phenol was removed by distillation and the resulting brown oil was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexanes then ethyl acetate. Quinazoline 27 (430 mg, 43%) was obtained as an off-white waxy solid. 1H NMR (CDCl3; 400 MHz): δ: 8.61 (s, 1H), 7.92 (m, 3H), 7.82 (m, 4H), 7.51 (m, 2H), 7.43 (m, 3H), 6.74 (d, 1H), 6.62 (d, 1H), 6.45 (dt, 1H), 4.74 (dd, 2H), 2.09 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([I:26])=[CH:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:19]=2[N:20]=[CH:21][N:22]=1>C(O)CCC>[I:26][C:25]1[C:18]2[C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:22][CH:21]=[N:20][C:19]=2[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:24]=1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21

Procedure:
Morpholine (2.45 g, 28.1 mmol) and N,N-diisopropylethylamine (6.63 g, 51.3 mmol) were added to a solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (10.5 g, 25.6 mmol) in n-butanol (300 mL), and the reaction mixture was heated at reflux for 18 hours, then concentrated under reduced pressure. Aqueous hydrochloric acid (0.1 M, 100 mL) was added and the resulting solid was collected by filtration, washed with water (20 mL) and dried under vacuum to provide the product as a yellow solid. Yield: 8.0 g, 17 mmol, 66%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.81 (s, 1H), 5.52 (s, 2H), 3.80-3.86 (m, 4H), 3.46-3.53 (m, 6H), 0.77-0.84 (m, 2H), −0.10 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:20](C1C=C2C(=CC=1)NC=C2)#[N:21]>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Product: N#Cc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 50 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-cyanoindole (29.98 g, 0.21 mol) to afford 29.32 g (50%) of the title compound as a white solid: mp 158-160° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[CH2:10]1[CH:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:14]2=[O:16])[C:12](=[O:13])[CH2:11]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN2C(=O)CCC12
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution prepared from 11.68 g of (+)-N-benzylpyroglutamic acid (See E. Campaigne and D. P. Matthews, J. Het. Chem., 12, 391 (1975)), 100 ml of CH2CL2 and a drop of dimethylformamide (DMF), 7.57 g of SOCl2 was added dropwise. The mixture was refluxed for five hours and allowed to stand overnight at ambient temperature. The reaction mixture was cooled in an ice-salt bath. Aluminum chloride (22.6 g) was added in portions with exclusion of moisture and vigorous stirring. The temperature did not exceed 10° C. during the addition. The mixture was stirred 1.5 hours and then ice was added gradually. The mixture was partitioned between water and CH2Cl2. The CH2Cl2 phase was washed with water, dried (Na2SO4), filtered and evaporated to give 10 g of a crude product. Recrystallization from toluene gave 7.45 g of crystals, m.p. 103°-105° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C>>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]([CH2:20][CH2:21][CH2:22][OH:23])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CC(C)(C)CNc1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1B from 4-[(2,2-dimethylpropyl)amino]-2-(trifluoromethyl)benzonitrile and [(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.9 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 6.87 (dd, J=8.9, 2.5 Hz, 1H), 3.70 (app. bq, J=4.7 Hz, 2H), 3.62 (app. t, J=7.3 Hz, 2H), 3.27 (s, 2H), 1.87-1.75 (m, 2H), 1.47 (bt, J=4.2 Hz, 1H), 0.99 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22](OC4C=CC=CC=4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.ClC(OC1C=CC=CC=1)=O.[CH3:46][NH2:47]>C(O)C>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:23])[NH:47][CH3:46])[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)Oc3ccccc3)CC2)CC1
Reactant: CN
Agent: O=C(Cl)Oc1ccccc1
Solvent: CCO
Product: CNC(=O)N1CCC(CN2CCC(NC(=O)c3cc(Cl)c(N)cc3OC)CC2)CC1
Temperature: 110 °C

Procedure:
To 4-amino-5-chloro-2-methoxy-N-[1-(1-phenoxycarbonyl-4-piperidinylmethyl)-4-piperidinyl]benzamide (880 mg), which is prepared in a similar manner as in Example 1 except that phenyl chloroformate is used instead of dimethylcarbamoyl chloride, is added a 30% solution of methylamine in ethanol (20 ml), and the mixture is heated at 110° C. for 8 hours in a sealed tube. The mixture is concentrated to dryness under reduced pressure, and to the residue is added chloroform. The solution is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=20:110:1) to give the desired compound (200 mg) as amorphous.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH2:9][C:10]([O:12][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:11])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reaction time: 1 h

Procedure:
N-Boc-glycine (7.31 g, 41.7 mmol) was dissolved in 100 mL of DCM and to the cooled (15° C.) solution N-hydroxysuccinimide (5.28 g, 45.9 mmol) was added. N,N′-dicyclohexylcarbodiimide (9.47 g, 45.9 mmol) was added to the formed suspension under vigorous stirring. After a few seconds, a cloudy white suspension formed, the mixture was allowed to reach room temperature and stirred for 1 h. It was subsequently filtrated over celite, washed with 50 mL saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to yield a crystalline powder. Yield: 7.02 g, 61.8%
Reaction SMILES: [C:1](O[C:5](=[O:7])C)(=[O:3])C.[OH:8][NH:9][CH2:10][CH2:11][CH2:12][P:13](=[O:16])([OH:15])[OH:14].CC(CC(O)=O)=O.[CH2:24]([NH:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.C(O)=O>[CH:5]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:14])([OH:16])[OH:15])[OH:8])=[O:7].[CH:1]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:15])([OH:14])[OH:16])[OH:8])=[O:3].[CH2:24]([NH:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=P(O)(O)CCCNO
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)CC(=O)O
Agent: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: O
Solvent: O=CO
Product: O=CN(O)CCCP(=O)(O)O
Reaction time: 0.5 h

Procedure:
formic acid (2 ml.) was added dropwise to acetic anhydride (2.45 ml.) at ambient temperature with stirring. After the stirring was continued at the same temperature for 30 minutes, 3-(N-hydroxyamino)propylphosphonic acid (3.10 g.) was added to the mixture. The reaction mixture was stirred at ambient temperature for an hour and then concentrated under reduced pressure to give an oily residue, which was dissolved in water (25 ml.). To the aqueous solution was added dropwise a solution of diacetic acid salts of N,N'-dibenzylethylenediamine (3.60 g.) in water (15 ml.) under ice-cooling and with stirring. The resultant mixture was concentrated under reduced pressure to give an oily residue, which was dissolved in water (30 ml.). The aqueous solution was concentrated under reduced pressure to give an oily residue, which was dissolved in water (30 ml.). The aqueous solution was concentrated under reduced pressure to give an oily residue, which was crystallized with a mixture of methanol (30 ml.) and ethanol (40 ml.). The crystals were separated by filtration, washed with ethanol (20 ml.) and then dried to give crystals (3.34 g.). The same crystals (1.00 g.) were recovered from the filtrate and the washings by concentrating them under reduced pressure to a volume of 40 ml. and allowing the concentrate to stand overnight at 4° C. A part (3 g.) of the combined crystals, as obtained above, was recrystallized from a mixture of water and ethanol (1:6) (40 ml.) to give N,N'-dibenzylethylenediamine bis[3-(N-formyl-N-hydroxyamino)propylphosphonate] (2.60 g.) in the form of needles. M.P. 155°-157° C. (dec.)
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])=[CH:5][CH:4]=1)[CH3:2].[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)[C:10]2=[O:38])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1

Procedure:
According to the procedure described for compound B92 tert-butyl 4-{1-[(5-ethylthiophen-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (1.18 g, compound B73) and a solution of hydrogen chloride in 1,4-dioxane (8.0 ml, 6.8 M) are reacted in 1,4-dioxane (35 ml) to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[Cl-].[NH4+].C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH2:33])=[O:28])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Yield: 51 %

Procedure:
Following the procedure for 243, 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid, ammonium chloride, HATU, diisopropylethylamine and DMF were reacted to give 104. Yield 51%. MS: 407.0. 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.74 (d, J=7.0, 1H), 7.69-7.54 (m, 4H), 7.47 (s, 1H), 7.44-7.36 (m, 2H), 4.48 (d, J=7.6, 4H)
Reaction SMILES: FC1C=C(C=CC=1OCCN1CCCCC1)CNC1C=C(OC)C=CC=1C1C=CC2C(=CC=C(OC)C=2)C=1.[CH2:39]([N:41]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH2:70][CH2:71][N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[C:65]([F:78])[CH:64]=1)[C:42]1[CH:47]=[C:46]([O:48]C)[CH:45]=[CH:44][C:43]=1[C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[C:55]([O:60]C)[CH:56]=2)[CH:51]=1)[CH3:40]>>[CH2:39]([N:41]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH2:70][CH2:71][N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[C:65]([F:78])[CH:64]=1)[C:42]1[CH:47]=[C:46]([OH:48])[CH:45]=[CH:44][C:43]=1[C:50]1[CH:51]=[C:52]2[C:57](=[CH:58][CH:59]=1)[CH:56]=[C:55]([OH:60])[CH:54]=[CH:53]2)[CH3:40]
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1-c1ccc2cc(OC)ccc2c1
Agent: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1-c1ccc2cc(O)ccc2c1
Yield: 80.6 %

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Example 36, ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]amine (297 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (227 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[C:42]2[CH:43]=[CH:44][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:46][C:41]=2[N:40]([CH3:56])[C:39]1=[O:57].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=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]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:45]4[CH:44]=[CH:43][C:42]5[N:38]([CH3:37])[C:39](=[O:57])[N:40]([CH3:56])[C:41]=5[CH:46]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 100 °C

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(2-(2-chloropyridin-4-yl)-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (26.0 mg, 0.046 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (20.0 mg, 0.069 mmol) and K3PO4 (29.2 mg, 0.138 mmol) in dioxane (1.0 mL) and H2O (0.1 mL) was degassed for 5 min, treated with PdCl2(dppf) (5.0 mg, 0.007 mmol). The resulting mixture was heated at 100° C. for 8 min. The reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H32F3N4O7S2: 693.2; found: 693.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[N:14]=[C:15](Cl)[CH:16]=[CH:17][C:8]2=1)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][OH:28]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:27][O:28][C:8]1[CH:17]=[CH:16][C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]2[N:14]=[CH:15][C:16]([CH:2]=[CH:3][C:5]4[CH:13]=[CH:12][CH:11]=[CH:7][CH:6]=4)=[CH:17][C:8]3=2)=[CH:2][CH:9]=1
Reactant: O=C(CBr)c1ccc2[nH]c3nc(Cl)ccc3c2c1
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc(-c2ccc3[nH]c4ncc(C=Cc5ccccc5)cc4c3c2)cc1
Temperature: 25 °C
Yield: 65 %

Procedure:
In sealed pressure tube and stir bar was charged Pd(OAc)2 (5 mg, 0.08 equiv.), 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl 1 (18 mg, 0.16 equiv.), a-carbolines (83 mg, 0.267 mmol), trans vinyl phenyl boronic acid (119 mg, 3.0 equiv.) and K3PO4 (142 mg, 2.5 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). 700 μl of anhydrous 1,4-dioxane was added (when degassed solvent was used) and the reaction mixture was allowed to stir at 100° C. overnight. After cooling to room temperature, the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/EtOAc 9:1) to afford R315 in 65% yield as a white solid; mp>220° C. (MeOH); IR: 3060, 2994, 2833, 1606, 1517, 1485, 1460, 1232, 957, 813, 740, 692 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 11.86 (bs, 1H), 8.95 (d, 1H, J=2.1 Hz), 8.61 (d, 1H, J=2.1 Hz), 8.47 (d, 1H, J=1.3 Hz), 7.74 (dd, 1H, J=1.9, 8.5 Hz), 7.71 (d, 214, J=8.9 Hz), 7.63 (d, 2H, J=7.1 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.46 (d, 1H, J=16.4 Hz), 7.43-7.39 (m, 2H), 7.37 (d, 1H, J=16.4 Hz), 7.27 (t, 1H, J=7.4 Hz), 7.07 (d, 2H, J=8.9 Hz), 3.82 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 158.4 (C), 152.0 (C), 146.5 (CH), 138.5 (C), 137.4 (C), 133.4 (C), 131.9 (C), 128.8 (2 CH), 127.7 (2 CH), 127.4 (CH), 126.8 (CH), 126.3 (CH), 126.2 (2 CH), 125.6 (CH), 124.9 (CH), 127.8 (C), 121.1 (C), 118.9 (CH), 115.8 (C), 114.4 (2 CH), 111.7 (CH), 55.2 (CH3); MS (ESI) m/z 377.3 [M+H+]; HRMS (ESI): Calcd for C26H20N2O: 377.1654. Found: 377.1653.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:17])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:17])[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)Cc2ccc(Cl)s2)ccc1N
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc(N(C)Cc2ccc(Cl)s2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of N(4)-(5-Chloro-thiophen-2-ylmethyl)-2,N(4)-dimethyl-benzene-1,4-diamine (54 mg, 0.20 mmol) and triethylamine (84 μL, 0.60 mmol) in dry tetrahydrofuran (1 mL) was added pentanoyl chloride (36 μL, 0.30 mmol), and the mixture was stirred for 1 hour at room temperature after which it was partitioned between saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The organic layer was dried over sodium sulfate, volatiles were evaporated, and the residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield the title compound as a white solid (61 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example J34) (227 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (313 mg, 77%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C(Cl)Cl.[F:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=2)=[C:12](CO)[CH:11]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(OCC)C>[Br:5][CH2:1][C:12]1[CH:11]=[C:10]([F:9])[C:15]([F:16])=[CH:14][C:13]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CBr)cn1
Temperature: 25 °C

Procedure:
Neat CBr4 (4.6 g, 13.7 mmol) was added to a 0° C., DCM solution (66 mL) of ethyl 3-(5-(4,5-difluoro-2-(hydroxymethyl)phenyl)picolinamido)propanoate (4.2 g, 11.4 mmol) and PPh3 (3.6 g, 13.7 mmol), the cold bath was removed, and the resulting mixture was allowed to warm to room temperature. After 2 h the resulting mixture was diluted with diethyl ether, filtered through a pad of CELITE, concentrated and purified via column chromatography to yield the title compound.