Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].O.[O:14]=[C:15]1[CH:22]2[CH:17]([CH2:18][CH:19]=[CH:20][CH2:21]2)[NH:16]1>C1C=CC=CC=1>[OH:3][CH:2]([N:16]1[C:15](=[O:14])[CH:22]2[CH:17]1[CH2:18][CH:19]=[CH:20][CH2:21]2)[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=CC(=O)OCc1ccccc1
Reactant: O=C1NC2CC=CCC12
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C(O)N1C(=O)C2CC=CCC21
Reaction time: 3 h

Procedure:
Benzyl glyoxylate (2.73 g) was refluxed in benzene (25 ml) with provision for the removal of water. After 45 minutes 8-oxo-7-azabicyclo[4,2,0]oct-3-ene (1) (ref: I. A. Paquette and T. Kakihana, J. Amer. Chem. Soc., 1968, 90, 2897) (1.23 g) was added and refluxing continued for 3 hours. Removal of solvent under reduced pressure followed by chromatography gave two separate isomers of the alcohol (2)(90%) Isomer I, m.p. 92°-93°, νmax (CHCl3)3450, 1750 (b) cm-1. δppm (CDCl3) 1.76-2.73 (4H, m, 2-CH2), 3.12-3.33 (1H, m, β-lactam proton), 3.76-3.93 (1H, m, β-lactam proton), 4.40 (1H, d, J 6 Hz, exch., D2O), 5.16 (2H, s CH2), 5.47 (1H, d, J 6 Hz collapsing to s on D 2 O exch., CH-OH), 5.67-5.83 (2H, m, CH=CH), 7.34 (5H, Ar). M+ at m/e 287 (Found: C, 66.2; H, 5.9; N, 4.9. C16H17NO4 requires C, 66.9; H, 6.0; N, 4.9%). Isomer II, m.p. 100°-101°, νmax (CHCl3) 3450, 1750 (b), δppm (CDCl3) 1.80-2.63 (4H, m,2-CH2), 3.13-3.36 (1H, m, β-lactam proton), 3.93-4.13 (1H, m, β-lactam proton), 4.20 (1H, bs, exch., D2O), 5.16 (2H, s, CH2), 5.50 (1H, b, sharpening to s on D2O exchange), 5.50-6.00 (2H, m, CH=CH), 7.34 (5H, Ar). H+ at m/e (Found: C, 67.2; H, 6.0; N, 4.8. C16H17NO4 requires C, 66.9; H, 6.0; N, 4.9%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:20]2)=[CH:16][CH:15]=1.[CH3:38][C:39]1[O:40][C:41]([CH3:46])=[C:42]([CH2:44]O)[N:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:38][C:39]1[O:40][C:41]([CH3:46])=[C:42]([CH2:44][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]3[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[N:20]3)=[CH:36][CH:37]=2)[N:43]=1
Reactant: Cc1nc(CO)c(C)o1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(C)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
Diethyl azodicarboxylate (40% in toluene, 1.00 g) was added dropwise slowly to a mixture of methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), (2,5-dimethyl-4-oxazolyl]methanol (275 mg), triphenylphosphine (585 mg) and tetrahydrofuran (10 ml) at room temperature. After the mixture was stirred at room temperature for 8 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-(2,5-dimethyl-4-oxazolylmethoxy)benzyl]3-phenyl-1H-pyrazol-4-yl]propionate (288 mg, yield: 44%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (6:5, volume ratio).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[Fe:9]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Fe+2:9]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: [Fe]
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Product: [Fe+2]

Procedure:
An aqueous solution composed of 40 g water, 11 .g maleic acid, and 5.6 g very fine iron dust is formed. The metal slowly reacts and dissolves to give iron maleate derivative solution. This solution is used as a monomer source in a polymerization reaction such as that described in Example 8, wherein equimolar amounts of maleate and vinyl acetate were used. After that, a hydrolysis is performed using the procedures described in Example 14. This reaction proceeded as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=O)=[O:5].C([O-])(=O)C.[K+].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.P(Cl)(Cl)(Cl)(Cl)[Cl:25]>C(O)(=O)C.C1(C)C=CC=CC=1>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:18])[N:1]1[CH2:2][CH2:3][S:4]([Cl:25])(=[O:7])=[O:5]
Reactant: NCCS(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Temperature: 25 °C
Yield: 60 %

Procedure:
A suspension of taurine (8.0 g, 63.9 mmol) and potassium acetate (6.7 g, 68.3 mmol) in acetic acid was refluxed for 15 min. Phthalic anhydride (10.1 g, 68.4 mmol) was added and the solution was refluxed for 3 h. The reaction was cooled to room temperature and the solid was filtered off, washed with cold acetic acid and dried under vacuum at 100° C. to give a white solid. The solid (14.3 g, 54.7 mmol) was suspended in toluene (50 ml) and phosphorus pentachloride (8.12 g, 39.0 mmol) was added under nitrogen. The reaction mixture was heated under reflux for 1 h. Further phosphorus pentachloride (8.12 g, 39.0 mmol) was added and the reaction mixture was refluxed for 2.5 h. The brownish solution was decanted from the small amount of solid formed and then concentrated in vacuo, the residue was poured onto ice:water (50:50, lOOmIl) and filtered. The solid was dried for 16 h in vacuo at 45° C. to give a pale brown solid (6.4 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C@@H:50]([NH2:52])[CH3:51]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:52][C@H:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[O:43][CH3:42])[CH3:51])=[O:33])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1[C@H](C)N
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccccc4OC)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 127.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-(2-methoxyphenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (67 mg, yield 59%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH3:16])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#N.[OH-:17].[K+].Cl.[OH2:20]>>[CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH3:16])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]([OH:20])=[O:17]
Reactant: [OH-]
Reactant: Cc1cc(C#N)cnc1N1CCCCC1C
Reactant: O
Agent: Cl
Agent: [K+]
Product: Cc1cc(C(=O)O)cnc1N1CCCCC1C
Yield: 100 %

Procedure:
A mixture of 5-methyl-6-(2-methylpiperidin-1-yl)nicotinonitrile (1 g; 4.64 mmol; 1 eq.) and potassium hydroxide (1.3 g; 23.2 mmol; 5 eq.) in water (60 mL) was stirred at reflux for 16 hours. The pH was adjusted to 5-6 with HCl 1M and the aqueous layer extracted with ethyl acetate. The combined organic phase was dried over magnesium sulphate and concentrated in vacuo to afford the title compound (1.1 g, 100%) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:25]([NH:27][CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1)[OH:32])[CH3:26].Cl>C1COCC1>[CH2:25]([N:27]([C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=1)[OH:32])[CH3:26]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: O=C(O)CC1CCCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)C(=O)CC1CCCC1
Reaction time: 1.5 h
Yield: 54 %

Procedure:
A stirred solution of cyclopentylacetic acid (2 ml, 0.0159 mol) and triethylamine (2.28 ml, 0.0163 mol) in THF (120 ml) was cooled to -8° C. and treated, dropwise with isobutyl chloroformate (2.12 ml, 0.0163 mol). The mixture was kept at -8° C. for 1.5 hour and then treated with a mixture of the product from Example 7, Step II, (4.0 g, 0.014 mol) and triethylamine (2.28 ml, 0.0163 mol) in THF (160 ml). It was kept at -8° C. for 1.5 hour and then treated slowly with 1N HCl (158 ml). The product was extracted with EtOAc. The extract was washed successively with water, saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 5% MeOH--CH2Cl2 to give 3.0 g of N-(4-(4-(ethyl(cyclopentylacetyl)amino)-1-hydroxybutyl)phenyl)methanesulfonamide. The mass spectrum had m/z 396 (M+).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[NH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C.[CH3:25][C:26]([C:29]1[CH:34]=[C:33]([SH:35])[CH:32]=[C:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]=1[OH:40])([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:28][C:26]([C:29]1[CH:34]=[C:33]([S:35][CH:2]([CH3:6])[C:3]([NH:8][CH2:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:4])[CH:32]=[C:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]=1[OH:40])([CH3:25])[CH3:27]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(Br)C(=O)Cl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Bromopropionyl chloride (5 mmole) is added to a cold (5° C.) solution of 2-aminoacetophenone hydrochloride (5 mmole) in methylene chloride followed by 14 ml of triethylamine in methylene chloride. The mixture is stirred at room temperature. After about 1 hour, the product of Example 2 is added and the solution heated to reflux. The mixture is allowed to cool to room temperature. The reaction mixture is treated as in Example 3 to produce 2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-N-(2-oxo-2-phenylethyl)propanamide.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O:24][C:25]([N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O)=[O:26])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:25]([OH:26])=[O:24].[CH2:18]([N:10]1[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=[C:9]1[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[NH:27][CH:31]=[CH:30][CH:29]=2)[N:3]=1)[CH3:19]
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc[nH]3)cnc2N)nc2cnccc21
Product: O=CO
Temperature: 200 °C
Yield: 12.2 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.020 g, 0.063 mmol) (made in example 2), 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (0.052 g, 0.25 mmol), Pd(PPh3)2Cl2 (0.004 g, 0.0057 mmol) and K2CO3 (0.050 g, 0.25 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0027 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.Cl.CCOC(C)=O.O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)=[N:4][CH:3]=1
Reactant: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC(O)(c2ncc(Br)s2)CC1
Yield: 81.9 %

Procedure:
The product of Step 1 (3.0 g, 9.4 mmol) was dissolved in 30 mL of 1:1 THF:HCl (3N) and heated at 50° C. for 8 hours and the solution neutralized with solid KHCO3 and then EtOAc (100 mL) and water (20 mL) were added. The aqueous layer was then extracted with EtOAc (50 mL) and the combined organic layers were washed with brine (50 mL), evaporated to a slurry which was treated with hexanes (20 mL). Filtration and drying afforded 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanone as a white solid (2.1 g, 7.7 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:18]=[CH:17][C:10]2[CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+].O.ClCCl>C(OC(=O)C)(=O)C>[C:22]([N:13]1[CH2:14][CH2:15][C:9]2[CH:8]=[C:7]([O:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[CH:3]=3)[CH:18]=[CH:17][C:10]=2[CH2:11][C:12]1=[O:16])(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: O=C1Cc2ccc(OCc3cccc(Cl)c3)cc2CCN1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(OCc3cccc(Cl)c3)ccc2CC1=O
Temperature: 145 °C
Yield: 65.4 %

Procedure:
A mixture of 50 mg (0.2 mmol) of 7-(3-chloro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and 33 mg (0.4 mmol) of sodium acetate in 0.12 ml of acetic acid anhydride was heated to 145° C. during 4.5 hours. For the working-up, the reaction mixture was cooled and treated with water and dichloromethane. The organic layer was separated, washed with a saturated solution of sodium hydrogencarbonate, and, finally, evaporated. For purification, the crude material obtained was chromatographed on silica gel using a 4:1-mixturet of heptane and ethyl acetate as the eluent. There were obtained 45 mg (79% of theory) of 3-acetyl-7-(3-chloro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one as a white foam; MS: m/e=344 (M+H)+.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH2:13][N:14]2[CH2:18][CH:17]([CH2:19][CH2:20][CH3:21])[CH2:16][C:15]2=[O:22])[CH:11]=[N:10][CH:9]=1)(C)(C)C>CC(O)=O.C1COCC1.O>[OH:6][CH2:7][C:8]1[N:12]([CH2:13][N:14]2[CH2:18][CH:17]([CH2:19][CH2:20][CH3:21])[CH2:16][C:15]2=[O:22])[CH:11]=[N:10][CH:9]=1
Reactant: CCCC1CC(=O)N(Cn2cncc2C(C)(C)O[SiH2]C(C)(C)C)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCC1CC(=O)N(Cn2cncc2CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, 1-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-ylmethyl]-4-propyl-pyrrolidin-2-one a30 (0.5 g, 0.0014 mol) is heated at 80° C. in a AcOH/THF/H2O mixture (9 ml/3 ml/3 ml) for 9 h, then stirred overnight at room temperature and concentrated in vacuo. The residue is dry by azeotropic distillation with toluene, purified by chromatography on silicagel (CH2Cl2/MeOH) and the solid is recrystallized from AcOEt to give 1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one 80 (0. 1 14 g, 35%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].I[CH3:16]>O1CCCC1>[NH:2]=[C:1]([S:3][CH3:16])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C)c(C(N)=S)c1
Reactant: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(C(=N)SC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a stirred solution of methyl 3-carbamothioyl-4-methylbenzoate (compound 38.3, 2.10 g, 9.85 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) was added iodomethane (2.8 g, 19.73 mmol, 2.00 equiv) dropwise. The resulting mixture was stirred at room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure and the residue was dried under vacuum to yield 1.6 g (73%) of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([CH2:11][CH3:12])=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=[O:52].[O:53]1[CH2:57]CCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([C:8]1[S:9][C:10]2[C:2]([C:57]([OH:53])=[O:52])=[CH:3][CH:4]=[C:5]([O:13][CH3:14])[C:6]=2[N:7]=1)[CH3:12]
Reactant: CCc1nc2c(OC)ccc(Br)c2s1
Reactant: C1CCOC1
Reactant: [C]=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 7-bromo-2-ethyl-4-methoxybenzothiazole (2.96 g), palladium (II) acetate (240 mg), bis-diphenylphosphinopropane (900 mg), and triethylamine (15 ml) in tetrahydrofuran (150 ml) and water (20 ml) was charged with 150 psi of carbon monoxide and stirred at 90° C. for 3 days. The organic solvent was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and aqueous sodium hydroxide (1M, 2×50 ml). The aqueous extracts were combined, acidified to pH 4 with glacial acetic acid, extracted with ethyl acetate (3×50 ml). The organic extracts were combined, dried over magnesium sulphate (5 g), filtered, and the filtrate evaporated in vacuo Recrystallisation from ethyl acetate/hexane gave the desired product as an off-white solid (2.2 g). TLC Rf 0.30 (50%ethyl acetate in hexane)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[O:15][C:16]([Br:19])=[CH:17][CH:18]=1)=O>C(O)C>[Br:19][C:16]1[O:15][C:14]([C:12]2[N:1]=[C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]3[CH:11]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(Br)o1
Solvent: CCO
Product: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1
Yield: 74 %

Procedure:
A mixture of 6-Amino-nicotinonitrile (1.19 g, 10 mmol) and 2-Bromo-1-(5-bromofuran-2-yl)-ethanone (2.66 g, 10 mmol) in ethanol (50 mL) was refluxed for 24 h. The precipitate was filtered and neutralized with aqueous NaHCO3 solution. The precipitate was filtered and dried to furnish 3a in 74% yield, mp 212-214° C. (EtOH). 1H NMR (DMSO-d6); δ 6.75 (d, J=3.6 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 9.30 (s, 1H). 13C NMR; δ 150.5, 144.2, 137.3, 134.3, 125.4, 121.9, 117.2, 116.9, 113.9, 110.4, 109.8, 97.2. MS (m/z, rel.int.); 288 (M+, 100), 161 (8). Anal. Calcd. for 3a (C12H6BrN3O): C % 50.03, H % 2.10. Found: C % 49.97, H % 2.17.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([O:35][CH3:36])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([O:35][CH3:36])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 49.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.1 g, 2.2 mmol) was reacted with methyl morpholine-3-carboxylate (0.4 g, 2.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.62 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[CH2:12]([N+:19](C)(C)C)[C:13]1C=CC=C[CH:14]=1>C(#N)C=C.C(OCC)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH2:14][CH2:13][C:12]#[N:19])=[CH:3][C:2]=1[CH3:1]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: COc1ccc(O)cc1C
Agent: [OH-]
Solvent: CCOCC
Solvent: C=CC#N
Product: COc1ccc(OCCC#N)cc1C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 7.0 grams (0.050 mole) of 3-methyl-4-methoxyphenol (known compound) in 20 mL of acrylonitrile was stirred, and 0.4 mL of benzyltrimethylammonium hydroxide (Triton® B) was added. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred during a 21 hour period. The reaction mixture was then cooled to ambient temperature and diluted with 100 mL of diethyl ether. The mixture was then first washed with three 50 mL portions of an aqueous solution of 10% potassium hydroxide, then with three 50 mL portions of aqueous 4N hydrochloric acid. The organic layer was dried with sodium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure, yielding 6.0 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[CH2:17][C:18]1([CH3:40])[C:22](=[O:23])[O:21]C(C2C=CC=CC=2)[N:19]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].CO.[OH-].[Na+]>C(Cl)Cl>[CH3:40][C:18]([NH:19][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])([CH2:17][C:3]1[C:4]([CH3:16])=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:2]=1[CH3:1])[C:22]([OH:23])=[O:21]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CC1(C)C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 86.6 %

Procedure:
The title compound of Example 54 (2.42 g) was dissolved in 5 ml of 1:1 CH2Cl2 : methanol, and added to methanolic NaOH (1N, 100 ml). After 3 hr of stirring, the mixture was concentrated to 75 ml, diluted to 500 ml with water, and extracted twice with ether to remove non-acidic contaminants. The aqueous phase was made acidic with 0.5N KHSO4, and then extracted four times with CH2Cl2. The CH2Cl2 fractions were combined, dried (MgSO4), filtered, and stripped to give the title compound (1.75 g). NMR:α methyl group at ∫2.75.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([N:20]2C(=O)C3C(=CC=CC=3)C2=O)[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O.NN>CO>[NH2:20][C@H:17]1[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@@H:10]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](N2C(=O)c3ccccc3C2=O)CC[C@H]1c1cccc(F)c1F
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In a 100 mL round-bottomed flask was dissolved tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(1,3-dioxoisoindolin-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (46.8 mg, 0.090 mmol) in methanol (1 mL) to give a white suspension. Hydrazine hydrate (0.1 mL, 3.2 mmol) was added, and the mixture was stirred in a preheated oil bath at 70° C. under nitrogen for 2 h. LCMS indicated the desired product. Methanol was removed in vacuo and the residue was partitioned between 0.5N sodium hydroxide and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated. Flash column chromatography upto 10% methanol (with 2M ammonia) in methylene chloride afforded the desired product as a colorless oil (26.9 mg, 77% for two steps): 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.3 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.25 (t, J=6.4 Hz, 1H), 7.12-6.98 (m, 2H), 6.24 (d, J=8.6 Hz, 1H), 5.25 (t, J=9.5 Hz, 1H), 4.50 (d, J=10.2 Hz, 1H), 3.03 (t, J=10.7 Hz, 1H), 2.60-2.43 (m, 1H), 2.39-2.07 (m, 4H), 1.61-1.40 (m, 1H), 1.23 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −138.95-−139.53 (m), −142.46 (d, J=18.8 Hz).