Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2]O.[C:4]([CH2:10][C:11]#[N:12])(=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]>>[NH2:12][C:11]1[CH:10]=[C:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[O:9][N:2]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Product: CC(C)(C)c1cc(N)no1

Procedure:
In adding the hydroxylamine hydrochloride to the reaction mixture, it appears that a quick addition is preferable. Best results appear to be obtained by adding an aqueous solution of the hydroxylamine hydrochloride to the basic solution of the pivalyl acetonitrile, and then, within the first 15 to 30 minutes, adjusting the pH to within the range of from about 5.0 to about 8.0, preferably from about 6.0 to about 7.0, with the pH range of choice being pH about 6.2 to about 6.5. This careful control of the pH of the reaction mixture is important in order to obtain the maximum yield of the 3-amino-5-(t-butyl)isoxazole since the reaction is very sensitive to the pH. A pH lower than about 5.0 results in the formation of an isoxazolone compound as the principal product. Higher pH values, that is, above about pH 8.0, result in unacceptably large amounts of the 5-amino-3-(t-butyl)isoxazole, compared to the amount of the desired 3-amino-5-(t-butyl)isoxazole. Even at pH 7.0, the ratio of the desired 3-amino compound to the 5-amino compound is less desirable.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].[C:21]([NH:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30][C:31](=O)[C:26]=12)=[O:29])(=[O:23])[CH3:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:31](=[O:30])[C:26]3[C:27](=[CH:33][CH:34]=[CH:35][C:25]=3[NH:24][C:21](=[O:23])[CH3:22])[C:28]2=[O:29])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 402.8 %

Procedure:
N-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of example 4 from 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.6 g, 0.2 mmol), 3-acetamido-phthalic anhydride (0.4 g, 0.2 mmol) and sodium acetate (0.16 g, 0.2 mmol) in acetic acid (15 ml) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as white solid (0.4 g, 40%): mp 118-120° C.; 1H NMR (CDCl3) δ 1.45 (t, J=7.0 Hz, 3H, CH3), 2.27 (s, 3H, CH3CO), 2.92 (s, 3H, SO2CH3), 3.66 (dd, J=3.8, 14 Hz, 1H, CH2), 4.11 (q, J=6.8 Hz, 2H, OCH2), 5.88-5.94 (m, 1H, NCH), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.12-7.16 (m, 3H, Ar), 7.49 (d, J=7.5 Hz, 1H, Ar), 7.66 (t, J=7.5 Hz, 1H, Ar), 8.77 (d, J=8.5 Hz, 1H, Ar), 9.44 (s, 1H, NH); 13C NMR (CDCl3) δ 14.5, 24.9, 41.7, 48.3, 54.1, 64.9, 11.5, 113.6, 115.0, 115.8, 118.3, 120.0, 120.2, 123.1, 125.1, 130.9, 135.4, 136.2, 137.7, 140.4, 150.9, 167.4, 169.1, 169.4; Anal Calcd for C22H22F2N2O7S: C, 53.22; H, 4.47; N, 5.64. Found: C, 53.18; H, 4.20; N, 5.64.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:13][Si:14]([CH3:22])([CH3:21])[C:15]#[C:16][Si](C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](=[O:7])[C:16]#[C:15][Si:14]([CH3:22])([CH3:21])[CH3:13])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[Si](C)(C)C#CC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 2-nitrobenzoyl chloride (13) (225 g; 1.2 moles) and 1,2-bis(trimethylsilyl)ethyne (205 g; 1.2 moles) in dichloromethane (3 L) was cooled to 0° C. Aluminum chloride (159.2 gram, 1.2 moles) was slowly added at 0° C. over 10 minutes while keeping the internal reaction temperature below 10° C. After the addition, the reaction mixture was stirred at 5-10° C. for 1 hour. With stirring, the black reaction mixture was poured into ice-water mixture (2 kg of ice and 1 kg of water). The resulting suspension was filtered and the filter cake was washed with dichloromethane (200 mL). The organic phase of the combined filtrate was separated. The aqueous phase was extracted 2-times with dichloromethane (2×2 L). The combined organic phase was washed with water (2 L), filtered through a Celite pad (200 g), dried over sodium sulfate (120 g), and concentrated at the temperature below 30° C. (bath temperature) to dryness to give 294 g (99% yield) of the desired product in 95% HPLC purity.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].Cl.[NH2:13][CH:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH:30]([F:32])[F:31])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:15][OH:16].C(=O)(O)[O-].[Na+]>ClCCl.O>[F:32][CH:30]([F:31])[S:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:14]([NH:13][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[CH2:15][OH:16])=[CH:18][CH:19]=2)=[CH:28][CH:27]=1
Reactant: NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 0.137 g (0.776 mmol) of 2,6-difluorobenzoyl chloride in 1 mL of dichloromethane was added dropwise to a mixture of 0.23 g (0.693 mmol) of β-amino-4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-ethanol hydrochloride salt, 1.5 mL of dichloromethane, and 1.5 mL of sodium bicarbonate (saturated aqueous solution). The mixture was stirred for 2 h, and was diluted with 10 mL of water. The mixture was extracted with 3×20 mL of dichloromethane, 35 mL of dichloromethane and the organic phase separated. The combined extracts were dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate/hexane (1:1)) gave the product 0.28 g (93% yield) as a white solid m.p. 156.5-157° C. IR(Nujol): 3294, 1649, 1624, 1589, 1535, 1309, 1233, 1071, 1004, 819 cm-1. 1H-NMR(CDCl3): δ2.15 (t, J=5.75 Hz, 1H), 4.03-4.06 (m, 2H), 5.33-5.37 (m, 1H), 6.81 (d, J=7.2 Hz, 1H), 6.86 (t, J=57 Hz, 1H), 6.94-6.99 (m, 2H), 7.35-7.43 (m, 1H), 7.48 (d, J=8 Hz, 2H), 7.50-7.65 (m, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:14][CH2:15]S(C)(=O)=O)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:51]=[CH:50][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[C:43]2([OH:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][N:46]2[CH2:47][CH2:48][C:43]([C:35]3[N:34]([CH2:33][C:32]4[CH:50]=[CH:51][C:29]([F:28])=[CH:30][CH:31]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)([OH:49])[CH2:44][CH2:45]2)([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCC1(Cc2ccccc2)CCCN(Cc2ccccc2)C1=O
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: O=C1N(Cc2ccccc2)CCCC1(CCN1CCC(O)(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1

Procedure:
Prepare by the method of Example 6.6.2 using 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-piperidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.66 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)#[CH:2].[C:12]([O:16][C:17](N1C2C(=CC=C(CCOC3C=C4C(=CC=3)NC=C4)N=2)CCC1)=[O:18])(C)(C)[CH3:13]>>[CH2:12]([O:16][C:17](=[O:18])[C:2]#[C:1][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: C#Cc1ccc2c(c1)OCO2
Product: CCOC(=O)C#Cc1ccc2c(c1)OCO2
Yield: 54 %

Procedure:
The title compound was synthesized from 5-ethynyl-benzo[1,3]dioxole and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 23, step (c), in 54% yield. 1H NMR (CDCl3) δ 7.16 (dd, 1H, J=1.6, 8.1 Hz), 7.00 (d, 1H, J=1.6 Hz,), 6.80 (d, 1H, J=8.1 Hz,), 6.02 (s, 2H), 4.29 (q, 2H, J=7.2 Hz,), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH:19]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[N:18]([C:35](Cl)=[O:36])[CH2:17][CH2:16]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:35]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:19]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)=[O:36])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)Cl)cc1OC
Reactant: CC(C)N(CCN)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)NCCN(C(C)C)C(C)C)cc1OC
Reaction time: 3.5 h

Procedure:
4.0 Parts of 2-diisopropylaminoethylamine in 75 parts of chloroform is added portionwise, at room temperature, to a mixture of 8.0 parts of 6,7-dimethoxy-1-(3,4-dimethoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarbonyl chloride and 15 parts of triethylamine in 225 parts of chloroform. After the addition is complete, the mixture is stirred for 3 to 4 hours, allowed to stand overnight, and then washed with water. The chloroform layer is separated, dried over anhydrous calcium sulfate and concentrated under reduced pressure. The solid material obtained in this manner is crystallized from ether to give N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-(3,4-dimethoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 114°-115°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>O>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 157.5 %

Procedure:
To a mixture of 2-chloro-4-fluoro-5-nitrophenol (9.6 g) and potassium carbonate (3.8 g) in acetontrile (50 ml), there was added methyl iodide (14 g), and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature (ca. 20° C.), water was added thereto, and the resulting mixture was extracted with ether. The ether extract was washed with water, dried and concentrated. The residue was recrystallized from ethanol to give 8.9 g of 4-chloro-2-fluoro-5-methoxynitrobenzene. M.P., 67.5°-69.8° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[NH2:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NC(CO)CO
Solvent: CN(C)C=O
Product: Cc1csc2c(NC(CO)CO)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
In 8 ml of DMF was dissolved 1.0 g (4.6 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then 977 mg (10.7 mmol) of 2-amino-1,3-propanediol was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 903 mg (yield: 72.3%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:10](N)=[O:11]>>[CH:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: NC=O
Product: CC(C)C[C@H](NC=O)C(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
165.2 g of L-leucine and 821.7 g of formamide are introduced, under a nitrogen atmosphere, into a reactor equipped with a stirrer system. The mixture is heated at 100° C. for approximately 6 hours. Approximately 513 g of formamide are then removed by distillation under a pressure of 20 -30 mm of mercury and at a pot temperature of 50°-60° C. 1082 g of water are subsequently added to the mixture. It is cooled to 20°-25° C. It is then acidified to pH 2.5 with sulphuric acid. It is stirred for 2 hours at approximately 20° C. and then for one hour at 5° C. Filtration is carried out and the cake is rinsed with 100 g of water at pH 2. It is dried under vacuum. 180.3 g of N-formyl-L-leucine are thus obtained (90% yield) with an optical rotation [α]D20=−17.7° (c=1 in ethanol), i.e. a purity of 98.3%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:26])=O)=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[NH2:34][CH2:35][C:36]([CH3:39])([OH:38])[CH3:37]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([NH:34][CH2:35][C:36]([OH:38])([CH3:39])[CH3:37])=[O:26])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CC(C)(O)CN
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)O)nc5)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)NCC(C)(C)O)nc5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid and 1-amino-2-methyl-2-propanol (Tyger, Cat. No. A57123). LCMS (M+H)+: m/z=517.4.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][C@H:12]1[N:15]([CH:16]([C:33]([CH3:35])=[CH2:34])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:36])[C@H:13]1[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O.[C:49]1([CH3:58])[CH:54]=[CH:53][C:52]([S:55]([O-:57])=[O:56])=[CH:51][CH:50]=1.[Na+]>CC(C)=O.O.[N+]([O-])([O-])=O.[Ag+]>[C:49]1([CH3:58])[CH:54]=[CH:53][C:52]([S:55]([S:11][C@H:12]2[N:15]([CH:16]([C:33]([CH3:35])=[CH2:34])[C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[C:14](=[O:36])[C@H:13]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Yield: 74.1 %

Procedure:
To a solution of diphenylmethyl 2-[(3R,4R)-4-[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XIIIa. 12.12 g, 0.0182 mole) in acetone (325 mL) and water (37 mL), silver nitrate (3.86 g, 0.0227 mole) was added all at once. A freshly prepared solution of sodium p-toluenesulfinate hydrate (4.05 g; 0.0227 mole) in acetone (255 mL) and water (37 mL) was added dropwise over 1 h, while the reaction mixture was protected from light. After an additional 1h period at room temperature, Celite (5 g) was added and the mixture was diluted with acetone (500 mL) and then was filtered. The filtrate was evaporated to a small volume, and the crude product was extracted into ether (3×250 mL). The ether phase was dried with magnesium sulfate and concentrated to afford a crude product. Flash chromatography (SiO2, eluting with 40% ethyl acetate in hexane) gave 9.05 g (73.5%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:10]2[CH:11]=[N:12]C=[N:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.NN.O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:10]2[CH:11]=[N:12][NH:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cncnc1
Agent: NN
Solvent: O
Solvent: CCO
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cn[nH]c1

Procedure:
The methiodide salt of α,α-bis(4-chlorophenyl)-pyrimidine-5-methanol (12.8 g) was heated to reflux with 3 g of anhydrous hydrazine in ethanol. The original slurry went into solution and then a precipitate formed, at which time 25 ml of water were added. The mixture was heated at reflux for 20 minutes, filtered hot, water was added and the mixture was extracted with ether. The ether was evaporated and the residue was crystallized from chloroform to provide the title product, m.p. 135°-137° C. The NMR and mass spectra were consistent with the desired structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[NH:12][C:11]3[CH2:24][O:25][CH2:26][C:27](=[O:28])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].BrN1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:27](=[O:28])[CH2:26][O:25][CH2:24][C:11]=3[NH:12][C:13]3[CH:20]([CH2:21][CH2:22][CH3:23])[O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC1=C(C(=O)OCC)C(c2ccc(F)c(Br)c2)C2=C(COCC2=O)N1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCC1OC(=O)C2=C1NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
The product from Example 97B (0.77 g, 1.7 mmol) in chloroform (30 mL) under nitrogen was treated with N-bromosuccinimide (0.36 g, 2.0 mmol), stirred at ambient temperature for 30 minutes, refluxed for 16 hours and concentrated to dryness. The resulting two isomers were separated by chromatography on silica gel eluting with (ethyl acetate:formic acid:water:hexane, 38:1:1:40 to 38:1:1:30 to 38:1:1:20). The faster moving isomer was rechromatographed on silica gel eluting with 2% methanol in ammonia saturated dichloromethane and then rechromatographed again on silica gel eluting with (hexanes:acetone, 3:1). The faster moving isomer was then crystallized from acetone/hexanes and the resulting crystals were collected by filtration, washed with acetone/hexanes and dried under reduced pressure to provide the title compound (0.058 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[Cl:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A mixture of 2,3-diamino-5-chlorobenzotrifluoride (180 mg, 0.86 mmol) and oxalic acid dihydrate (108 mg, 0.86 mmol, used as received) in 2N HCl (4 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 136 mg of crude title compound (53%) as a yellow powder. The crude title compound was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=6, affording 115 mg of title compound. Recrystallization from DMSO/H2O gave 95 mg of pure title compound (37%) as yellow microcrystals. Mp: 302°-4° C. (dec. from 295° C.). IR (KBr, cm-1) 3401, 3255, 1754, 1694, 1528. 1H NMR (DMSO-d6): δ7.374 (d, 1H, J=1.8 Hz); 7.474 (d, 1H, J=1.8 Hz); 11.347 (s, 1H); 12.215 (s, 1H). HRMS: calcd for C9H4ClF3N2O2 (M+) m/z: 263.9912; found: 263.9909.
Reaction SMILES: C[O:2][C:3](=[O:26])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[CH:5]/[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>C(O)C>[CH:7]1([CH2:6]/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)/[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)/C(=C/CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 40 °C
Yield: 92.4 %

Procedure:
A solution of (E)-4-cyclopentyl-2-[4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-but-2-enoic acid methyl ester (0.82 g, 2.1 mmol) in ethanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (5 mL). The solution was heated at 40° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (30 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-4-cyclopentyl-2-[4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-but-2-enoic acid (0.73 g, 92%) as a gummy solid: EI-HRMS m/e calcd for C17H19F3O4S (M+) 376.0243, found 376.0261.
Reaction SMILES: [C:1]([N:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2].[CH3:11][O:12][C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2OS(C(F)(F)F)(=O)=O.C(N(CC)CC)C>O1CCOCC1>[CH3:11][O:12][C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2[N:8]1[CH2:9][CH2:10][CH:6]([N:4]([CH3:5])[C:1](=[O:3])[CH3:2])[CH2:7]1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: CC(=O)N(C)C1CCNC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2nccc(N3CCC(N(C)C(C)=O)C3)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
3-(N-acetyl-N-methylamino)pyrrolidine (1.00 g, 7.0 mmol) was dissolved in dioxane (15 mL) and treated with 1,1,1-Trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (1.67 g, 5.4 mmol) and triethylamine (0.98 mL, 7.0 mmol). After stirring at 50° C. overnight the reaction mixture was cooled, concentrated to dryness and purified via column chromatography (silica, 2% MeOH in chloroform) to afford the title compound as an off-white solid (1.72 g, quantitive): LC-MS m/z 301 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)=[CH2:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23](=[O:24])[CH:22]=[CH:21][C:20]2=[O:25])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:23](=[O:24])[CH:22]3[CH:21]([CH2:2][CH:1]=[C:3]4[O:4][C:5]5[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=5[CH:7]43)[C:20]2=[O:25])=[CH:17][CH:18]=1
Reactant: Cc1ccc(N2C(=O)C=CC2=O)cc1
Reactant: C=Cc1cc2ccccc2o1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2C(=O)C3CC=C4Oc5ccccc5C4C3C2=O)cc1
Yield: 48.9 %

Procedure:
10 ml of toluene was added to a mixture of 0.40 g of 2-vinylbenzofuran and 0.52 g of N-(4-methylphenyl)maleimide. The mixture was refluxed for 3 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1 to 20/1) to obtain 0.45 g (yield: 49%) of 2-(4-methylphenyl)-3a,4,10b,10c-tetrahydro-1H-benzofuro-[3,2-e]isoindole-1,3(2H)-dione as colorless crystals.