Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][N:6]=1)([CH3:4])[CH3:3].[F:19][C:20]1[C:27]([F:28])=[C:26]([CH2:29][O:30][CH3:31])[C:25]([F:32])=[C:24]([F:33])[C:21]=1[CH2:22]O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:4][C:2]([C:5]1[N:6]=[CH:7][C:8]([CH:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([O:14][CH2:22][C:21]2[C:24]([F:33])=[C:25]([F:32])[C:26]([CH2:29][O:30][CH3:31])=[C:27]([F:28])[C:20]=2[F:19])=[O:13])=[CH:9][N:10]=1)([CH3:1])[CH3:3]
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C)(C)c1ncc(C(C(=O)O)C(C)(C)C)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCc1c(F)c(F)c(COC(=O)C(c2cnc(C(C)(C)C)nc2)C(C)(C)C)c(F)c1F
Reaction time: 18 h

Procedure:
A solution of (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoic acid (0.1 q), 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol (0.089 g) and 4-dimethylaminopyridine (0.002 g) in dry dichloromethane (4 cm3) was stirred at the ambient temperature (20° C.) whilst N,N'-dicyclohexylcarbodiimide (0.084 g) was added in portions; the mixture was stirred for 18 hours. The solution was passed through silica gel and the silica gel eluted with, firstly, dichloromethane and, secondly a 50:1 mixture (by volume) of dichloromethane and ethyl acetate Evaporation of the solvents of the combined filtrate and eluted fractions gave the title compound (0.09 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][NH2:20])=[N:17][CH:18]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:20][CH2:19][C:16]3[CH:15]=[N:14][C:13]([CH3:12])=[CH:18][N:17]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Cc1cnc(CN)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(CNc2ccc3ncc(Br)n3n2)cn1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and (5-methylpyrazin-2-yl)methanamine according to general procedure 1 providing the intermediate (64 mg, 34%) as a yellow solid: Rf=0.67 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.69 (s, 1H), 8.47 (s, 1H), 7.60 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.79 (d, J=9.7 Hz, 1H), 4.66 (s, 2H), 2.53 (s, 3H); ES-MS: (M+H)=319, 321 m/z.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (498 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5]S(O)(=O)=O.[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>CCOCC>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][Cl:16]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)COc1ccccc1Br
Agent: [Na]
Solvent: CCOCC
Product: ClCOc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
A mixture of 29.0 g of (o-bromophenoxy)methane sulfonic acid, sodium salt and 50.0 g of PCl5 are thoroughly blended in a mortar. After about 10 minutes of continuous mixing, the mixture partly melts, a vigorous reaction occurs, and the whole turns to a liquid. The mixture is kept 15 minutes with occasional stirring, 700 ml of ether is added (a white solid separates) and the mixture is poured into 750 g of crushed ice. The ether solution is separated, washed, dried, and concentrated in vacuo to give about 21.0 g of a liquid residue. This is distilled under reduced pressure to give about 19.5 g of the colorless liquid product, b2.0 74°-75°, nD24.5 1.5799.
Reaction SMILES: [Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3].[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([C:25]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=O)=[O:26])=[CH:23][CH:22]=1>>[CH:34]1[CH:35]=[C:27]2[C:25]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:37][C:36]=3[C:29](=[O:31])[C:28]2=[CH:32][CH:33]=1)=[O:26]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [O-][Si]([O-])([O-])[O-]
Product: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Temperature: 305 °C

Procedure:
A fluidized bed reactor equipped with a heating jacket is filled with 70 parts of aluminum silicate grit (25% by weight of SiO2 and 75% by weight of Al2O3 ; φ from 0.1 to 0.3 mm) and is heated to 305° C. The specific total surface area of the cyclizing agent is 400 square meters per gram. The catalyst is kept fluidized by means of 300 parts by volume of nitrogen/hour. Per hour, 70 parts of o-(4-chlorobenzoyl)-benzoic acid are fed into the reactor. The β-chloroanthraquinone formed is precipitated by scrubbing the stream of gas with water. The conversion is practically quantitative. Per hour, 62 parts (95% of theory) of β-chloroanthraquinone of melting point 203° to 205° C. are obtained.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OCC)C=1)[CH2:3]C(O)=O.[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22]>>[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=1)[CH2:20][C:21]([O:23][CH2:2][CH3:3])=[O:22]
Reactant: CCOc1ccc(C(N)CC(=O)O)cc1OC
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Product: CCOC(=O)CC(N)c1ccc(OCC)c(OC)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 26 except that 3-amino-3-(3-ethoxy-4-methoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-methoxy-4-ethoxy-phenyl)propionic acid. MS (m/z): 268 [M+1]+.
Reaction SMILES: [C:1](NCC(O)=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/C=C\CCCCCCCC.N[C@H](C(O)=O)C.N(CC(O)=O)C.[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44]>>[C:1]([CH:42]([CH2:41][CH2:40][CH2:39][CH2:38][NH2:37])[C:43]([OH:45])=[O:44])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(=O)O
Agent: CNCC(=O)O
Agent: C[C@H](N)C(=O)O
Product: CCCCCCCC(=O)C(CCCCN)C(=O)O

Procedure:
oleoylglycine, -alanine, -sarcosine and -6-aminocaproic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[C:13]([CH3:14])=[C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[O:11][N:10]=1.Cl[C:25]1[S:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:26]=1.C(N(CC)CC)C.CN(C)C=O>O>[CH3:8][C:9]1[C:13]([CH3:14])=[C:12]([NH:15][C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:25]3[S:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[N:26]=3)[CH2:22][CH2:23]2)=[O:17])[O:11][N:10]=1
Reactant: Cc1noc(NC(=O)N2CCNCC2)c1C
Reactant: Fc1ccc(-c2nsc(Cl)n2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4)ns3)CC2)c1C
Yield: 19.8 %

Procedure:
A solution of N-(3,4-dimethylisoxazol-5-yl)piperazine-1-carboxamide trifluoroacetate (210 mg, 0.621 mmol), 5-chloro-3-(4-fluorophenyl)-1,2,4-thiadiazole (133 mg, 0.621 mmol), triethylamine (0.432 ml, 3.11 mmol) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 0.5 hours and the reaction mixture was poured into water. A solid was collected by filtration and recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (49.5 mg, 19.8%) as a solid.
Reaction SMILES: N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CC=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.[NH2:39][C@@H:40]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@@H:41]([C@H:43]1[CH2:47][C@H:46]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=2)[CH2:45][N:44]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:42].[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)[C:87](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78].[Li+].[OH-]>CCO.O.CO.C(Cl)(Cl)Cl>[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:124]=[CH:125][CH:126]=[CH:127][CH:128]=2)[C:87]([NH:39][C@@H:40]([CH2:68][C:69]2[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=2)[C@H:41]([OH:42])[C@H:43]2[CH2:47][C@H:46]([O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH2:45][NH:44]2)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](Oc2ccccn2)CN1C(c1ccccc1)c1ccccc1
Agent: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](Oc2ccccc2)CN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2)C1=O
Temperature: 25 °C
Yield: 61 %

Procedure:
Step 10 (B): (1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)oxazolidin-2-one (Step 10 (A), 50 mg, 0.092 mmol) in EtOH (5 mL) was added a solution of LiOH (44 mg, 1.84 mmol) in H2O (1.5 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave 29.0 mg (61% yield) of the title compound: 1H NMR (CDCl3, 300 MHz) δ 2.03-2.11 (2H, m), 2.23-2.42 (2H, m), 2.69 (2H, s), 2.92-2.97 (2H, m), 3.48 (1H, dd, J=3, 12 Hz), 3.73 (1H, m), 5.07 (1H, s), 5.44 (1H, s), 6.61-6.68 (4H, m), 6.82 (1H, m), 7.12-7.29 (6H, m), 7.32-7.44 (4H, m), 7.54 (1H, m), 8.06 (1H, dd, J=3, 6 Hz). HPLC retention time: 1.54 min (method C). MS (ESI) (M+H)+ 516.35.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C1COCC1.CO.CCOCC>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc(OC)nc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)c(C)c2)cn1
Reaction time: 12 h

Procedure:
To a solution of Methyl 2-methyl-4-(2-methoxypyridin-5-yl)-benzoate (600 mg, 2.6 mmol) (reference example 34a) in THF/MeOH (8 mL, 1/1) is added NaOH (3 mL, 1M). The resulting mixture is stirred for 12 hours then acidified with hydrochloric acid (2M, to give pH 5). The mixture is diluted with ether then washed with brine, dried over MgSO4 and concentrated. The residual solid is triturated with ether/hexane (1/20). The resulting product (500 mg) is used without further purification. 1H NMR (CDCl3) d 2.71 (s, 3H), 3.98 (s, 3H), 6.82 (d, J=8 Hz, 1H), 7.41 (m, 2H), 7.81 (dd, J=8, 2 Hz, 1H), 8.13 (d, J=8 Hz, 1H), 8.43 (d, J=2 Hz, 1H). MS (EI) m/z 243 (M+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][C:17]([CH:37]=C)=[N:16][C:15]=23)[CH:2]=1.[O:39]1CCOCC1.N1C(C)=CC=CC=1C.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:19]1[N:14]2[N:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[C:15]2[N:16]=[C:17]([CH:37]=[O:39])[CH:18]=1
Reactant: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccccc4c3)c2n1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6000 %

Procedure:
To 3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine (0.7 g, 1.3 mmol) in 1,4-dioxide (10 mL) was added 2.5 wt % OsO4 in 1,4-dioxane (1.0 g, 0.02 mmol), 2,6-lutidine (0.6 mL, 5.2 mmol) and H2O (2 mL), and the resulting mixture was stirred at room temperature for 20 minutes. NaIO4 (0.8 g, 3.81 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. LC/MS analysis at that time showed the diol intermediate still present. Therefore, more NaIO4 (0.3 g, 1.3 mmol) was added, and the reaction mixture was stirred for 12 hours for full conversion to the product. Saturated Na2S2O3 solution (10 mL) was added and the mixture was stirred for 10 minutes. Organics were then extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde as a yellow solid (0.6 g, 1.2 mmol, 92%). LCMS: 2.67 mins, m/z=550.0 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:35])[C:12]([NH:14][CH2:15][CH:16]([OH:34])[CH2:17][NH:18][C:19](=[O:33])[C@H:20]([CH3:32])[NH:21]C(OCC2C=CC=CC=2)=O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[ClH:36]>CO.[Pd]>[ClH:36].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:35])[C:12]([NH:14][CH2:15][CH:16]([OH:34])[CH2:17][NH:18][C:19](=[O:33])[C@H:20]([CH3:32])[NH2:21])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)NCC(O)CNC(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)NCC(O)CNC(=O)[C@H](C)N)cc1

Procedure:
In a manner analogous to that described in Stage 15.4, from 3.24 g (6.7 mmol) of N-benzyloxycarbonyl-L-alanine-3-[2-(4-isobutylphenyl)-propionylamino]-2-hydroxypropylamide by means of catalytic hydrogenation [1 g of palladium-on-carbon (10% palladium), 15 minutes, room temperature, normal pressure] in methanol at pH 7 (titration with 1N hydrochloric acid), there is obtained L-alanine-3-[2-(4-isobutylphenyl)-propionylamino]-2-hydroxypropylamide hydrochloride in the form of colourless crystals which decompose at 88° and above (triturated with diethyl ether) and contain 0.43 mol of water; [α]D20 =+8.3± 0.9° (c=1.065; methanol), Rf =0.30 (chloroform:methanol=4:1), Rf =0.58 (chloroform:methanol:water=70:30:5).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:30]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:6]([OH:38])=[O:5])=[O:11])[N:13]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC(C(=O)O)c2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A mixture of 3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-phenyl-propionic acid tert-butyl ester (60 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 3 h. The mixture was concentrated and resulting residue was treated with water; solids were collected via filtration and air dried to give desired product (50 mg). LC-MS ESI+: 454 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[NH:25][CH:24]=[C:23]2[C:22]=1[CH2:21][CH2:20][NH:19][C:18]2=[O:17])(=[O:5])=[O:4]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (48 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)[CH3:3].C(=O)([O-])[OH:43].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[OH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N+:38]([O-:43])[CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:15]=1)[CH3:3]
Reactant: CC(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc[n+]([O-])c4)n3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 6 %

Procedure:
To a solution of 10-{[2′-(1-hydroxyethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 52 (0.500 g, 0.92 mmol) in dichloromethane (20 mL) was added saturated aqueous sodium hydrogencarbonate solution (20 mL) followed by 70% 3-chloroperoxybenzoic acid (909 mg, 3.69 mmol) and the biphasic mixture was stirred vigorously for 1 hour. The reaction was quenched by the addition of 5% aqueous sodium metabisulfite solution (20 mL), the mixture stirred vigorously for 5 minutes, then partitioned between ethyl acetate (100 mL) and 2 M sodium hydroxide (100 mL). The organic layer was separated, washed with 2 M sodium hydroxide (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white solid. Purification by flash chromatography using a solvent gradient of 3 to 10% methanol in dichloromethane gave the title compound (31.1 mg, 6%) as a white solid, m.p. 213-215° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]([CH3:18])([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:12])=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([CH3:18])([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)(C(=O)NNc1ccc(F)cn1)N1CCCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(c1nnc2ccc(F)cn12)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of Intermediate 80a (260 mg, 0.98 mmol), Ph3P (511 mg, 1.95 mmol) and Et3N (544 μL, 3.91 mmol) in THF (10.0 mL) at 0° C. was added hexachloroethane (462 mg, 1.95 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The reaction showed 50% conversion so was re-submitted to the reaction conditions overnight at 50° C. The workup and purification procedures were repeated to give the title compound (209 mg, 86%). 1H NMR (300 MHz, CDCl3): 1.64 (6H, s), 1.74-1.82 (4H, m), 2.52-2.57 (4H, m), 7.16 (1H, ddd, J 9.8, 7.4, 2.3), 7.69 (1H, m), 8.93 (1H, ddd, J 4.5, 2.3, 0.7).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@H:6](O)[CH2:5][C@@H:4]1[C:9]([OH:11])=[O:10])[CH3:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCOCC>C(Cl)Cl>[CH2:1]([C@@H:3]1[CH2:7][C@H:6]2[CH2:5][C@@H:4]1[C:9](=[O:10])[O:11]2)[CH3:2]
Reactant: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 5.96 mmol, Example #4, Step H) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol) and BOP-Cl (1.82 g, 7.15 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then poured into Et2O (350 mL). The solid was removed by filtration while washing with Et2O (50 mL). The filtrate was concd under reduced pressure to give a yellow oil which was dissolved in DCM (5 mL) and Et2O was added to give a solid. The supernatant was decanted and the solid was washed with additional Et2O. The combined organic extracts were concd under reduced pressure to give (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about 15 mol % TEA (0.912 g, 99% crude): 1H NMR (CDCl3) δ 4.85 (s, 1H), 2.88 (s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H), 1.41 (m, 3H), 0.97 (t, J=5.4, 3H).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.[BH4-].[Na+]>CN(C=O)C>[CH2:22]([N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:1][C:5]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2ccncc2n1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c([nH]1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butyl 2-ethyl 1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (1.0 eq) in DMF was added benzyl bromide (1.0 eq.) and heated to 80° C. for 4 hrs. Reaction mixture was evaporated to dryness. The product obtained was dissolved aqueous ethanol and NaBH4 (1.5 eq.) was added at 0° C. and stirred for 4 hrs. Reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded ethyl 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.