Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2C=C(C(O)=O)[N:12]=[C:11]2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OC1C=C(N2C=C(C(OCC)=O)N=C2C2C=CC(C)=CC=2)C=CC=1)C.[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(C)cc2)c1
Agent: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(C)cc2)n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1cccc(NC(=N)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambient temperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2.0 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 255.2 (M+1). Step B: Ethyl 1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate. To a mixture of 1.1 g (4.0 mmol) of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 5 to 40% ethyl acetate in hexanes gradient then 40% ethyl acetate in hexanes) gave the title compound as a yellow oil. LC/MS 351.2 (M+1). Step C: 1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid. To a solution of 0.75 g (2.1 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Next, hydrochloric acid (2.0 M) was added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 323.3 (M+1).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][CH:9]([C:11]1[N:22]([C@@H:23]2[CH2:28][O:27][C@@H:26]([CH2:29][C:30]#[N:31])[CH2:25][CH2:24]2)[C:14]2=[C:15]3[S:21][CH:20]=[CH:19][C:16]3=[N:17][CH:18]=[C:13]2[N:12]=1)[CH3:10].C(N(CC)CC)C.C(Cl)(=O)C>C(Cl)Cl>[C:30]([CH2:29][C@@H:26]1[O:27][CH2:28][C@@H:23]([N:22]2[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=[C:11]2[CH:9]([NH:8][C:3](=[O:5])[CH3:2])[CH3:10])[CH2:24][CH2:25]1)#[N:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(N)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)NC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a mixture of {(2R,5S)-5-[2-(1-aminoethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile trifluoroacetate (8.0 mg, 0.018 mmol) (Example 68) and triethylamine (12 μL, 0.088 mmol) in methylene chloride (0.15 mL) was added acetyl chloride (2.0 μL, 0.028 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated. The residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.5 mg (52%) of the desired product. LCMS calculated for C19H22N5O2S (M+H)+: m/z=384.1. Found: 384.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCCC2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(=O)OCc2ccccc2)C2CCCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopentylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: Cl.Cl.NC1CCN(C[C@H]2N3C4N(C(=O)C=CC=4C=CC3=O)C2)CC1.[Cl:25][C:26]1[C:35]([CH:36]=[O:37])=[N:34][C:33]2[NH:32][CH2:31][CH2:30][O:29][C:28]=2[CH:27]=1.[N+](C1C=CC=CN=1)([O-])=O.ClC1C(C=O)=NC2NC(=O)COC=2C=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[Cl:25][C:26]1[C:35]([CH2:36][OH:37])=[N:34][C:33]2[NH:32][CH2:31][CH2:30][O:29][C:28]=2[CH:27]=1
Reactant: O=Cc1nc2c(cc1Cl)OCCN2
Agent: Cl
Agent: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Product: OCc1nc2c(cc1Cl)OCCN2

Procedure:
To a 10 mL round-bottomed flask were added (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (45 mg, 0.134 mmol), 7-chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (prepared by (1) reduction of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (for a synthesis see WO2003064421 Example 15(c)) with LiAlH4 to give (7-chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methanol and then (2) oxidation with MnO2) (29.2 mg, 0.147 mmol), and NaHCO3 (100 mg, 1.190 mmol) in dichloromethane (DCM) (4 ml) and methanol (1 ml) to give a brown suspension. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction was stirred at rt overnight. After 15 h sodium triacetoxyborohydride (56.6 mg, 0.267 mmol) was added and the reaction was stirred at 25° C. under nitrogen for 4 h. The reaction mixture was adsorbed onto silica and purified using 0-10% MeOH/DCM (1% NH4OH) to give the title compound as a free base (9.4 mg, 0.019 mmol, 14.57% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[C:8]([C:14]([NH2:16])=O)=[N:9][C:10]([I:13])=[CH:11][N:12]=1.O.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[C:14]([C:8]1[C:7]([N:6]=[CH:18][N:19]([CH3:22])[CH3:20])=[N:12][CH:11]=[C:10]([I:13])[N:9]=1)#[N:16]
Reactant: NC(=O)c1nc(I)cnc1N
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1ncc(I)nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
13.59 ml (146 mmol) of phosphorus oxychloride is added drop by drop at 0° C. to 11 g (41.7 mmol) of a solution of 3-amino-6-iodopyrazine-2-carboxamide in 80 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight and then poured in a beaker containing ice and a little water. The pH is adjusted to 8 with 1 N soda solution; a precipitate is formed. The mixture is allowed to gradually return to room temperature and then the solid formed is filtered, rinsed with water and dried at 50° C. to yield 10.50 g of N′-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethyl formimidamide (84%) in the form of a beige solid.
Reaction SMILES: [C:1]1([N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:24]=3[N:25]=[C:26]([NH:28][C:29](=[O:32])[NH:30][CH3:31])[N:27]=2)[C@@H:16]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][C:41]1[CH:62]=[CH:61][C:44]([C:45](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)=[CH:43][CH:42]=1>N1C=CC=CC=1>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([O:22][CH2:21][C@H:20]2[O:23][C@@H:16]([N:15]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:32])[NH:30][CH3:31])[N:27]=[C:11]([O:10][C:8](=[O:9])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:12]=4[N:13]=[CH:14]3)[CH2:17][C@@H:18]2[OH:19])([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:44]2[CH:61]=[CH:62][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)=[CH:51][CH:50]=1
Reactant: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)O3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
The thus obtained 6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (643 mg, 1.24 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (21 mL), and 4,4′-dimethoxytrityl chloride (629 mg, 1.86 mmol) was added thereto. The mixture was stirred at room temperature for 3 hours. Then, the reaction was terminated by adding sodium bicarbonate water (5 mL) thereto. The reaction solution was extracted with ethyl acetate (100 mL)/sodium bicarbonate water (100 mL) once and then with ethyl acetate (100 mL)/brine (80 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with ethyl acetate/50% to 60% hexane containing 1% triethylamine to give 5′-O-(4,4′-dimethoxytrityl)-6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (889 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl.O.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (D15) (73 mg) and methyl 3-azetidinecarboxylate (138 mg) in methanol (10.00 mL) stirred at room temperature was added sodium acetate (74.7 mg) and AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. The residue was dissolved in dichloromethane (DCM) (10 mL), and sodium triacetoxyborohydride (116 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to give methyl 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D17) (18.21 mg). MS (ES): C26H30ClN3O3S requires 499. found 500.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1OS(C(F)(F)F)(=O)=O.[Si:27]([O:34][CH2:35][CH2:36][NH2:37])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.CCOC(C)=O>[C:30]([Si:27]([CH3:29])([CH3:28])[O:34][CH2:35][CH2:36][NH:37][C:7]1[CH:6]=[CH:5][C:4]([CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]2)=[CH:3][C:2]=1[F:1])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)CC1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCC(c2ccc(NCCO[Si](C)(C)C(C)(C)C)c(F)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(4-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetate (190 mg, 0.477 mmol), 2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (100 mg, 0.572 mmol), cesium carbonate (171 mg, 0.525 mmol), palladium acetate (11 mg, 0.048 mmol) and (X-PHOS) (23 mg, 0.048 mmol) in toluene (5 mL), under nitrogen, was heated in a sealed tube at 120° C. for 16 hours. The reaction was cooled, diluted into EtOAc, washed with water (2×), saturated aqueous brine, dried over sodium sulfate and concentrated to afford a dark oil. Chromatography (12 g silica gel column, 3-15% EtOAc:heptane) afforded methyl 2-(4-(4-(2-(tert-butyldimethyl-silyloxy)ethylamino)-3-fluorophenyl)-cyclohexyl)acetate as a light-yellow oil, 110 mg. 1H NMR (400 MHz, CDCl3); δ 7.2 (m, 1H), 6.95 (m, 1H), 6.8 (m, 1H), 3.8 (m, 2H), 3.64 (s, 3H), 3.2 (m, 2H), 2.5, 2.3 (m, 1H), 2.4, 2.2 (d, 2H), 1.85 (m, 2H), 1.64 (m, 5H), 1.4 (m, 1H), 1.1 (m, 1H), 0.88 (s, 9H), 0.06 (s, 6H). m/z=424.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>S(=O)(=O)(O)O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:5]3[C:4]([F:36])=[CH:3][C:2]([F:1])=[C:26]([NH:27][CH2:28][CH2:29][CH2:30][N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)[C:6]=3[C:7](=[O:25])[CH:8]=2)=[CH:12][C:13]=1[F:24]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCn4ccnc4)c(F)cc(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Product: Nc1ccc(-c2cc(=O)c3c(NCCCn4ccnc4)c(F)cc(F)c3o2)cc1F
Yield: 68 %

Procedure:
Substantially the same manner as that in Example 127 (4) was repeated except that 600 mg (1.21 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(imidazol-1-yl)propylamino]-4H-1-benzopyran-4-one was used, treatment with 20 mL of concentrated sulfuric acid was carried out and the resulting compound was recrystallized from methanol, to give 341 mg of Compound 129 (yield: 68%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2.[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3ccco3)cc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccco1)n2Cc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To a solution of the compound obtained in Example 8 (6) (150 mg) in N,N-dimethylformamide (6 ml), 60% sodium hydride (34.4 mg) was added at 0° C. under nitrogen atmosphere, and the mixture was stirred for 15 minutes. To the mixture was added 4-fluorobenzyl bromide (160 mg), followed by stirring for 2 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with toluene, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:chloroform=1:100) and silica gel preparative thin-layer chromatography (methanol:chloroform=1:100) to obtain 130 mg of the desired product as a pale brown oil.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH:5]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:30])[C:14]2[O:20][C:19]3[C:21]([Cl:26])=[CH:22][C:23]([NH2:25])=[CH:24][C:18]=3[CH2:17][S:16](=[O:28])(=[O:27])[C:15]=2[CH:29]=1)=[O:10])([CH3:7])[CH3:6].COC(C1C=C(C)C2OC3C(Cl)=CC(N)=CC=3CS(=O)(=O)C=2C=1)=O>C(O)=O>[CH:5]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:30])[C:14]2[O:20][C:19]3[C:21]([Cl:26])=[CH:22][C:23]([NH:25][CH:1]=[O:2])=[CH:24][C:18]=3[CH2:17][S:16](=[O:28])(=[O:27])[C:15]=2[CH:29]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: O=C[O-]
Reactant: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Agent: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Solvent: O=CO
Product: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Temperature: 0 °C

Procedure:
Sodium formate (0.040 g, 0.581 mmol) was added to a suspension of 2-amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid isopropyl ester (0.23 g, 0.581 mmol) [prepared by hydrolysis of compound of Example 1 and followed by esterification using isopropanol/H2SO4] in formic acid (20 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (100 mL). The solid precipitated was filtered, washed with water and dried. The crude product was crystallised with ethylacetate/pet. ether 60-80° C. to obtain the title compound. Yield: 0.12 g (48%); mp: 212-215° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.30 (d, 6H, OCH(CH3)2, 2.64 (s, 3H, CH3), 5.12 (m, 1H, OCH(CH3)2), 5.25 (s, 2H, CH2, trans minor isomer), 5.32 (s, 2H, CH2, cis major isomer), 7.33 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.30 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer); MS: m/e (ES−) 422 (M−1); analysis: C19H18ClNO6S requires C, 53.84; H, 4.28; N, 3.30; Cl, 8.36; S, 7.56. found: C, 54.27; H, 4.45; N, 2.94; Cl, 8.76; S, 7.77%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-].[Cs+].[CH2:35]([Sn](CCCC)(CCCC)C=C)[CH2:36]CC>O1CCOCC1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:32][C:26]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=1[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:35]=[CH2:36])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([C:21]([F:24])([F:22])[F:23])(=[O:19])=[O:20])[CH2:15][CH2:16]1
Reactant: O=S(=O)(NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Temperature: 100 °C
Yield: 271.5 %

Procedure:
Nitrogen was bubbled through a solution containing the product of Example 47 (1.0 g, 1.93 mmol), tri-t-butylphosphine (0.1 M in dioxane, 190 μl, 0.19 mmol), cesium fluoride (0.65 g, 4.28 mmol) and Pd2(dba)3 (0.10 g, 0.11 mmol) in dioxane (8 ml) in a sealed tube for 5 minutes. Tributyl(vinyl)tin (0.65 g, 2.05 mmol) was added and the mixture heated at 100° C. for 2 hours. This sequence was repeated on the same scale a further four times. All five reaction mixtures were combined and diluted with diethyl ether (50 ml) and filtered through a silica gel pad, evaporated in vacuo to give crude product which was chromatographed on silica eluting with 5-20% ethyl acetate/isohexane, then azeotroped with dichloromethane to give the desired product (2.67 g, 55%). 1H NMR (CDCl3, 360 MHz): 1.59-1.70 (2H, m), 2.02-2.06 (2H, m), 2.44 (2H, t, J=12.7 Hz), 2.61-2.65 (2H, m), 3.78 (1H, m), 5.47 (1H, d, J=10.9 Hz), 5.82 (1H, bd, J=7.8 Hz), 5.88 (1H, d, J=17.5 Hz), 6.68-6.87 (1H, m), 7.01-7.08 (2H, m), 7.32 (2H, d, J=8.3), 7.40 (2H, d, J=8.1), 10.10 (1H, s)
Reaction SMILES: [BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH3:36])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[S:28][C:29]=1[CH:30]=[O:31]>C1COCC1>[C:19]1([CH3:36])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][OH:31]
Reactant: Cc1ccccc1-c1c(C=O)sc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1c(CO)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Tetrabutylammonium borohydride (800 mg, 3.10 mmol) was added at RT to a solution of 3-o-tolylbenzo[b]thiophene-2-carbaldehyde (2.07 mmol) in THF (10 mL) and IMS (1 mL) and the mixture stirred at RT for 1 h. The reaction mixture was quenched by addition of MeOH and volatiles were removed under reduced pressure. The resulting residues was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) affording the title compound as an oil (432 mg, 82% over 2 steps). LCMS (Method C): RT 3.74 min [M-OH]+ 237.1.
Reaction SMILES: Br.NN=[CH:4][S:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21]CS(OC1C=CC(C)=CC=1)(=O)=O.C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][CH2:4][S:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: Cc1ccc(OS(=O)(=O)CCc2cccs2)cc1
Reactant: NN=CSCc1ccc(C(=O)O)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(CSCCc2cccs2)cc1
Temperature: 50 °C

Procedure:
A mixture containing 7.2 grams of 4-(((aminoiminomethyl)thio)methyl)benzoic acid monohydrobromide (0.025 mole), 7.1 grams of 4-methylphenyl 2-thiopheneethanesulfonate (0.025 mole), 50 ml of ethanol, 25 ml of 20% sodium hydroxide in water, and 25 ml of water were warmed to approximately 50° C. The orange solution obtained was mixed with 1 liter of ice-water and acidified with glacial acetic acid giving a pink solid. The pink solid was collected and recrystallized from acetonitrile to give the final product 4-(((2-(2-thienyl)ethyl)thio)methyl)benzoic acid as a pale pink solid having a melting point of 136°-137° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C:17]2[CH:25]=[CH:26][CH:27]=[C:15]([C:14]([F:13])([F:29])[F:28])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1

Procedure:
3-Amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech, 1.2 g, 6.97 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet Building Blocks, 1.57 g, 6.36 mmol) were treated with EDCI (Aldrich, 1.57 g, 6.36 mmol), HOBT (Aldrich, 1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, and purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.