Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:19][NH:20][C:21]([C:23]1[C:24]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:25]=2[S:26][C:27]=1[CH2:28][CH3:29])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][NH:20][C:21]([C:23]1[C:24]2[CH:33]=[CH:32][C:31]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][C:25]=2[S:26][C:27]=1[CH2:28][CH3:29])=[O:22]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)NC
Yield: 63.1 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 4a (71 mg, 0.25 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (71 mg, 0.30 mmole) and Cs2CO3 (244 mg, 0.75 mmole) in a manner analogous to that described for example 1 to give a light brown solid (76 mg, 63%). 1H NMR (DMSO-d6, 300 MHz), δ 8.58 (1H, d, J=5.56 Hz), 8.32 (1H, q, J=4.38 Hz), 8.07, 8.00 (1H, s), 7.98 (1H, d, J=2.27 Hz), 7.80 (1H, d, J=8.84 Hz), 7.33 (1H, dd, J=2.27, 8.59 Hz), 6.75 (1H, d, J=5.31 Hz), 4.38, 4.33 (1H, br s), 4.01–3.93 (2H, m), 3.67–3.45 (3H, m), 3.00 (2H, t, J=7.49 Hz), 2.83 (3H, d, J=4.55 Hz), 2.06–1.80 (2H, m), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1([CH2:31][CH2:32][NH2:33])[CH:30]=[CH:29][N:28]=[CH:27]1.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:33][CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCn1ccnc1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 4 h

Procedure:
A mixture of 1.8 g of 5-chloroindole-2-carboxylic acid in 50 ml of tetrahydrofuran was treated with 1.5 g of 1,1'-carbonyldiimidazole and allowed to stand at room temperature for 4 hours. A solution of 1.15 g of 1H-imidazole-1-ethanamine in 25 ml of tetrahydrofuran was added and the reaction mixture was heated at reflux temperature for 3 hours, treated with 10 ml of water and again heated for one hour and then concentrated to remove the solvent. The residue was shaken with 5 ml of 1N sodium hydroxide and 300 ml of dichloromethane and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated to recover the desired compound, mp 167°-169° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)#[CH:5]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(=O)OC)cc1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a stirred solution at 0° C. under nitrogen of XXXI (9.05 g, 38.95 mmol) in MeOH (280 ml) was added potassium carbonate (1.62 g, 11.72 mmol). After 3 h, the reaction mixture was concentrated and directly purified by flash chromatography on silica gel (CH2Cl2:100) to afford the title compound XXXII (6.16 g, 38.46 mmol, 98% yield) as a pale yellow solid. 1H NMR: (400 MHz, CDCl3) δ (ppm): AB system (δA=7.98, δB=7.54, JAB=8.6 Hz, 4H), 3.93 (s, 3H), 3.24 (s, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]([F:24])([F:23])[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)=[O:12].O>CN(C)C=O>[F:24][C:10]([F:9])([F:23])[C:11]([N:13]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)[CH3:1])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc2[nH]ncc2c1)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Potassium carbonate (415 mg, 3.00 mmol) and methyl iodide (0.20 ml, 3.21 mmol) were added to a solution of 2,2,2-trifluoro-N-(1H-indazol-5-yl)acetamide (688 mg, 3.00 mmol) in N,N-dimethylformamide (4 ml) at room temperature and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=99/1) to obtain 2,2,2-trifluoro-N-(1H-indazol-5-yl)-N-methylacetamide (466 mg, 64%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@H:13]([B:19]1[O:23][C@@H]2C[C@@H]3C[C@H]([C@]2(C)[O:20]1)C3(C)C)[CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:11])=[O:7])(=[O:3])[CH3:2].CO.CCCCCC.Cl.CC(C)CB(O)O>>[C:1]([NH:4][C@@H:5]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:10]([NH:12][C@H:13]([B:19]([OH:23])[OH:20])[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18]1)=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CC(C)CB(O)O
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Product: CC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
Into a 1-neck round-bottom flask was added (2S)-2-(acetylamino)-N-[(1S)-1-benzyl-2-({(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}amino)-2-oxoethyl]-4-phenylbutanamide (24.8 mg, 0.0395 mmol), methanol (0.237 mL, 5.86 mmol), hexane (0.237 mL, 1.81 mmol), hydrochloric acid (0.0889 mmol, 0.0889 mmol) and 2-methylpropylboronic acid (8.65 mg, 0.0849 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative TLC in 10% MeOH/CH2Cl2 to give 9.90 mg (51% yield) of desired product as a white solid. 1H NMR (CD3OD, 300 MHz, δ): 7.32-7.12 (m, 10H); 4.74 (t, J=7.94 Hz, 1H); 4.26 (dd, J=5.49, 8.55 Hz, 1H); 3.14-3.05 (m, 2H); 2.66-2.55 (m, 2H); 2.48-2.41 (m, 1H); 2.19-2.05 (m, 1H); 2.04-1.89 (m, 8H); 1.89-1.69 (m, 3H); 1.58-1.36 (m, 3H); 1.33-1.22 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35]C(OC(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.C(N(C(C)C)CC)(C)C.[C:73]1([N:79]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:80](Cl)=[O:81])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>ClCCl>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:80](=[O:81])[N:79]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)N(c2ccccc2)c2ccccc2)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 110 h
Yield: 97 %

Procedure:
150 mg (0.17 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3) and 150 μl (0.89 mmol) of diisopropylethylamine are dissolved in 6 ml of dichloromethane, mixed with 155 mg (0.37 mmol) of diphenylcarbamoyl chloride and stirred for 110 hours at room temperature. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography (Lichroprep Si60A pre-packed column, hexane→hexane/dichloromethane/methanol 30:60:10) yields 158 mg (97%) of N-(N -(N-(N-(diphenylcarbamoyl)-L-alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna -1,4-dien-21-yl] ester, and after recrystallization, 112 mg (68%) in crystalline form from dichloromethane/diisopropyl ether.
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3].Br[C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1.C(N(CC)CC)C.C1CCCCC1>CN(C=O)C.CCOC(C)=O.CO>[Br:21][C:18]1[S:17][C:16]([N:7]2[CH2:6][CH2:5][C:4]([CH2:2][CH3:3])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]2)=[N:20][CH:19]=1
Reactant: CCOC(=O)C1(CC)CCNCC1
Reactant: Brc1cnc(Br)s1
Agent: Cl
Solvent: CO
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC)CCN(c2ncc(Br)s2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of ethyl 4-ethylpiperidine-4-carboxylate hydrochloride (140 mg, 0.62 mmol) and 2,5-dibromothiazole (100 mg, 0.41 mmol) in DMF (0.3 mL) was added triethylamine (0.26 mL, 1.9 mmol) at rt and the mixture heated to 100° C. and stirred for 2 h. The mixture was cooled to rt, diluted with EtOAc (2 mL) and MeOH (2 mL). then evaporated to dryness under reduced pressure. The crude residue was purified over 12 g silica-gel using EtOAc: cyclohexane (10% to 60%) to obtain the desired product as viscous oil (110 mg, 77% yield). MS: 347.03, 349.01 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH2:20][CH3:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:35][O:36][CH2:37][CH2:38][OH:39]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH2:20][CH3:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:35][O:36][CH2:37][CH2:38][OH:39])=[O:7]
Reactant: NOCCO
Reactant: CCSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCSc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1

Procedure:
The title compound was prepared from reaction of the product of Example 27, Step B, 3,4-difluoro-2-[[2-fluoro-4-(ethylthio)phenyl]amino]benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1,
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[O:12][C:8]3=2)[N:3]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCNCC1)O3
Temperature: 75 °C
Yield: 82 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromobenzene sulfonate (1.35 g, 3 mmol) and piperazine (2.58 g, 30 mmol) in dimethylsulfoxide (16 mL) is heated at 75° C. under nitrogen for 1 hour, cooled and poured into saturated aqueous sodium bicarbonate. The mixture is extracted with ethyl acetate and the extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (5–25%) in dichloromethane containing 0.2% ammonium hydroxide to provide the title compound as an off-white oil (0.736 g) identical to the compound of example 1B, step B′.
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:22][B-:23]([F:26])([F:25])[F:24].[H+]>CO.O>[F:22][B-:23]([F:26])([F:25])[F:24].[C:16]1([PH+:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: F[B-](F)(F)F
Agent: N#N
Agent: [H+]
Solvent: CO
Solvent: O
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Temperature: 10 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 250.8 g (1.1 mol) of fluoroboric acid aqueous solution (40 wt %) was then added dropwise under strong stirring. After one hour of reaction, the reaction temperature was increased to about 50° C., and the unreacted materials as well as the solvents, including water and methanol, were removed by distillation under vacuum to obtain triphenylphosphonium tetrafluoroborate. The phosphonium salt was then transferred to an autoclave, and 202.0 g (2.2 mol) of dimethyl carbonate was also introduced. After 6 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 375.0 g of methyl triphenyl phosphonium tetrafluoroborate was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([C:8]([CH3:11])([CH3:10])[OH:9])[CH:7]=1.[NH2-].[Na+].Cl[CH:16](Cl)[C:17]([O-:19])=[O:18].[K+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][CH:16]([C:17]([OH:19])=[O:18])[O:9][C:8]([CH3:10])([CH3:11])[C:6]=2[CH:7]=1
Reactant: CC(C)(O)c1cc(Cl)ccc1O
Reactant: O=C([O-])C(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CC1(C)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 50 °C
Yield: 85 %

Procedure:
A solution of 1.9 g of 5-chloro-α,α-dimethyl-2-hydroxybenzene-methanol in 15 ml of toluene was added dropwise to a stirred mixture of 0.8 g of sodium amide and 100 ml of toluene and the mixture was refluxed for 5 hours and was cooled to 50° C. 2 g of potassium dichloroacetate were added thereto and the mixture was refluxed for 6 hours and was cooled to 20° C. The mixture was poured into 200 ml of ice and 100 ml of N hydrochloric acid. The decanted aqueous phase was extracted 3 times with 50 ml of ether and the combined organic phases were made alkaline by stirring with 100 ml of 2 N sodium hydroxide solution. The organic phase was washed 3 times with 50 ml of N sodium hydroxide solution and the aqueous phase was acidified with concentrated hydrochloric acid and was extracted 3 times with 100 ml of ether. The ether phase was treated with 100 ml of 10% aqueous sodium bicarbonate solution and the aqueous phase was acidified with concentrated hydrochloric acid and was extracted 3 times with 50 ml of methylene chloride. The organic phase was washed with water until neutral, dried over magnesium sulfate and evaporated to dryness to obtain 2.1 g of 6-chloro-4,4-dimethyl-[4H]-1,3-benzodioxin-2-carboxylic acid which after crystallization from cyclohexane melted at 142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:43]3[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(S(C)(=O)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-methylsulfonyl-piperazine (Aldrich) to give the title compound. LC-MS: 659.2 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:12][O:11][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1)[CH:6]=[O:7]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C=O)cc(OC)c1
Product: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
The 3,5-Dimethoxybenzaldehyde (0.5 g, 3 mmol) was added to 70% nitric acid (0.88 mL, 14.44 mmol) at 0° C. in portion. After stirring for 1 hour, the reaction mixture was quenched and extracted by water and CH2Cl2. The organic layers were combined and evaporated to give a residue, which was purified by flash chromatography (EtOAc:n-hexane=1:2.5) to give the brown crystals, yield 64%. mp 104.0-104.6° C., 1H NMR (500 MHz, CDCl3) δ 3.93 (s, 3H), 3.93 (s, 3H), 6.76 (d, J=2.4 Hz), 6.96 (d, J=2.4 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:40]=[CH:39][N:14]3[C:15](=[O:38])[C:16](/[CH:29]=[CH:30]/[C:31]([O:33]C(C)(C)C)=[O:32])=[C:17]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([C:25]([NH:27][CH3:28])=[O:26])[CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:40]=[CH:39][N:14]3[C:15](=[O:38])[C:16](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[C:17]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([C:25]([NH:27][CH3:28])=[O:26])[CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)C1CCCN(c2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1CCCN(c2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.3 %

Procedure:
The tert-butyl (E)-3-(8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-{3-[(methylamino)carbonyl]piperidino}-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-2-propenoate (192 mg, 0.341 mmol) obtained in (B) was added with trifluoroacetic acid (5.0 ml) and stirred at room temperature for 1.5 hours. After the reaction was completed, the trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with 0.1 N sodium hydroxide and phosphate buffer (pH 7-8) and extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (chloroform:methanol and chloroform:methanol:water=8:3:1, v/v, lower layer) to obtain the title compound (49.0 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[C@H:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:21]=O>C(O)=O>[Cl:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[C@H:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][N:8]([CH3:21])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Cl)CCNC[C@H]2c1ccccc1
Reactant: C=O
Solvent: O=CO
Product: COc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1

Procedure:
Reflux for 4 hours, a solution of 52.0 g (0.18 moles) of the product of step C in a mixture of 96 ml of 37% formaldehyde and 144 ml of 90% formic acid. Distill almost to dryness at 100° C. under reduced pressure (about 100 mm). Dissolve the residue in a mixture of 500 ml of 1 N sodium hydroxide and 500 ml of ethyl ether with cooling and stirring. Separate the ether layer, dry over anhydrous sodium sulfate, and evaporate to give (S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine as a colorless solid. Obtain an analytically pure sample by crystallization from ethyl ether, m.p. 91°-92° C., [α]D26 =+47.3°(c=1, ethanol).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10]C=C2[C:3]=1[CH:4]=[CH:5]C=[C:7]2[CH2:12][OH:13].C[O:15][C:16]1C=C(C(F)(F)F)C=C[C:17]=1B(O)O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O.O1CCOCC1>[CH3:17][CH2:16][O:15][C:12]([CH3:7])=[O:13].[CH3:10][CH2:11][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OCc1cccc2c(Br)cccc12
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCCC
Temperature: 100 °C

Procedure:
(5-Bromonaphthalen-1-yl)methanol (150 mg), 2-methoxy-4-trifluoromethylphenylboronic acid (167 mg, 1.2 eq.), Pd(OAc)2 (14 mg, 0.1 eq.), Xphos (60 mg, 0.2 eq.), and K2CO3 (262 mg, 3 eq.) were combined in a flask with 5 mL dioxane and 1.6 mL H2O and degassed. Reaction mixture was then refluxed at 100° C. for 2 hours. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 35% EtOAc/hexane yielding product as a clear oil (55 mg, 86% yield). 1H NMR (400 MHz) (CDCl3) δ 8.24-8.22 (m, 1H), 7.64 (dd, J=8 Hz, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.45-7.37 (m, 4H), 7.29 (s, 1H), 5.22 (s, 2H), 3.76 (s, 3H). 13C NMR (100 MHz) (CDCl3) δ157.45, 136.48, 136.27, 133.49, 132.21, 132.16, 131.47, 131.29, 131.15, 127.29, 126.61, 125.77, 125.48, 125.41, 123.88, 122.79, 117.44, 117.40, 107.72, 63.94, 55.76.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[CH:17]([S:20](Cl)(=[O:22])=[O:21])([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([S:20]([NH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:22])=[O:21])([CH3:19])[CH3:18]
Reactant: COC(=O)C(C)(C)CN
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CNS(=O)(=O)C(C)C
Reaction time: 24 h
Yield: 21.2 %

Procedure:
To a solution of methyl 3-amino-2,2-dimethylpropanoate (200 mg, 1.53 mmol) and Et3N (0.64 mL, 4.59 mmol) in 2 mL CH2Cl2 was added isopropylsulfonyl chloride (0.34 mL, 3.05 mmol). The reaction was stirred for 24 h, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCl3, and chromatographed (1:1 hex:EtOAc) to provide methyl 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoate (77 mg, 21%) as a solid. 1H NMR (400 MHz, CDCl3), 4.78 (t, 1H, J=6.6 Hz), 3.68 (s, 3H), 3.20-3.11 (m, 3H), 1.36 (d, 6H, J=6.9 Hz), 1.23 (s, 6H). Methyl 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoate was hydrolyzed using aqueous NaOH to provide 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoic acid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:26])[CH:6]=[C:7]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[O:8]2>O1CCOCC1.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:7]2[O:8][C:9]3[C:4]([C:5](=[O:26])[CH:6]=2)=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=3)=[CH:22][CH:21]=1
Reactant: COc1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc(=O)c2c(OC)c1OC
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1cc2oc(-c3ccc(N)cc3)cc(=O)c2c(OC)c1OC
Yield: 76.4 %

Procedure:
A solution of the flavone 8 (0.07 g, 0.2 mmol) in dioxane (10 ml) was hydrogenated at 40 psi in the presence of 5% palladium on charcoal (20 mg) for 8 h and the catalyst was filtered off. Dioxane was removed from the filtrate under reduced pressure to give 10a (0.05 g, 87%). 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 3.94 (s, 3M), 3.95 (s, 3H), 6.45 (s, 1H), 6.71 (d, J=8.8 Hz, 2H), 6.75 (s, 1H), 7.65 (d, J=8.8 Hz, 2H).