Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:62]OC(NC(C1C=CC=CC=1C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=6[CH3:62])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1C
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1C
Yield: 50 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-o-tolyl-acetic acid (0.03 g, 0.12 mmol, 1.75 equiv.) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 50%) as a white powder. LCMS-ESI+: calc'd for C48H52N8O6: 836.4 (M+). Found: 837.4 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of diastereomers) 7.61-8.00 (m, 16H), 7.18-7.41 (m, 12H), 7.10 (s, 2H), 5.28-5.63 (m, 10H), 4.36 (t, 2H), 3.72-3.86 (m, 4H), 3.68 (s, 6H), 3.66 (s, 6H), 2.79-3.07 (m, 8H), 2.50 (s, 3H), 2.44 (s, 3H), 2.38 (m, 4H), 1.86-2.28 (m, 8H), 0.88-0.94 (m, 12H).
Reaction SMILES: [CH2:1]([S:8][CH:9]1[NH:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]2[CH:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]2=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CC(SCc2ccccc2)N1
Reactant: O=S(=O)(OCCCCCCCCCc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(SCc2ccccc2)N1CCCCCCCCCc1ccccc1
Yield: 68 %

Procedure:
Treatment of 4-benzylthio-2-oxo-azetidine (1.35 g) in THF with NaH (0.18 g) followed by 9-phenylnonyltriflate (2.8 g) gave the title compound as a colourless oil, 1.9 g, 68% yield. 1H NMR δ (CDCl3) 1.2-1.7 (14H, m, 7×CH2), 2.60 (2H, t, J=8 Hz, CH2Ar), 2.8, 3.2 (each 2H, m, H3 +NCH2), 3.76 (2H, s, SCH2), 4.59 (1H, m, H4), 7.15-7.35 (10H, m, Ph--H)
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCCl
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCN(C)C)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were stirred in dry dimethylformamide at 80° and 2-dimethylaminoethyl chloride hydrochloride (2.9 g, 20 mmol) added. The mixture was stirred for 2 hours, poured into water and extracted with ether. The extracts were dried and evaporated. Chromatography (silica gel, 3-5% methanolic ammonia in dichloromethane) and recrystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-dimethylaminoethoxy)quinoline (1.0 g, 34%), m.p. 88°-90°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]([CH:13]([O:15][C:16]([C:18]1[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22]=1[CH2:23][CH3:24])=[O:17])[CH3:14])#[N:12].C([O-])(=O)C.[Na+]>ClC(Cl)C>[C:11]([CH:13]([O:15][C:16]([C:18]1[NH:19][C:20]([CH:8]=[O:9])=[C:21]([CH2:25][CH3:26])[C:22]=1[CH2:23][CH3:24])=[O:17])[CH3:14])#[N:12]
Reactant: CCc1c[nH]c(C(=O)OC(C)C#N)c1CC
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCc1c(C=O)[nH]c(C(=O)OC(C)C#N)c1CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
15 ml (160 mmol) phosphorous oxychloride were added dropwise for a period of 20 minutes to 13 ml (160 mmol) dimethylformamide at a temperature of 0° C. The mixture was stirred for another 15 minutes at room temperature and then 100 ml of dichloroethane were added. A solution of 10 g (40 mmol) of compound 11 in 50 ml dichloroethane were added dropwise. After gentle reflux for 15 minutes, the mixture was poured into 500 ml of a 4-molar sodium acetate solution and heated for a further 15 minutes. The organic layer was separated, washed with water and yielded after evaporation of the solvent, a brown oil, which was directly used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15](CC)[CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]=2[CH:36]=1.O.NN.[CH2:40](O)[CH3:41]>>[NH2:17][CH:16]([CH2:40][CH3:41])[CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:36][C:6]=3[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: CCC(CN1C(=O)c2ccccc2C1=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CCO
Agent: NN
Solvent: O
Product: CCC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 21, N-[2-(8-chloro-6-phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepin-1-yl)butyl]-phthalimide in ethanol is warmed with hydrazine hydrate to give 1-(2-aminobutyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:18]1([NH2:27])[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[N:18]1([NH:27][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Reactant: Nn1ccc2ncccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (0.45 mmol) in EtOAc (8 mL) is added to a stirred solution of pyrrolo[3,2-b]pyridin-1-ylamine (0.45 mmol) and potassium carbonate (0.45 mmol) in EtOAc (4 mL) and H2O (8 mL) at rt and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 20-80% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid pyrrolo[3,2-b]pyridin-1-ylamide (38 mg, 24%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.76 (s, 3H), 6.59 (m, H) 7.07-7.64 (m, 4H), 7.96 (m, H), 8.23 (m, H), 8.32 (m, 2H), 9.12 (s, H), 10.01 (br, N—H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].[CH2:13](O)[CH2:14][OH:15].O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]1[O:15][CH2:14][CH2:13][O:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C=O
Reactant: OCCO
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccccc1C1OCCO1

Procedure:
2-Hydroxygenzaldehyde (10 g) was dissolved in acetic anhydride (30 ml) and pyridine (30 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting precipitate was recovered by filtration. The precipitate was dissolved in chloroform (100 ml), washed with water, dried and evaporated to give 2-acetoxybenzaldehyde. To a solution of 2-acetoxy-benzaldehyde (13 g) and ethyleneglycol (10 ml) in benzene (80 ml) was added Amberlist 15 (Rohm and Haas Co.) (3 g) and followed by refluxing for 5 hours. Water generated during refluxing was removed as an azeotropic mixture. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, and then with water, and dried and evaporated. The residue was distilled under reduced pressure to collect a fraction distilled out at 115°-125° C./4 mmHg to give 10 g of 2-(2-acetoxyphenyl)-1,3-dioxolan. To a solution of 2-(2-acetoxy-phenyl)-1,3-dioxolan (19.6 g) in dichloromethane (50 ml), bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g) was added and treated as in Example 10 to give 4.2 g of crystalline 1-[α-(2-hydroxyethoxy)-2-acetoxybenzyl]-5-fluorouracil.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C1COCC1>[CH3:13][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][O:14]1
Reactant: CC(=O)c1ccccc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccccc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of acetophenone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:24])[O:21][C@@H:20]([CH2:22][NH2:23])[CH2:19][O:18]1.C(O)C>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][C@H:20]3[CH2:19][O:18][C:17]([CH3:24])([CH3:16])[O:21]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CN)O1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: ClCCl
Solvent: CCO
Product: CC1(C)OC[C@H](CNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)O1
Yield: 96.1 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (11.00 g, 38.26 mmol) was reacted with (S)-2,2-dimethyl-[1,3]dioxolane-4-methanamine (5.81 g, 57.4 mmol) according to the method described in Part A of Examples 125-135. When the reaction was complete, it was concentrated under reduced pressure, and the residue was stirred with water (100 mL). The resulting solid was isolated by filtration, mixed twice with ethanol and concentrated under reduced pressure. The solid was then triturated with diethyl ether, isolated by filtration, and dissolved in dichloromethane. An insoluble impurity was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 14.05 g of (S)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.O.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1cc(Br)cc(OC)c1N
Temperature: 80 °C

Procedure:
5-Bromo-1,3-dimethoxy-2-nitro-benzene (2.6 g, 10 mmol) was dissolved in 200 mL of methanol and 40 mL of water was added, followed by 2.5 g of Fe powder and 2.5 g of ammonium chloride. The mixture was heated to reflux at 80° C. for 2 hours and the cooled reaction mixture was filtered and washed with methanol. The filtrate was evaporated under reduce pressure to give the crude product, which was used for next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:37][NH2:38]>C(O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])([C:10]2[NH:38][N:37]=[C:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(=O)Cc2ccccc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(c2cc(Cc3ccccc3)n[nH]2)CC1
Temperature: 85 °C
Yield: 71.5 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-1,3-dioxobut-1-yl)-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (343 mg, 0.68 mmol) from Step G in ethanol (7 mL) was added hydrazine hydrate (0.040 mL, 0.82 mmol). The reaction was heated at 85° C. for 3 h and was then concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to afford the title product (243 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32][C:33]1[N:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:36]=[CH:35][N:34]=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:35]2[CH:36]=[CH:37][N:38]=[C:33]([S:32][CH3:31])[N:34]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2nc(-c3ccnc(SC)n3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 50.2 %

Procedure:
To a teflon-lined septum-sealed Schlenk tube, a mixture of Compound 1e (213 mg; 0.49 mmol), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (Compound 7a) (305 mg; 0.735 mmol) and tetrakis-(triphenylphosphine)palladium(0) (57 mg; 0.049 mmol) in dioxane (1.0 mL) was irradiated in a Microwave reactor at 150° C. for 30 min. The resultant mixture was diluted with EtOAc, and washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 7b (129 mg; 50% yield). 1H-NMR (400 MHz, CDCl3): δ 8.48-8.50 (m, 1H), 8.08-8.12 (m, 1H), 7.54-7.57 (m, 1H), 7.16-7.23 (m, 2H), 6.96-7.01 (m, 2H), 6.27 (br. s, 0.7H), 5.18 (br, 0.3H), 4.25-4.36 (m, 1H), 3.88 (s, 3H), 3.24-3.59 (m, 4H), 2.68 (s, 3H), 1.79-2.16 (m, 4H), 1.44-1.54 (m, 9H); MS: m/z 525.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([Cl:20])[C:10]=2[Cl:21])=[O:8])=[CH:5][CH:4]=1.I>CCOCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([Cl:20])[C:10]=2[Cl:21])=[O:8])=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)c2ccc(OCC(=O)O)c(Cl)c2Cl)cc1
Agent: I
Solvent: CCOCC
Product: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 4-(4-methoxybenzoyl)-2,3-dichlorophenoxy acetic acid (3.55 g., 0.01 mole) and hydriodic acid (7.5 ml.) was refluxed at 180°-190° C. for 4 hours. The reaction mixture was concentrated and the solid residue was stirred with water for one hour and filtered. The solid obtained was dissolved in ether and dried (MgSO4). The solvent was removed in vacuo and the residue was recrystallized from ether - pet. ether mixture to give 2 g. (60%) of the product; m.p. 218°-219° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:17]=1[CH2:18][CH2:19][C:20]([OH:22])=O)=[O:15])=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(N(CC)CC)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:17]=1[CH2:18][CH2:19][C:20]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:22])=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.00 g (0.015 mol) of 2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamic acid and 2.57 g (0.016 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature for 1.5 hours in 60 ml of tetrahydrofuran and 2.22 g (0.016 mol) of ethyl glycinate hydrochloride and 2.2 ml (0.016 mol) of triethylamine are added thereto. After stirring at room temperature for 1 hour, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetate-ethanol (9:1) and crystallization from methanol-ether gives ethyl N-[2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamoyl]glycinate as white crystals with melting point 94°-96°.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([N:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].I([O-])(=O)(=O)=[O:30].[Na+]>CO.O>[CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([N:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16](=[O:30])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCSc3ccccc32)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCS(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
To a suspension of 4-[4-(2-methylbenzoylamino)benzoyl]-3,4-dihydro-2H-1,4-benzothiazine (0.5 g) in methanol (15 ml) is added an aqueous solution of sodium metaperiodate (0.28 g) in water (2.5 ml) and the mixture is stirred at room temperature for 72 hours. Water is added to the reaction solution and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=100:1), and recrystallized from dichloromethane/diethyl ether to give 4-[4-(2-methylbenzoylamino)benzoyl]-3,4-dihydro-2H-1,4-benzothiazin-1-oxide (0.34 g) as white powder, m.p. 240°-241° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=4)[CH2:6][CH2:5]3)[CH:8]=[N:9][C:10]=2[CH:15]=1
Reactant: Nc1ccc2c(c1)ncn2C1CCNCC1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(c1)ncn2C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1

Procedure:
1-(Piperidin-4-yl)-1H-benzo[d]imidazol-5-amine, 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.82 mmol, 1.624 g) and potassium carbonate (9.64 mmol, 1.332 g) were combined and stirred in acetonitrile (25 mL) at room temperature for 3 days. The reaction mixture was concentrated under vacuum, taken up in dichloromethane, washed with water and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (594 mg). MS (ESI) m/z 473.0 [M+H]+
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Cl:9][CH:10]([Cl:24])[CH:11]=[CH:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-])=O)[CH:15]=1>CO.O>[Cl:24][C:10]([Cl:9])=[CH:11][CH2:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([NH2:21])[CH:15]=1
Reactant: Nc1ccc(SC=CC(Cl)Cl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(SCC=C(Cl)Cl)cc1N

Procedure:
In 340 cc of a 1:1 (by volume) mixture of methanol-water containing 43 g of Na2S2O4 were suspended 34.4 millimols of 4-[(3,3-dichloropropenyl)-thio]-2-nitroaniline. The reduction of the nitro-group was achieved in very short times (10-15 min.) as was ascertained by thin-layer chromatography. After the reduction was completed, the methanol and part of the water were removed under vacuum thereby obtaining an oily suspension which was then extracted with chloroform. The organic extracts, after drying on anhydrous Na2SO4, and evaporation of the solvent under vacuum, yielded, with practically quantitative yields, the raw diamine (an intensely colored thick oil) which was directly used for the successive stage.