Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.Cl[C:32]([O:34][CH3:35])=[O:33]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:35][O:34][C:32]([NH:1][CH2:2][CH2:3][O:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:33]
Reactant: COC(=O)Cl
Reactant: CN(CCC(OCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCOC(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
To a 0° C. solution of tert-butyl 3-(2-aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (6 g, 4.11 mmol), Et3N (1.25 g, 12.3 mL), DMAP (0.25 g, 2.06 mmol) in dry CH2Cl2 (100 mL), methyl chloroformate (1.9 g, 20.6 mmol) in dry CH2Cl2 (30 mL) was added drop wise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. The reaction was quenched with water. The aqueous layer was extracted with CH2Cl2, the combined organic layers were washed with 10% citric acid and brine, then dried over Na2SO4, filtered and concentrated to the crude product. The crude product was purified by silica gel to afford tert-butyl 3-(2-(methoxycarbonyl)aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (600 mg, 40%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.83 (m, 2H), 2.80 (s, 3H), 3.31 (m, 7H), 3.65 (s, 3H), 4.13 (m, 1H), 7.26 (m, 4H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(OC2CCN(Cc3ccccc3)C2)cc1Cl
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2ccc(F)c(Cl)c2)C1
Reaction time: 48 h
Yield: 7.2 %

Procedure:
To a stirred solution of 19.6 g (0.2 mole) of phosgene in benzene (100 ml of 2 molar solution) under nitrogen gas was added dropwise 61.1 g (0.2 mole) of 1-benzyl-3-(3-chloro-4-fluorophenoxy)pyrrolidine in 100 ml of dry benzene. The mixture was stirred for about 21/2 days. The mixture was filtered to remove 8 g of starting compound as the hydrochloride salt and the filtrate was concentrated under reduced pressure. The resulting oil was triturated in succession with three 100 ml portions of 30/60 petroleum ether. The oil residue was again subjected to reduced pressure to remove petroleum ether. The oil residue, 46 g contained 5-10% benzyl chloride. The combined ether washes yielded 4 g of crystalline product on standing. Yield of product was 50 g (93%)., m.p. 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:9])=[CH:4][N:3]=1.[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>COCCOC>[NH2:8][C:7]1[CH:6]=[C:5]([NH:9][C:17](=[N:18][C:19]#[N:20])[O:16][C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: Nc1cnc(Cl)c(N)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: COCCOC
Product: N#CN=C(Nc1cnc(Cl)c(N)c1)Oc1ccccc1
Yield: 60.1 %

Procedure:
A stirred solution of the product from Step 1 (1.80 g, 0.0125 mol) in ethylene glycol dimethyl ether (DME, 50 ml) was treated with diphenylcyanocarbonimidate (3.0 g, 0.0126 mol) and kept under nitrogen at ambient temperature (25° C.) for 96 hours. The precipitate was collected by filtration, washed with DME and dried to give 2.16 g of the titled product, mp 219°-220° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:49]=[CH:48][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C@H:38]([C:41]([O:43]C(C)(C)C)=[O:42])[CH2:39][OH:40])=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C@H:38]([C:41]([OH:43])=[O:42])[CH2:39][OH:40])=[O:36])=[CH:48][CH:49]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CO)C(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CO)C(=O)O)cc2)cc1

Procedure:
The product from Example 258A was treated with 10% trifluoroacetic acid in dichloromethane (2 ml) for 5 hours at room temperature and concentrated in vacuo. Residue purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.04-12.95 (br.s, 1 H), 8.94 (s, 1 H), 8.00 (d, 1 H), 7.24 (m, 7 H), 6.88-7.09 (m, 7 H), 6.82 (d, 2 H), 4.29 (m, 1 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 3.95 (t, 2 H), 3.65 (m, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.32 (m, 2 H), 1.94 (m, 2 H); MS (ESI+) m/z 662 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27].[S:28]1[CH2:33][CH:32]=[C:31](B(O)O)[CH2:30][CH2:29]1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:28]1[CH2:29][CH:30]=[C:31]([C:6]2[CH:5]=[C:4]([F:16])[C:3]([C:17]3[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=3[F:27])=[C:2]([F:1])[CH:7]=2)[CH2:32][CH2:33]1
Reactant: OB(O)C1=CCSCC1
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OS(=O)(=O)C(F)(F)F)cc2F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3=CCSCC3)cc2F)n1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a degassed solution of methyl 6-(2,6-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)-5-fluoropicolinate (1.0 equiv.) and 3,6-dihydro-2H-thiopyran-4-ylboronic acid (1.5 equiv.) in DME/2M Na2CO3 (3/1, 0.10 M) was added PdCl2(dppf).CH2Cl2 adduct (0.10 equiv.). The reaction was heated to 90° C. in an oil bath for 15 min. The reaction mixture was partitioned with water and EtOAc; the organics were dried over MgSO4, filtered, and concentrated. The crude was purified via ISCO SiO2 chromatography. Pure fractions were combined and concentrated to yield methyl 6-(4-(3,6-dihydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinate in 60% yield. LC/MS=366.1 (M+H), Rt=1.00 min.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:35](=[O:45])[CH2:34]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(C)C=CC(S([N:55]=[N+:56]=[N-:57])(=O)=O)=CC=1.C[Si](Cl)(C)C>O1CCCC1>[N:55]([CH:34]1[CH:33]([C@@H:21]2[CH2:22][C@@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:24][N:20]2[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:35]1=[O:45])=[N+:56]=[N-:57]
Reactant: CC(C)(C)OC(=O)N1CC([C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)CC1=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC([C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)C(N=[N+]=[N-])C1=O
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
1.6M n-butyllithium (2.5 ml, 4 mmol) was dropwise added to a solution of diisopropylamine (0.64 ml, 4.6 mmol) in tetrahydrofuran (40 ml) under a nitrogen stream at -78° C., and the reaction solution was stirred for 45 minutes. A solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-tert-butoxycarbonyl-2-pyrrolidon-4-yl)pyrrolidine (986 mg, 2 mmol, compound of Reference Example 5-1) in tetrahydrofuran (10 ml) was dropwise added to this solution, and the mixture was stirred at the same temperature for 2 hours. Then, p-toluenesulfonyl azide (945 mg, 4.8 mmol) was added thereto, and the mixture was stirred further for 1 hour. Then, trimethylsilyl chloride (1.29 ml, 10 mmol) was added to this reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the residue, and then the mixture was extracted with methylene chloride (50 ml). The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, chloroform) to obtain (2S,4R)-2-(3-azido-N-tert-butoxycarbonyl-2-pyrrolidon-4-yl)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)pyrrolidine (720 mg, yield: 68.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.[OH:24][C:25]1[C:34]2[C:29](=[N:30][C:31]([CH3:35])=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[C:36]([OH:38])=[O:37].[OH-].[Na+:40]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[C:25](=[O:24])[C:26]([C:36]([O-:38])=[O:37])=[CH:27]1.[Na+:40]
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCCCn2cc(C(=O)[O-])c(=O)c3ccc(C)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir overnight at room temperature 1 gm. of the iodide prepared in Examples 2 or 3, 10 ml. DMF, 834 mg. 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid and 326 mg. sodium hydroxide in a reaction flask. Wash with water in methylene chloride. Elute on a coarse silica column with methylene chloride then 3% methanol/methylene chloride to isolate the title compound as the carboxylic acid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[S:16](Cl)(=[O:18])=[O:17]>C(O)C>[C:1]([NH:5][S:16]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:7]=1[Cl:6])[C:11]([OH:13])=[O:12])(=[O:17])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Temperature: 30 °C

Procedure:
To a mixture of 36.5 g (0.5 mol) of tert.-butylamine and 250 ml of ethanol were added 25.5 g (0.1 mol) of 4-chloro-3-chlorosulfonylbenzoic acid in small portions while stirring and cooling, the reaction temperature being maintained at about 30° C. After a dwelling time over night at room temperature, the solvent was distilled off, the residue was dissolved in about 200 ml of water, the pH was adjusted to 1 with concentrated HCl and the crystals were filtered off. Melting point: 250° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][CH:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[NH:24][C:25]([CH3:27])([CH3:28])[CH2:26]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(OCCBr)CC(C)(C)N1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Product: CC1(C)CC(OCCOc2ccc(-c3nc4ccccc4s3)cc2)CC(C)(C)N1

Procedure:
A hot solution of 16 g. of zinc, o-aminophenylmercaptide and 12.5 g. of p-hydroxybenzaldehyde in 1 l. of acetic acid was treated with hydrogen sulfide for two hours, filtered hot, diluted with an equal volume of water and cooled. 2-(p-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229° F.) was obtained. The 2-(p-hydroxyphenyl)benzothiazole was reacted with 4-(2-bromoethoxy)-2,2,6,6-tetramethylpiperidine as in Example 1 to produce 4-{2-[4-(2-benzothiazolyl)phenoxy]ethoxy}-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Oc1ccc(Cn2cccn2)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cn2cccn2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 60 g of 4-(1-pyrazolyl)methylphenol, 54.9 g of ethyl chloroacetate, 95.1 g of potassium carbonate, and 500 ml of anhydrous dimethylformamide was heated at 50° C. under stirring for 5 hours, followed by cooling to room temperature. The reaction mixture was poured into 1 liter of water, which was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with water, saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 4-(l-pyrazolyl)methylphenoxyacetate as an oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:29])[N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](=[O:28])[CH:11]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:31][C:32]([Mg]Cl)([CH3:35])[CH2:33][CH3:34].[Cl-].[NH4+]>C1COCC1>[CH3:31][C:32]([CH3:35])([CH2:33][CH3:34])[C:3](=[O:2])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](=[O:28])[CH:11]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:29]
Reactant: CCC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)N1CCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of 0.18 g (0.45 mmol) of 12a in anhydrous THF (2 mL) was added dropwise at −78° C. a 1.0M solution of 2.2 mL (2.20 mmol) of 1,1-dimethylpropyl magnesium chloride in THF, and the mixture was stirred for 3 hours at −78° C. The solution was poured over saturated ammonium chloride (50 mL) and extracted with EtOAc (3×100 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:3) to yield 0.14 g (76.5%) of 13a as a clear oil. TLC Rf=0.5 (EtOAc/Hexanes, 1:3) 1H NMR (CDCl3, 400 MHz): δ 0.82–0.90 (m, 3H); 1.12–1.33 (m, 6H); 1.59–1.79 (m, 7H); 2.00–2.20 (m, 3H); 2.40–2.70 (t, 5H); 3.41–3.52 (m, 2H); 4.63–4.64 (m, 1H); 7.12–7.29 (m, 10H); Anal. (C29H37NO3) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:31])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A degassed mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.167 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.042 g, 0.334 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.027 g, 0.033 mmol) and K2CO3 (0.046 g, 0.334 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative-TLC (eluting with 50% EtOAc in petroleum ether) to give 4-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.03 g, 43%) as a pale white solid. LC/MS (Table 1, Method 3) Rt=1.415 min.; MS m/z: 415 [M+H]+.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Si:23]([O:40][CH:41]([CH3:45])[C:42]([NH2:44])=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Si:23]([O:40][CH:41]([CH3:45])[C:42](=[S:10])[NH2:44])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=S
Temperature: 60 °C

Procedure:
A flask containing 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (387 mg, 0.957 mmol) was put under nitrogen atmosphere. 2-(tert-butyldiphenylsilyloxy)propanamide (622 mg, 1.899 mmol) dissolved in dry THF (10 ml) was added, temperature was raised to 60° C. and the mixture was allowed to react for 3 h. The solvent was evaporated and the product was extracted from DCM/water. The product was used in the next step without further purification. LC-MS: [M+1]=344.56.
Reaction SMILES: [CH:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][C:9]([CH3:30])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+]>>[N:33]([CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:9]([O:8][C:7]2[CH:31]=[CH:32][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)([CH3:30])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Product: CCOC(=O)C(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(C(C)C)cc1
Yield: 98.8 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)-3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methylpropionate (0.64 g), which is the product of Reference example 9(e), and sodium azide (0.27 g) and the reaction mixture was treated to afford the desired compound (0.56 g) as a syrup.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1[NH:23][C:24]2[CH:30]=[C:29]([O:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:28]=[CH:27][C:25]=2[N:26]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]([NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([O:31][S:32]([C:35]4[CH:36]=[CH:37][C:38]([NH:41][CH:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)=[CH:39][CH:40]=4)(=[O:33])=[O:34])=[CH:30][C:24]=3[N:23]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A solution of 3-phenyl propionic acid (9.7 mg) in dry dimethylformamide (0.6 ml) was treated with N-{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)methylene}-N-methylmethanaminium hexafluorophosphate N-oxide (21 mg) and diisopropylethylamine (12 μl). After stirring at ambient temperature for 30 minutes, 4-cyclopentylamino-benzenesulfonic acid 2-amino-3H-benzoimidazol-5-yl ester (20 mg) was added and the mixture stirred at room temperature for a further 3 hours. The solvent was removed under vacuo and the residue was purified by triggered LC/MS to give 4-cyclopentylamino-benzenesulfonic acid 2-(3-phenyl-propionylamino)-1H-benzoimidazol-5-yl ester as an off-white solid (11 mg). Mass spectrum: 505 [M+H]+; retention time=4.59 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][CH:18]=1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(2-Chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.30 g, 15.0 mmol), 4-iodophenol (3.96 g, 18.0 mmol), cesium carbonate (10.6 g, 30.0 mmol), and 15 mL of DMSO were added into a 50-mL round bottom flask. The flask was sealed with a septum and placed in a preheated oil bath at 130° C. After 3 h, the reaction was completed according to TLC and LC-MS analysis. The reaction was cooled to room temperature. Water was added into the reaction mixture until all product precipitated out of the solution. The solid was filtered, ground, and washed with water. The product was collected and dried in a vacuum oven overnight. The product, 4-(2-(4-iodophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine was obtained as a light brown solid. 1H NMR (Varian, 300 MHz, CDCl3): 8.40 (br s, 1H), 8.34 (d, J=4.1 Hz, 1H), 8.19 (dd, J=4.8, 2.2 Hz, 1H), 7.73 (m, 2H), 7.30 (dd, J=7.4, 4.8 Hz, 1H), 7.19 (m, 2H), 7.00 (m, 2H), 2.84 (d, J=4.8 Hz, 3H).
Reaction SMILES: Cl.Cl[C:3]1[N:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9][N:8]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:7]=2[N:24]=1.[NH2:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])=[CH:28][C:27]=1[O:38][CH3:39]>C(O)C.O>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:36]=[CH:37][C:26]([NH:25][C:3]3[N:4]=[CH:5][C:6]4[N:12]([CH3:13])[C:11](=[O:14])[C:10]([CH3:15])([CH3:16])[CH2:9][N:8]([C@@H:17]5[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]5)[C:7]=4[N:24]=3)=[C:27]([O:38][CH3:39])[CH:28]=2)[CH2:34][CH2:35]1
Reactant: CN1C(=O)C(C)(C)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CC2)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N([C@@H]1CCC(F)(F)C1)CC(C)(C)C(=O)N2C
Temperature: 85 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
Concentrated hydrochloric acid (52 μl) was added to a mixture of (R)-2-chloro-9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.29 mmol) and 4-amino-N-cyclopropyl-3-methoxybenzamide (90 mg, 0.44 mmol) in ethanol (1.4 mL) and water (5.2 mL). The reaction mixture was heated to 85° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (83 mg, 56% yield).