Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([OH:29])=[O:28].C1C=CC2N(O)N=NC=2C=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:28][C:27](=[O:29])[CH:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1ccccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reaction time: 0.17 h
Yield: 116.8 %

Procedure:
PS-DCC (2.05 g, 2.57 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL) and shaken for few minutes. Then (2-methoxy-phenylamino)-phenyl-acetic acid hydrochloride (I36) (377 mg, 1.28 mmol) and HOBT (393 mg, 2.57 mmol) are added. After 10 minutes, (R)-quinuclidin-3-ol (490 mg, 3.85 mmol) is added and the mixture is shaken at RT for 16 hours (Conversion complete by UPLC/MS-UV). PS-DCC is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated to afford the title compound as a yellow oil (548 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](NCCNC(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)CC)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=O)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:62][C:63]([F:68])([F:67])[C:64]([OH:66])=[O:65].[C:69]1([CH:75]([C:113]2[CH:118]=[CH:117][CH:116]=[CH:115][CH:114]=2)[CH2:76][NH:77][C:78]2[N:86]=[C:85]([N:87]3[CH2:91][CH2:90][C@@H:89]([NH:92][C:93]([NH:95][C@@H:96]4[CH2:100][CH2:99][NH:98][CH2:97]4)=[O:94])[CH2:88]3)[N:84]=[C:83]3[C:79]=2[N:80]=[CH:81][N:82]3[C@@H:101]2[CH2:105][C@H:104]([NH:106][C:107](=[O:110])[CH2:108][CH3:109])[C@@H:103]([OH:111])[C@H:102]2[OH:112])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[F:62][C:63]([F:68])([F:67])[C:64]([OH:66])=[O:65].[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([N:98]2[CH2:99][CH2:100][C@@H:96]([NH:95][C:93]([NH:92][C@@H:89]3[CH2:90][CH2:91][N:87]([C:85]4[N:84]=[C:83]5[C:79]([N:80]=[CH:81][N:82]5[C@@H:101]5[CH2:105][C@H:104]([NH:106][C:107](=[O:110])[CH2:108][CH3:109])[C@@H:103]([OH:111])[C@H:102]5[OH:112])=[C:78]([NH:77][CH2:76][CH:75]([C:113]5[CH:114]=[CH:115][CH:116]=[CH:117][CH:118]=5)[C:69]5[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=5)[N:86]=4)[CH2:88]3)=[O:94])[CH2:97]2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)OCc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCN(C(=O)NC6CCN(C(=O)OCc7ccccc7)CC6)C5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to 4-[3-(2-{[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carbonyl]-amino}-ethyl)-ureido]-piperidine-1-carboxylic acid benzyl ester (Example 108) by replacing 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide with N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (Example 17 step 1). (MH+ 943.4)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][CH:19]=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:18]=[CH:19][N:16]=2)[C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Br)ccc1OCc1ccccc1
Reactant: O=CCCl
Product: Brc1ccc(OCc2ccccc2)c2nccn12
Yield: 88 %

Procedure:
A mixture of 3-benzyloxy-6-bromopyridin-2-ylamine (1.0 g, 3.6 mmol) and chloroacetaldehyde (1.2 mL, 50 wt. % in water) in IMS (12 mL) was stirred at reflux for 1 hour, then concentrated under reduced pressure. The residue was partitioned between an aqueous saturated solution of sodium bicarbonate and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:Et2O, gradient 0:100 to 1:99) to give 8-Benzyloxy-5-bromo-imidazo[1,2-a]pyridine as an beige solid (960 mg, 88%). LCMS (Method H) RT 3.08 min; [M+H]+ 303 (79Br) and 305 (81Br)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1>CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:14])[CH3:15])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:47](=[O:48])[C:46]3[CH:50]=[CH:51][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH3:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CNc1ccc(Cc2nc(Cl)c(CC(=O)OC)c(N(C)C)n2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl {4-chloro-6-(dimethylamino)-2-[4-(methylamino)benzyl]pyrimidin-5-yl}acetate (0.080 g, 0.23 mmol), 1-hydroxybenzotriazole (0.043 g, 0.32 mmol), triethylamine (0.11 mL, 0.80 mmol), and 4-chlorobenzoic acid (0.043 g, 0.28 mmol) was treated with WSCI (0.066 g, 0.34 mmol) at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was then added and the organic layer was washed sequentially with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product methyl [4-chloro-2-{4-[(4-chloro-benzoyl)(methyl)amino]benzyl}-6-(dimethylamino)pyrimidin-5-yl]acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: COc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc1

Procedure:
51.1 mg of pale yellow solid 3-{4-[3-(4-methoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-methoxyphenyl isocyanate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:15]4=[C:14]([CH3:31])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:34]([F:37])([F:36])[F:35])([CH3:3])[CH3:2].[Li+].[OH-]>CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:15]4=[C:14]([CH3:31])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:34]([F:37])([F:35])[F:36])([CH3:3])[CH3:2]
Reactant: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C(F)(F)F)c4)cc13)CCC2CC(=O)O
Temperature: 75 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.366 g, 0.707 mmol) in dioxanes was added aq LiOH (3.0 mmol). The reaction was stirred at 75° C. for 16 h, diluted with EtOAc and washed with 1M HCl(aq), dried over MgSO4, filtered, and concentrated. The residue was triturated with hexanes to give the title compound as a solid (0.313 g). LCMS m/z=462.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.94 Hz, 6H), 2.15 (s, 3H), 2.19-2.29 (m, 1H), 2.42-2.48 (m, 1H), 2.69-2.82 (m, 2H), 3.57-3.65 (m, 1H), 3.86-3.97 (m, 1H), 3.97-4.08 (m, 1H), 4.73-4.84 (m, 1H), 5.07 (s, 2H), 6.74 (dd, J=8.72, 2.40 Hz, 1H), 7.01 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.59 Hz, 1H), 7.29 (d, J=9.22 Hz, 1H), 7.64-7.72 (m, 2H), 12.26 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.[CH3:21][O:22][CH2:23]Cl.[H-].[Na+].O>CN(C)C=O>[CH3:21][O:22][CH2:23][N:18]1[CH:19]=[C:15]([C:12]2[C:11]3[CH:20]=[C:7]([C:4]4[O:3][C:2]([CH3:1])=[N:6][N:5]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)[CH:16]=[N:17]1
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1cc(-c2coc3ccc(-c4nnc(C)o4)cc23)cn1
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole (213 mg, 0.80 mmol) and (chloromethyl) methyl ether (0.091 mL, 1.2 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 60 mg, 1.2 mmol) by small portions at room temperature, and the resulting mixture was stirred for 10 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and crystallized from hexane/ethyl acetate to give the title compound (128 mg, yield 52%) as colorless crystals.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C.O>[CH:14]1([S:19][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CBr
Reactant: SC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSC1CCCC1
Temperature: 65 °C

Procedure:
Solid K2CO3 (9.01 g, 65.2 mmol) was added to a stirring solution of ethyl bromoacetate (5.16 mL, 46.6 mmol) and cyclopentanethiol (4.97 mL, 46.6 mmol) in DMF (25 mL). The resulting suspension was warmed at 65° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with hexanes (3×50 mL). The combined extract was washed with saturated brine (30 mL) and concentrated under vacuum to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (t, J=7.1 Hz, 3H), 1.43-1.65 (m, 4H), 1.66-1.81 (m, 2H), 1.93-2.10 (m, 2H), 3.13-3.30 (m, 1H), 3.25 (s, 2H), 4.19 (q, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])=[O:24])=[N:5][N:4]=[C:3]1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2ccc3ccccc3c2)n1C
Solvent: ClCCl
Product: Cn1c(-c2ccc3ccccc3c2)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio-3-(2-naphthyl)-4H-1,2,4-triazole (4.00 g, 1.57×10-2 mole) and CH2Cl2 (110 ml) was added portionwise m-chloroperoxybenzoic acid (3.38 g, 1.57×10-2 mole). After stirring overnight at room temperature the reaction was diluted with CH2Cl2 (200 ml), washed two times with saturated aqueous NaHCO3 and one time with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an off-white solid which was purified by flash chromatography (4% CH3OH/CH2Cl2). Crystallization from toluene afforded small colorless plates: Mp 224°-226° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:36][NH:37][CH3:38]>>[CH3:36][N:37]([CH3:38])[C:30](=[O:32])[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:35])[F:1])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:28][CH:27]=1)[CH3:33]
Reactant: CNC
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Product: CC(C(=O)N(C)C)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and N,N-dimethylamine. LCMS (M+H)+: m/z=511.2
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH3:31])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([OH:24])[CH2:22][N:23]=2)=[CH:14][CH:13]=1>ClCCCl>[CH3:10][N:11]([CH3:31])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: ClCCCl
Product: CN(C)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Yield: 39.2 %

Procedure:
Phenyl isocyanate (0.49 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-[4-(dimethylamino)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1 g) in 1,2-dichloroethane (12 cc). The solution obtained is heated to reflux for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa), The residue is purified by chromatography on silica (0.063-0.02 mm; 50 g) contained in a column 2.5 cm in diameter (eluent: cyclohexane/ethyl acetate (7:3 by volume)]collecting 20-cc fractions. Fractions 9 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diethyl ether, (5RS, 6SR)-2-[4-(dimethylamino)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.55 g), m.p. 183° C., is obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])(C(C)(C)C)(C)C.Cl.O>O1CCCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 92.1 %

Procedure:
4-[9-(t-Butyldimethylsilyloxy)nonyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (2.2 g, 3.95 mmol) was dissolved in tetrahydrofuran (150 ml), and 3N-HCl (11 ml) was added thereto. The reaction mixture was stirred at room temperature for 140 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=8:2 and 1:1) to give the title compound (1.61 g, yield 92%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>CC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:26](=[O:27])[CH2:25][Cl:24])[CH:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Nc1ccc(Br)cc1)c1c(Cl)ccc(Cl)c1Cl
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(c1c(Cl)ccc(Cl)c1Cl)N(C(=O)CCl)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3 parts of ethyl α-[(4-bromophenyl)amino]-2,3,6-trichlorobenzeneacetate and 4.5 parts of 2-chloroacetyl chloride is stirred for 4 hours at 80° C. The mixture is taken up twice in methylbenzene and the latter is evaporated each time. The oily residue solidifies on triturating in petroleumether. The latter is decanted and the residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding a first fraction of 1.7 parts of ethyl α-[(4-bromophenyl) (2-chloroacetyl)-amino]-2,3,6-trichlorobenzeneacetate; mp. 140.8° C. The mother liquor is concentrated and a second fraction of 1.2 parts of ethyl α-[(4-bromophenyl) (2-chloroacetyl)amino]-2,3,6-trichlorobenzeneacetate is filtered off.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15]([C:16](O)=[O:17])=[C:11]3[CH2:10][N:9]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:25]=1)#[CH:2].[ClH:26].[CH2:27]([N:29]=C=NCCCN(C)C)[CH3:28].N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N)C>CN(C=O)C>[ClH:26].[ClH:26].[CH2:27]([NH:29][C:16]([C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:25][C:7]=3[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9][CH2:10][C:11]=12)=[O:17])[CH3:28]
Reactant: C#Cc1ccc2c(c1)C(c1ccccc1)=NCc1c(C(=O)O)ncn1-2
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)C(c1ccccc1)=NCc1c(C(=O)NCC)ncn1-2
Reaction time: 0.25 h

Procedure:
8-Ethynyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylic acid (82 mg, 0.251 mmol) was dissolved in DMF (6 ml) and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (48 mg, 0.251 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (33.8 mg, 0.251 mmol), and triethylamine (70 μL, 0.501 mmol) were added. The solution was stirred for 15 min and then ethylamine hydrochloride (20.4 mg, 0.251 mmol) was added. The solution was stirred at room temperature for 3 days. The DMF was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with water twice, then dried with brine. The ethyl acetate layer was then condensed with a stream of nitrogen, and dried in vacuo. The residue was dissolved in methylene chloride, and applied to a silica gel column. The product was eluted with ethyl acetate. The product fractions were concentrated in vacuo. The oily residue was dissolved in acetonitrile and several drops of concentrated HCl were added to give the HCl salt. The acetonitrile was removed in vacuo and the HCl salt was dried under high vacuum to give a yellow powder (75 mg, 77%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:8](=[CH2:13])[C:9](OC)=[O:10].[Na]>>[OH:10][C:9]1[CH:8]=[CH:13][NH:1][C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CN
Reactant: C=C(Cl)C(=O)OC
Agent: [Na]
Product: COC(=O)c1[nH]ccc1O

Procedure:
Prepared by the method described in Example 101 from methyl glycinate (22 g, 0.25 moles), methyl α-chloroacrylate (29.8 g, 0.25 moles), and sodium (17 g, 0.74 moles). Following filtration through silica gel and evaporation of the filtrate, the product is obtained pure and crystalline (18.6 g ; mp 100°-102° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[N+]([C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])([O-])=O>O>[CH3:1][O:2][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1C#N
Reaction time: 1 h

Procedure:
Twenty-five percent sodium methoxide in methanol (24.3 g, 11 mol) was added dropwise to a stirred mixture of 19 g (0.091 mol) 2-nitro-4-(trifluoromethyl)benzonitrile and 100 mL of methanol at 20°-30° C. After 1 hour at 25° C., 100 mL of water was added. The solids were collected on a filter and washed with water. The solids were dried to yield 12.5 g of product melting at 59°-61° C. 1H NMR (CDCl3) δ4.00 (s, 3H), 7.2-7.7 (3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:27](Cl)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)[C:27]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80 42 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (83 mg, 81%) as a white foam: [α]31589=−25.0° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C22H28N3O2F3 (M+H)+ 424.2207, observed 424.2207; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.05-1.19 (m, 2H, CH2), 1.32-1.80 (m, 8 H, 4×CH2), 2.01-2.21 (m, 1H, CH), 3.86 (s, 2H, NCH2), 3.82-3.94 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.46 (d, J=2.3 Hz, 1H, Ar), 7.50 (d, J=2.3 Hz, 1H, Ar), 7.52-7.74 (m, 4H, Ar), 10.75 (s, 1H, NH).