Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[Mg].Br[C:5]1[C:13]2[O:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:20](=[O:22])=[O:21].Cl>O1CCCC1>[C:14]1([C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:20]([OH:22])=[O:21])[C:13]=3[O:12][CH:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccc2c(-c3ccccc3)coc12
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c(-c3ccccc3)coc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3)-(i) 2.4 ml of methyl iodide are added dropwise to a solution of 3.9 g of magnesium in 16 ml of tetrahydrofuran and the mixture is stirred at room temperature for 20 minutes. A solution of 11.0 g of 7-bromo-3-phenylbenzofuran in tetrahydrofuran is added dropwise to the mixture and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is poured to dry ice, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 6.31 g of 3-phenylbenzofuran-7-carboxylic acid as pale yellow prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1

Procedure:
Methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate (160 mg, 0.34 mmol) was dissolved in ethanol (15 ml). Palladium on carbon (30 mg) was added and the resulting mixture was vigorously stirred under 1 atm hydrogen atmosphere for 24 hours. The reaction mixture was filtered and then, concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (94 mg, 58%) was obtained as needle crystals.
Reaction SMILES: I[C:2]1[CH:27]=[CH:26][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3[C:15]([C@@H:17]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:18]([CH3:20])[CH3:19])=[O:16])=[N:8][C:4]=2[CH:3]=1.I[C:29]1[N:30]=[C:31]([C@@H:34]2[CH2:38][C@H:37]([CH3:39])[CH2:36][N:35]2[C:40](=[O:50])[C@@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[CH:42]([CH3:44])[CH3:43])[NH:32][CH:33]=1.B(O)(O)[C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=2)=[CH:54][CH:53]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>CC(O)C>[CH3:24][O:23][C:22](=[O:25])[NH:21][C@H:17]([C:15]([N:10]1[CH2:11][C@@H:12]([CH3:14])[CH2:13][C@H:9]1[C:7]1[NH:6][C:5]2[CH:26]=[CH:27][C:2]([C:61]3[CH:62]=[CH:63][C:58]([C:55]4[CH:56]=[CH:57][C:52]([C:29]5[N:30]=[C:31]([C@@H:34]6[CH2:38][C@H:37]([CH3:39])[CH2:36][N:35]6[C:40](=[O:50])[C@@H:41]([NH:45][C:46]([O:47][CH3:48])=[O:49])[CH:42]([CH3:44])[CH3:43])[NH:32][CH:33]=5)=[CH:53][CH:54]=4)=[CH:59][CH:60]=3)=[CH:3][C:4]=2[N:8]=1)=[O:16])[CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(I)c[nH]1)C(C)C
Reactant: OB(O)c1ccc(-c2ccc(B(O)O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3ccc(-c4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)nc5c4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 13.6 %

Procedure:
To a suspension of methyl N-[(1S)-1-[(2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (52.40 mg, 0.1082 mmol), methyl ((S)-1-((2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (47 mg, 0.1082 mmol), [1,1′-biphenyl]-4,4′-diyldiboronic acid (26.17 mg, 0.1082 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (4.418 mg, 0.005410 mmol) and 1 mL of 2-propanol in a microwave vial is added 1M aqueous NaHCO3 (541.0 μL, 0.5410 mmol). The reaction mixture is stirred for 3 minutes at room temperature and is heated to 150° C. in the microwave for 10 minutes. The reaction mixture is concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 10% methanol in CH2Cl2) and is further purified by reverse phase preparative HPLC to give ((S)-1-{(2S,4S)-2-[5-(4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-yl)-1H-benzoimidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 25%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl-].[NH4+:23].[CH3:24]S(C)=O>>[C:24]([C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23)#[N:23]
Reactant: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: [NH4+]
Reactant: CS(C)=O
Agent: [Cl-]
Product: COC(=O)CC1CCc2cc(C#N)cc3[nH]c(=O)c(=O)n1c23
Temperature: 180 °C
Yield: 39 %

Procedure:
A mixture of 9-bromo-5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (530 mg, 1.50 mmol) and cuprous cyanide (890 mg, 9.9 mmol) in dimethyl sulfoxide (5 mL) was heated at 180° C. for 8.5 h and poured into 1N aqueous ammonium chloride (200 mL). The mixture was extracted with a mixed solvent of THF and ethyl acetate (600 mL). The extract was washed with 1N aqueous ammonium chloride (200 mL×2) and brine (200 mL), dried over magnesium sulfate, and concentrated. The residue was rinsed with dichloromethane to give 176 mg of the title compound (39%): mp 255°~258° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.22 (bs, 1H), 7.47 (d, 1H, J=2 Hz), 7.31 (d, 1H, J=2 Hz), 5.02~5.16 (m, 1H), 3.63 (s, 3H), 2.95 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.85 (dm, 1H, J=17.1 Hz), 2.55~2.72 (m, 2H), 2.15 (dm, 1H, J=13.5 Hz), 1.80~1.98 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]([CH2:21][NH2:22])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]=[C:25]=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][NH:22][C:25]([NH:24][CH3:23])=[O:26])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Product: CNC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
(R)-1-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-3-methyl-urea was prepared by treatment of C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]methylamine with methyl isocyanate according to the procedure of Najer et al.; Bull. Soc. Chim. Fr.; 1069-1071 (1957).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16])=[O:4].[CH2:17]([NH:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[S:23])[CH2:18][CH2:19][CH3:20]>>[BrH:1].[CH2:25]([N:24]1[C:3]([C:5]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=2[Cl:16])([OH:4])[CH2:2][S:23][C:22]1=[N:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:26][CH2:27][CH3:28]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)c(Cl)cc1Cl
Reactant: CCCCNC(=S)NCCCC
Product: Br
Product: CCCCN=C1SCC(O)(c2cc(S(N)(=O)=O)c(Cl)cc2Cl)N1CCCC

Procedure:
was obtained in a manner analogous to the method described in Example 10 from 3.5 g of 2-bromo-2',4'-dichloro-5'-sulfamoylacetophenone and 1.9 g of 1.3-dibutyl-thiourea. M.p. 194° C (decomposition).
Reaction SMILES: N([Si](C)(C)C)=[N+:2]=[N-:3].[CH2:8]([Sn](=O)CCCC)CCC.[C:18]([C:20]1[C:24]2[CH:25]=[C:26]([O:34][CH:35]([CH3:37])[CH3:36])[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:23]=2[O:22][C:21]=1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)#[N:19]>O1CCOCC1>[F:44][C:41]1[CH:40]=[CH:39][C:38]([C:21]2[O:22][C:23]3[CH:28]=[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:26]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:25][C:24]=3[C:20]=2[C:18]2[NH:3][N:2]=[CH:8][N:19]=2)=[CH:43][CH:42]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CC(C)Oc1cc2c(C#N)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Solvent: C1COCCO1
Product: CC(C)Oc1cc2c(-c3ncn[nH]3)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
Azidotrimethylsilane (34.2 μL, 0.257 mmol) was added to a stirring solution of dibutyltin oxide (6.41 mg, 0.026 mmol) and N-(3-cyano-2-(4-fluorophenyl)-5-isopropoxybenzofuran-6-yl)methanesulfonamide (50 mg, 0.129 mmol) in dioxane (1.3 mL) at rt. It was subjected to microwave irradiation for 15 min at 150° C. It was treated with additional equivalents of reagents and re-subjected for 30 min followed by 60 min. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered gradient, and concentrated to give the titled compound (12 mg, 22%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.29-1.39 (m, 6H) 3.01 (s, 3H) 4.62-4.81 (m, 1H) 7.28-7.45 (m, 3H) 7.65 (s, 1H) 7.84-7.98 (m, 2H) 8.92 (s, 1H). LC-MS retention time: 1.04 min; m/z (MH+): 432. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=11.56 min, purity=94%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=10.55 min, purity=96%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.[NH2:13][C:14]1[C:19]([Cl:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][C:15]=1[C:23](=[O:25])[CH3:24].C(C1C(NC(C2SCC(C(F)(F)F)N=2)=O)=C(C)C(OC)=CC=1)(=O)C>>[C:23]([C:15]1[C:14]([NH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([C:2]([F:1])([F:12])[F:11])[N:4]=2)=[O:10])=[C:19]([Cl:20])[C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:25])[CH3:24]
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: COc1ccc(C(C)=O)c(NC(=O)C2=NC(C(F)(F)F)CS2)c1C
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1Cl
Yield: 65 %

Procedure:
N-(6-Acetyl-2-chloro-3-methoxyphenyl)-4-trifluoromethylthiazole-2-carboxamide 202d was synthesized from 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid and 1-(2-amino-3-chloro-4-methoxyphenyl)-ethanone as a beige solid in 65% yield, following the procedure as described for compound 202b.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.O>C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][NH:12][S:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:17][CH2:18]1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: NCCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCOCC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
4-Iodophenylsulphonyl chloride (3.03 g, 10 mmol) in DCM (30 ml) was added dropwise over 15 minutes to a solution of 4-(3-aminopropyl)morpholine (1.75 ml, 12 mmol) and triethylamine (1.7 ml, 12 mmol) in DCM (50 ml) cooled in an ice bath. The mixture was allowed to warm to ambient temperature and stirred for 15 minutes. Water (50 ml) was added and the phases separated. The organic layer was washed with water (50 ml) and brine (50 ml), dried (Chemelut column 1010) and evaporated to give the title compound (4.10 g, 100%) as a beige solid. NMR 1.70 (m, 2H), 2.43 (m, 6), 3.14 (t, 2H), 3.71 (m, 4H), 7.08 (s, 1H), 7.58 (d, 2H), 7.85 (d, 2H); m/z 411.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[S:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=2)=[N:8]1.[F:25][C:26]1[CH:27]=[C:28]([CH:40]=[CH:41][C:42]=1[F:43])[CH2:29][N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36](O)=[O:37])[C:31]1=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=O.C(N(CC)C(C)C)(C)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[NH:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[S:20][C:19]([CH2:21][NH:22][C:36]([C:32]3[C:31](=[O:39])[N:30]([CH2:29][C:28]4[CH:40]=[CH:41][C:42]([F:43])=[C:26]([F:25])[CH:27]=4)[CH:35]=[CH:34][CH:33]=3)=[O:37])=[CH:18][CH:17]=2)=[N:8]1
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(CN)s2)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2n[nH]c3ncccc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
C-{5-[1-(2-Trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-thiophen-2-yl}-methylamine (23 mg, 0.000064 mol), 1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (2.0E1 mg, 0.000075 mol) and HATU (44 mg, 0.00012 mol; Applied Biosystems) were dissolved in N,N-dimethylformamide (1.25 mL, 0.0161 mol; Acros). To this was added N,N-diisopropylethylamine (56 uL, 0.00032 mol; Aldrich) and the reaction was stirred for 1 hour at room temperature. The reaction was diluted with 5% citric acid in water, then extracted with ethyl acetate. Saturated sodium chloride was added to aid separation. The organic layer was washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated to yield the crude title compound. MS m/z=608.34 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl-].[CH3:10][O:11][CH2:12][P+:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:32]1CCCC1>C1(C)C=CC=CC=1>[CH3:10][O:11][CH:12]=[P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:14]1([P:13](=[O:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methoxymethylenetriphenylphosphorane is prepared by addition of lithium diisopropyl amide (10.6 g, 0.1 mole) in dry tetrahydrofuran (100 ml) to a slurry of methoxy methyl triphenyl phosphonium chloride (34.3 g, 0.1 mole) in dry toluene (400 ml) under nitrogen at 0° C. The resulting red Wittig reagent is stirred at 0° C. for 30 minutes prior to use. To this solution is added endo-5-t-butyldimethylsilyloxy-exo-3a, 4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-2-ol (14.3 g, 0.05 mole) via a solids addition funnel and the resulting mixture is stirred at 25° C. for 2 hours. The mixture is acidified to pH 5 with 10hydrochloric acid and extracted with ether (three 200 ml portions). The solvents are removed under vacuum and the residue is dissolved in ether and this solution chilled yielding crystalline triphenylphosphine oxide. The filtrate is concentrated yielding the title compound which is purified by column chromatography on silica gel.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.[CH2:40]([CH2:42][NH2:43])[OH:41]>C(OCC)(=O)C>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:32])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:43][CH2:42][CH2:40][OH:41])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: NCCO
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCCO)cc1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
A mixture of 28.6 g (56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 50 ml dimethyl sulfoxide and 50 ml (830 mmol) ethanolamine was stirred at 140° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with 200 ml ethyl acetate and washed with 200 ml 1 N sodium carbonate solution and 100 ml water. The aqueous layers were extracted with two 200-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of 150 ml diisopropyl ether and 150 ml heptane to give 29.1 g (93%) of the title compound as white crystals. M.p. 117-118° C.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>CCOC(C)=O>[C:2]1([CH:8]([CH3:11])[CH2:9][NH:10][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(CN)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(CNC(=O)c1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 250-mL round-bottomed flask was charged with 2-phenylpropan-1-amine hydrochloride (7.75 g, 45.1 mmol), DCM (75 mL) and cooled down to 0° C. Triethylamine (13.8 mL, 99.3 mmol) was added followed by slow addition of 4-(trifluoromethyl)benzoyl chloride (7.4 mL, 49.7 mmol). After the addition was completed the mixture was stirred at RT for 1 h, diluted with EtOAc, washed with 10% HCl, sat NaHCO3, sat NaCl and dried over Na2SO4. The white residue was recrystallized from ether:hexanes and the title compound was obtained as a white solid. MS (ESI, positive ion) m/z: 308 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=3[Cl:27])[C:14](=[O:29])[NH:13][C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:34](=[O:37])([O-:36])[O-].[K+].[K+].Cl.[CH3:41][N:42]([CH2:45][CH2:46]Cl)[CH2:43][CH3:44]>CC(C)=O>[C:17]([OH:28])(=[O:16])[C:34]([OH:36])=[O:37].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=3[Cl:27])[C:14](=[O:29])[N:13]([CH2:44][CH2:43][N:42]([CH3:41])[CH2:45][CH3:46])[C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(C)CCN1C(=O)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2Cl)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Product: O=C(O)C(=O)O
Yield: 181.8 %

Procedure:
970 mg of (-)-cis-2-(4-methoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 20 ml of acetone, and 690 mg of potassium carbonate and 410 mg of 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride are added thereto. The mixture is refluxed for 3 hour under stirring. After the reaction, the mixture is evaporated under reduced pressure to remove solvent. Ethyl acetate is added to the residue, and the mixture is washed with water. The ethyl acetate solution is dried and evaporated under reduced pressure to remove solvent. 180 mg of oxalic acid and 15 ml of ethanol are added to the residue, and the mixture is heated to make a clear solution. The clear solution is allowed to stand. Crystalline precipitates are collected by filtration and dried, whereby 1.20 g of (+)-cis-2-(4-methoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate are obtained as colorless needles. Yield: 91%.
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH2:16][C:17]#[C:18][CH3:19]>C(O)(C)C>[Na+:1].[CH2:16]([O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:5][CH:4]=1)[C:17]#[C:18][CH3:19]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: CC#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC#CCOc1ccc(S(=O)(=O)[O-])cc1
Yield: 100.3 %

Procedure:
To a solution of 52.35 g (0.225 mol) of 4-hydroxybenzenesulfonate sodium salt in 1L of isopropanol and 225 mL of a 1.0N solution of sodium hydroxide was added 59.96 g (0.45 mol) of 1-bromo-2-butyne. The resulting mixture was heated to 70° for 15 h and then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtration, washed with isopropanol and ether and dried under vacuum to give 56.0 g (100%) of 4-but-2-ynyloxybenzenesulfonic acid sodium salt as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:30](=[O:34])[C@@H:31]([OH:32])[CH3:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](NC(=O)[C@H](C)O)C4)cc3)ncc2F)n1C(C)C
Yield: 30.4 %

Procedure:
N-{4-[(3S)-3-Aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 153; 220 mg, 0.556 mmol), L—lactic acid (61 mg, 0.667 mmol), HOBt mono hydrate (103 mg, 0.667 mmol) and Hunig's base (0.12 ml, 0.667 mmol) in DCM (5 ml) were reacted with EDAC (128 mg, 0.667 mmol) at room temperature under nitrogen for 18 hours. The mixture was diluted with DCM (20 ml) and washed with water (20 ml), 1 N aqueous potassium hydroxide (20 ml) and saturated aqueous sodium chloride (15 ml). The mixture was dried and after evaporation under reduced pressure purified by HPLC on a Phenomenex column, (0-50% acetonitrile/water, 0.2% TFA). The fractions were diluted with water (20 ml), basified with solid potassium carbonate, and extracted twice with EtOAc/DCM (20 ml, 2:1). The solution was washed with saturated aqueous sodium chloride (15 ml), dried and after evaporation under reduced pressure gave the title compound as a yellow solid, (79 mg, 30%). NMR: 1.20 (d, 3H), 1.37 (d, 6H), 1.90-2.04 (m, 1H), 2.11-2.27 (m, 1H), 2.47 (s, 3H), 3.00-3.09 (m, 1H), 3.20-3.47 (m, 3H), 3.91-4.00 (m, 1H), 4.32-4.47 (m, 1H), 5.38 (s, 1H), 5.40-5.49 (m, 1H), 6.49 (d, 2H), 7.30 (s, 1H), 7.32 (d, 2H), 7.76 (d, 1H), 8.40 (d, 1H), 9.06 (s, 1H); m/z 468.