Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12])=[O:6]>>[CH:5]([NH:7][C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[C:10]([C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12])=[O:6]
Reactant: Cc1cc(Br)c(C(=O)O)cc1NC=O
Reactant: O=[N+]([O-])O
Product: Cc1cc(Br)c(C(=O)O)c([N+](=O)[O-])c1NC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (120 mL, 2.8 mol) is cooled to about 0° C., whereupon 3-(Formylamino)-6-bromo-4-methylbenzoic Acid (20) (28.243 g, 109.5 mmol) is added in small portions over about 45 minutes, at such a rate to maintain the internal reaction temperature <5° C. The reaction mixture is then stirred at about 0° C. for about 1 hour. The reaction mixture is added to ice water (500 mL) and stirred for about 1 hour. The solids that form are filtered and dried to provide 3-(Formylamino)-6-bromo-4-methyl-2-nitrobenzoic Acid (21), as a beige powder (31.465 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:48])[C:15]([C:23]3[N:24]=[C:25]([NH:28][C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:26][CH:27]=3)=[N:16][O:17]C(C)(OC)C)[C:11](=[O:49])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(NCC)C.CC(C)=O.Cl>O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:48])[C:15]([C:23]3[N:24]=[C:25]([NH:28][C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[S:26][CH:27]=3)=[N:16][OH:17])[C:11](=[O:49])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: CCNCC
Solvent: CC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 21 g of the product of Step A, 80 ml of acetone and 27 ml of 2 N hydrochloric acid was stirred at room temperature for 90 minutes and 55 ml of water were added thereto with stirring. The acetone was evaporated under reduced pressure and 140 ml of ethyl acetate were added with stirring. The decanted aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with half saturated aqueous sodium chloride solution, was dried and vacuum filtered to obtain the syn isomer of 3-methyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4]I.C([Li])CCC.[CH3:19][Sn:20](Cl)([CH3:22])[CH3:21].O>O1CCCC1>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4][Sn:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C=CI)c1ccc(Cl)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C=C[Sn](C)(C)C)c1ccc(Cl)cc1
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A stirring solution of 4.8 grams (0.016 mole) of 3-methyl-3-(4-chlorophenyl)-1-iodo-1-butene in 50 mL of tetrahydrofuran is cooled to about -90° C., and 6.9 mL (0.018 mole) of n-butyllithium (2.5M in hexane) is added dropwise at a rate to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of the addition, the reaction mixture is stirred at -90° C. for 30 minutes. After this time, a solution of 3.7 grams (0.019 mole) of trimethyltin chloride in 10 mL of tetrahydrofuran is added dropwise at a rate sufficient to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of addition, the reaction mixture is again stirred at -90° C. for 30 minutes. After this time, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then poured into 150 mL of water and extracted with 150 mL of diethyl ether. The ether extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 4.8 grams of 3-methyl-3-(4-chlorophenyl)-1-trimethylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:14]([OH:15])[C:13]([CH2:16][CH2:17][N:18]([CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH2:40][O:41][CH3:42])[CH:34]=[O:35].P(CCCC)(CCCC)CCCC.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@@H:14]([O:15][C:31]2[CH:32]=[C:33]([CH:34]=[O:35])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][O:41][CH3:42])[C:13]([CH2:16][CH2:17][N:18]([CH3:29])[S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[CH:12][CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N(C)CCC2=CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)cc1
Reactant: COCOc1ccc(C=O)cc1O
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(C=O)cc1O[C@H]1C(CCN(C)S(=O)(=O)c2ccc(C)cc2)=CCC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.2 %

Procedure:
To a solution of alcohol 14 (190 mg, 0.43 mmol) and phenol 18 (102 mg, 0.56 mmol) in THF (6 mL) at −10° C. was added PBu3 (0.15 mL, 0.65 mmol) followed by tetramethylazodicarboxamide (TMAD) (111 mg, 0.65 mmol). The reaction mixture was slowly warmed to room temperature and was stirred for 22 hours. Solvent was evaporated under reduced pressure and purified by flash column chromatography on silica gel using [hexane/EtOAc (80:20)→hexane/EtOAc (50:50)] as eluent to isolate product 19b (130 mg, 0.22 mmol, 50%) as a clear oil.
Reaction SMILES: [Li:1]CCCC.[C:6](=[NH:13])([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[C:6](=[N:13][Li:1])([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8]
Reactant: CN(C)C(=N)N(C)C
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Product: [Li]N=C(N(C)C)N(C)C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
BuLi (1.6 M in hexane, 6.25 mL, 10 mmol) was added to a toluene solution (˜15 mL) of (Me2N)2C═NH (1.151 g, 10 mmol) at −78° C. The solution was warmed to 23° C. in 10 minutes and was further stirred for 30 minutes to give a toluene solution of (Me2N)2C═NLi (10 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN(CC)CC.Cl.[CH3:22][O:23][NH2:24].O>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:24][O:23][CH3:22])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CONS(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Ex-30A: To a solution of 4-acetylbenzenesulfonyl chloride (2.18 g, 10.0 mmol) in 100 ml of THF at 0° C., Et3N (2.5 g, 25 mmol) was added followed by O-methyl hydroxyamine hydrochloride (0.84 g, 10 mmol). The mixture was stirred for 1 hr at room temperature and then poured into water, and the precipitate was filtered and dried. Recrystallization from THF/hexanes gave 1.5 g (65.8%) of 4-acetyl-N-methoxybenzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.10 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 7.23 (brs, 1H), 3.82 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[C:28]([C:31]1[CH:32]=[C:33]([CH:37]=O)[N:34]([CH3:36])[CH:35]=1)(=[O:30])[CH3:29]>>[C:28]([C:31]1[CH:32]=[C:33]([C:37]2[N:2]([CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([Cl:16])[CH:18]=4)[NH:22][CH:21]=3)[N:1]=[C:3]3[C:4]=2[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[N:8]3[CH2:9][CH:10]([CH3:11])[CH3:12])[N:34]([CH3:36])[CH:35]=1)(=[O:30])[CH3:29]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(=O)c1cc(C=O)n(C)c1
Product: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 4-acetyl-1-methyl-1H-pyrrole-2-carbaldehyde. 508.5 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:29])=[CH:38][CH:39]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)ncc21
Yield: 51.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138), 0.04 g (0.18 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.23 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.041 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-141).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH2:26][CH2:27]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.7 %

Procedure:
Benzyl chloroformate (0.7 ml, 4.9 mmol) was added drop wise to a cool (0° C.) solution of 4-nitro-N-piperidin-4-yl-benzenesulfonamide (1.4 g, 4.9 mmol) and diisopropylethylamine (1.6 ml, 9.8 mmol) in THF (10 ml). The resulting mixture was warmed to room temperature and stirred under a nitrogen atmosphere for 18 hours. After this time, the mixture was diluted with ethyl acetate (50 ml), washed with water (50 ml), the organic layer was separated and dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 50% heptane, 50% ethyl acetate) to give the title compound (0.98 g, 48% yield) as a white solid. Tr=2.04 min m/z (ES+) (M+H+) 420.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]=4[O:37][Si](C)(C)C)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].[F-].C([N+](C)(C)C)C1C=CC=CC=1>C1COCC1.CCCCCC>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@:16]4([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]4=[O:37])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CI
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(O[Si](C)(C)C)=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C[C@@H]1CC3
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@]12C(=O)C[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CCC1=C2CC[C@H]2C[C@@H](OC(=O)c3ccccc3)CC[C@]12C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
3β-benzoyloxy-15-trimethylsiloxy-5α-cholest-8,14-diene (1.93 g, 3.35 mmole) in THF (10 mL) and ethyl iodoacetate (0.79 mL, 6.7 mmole) was added at -10° C. to a mixture of benzyl trimethylammonium fluoride (850 mg, 5 mmole) in THF (15 mL). The mixture was stirred at -10° C. for 15 minutes and at ambient temperature for 30 minutes, diluted with hexane, filtered and the filtrate was concentrated. Using the workup described in Example 1(ii), 625 mg of 3β-benzoyloxy-14α-carbethoxymethyl-5α-cholest-8-en-15-one was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[F:19][C:5]1[C:6]([N:8]([CH3:18])[C:9]2[CH:10]=[C:11]([NH:15][C:30](=[O:29])[CH:31]=[CH2:32])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][O:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20])=[CH:36][CH:35]=2)=[N:3][CH:4]=1
Reactant: CN(c1cccc([N+](=O)[O-])c1)c1nc(Cl)ncc1F
Reactant: COCCOCOCCOc1ccc(N)cc1
Product: C=CC(=O)Nc1cccc(N(C)c2nc(Nc3ccc(OCCOCOCCOC)cc3)ncc2F)c1

Procedure:
Synthesis of I-24 was performed as described for I-3 (Example 1) using 2-chloro-5-fluoro-N-methyl-N-(3-nitrophenyl)pyrimidin-4-amine in place of 2-chloro-5-fluoro-N-(3-nitrophenyl)pyrimidin-4-amine and 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline in place of 4-[(2-methoxyethoxy)methoxy]aniline. M+1=423.9. 1H NMR (DMSO-d6, 400 MHz) 3.44 (s, 3H), 3.664-3.688 (t, 2H, J=4.8), 3.900-3.924 (t, 2H, J=4.8), 5.754-5.779 (d, 1H, J=10), 6.232-6.274 (d, 1H, J=16.8), 6.385-6.453 (m, 2H), 6.810-6.832 (d, 1H, J=8.8), 7.009-7.028 (d, 1H, J=7.6), 7.328-7.368 (t, 1H, J=8), 7.512-7.572 (m, 3H), 7.652 (s, 1H), 7.965-9.978 (d, 1H, J=5.2), 8.196 (s, 1H), 9.120 (s, 1H), 10.245 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].Br[CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].C(=O)=O>CCCCCC>[O:14]1[CH2:13][CH:8]([C:9]([O:11][CH3:12])=[O:10])[O:3][CH:2]1[C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C=O
Reactant: COC(=O)C(Br)CO
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CCCCCC
Product: COC(=O)C1COC(C(=O)OC)O1
Reaction time: 8 h
Yield: 21.4 %

Procedure:
Methyl glyoxylate 11.3 g (0.128 mol) and methyl 2-bromo-3-hydroxypropionate 31 g (0.129 mol) were mixed and the mildly exothermic reaction allowed to cool. The mixture was then treated with hexane (50 ml) and 17.8 g (0.129 mol) potassium carbonate. Evolution of CO2 was sluggish; the mixture was warmed to 45° and allowed to stir overnight. The work-up as described in Example 1 yielded after ether removal, 13.0 g of a light yellow liquid. Distillation in vacuo gave 5.2 g (21%) of the title compound bp 84°-86° at 0.3 mm Hg as a clear colorless liquid. Analysis by GlPC indicated >96% purity, and the pmr spectrum indicated a mixture of trans & cis isomers approximately 70-80% trans.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CCO.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][CH2:26][C:21]([OH:20])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)(c3ccccc3)CC2)nc1
Temperature: 140 °C

Procedure:
To a solution of 2-chloro-5-nitropyridine (0.9 g) in EtOH (5 mL) was added N,N-diisopropylethylamine (2.9 mL) and 4-hydroxy-4-phenylpiperidine (1.5 g). The reaction mixture was heated at 140° C. for 20 min by microwave. Then the reaction mixture was cooled to RT, diluted with EtOAc (150 mL), washed with H2O (2×100 mL), saturated NH4Cl (3×100 mL), brine (1×100 mL), dried over Na2SO4, filtered, and concentrated to give B-1.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][N:44]=[C:45]=[O:46])=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([N:19]([C:45]([NH:44][CH2:43][CH2:42][C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)=[O:46])[CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C=NCCc1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCCNCC(=O)Nc1c(OC)cc(OC)cc1OC
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CC(=O)Nc1c(OC)cc(OC)cc1OC)C(=O)NCCc1ccccc1
Reaction time: 72 h

Procedure:
A mixture of 0.50 g of the product of Example 7, 0.2 g 2-phenethyl isocyanate, and a few mL ethyl acetate were briefly heated on the steambath and then allowed to sit 3 days at room temperature. The reaction mixture was then washed with dilute H3PO4, NaHCO3, and HaCl solutions, dried over MgSO4, filtered, and concentrated to an oil. The oil was chromatographed on SiO2 (70-230 mesh) using EtoAc as eluant. The product was obtained as an oil which crystallized on standing. 0.28 g (44%). NMR (CDCl3) δ 0.88 (3H, t), δ 1.25 (24H, m), δ 1.96 (4H, m) δ 2.84 (2H, t), δ 3.23 (2H, t), δ 3.51 (2H, q), δ 3.69 (6H, s), δ 3.77 (3H, s), δ 4.03 (2H, s), δ 4.70 (1H, t), δ 5.35 (2H, t), δ 6.13 (2H, s), δ 7.16-7.31 (5H, m), δ 7.46 (1H, s). IR (KBr) 3251, 2925, 1662, 1621, 1533, 1465, 1156, 1128, 810 cm-1.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].O1CCOCC1.[Cl:12][C:13](=[CH2:18])[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[Cl:12][CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:18][S:1][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: NC(=O)CS
Reactant: C=C(Cl)C(=O)OC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)C(Cl)CSCC(N)=O
Reaction time: 1 h

Procedure:
2-Mercaptoacetamide (18.79 g) was stirred in a mixture of dry 1,4-dioxan (200 ml) and dry pyridine (33.5 ml)) whilst methyl 2-chloroacrylate (24.88 g) was added dropwise over 15 minutes. The mixture was stirred for 1 hour then stood overnight. The resultant mixture contained the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: BrCCCCBr
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCCBr)cc1)c1c(-c2ccccc2)oc2ccccc12

Procedure:
A mixture of 3.0 g. (9.5 mmol.) of 3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 6.2 g. (0.029 mol.) of 1,4-dibromobutane and 3.9 g. (0.029 mol.) of potassium carbonate in 100 ml. of dry acetone is refluxed for 18 hours. The reaction mixture is cooled, filtered and the filtrate is concentrated under reduced pressure then heated on a steam bath in vacuo to remove excess 1,4-dibromobutane and leave 3-[4-(4-bromobutoxy)benzoyl]-2-phenylbenzofuran as a residue.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=[O:7])=[O:6]>C1CCCCC1.C(OCC)(=O)C>[N:8]1([S:5]([CH2:4][C:3]([OH:14])=[O:2])(=[O:7])=[O:6])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: COC(=O)CS(=O)(=O)N1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(O)CS(=O)(=O)N1CCOCC1

Procedure:
(Morpholine-4-sulfonyl)acetic acid methyl ester (0.5 g, 2.24 mmol) is dissolved in 0.66 N KOH aqueous ethanol solution (1/1, 150 mL) and the mixture is heated at reflux during 16 h. The solvent is evaporated and residue is extracted with dichloromethane/methanol 4:1 to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:32])[C@@H:16]([NH:24]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.Cl.O1CCOCC1.[S:40]1[CH:44]=[C:43]([CH:45]=O)[N:42]=[CH:41]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:32])[C@@H:16]([NH:24][CH2:45][C:43]3[N:42]=[CH:41][S:40][CH:44]=3)[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccnc(N)c2)c1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(-c2cccc(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a solution of tert-butyl (S)-1-(3-(2-aminopyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (36.C) (200 mg, 0.46 mmol) in THF (2 mL) was added 4M HCl in dioxane (2 mL, 8 mmol). The mixture was stirred at room temperature for 2 hours and then was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with 4:1 DCM/isopropanol. The organic layers were combined, washed with brine, dried on MgSO4 and concentrated. The residue was dissolved in DCM and then thiazole-4-carbaldehyde (56 mg, 0.50 mmol) was added. The mixture was stirred for 1 h at room temperature at which time acetic acid (28 μL, 0.46 mmol) and sodium triacetoxyborohydride (293 mg, 1.38 mmol) were added. The mixture was stirred at room temperature for additional 2 hours, concentrated and the residue purified by reverse phase preparative HPLC to afford (2S)—N-(3-(2-aminopyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 36 (58 mg, 29% yield) as a white solid. LCMS ESI (pos.) m/e: 430.1 (M+1): 1H NMR (400 MHz, MeOH-D4) δ ppm 9.12 (d, J=1.96 Hz, 1H), 7.91-7.97 (m, 2H), 7.79 (d, J=1.96 Hz, 1H), 7.42-7.57 (m, 3H), 7.25-7.36 (m, 5H), 7.18-7.21 (m, 1H), 7.13-7.17 (m, 1H), 4.42-4.54 (m, 2H), 4.25 (dd, J=9.39, 5.87 Hz, 1H), 3.42 (dd, J=13.30, 5.87 Hz, 1H), 3.25 (dd, J=13.30, 9.00 Hz, 1H).