Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C[Si](C)(C)Cl.C(N(CC)CC)C.[C:27](OC=O)(=[O:29])C.C(O)=O.C(Cl)(=O)C.Cl.C(N(CC)CC)C.C(C(CCCC)C([O-])=O)C.[Na+:58]>O1CCCC1.CCOCC>[CH:27]([NH:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C@@H:5]([C:10]([O-:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12)=[O:29].[Na+:58]
Reactant: CC(=O)OC=O
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O=CO
Product: CC1(C)S[C@@H]2[C@H](NC=O)C(=O)N2[C@H]1C(=O)[O-]
Reaction time: 1 h

Procedure:
A mixture of (3S,5R,6R)-6-amino-2,2-dimethylpenam-3-carboxylic acid (6APA, 2.2056 g., 10.21 mmole), trimethyl chlorosilane (2.615 ml., 20.42 mmole), and triethylamine (2.84 ml., 20.3 mmole) in tetrahydrofuran, (50 ml.) was stirred for 1 hour at +20° to +25° and then cooled to -70°. To this solution at -70° was added a cold (-60 to -70°) solution of formic-acetic anhydride [generated by stirring formic acid (470 mg., 10.2 mmole), acetyl chloride (0.726 ml., 10.2 mmole) and triethylamine (1.42 ml., 10.2 mmole) at -60 to -70° in tetrahydrofuran (40 ml.). The solution contained suspended triethylamine hydrochloride] and triethylamine (1.42 ml., 10.2 mmole). The temperature of the mixture was allowed to rise to +20° over ca. 1 hour and the mixture was then filtered. The filtrate and washings were stirred and a solution of sodium 2ethylhexanoate (2 g., 12 mmole) in tetrahydrofuran (2ml.) and ether (18 ml.) was added. The white precipitate was isolated by filtration, washed with ether and dried to give sodium (3S,5R,6R)-6-formamido-2,2-dimethylpenam-3-carboxylate as a white powder (1.6127 g., 6.06 mmole, 59.4%); m.p. 238° to 242° (dec.); [α]D + 281° (H2O); νmax. 3412 (NH), 1790 (azetidin-2-one), 1677 and 1505 (CONH), 1602 cm.-1 (CO2 -); τ 1.28 (1H, d, J 9 Hz, NH), 1.90 (1H, s, HCO), 4.40 to 4.60 (2H, m, C5 -H and C6 -H), 6.01 (1H,s, C3 -H), 8.42 (3H, s) and 8.50 (3H,s) (C[CH3 ]2). (Found : C, 40.7; H, 4.3; N, 10.3; Na, 8.6; S, 11.7. C9H11N2NaO4S (266.3) requires C, 40.5; H, 4.1; N, 10.5; Na, 8.6; S, 12.0%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)o1
Yield: 48 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methylfuran-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.6 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.45-7.31 (m, 5H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 6.09 (d, J=3.0 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 5.16 (s, 2H), 4.30 (d, J=5.6 Hz, 2H), 2.52 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 436.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:12]([CH3:14])[CH3:13].[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:15]#[N:16])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(C)c1c[nH]c2c(I)cc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)c1c[nH]c2c(C#N)cc(Br)cc12
Temperature: 90 °C
Yield: 76 %

Procedure:
To a stirred solution of 5-bromo-7-iodo-3-(1-methylethyl)-1H-indole (3.05 g, 8.38 mmol) in DMF (50 mL) was added zinc cyanide (0.52 g, 4.43 mmol) and tetrakis(triphenylphosphine)palladium (0.8 g, 0.692 mmol). The reaction was purged with N2, stirred and heated at 90° C. LCMS indicated that the reaction was complete. The reaction was evaporated to dryness under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) and trituration with hexanes, filtering and drying under vacuum gave the product 5-bromo-3-(1-methylethyl)-1H-indole-7-carbonitrile (1.67 g, 6.35 mmol, 76% yield) as a light yellow solid. MS (ES)+ m/e 263.0 [M+H]+.
Reaction SMILES: C(O)=O.[NH2:4][C:5]1[C:10]([NH:11][C:12](=O)[O:13]C)=[C:9]([CH3:16])[N:8]=[C:7]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:18]=2)[N:6]=1.O>O1CCCC1>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([C:7]2[N:6]=[C:5]3[C:10]([NH:11][C:12](=[O:13])[NH:4]3)=[C:9]([CH3:16])[N:8]=2)=[N:18]1
Reactant: COC(=O)Nc1c(C)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 245 mg (0.60 mmol) of the compound from example 69A were initially charged in tetrahydrofuran (2.6 ml) and cooled to 0° C., and 0.90 ml (0.90 mmol) of bis(trimethylsilyl)sodium amide (1.0 M in tetrahydrofuran) was added dropwise. The mixture was stirred at 0° C. for 1 h and then at RT overnight. Subsequently, the mixture was stirred at 60° C. for 8 h. Thereafter, water was added and the reaction mixture was concentrated. The residue was extracted twice with ethyl acetate, and the collected organic phases were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 110 mg (85% purity, 41% of theory) of the title compound in solid form. A solid likewise precipitated out of the aqueous phase, which was filtered off, washed with water and dried under high vacuum. This gave a further 100 mg (44% of theory) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[CH3:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=Cc1ccc[nH]1
Product: CCO[Si](C)(C)C(C)(C)C

Procedure:
1H-Pyrrole-2-carbaldehyde was alkylated with (2-bromoethoxy)(tert-butyl)dimethylsilane as described in Example 12, step 1 to provide 1-(2-ethoxy-tert-butyldimethylsilane-1H-pyrrole-2-carbaldehyde as a light yellow oil.
Reaction SMILES: O1C=CNC1=O.[C:7]1([NH:13][C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[NH:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O[CH:25]=[C:26]1[C:30](=[O:31])[O:29][C:28]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)=[N:27]1)C>CS(C)=O>[C:32]1([C:28]2[O:29][C:30](=[O:31])[C:26](=[CH:25][N:19]3[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[NH:15])[CH2:17][CH2:18]3)[N:27]=2)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: N=C(Nc1ccccc1)N1CCNCC1
Reactant: CCOC=C1N=C(c2cccc3ccccc23)OC1=O
Agent: O=c1[nH]cco1
Solvent: CS(C)=O
Product: N=C(Nc1ccccc1)N1CCN(C=C2N=C(c3cccc4ccccc34)OC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine was prepared as described in commonly owned U.S. patent applications U.S. S.No. 60/124,781; filed on Mar. 17, 1999; U.S. S.No. 60/165,312, filed on Nov. 12, 1999; and U.S. Ser. No. 09/521,185, filed Mar. 8, 2000 by Coffen, et al. entitled “Oxazolone Derivatives and Uses Thereof”, filed herewith. Briefly, to a 0.25 M solution of N-phenyl-piperazine-1-carboxamidine (200 μL, 50 μmole) was added a 0.25 M solution of 4-ethoxymethylene-2-naphthalene-1-yl-4H-oxazol-5-one in DMSO (200 μL, 25 μmole). The reaction vessel was sealed and the resulting mixture shaken at room temperature for 1 h to yield the desired product as a DMSO solution (MH+426).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[N:36]2>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[CH2:45][CH2:46][N:41]([C:35]4[CH:34]=[CH:33][C:32]5[C:37](=[CH:38][CH:39]=[CH:40][C:31]=5[Cl:30])[N:36]=4)[CH2:42][CH2:43]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: Clc1cccc2nc(N3CCNCC3)ccc12
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ccc4c(Cl)cccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 5-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O.C(O)C>O>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH2:19][CH2:18][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCc2cccs2)cc1

Procedure:
A mixture of 33.0 g. of ethyl p-aminobenzoate, 21.8 g. of 2-(2-thienyl)ethanol O-methanesulfonate (prepared as described in Example 49) and 100 ml. of hexamethylphosphoramide is heated in an oil bath at 125° C. for 16 hours. The mixture is chilled, diluted with 15 ml. of ethanol and 150 ml. of water. The mixture is extracted with ether and the ether extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give a crude oil. A sample of this oil is chromatographed over silica gel and the fractions containing the product are combined and recrystallized from hexane to give ethyl 4-[2-(2-thienyl)ethylamino]benzoate as yellow-tan crystals, m.p. 93°-95° C.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=3[CH:24]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[C@H:1]([N:5]([CH3:32])[C:6]1[C:7]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=3[CH:24]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CI
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of (R)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate (100 mg, 0.33 mmol) in THF (20 mL) was added NaH (90 mg, 2.24 mmol) and CH3I (159 mg, 1.12 mmol). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 5 with hydrochloric acid (1N). The resulting solution was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting (10% dichloromethane in methanol) to afford (R)-3-(sec-butyl(methyl)amino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylic acid as a yellow solid (25 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCNCC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 79 mg (0.214 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-1,4-diazepane and 47 μl (0.321 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCc2ccccc2)cc1
Yield: 30.7 %

Procedure:
A solution of 1-benzyloxy-4-(3-bromopropyloxy)benzene (29.4 g) and potassium phthalimide (20.4 g) in dimethylformamide (150 ml) was stirred and heated on a steam bath for 17 hours under nitrogen. The solvent was distilled in vacuo and water (250 ml) was added to the residue. The mixture was extracted with dichloromethane and the extract dried over anhydrous potassium carbonate. The solvent was evaporated in vacuo and the residue was crystallized from ethanol-acetone to give 10.9 g (31%) of 1-benzyloxy-4-(3-phthalimidopropoxy)benzene, mp 143°-145°. A second crop which was obtained by concentrating the filtrate, weighed 9.2 g (26%), mp 137°-140°. The analysis of a sample, mp 141°-143°, from an earlier run was as follows:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:7])[CH3:3].[C:18]([NH:25][C:26]([CH3:31])([C:28](O)=[O:29])[CH3:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:7][C:28](=[O:29])[C:26]([NH:25][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:31])[CH3:27])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CSCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of S-benzyl-L-cysteine ethyl ester hydrochloride (7.98 g, 29 mmol), BOC-α-methylalanine (5.89 g, 29 mmol), triethylamine (2.93 g, 29 mmol), 1-hydroxybenzotriazole (HOBT, 3.92 g, 29 mmol) and EDCI (5.57 g, 29 mmol) in methylene chloride (200 mL) is stirred under an argon atmosphere at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with water (50 mL), 1 N HCl (50 mL), water (50 mL), 5% sodium bicarbonate (50 mL), water (50 mL) and finally brine (25 mL). The solution is then dried over sodium sulfate, filtered and evaporated to dryness to give N-[2-(BOC-amino)-2-methylpropionyl]-S -benzyl-L-cysteine ethyl ester.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[F-]>C(O)(C)C>[CH:17]([O:20][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:18])[CH3:16]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(OC(C)C)nc3ccccc23)cc1

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.150 g (0.5 mmol) with NH4F 0.500 g (13.5 mmol) in isopropanol 4 mL was stirred at reflux for 14 h. After removal of isopropanol, the residue was dissolved in dichloromethane, and the organic solution was washed with water, and dried over anhydrous MgSO4. After removal of solvent under reduced pressure, the title compound was obtained. 1H NMR (CD3OD, 400 MHz) δ 7.57-7.60 (m, 1H), 7.42-7.46 (m, 1H), 7.10-7.18 (m, 2H), 6.89-6.97 (m, 3H), 6.79-6.84 (m, 1H), 5.45-5.51 (m, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 1.46 (d, J=6.3 Hz, 6H); HRMS (ES) m/z calcd for C19H21N3O2 (M+H) 324.1706, found 324.1954.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.[CH3:22][N:23]([CH3:26])[CH:24]=O>>[CH3:22][N:23]([CH3:26])[C:24]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C)c1ccccc1
Reaction time: 8 h

Procedure:
The aniline derivative (1.4 g, 7.3 mmol) obtained in Step 1 was dissolved in dimethylformamide (50 ml), methyl iodide (1.4 ml, 22 mmol) and potassium carbonate (3.0 g, 22 mmol) were added, and the mixture was stirred overnight. A treatment according to a conventional method using ethyl acetate as an extraction solvent gave a crude product, which was successively purified by silica gel column chromatography to give a dimethylaniline derivative (1.1 g, 5.0 mmol).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:10]([OH:19])[CH2:11][N:12]([CH3:18])[S:13](=[O:17])(=[O:16])[NH:14][CH3:15])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:10]([OH:19])[CH2:11][N:12]([CH3:18])[S:13](=[O:17])(=[O:16])[NH:14][CH3:15]
Reactant: CNS(=O)(=O)N(C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)N(C)C[C@H](O)[C@@H](N)CC1CCCCC1
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 89.1 %

Procedure:
A sample of the resultant compound from Example 121 (501 mg, 1.27 mmol) was dissolved in 3 ml CH2Cl2, cooled to 0° C. under a dry nitrogen atmosphere, and treated with 3 ml trifluoroacetic acid. The solution was stirred for 5.5 h, then the solvents were removed under reduced pressure, and the residue was basified with 1.0M aq. Na2CO3. The product was extracted with 4×20 ml CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to yield 332 mg (89%) of (2S,3S)-3-amino-4-cyclohexyl-2-hydroxy-1-(methyl(methylsulfamoyl)amino)butane as a white powder. 1H NMR (CDCl3) δ0.8-1.45 (several bm, 8H), 1.6-1.8 (bm, 5H), 1.9 (vbm, 3H), 2.75 (s, 3H), 2.85 (m, 1H), 2.94 (s, 3H), 3.21 (dd, 1H), 3.30 (dd, 1H), 3.48 (m, 1H). Mass spectrum: (M+H)+ =294.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:51])[C@@H:9]([CH3:50])[C:10]([NH:12][C@@H:13]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:14]([N:16]1[C@H:20]([C:21](=[O:33])[NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)[CH2:19][C@H:18]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=[O:41])=[CH:38][CH:37]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]([CH3:51])[C@@H:9]([CH3:50])[C:10]([NH:12][C@@H:13]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:14]([N:16]1[C@H:20]([C:21](=[O:33])[NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)[CH2:19][C@H:18]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)N[C@@H]3CCCc4ccccc43)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](OCc2ccc(C(=O)O)cc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of methyl 4-((((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)benzoate (1.35 g, 1.91 mmol) in THF (5 mL) and MeOH (3 mL) was added a solution of NaOH (0.31 g, 7.64 mmol) in water (6 mL). The reaction mixture was stirred at rt for 4 h, acidified with 1N HCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as a white solid (1.30 g, 98%). 1H NMR (DMSO-d6) δ 8.01 (d, J=8.6 Hz, 0.5H), 7.91 (d, J=8.4 Hz, 1.5H), 7.43 (d, J=8.4 Hz, 2H), 7.24 (d, J=7.7 Hz, 1H), 7.15-6.98 (m, 3H), 4.98-4.83 (m, 1H), 4.60 (s, 2H), 4.47 (d, J=9.0 Hz, 1H), 4.34 (t, J=7.7 Hz, 1H), 4.21 (t, J=6.2 Hz, 1H), 4.12-4.05 (m, 1H), 3.86-3.71 (m, 1H), 3.54 (dd, J=10.2, 6.1 Hz, 1H), 2.81-2.65 (m, 5H), 2.45-2.36 (m, 1H), 2.02-1.92 (m, 1H), 1.86-1.56 (m, 4H), 1.40 (br. s., 9H), 1.26-1.15 (m, 3H), 1.03-0.86 (m, 9H); MS(ESI+) m/z 693.6 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12](C(OC(C)(C)C)=O)[CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14].FC(F)(F)C(O)=O>[Pd]>[CH3:11][NH:12][CH:13]([CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:3]=[C:4]2[O:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1)[CH3:14]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Brc1cnc2ncoc2c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1cnc2ncoc2c1

Procedure:
In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M—C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia.