Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>ClCCl>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:38][CH:39]=1)=[O:8]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Yield: 70.7 %

Procedure:
To 0.193 g (1.2 mmol) of 3-methylthiophene-2-carbonyl chloride in 3 ml of dichloromethane, cooled to 0° C., is added 209 μl of triethylamine. The mixture is stirred and 0.30 g (1 mmol) of 5-(4-aminobenzoyl)-5,6-dihydrophenanthridine is added. The mixture is stirred at room temperature overnight and then concentrated under vacuum. To the residue is added 30 ml of ethyl acetate and the mixture washed with 2 ml each of water 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried (Na2SO4) and the solvent removed to give 0.30 g of solid. The solid is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 150 mg of product as a yellow foam.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Cl[C:13]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>O1CCCC1.CN(C)C=O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(Cl)=CC(=O)N2CCOCC2)cc1OC
Reactant: OCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=CC(=O)N2CCOCC2)OCc2ccc(Cl)cc2)cc1OC
Temperature: 90 °C
Reaction time: 20 h

Procedure:
0.3 g (10 mmol) of sodium hydride (80%) are stirred in 15 ml of tetrahydrofuran and 1.42 g (10 mmol) of 4-chlorobenzyl alcohol in 10 ml of tetrahydrofuran are added dropwise. The resulting clear solution is evaporated to dryness and a solution of 2.02 g (6.5 mmol) of 3-chloro-3-(3,4-dimethoxyphenyl)-1-morpholin-4-ylprop-2-en-1-one in 25 ml of dimethylformamide is added. The mixture is stirred at 90° C. for 20 hours. The solvent is then evaporated and the residue shaken with toluene/water. The organic phase is separated, washed with water, dried and purified over a flash column with 40 g of silicagel. Elution is carried out with toluene containing 10, 20 and 30% of acetone. The fractions with the TLC Rf-values 0.45 and 0.31 (toluene/acetone 7:3) are collected and evaporated.
Reaction SMILES: I[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[S:20][C:19]3[N:21]=[CH:22][CH:23]=[N:24][C:18]=3[N:17](COC)[C:16]=2[CH:28]=1.IC1N=CN=C2C=1N=CN2CC1C=CC2SC3N=CC=NC=3NC=2C=1.[O:54]([CH2:62][C:63]([CH2:67][O:68][Si](C(C)(C)C)(C)C)([OH:66])[C:64]#[CH:65])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[N:24]1[C:18]2[NH:17][C:16]3[CH:28]=[C:12]([CH2:11][N:6]4[CH:5]=[N:4][C:3]5[C:7]4=[N:8][CH:9]=[N:10][C:2]=5[CH:62]([OH:54])[C:63]([CH2:67][OH:68])([OH:66])[C:64]#[CH:65])[CH:13]=[CH:14][C:15]=3[S:20][C:19]=2[N:21]=[CH:22][CH:23]=1
Reactant: C#CC(O)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reactant: COCN1c2cc(Cn3cnc4c(I)ncnc43)ccc2Sc2nccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Ic1ncnc2c1ncn2Cc1ccc2c(c1)Nc1nccnc1S2
Agent: [F-]
Product: C#CC(O)(CO)C(O)c1ncnc2c1ncn2Cc1ccc2c(c1)Nc1nccnc1S2

Procedure:
8-(6-Iodopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was treated by the same method as the one of Example 9 to thereby give 8-(6-iodopurin-9-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine. Next, this product was treated with bis(tert-butyldimethylsiloxymethyl)-2-propyn-1-ol by the same method as the one of Example 1417. The compound thus obtained was further treated with tetrabutylammonium fluoride in accordance with the method of Example 1386-3 to thereby give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][C:64]=1[Cl:65])[CH2:60]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:60][C:59]5[CH:62]=[CH:63][C:64]([Cl:65])=[C:57]([Cl:56])[CH:58]=5)=[CH:43][CH:44]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
(S)-2-{[(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (64 mg, 0.087 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.43 mmol) and potassium carbonate (0.43 mmol) were added. The mixture was stirred at room temperature for 8 hours and was poured onto ethyl acetate and 10% sodium carbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (24 mg, LC/MS: m/z 899).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC(C)([O-])C.[K+].[F:22][C:23]([F:40])([F:39])[C:24](=[O:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1>C(OCC)C.C1COCC1>[F:40][C:23]([F:22])([F:39])[C:24]([CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(CC(O)(Cc2cc3ccccc3[nH]2)C(F)(F)F)CCOc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a chilled (−78° C.) solution of 95.0 mg (0.72 mmol) of 2-methylindole in 10 mL of diethyl ether was added 710 μL (1.77 mmol) of a 2.5 M solution of n-BuLi in hexanes. After 5 minutes, 1.16 mL (1.16 mmol) of a 1 M solution of potassium tert-butoxide in THF was added and the mixture was warmed until a yellow precipitate formed. After 20 minutes, the reaction was cooled to −78° C. and 200 mg (0.72 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one (Example 1) in 2 mL of diethyl ether was added. The reaction stirred at −78° C. for 30 minutes and was then warmed to room temperature, quenched with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a PLC plate with hexanes-EtOAc (8:2) to afford a mixture of two diastereomers. The diastereomers were separated on a PLC plate (hexanes-CH2Cl2 (1:1)) to give two diastereomer. One was purified again by PLC plate (hexanes-CH2Cl2 (1:1)) to afford 20 mg of the first diastereomer (M+1=408) and the second was triturated with hexanes and the solid collected by filtration to afford 15 mg of the other diastereomer (M+1=408) of the title compound.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:11])[N:28]=2)=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCOc1cc(C#N)ccc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCOc1cc(-c2nc(-c3ccccc3Cl)nn2C)ccc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.50 g), 4-chloro-3-octyloxybenzonitrile (1.30 g), anhydrous iron (III) chloride (0.80 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.80 g of desired compound.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:9]([O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)O
Reactant: OCC1=CCCCC1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCC1=CCCCC1
Yield: 73 %

Procedure:
CHA was prepared by the above procedure from cyclohexenyl methanol (100 gram, 0.89 mole), acrylic acid (57.6 grams, 0.8 mole), p-toluenesulfonic acid (4 grams, 21 mmole), MEHQ (2 grams, 5.7 mmole), and toluene (500 ml) in a 1 liter reaction flask. The aqueous washes were performed with 400 ml portions each. The CHA was obtained in an amount of 96.5 grams (73% yield). The CHA was determined to have a boiling point in the range of 68-69° C. at a reduced pressure of 0.35 Torr.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:34]([O:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:21]#[N:22])[CH:23]=4)[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4O)no2)cc1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4OC(=O)C(C)(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.6 %

Procedure:
To a flask containing (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 (36 mg, 0.10 mmol) in DCM (1 mL) was added pyridine (24 μL, 0.3 mmol) and pivaloyl chloride (37 μL, 0.3 mmol). The reaction was stirred at room temperature for 4 days. The crude reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate, and purified by chromatography (EA/hexane) to give 23 mg (52%) of (R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl pivalate 14 as a white solid. LCMS-ESI (m/z) calculated for C26H27N3O4: 445.2, tR=4.7 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.2, 1H), 8.28 (dd, J=8.9, 2.2, 1H), 8.12-8.05 (m, 1H), 7.46 (d, J=7.4, 1H), 7.34 (t, J=7.6, 1H), 7.06 (d, J=9.0, 1H), 6.19 (dd, J=7.3, 4.6, 1H), 4.73 (hept, J=6.1, 1H), 3.44 (ddd, J=17.5, 8.7, 5.4, 1H), 3.24 (ddd, J=17.5, 8.6, 5.7, 1H), 2.56 (tdd, J=8.6, 7.4, 5.4, 1H), 2.12-1.99 (m, 1H), 1.41 (d, J=6.1, 6H), 1.14 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=O)=[C:4]1[CH3:23])[CH3:2].C(N1C2C(=CC=CC=2)C(C(C2C(C(O)=O)=NC=CC=2)=O)=C1C)C.[C:47]1([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:53]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[CH2:20][O:21]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Agent: CCn1c(C)c(C(=O)c2cccnc2C(=O)O)c2ccccc21
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccccc3)OCc3cccnc32)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture containing 4.5 g. of an isomer mixture comprising 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3-pyridinecarboxylic acid and 3-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-2-pyridinecarboxylic acid, 2.5 g. of diphenylamine and 30 ml. of acetic anhydride was stirred 6.5 hours, then treated with one ml. of pyridine and allowed to stand overnight. The reaction mixture was poured into 750 ml. of water and the resulting solid product was purified by column chromatography affording 7-(1-ethyl-2-methyl-3-indolyl)-7-(diphenylamino)furo[3,4-b]pyridine-(5(7H)-one as a light orange solid, m.p. 132.5°-136° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][N:11]=[CH:12][C:13]1[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1.[N+](C1OC(C=O)=CC=1)([O-])=O.N(C1SC2C=C([F:42])C=CC=2N=1)N>>[F:42][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([NH:10][N:11]=[CH:12][C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[S:1][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Reactant: NNc1nc2ccc(F)cc2s1
Agent: O=Cc1ccc([N+](=O)[O-])o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(F)cc3s2)o1

Procedure:
The compound 3k was prepared according procedure described for 3a by employing 5-nitrofuran aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-fluoro-benzothiazole (183 mg, 1 mmol) at 70° C. for 2 h (yield 230 mg, 75%).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=1.COC1C2N=C(NC(=O)C3C=CC=CC=3)SC=2C(C2C=CC=CC=2)=CC=1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26]([C:24]4[S:25][C:21]([CH3:20])=[CH:22][CH:23]=4)=[O:27])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Agent: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccccc3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 5-methyl-thiophene-2-carboxylic acid were reacted as described for N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide in WO01/9786. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as white powder. MS: m/e=405(M+H+). Following the general method of example 1 the compounds of examples 9 to 16 were prepared.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:27]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[N:30]=4)=[O:26])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Reactant: Nc1ccc(-c2cc(CO)n3ncnc(N)c23)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CO)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Yield: 7.1 %

Procedure:
A solution of [4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanol (170.0 mg, 0.67 mmol), phenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate (281.9 mg, 1.00 mmol), and triethylamine (0.46 mL, 1.33 mmol) in DMF (5 mL) was stirred at rt for 3 d. The crude reaction mixture was purified directly by HPLC using a gradient of 20-90% MeCN in water to yield 21.1 mg (7%) of the title compound. 1H-NMR (DMSO-d6) 9.89 (bs, 1 H), 9.72 (bs, 1 H), 8.05-7.98 (m, 2 H), 7.89 (s, 1 H), 7.57 (d, J=8.6 Hz, 2 H), 7.51-7.49 (m, 1 H), 7.40 (d, J=8.6 Hz, 1 H), 6.64 (s, 1 H), 5.19 (t, J=5.7 Hz, 1 H), 4.74 (d, J=5.6 Hz, 3 H); MS [M+H]+=444.1; LCMS RT=2.63 min.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([OH:21])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([O:21][C:1](=[O:4])[CH2:2][CH3:3])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])[CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:10][CH:9]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1C(=O)N(CCN(C)C(=O)OCc2ccccc2)c2ccc(Cl)cc2S[C@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
490 mg of propionyl chloride are added under ice-cooling to a solution of 2.15 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 20 ml of pyridine, and the mixture is stirred at room temperature for 3 hours. Then, the mixture is evaporated under reduced pressure. The residue is several times evaporated together with benzene, and ice-water is added to said residue. The aqueous mixture is extracted with ethyl acetate, and the extract is washed with water, 10% hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and water, successively. Said extract is dried and evaporated under reduced pressure to remove solvent. 2.19 g of (-)-cis-2-(4-methoxyphenyl)-3-propionyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as caramel.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:21]2[C:29]3[C:24](=[C:25]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)([CH2:19][CH3:20])[CH:17]=[O:18])=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:21]2[C:29]3[C:24](=[C:25]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)([CH:17]2[CH2:4][O:18]2)[CH2:19][CH3:20])=[CH:12][CH:11]=1
Reactant: C[S+](C)(C)=O
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(C1CO1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C

Procedure:
To a solution of NaH (41 mg, 0.764 mmol, 60% in oil) in DMSO (15 mL) at 0° C. was added trimethylsulfoxonium iodide (235 mg, 1.07 mmol) divided into several portions. The mixture was stirred at room temperature until the mixture became clear. To the solution of tert-butyl 1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indol-4-ylcarbamate (210 mg, 0.509 mmol), as described in Example 21 Step B, in THF (15 mL) was added the upper solution dropwise at 0° C. Then the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a colorless solid. LC/MS m/z=448.9[M+Na]+.
Reaction SMILES: CN([CH:4]=[O:5])C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][C:8]=1[F:14].C([O-])([O-])=O.[K+].[K+].CI>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:5][CH3:4])=[CH:9][C:8]=1[F:14]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>CS(C)=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1c(N)sc2ccc(C)cc12
Solvent: CS(C)=O
Product: COC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccc(C)cc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using methyl 2-amino-5-methylbenzo[b]thiophene-3-carboxylate, 2-fluoronitrobenzene and dimethyl sulfoxide, methyl 2-(2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate was obtained.