Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]=1>C1(C)C=CC=CC=1>[CH2:7]([C:8]1[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[N:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: COC1=NCCCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(Cc2nnc3n2CCCCCC3)cc1
Temperature: 60 °C

Procedure:
2-Phenylacetohydrazide (1.01 g) was added to a solution of anhydrous toluene (11 mL) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (0.96 mL). The mixture was warmed to 60° C. for 3 hours and heated to 110° C. overnight. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give 3-benzyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1N
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Nc2ccccc2)cc1

Procedure:
The sulfonamide was synthesized from 4-acetamidophenyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(1.27 g,40%)EI-MS m/z 304(M−H)−.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Fc1cccc(Br)c1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 1-bromo-3-fluorobenzene
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:14]=[CH:13]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:40]([CH:45]1[CH2:50][CH2:49][CH:48]([CH:51]=O)[CH2:47][CH2:46]1)[CH2:41][CH2:42][CH2:43][CH3:44].CC(C)([O-])C.[K+]>COC(C)(C)C>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:20]=[CH:51][CH:48]3[CH2:47][CH2:46][CH:45]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:50][CH2:49]3)[CH:16]=2)[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCC1CCC(C=O)CC1
Reactant: c1ccc(COc2ccc3cc(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCCCCC1CCC(C=Cc2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Yield: 74 %

Procedure:
The solution of (6-benzyloxy-naphthalen-2-ylmethyl)-triphenyl-phosphonium bromide (19) (1 equi.), 4-pentyl-cyclohexanecarboxaldehyde (22), and potassium tert-butoxide (1.3 equi.) in tert-butyl methyl ether (6 mL/mmole) was stirred at room temperature for 24 h, then quenched with water, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (1.25% EtOAc/hexane) afforded 2-benzyloxy-6-[2-(4-pentyl-cyclohexyl)-vinyl]-naphthalene (23) as a white solid (74%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4](/[CH:13]=C/C2C=CC=CC=2)[N:3]=1.[O:21]1CCOCC1>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH:13]=[O:21])[NH:5][C:6]2[C:7]=1[O:8][CH2:9][C:10](=[O:12])[N:11]=2
Reactant: O=C1COc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=CC1=NC(Cl)=C2OCC(=O)N=C2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of 4-chloro-2-[(E)-2-phenylethenyl]-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (0.45 g, 1.16 mmol) in 1,4-dioxane (25 mL) and water (10 mL) was added NaIO4 (1.26 g, 4.4 mmol) along with a catalytic amount of OsO4 (0.36 mL, 4 wt. % in water). The resulting mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure and the residue was extracted with 10% methanol in DCM (3×50 ml). The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a solid which was purified by column chromatography (silica gel) with a 0-10% methanol in DCM gradient to give the desired product as light yellow solid (0.28 g, 84%).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[C:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)=[O:27])([CH3:24])([CH3:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.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:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4n3C(=O)OC(C)(C)C)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL) was added 1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-ylboronic acid (320.0 mg, 1.40 mmol), K3PO4 (440.0 mg, 2.08 mmol), Pd(PPh3)4 (40.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in dichloromethane (50 mL), washed with water (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.1%-1% ethyl acetate in petroleum ether to afford methyl 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (280.0 mg, 81%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>O1CCCC1.CN(C)C=O>[F:14][C:15]([F:17])([F:16])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: O=Cc1cccs1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OC(c1cccs1)C(F)(F)F
Yield: 77.7 %

Procedure:
According to Reference Example 8-2, by use of thiophene-2-carbaldehyde (300 mg, 2.67 mmol) dissolved in tetrahydrofuran (4.5 mL) and N,N-dimethylformamide (1.5 mL), potassium carbonate (74 mg, 0.53 mmol) and (trifluoromethyl)trimethylsilane (0.772 mL, 5.34 mmol), the mixture was stirred and reacted at room temperature for 16 hours. Then, purification by extraction gave 2,2,2-trifluoro-1-(thiophen-2-yl)ethanol (Compound DN) (378 mg, yield: 78%).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[Br:27][CH2:28][C:29](Br)=[O:30]>C1COCC1>[Br:27][CH2:28][C:29]([N:17]1[CH2:18][CH2:19][CH:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)[CH2:16]1)=[O:30]
Reactant: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (prepared using general procedures E, F, 0.051 g, 0.17 mmol) and Et3N (0.05 mL, 0.34 mmol) in THF (1.7 mL) was added bromoacetylbromide (0.015 mL, 0.17 mmol). The reaction mixture was stirred at ambient temperature for about 12 h then concentrated in vacuo to give 2-bromo-1-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethanone that was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])=[CH:37][CH:36]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])=[CH:39][CH:40]=4)[N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Nc1ccc(N)cc1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(Nc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)n2)cc1
Temperature: 100 °C

Procedure:
To a slurry of (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (Example 3, Step 3) (80.0 mg, 0.238 mmol) in IpOH (3.0 ml) was added DIEA (0.062 mL, 0.356 mmol) and N-(4-aminophenyl)acrylamide (Example 2, Step 2) (42.4 mg, 0.261 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fells out of solution, was filtered off and dried under reduced pressure to give N-{4-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=463[M+H]+. Calc'd for C26H22N8O: 462.19.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and phenyl boronic acid: MS (m/z) 343.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li+].CC([N-]C(C)C)C.[O:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:19]2([OH:22])[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1ccsc1Br
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2(O)CCOCC2)sc1Br
Temperature: 25 °C
Yield: 46.8 %

Procedure:
To a −78° C. solution of 2-bromo-3-methyl-thiophene (2.0 g, 17.75 mmol) and THF (30 mL) is added 2.0 M LDA (9.32 mL, 18.63 mmol). After 30 minutes at −78° C. tetrahydro-pyran-4-one (2.3 mL, 23.07 mmol) is added and the solution is warmed to ambient temperature. The solution is washed with sat. NH4Cl (30 mL). The aqueous phases is extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (30%-100% EtOAc/hexane gradient) furnish the title compound (2.3 g, 8.30 mmol, 47%). 1H NMR (CDCl3), δ 1.82 (m, 2H), 2.00 (s, 3H), 2.06-2.15 (m, 3H), 2.16 (s, 3H), 3.77-3.84 (m, 2H), 3.87 dt, J=11.3, 2.2 Hz, 2H), 6.67 (s, 1H). LC/MS (m/z): calcd. for C10H13BrO2S (M+H)+: 277.0; found: 260.9.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:5])[CH3:4].[N+]([C:17]1[CH:18]=[C:19]([CH:22]=[O:23])[S:20][CH:21]=1)([O-])=O.O>CS(C)=O>[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:21]2[S:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: O=Cc1cc([N+](=O)[O-])cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2ccc(C=O)s2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
NaH (60%, 480 mg, 12.0 mmol) was added in several portions to a stirred solution of Example 17A (1.52 g, 10.0 mmol) in DMSO (15 mL) at room temperature. After 20 min, 4-nitrothiophene-2-carbaldehyde (1.57 g, 10.0 mmol) was added in one portion. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with ether (2×). The ether layer was washed with 10% NaOH (1×), brine (1×), dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate: hexane gradient to give the desired product as a brown oil (206 mg, 7.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[O:26][C:27]([CH3:30])=[CH:28][CH:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1ccc(-c2ccc3c(c2)CCNC3C)o1
Product: Cc1ccc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH2:5][C:6](=[O:8])[CH3:7])[C@H:3]1[CH2:9][CH:10]=[O:11]>C1(C)C=CC=CC=1>[OH:11][CH2:10][CH2:9][C@@H:3]1[C@H:4]([CH2:5][C:6](=[O:8])[CH3:7])[C:2]1([CH3:12])[CH3:1]
Reactant: CC(=O)C[C@H]1[C@@H](CC=O)C1(C)C
Solvent: Cc1ccccc1
Product: CC(=O)C[C@H]1[C@@H](CCO)C1(C)C
Temperature: 90 °C

Procedure:
2-((1R,3S)-2,2-dimethyl-3-(2-oxopropyl)cyclopropyl)acetaldehyde (8.4 g, 0.05 mol.), to toluene (50 g, 600 wt. %) and (ethylenediamine)[1,2-bis(diphenylphosphino) ethane]ruthenium(bispivalate) (4.8 mg, 0.00625 mmol, 0.0125 mol.%) were loaded altogether in a 125 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 90° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 95% selectivity. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After flash chromatography, 1-((1S,3R)-3-(2-hydroxyethyl)-2,2-dimethylcyclopropyl)propan-2-one was obtained in 90% yield.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>N1C=CC=CC=1>[CH2:1]([N:17]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:31](=[O:33])[CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCC)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(CCC(=O)OCC)cc1

Procedure:
A mixture of 10.0 g. of ethyl 4-(hexadecylamino)hydrocinnamate, 50 ml. of pyridine and 25 ml. of acetic anhydride is heated on a steam bath for 15 hours. The solution is poured onto ice and adjusted to pH 6 with concentrated hydrochloric acid. The mixture is filtered and the crystals washed with water. The solid is recrystallized from ethanol, yielding ethyl 4-(N-hexadecylacetamido)hydrocinnamate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[CH2:35][NH:36][CH3:37]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:31])[N:36]([CH2:35][C:34]4[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=4[F:32])[CH3:37])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: CNCc1ccccc1F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N(C)Cc4ccccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-fluoro-N-methylbenzylamine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20]Br)=[O:17])([CH3:14])([CH3:13])[CH3:12].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][CH2:19][NH:18][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1

Procedure:
To a solution of 4-hydroxyacetophenone (10 g) and 2-tert-butoxycarbonylaminoethylbromide (24.7 g) in N,N-dimethylformamide (50 ml) was added potassium iodide (12.2 g) and potassium carbonate (15.2 g).
Reaction SMILES: [C:1]([C:5]1[CH:47]=[CH:46][C:8]2[C:9](=[O:45])[N:10]([C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([C:35]([N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:36])=[CH:31][N:30]=5)[C:25](=[O:43])[N:24]([CH3:44])[CH:23]=4)[C:15]=3[CH:16]=[O:17])[CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)(C)C.C1COCC1>[C:1]([C:5]1[CH:47]=[CH:46][C:8]2[C:9](=[O:45])[N:10]([C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([C:35]([N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:36])=[CH:31][N:30]=5)[C:25](=[O:43])[N:24]([CH3:44])[CH:23]=4)[C:15]=3[CH2:16][OH:17])[CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(N3CCOc4cc(C(C)(C)C)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(N3CCOc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
To 2-(8-tert-Butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde (0.27 mmol) in isopropanol (5 mL) and THF (10 mL) at 0 C with stirring was added sodium borohydride (21 mg, 2 eq) and then the ice bath was removed and the resulting mixture was stirred at room temperature for 45 minutes. TLC analysis indicated that the reaction was complete so the mixture was diluted with ethyl acetate (150 mL) and water (50 mL). The layers were partitioned, then separated and the organic layer was further washed with water (3×50 mL) and then finally washed with brine ((1×50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. Purification by Thin Layer Chromatography on silica gel eluting with 10% methanol in dichloromethane afforded the title compound as a light grey powder (94 mg), (M+H)+=638.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH:16]=2)[S:29]([CH3:28])(=[O:31])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)C1

Procedure:
Intermediate 35 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 467.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CN1CCCC1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCOc1ccc(C2(C#N)CCOCC2)cc1
Yield: 14.7 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.0 g, 4.9 mmol), 2-(2-chloro-ethyl)-1-methyl-pyrrolidine (722 mg, 3.90 mmol), DMF (20 ml) and K2CO3 (2.71 g, 19.60 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. and purified by prep TLC, eluting with DCM:MeOH:NH3 (95:5:3), to provide the title compound (180 mg, 15%) as a yellow oil. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.12-4.03 (m, 4H), 3.89 (td, 2H), 3.08 (m, 1H), 2.35 (s, 3H), 2.29-1.94 (m, 8H), 1.85-1.65 (m, 2H), 1.62-1.50 (m, 2H).
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])([CH3:19])[CH3:18]>>[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:1](=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])([CH3:19])[CH3:18]
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: CC(C)c1ccccc1N
Product: CC(C)c1ccccc1NC(=O)c1ccccc1O

Procedure:
The 2′-isopropyl-salicylanilide was prepared by condensing phenyl salicylate with 2-isopropylaniline then purified as described in Example 2a. The ligand mixture was then prepared from 2′-isopropyl-salicylanilide and binaphthol using the procedure described in Example 2a. 31P NMR (121.77 MHz): several peaks between 117.1-120.9 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1OC
Yield: 95.2 %

Procedure:
The product was prepared by the alkylation of 4-nitro-2-methoxyphenol (10.0 g, 0.059 mol) with ethyl bromoacetate (10.0 g, 0.06 mol) in acetonitrile (50 mL) in the presence of potassium carbonate (8.0 g) to afford 14.33 g (95%) of ethyl 4-nitro-2-methoxyphenoxyacetate as a yellow solid, m.p. 87°-88° C., after recrystallization from tert-butylmethyl ether; hydrogenation of the latter (13.08 g, 0.051 mol) in THF (125 mL)/ethanol (125 mL) in the presence of 10% Pd/C (1.0 g) to afford 11.5 g (100%) of ethyl 4-amino-2-methoxyphenoxyacetate as a pink oil; and then treatment of the latter (11.5 g, 0.051 mol) in CH2Cl2 (100 mL) with pyridine (10 mL), followed by methanesulfonyl chloride (6.43 g, 0.056 mol) to afford 12.328 g (79.6%) of N-[4-(ethoxycarbonylmethoxy)-3-(methoxy)phenyl]methanesulfonamide, m.p. 118°-119° C., after purification by treatment with charcoal and filtration through silica eluting with ethyl acetate.