Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[C:8]([OH:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=[CH2:2])[C:8]=1[OH:15]
Reactant: [Li]CCCC
Reactant: O=Cc1cccc(F)c1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(F)c1O
Temperature: 0 °C

Procedure:
To a round-bottomed flask containing a stir-bar were added, methyltriphenylphosphonium bromide (5.6 g, 16 mmol) and anhydrous THF (50 mL). The mixture was stirred until homogeneous and then cooled to 0° Celsius. The flask was then charged drop-wise with n-BuLi (6.85 mL, 2.5 M in hexanes). The resultant solution was stirred for 30 minutes and then transferred via cannula to a stirred mixture of 3-fluoro-2-hydroxybenzaldehyde (1 g, 7 mmol) and THF (28 mL) at rt under an argon atmosphere. The resultant mixture was stirred for 3 h before quenching with saturated NH4Cl (50 mL), diluting with water, and extracting with ether (3×100 mL). The combined ethereal extracts were dried over magnesium sulfate, filtered through a plug of silica gel, and then concentrated to dryness to provide the title compound that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.20 (m, 1H), 7.04-6.92 (m, 2H), 6.80 (m, 1H), 5.81 (dd, J=17.8, 1.3, 1H), 5.69 (s, 1H), 5.35 (dd, J=11.2, 1.3, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].COC1C=C([N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)C=C([N+]([O-])=O)C=1>CO>[N+:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)[CH:10]=1)[C:5]([OH:7])=[O:6])([O-:13])=[O:12]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: COc1cc(-n2cncn2)cc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(O)c1cc(-n2cncn2)cc([N+](=O)[O-])c1

Procedure:
3-Nitro-5-(1H-1,2,4-triazol-1-yl)benzoic acid was prepared from 3-bromo-5-nitrobenzoic acid following the procedure in Intermediate 2A. HPLC: Rt=1.12 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=235.07 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([C:37]1[C:46](F)=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[C:40]([NH:49][CH:50]1[CH2:52][CH2:51]1)[C:41]([CH3:48])=[N:42]2)=[O:36].CN(C=O)C>[NH4+].[Cl-]>[CH2:1]([O:8][CH2:9][CH:10]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:11](=[O:18])[CH:12]([CH2:34][C:35]([C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[C:40]([NH:49][CH:50]1[CH2:52][CH2:51]1)[C:41]([CH3:48])=[N:42]2)=[O:36])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC3CC3)nc12)C(=O)C(COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 25-mL round-bottomed flask was added (R)-ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (612) (0.78 g, 2.15 mmol), K2CO3 (0.67 g, 4.88 mmol), 2-bromo-1-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)ethanone (613) (0.62 g, 1.95 mmol), and DMF (4 mL). The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with sat NH4Cl (5 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (5 mL), dried over Na2SO4, and concentrated. Ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (364a) was obtained as a yellow solid and used without further purification. m/z (ESI, +ve) 605.3 (M+H)+. To a 20-mL glass tube was added ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (364a), crude from previous step, NH4OAc (0.45 g, 5.85 mmol), EtOH (6 mL), and AcOH (1.5 mL). The tube was sealed and heated at 60° C. for 5 h. The reaction mixture was cooled to RT and was concentrated to half of its volume. The mixture was diluted with EtOAc (10 mL) and water (5 mL). The organic extract was washed with NaOH (1 N, 5 mL), water (5 mL), brine (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10-30% EtOAc in hexanes to give ethyl 2-(2-(benzyloxy)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (364b) (0.48 g, 42% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.56 (br. s., 1H), 7.60 (dd, J=0.98, 8.02 Hz, 1H), 7.54 (d, J=1.96 Hz, 1H), 7.31-7.39 (m, 2H), 7.06 (br. s., 1H), 4.50 (d, J=5.48 Hz, 2H), 4.22 (q, J=7.04 Hz, 2H), 3.03 (br. s., 1H), 2.49 (s, 3H) 1.38 (s, 9H), 1.30 (t, J=7.04 Hz, 3H), 0.96-1.02 (m, 2H), 0.62-0.69 (m, 2H). m/z (ESI, +ve) 586.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.216 g, 0.649 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.164 g, 0.649 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.681 mmol). Then N-methylmorpholine (0.138 g, 1.36 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H36N4O7S2 568.2, found 569.5 [M+H+].
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C1(C)C=CC=CC=1.[C:25](Cl)(=[O:29])[C:26]([CH3:28])=[O:27].CO.C(Cl)Cl>CN(C=O)C.N1C=CC=CC=1>[C:25]([O:8][CH2:7][C@H:6]1[O:9][C@@H:1]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([OH:3])[C@@H:4]1[OH:5])(=[O:29])[C:26]([CH3:28])=[O:27]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Uridine (3.0 g, 12 mmol) was dried by toluene azeotrope under vacuum (3×), and then dissolved in DMF (20 mL) and pyridine (20 mL). The resultant solution was cooled to −10 degrees C. and 6.0 mL of pyruvyl chloride (produced in step A above) was added dropwise. The reaction mixture was stirred at room temperature under argon for 24 hours. Analysis by TLC (5% MeOH/CH2Cl2) showed the consumption of uridine. The reaction mixture was evaporated to dryness and partitioned between CH2Cl2 and aqueous sodium bicarbonate. The organic layer was washed with water, aqueous HCl (pH 3.0), and water; dried over sodium sulfate; —concentrated; and purified using flash chromatography (silicagel, 5% MeOH/CH2Cl2) to yield 1.4 g of uridine pyruvate, or 2′,3′,5′-tri-O-pyruvyluridine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:12](=[O:13])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 250 mL round-bottom flask under N2 was dissolved 2-amino-6-chlorobenzoic acid (11.69 g, 68 mmol) in 100 mL of 1,4-dioxane. The solution was cooled to 0° C. and to this solution was added phosgene (36 ml, 68 mmol) via a dropping funnel The reaction mixture was stirred for 24 hours allowing to warm to 23° C. (rt). The resulting white solid was filtered off and washed with 1,4-dioxane and Et2O. Yield=12.5 g, 93%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=[O:40])[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:20]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(O)(C)(C)C>[C:30]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=[C:28]([C:27]2[C:26](=[O:40])[C:25]([C:21]3[CH:20]=[C:19]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:24]=[CH:23][CH:22]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH:29]=1
Reactant: O=C(Cc1cccc(-c2ccccc2)c1)Cc1cccc(-c2ccccc2)c1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1C(c2cccc(-c3ccccc3)c2)=C(c2ccc(Br)cc2)C(c2ccc(Br)cc2)=C1c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a degassed solution of 2.84 g of 4,4′-dibromobenzil (7.73 mmol) and 2.80 g of 1,3-di(biphenyl-3-yl)propan-2-one (7, 7.73 mmol) in 30 ml of tert-butanol was added, at 80° C., a methanolic tetrabutylammonium hydroxide solution (1 M, 2.84 ml, 2.84 mmol). The reaction solution was stirred at 80° C. for 20 minutes and then stopped by adding water. Extraction was effected three times with dichloromethane, and the collected organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate before the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: hexane with 20% DCM) and gave 2.85 g of the tetraarylcyclopentadienone 8a as a violet wax (53%, 4.10 mmol). Elemental analysis measured: C 70.5; H 3.3% (calculated for C41H26Br2O: C, 70.9; H, 3.8%); 1H NMR (700 MHz, d8-THF) δ=7.51-7.49 (m, 4H, CH), 7.49-7.46 (m, 4H, CH), 7.41 (dd, J=8.2, 1.1 Hz, 4H, CH), 7.36 (t, J=7.8 Hz, 4H, CH), 7.32 (t, J=8.0 Hz, 2H, CH), 7.29-7.25 (m, 2H, CH), 7.25-7.22 (m, 2H, CH), 7.01-6.99 (m, 4H, CH); 13C NMR (175 MHz, d8-THF) δ=154.28, 141.92, 141.83, 133.58, 132.72, 132.34, 132.30, 132.12, 129.99, 129.89, 129.71, 129.53, 128.26, 127.80, 127.21, 126.74, 123.92; MS (FD, 8 kV): m/z (%): 693.8 (100) [M+] (calculated for C41H26Br2O: 694.0); Rf (hexane with 6% ethyl acetate)=0.47.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([Si:8]([CH2:17][CH3:18])([CH2:15][CH3:16])[C:9]#[C:10][CH2:11][CH2:12][CH2:13]I)[CH3:7].[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.[Cl-].[NH4+]>CCCCC.C(OCC)C>[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24]([CH2:13][CH2:12][CH2:11][C:10]#[C:9][Si:8]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:6][CH3:7])([OH:27])[CH2:23][CH2:22]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CC[Si](C#CCCCI)(CC)CC
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Product: CC[Si](C#CCCCC1(O)CCC(c2ccccc2)(N(C)C)CC1)(CC)CC
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A 1.7 M solution of tert-butyl lithium (18.4 mL, 31.2 mmol) in pentane was incorporated directly by cannula into a solution of triethyl-(5-iodopent-1-inyl)silane (4.81 g, 15.6 mmol) in anhydrous diethyl ether (150 mL) at −75° C. with argon, wherein the inside temperature was held between −70° C. and −75° C. After stirring for 2 h at −75° C. a solution of 4-(dimethylamino)-4-phenylcyclohexanone (3.39 g, 15.6 mmol, synthesis cf. WO2008009415, ketone unit Ket-10) in anhydrous diethyl ether (150 mL) was slowly added in drops, stirred for a further 30 min at −75° C. and the reaction solution was then heated to room temperature. The reaction mixture was then mixed with saturated ammonium chloride solution (100 mL), the phases were separated, the aqueous phase extracted with diethyl ether (3×50 mL), the combined organic phases washed with sodium chloride solution (50 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product was purified by means of flash chromatography (400 g, 20×7.5 cm) with ethyl acetate/methanol (9:1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+:29]>>[NH2:29][C:14](=[O:16])[CH:13]([NH:12][C:10]([C:7]1[CH:6]=[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:26])[F:25])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:11])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: [NH4+]
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Agent: [Cl-]
Product: C[C@H](Oc1cc(C(=O)NC(C(N)=O)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and ammonium chloride as starting materials and isolated (105 mg, 88%); MS (ESI, m/z): 388.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4]([N:20]2[CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CNC1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(N2CCC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1

Procedure:
(+)-(1S, 2R, 4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (340 mg, 1.20 mmol) and azetidine (98%, ALdrich, 1.0 mL) and methanol (6 mL) were maintained at 60° C. in a sealed tube for 18 hours. To the cooled solution was added 1N sodium hydroxide (1.2 mL). Volatiles were evaporated and the residue chromatographed on silica gel. Title compound was eluted with methanol: ethyl acetatel 15:85 as a white foam which solidified to white powder from methanol-acetonitrile (333 mg, 91%), mp 194°-195°; mass spectrum (Cl, CH4) 305 (M+1)- ; 1H-NMR (DMSO-d6)δ: 7.81 (s, 1, H8), 5.88 (br s, 2, NH2), 495-4.80 (m. 1, CH-N), 4.76 (d, J=3.9 Hz, 1, OH),4.66 (t, J=5.0 Hz, 1, CH2 -OH). 4.4-4.15(br m, 4, 2CH2N), 4.10-4.0 (m, 1, CHO), 3.6-3.4 (m, 2, CH2O), 2.5-1.9 (m, 6, methylene), 1.75-1.5 (m, 1, 1/2CH2):[α]20589 +10.1°,[α]20578 +10.7°, [α]20540 +11.9°, [α]20436 +18.3°, [α]20356 +25.2°(c=0.812, methanol).
Reaction SMILES: CC(OC(C)=O)=O.[CH3:8][S:9][C:10]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12][N:11]=1.C1C(=O)N([Cl:24])C(=O)C1>CC(O)=O>[Cl:24][C:13]1[C:14](=[O:16])[NH:15][C:10]([S:9][CH3:8])=[N:11][CH:12]=1
Reactant: CSc1nccc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSc1ncc(Cl)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
To a mixture of HOAc (500 mL) and Ac2O (10 mL) was added compound 2-(methylthio)pyrimidin-4(3H)-one (40 g, 0.28 mol). The resulting mixture was heated at 80° C. for 30 min to remove any moisture. Then NCS (49 g, 0.37 mol) was added at 50˜60° C. The resulting mixture was stirred at 50˜60° C. for 24 h. The mixture was then cooled to room temperature and was poured into ice-water (500 mL). The solid formed was collected and was treated with MeOH (100 mL) at reflux. Then the solid was filtered and dried on vacuum to give title compound (24 g, 48%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]=1[OH:18])[CH:2]=[CH2:3]>C(Cl)Cl.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]=[CH:2][CH3:3])=[C:5]([OH:18])[C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: C=CCc1ccc(Cl)c(-c2ccccc2C)c1O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: CC=Cc1ccc(Cl)c(-c2ccccc2C)c1O
Yield: 50.2 %

Procedure:
To a solution of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (2.0 g, 7.7 mmol) in methylene chloride (70 mL) was added dichlorobis(acetonitrile)palladium (II) (0.22 g, 0.84 mmol). The resulting mixture was refluxed overnight. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 5 to 20% ethyl acetate in hexanes provided 1.0 g (50%) of 6-chloro-2′-methyl-3-(prop-1-enyl)biphenyl-2-ol as a colorless oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([OH:13])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6]
Reactant: C=CC=CCCOc1ccc(C(=O)c2ccc(OCCC=CC=C)cc2)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: C=CC=CCCOc1ccc(C(O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
Compound 29 (5.96 g, 15.91 mmol) was dissolved in anhydrous THF (133 mL) with slight heating. Phenylmagnesium bromide (32 mL of a 1.0M solution in THF, 32 mmol) was added to the solution and the mixture was stirred at room temperature under argon for 5 hours and evaporated to dryness under vacuum. The residue was redissolved in dichloromethane and washed with a saturated solution of ammonium chloride, followed by water. The organic phase was dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel; hexane/CH2Cl2, 1/9) to yield 4.45 grams (62%) of compound 30 as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ2.45-2.56 (m, 4H), 3.98 (t, J=6.6 Hz, 4H), 5.01 (dd, J=1.5, 9.9 Hz, 2H), 5.14 (dd, J=1.5, 16.5 Hz, 2H), 5.73-5.87 (m, 2H), 6.12-6.41 (m, 4H), 6.25 (s, 1H), 6.84 (d, J=6.9 Hz, 4H), 7.06 (d, J=7.8 Hz, 4H), 7.15-7.33 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: NNc1ncccc1Cl
Yield: 89.4 %

Procedure:
To 30 ml of an n-butanol solution containing 7.0 g of 2,3-dichloropyridine were added 7.1 g of hydrazine monohydrate and 6.54 g of anhydrous potassium carbonate, and the mixture was heated under reflux for 17.5 hours. After cooling, the precipitate was collected by filtration to yield 6.07 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 100 ml (100 mM) of 1M borane-THF complex was added 25.13 g (100 mM) of 4-[N-(tert-butoxycarbonyl)aminomethyl]benzoic acid at 0° C. and the mixture was stirred at room temperature for 1.5 hours. The reaction was stopped by adding iced water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure and the resulting crystal crop was harvested by filtration and rinsed with hexane to provide the title compound as white crystals.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1.[Na].C(=O)([O-])[O-].[Na+].[Na+].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>ClCCl>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:8]2[C:7]3[CH:24]=[CH:25][C:4]([O:3][CH:2]([F:1])[F:26])=[CH:5][C:6]=3[N:10]=[C:9]2[S:11]([CH2:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=2)=[O:12])(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3n2S(=O)(=O)c2ccc(Cl)cc2)c1OC
Temperature: 4 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole, sodium salt sesquihydrate (432 mg, 1 mmole) was suspended in 30 ml of dichloromethane in the presence of anhydrous sodium carbonate (100 mg). 4-Chlorobenzenesulfonyl chloride (211 mg, 1 mmole) was added to the suspension and stirred at 4° C. overnight. The organic layer was separated by filtration and concentrated under reduced pressure. The residual solid was crystallized from dichloromethane-ethyl ether-heptane. 417 mg of 1-(4-chlorobenzenesulfonyl)-5-difluoromethoxy-2- [(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole was obtained. Yield 74.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1)=[O:5]
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccc2ccc(Cl)nc2n1
Yield: 94 %

Procedure:
2-Methyl-4-nitro-benzoyl chloride (16.1 g.) is added all at once to a suspension of 2-amino-7-chloro-1,8-naphthyridine (14.5 g.) in pyridine (161 cc.). The temperature rises to 40° C. The mixture is stirred for a further hour and water (640 cc.) is then added. The precipitate is filtered off and washed with water (225 cc.) and then with acetone (150 cc.). After recrystallisation from acetonitrile (1,600 cc.), 2-methyl-4-nitro-N-(7-chloro-1,8-naphthyridin-2-yl)-benzamide (26 g.) melting at 229° C is obtained.