Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](OC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: NCCN1CCCCC1
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 85.4 %

Procedure:
Methyl 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carboxylate (Preparation 4) (100 mg, 0.22 mmol) and 1-(2-aminoethyl)piperidine (0.31 ml, 2.19 mmol) were heated together at 130° C. for 2 hours. The excess amine was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane methanol (95:5 by volume) to afford the title compound as a yellow foam (104 mg).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([CH3:16])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].O>C1C=CC=CC=1>[CH3:16][C:7]1[C:6]([N:5]=[S:1]=[O:2])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cccc(N=S=O)c1C
Yield: 90 %

Procedure:
To a solution of thionyl chloride (6.63 mL, 91.0 mmol) in benzene (60 mL) was added a solution of methyl 3-amino-2-methylbenzoate (13.1 g, 91.0 mmol) in benzene (31 mL) at room temperature, and the mixture was heated under reflux for 18 hr. Water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (17.3 g, yield 90%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]4[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(C)(C)C)cc4)cc3CC[C@@H]12
Yield: 69.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-t-butylphenylboronic acid (139 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 163 mg (69%) of the title compound as an amorphous solid. mp 141°-147°. FDMS: m/e=361 α[D]589 =+67.88 (c=1.05, chloroform).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:26]2[C:25]3[C:20](=[CH:21][C:22]([OH:27])=[CH:23][CH:24]=3)[NH:19][C:18]=2[C:17]([C:28]([NH2:30])=[O:29])=[CH:16][CH:15]=1>N1C=CC=CC=1.CCOC(C)=O>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:27][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[C:18](=[C:17]([C:28](=[O:29])[NH2:30])[CH:16]=[CH:15][C:14]=3[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[F:7])[NH:19][C:20]=2[CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Reaction time: 17 h
Yield: 30.8 %

Procedure:
Ethyl chloroformate (8.19 mg, 0.075 mmol) was added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 18.6 mg, 0.058 mmol) in pyridine (1 mL). After 17 h, additional ethyl chloroformate (8.19 mg, 0.075 mmol) was added. After 5 h more, additional ethyl chloroformate (0.05 mL) was added. After 15 h more, the mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (5 mL), dried and concentrated. The residue was purified by preparative HPLC to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl ethyl carbonate as a white solid (7.0 mg, 28%). 1H NMR (400 MHz, chloroform-d) δ 10.44 (1H, br. s.), 7.62 (1H, dd, J=7.92, 1.98 Hz), 7.41-7.57 (2H, m), 7.20-7.40 (4H, m), 7.16 (1H, dd, J=7.81, 1.65 Hz), 6.79-6.92 (1H, m), 6.60 (2H, br. s.), 4.34 (2H, q, J=7.26 Hz), 1.41 (3H, t, J=7.15 Hz). Mass spectrum m/z 393.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.[CH:22]1([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[SH:37])[CH2:26][CH2:25][CH2:24][CH2:23]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:22]1([N:27]2[C:28](=[O:38])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[S:37]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C(=O)NC2CCCC2)c(S)c1
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(=O)n(C3CCCC3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of bis(trifluoroacetoxy)iodobenzene (PIFA) (0.645 g, 1.5 mmol) in CH2Cl2 was added to a solution of N-cyclopentyl-2-mercapto-4-methoxybenzamide (0.251 g, 1 mmol) and trifluoroacetic acid (TFA) (0.23 mL, 3 mmol) in CH2Cl2 at 0° C. The resulting mixture was gradually warmed to room temperature. After 1 h, the solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography using dichloromethane to afford 2-cyclopentyl-6-methoxybenzo[d]isothiazol-3(2H)-one as a white solid (84%, 0.210 g). 1H NMR (300 MHz, CDCl3): δ 7.87 (d, 1H, J=8.5 Hz), 6.93 (s, 1H), 6.92 (d, 1H, J=8.2 Hz), 5.50-5.01 (m, 1H), 3.86 (s, 3H), 2.13-2.12 (m, 2H), 1.83-1.67 (m, 6H). LC-MS (ESI) Calcd for C13H15NO2S [M+H]+: 250.08. Found: 249.95.
Reaction SMILES: Br[CH:2]1[CH2:20][CH2:19][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@@H:32]([O:34][CH2:35][CH3:36])[CH2:31][C@H:30]1[C:37]([OH:39])=[O:38])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH2:35]([O:34][C@@H:32]1[CH2:33][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[C@H:30]([C:37]([O:39][CH:2]2[CH2:20][CH2:19][C:5]3=[CH:6][C:7]4[C:8]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=5[CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[C:3]2=[O:21])=[O:38])[CH2:31]1)[CH3:36]
Reactant: CCO[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C1c2cc3c(cc2CCC1Br)-c1ccc(Cl)cc1CO3
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCO[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(Cl)ccc2-4)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a slurry of 9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.50 g, 6.8 mmol) in MeCN (20 mL) was added (2S,4S)-1-(tert-butoxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid (2.68 g, 10.3 mmol) and DIPEA (1.3 mL, 7.5 mmol). The reaction was heated with stirring to 50° C. for 18 h. The reaction was then cooled to room temperature and diluted with EtOAc. The solution was washed with HCl (1N) and brine. The aqueous layers were backextracted with EtOAc and the resulting organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (15% to 50% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 4-ethoxypyrrolidine-1,2-dicarboxylate (2.08 g, 56%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2/[N:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13](=[O:17])[NH:14][C:15]/2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:39].[CH3:40][C:41]1[S:42][CH:43]=[C:44]([CH2:46][Cl:47])[N:45]=1>CN(C=O)C>[ClH:47].[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2/[N:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13](=[O:17])[N:14]([CH2:46][C:44]3[N:45]=[C:41]([CH3:40])[S:42][CH:43]=3)[C:15]/2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2\C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2\C(=O)N(Cc3csc(C)n3)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 16 h

Procedure:
To a solution of methyl E-4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.66 g, 1.5 mmol) in DMF (10 mL) is added K2CO3 (3.0 g, 15 mmol). After stirring for 5 minutes 2-methyl-4-chloromethylthiazole hydrochloride (0.28 g, 1.5 mmol) is added. The mixture is stirred for 16 hours and then filtered. The filtrate is concentrated in vacuo and dissolved in ether (50 mL). This solution is washed with water and dried over K2CO3 and charcoal. The mixture is filtered and allowed to stand in which time the product crystallizes. Petroleum ether is added to complete crystallization.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([NH:18][N:19]([CH3:21])[CH3:20])=[O:17])[S:15][C:8]=23)=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:39])[CH2:35][C:36]([OH:38])=O.C(Cl)CCl.C[N:45](C=O)C>CCOC(C)=O>[CH3:20][N:19]([CH3:21])[NH:18][C:16]([C:14]1[S:15][C:8]2[C:9](=[N:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:22]=[CH:23][C:2]([N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[C:34](=[O:39])[CH2:35][C:36]([NH2:45])=[O:38])=[CH:3][C:4]=2[F:24])[CH:13]=1)=[O:17]
Reactant: CN(C)C=O
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN(C)NC(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1N(C(=O)CC(N)=O)c1ccc(Oc2ccnc3cc(C(=O)NN(C)C)sc23)c(F)c1
Reaction time: 6 h
Yield: 67 %

Procedure:
A solution of 7-(4-amino-2-fluorophenoxy)-N′,N′-dimethylthieno[3,2-b]pyridine-2-carbohydrazide 239 (200 mg, 0.578 mmol), 3-(2-methoxyphenylamino)-3-oxopropanoic acid 27 (195 mg, 0.693 mmol), and EDC (230 mg, 0.693 mmol) in DMF (8.3 mL) was stirred overnight at room temperature. More 27 (195 mg, 0.693 mmol) and EDC (230 mg, 0.693 mmol) were added and the mixture stirred 6 h more. The crude was diluted with EtOAc, extracted with water, over with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was re dissolved in MeOH and purified twice by flash chromatography (DCM/MeOH 9:1) affording 236 (207 mg, 0.385 mmol, 67% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.60 (s, 1H), 9.94 (s, 0.5H), 9.63 (s, 1H), 9.49 (s, 0.5H), 8.57 (dd, J=5.5 Hz, J=7.2 Hz, 1H), 8.26 (m, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.88 (d, J=12.9 Hz, 1H), 7.54-7.43 (m, 2H), 7.07 (m, 2H), 6.91 (m, 1H), 6.73 (m, 1H), 3.86 (s, 3H), 3.65 (s, 2H), 2.63 (s, 3H), 2.61 (s, 3H). MS (m/z): (M+1) 538.0 (100%).
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[C:13]1(C)C=CC=CC=1>>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: Cc1ccccc1
Reactant: CC(=O)OCC=CCOC(C)=O
Product: C=C(C=O)CCOC(C)=O
Temperature: 75 °C
Yield: 99.9 %

Procedure:
A solution of 1,4-diacetoxy-2-butene (0.5 g) and HRh(CO)(PPh3)3-anchored in MCM-48 (0.05 g) in toluene (25 ml) was heated in an autoclave at 75° C., under 800 psig of synthesis gas (50% by volume H2 and 50% by volume CO gas). The reaction was monitored for gas absorption. After the theoretical amount of gas absorption (44 psig) took place and consequently there was no further gas uptake, the reaction was stopped and then the autoclave was cooled to room temperature. The solid catalyst was recovered by decantation of the reaction mixture. The reaction mixture was analyzed by HP 6890 gas chromatograph to give pure 2-Formyl-4-acetoxybutene (99.9% yield and 100% selectivity to 2-Formyl-4-acetoxybutene). Later toluene was removed from the reaction mixture by distillation to get the pure fraction of 2-Formyl-4-acetoxybutene (b.p. 78-79° C./5 mm Hg). The recovered catalyst was recycled five times. It was found that there was no loss in activity upon each recycle. ICP analysis also showed no leaching of the rhodium catalyst.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5]2.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.CCOC(C)=O>[CH2:20]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH2:5][CH:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Cl)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl 6-chloro-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (310 mg, 1.096 mmol), prepared as described in Example 19A, in 1,2-dichloroethane (7 mL) was added benzaldehyde (235 mg, 2.193 mmol), followed by sodium triacetoxyborohydride (650 mg, 3.069 mmol) and AcOH (200 mg, 3.29 mmol). The reaction mixture was stirred at RT for 4 h, then diluted with EtOAc, washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl, dried Na2SO4) and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc/hexanes (1:5 ratio) to give the title compound as light yellow foam (325 mg, 80%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:46])[CH2:6][C@@H:7]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:33])/[CH:18]=[CH:19]/[CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:12]1)=[O:10].CCO>O.O1CCCC1>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20](/[CH:19]=[CH:18]/[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:9]([NH:8][C@H:7]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)[CH2:6][C:5]([OH:46])=[O:4])=[O:10])[CH2:12]2)=[O:33])[CH2:21][CH2:22]1)=[O:27])([CH3:31])([CH3:30])[CH3:32]
Reactant: COC(=O)C[C@@H](CCc1ccc(OC)c(OC)c1)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CC[C@H](CC(=O)O)NC(=O)[C@@H]2CCCN(C(=O)/C=C/C3CCN(C(=O)OC(C)(C)C)CC3)C2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
A solution of LiOH (0.11 g) in H2O (10 ml) was added to a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester (1.83 g) in tetrahydrofuran (10 ml)-EtOH (10 ml) at 0° C. The reaction mixture was stirred for 3 hours at room temperature, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aq. KHSO4. The whole was washed with water and brine, dried over MgSO4, and evaporated in vacuo to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine as a colorless oil (1.33 g, 74.4%).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.O>C(O)(=O)C>[Br:22][CH:1]([C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCCn1c(CC)nc2ccccc2c1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(C(C)Br)nc2ccccc2c1=O
Yield: 92.3 %

Procedure:
To a solution of 2-ethyl-3-propyl-3H-quinazolin-4-one (125 mg, 0.58 mmol) and sodium acetate (48 mg, 0.58 mmol) in glacial acetic acid (1 mL) cooled in an ice bath was added dropwise a solution of bromine (29.8 μL, 0.58 mmol) in glacial acetic acid (0.5 mL). After addition was complete the reaction was heated to reflux for 2 hours. Water was then added to the solution and the mixture extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, water and then dried over magnesium sulfate, filtered and concentrated to yield the product as a brown oil (158 mg, 92%). 1H NMR (CDCl3) δ 1.05 (t, 3H, J=7.3 Hz), 1.66 (m, 1H), 1.91 (m, 1H), 2.19 (d, 3H, J=6.3 Hz), 3.89 (m, 1H,), 4.53 (m, 1H,), 5.04 (q, 1H, J=6.6 Hz), 7.49 (t, 1H, J=7.3 Hz), 7.73 (m, 2H), 8.27 (d, 1H, J=8.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O.C(Cl)(Cl)(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 57.9 %

Procedure:
4.2 g (0.03 mole) of 3-amino-5-t-butylpyrazole as prepared in Example 1 was dissolved in 50 ml of water, and 3.2 g of sodium carbonate was added thereto. To the resulting aqueous solution was added dropwise 3.2 g of methacryloyl chloride dissolved in 20 ml of carbon tetrachloride at 0° C. while cooling with ice for one hour. The reaction mixture was placed at room temperature (i.e., about 20° to 30° C.), followed by filtration and washing with water to obtain 3.6 g of 5-t-butyl-3-methacryloylaminopyrazole. The mass analysis showed the presence of a molecular ion peak at 207.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:75]=[CH:74][C:67]2[B:68]([OH:73])[O:69][C:70]([CH3:72])([CH3:71])[C:66]=2[CH:65]=1.Cl>C(#N)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:62][CH2:63][C:64]5[CH:75]=[CH:74][C:67]6[B:68]([OH:73])[O:69][C:70]([CH3:72])([CH3:71])[C:66]=6[CH:65]=5)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OB(O)c2ccc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.72 mmol) in acetonitrile (5 ml) at 0° C. can be added Et3N (291.1 mg, 2.88 mmol), HATU (546.76 mg, 1.44 mmol) and 5-(aminomethyl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (194.2 mg, 0.86 mmol). The reaction mixture can be stirred overnight at rt. The mixture can be poured into 1N HCl solution and extracted with EA (20 ml×3). The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-TLC and prep-HPLC to give the final title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6](O)[C:7]([CH2:9][CH2:10][CH3:11])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])/[CH:6]=[C:7](\[CH2:9][CH2:10][CH3:11])/[CH2:8][P:21]([O:24][CH3:25])([O:22][CH3:23])=[O:26])[CH3:2]
Reactant: C=C(CCC)C(O)C(NC=O)C(=O)OCC
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCC/C(=C\C(NC=O)C(=O)OCC)CP(=O)(OC)OC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15, 2-formylamino- 3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[NH2:10])#[N:6].Cl.O.O.[Sn](Cl)[Cl:20]>O>[ClH:20].[C:5]([C:7]1[CH:8]=[C:9]([NH:10][NH2:1])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])#[N:6]
Reactant: COc1ccc(N)cc1C#N
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 142.6 %

Procedure:
A solution of sodium nitrite (4.0 g) in water (7 ml) was added to an ice cooled mixture of 3-cyano-4-methoxyaniline (7.7 g) and concentrated hydrochloric acid (21 ml). The mixture was stirred at 0° C. for 30 minutes. To the resultant mixture a solution of tin(II) chloride dihydrate (49 g) and concentrated hydrochloric acid (5 ml) was added at 0° C. and stirred for 1 hour. The precipitates were filtered and washed with ice cooled concentrated hydrochloric acid (10 ml) to give crude (3-cyano-4-methoxyphenyl)hydrazine hydrochloride (14.8 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:40])[C:37]([OH:39])=[O:38]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:40])[C:37]([OH:39])=[O:38])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(O)C(=O)O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)C(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-3-amino-2-hydroxypropanoic acid, the title compound was obtained in 44% purity by HPLC. MS(ESI+): m/z=426.