Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][CH2:7][CH2:8][CH:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[N:10]1[CH2:15][CH2:14][C:13]2[S:16][CH:17]=[CH:18][C:12]=2[CH2:11]1)C.C(O)C.[OH-].[Na+]>O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:9]([N:10]1[CH2:15][CH2:14][C:13]2[S:16][CH:17]=[CH:18][C:12]=2[CH2:11]1)[CH2:8][CH2:7][CH2:6][C:5]([CH3:26])([CH3:27])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Yield: 55.7 %

Procedure:
6-(2-Chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid ethyl ester (2.5 g, 7.33 mmol) was added to a solution of ethanol (100 mL) and sodium hydroxide (1.8 g, 43.8 mmol) in water (32 mL). The mixture was heated to reflux for 6.5 hours. The solution was evaporated under reduced pressure and water (100 mL) was added to the residue. The water solution was extracted with ethyl acetate/heptane=1/10 (100 mL). The organic layers were discarded and the aqueous solution was adjusted with 10 N hydrochloric acid solution to pH=6. The product was extracted with dichloromethane (3×100 mL), which was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid (1.6 g, 68.7%) as a yellow oil. 6-(2-Chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid (3.97 g, 10.2 mmol) was dissolved in 36% HCl (0.95 mL) and water (59 mL). After stirring for 10 minutes, the aqueous solution was extracted with ethyl acetate/heptane (20/80, 110 mL). The organic extract was discarded and the aqueous fraction was freeze-dried to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid, hydrochloride salt (Compound Ic hydrochloride, 3.48 g, 79.8% yield, 99.7% purity by HPLC) as a white solid melting at 136-138° C. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.69 (s, 1H), 7.47-7.38 (m, 3H), 7.21 (d, 1H, J=3.9 Hz), 6.71 (d, 1H, J=3.9 Hz), 4.92 (m, 1H), 4.31-4.15 (m, 2H), 3.15-3.05 (m, 4H), 2.24-2.14 (m, 2H), 1.47-1.36 (m, 2H), 1.08-1.06 (m, 2H), 0.99 (s, 6H). (mixture of rotation isomers in NMR). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 181.10, 137.13, 132.80, 132.77, 132.04, 131.79, 130.48, 129.73, 128.73, 126.62, 126.14, 66.14, 51.52, 42.87, 40.92, 32.04, 25.88, 25.47, 23.45, 22.50. MS (FIA-ESI-TOF): Calculated for C21H26ClNO2S (MH)+: 392.1446; found 392.1453. CHN analysis: Calculated; 58.87 C, 6.35 H, 3.27 N, 16.55 Cl, 7.48 S, found; 57.80 C, 6.44 H, 3.15 N, 16.14 Cl, 7.15 S, Best fit for CHN Data: C21H27Cl2NO2S+0.55 H2O
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH:5]=[CH:4]1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:19][O:18][C:14]([CH2:15][CH2:16][N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH:5]=[CH:4]1)=[O:17]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)CCn1ccc2c(C=O)cccc21
Yield: 26.6 %

Procedure:
Sodium hydride (95%; 383 mg) was suspended in 10 ml of dimethylformamide under an argon gas atmosphere. To the suspension, there was dropwise added a solution of 2.00 g of indole-4-carbaldehyde in 10 ml of dimethylformamide with ice-cooling and stirring. After stirring the reaction mixture at room temperature for 25 minutes, it was again ice-cooled followed by dropwise addition of a solution of 1.33 g of methyl acrylate in 10 ml of dimethylformamide and stirring at room temperature for 19 hours. The reaction system was poured into 400 ml of a 10% ammonium chloride solution, followed by addition of a 2% HCl aqueous solution till the system became acidic and extraction with ethyl acetate (200 ml×2). After drying the extract over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to thus give 3.68 g of a pale yellow oily substance. This was dissolved in 40 ml of dimethylformamide, followed by addition of 2.70 g of methyl iodide and 2. 58 g of potassium carbonate and stirring the mixture at room temperature for 1.5 hour. The mixture was poured into 400 ml of a 10% ammonium chloride aqueous solution and extracted with ethyl acetate (200 ml×2). After drying the resulting extract over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure and the resulting crude product was purified by silica gel column chromatography to give 848 mg of 1-(2-methoxycarbonylethyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 27%.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>CN(C)P(N(C)C)(N(C)C)=O>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:22])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(NCCC2CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Cc1ccc(NCCC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 20.7 g. of 4-(2-cyclohexylethylamino)-phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 4-(2-cyclohexylethylamino)phenylacetate.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2snc(C)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
To a solution of 5-benzyl-3-methyl-6-propyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 8) (369 mg, 1.23 mmol) and sodium acetate (1 g) in acetic acid (5 mL) at 100° C., a solution of the bromine (318 mg, 2 mmol) in acetic acid (10 mL) was added dropwise over a period of 20 minutes. The reaction mixture was cooled after the addition and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×60 mL) and the organic layers were combined and washed with 2% sodium thiosulfate solution (60 mL), water (100 mL), brine (100 mL) and dried over Na2SO4. Concentration of the organic layer provided the pure 5-benzyl-6-(1-bromo-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one, (460 mg, 100%) as white crystalline solid. 1H NMR (300 MHz) δ 0.76 (t, 3H), 2.1-2.47 (m, 2H), 2.84 (s, 3H), 4.62 (t, 1H), 4.88 (d, 1H), 6.20 (d, 1H), 7.10-7.40 (m, 5H).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.[NH2:46][C@H:47]([C:55]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH2:60][S:61][CH3:62])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl>CN(C=O)C.CO>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([NH:46][C@H:47]([C:55]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH2:60][S:61][CH3:62])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:6])[CH3:3]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Yield: 87 %

Procedure:
In an analogous fashion as described in Step A, 7.56 g of Boc-DAla-OH, 5.06 g of HOSu, 8.25 g of DCC, 13.8 ml of DIEA and the HCl salt above were allowed to react in 100 ml of DMF to give 16.67 g (87% of Boc-DAla-Phe-Met-OCH3, m.p. 109°-110° C., [α]D24.5 =-19.73° (c, 1.00 in methanol).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:28]>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([NH2:28])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Agent: CC(=O)[O-]
Product: CCCc1nc2cnc3ccccc3c2n1CCC(N)=O
Yield: 86.3 %

Procedure:
Ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (5.0 g, 16 mmol) was treated with ammonium acetate (25.0 g) according to the method described in Part B of Example 9 to provide 3.9 g of 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide, which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.CN1CCCC1=O.[C:25](Cl)(=O)[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C1C=CN=CC=1.O>[C:26]([C:29]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:1]=1)([CH3:28])([CH3:27])[CH3:25]
Reactant: Nc1ncccc1C(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc2ncccc2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a mixture of 2-aminonicotinic acid (13.8 g, 100 mmol), 4-dimethylaminopyridine (1.2 g, 10 mmol), triethylamine (55.8 mL, 400 mmol) and N-methylpyrrolidone (140 mL, 42 mmol) was added pivaloyl chloride (24.1 g, 200 mmol) dropwise at 0° C., and after the drop wise addition was finished, which was stirred overnight at room temperature. To the reaction mixture was added water, extracted with toluene, and the organic layer was washed with water and saturated sodium chloride water. After the solution was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under a reduced pressure. To the residue was added n-heptane, which was suspended and stirred at 0° C., which was filtered, so as to obtain the title compound (16.6 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=[O:3])[CH3:2].C[C:20]1(C)[CH:22]([CH:23]=[C:24]([Cl:26])[Cl:25])[CH:21]1[C:27](OCC)=O>CCO.CCO.CCO.CCO.[Ti].C1(C)C=CC=CC=1>[CH3:20][C:21]1([CH3:27])[CH:22]([CH:23]=[C:24]([Cl:26])[Cl:25])[CH:2]1[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)=[O:3]
Reactant: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
A solution of 24.2 parts of m-phenoxybenzyl acetate, 28.4 parts of ethyl 2,2-dimethyl-3-(2'-,2'-dichlorovinyl)-cyclopropanecarboxylate (cis:trans ratio, 58/42) and 1.3 parts of tetraethyl titanate in 200 parts of dry toluene was stirred and heated at the boiling point. The azeotrope of ethyl acetate and toluene was removed by distillation at the rate of 50 parts per hour while maintaining the reaction volume by the addition of fresh toluene. After 4 hours 5 parts of water were added and precipitated titanium dioxide removed by filtration. The toluene was then removed by heating under reduced pressure and 0.3 mm. of mercury. Volatile fractions removed were 9.0 parts of unreacted ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropanecarboxylate, boiling at 75°-80° and 6.3 parts of unchanged m-phenoxybenzyl acetate, boiling at 125°-135°. There was obtained 26.85 parts of m-phenoxybenzyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylate (cis trans ratio, 44/56).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:42]1([NH2:45])[CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[CH:42]1([NH:45][CH2:2][C:3]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4[CH2:21][C:20](=[O:22])[NH:19][C:18]5[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=5[N:16]=4)[CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:5][N:4]=2)[CH2:44][CH2:43]1
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Reactant: NC1CC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CC(c2cccc(-c3ccnc(CNC4CC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with cyclopropylamine in DMF according to the general procedure of example 288. Obtained as a light brown solid (152 mg, 55%).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:37])C.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH:31]1([CH2:30][CH2:29][O:28][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:38])=[O:3])=[C:8]([CH3:37])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCC3CCCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(OCCC3CCCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (110 mg; 0.208 mmol) was dissolved in THF (2 mL), ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 105 mg. HPLC-MS: m/z: 500.1 (M)+; Rt: 3.20 min.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:22])([F:21])[C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=C(C(O)=O)[S:14][C:13]=2[CH:20]=1>CN(C=O)C>[F:22][C:8]([F:7])([F:21])[C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:1]([C:2]([Cl:4])=[O:3])[S:14][C:13]=2[CH:20]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (2.29 mmol, 0.20 mL) was added to a solution of 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (2.03 mmol, 500 mg) CH2Cl2 (15 mL). DMF (15 μL) was added and the resulting mixture was stirred for 4 h at room temperature. The resulting solution was concentrated to yield 6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl chloride, which was used in the next step without purification.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O.CN(C)C1C=CC=CC=1.N(Cl)Cl>>[Cl:19][C:7]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: ClNCl
Solvent: CN(C)c1ccccc1
Product: ClC1=Nc2ccccc2Sc2ccccc21
Temperature: 25 °C

Procedure:
A 2 liter round-bottom flask equipped with a magnetic stirring bar and reflux condenser with a nitrogen inlet was charged with 115.0 g (0.506 mole) of dibenzo[b,f][1,4]thiazepine-11(10-H)one, phosphorous oxychloride 700 ml (7.5 moles) and N,N-dimethylaniline 38.0 g (0.313 mole). The grey suspension was heated to gentle refluxing using a heating mantle. After 6 hours of heating, the resulting amber solution was allowed to cool to room temperature (from about 18°-25°C.) and was analyzed by thin-layer chromatography (TLC) using silica gel plates, developed with ether-hexane (1:1) and detected with ultraviolet light. Analysis revealed the desired imino chloride, Rf =0.70, and an absence of starting lactam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7](=O)[C:6]=2[CH:14]=1.[NH2:15][CH2:16]C(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:16][NH:15][C:7](=[O:8])[C:6]=2[CH:14]=1
Reactant: NCC(=O)O
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Solvent: CC(=O)O
Product: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
As illustrated in the scheme above, a mixture of 6-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (6.00 g, 28.4 mmol) and glycine (2.14 g, 28.4 mmol) in glacial acetic acid (72 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo. Water was added to the residue, and the mixture was cooled to 0° C. NaHCO3 was added to adjust the pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2Cl2 (3×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with Et2O, the solvent was removed by filtration, and the resulting solid was washed with additional Et2O to provide the title compound as a slightly yellow solid (5.657 g, 89%). 1H-NMR (CDCl3): δ 7.88 (d, J=2.5 Hz, 1H), 7.57 (br s, 1H), 7.53 (dd, J=2.6 Hz, J=8.7 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 3.84 (d, J=6.1 Hz, 2H), 3.39 (s, 3H). MS (ESI) (M+H)+=225.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C@H:13]([NH:15][S@@](C(C)(C)C)=O)[CH3:14])=[N:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C@H:13]([NH2:15])[CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccn(-c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccn(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of (R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml, 6.01 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO3 solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na2SO4) and concentrated to give product (0.556 g). LCMS (B) m/z 222.2 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:10]([O:11][CH2:12][CH:13]=[CH2:14])[C@@H:9]([O:15][CH2:16][CH:17]=[CH2:18])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][CH:28]=3)[CH:20]=2)[NH:7][C@@H:6]1[CH2:36][O:37][CH2:38][CH:39]=[CH2:40])[CH:2]=[CH2:3]>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([O:15]/[CH:16]=[CH:17]/[CH3:18])[C@@H:10]([O:11]/[CH:12]=[CH:13]/[CH3:14])[C@H:5]([O:4]/[CH:1]=[CH:2]/[CH3:3])[C@@H:6]([CH2:36][O:37]/[CH:38]=[CH:39]/[CH3:40])[NH:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH3:35])=[CH:31][CH:32]=1
Reactant: C=CCOC[C@H]1N[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCC=C)[C@@H](OCC=C)[C@@H]1OCC=C
Solvent: C1CCOC1
Product: C/C=C/OC[C@H]1N[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](O/C=C/C)[C@@H](O/C=C/C)[C@@H]1O/C=C/C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 0.1 %

Procedure:
Ir(COD)[PCH3Ph2]PF6 (8 mg, 30 mol %) in THF (0.3 ml) was stirred under an atmosphere of H2 until the color changed from red to pale yellow (˜5 minutes). Compound from Step F (19 mg, 0.033 mol) in THF (0.5 ml) was then added and the mixture stirred at room temperature for 45 minutes and then concentrated. Purification by silica gel chromatography (20% EtOAc/hexanes) afforded (2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-tris-[((E)-propenyl)oxy]-6-[((E)-propenyl)oxymethyl]-piperidine (15 mg, 0.026 mmol, 80%) as a colorless oil. MS (ES+) [M+H]+=568.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].Br.[Br:23][CH2:24][CH2:25][NH2:26].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[Br:23][CH2:24][CH2:25][NH:26][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: NCCBr
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCBr)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), (2-bromoethyl)amine hydrobromide (0.49 g), 1H-1,2,3-benzotriazol-1-ol (0.32 g), triethylamine (0.34 mL) and N,N-dimethylformamide (20 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.46 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.35 g, 37%) as colorless crystals. melting point 218-219° C. (decomposition).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[OH:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][NH-:55].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][NH-:55]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCNCCO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 118 mg of Z-Phe-His-OH, 78 mg of H-Leu-Val-2-(2-hydroxyethylamino)-ethyl amide, 42 mg of HOBt and 66 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B11). Rf (B11)=0.32.