Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (10.7 g), ethyl 2-butynoate (8.2 mL), tributylphosphine (7.0 mL) and tetrahydrofuran (400 mL) was stirred at 60° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95 to 100/0, volume ratio) to give the title compound (11.06 g, 80%) as an orange amorphous solid. MS 490 (MH+).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:49]=[CH:48][C:40]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:39][N:38]=1>>[C:44]([NH:43][C:41](=[O:42])[C:40]1[CH:48]=[CH:49][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[N:38][CH:39]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(C)NC(=O)c1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC(C)(C)C)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-N-tert-butylnicotinamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.898 min, m/z=472.2; 1H NMR (CDCl3) 1.08 (s, 3H), 1.15 (s, 3H), 1.34 (s, 9H), 1.49 (d, 3H), 2.16 (m, 3H), 2.19 (m, 1H), 2.32 (m, 1H), 2.42 (m, 3H), 2.79 (m, 1H), 4.32 (m, 2H), 5.66 (m, 1H), 6.55 (s, 1H), 6.76 (s, 1H), 6.98 (m, 2H), 7.19-7.29 (m, 7H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]>CO.[C].[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][C:15]=2[CH2:18][CH3:19])=[N:22][CH:23]=1
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{4-ethyl-3-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (2.78 g, 6.48 mmol) in methanol (70 mL) was added 10% palladium-carbon powder (640 mg), and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere of 3.0 pressure. Palladium-carbon powder was filtered off by celite filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate/tetrahydrofuran (10:1) to give the title compound (2.18 g, 84%) as a gray powder.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+]([O-])=O)[C:5](O)=[O:6].CC[N:16]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl[Sn]Cl>CCO.CN(C=O)C>[C:5]([NH2:16])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Product: NC(=O)c1ccccc1

Procedure:
In one embodiment, intermediate [1C] is prepared according to Scheme 5A. In this route, 3-fluoro-4-nitro benzoic acid [Q1] is converted to corresponding amide [R1] using R7R8NH, EDCI.HCl, HOBt, TEA, and DMF at about rt for about 10 h. Amide [R1] is then reduced using SnCl2 in EtOH at reflux for about 3-4 h to provide benzamide [S1]. Benzamide [S1] is then converted to urea [T1] using 4-bromophenylisocyanate in the presence of TEA and DCM at about rt. Conversion of urea [T1] to intermediate [1C] is accomplished using Pd(dppf)Cl2.DCM, bis(pinacolato)diboron, KOAc, and 1,4-dioxane, at about 110° C. for about 10 h.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].O=[C:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15]([C:14]1[C:13]([CH3:20])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:16])[CH3:19]
Reactant: COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-methoxybenzonitrile and ethyl 3-oxobutanoate as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.2 Hz, 3H), 2.55 (s, 3H), 3.96 (s, 3H), 4.30 (q, J=7.2 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 8.15 (s, 2H). MS 261 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:54])[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[C:31]3[C:23](=[CH:24][C:25]4[CH2:26][O:27][CH2:28][C:29]=4[CH:30]=3)[C@@H:22]([N:32]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=3)[C:33]3[N:34]=[N:35][N:36]([CH3:38])[N:37]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:13][CH2:12]1)C1C=CC=CC=1.[OH-].[Na+].Cl>CO.O>[F:53][C:50]([F:51])([F:52])[C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=1)[CH2:39][N:32]([C:33]1[N:34]=[N:35][N:36]([CH3:38])[N:37]=1)[C@@H:22]1[C:23]2=[CH:24][C:25]3[CH2:26][O:27][CH2:28][C:29]=3[CH:30]=[C:31]2[N:18]([CH2:17][CH:14]2[CH2:15][CH2:16][CH:11]([CH2:10][C:9]([OH:54])=[O:8])[CH2:12][CH2:13]2)[CH2:19][CH2:20][CH2:21]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CC3CCC(CC(=O)OCc4ccccc4)CC3)c3cc4c(cc32)COC4)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CC3CCC(CC(=O)O)CC3)c3cc4c(cc32)COC4)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-cyclohexyl)-acetic acid benzyl ester (0.07 mmol) in methanol (5 mL), add NaOH (3 mL of 5N) and heat to 60° C. for 2 h. After cooling to room temperature, dilute with water (20 mL) and neutralize using 5 M HCl. Extract the organic phase using ethyl acetate (3×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum, to provide the title compound as a colorless foam. MS (ES+): 667 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:29]1([C:35]([C:37]2[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.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>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:41]3[CH:42]=[C:37]([C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:36])[CH:38]=[CH:39][CH:40]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(On1ccc2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
To a solution of 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine (75 mg, 0.195 mmol, 1.0 eq) in DMF (1.2 mL), was added Pd(PPh3)4 (15 mg), 2.0 M K2CO3 (1.0 mL), and [3-(morpholin-4-ylcarbonyl)phenyl]boronic acid (1.8 eq, 0.351 mmol). The reaction mixture was microwaved at 90° C. for 30 minutes. The upper layer was removed with a pipette, filtered, and purified with preparation HPLC to give the product.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (363 mg, 0.94 mmol) (Intermediate #11) was dissolved in methanol (20 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (2.35 mL). The mixture was stirred at ambient temperature for 18 h and then volatiles were removed by evaporation under reduced pressure. The residue was dissolved in water (25 ml) and 2M HCl was added until the pH=4. The mixture was extracted with ethyl acetate (2×25 mL) and the combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and to evaporated to give the title product as a white solid. (300 mg 85%)
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH2:22][CH:23]([C:28]([O:30]C)=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CO.O1CCCC1>[CH3:27][O:26][C:24]([CH:23]([CH2:22][C:21]1[CH:32]=[CH:33][C:18]([O:17][CH2:16][CH2:15][O:14][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:34])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[CH:19][CH:20]=1)[C:28]([OH:30])=[O:29])=[O:25]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of dimethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylmalonate (0.50 g, 1.07 mmol) in a mixture of methanol (4.3 ml) and tetrahydrofuran (2.1 ml) at 0° C. is added a 2 mol/L aqueous solution of sodium hydroxide (0.59 ml, 1.18 mmol). The mixture is stirred for 2 hours at room temperature, and then the solvent was removed under a vacuum. The residue is dissolved in saturated aqueous sodium bicarbonate (10 ml) and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (0.45 g, 93%). HRMS calcd for C27H34O6: 454.5634. Found: 454.5636. MA calcd for C27H34O6: C, 71.34%; H, 7.54%. Found: C, 71.42%; H, 7.52%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(Cl)(=O)C.Br[CH2:10][N:11]1[CH2:18][N:17]([N+:19]([O-:21])=[O:20])[CH2:16][N:15]([N+:22]([O-:24])=[O:23])[CH2:14][N:13]([N+:25]([O-:27])=[O:26])[CH2:12]1>O.C(Cl)Cl>[N:1]([CH2:10][N:11]1[CH2:18][N:17]([N+:19]([O-:21])=[O:20])[CH2:16][N:15]([N+:22]([O-:24])=[O:23])[CH2:14][N:13]([N+:25]([O-:27])=[O:26])[CH2:12]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])N1CN(CBr)CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: O
Product: [N-]=[N+]=NCN1CN([N+](=O)[O-])CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of sodium azide (345 g, 5.45 mole) in water (1200 mL) was cooled to 5° C. and with good stirring a solution of acetyl chloride (286 g, 3.64 mol) in methylene chloride (640 mL) was added in 2.5 h, maintaining the temperature at 5° C. with external cooling. The upper aqueous layer was siphoned off and Compound 4 (101 g, 0.294 mol) was added. The mixture was stirred for 3 h at 10°-15° C. and filtered. The white solid was washed with methylene chloride (2×200 mL), water (200 mL), and ether (2×200 mL), and dried in a vacuum oven overnight at 40° C. The yield of Compound 5 was 71 g (79%), m.p. 130°-131° C. IR (KBr) 2080 cm-1 (N3), 1540 cm-1 (N--NO2). HPLC analysis showed a single peak. Analysis calculated for C5H10N10O6 : C,19.61: H,3.27; N,45.75. Found: C,19.99: H,3.28; N,44.99.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH2:8]([O:10][C:11]([C:13]1[C:18]([O:19][CH2:20][CH3:21])=[C:17]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:16]=[C:15]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[N:14]=1)=[O:12])[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]([C:13]1[C:18]([O:19][CH2:20][CH3:21])=[C:17]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:16]=[C:15]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:6]([NH2:5])=[O:7])=[CH:32][CH:33]=2)[N:14]=1)=[O:12])[CH3:9]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(NC(N)=O)cc2)nc(N2CCOCC2)c1OCC
Yield: 40 %

Procedure:
Trimethylsilyl isocyanate (0.1 ml, 5 eq.) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (60 mg, 1 eq.) in THF (2 ml) and the mixture was reacted to reflux overnight. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (26.2 mg, 40%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][OH:38])=[C:26]([C:28]([O:30]C(C)(C)C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[ClH:47].CO>C(Cl)Cl.CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][OH:38])=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[ClH:47]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCO)s1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxypropyl)thiazole-4-carboxylate (38E) (68 mg, 0.1 mmol) in DCM (2 mL) was added 2 mL of 2N HCl in ether. The mixture was stirred at rt overnight. MeOH (0.5 mL) was added to the mixture to dissolve the solid. The mixture was stirred at rt for another 2 hours. The reaction mixture was concentrated under reduced pressure to provide the desired product as an HCl salt: 1H NMR (300 MHz, DMSO-D6) δ ppm 8.03 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.41 (5H, m), 4.83 (2H, s), 3.73 (4H, t), 3.50 (2H, t), 3.41 (2H, t), 3.04 (4H, t), 1.69 (2H, m). MS (ESI(+)): m/z 495 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:19]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
2-Amino-4-chloro-5-nitrophenol (20.03 g, 0.133 mol), anhydrous potassium carbonate (20.0 g, 0.14 5mol) and tetrabutylammonium iodide (0.025 g, 0.068 mmol) were added to a dry 500 mL and covered with a septum. Freshly distilled and dry DMF (90 mL) was added, followed by benzyl bromide (13.8 mL, 0.116 mol) and the reaction was stirred overnight at room temperature under N2. The solution was then concentrated by removing the DMF on the Kugelrohr apparatus (50° C., 0.25 mm Hg). The oily residue was dissolved in CHCl3, suction filtered to remove the excess potassium carbonate and washed with water. The filtrate was concentrated on a rotovap until a yellow solid remained. The crude product was first purified using a chloroform silica gel column. The product, 2-benzyloxy-5-chloro-4-nitroaniline, was collected from the first few fractions. The product was then purified on a silica gel column using 20% ethyl acetate/hexane eluent. The product was collected, concentrated on a rotovap and dried under high-vacuum to give 2-benzyloxy-5-chloro-4-nitroaniline as a yellow solid (13.44 g, 48.34 mmol, 56%). Mp 98-103° C. TLC (20% ethyl acetate/hexane) Rf=0.38; 500 MHz 1H-NMR (CDCl3) 7.68 (s, 1H), 7.42 (m, 5H), 6.72 (s, 1H), 5.13 (s, 2H), 4.52 (s br, 2H); IR (nujol) 3469, 3378, 3355, 1613, 1567, 1522, 1483, 1464, 1377, 1217, 1126; EI-MS m/z (relative intensity) 278 (M+, 11). Accurate mass for C13H11N2O3Cl: calcd. 278.0458, obsd. 278.0468.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C@H:17]4[CH2:18][CH2:19][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]4)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=3)[N:3]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, 6-chloro-N-{trans-4-[(dimethylamino)methyl]-cyclohexyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (56 mg, 0.14 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (43 mg, 51%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.90 (s, 1H), 8.51 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.14 (s, 2H), 5.76-5.66 (m, 1H), 3.38 (s, 3H), 3.09 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.50-2.43 (m, 2H), 2.08-1.96 (m, 3H), 1.74-1.64 (m, 2H), 1.47-1.35 (m, 2H). ESI MS m/z 523 [M+H]+; HPLC>99% (AUC), tR=10.04 min.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9]([C:11]2[CH2:12][N:13]([C:17](OC(C)(C)C)=O)[CH2:14][CH2:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:25]1[C:30](N)=CC=CN=1.COC(C1CN(C(OC(C)(C)C)=O)CCC=1)=O.C[Al](C)C>C(Cl)Cl>[CH2:17]([N:13]1[CH2:14][CH2:15][CH2:16][C:11]2([C:2]3[C:7](=[CH:6][CH:5]=[CH:4][N:3]=3)[NH:8][C:9]2=[O:10])[CH2:12]1)[CH2:25][CH3:30]
Reactant: Nc1cccnc1Br
Reactant: CC(C)(C)OC(=O)N1CCC=C(C(=O)Nc2cccnc2Br)C1
Agent: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCN1CCCC2(C1)C(=O)Nc1cccnc12
Yield: 85 %

Procedure:
tert-Butyl 3-[(2-bromo-3-pyridyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate. 2-Bromo-3-pyridineamine (3.0 g, 17.3 mmol) and 1,2,5,6-tetrahydro-1,3-pyridinedicarboxylic acid 1-tert-butyl ester 3-methyl ester (5.05 g, 20.8 mmol) were dissolved in DCM (80 ml). To the solution trimethylaluminium (26 mmol, 2M solution) was slowly added at 0° C. The mixture was refluxed overnight. Work-up and purification on silica gel using 60% ethyl acetate in heptane as an eluent gave 5.65 g (85%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>CN(C=O)C>[Cl:17][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:20]=[C:19]([CH3:21])[CH:18]=2)[CH2:2][O:25][C:22](=[O:24])[CH3:23])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=1
Reactant: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a stirred solution of 4-(3-bromomethyl-5-methyl-phenoxy)-2,6-dichloro-5-isopropyl-pyrimidine (14.4 g, 36.9 mmol) in anhydrous DMF (50 ml), was added sodium acetate (6.05 g, 73.8 mmol) and the mixture was stirred in an oil bath (90˜100° C.) for overnight. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:9 to 1:4)) to afford 10 g (73%) of a white solid. m.p. 76-77° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.12 (3H, s), 2.39 (3H, s), 3.58 (1H, m), 5.09 (2H, s), 6.88 (1H, s), 6.93 (1H, s), 7.08 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Product: Nc1ccccc1Sc1cc([N+](=O)[O-])ccc1C(=O)O

Procedure:
9-Cyano-6H-dibenz[b,e][1,4]thiepin (IIa) may be prepared according to the following general reaction scheme: ##STR6## wherein R2 anc R3 are as previously defined, by treating an appropriately substituted (R2 and/or R3) o-aminothiophenol with 2-chloro-4-nitrobenzoic acid in the presence of cuprous oxide to form the corresponding 2-(o-aminophenylthio)-4-nitrobenzoic acid which then is suspended in water, acidified with sulfuric acid, treated with sodium nitrite followed by sodium fluoroborate to obtain the diazonium fluoroborate which is heated in 50% sulfuric acid to obtain the corresponding 2-(o-hydroxyphenylthio)-4-nitrobenzoic acid. The acid product is treated with borane in tetrahydrofuran to form the corresponding 2-(o-hydroxyphenylthio)-4-nitrobenzyl alcohol which is cyclized in the presence of dicyclohexylcarbodiimide (DCC) to form the corresponding 9-nitro-6H-dibenz[b,e][1,4]oxathiepin. The nitro group then is reduced to the 9-amino compound with stannous chloride and the amine is treated with sodium nitrite followed by a mixture of cuprous cyanide and potassium cyanide to obtain the desired 9-cyano-6H-dibenz[b,e][1,4]oxathiepin of formula IIa.