Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(NCC4C=CC=CC=4)=CN=C3CC2)=O)=CC=1)=N)(C)(C)[CH3:2].[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH2:60])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH:60][CH2:1][CH3:2])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)NCC
Yield: 54 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, 26a (30.0 mg, 0.045 mmol), acetaldehyde (2.2 mg, 0.050 mmol) and NaBH(OAc)3 (14.4 mg, 0.068 mmol) yielded 16.9 mg (54%) of 26b. MS (ESI) 692.5 (M+H+).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]1[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH2:15][CH2:14][N:13]1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:27][N:26]=1.CN(C=[O:41])C>>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[N:30][C:25]([N:13]2[CH2:14][C:15]3[C:16](=[O:41])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[NH:23][C:24]=3[CH:12]2[CH:4]2[CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:3]2)=[N:26][CH:27]=1
Reactant: c1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3C3Cc4ccccc4O3)nc2)nc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=c1c2c([nH]c3ccccc13)C(C1Cc3ccccc3O1)N(c1ncc(-c3ccccn3)cn1)C2

Procedure:
Sodium hydride (60% in mineral oil, 182 mg, 4.55 mmol) and 1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1H-β-carboline (16176-23) (882 mg, 1.98 mmol) (prepared as in Example 49) in DMF (30 mL, anhydrous) were stirred at room temperature for 30 min. Dry air then was bubbled through the reaction mixture for 16 h. Ethyl acetate (200 mL) was added, and the resulting mixture was washed with 10% NaCl solution, brine, and then dried with MgSO4. The reaction mixture solvent was evaporated and the residue triturated with ethyl acetate to yield the product as a white solid.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: CC(C)CBr
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OCC(C)C)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 367 and isobutyl bromide, white powdery N-[2-(3-difluoromethoxy-4-isobutoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 98.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2([C:19]([OH:21])=[O:20])[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[CH2:12]2)=[CH:2]1>N.[Rh]>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C@@:11]([OH:15])([C:19]([OH:21])=[O:20])[CH2:12][C@H:13]([NH2:14])[C:16]([OH:18])=[O:17])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=C(O)C1=NOC(Cc2c[nH]c3ccccc23)(C(=O)O)C1
Agent: [Rh]
Agent: N
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Yield: 87.8 %

Procedure:
380 mg (1.31 mmols) of 5-(RS)-(3-indolylmethyl)-4,5-dihydroisoxazole-3,5-dicarboxylic acid was dissolved in 8 ml of 28% aqueous ammonia solution, 200 mg of a 5% rhodium-active carbon catalyst was added thereto, and catalytic hydrogenation was conducted under a hydrogen pressure of 1 MPa for 16 hours. The catalyst was removed by filtration, and the filtrate was freeze-dried to obtain 336 mg of monatin and a small amount of DL-alanine as a by-product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33]>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:26][C:25]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C(F)(F)F)c3)CC2)cc1
Yield: 56.3 %

Procedure:
The title compound (D30) (35 mg) was prepared according sperimental procedure described in description 29 starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (40 mg, 0.13 mmol) and 4-fluoro-3-(trifluoromethyl)benzaldehyde (0.02 ml, 0.16 mmol)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:21]=[CH:22][C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:33])(=[O:32])[C:24]=2[CH:34]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:30]1[CH:29]=[CH:28][C:27]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:34][C:24]=3[S:25](=[O:32])(=[O:33])[C:26]=2[CH:31]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)c2ccccc2-c2ccc(I)cc21
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1-2

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) 3-iododibenzo[b,d]thiophene 5,5-dioxide (Intermediate 232), the title compound was obtained as a pink solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([C:9](C#N)([CH:15]([CH:21]([CH3:23])[CH3:22])[C:16]([O:18]CC)=[O:17])[C:10]([O:12]CC)=[O:11])([CH3:8])[CH3:7]>O.[OH-].[K+]>[CH:6]([CH:9]([CH:15]([CH:21]([CH3:23])[CH3:22])[C:16]([OH:18])=[O:17])[C:10]([OH:12])=[O:11])([CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C(C)C)C(C#N)(C(=O)OCC)C(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(C(=O)O)C(C(=O)O)C(C)C
Temperature: 160 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
10 ml of 95% concentrated sulfuric acid was slowly added dropwise into 5 ml of water, and the mixture was cooled to room temperature, to obtain a sulfuric acid solution. The prepared sulfuric acid solution was added into a three-necked flask containing 0.22 g of diethyl 2,3-diisopropyl-2-cyanosuccinate, and the reaction mixture was stirred at an oil-bath temperature of 160° C. for 16 h. Upon the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30 ml of water, and cooled to room temperature again. The reaction mixture was extracted with anhydrous diethyl ether, and the solvent was removed from the extract liquor, to afford a mixture of white solids and oily liquid. This mixture was dissolved in 10 ml of 10% aqueous KOH solution, and the resultant solution was stirred at 50° C. for 45 min. The reaction mixture was extracted with diethyl ether, and the organic phase was discarded. The aqueous phase was acidified with concentrated hydrochloric acid, whereby white precipitates formed. The precipitates were filtered and dried, to afford the product, 2,3-diisopropyl succinic acid (yield: 60%).
Reaction SMILES: [CH2:1]([C:5]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:26]([O:36]C)=[CH:25][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH2:2][CH2:3][CH3:4].C([S-])C.[Na+]>CN(C)C=O.Cl>[CH2:1]([C:5]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:26]([OH:36])=[CH:25][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(-c2ccc(F)cc2)c(OC)cc1OCCCOc1ccccc1CCC(=O)OCC
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCC(=O)O
Yield: 66 %

Procedure:
A solution of ethyl 3-(2-(3-(2-butyl-4-(4-fluorophenyl)-5-methoxyphenoxy)propoxy)phenyl)propionate and 5 equivalents of sodium ethanthiolate in dimethylformamide was heated at 110° C. for 2 hours, cooled, diluted with aqueous hydrochloric acid, and extracted with ethyl acetate. The organic solution was washed with water, dried, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl ether and with ethyl acetate providing the desired title product in 66% yield. NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:8]2[C:12]=1[O:11][CH:10]=[CH:9]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:8]2[C:12]=1[O:11][CH2:10][CH2:9]2
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2occc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c2c1CCO2
Reaction time: 16 h
Yield: 62.4 %

Procedure:
Methyl 7-nitrobenzofuran-4-carboxylate 1f (820 mg, 3.70 mmol) was dissolved in 150 mL of methanol in an ice-water bath, added with (164 mg, 10%) palladium/carbon, methanol (0.3 mL). The resulting solution was subjected to hydrogenation for 16 hours at 3 atmosphere at room temperature. The resulting mixture was filtered and washed with 50 mL of methanol, concentrated under reduced pressure. The crude residue was recrystallised by the mixture solvent of 25 mL ethyl acetate and n-hexane (V/V=1:4) to obtain the title compound methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (446 mg, yield: 62.0%) as a gray solid.
Reaction SMILES: [O:1]=[CH:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[BH4-].[Na+].O>CO>[OH:1][CH2:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C=O)c1cc(C)cc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(CO)c1cc(C)cc(OC)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
A stirred solution of ethyl 3-oxo-2-(3-methoxy-5-methylphenyl)propionate (1.9 g; 8.1 mmol; from step (v) above) in MeOH (50 mL) was cooled to −15° C. NaBH4 (0.61 g; 16 mmol) was then added in portions. The mixture was stirred for 3 hours at −15 to −5° C. Water was then added, and resultant mixture concentrated. The aqueous phase was extracted with EtOAc, the organic phase was washed with water, dried (Na2SO4) and evaporated to yield 2.0 g (59%) of sub-title compound
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>C(#N)C>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Solvent: CC#N
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)NC(=O)C(C)O4)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.5 g) and 2-amino-4-picoline (1.6 g) in acetonitrile (60 ml) was refluxed for 2.5 hours and the reaction mixture was evaporated under reduced pressure. A mixture of ethyl acetate and 5% hydrochloric acid was added to the residue and the resultant mixture was stirred at ambient temperature for 30 minutes. The precipitate was collected by filtration and suspended in water. The mixture was adjusted to pH 7.5 with 20% aqueous potassium carbonate. The resultant mixture was extracted with chloroform and the extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 6-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.7 g).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSc1nnc(Cc2cccnc2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCNc1nnc(Cc2cccnc2)c(=O)[nH]1
Yield: 70.9 %

Procedure:
3-Methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (2.34 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.88 g) were heated together on anoil bath (160°-70°). The cooled mixture was triturated with boiling methanol and the solid was recrystallised from dimethylformamide to give the title compound as a colourless solid (2.53 g) m.p. 232°14 233°.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1[O:19][C@@H:20]1[CH2:33][C@@H:23]2[O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][C@@H:22]2[C@H:21]1/[CH:34]=[CH:35]/[C@@H:36]([O:49]C1CCCCO1)[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=1>CO>[OH:19][C@@H:20]1[CH2:33][C@@H:23]2[O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][C@@H:22]2[C@H:21]1/[CH:34]=[CH:35]/[C@@H:36]([OH:49])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:46])[F:47])[CH:40]=1
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: O
Solvent: CO
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Toluenesulfonic acid monohydrate (0.20 g, 1.1 mmol) was add to a stirred solution of (8aR,9R,10R,11 aS,Z)-10-((tetrahydro-2H-pyran-2-yl)oxy)-9-((3R,E)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)-4,5,8,8a,9,10,11,11a-octahydrocyclopenta[b]oxecin-2(3H)-one (14.0 g, 23.0 mmol) in methanol (150 mL). The mixture was stirred for 2 hr at room temperature (TLC monitoring). Then, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (200 mL), and the methanol was removed under reduced pressure. The residue was extracted with ethyl acetate (200 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 15.0 g of the crude product. The crude product was subjected to further purification by flash column chromatography to obtain 8.2 g of the title compound as a solid. DSC analysis showed that the solid contained two crystalline forms (mp 92˜97° C. and mp 113˜118° C.) The solid was recrystallized from a mixture of hexane and ethyl acetate to give 7.3 g of title compound as a single crystalline form (mp 113˜118° C.). The x-ray powder diffraction pattern of crystalline title compound (mp 115˜120° C.) has characteristic peaks expressed in degrees 2θ at approximately 10.7, 12.1, 13.4, 14.5, 14.8, 16.0, 16.6, 17.7, 18.4, 18.5, 19.4, 20.5, 21.0, 22.0, 22.4, 23.3, 24.6, 24.7, 25.1, 28.9, 29.9, 37.9, 44.1.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][C:10]=2[Cl:33])[CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[Cl:33][C:10]1[CH:11]=[C:12]([C:15]2[CH2:19][C:18]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=2)[CH:13]=[CH:14][C:9]=1[N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]1
Reactant: COC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
To a stirred suspension of 1-{2-Chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid methyl ester (Preparation 13, 0.55 g, 1.086 mmol) in THF:MeOH:H2O (1:1:1, 9 mL) was added lithium hydroxide (0.228 g, 5.43 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours. After consumption of starting material, reaction mixture was concentrated in vacuo; acidified with 1N HCl up to pH ˜5. Acidified aqueous layer was extracted with ethyl acetate (5×20 mL). Combined organic layer was dried over sodium sulphate and evaporated under reduced pressure and was triturated with n-pentane (25 mL) to afford off white solid (0.4 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ: 3.45-3.50 (m, 1H), 4.12-4.16 (m, 2H), 4.26-4.33 (m, 4H), 6.67 (d, 1H, J=9.04 Hz), 7.51-7.53 (m, 2H), 7.81 (s, 2H), 12.75 (bs, 1H); LC-MS (M+H): =528.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N.O=[C:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.C(O)(=O)C>CO>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)[CH2:31][CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a stirred solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (122 mg, 0.5 mmol) in 10 ml of methanol, tert-butyl 4-oxopiperidine-1-carboxylate (102 mg, 0.512 mmol), was added acetic acid (0.05 mL). The mixture was stirred at rt for 15 min, after which picolineborane (112 mg, 1.047 mmol) was added. The mixture was stirred at rt overnight. LCMS indicated 87% product and 13% SM. Additional picolineborane (50 mg, 0.467 mmol) was added and the mixture was stirred for an additional 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride and treated with saturated sodium bicarbonate to pH=9. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×10 mL). The solvent was reduced to about 4 mL and the residue was loaded onto a silica gel column. Eluting with 5% methanol/methylene chloride gave 188 mg (88%) of desired product as white solid. MS +m/z: 427.0 (M+H)+
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][CH2:7][C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[C:12]2=[CH:22][S:23][CH:24]=[C:11]12)=[O:9]>C(Cl)Cl>[Cl:4][C:24]1[S:23][CH:22]=[C:12]2[C:13](=[O:21])[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8](=[O:9])[CH2:7][Cl:6])[C:11]=12
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ccccc2N(C(=O)CCl)c2c1csc2Cl
Reaction time: 12 h

Procedure:
5 ml of sulfuryl chloride in 100 ml methylene chloride are added dropwise to a solution of 12 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one in 300 ml of methylene chloride at 20° C. The mixture is left to stand at room temperature for a further 12 hours and is then extracted by shaking it with sodium bicarbonate solution and washing it with water; the organic phase is dried and concentrated. The residue is made to crystallize with a little methanol. 7 g of 3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one is thus obtained, m. 214° to 216° C. (acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=O)=[CH:3]1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)=[O:14])=[CH:3]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Product: Cn1cc(CC(=O)Nc2cccc(C(F)(F)F)c2)c2ccccc21
Yield: 62 %

Procedure:
The title compound was synthesized in 62% yield (41.1 mg) according to a procedure described in Example 107 starting from (1-methyl-1H-indol-3-yl)-acetic acid and 3-trifluoromethyl-aniline. Calculated for C16H23N3O m/z: 332.11, found 332.89 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 2H), 3.75 (s, 3H), 7.01 (m, 1H), 7.14 (m, 1H), 7.25 (s, 1H), 7.38 (t, J=8.1 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 8.10 (s, 1H), 10.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:25][CH3:24])[C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Yield: 67.6 %

Procedure:
4-Chloro-2-(2-ethoxy-3-formylphenoxy)benzonitrile (0.55 g, 1.8 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (0.13 g, 2.1 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (55 mL) for 3 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. Fumaric acid (0.21 g, 1.8 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated overnight with ethyl acetate, collected by filtration, and dried to give 4-chloro-2-[2-ethoxy-3-(methylaminomethyl)phenoxy]benzonitrile fumarate (527 mg, 67%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([CH3:22])[CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[CH3:22][N:18]1[CH2:17][CH:16]([CH2:15][CH2:14][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[O:20][C:19]1=[O:21]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)O
Product: CN1CC(CCN2CCN(c3ccccn3)CC2)OC1=O
Yield: 75.8 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 4.1 g (0.025 mol) of 1-(2-pyridinyl)piperazine, 4.1 g (0.025 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 8.0 g (0.075 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of 1-butanol gave 5.5 g (75%) of white solid, mp 107.5°-109° C. (2-propanol).