Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH2:26]([SH:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH2:26]([S:38][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCS
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 150 °C

Procedure:
To a 3 liter three-necked flask equipped with stirrer, thermometer, nitrogen inlet and distillation set-up are charged 57.8 g (1 mole) of 5-chloro-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole, available from CIBA-GEIGY Corp. as TINUVIN® 327, 216.8 g (1.05 mole) of n-dodecyl mercaptan and 600 mL of N,N-dimethylformamide (DMF). Then 73.9 g (0.54 moles) of potassium carbonate and 2 g of potassium iodide are added and the mixture heated for 20 hrs at 150° C. under a nitrogen atmosphere. Any water which is liberated as a result of the reaction distills off as an azeotrope until the head-temperature reaches 132° C. After 20 hrs at 150° C. the starting 2H-benzotriazole is totally consumed. With partial vacuum at 80°-100° C., most of the DMF is distilled off. To the resulting oil is added at 80° C. 1 L of toluene and 500 mL of water. The aqueous phase is drained off. The toluene solution is washed twice more with 500 mL water containing 1 mL of acetic acid. The organic solution is freed from residual water by azeotropic distillation until a clear solution is obtained. Under partial vacuum all but about 100 mL of toluene is distilled off at 70° C. The residue is diluted at 60° C with 2 L of isopropanol and some product seeds are added. The product gradually crystallizes and the mixture is slowly cooled to 10° C. The product is filtered off and washed with 300 mL of isopropanol to yield 490.4 g (93.6% of theory) of the title compound, mp. 62°-64° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[CH:26]([N:29](CC)C(C)C)(C)C.CN>C(#N)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:29][CH3:26])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Agent: CN
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1nc(NC)n(C)c(=O)c1OCc1ccccc1
Reaction time: 0.5 h
Yield: 303.5 %

Procedure:
A solution of 2-methanesulfonyl-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.180 g, 3.22 mmol) in acetonitrile (20 ml) was treated at 25° C. with N,N-diisopropylethylamine (1.5 ml, 0.87 mmol) followed by 4.8 ml (9.6 mmol) of a 2M solution of methylamine in tetrahydrofuran. After 30 min, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate, 25:75) to give 0.838 g (82% yield) of the title ester as a clear syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.30 (3H, t, J=7.1 Hz, CH3), 3.04 (3H, d, J=5.1 Hz, NCH3), 3.42 (3H, s, NCH3), 4.32 (2H, q, J=7.1 Hz, OCH2), 4.58 (1H, broad q, NH), 5.07 (2H, s, OCH2), 7.3–7.37 (3H, m, aromatics), 7.47 (2H, m, aromatics). HRMS (FAB POS) calculated for C16H20N3O4 [M+H+]: 318.145381. found: 318.144860.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])([CH3:3])[CH3:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc(CN)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (3-isopropylphenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 531 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O>C1(C)C=CC=CC=1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:1]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]2=[O:18])=[CH:5]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12

Procedure:
A solution of tryptamine (3.04 g, 19.0 mmol) and phthalic anhydride (3.0 g, 20.0 mmol) in toluene (300 ml) was boiled under reflux for 12 h using a water separator. The solvent was removed i. vac. and the residue was recrystallized from methylene chloride/cyclohexane. Yield: 4.46 g (81%)
Reaction SMILES: [CH:1](OCC)=[O:2].Cl.[CH3:7][O:8][C:9](=[O:13])[CH2:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CCO>[CH3:7][O:8][C:9](=[O:13])[CH2:10][N:11]([CH:1]=[O:2])[CH3:12]
Reactant: CNCC(=O)OC
Reactant: CCOC=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)CN(C)C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Ethyl formate (850 mL) was added to sarcosine methyl ester HCl salt (205 g, 1.46 mol, grounded into powder prior to use), potassium carbonate (205 g, 1.48 mol), and EtOH (800 mL, stirred overnight at rt, and filtered. The filtrate was concentrated in a rotary evaporator during which the residue separated into two layers. The upper layer was separated and the lower layer was extracted with EA. Combined EA extracts and the upper layer were dried over MgSO4, filtered, and concentrated to yield 185 g (81%) of N-formyl sarcosine methyl ester which was used for the following reaction. NaH (60% oil suspension, 16.0 g, 0.4 mol) was carefully added in several portions in 1 h to a mixture of N-formyl sarcosine methyl ester (50 g, 0.34 mol) and ethyl formate (160 mL) cooled in an ice-water bath. The reaction mixture was stirred, the temperature raised to rt, and the stirring continued overnight. The reaction mixture was triturated twice with hexane (100 mL each time), the residue dissolved in EtOH (100 mL) and concentrated HCl (60 mL), and the reaction mixture stirred at 110° C. After 1 h, the reaction mixture was cooled, filtered, the residue washed with EtOH and the filtrate concentrated to yield a thick brown oil. The oil was added to 10% HOAc in water (200 mL), NH2CN (35 g) and sodium acetate (90 g), stirred at 95° C. After 1 h the reaction mixture was concentrated to ⅓ its original volume in a rotary evaporator and its pH adjusted to about 9 by addition of sodium carbonate. The reaction mixture was then extracted with EA (8×100 mL), the combined EA layers dried, filtered, and concentrated to yield a residue which was purified by recrystallization to yield 1-N-methyl-2-amino imidazole-5-carboxylic acid ethyl ester (“amino ester”).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C@H:4]([C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])[NH2:5].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[S:28][C:27]=2[CH:34]=1>>[ClH:22].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[CH:30]=[C:29]([C:31]([NH:5][C@@H:4]([C:6]([N:8]3[CH2:9][CH2:10][CH:11]([CH:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)[CH2:12][CH2:13]3)=[O:7])[CH2:3][N:2]([CH3:21])[CH3:1])=[O:32])[S:28][C:27]=2[CH:34]=1
Reactant: CN(C)C[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Product: CN(C)C[C@@H](NC(=O)c1cc2ccc(Cl)cc2s1)C(=O)N1CCC(C2CCN(C)CC2)CC1
Product: Cl

Procedure:
Prepared from 1-[β-dimethylamino-D-alaninyl]-4-(1-methylpiperidin-4-yl)piperidine and 6-chlorobenzo[b]thiophene-2-carboxylic acid using methods substantially equivalent to General Coupling Method 1. The HCl salt is prepared following General Salt Formation Method 1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl.CC(OC)(C)C>[CH3:21][O:22][CH2:23][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COCCl
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A solution of 2-(trifluoromethyl)phenol (12.0 g, 74.0 mmol) in dichloromethane (49 mL) was cooled to 5° C., and N,N-diisopropylethylamine (25.9 mL, 148 mmol) and methoxymethyl chloride (8.43 mL, 111 mmol) were added dropwise, keeping the internal temperature ≦15° C. After stirring for 15 min at ambient temperature, the reaction mixture was diluted with MTBE (250 mL) and washed with 2N HCl (2×50 mL), water (50 mL), 2N NaOH (2×30 mL), water (30 mL), and brine (30 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (14.1 g, 68.4 mmol, 92%) which was used without further purification. MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[CH2:15][CH2:14]1>CCOCC>[F:9][C:2]([F:1])([F:8])[C:3]([CH:15]1[C:16](=[O:23])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][CH2:14]1)=[O:5]
Reactant: O=C1CCOc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2ccccc2OCC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18.3 h
Yield: 64.6 %

Procedure:
Ethyl trifluoroacetate (9.78 g, 68 mmol) was placed in a 250 mL round bottom flask, and dissolved in ether (50 mL). To the stirred solution was added 25% sodium methoxide (15.11 g, 70 mmol), followed by 4-chromanone (10.07 g, 68 mmol) dissolved in ether (25 mL). The reaction was stirred at room temperature overnight (18.3 hours), poured into a separatory funnel and washed with 3N hydrochloric acid (20 mL) and with brine (20 mL), dried over MgSO4, concentrated in vacuo, and recrystallized from ether/hexane to give a yellow solid (10.72 g, 65%): mp 81°-83° C.; 1H NMR (CDCl3) 300 MHz 16.04 (br s, 1H) 7.84 (d, J=7.9 Hz, 1H) 7.51 (m, 1H) 7.09 (m, 1H) 6.98 (d, J=8.5 Hz, 1H) 5.08 (s, 2H); 19F NMR (CDCl3) 300 MHz: -72.56 (s). Mass spectrum: M+=244.
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.[BH3-]C#N.[Na+]>>[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH2:50][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:47]=[N:48][CH:49]=2)[O:38]1
Reactant: C1COCCN1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC1(C)OB(c2cncc(CN3CCOCC3)c2)OC1(C)C
Yield: 71.4 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), morpholine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 28 mg of crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine. The crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15.8 mg of the title compound (43%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([CH:18]=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1.[Br:35]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>II.C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([C:18]([Br:35])=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2cc(-c3ccc4ccc(-c5c6ccccc6cc6ccccc56)cc4c3)ccc2c1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2ccc3ccc(-c4ccc5ccccc5c4)cc3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Under the nitrogen atmosphere, 9-([2,2′-binaphthalen]-7-yl) anthracene (10.0 g) as the ninth intermediate compound, N-bromosuccinimide (NBS) (4.6 g), iodine (0.1 g), and THF (60 ml) were added to a flask and stirred overnight at room temperature. By adding an aqueous solution of sodium thiosulfate, the reaction was terminated. Liquid separation was performed by adding water and toluene. Subsequently, the solid obtained by distillation of the organic layer under reduced pressure was purified by silica gel column chromatography (solvent: toluene). The solid obtained by distillation of the solvent under reduced pressure was washed with heptane to give 9-([2,2′-binaphthalen]-7-yl)-10-bromoanthracene (11.0 g) as a tenth intermediate compound. The scheme is shown in the following “Reaction 15”.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]=CC=CC>>[CH3:12][CH:10]1[CH2:9][CH:8]=[CH:7][CH:3]2[C:4]([O:6][C:1](=[O:11])[CH:2]12)=[O:5]
Reactant: C=CC=CC
Reactant: O=C1OC(=O)c2ccccc21
Product: CC1CC=CC2C(=O)OC(=O)C12

Procedure:
The Diels-Alder adduct from phthalic anhydride and piperylene is hydrolyzed and partially oxidized as in Example 1 and further oxidized as in Examples 1 and 2. Similar results are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27](O)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.P(C#N)(OCC)(OCC)=O.[ClH:54]>CN(C)C=O.O.C(N(CC)CC)C>[ClH:54].[ClH:54].[CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([N:41]2[CH2:40][CH2:39][CH:38]([N:35]3[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]3)[CH2:43][CH2:42]2)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: CC(C)c1cc(C(=O)C=CC(=O)O)ccc1OCC(=O)Nc1nc2ccccc2s1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)C=CC(=O)N2CCC(N3CCN(C)CC3)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (0.97 g) in dimethylformamide (10 ml) are added dropwise 4-(4-methyl-1-piperazinyl)piperidine (0.65 g) and diethyl cyanophosphate (0.6 ml) at room temperature. To the mixture is added triethylamine (0.5 ml), and the mixture is stirred at room temperature for 10 minutes. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:1→10:1). The compound thus obtained is converted into a hydrochloride thereof in ethanol by a conventional method, and recrystallized from ethanol-diethyl ether to give 2-{2-isopropyl-4-[3-[4-(4-methyl-1-piperazinyl)-1-piperidinylcarbonyl]acryloyl]phenoxymethylcarbonylamino}benzothiazole dihydrochloride (0.45 g).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5]1)([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1(C)C=CC=CC=1>[CH:1]([CH:4]1[C:9](=[S:21])[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)C(C(C)C)Sc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=S)C(C(C)C)Sc2ccccc21

Procedure:
A mixture of methyl 3,4-dihydro-2-isopropyl-3-oxo-2H1,4-benzothiazine-4-acetate (50.0 g), phosphorus pentasulfide (79.5 g), and toluene (450 ml) was refluxed for 5.5 hours with stirring. After cooling, the insoluble matter was removed by filtration, and the solvent was evaporated off. To the residue isopropyl ether (300 ml) was added, and the insoluble matter was removed by filtration. The filtrate was concentrated, and the residue was crystallized from 2-propanol, to give methyl 3,4-dihydro-2- isopropyl-3-thioxo-2H-1,4-benzothiazine-4-acetate as crystals. Yield was 27.0 g (51.0%). Recrystallization from 2-propanol gave yellow prisms. mp 99°-100° C.
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:15]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:16]4[C:15]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:22])=[N:29][CH:28]=3)=[O:31])[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Reactant: c1ccc2c(c1)NCCc1ccsc1-2
Product: O=C(Nc1ccc(C(=O)N2CCc3ccsc3-c3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 12, 4,5-dihydro-6H-thieno[3,2-d][1]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].[CH3:5]OC(OC)N(C)C.[Br:13][C:14]1[CH:15]=[C:16]([NH:22][NH2:23])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>O1CCOCC1.C(O)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]([N:22]2[C:1]([CH3:2])=[N:4][CH:5]=[N:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CC(N)=O
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(NN)cc1Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(-n2ncnc2C)cc1Br
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
Acetamide (6.07 g, 0.103 mol) and dimethylformamide dimethyl acetal (20 ml, 0.15 mol) were stirred at 80° C. in dioxane (20 ml) for 2 hours. The reaction mixture was concentrated in vacuo, ether (50 ml) added, the solution refridgerated for 30 minutes then triturated to give an orange solid. The solid was collected under suction and the fitrate concentrated in vacuo to a red oil (4.63 g). A portion of this oil (1.20 g) was added to a solution of 3-bromo-4-methoxyphenylhydrazine (Desc. 14; 2.12 g, 9.77 mmol) in acetic acid (20 ml) and the mixture stirred at 90° C. for 2 hours. The reaction mixture was concentrated, treated with saturated sodium hydrogen carbonate (150 ml) and extracted with dichloromethane (2×50 ml). The combined extracts were dried (MgSO4), evaporated and the residue purified by flash chromatography, eluting with 1:1 then 3:1 ethyl acetate/hexane then ethyl acetate, to give the title compound (0.33 g, 13%); δH (250MHz, CDCl3) 2.51 (3H, s, 5'--CH3), 3.97 (3H, s, ArOCH3), 7.00 (1H, d J 8.7Hz, 6-H), 7.37 (1H, dd, J8.7, 2.6Hz, 5-H), 7.67 (1H, d, J 2.6Hz, 3-H), 7.92 (1H, s, 3'-H).
Reaction SMILES: Br[CH:2]1[CH2:28][O:27][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:15])[N:10]=[CH:9]3)=[C:4]2[CH:3]1[OH:29].[OH-:30].[Na+].[CH3:32]O>O1CCCC1>[OH:30][CH:2]1[CH2:28][O:27][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:15])[N:10]=[CH:9]3)=[C:4]2[CH:3]1[O:29][CH3:32]
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)C(O)C(Br)CO3)NC(=O)OCc1ccccc1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1c2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c23)OCC1O
Reaction time: 0.17 h

Procedure:
To a solution of the product from Example 11, Step A (0.46 g, 1.12 mmol) in tetrahydrofuran (50 mL) was added 2 N sodium hydroxide (6 mL). After stirring for 10 min, methanol (10 mL) was added and the mixture stirred for 1 h followed by evaporation to a residue, which was mixed with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to a residue, which was purified by chromatography (silica, 20 to 35% ethyl acetate in hexane) to give an oil (0.45 g): LC/MS (+APCI) m/z 378 (M+H).