Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 68.7 %

Procedure:
A 200 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (1.36g, 5.20 mmol), potassium carbonate (2.16 g, 15.6 mmol), 2-chloro-4-ethyl-benzothiazole (1.23 g, 6.20 mmol) and 14 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (750 mL) and washed with brine (6×250 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 1.51 g (69%) of the title compound as an amorphous foam. FDMS: m/e=422. α[D]589 =+62.74 (c=0.67, chloroform).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[O-]CC.[Na+].[F:13][C:14]1[CH:26]=[CH:25][C:17]([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1>C(O)C>[C:1]([CH:3]([CH:18]([C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:26][CH:25]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(F)cc1)C(C#N)C(=O)OCC
Yield: 47.4 %

Procedure:
To 12 g of ethyl cyanoacetate dissolved in 20 mL of ethanol, 8 g of sodium ethoxide and 40 mL of ethanol were added under cooling with ice, and then 20 g of ethyl p-fluorocinnamate and 40 mL of ethanol were added. The reaction mixture was heated under reflux for 20 hours and then filtered. The filtrate was poured into a mixture of 200 g of ice and 10 mL of concentrated hydrochloric acid and extracted with chloroform. The extract was concentrated and separated by silica gel column chromatography (hexane: ethyl acetate=9:1) to obtain 15 g of diethyl 2-cyano-3-(p-fluorophenyl)glutarate as a diastereomer mixture.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:9][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:22])=[O:21]
Reactant: COc1nc(Cl)c(Cl)nc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 2,3-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.12 g.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:15]([F:17])([F:16])[CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[OH:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1-n1ccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-n1ccnc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
To 2-imidazol-1-yl-benzaldehyde (0.344 g, 2 mmol) in THF (8 ml) was added trifluoromethyltrimethyl silane (0.341 g, 2.4 mmol). The reaction mixture was cooled to 0-5° C. (ice water bath) and tetra-n-butyl ammonium fluoride (0.035 ml, 0.035 mmol, 1M in THF) was added. The ice bath was removed, and the mixture was stirred at room temperature for 6 hours. 2N HCl (5 ml) was added, and the reaction mixture was further stirred for 3 hours at room temperature. Solvent was removed on the rotavap under reduced pressure. Crude residue was dissolved in DCM (30 ml), washed with water (20 ml), brine (20 ml) and dried with sodium sulfate. The solvent was removed to give crude 2,2,2-trifluoro-1-(2-imidazol-1-yl-phenyl)-ethanol (0.45 g, 93%), which was directly used in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C([O-])(=O)C.[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:37]4[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3cnn(CCO)c3)cc1-2
Reaction time: 0.33 h
Yield: 6.2 %

Procedure:
9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (57 mg, 0.138 mmol), 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 mg, 0.208 mmol), Tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.0138 mmol), 1.5 mL 1 M potassium acetate in water, and 1.5 mL acetonitrile were combined in a microwave vial and placed on the CEM microwave for 20 minutes at 140° C. Complete reaction by LCMS. Diluted reaction with 2 M HCl and extracted product with ethyl acetate. Some of the THP group fell off during work-up. The final Intermediate was in the ethyl acetate layer, which was dried over magnesium sulfate and concentrated in vacuo. Flash purified 0 to 10% MeOH in dichloromethane and again concentrated in vacuo. The THP intermediate was deprotected with 1 M HCl in dioxane (5 mL0 over 72 hours). Complete deprotection by LCMS. Concentrated in vacuo and purified by HPLC to give 277 (3.8 mg, 6% yield, M+1 443.1)
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[CH3:114][C@@H:115]([C@@H:122]1[C@@:126]2([CH3:142])[CH2:127][CH2:128][CH2:129]/[C:130](=[CH:131]\[CH:132]=[C:133]3\[CH2:134][C@@H:135]([OH:141])[CH2:136][C@H:137]([OH:140])[C:138]\3=[CH2:139])/[C@@H:125]2[CH2:124][CH2:123]1)[CH2:116][CH2:117][CH2:118][CH:119]([CH3:121])[CH3:120].C(Cl)Cl>C(O)C>[CH3:114][C@@H:115]([C@@H:122]1[C@@:126]2([CH3:142])[CH2:127][CH2:128][CH2:129]/[C:130](=[CH:131]\[CH:132]=[C:133]3\[CH2:134][C@@H:135]([OH:141])[CH2:136][C@H:137]([OH:140])[C:138]\3=[CH2:139])/[C@@H:125]2[CH2:124][CH2:123]1)[CH2:116][CH2:117][CH2:118][C:119]([OH:20])([CH3:120])[CH3:121]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Solvent: CCO
Solvent: ClCCl
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture medium were added 10 ml of a 5% aqueous β-cyclodextrin solution (0.01 M phosphate buffer, pH 7.0), a solution of 1% 1-hydroxyvitamin D3 in 1 ml of ethanol (in the amount of 140 mol of β-cyclodextrin relative to 1 mol of 1α-hydroxyvitamin D3) and a solution of 20% Tween 80 in 1 ml of ethanol. After cultivation for a further 2 hours, methylene chloride was added to the flask, and the determination as described in Example 1 was carried out. The peak fraction having a retention time of 3.8 minutes was collected, concentrated to dryness at 40° C. or below under reduced pressure, and applied to HPLC on Zorbax ODS (made by Du Pont Co.) with water-methanol (1:9) as a mobile phase at a flow rate of 1.0 ml/min. After elution, the peak reaction having a retention time of 5.6 minutes was collected, and concentrated to dryness under pressure at 40° C. or below with a nitrogen gas replacement to give 645 μg (64.5% of conversion ratio from the material) of 1α,25-dihydroxyvitamin D3. In case of the same procedure as described above but without β-cyclodextrin, the yield was 350 μg (35% of the conversion ratio from the material).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=1)=[O:7].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:39][O:38][C:36](=[O:37])[CH2:35][N:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([NH:17][C:16](=[O:28])[C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:11]=3)=[CH:19][CH:20]=2)[CH2:25]1
Reactant: COC(=O)CBr
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(OC)c(OC)c4)c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 3,4-dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide (50.0 mg, 0.12 mmol) in 1 mL of DMF. To the mixture was added methyl bromoacetate (0.02 mL, 0.20 mmol) and K2CO3 (50 mg, 0.36 mmol). The mixture was stirred at room temperature overnight. LC-MS indicated the desired product. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-95% CH3CN/H2O) to give 37 mg (7-{3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoylamino}-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid methyl ester. MS, electrospray 590.6 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8](/[C:10](=[N:16]/[O:17][CH:18]2[CH2:22][CH2:21][NH:20][C:19]2=[O:23])/[C:11]([O:13]CC)=[O:12])[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8](/[C:10](=[N:16]/[O:17][CH:18]2[CH2:22][CH2:21][NH:20][C:19]2=[O:23])/[C:11]([OH:13])=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1nc(/C(=N/OC2CCNC2=O)C(=O)O)cs1
Yield: 51.3 %

Procedure:
1.7 g of ethyl (Z)-2-(2-acetamidothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are suspended in 17 ml of methanol, and 5 ml of 2N sodium hydroxide are added thereto. The mixture is refluxed for 30 minutes with heating. Then, the mixture is concentrated under reduced pressure to remove methanol. The residue is adjusted to pH 2 with diluted hydrochloric acid, and the aqueous mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran (2:1). The extract is dried and concentrated under reduced pressure to dryness. The residue is crystallized with isopropanol, and the crystals are collected by filtration and then recrystallized from water. 0.8 g of (Z)-2-(2-acetamidothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[H-].[Na+].Br[CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=[CH:12]2)#[N:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)OCC)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
5-(2-Cyanophenyl)indole (5.04 mmoles, 1.1 g) in 70 ml THF was treated with sodium hydride (255 mg, 50% in mineral oil) and stirred at 0° C. for 30 minutes. Ethyl 2-bromooctanoate (5.5 mmoles) in 40 ml THF was added dropwise. The reaction was stirred at room temperature for 4 hours, cooled, poured onto ice, extracted with ethyl acetate. The organic phase was dried and concentrated. The intermediate was chromatographed over silica gel eluted with 20% ether in hexane. The reaction yielded 1.1 g of ethyl 2-[5-(2-cyanophenyl)indol-1-yl]octanoate. (MS)
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14].[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([C:4]1[C:5]2[N:6]([N:9]=[CH:10][N:11]=2)[CH:7]=[N:8][C:3]=1[CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[CH2:13][CH3:14]
Reactant: N#Cc1cccnc1-c1ncc[nH]1
Reactant: CCCc1c(CBr)ncn2ncnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2ncccc2C#N)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 169 (56 mg, 0.22 mmol), 170 (42 mg, 0.25 mmol) and K2CO3 (138 mg) in DMF (4 mL) is stirred at room temperature overnight. Solvent is removed in vacuo. Water (10 mL) is added and the mixture is extracted with ethyl acetate (3×25 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% MeOH in methylene chloride) to give the title product (167) as a solid. 1H NMR 9.13 (s, 1H), 8.64–8.66 (m, 1H), 8.36 (s, 1H), 8.07–8.10 (m, 1H), 7.29–7.34 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 5.94 (s, 2H), 3.02–3.08 (m, 2H) 1.66–1.74 (m, 2H), 1.00 (t, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][N:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: CC(C)c1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C(C)C)c3)nc12

Procedure:
From 2-isopropyl-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])[CH2:17][O:16][C:15]3[CH:35]=[CH:36][CH:37]=[CH:38][C:14]1=3)=[C:7]([O:39][CH3:40])[CH:6]=[CH:5]2.[ClH:41]>O1CCOCC1>[ClH:41].[NH2:26][C@@H:23]([CH2:24][CH3:25])[C:22]([NH:21][C@H:18]1[CH2:17][O:16][C:15]2[CH:35]=[CH:36][CH:37]=[CH:38][C:14]=2[N:13]([CH2:12][C:8]2[C:9]3[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[O:39][CH3:40])[C:19]1=[O:20])=[O:34]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](N)C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Yield: 93 %

Procedure:
A solution of tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxobutan-2-ylcarbamate (430 mg, 702 μmol) in 4 M HCl in dioxane (3.51 mL) was stirred at RT for 1 h, and concentrated. the residue was triturated with Et2O to provide (S)-2-amino-N -((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)butanamide hydrochloride (357 mg, 93%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:27][CH:28]=4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]=[CH2:12])[C:3]=12.Cl.O>[Pt].CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:27][CH:28]=4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH2:11][CH3:12])[C:3]=12
Reactant: C=Cc1nn(C(C)c2cc(Cl)c(C)c(-c3ccc(C(=O)N(C)C)nc3)c2OCC)c2ncnc(N)c12
Agent: [Pt]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1c(C(C)n2nc(CC)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 3 h
Yield: 27.4 %

Procedure:
5-{3-[1-(4-Amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (14 mg, 0.028 mmol) and 5% platinum on carbon (14 mg) was combined in methanol (1 mL), to which was added 0.25 M hydrogen chloride in water (0.28 mL, 0.069 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 3 h. The suspension was filtered and the filtrate purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.9 mg, 28%). The product was isolated as a racemic mixture. LCMS calculated for C26H31ClN7O2(M+H)+: m/z=508.2; Found: 508.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C@@H:8](CO)[NH:9]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 213.1 %

Procedure:
To a mixture of N(benzyloxycarbonyl)-3(S)-hydroxymethyl-β-alanine tert-butyl ester (3.1 g) and triethylamine (1.35 ml) in dichloromethane (25 ml) was added a solution of methanesulfonyl chloride (1.35 ml) in dichloromethane (5 ml), under ice cooling. After stirring at room temperature for 1 hour. The mixture was poured into water and extracted with dichloromethane. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with CHCl3 to give N-(benzyloxycarbonyl)-3(S)-methanesulfonyloxymethyl)-β-alanine tert-butyl ester (3.1 g) as an colorless oil.
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to ethanol (1 ml). 10% Palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with ethanol (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). 1H NMR (CDCl3): 1.06-1.12, 1.31-1.36, 1.80-193, 2.25-2.49, 2.62-2.92, 3.74-4.08, 4.81 and 5.27, 6.20 and 6.54, 7.24-7.57.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC1C=C[C:9]([O:12]C)=CC=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].ClC1C=CC(C=O)=CC=1C>Cl>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[CH3:21])[CH:9]=[O:12]
Reactant: Cc1ccccc1Cl
Reactant: COc1ccc(C)cc1
Agent: Cc1cc(C=O)ccc1Cl
Agent: Cl
Agent: [Al+3]
Product: Cc1ccc(C=O)cc1Cl
Temperature: 30 °C
Yield: 389.3 %

Procedure:
216.00 g of aluminum chloride (mol. Wt. 133.34; 1,619.9 mmol), 109.09 g (4-Methylanisole (mol. Wt. 122.17; 892.9 mmol), and about 522.35 g of 2-chlorotoluene (mol. Wt. 126.59; 4,126.3 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 30° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 550 psi, the pressure at which the reaction was maintained for the total reaction time of about 66 hours (the reaction temperature was maintained at 30° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-chlorotoluene, and left about 76.01 g of a benzaldehyde mixture consisting of 4-chloro-3-methylbenzaldehyde (76.5%) and 3-chloro-4-methylbenzaldehyde (23.5%) (mol. Wt. 154.59; 491.7 mmol; yield of approximately 67.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5].[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:7][CH3:8])[CH2:9][CH3:10])=[O:5]
Reactant: [H][H]
Reactant: C/C=C/c1ccc(C(=O)N(CC)CC)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(C(=O)N(CC)CC)c(Cl)c1
Reaction time: 24 h
Yield: 67 %

Procedure:
To the crude (E)-2-chloro-N,N-diethyl-4-(prop-1-enyl)benzamide in 100 mL of absolute ethanol was added 10% Pd/C catalyst (1 g). The mixture was stirred under 1 atm of hydrogen, maintained by a balloon, for 18 h. Starting material still remained and so additional 10% Pd/C (0.5 g) was added and the reaction was charged with a fresh hydrogen balloon and stirred and additional 24 h. The reaction mixture was filtered through a pad of Celite and concentrated. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 8:1 to 6:1 hexane/EtOAc) to afford 2.15 g (67%) of the title compound. 1H NMR (CDCl3): δ 7.12 (d, 1H, J=1.1 Hz), 7.09 (d, 1H, J=7.7 Hz), 7.02 (dd, 1H, J=1.6, 7.7 Hz), 3.75-3.68 (m, 1H), 3.32-3.25 (m, 1H), 3.11-3.06 (m, 2H), 2.50 (t, 2H, J=7.7 Hz), 1.60-1.52 (m, 2H), 1.19 (t, 3H, J=7.1 Hz), 0.99 (t, 3H, J=7.1 Hz), 0.87 (t, 3H, J=7.4 Hz). LRMS (ESI): 254.10/256.10 (M+H)+.