Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34]C)[O:27]2)=[C:19]([NH:36][CH2:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:18]=1.[CH3:51][N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1.C(O)(=O)C>O1CCCC1>[C:39]1([CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:37][NH:36][C:19]2[N:18]=[C:17]([CH2:16][NH:15][CH:55]3[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][OH:34])[O:27]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CN1CCC(=O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCC(NCc2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (250 mg, 0.51 mmol) (example 1), 1-methyl-4-piperidinone (52 mg, 0.46 mmol) and acetic acid (30 mg, 0.5 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure and the residue partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml). The aqueous layer was discarded and the organic layer washed with water (10 ml), separated and the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0.5) increasing in polarity to (85:15:0.75) to give the title compound contaminated with example 1. The mixture was treated with diethyl ether (10 ml) and the solid filtered off. This solid was treated with diethyl ether (10 ml) and then filtered. The diethyl ether filtrates were combined and the solvent removed under reduced pressure to give the title compound (60 mg) as a solid. MS: 589 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19](=[O:20])[O:18][CH:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:11][CH:10]=1.[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])[CH:30]=1>C1(C)C=CC=CC=1.Cl.CCOCC>[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH:31]([C:17]2([C:21]([F:22])([F:24])[F:23])[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[C:19](=[O:20])[O:18]2)[CH2:32][N+:33]([O-:35])=[O:34])[CH:30]=1
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Reactant: O=[N+]([O-])C=Cc1csc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1OC(C(C[N+](=O)[O-])c2csc(Br)c2)(C(F)(F)F)N=C1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of triethylamine (0.30 g, 3 mmol) in toluene is added to a solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-3-oxazolin-5-one (10.0 g, 38 mmol) and 2-bromo-4-(2-nitrovinyl)thiophene (8.98 g, 32 mmol) in toluene at 0° C. The reaction mixture is warmed to room temperature and diluted with dilute hydrochloric acid and ether. The organic layer is separated, dried over MgSO4, concentrated in vacuo, diluted with hexane, stirred at reflux, cooled to room temperature and decanted to obtain a clear solution. The solution is concentrated in vacuo and chromatographed to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([O:22]CC)=O)=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([NH2:25])=[O:22])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Product: CCc1c(Sc2cc(Cl)cc(Cl)c2)c(C(N)=O)nn1CCO

Procedure:
A mixture of Example 46 (407 mg, 1.05 mmol) and 0.880 ammonia solution was heated at 90° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. The precipitate was filtered off and washed with water (5 ml) to afford the title compound (273 mg) as a white solid, m.p. 214–216° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C@@H:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][C@H:33]([CH3:32])[CH:34]([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](C)N
Product: CC(C)[C@@H](C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 13 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (R)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1,2) gave 30 mg (13%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:59][C:60]([NH2:64])([CH3:63])[CH2:61][NH2:62]>CN(C=O)C.ClCCl>[NH2:64][C:60]([CH3:63])([CH3:59])[CH2:61][NH:62][C:23]([C:22]1[N:5]2[CH:6]=[C:7]([CH3:21])[CH:8]=[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:24]
Reactant: CC(C)(N)CN
Reactant: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)NCC(C)(C)N)n2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
70 mg (0.20 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylic acid Example 265A, 84 mg (0.22 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) and 77 mg (0.60 mmol) of N,N-diisopropylethylamine were dissolved in 1.3 ml of DMF, and after 20 min at 0° C., 19.4 mg (0.22 mmol) of 2-methylpropane-1,2-diamine were added. The mixture was stirred at 0° C. for 45 min and then purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fraction obtained was taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 54 mg (64% of theory) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(OC([NH:39][CH2:40][CH2:41]O)=O)(C)(C)C.[Cl:43][C:44]1[CH:45]=[CH:46][C:47]2[O:51][N:50]=[C:49]([OH:52])[C:48]=2[CH:53]=1>O1CCCC1>[ClH:43].[NH2:39][CH2:40][CH2:41][O:52][C:49]1[C:48]2[CH:53]=[C:44]([Cl:43])[CH:45]=[CH:46][C:47]=2[O:51][N:50]=1
Reactant: Oc1noc2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cl
Product: NCCOc1noc2ccc(Cl)cc12
Yield: 186.9 %

Procedure:
To a solution of triphenylphosphine (0.87 g) in tetrahydrofuran (10 ml), was added diethyl azodicarboxylate (0.57 g) dropwise with stirring under ice cooling. The reaction mixture was stirred at the same temperature for 10 minutes. Then, 2-(N-t-butoxycarbonylamino)ethanol (0.48 g) and 5-chloro-3-hydroxy-1,2-benzisoxazole (0.51 g) were added to the reaction mixture successively and stirred under ice cooling for 10 minutes and at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent. The title compound (0.70 g) was obtained as colorless crystals by crystallization from isopropylether.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[CH3:15][N:16]([CH:18]=O)[CH3:17].CN(C(OC)OC)C>C(OC(=O)C)C>[CH3:15][N:16]([CH3:18])[CH:17]=[N:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:10][CH:9]=1)(=[O:12])=[O:13]
Reactant: CCC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a stirred solution of 4-propionylbenzenesulfonamide (prepared according to the procedure reported in Bioorganic Chemistry 1994, 22, 387-394), 2.2 g (10.3 mmol) in ethylacetate (20 ml) was added DMF (2.0 ml) followed by the addition of N,N-dimethylformamidedimethyl acetal (1.36 g, 1.51 ml, 11.36 mmol) in a dropwise manner at room temperature. The resulting mixture was stirred at room temperature for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain a solid product, which was washed with diisopropylether to obtain the title compound (2.6 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14]N(C3C=CC(OC)=CC=3)CN(C3C=CC(OC)=CC=3)[CH2:10]2)=[CH:5][CH:4]=1.ClC(OC(Cl)(Cl)Cl)=[O:33].[CH:39]([NH:43][C:44]([NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[S:45])([CH2:41][CH3:42])[CH3:40].[OH-].[Na+]>>[C:47]([N:46]=[C:44]1[N:43]([CH:39]([CH2:41][CH3:42])[CH3:40])[C:14](=[O:33])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][S:45]1)([CH3:48])([CH3:50])[CH3:49]
Reactant: CCC(C)NC(=S)NC(C)(C)C
Reactant: COc1ccc(N2CN(c3ccc(OC)cc3)CN(c3ccc(OC)cc3)C2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)N1C(=O)N(c2ccc(OC)cc2)CSC1=NC(C)(C)C
Yield: 76.9 %

Procedure:
Similarly, 2.7 g (0.0067 mole) of 1,3,5-tris(p-methoxyphenyl)-hexahydro-s-triazine, 2.0 g (0.01 mole) of trichloromethyl chloroformate, 3.8 g (0.02 mole) of 1-s-butyl-3-t-butylthiourea, and 16 ml of a 10% sodium hydroxide solution were used to obtain 1.8 g (26% yield) of 2-t-butylimino-3-s-butyl-5-(p-methoxyphenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 355) of the formula: ##STR156## as white crystals melting at 63° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33]Br)[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][O:15][C:3]2[C:2]([Br:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)c(Br)cc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Br)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Yield: 55.1 %

Procedure:
A mixture of 2 g (0.0073 mol) of 1-(5-bromo-2,4-dihydroxy-3-propylphenyl)-ethanone, 2.84 g (0.0073 mol) of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester and 1.52 g (0.011 mol) of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux for 20 hours. An additional 1 g of potassium carbonate was added and reflux was continued for a total of 35 hours. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to a oil which was dissolved in ethyl acetate and washed with 1N sodium hydroxide and sodium chloride solution. The crude product was purified by HPLC, eluting with 25% ethyl acetate in hexane to yield 2.33 g (55% yield) of [4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as a pale yellow oil.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH3:31])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([OH:29])=O)[CH2:8]2)=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:49][C@:50]1([C:55]([NH:57][S:58]([CH:61]2[CH2:63][CH2:62]2)(=[O:60])=[O:59])=[O:56])[CH2:52][C@H:51]1[CH:53]=[CH2:54].O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH3:31])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:14]([CH3:16])([CH3:17])[CH3:15])[C@H:9]([C:27](=[O:29])[NH:49][C@:50]3([C:55](=[O:56])[NH:57][S:58]([CH:61]4[CH2:63][CH2:62]4)(=[O:60])=[O:59])[CH2:52][C@H:51]3[CH:53]=[CH2:54])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid (26 mg, 0.049 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, p-toluenesulfonate salt, H2O (24.85 mg, 0.059 mmol), and HATU (28.1 mg, 0.074 mmol) in DCM (1 mL) was added N,N-diisopropylethylamine (0.026 mL, 0.148 mmol). The formed colorless slurry was stirred at room temperature overnight (it became light yellow solution). Diluted with DCM, quenched with 5% citric acid. The separated organic layer was washed with sat. sodium citrate and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by prep-HPLC to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(methylthio)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (18 mg, 0.024 mmol, 49.3% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 1.03-1.12 (m, 11H), 1.25 (d, J=3.36 Hz, 2H), 1.43-1.48 (m, 1H), 1.50 (s, 9H), 1.88 (dd, J=8.09, 5.34 Hz, 1H), 1.92 (s, 3H), 2.16-2.27 (m, 1H), 2.38 (t, J=11.29 Hz, 1H), 2.82 (dd, J=11.90, 6.10 Hz, 1H), 2.90-2.99 (m, 1H), 3.97-4.04 (m, 2H), 4.48-4.53 (m, 1H), 5.03 (d, J=10.99 Hz, 1H), 5.13 (d, J=10.68 Hz, 1H), 5.30 (d, J=17.40 Hz, 1H), 5.70-5.81 (m, 1H), 7.37 (t, J=7.02 Hz, 1H), 7.46 (t, J=7.48 Hz, 2H), 7.57-7.64 (m, 4H), 7.64-7.73 (m, 2H). LC-MS (retention time: 3.28 min, method B), MS m/z 739 (M+H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[CH2:12]Br.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:15]([N:22]1[CH2:12][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH3:11])[C:3]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(OC)c1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc2c1CN(Cc1ccccc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A mixture of 2-bromomethyl-3-methoxy-benzoic acid methyl ester (0.119 g, 0.5 mmol), benzylamine (0.065 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-4-methoxy-2,3-dihydro-isoindol-1-one (0.078 g, 61.4%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.83 (s, 3H), 4.21 (s, 2H), 4.69 (s, 2H), 6.98 (d, 1H), 7.25-7.51 (m, 7H). GC-MS: m/z 253 (M)+, 176 (M-77)+.
Reaction SMILES: C(OC([NH:8]CC(O)=O)=O)(C)(C)C.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NC[C@@H]1CCCN1CC.[CH:31](=[O:33])[CH3:32]>>[NH2:8][CH2:32][C:31]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:13])=[O:33]
Reactant: CNCc1ccccc1
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN1CCC[C@H]1CN
Product: CN(Cc1ccccc1)C(=O)CN

Procedure:
By using N-(t-butoxycarbonyl)glycine (1.0 g) and N-methylbenzylamine (736 μl) as a starting material, the title compound (740 mg) was obtained in the same manners as those of Reference Example 88, (1) and Reference Example 78, (3).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([O:16][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: OCCN1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(=O)OCCN1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-3-methylbutanoic acid (reported in international publication number WO 2008/083347 A1) (9.18 g, 36.5 mmol) in N,N-dimethylformamide (200 ml) was added N,N-carbonyldiimidazole (6.52 g, 40.2 mmol). The reaction mixture was stirred for 1 hour at room temperature followed by the addition of 1-(2-hydroxyethyl)piperidine (36.3 ml, 47.4 mmol) was added was added to the reaction mixture. The mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed two more times with water and dried over sodium sulfate. The dried organic layer was filtered and concentrated in vacuo. The crude product was purified column chromatography (0 to 10% methanol in dichloromethane) to give 9.45 g (71% yield) of 2-(piperidin-1-yl)ethyl 3-(benzyloxycarbonylamino)-3-methylbutanoate. 1H NMR (CDCl3) δ 7.44-7.26 (m, 5 H), 5.47 (s, 1 H), 5.06 (s, 2 H), 4.19 (t, J=6.0 Hz, 2 H), 2.69 (s, 2 H), 2.50 (t, J=6.0 Hz, 2 H), 2.40-2.32 (m, 4 H), 1.60-1.48 (m, 4 H) 1.46-1.36 (m, 8 H); MS (ESI+) calculated for C20H31N2O4: 362.23, Found: 363.2 (M+H+).
Reaction SMILES: [OH-].[Na+].C(NN1[N:11]=[C:10]([Cl:12])C=C(Cl)N1)C.[N:14]1[C:21]([Cl:22])=[N:20][C:18]([Cl:19])=[N:17][C:15]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].C[C:30]([CH3:32])=O>O>[CH2:30]([N:14]([C:15]1[N:11]=[C:10]([Cl:12])[N:20]=[C:18]([Cl:19])[N:17]=1)[C:15]1[N:14]=[C:21]([Cl:22])[N:20]=[C:18]([Cl:19])[N:17]=1)[CH3:32]
Reactant: CCNN1N=C(Cl)C=C(Cl)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(c1nc(Cl)nc(Cl)n1)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 0.4 g of sodium hydroxide in 4 ml of water was added dropwise with stirring over a period of 20 minutes to a solution of 1.93 g of 2-ethylamino-4,6-dichlorotriazine and 1.85 g of cyanuric chloride in 50 cc of acetone which had been cooled to 0°-5° C. Stirring was continued for 6 hours after all the sodium hydroxide solution had been added. The resulting solution was then neutralised with sodium carbonate and stirred into ice water. The precipitate was collected, dried and recrystallised from ligroin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:14])=[O:13].[N:35]([Si](C)(C)C)=[N+:36]=[N-:37].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[NH:37][N:36]=[N:35][N:33]=4)=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:13])=[O:14]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc2sc(Oc3cc(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)c3)nc2c1
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)cc(Oc2nc3cc(-c4nnn[nH]4)ccc3s2)c1)c1ccc(C(F)(F)F)cc1Cl
Temperature: 90 °C
Yield: 85.1 %

Procedure:
To a solution of 2-Chloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide (Example 286, 55 mg, 0.1 mmol) in 5 mL of toluene was added azidotrimethylsilane (Aldrich, 26 μL, 0.2 mmol) and dibutyltin oxide (Aldrich,3 mg, 0.01 mmol). The mixture was heated at 90° C. overnight till there was no starting material remained by TLC. Cooled to room temperature, 1N HCl and EtOAc was added. The mixture was extracted 3× with EtOAc (30 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography, eluted with 10% EtOAc/CH2Cl2 then 10% MeOH/CH2Cl2 to give 50 mg (85%) of product.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([NH:60][CH:61]=[O:62])[CH:54]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[C:38]([CH3:40])[CH:39]=2)[N:36]=[CH:35][C:34]([C:41]([NH2:43])=[O:42])=[C:33]3[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:63]OC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)N(C)CCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1>>[Si:1]([O:8][C@H:9]([C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([NH:60][CH:61]=[O:62])[CH:54]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:63])[C:19]([C:21]1[CH:22]=[C:23]([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[C:38]([CH3:40])[CH:39]=2)[N:36]=[CH:35][C:34]([C:41]([NH2:43])=[O:42])=[C:33]3[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=2)(=[O:28])=[O:29])[CH:24]=[CH:25][CH:26]=1)=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCC=O)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c(NC=O)c5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c(NC=O)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 167, using Intermediate 114 in place of Intermediate 113. ES/MS calcd. C47H60N6O8SSi 896.4. Found m/z=897 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:21]([OH:24])[OH:22])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
4-Bromobenzonitrile (20 g, 0.1099 m) was dissolved in tetrahydrofuran (240 mls) and hexane (80 mls) and the mixture treated with butyl-lithium (1.6M solution in hexane 80 mls, 0.1204m) at -100° C. The mixture was then stirred for five minutes before adding trimethyl borate (25 mls, 0.2178 m) at -100° C. The mixture was then allowed to warm to 20° C. before adding it to 100 mls of 10% HCL. The organic layer was then separated and the aqueous layer extracted twice with dichloromethane (100 mls). The organic layers were then combined and washed till acid free with water. The solution was then dried using magnesium sulphate and evaporated to give 4-cyanophenyl boronic acid as an off-white solid 93% yield) which was dried under vacuum.