Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)=Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(CC(C)C)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-isobutyl-3-methylnaphthalen-2-yl)acetic acid (94) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(2-methylprop-1-enyl)naphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.66 (m, 3H), 7.55 (m, 2H), 7.28 (m, 2H), 6.97 (s, 1H), 5.13 (s, 1H), 2.59 (s, 3H), 2.44 (d, J=7 Hz, 2H), 0.96 (s, 9H), 0.83 (m, 6H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 4.0 min run): tR (min)=3.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:24]3[N:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:23]=3[C:22]([I:30])=[N:21]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:24]3=[N:25][CH:26]=[CH:27][C:28]([O:29][C:6]4[CH:7]=[C:2]([Cl:1])[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]=4[F:9])=[C:23]3[C:22]([I:30])=[N:21]2)=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: COc1ccc(Cn2nc(I)c3c(O)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 50 °C
Yield: 40.3 %

Procedure:
A mixture of 1-chloro-4,5-difluoro-2-nitrobenzene (2.23 g, 11.5 mmol), 1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-ol (4.00 g, 10.5 mmol), K2CO3 (1.60 g, 11.5 mmol) and DMF (100 mL) was heated to 50° C. for 18 hours. The reaction was cooled to ambient temperature, diluted with water (500 mL), extracted with EtOAc, dry over sodium sulfate, filter and concentrate. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to provide a light pink solid. The solid was triturated with hot MeOH to afford the product (2.35 g, 40% yield) as a white solid. LRMS (APCI pos) m/e 554.8 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:18](C(OCC2C=CC=CC=2)=O)[CH3:19])[CH3:17])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[C:30]([C:10]1[CH:11]=[C:12]([CH2:15][CH:16]([NH:18][CH3:19])[CH3:17])[CH:13]=[CH:14][C:9]=1[OH:8])([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)N(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC(C)Cc1ccc(O)c(C(C)(C)C)c1
Yield: 99.6 %

Procedure:
A suspension of 2-(4-benzyloxy-3-tert-butylphenyl)-N-benzyloxycarbonyl-N-methyl-1-methylethylamine (3.30 g, 7.35 mmol) and 20% palladium hydroxide/carbon catalyst (350 mg) in methanol (100 ml) was stirred in a hydrogen atmosphere for 1.5 hours. The mixture was filtered to remove the catalyst and the filtrate was evaporated to remove the solvent under reduced pressure, giving 2-(3-tert-butyl-4-hydroxyphenyl)-N-methyl-1-methylethylamine (T20) (1.62 g, 100%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12]([O:19][CH2:20][CH2:21]I)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:12]([O:19][CH2:20][CH2:21][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ICCOCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(C=O)cc1OCCOCc1ccccc1
Temperature: 25 °C

Procedure:
20 g isovanillin (Formula IIIa), 41.3 g 2-benzyloxyethyl iodide (Formula IIIb) and 21.8 g potassium carbonate in 200 ml ethyl methyl ketone are stirred for 12 hrs. under reflux. The obtained suspension is cooled to room temperature and the precipitate filtered off, washed with acetone and evaporated. The residue is taken up in ethyl acetate and extracted with H2O (3×) and brine (1×). The organic phase is dried, filtered and evaporated to yield the title compound as an oil.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([NH:21][C@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([O:25]C)=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[N:9][CH:10]=1.Cl>O.CO.O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([NH:21][C@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[N:9][CH:10]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)O
Temperature: 45 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of lithium hydroxide monohydrate (0.35 g, 8.3 mmol) in water (5 ml) was added to a solution of methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate (1.7 g, 4.2 mmol), [prepared as described in Example 2], in methanol/tetrahydrofuran (1:1, 25 ml) and the reaction mixture was warmed to 45° C. After stirring overnight, reaction mixture was adjusted to pH 6 using 1M HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, 2% methanol/methylene chloride) to give 2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyric acid as a white gummy solid (66%).
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1.O>O1CCCC1>[CH2:1]([O:5][C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1)[C:2]#[C:3][CH3:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butyn-1-ol (530 mg, 7.5 mmol) and sodiumhydride (180 mg, 7.5 mmol) dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>ClCCl>[CH:15]1([NH:18][C:12](=[O:13])/[CH:11]=[C:8]2\[CH2:7][CH2:6][C:5]3[C:9]\2=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:17][CH2:16]1
Reactant: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Reactant: NC1CC1
Solvent: ClCCl
Product: O=C(/C=C1\CCc2ccc(F)cc21)NC1CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
To an ice-cold stirred solution of (E)-2-(6-Fluoro-1-indanylidene)acetyl Chloride in dichloromethane (50 ml) was added cyclopropylamine (1.65 g, 28.86 mmol) and the reaction was warmed to room temperature overnight. The reaction was evaporated in vacuo to a solid residue. This residue was dissolved in ethyl acetate (300 ml), washed with water (75 ml), and the organic layer was concentrated by spin evaporation in vacuo. The residue was chromatographed on silica gel using ethyl acetate-hexanes (0:1 to 1:1 gradient) as eluent. Fractions containing only the product were combined and concentrated by spin evaporation in vacuo. Recrystallization of the residue from dichloromethane-hexanes gave 1.6 g (76%) of (E)-N-cyclopropyl-2-(6-fluoro-1-indanylidene)acetamide as a white powdery solid, m.p. 124°-127° C.;
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:24]1([C:30]2([CH2:37][NH:38][C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[O:47][CH3:48])=[O:40])[CH2:35][CH2:34]C(=O)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:13][O:12][C:10]([CH:9]1[CH2:34][CH2:35][C:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:37][NH:38][C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][C:48]#[CH:14])=[O:40])[CH2:31][CH2:32]1)=[O:11]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(=O)CC1
Agent: [Li+]
Solvent: C1CCOC1
Product: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of methyl diethylphosphonoacetate (0.088 mL, 0.48 mmol) in 2 mL of THF was added lithium bis(trimethylsilyl)amide (0.48 mL, 1N, 0.48 mmol in THF) at 0° C. and the reaction mixture stirred for 50 min The solution was then added to a solution of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)cyclohexanone (67.1 mg, 0.20 mmol) in 2 mL of THF at −78° C. and the solution was allowed to warm to rt overnight. The solution was then filtered through a plug of silica gel, concentrated and was purified by flash chromatography (silica, EtOAc/Hexane, 3:7) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=[O:12].[I-:14].[K+].II.[NH:18]1[CH2:23][CH2:22][CH2:21][N:20]=[C:19]1[SH:24]>CO.O>[IH:14].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:24][C:19]2[NH:20][CH2:21][CH2:22][CH2:23][N:18]=2)=[C:3]1[C:11]([OH:13])=[O:12]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: SC1=NCCCN1
Reactant: [I-]
Agent: II
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cn1c(C(=O)O)c(SC2=NCCCN2)c2ccccc21
Product: I

Procedure:
A solution of 8.6 g of 1-methylindole-2-carboxylic acid in 250 ml of warm methanol is added to a well-stirred solution of 25 g of potassium iodide and 12.2 g of iodine in 75 ml of water and treated with a solution of 5.8 g of 1,4,5,6-tetrahydro-2-pyrimidinethiol. The reaction is carried out and then worked up in the manner described under Example 1 to yield 1-methyl-3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole-2-carboxylic acid hydriodide which melts at 227° (with decomposition) after recrystallization from a mixture of methanol and ethyl acetate.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][C@H:20]([CH3:39])[C@H:21]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=1.N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C>[Si:5]([O:19][C@H:20]([CH3:39])[C@H:21]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butylchlorodiphenylsilane (2.0 ml) was added in four portions to a solution of tert-butyl [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamate (610 mg) and imidazole (817 mg) in DMF (3 ml) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for three hours. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water, 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:diethyl ether 49:1 to 19:1) to obtain 684 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]=[C:29]([C:31](O)=[O:32])[O:28][N:27]=2)[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[O:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[N:30]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1nc(-c2cccnc2)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1nc(-c2cccnc2)no1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.2 g, 0.72 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.137 g, 0.72 mmol), HOBt (0.145 g, 1.07 mmol), DIPEA (0.375 mL, 2.15 mmol) and EDCI (0.2 g, 1.07 mmol) using DMF as solvent using the method of Example 34(d). Yield 33.4 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.23 (d, 3H), 4.41 (m, 2H), 4.52 (m, 1H), 6.79 (m, 1H), 7.65 (m, 1H), 7.78 (m, 1H), 7.95 (d, 1H), 8.03 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd, 1H), 9.51 (m, 1H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH3:21][N:22]([CH3:29])[CH2:23][CH2:24][CH2:25]C(Cl)=O.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH2:25][CH2:24][CH2:23][N:22]([CH3:29])[CH3:21])[C@H:8]([C:18]([NH:45][C:41]2[CH:42]=[CH:43][C:44]3[N:32]([CH2:30][CH3:31])[C:33]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CN(C)CCCC(=O)Cl
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)CCCN(C)C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-(dimethylamino)-butanoyl chloride and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 40% purity by LC/MS. MS(ESI+): m/z=490.4.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[C@@H:9]([O:10][CH3:11])[C@H:8]([CH3:12])[O:7][C@@H:6]([O:13][N:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)[C@@H:5]1[O:41][CH3:42])[CH3:2].C(O)C.Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:1]([O:3][C@@H:4]1[C@@H:9]([O:10][CH3:11])[C@H:8]([CH3:12])[O:7][C@@H:6]([O:13][NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:40])([F:39])[C:35]([F:37])([F:38])[F:36])=[CH:29][CH:28]=4)[N:23]=3)=[CH:20][CH:21]=2)[C@@H:5]1[O:41][CH3:42])[CH3:2]
Reactant: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.4 %

Procedure:
To a solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde O-((2S,3R,4R,5S,6S)-4-ethoxy-3,5-dimethoxy-6-methyl-tetrahydropyran-2-yl)-oxime (P-1; 257 milligrams (mg), 0.429 millimoles (mmol)) in 190 proof ethyl alcohol (EtOH; 10 milliliters (mL)) at room temperature was added pyridine borane complex (200 microliters (μL), 1.99 mmol) in one portion. 3 N Hydrochloric acid (HCl; 1.4 mL) was then added dropwise. When the addition was complete, the mixture stirred at room temperature for 23 hours (h). The mixture was then diluted with EtOH/water (H2O) and treated with saturated sodium bicarbonate (NaHCO3). The resulting aqueous mixture was extracted with ethyl acetate (EtOAc; 2×). The organic extracts were combined, dried, washed with brine and dried with anhydrous sodium sulfate (Na2SO4). The solvent was evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 50% EtOAc in Hexane). The title product (164 mg, 63%) was isolated as a white sticky solid: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.22-8.16 (m, 2H), 7.87-7.80 (m, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.46-7.38 (m, 2H), 6.04 (s, 1H), 5.01 (d, J=1.4 Hz, 1H), 4.18 (s, 2H), 3.84-3.28 (m, 12H), 3.11 (dd, J=12.0, 6.5 Hz, 1H), 1.30 (ddd, J=20.9, 10.3, 4.6 Hz, 6H); ESIMS m/z 603 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[O:15]>O1CCOCC1>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:26](=[O:27])[NH:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1)(=[O:23])=[O:24])=[O:15]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CSc1nnc(N)c(=O)n1C
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nnc(SC)n(C)c1=O
Yield: 73.1 %

Procedure:
3.42 g of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one are suspended in 100 ml of absolute dioxane, and 4.99 g of 2-methoxycarbonylphenylsulfonyl isocyanate are added at room temperature. The reaction proceeds slightly exothermically. After a reaction time of one hour at room temperature, the reaction has ended. The precipitate which has separated out is filtered off and washed with a small amount of dioxane. After drying, 6.0 g of 6-[3-(2-methoxycarbonylphenylsulfonyl)-ureido]-4-methyl-3-methylthio-1,2,4-triazin-5-one with a melting point of 186°-187° C. are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH:28][C:29](O)=[O:30])[CH:22]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[O:30]=[C:29]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])/[CH:28]=[CH:27]/[C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1cccnc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
To a stirring solution of 2.82 g (9.7 mmol) of 8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in 25 mL of dimethyl formamide (DMF) cooled in an ice bath was added 1.54 g (9.7 mmol) of 3-(3-pyridyl) acrylic acid. To the heterogenous mixture was added 1.74 mL (10 mmol) of N,N-diisopropylethylamine and 1.92 g (10 mmol) of N,N-dimethylaminopropylethylcarbodiimide hydrochloride. The reaction was stirred over night at ambient temperature. To the reaction was added 100 mL of ethyl acetate (EtOAc) and 100 mL of a saturated solution of KHCO3. The resulting layers were separated, and the organic layer was washed three times with saturated KHCO3 and two times with water. The organic layer was then dried over Na2SO4 anhydrous and filtered. The solvent was removed under vacuum, and the resultant solid was chromatographed. The yield of isolated product was 2.16 g (53%). Analysis calculated for C22H17N4O3Cl (M.W. 420.86): C, 62.79; H, 4.07; N, 13.31; Cl, 8.42. Found: C, 62.72; H, 4.27; N, 12.78; Cl, 8.21.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(CCc2ccc(C(=O)O)cc2)ccc1C1(OCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate (Compound 87, 60.0 mg, 0.15 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 24.0 mg (43%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:29])[F:15])=[CH:27][CH:26]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)CCc2ccc(C(F)(F)F)cc2)nn2cccnc12

Procedure:
The product from Example 105B and 4-(trifluoromethyl)hydrocinnamic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 2.61-2.73 (m, 2H), 3.00 (t, J=7.5 Hz, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.78-7.51 (m, 2H), 7.63-7.66 (m, 2H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.75 (s, 1H); MS (DCI) m/z 391 (M+H)+.
Reaction SMILES: BrC1C=CC([C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)=CC=1.[Br:21][C:22]1[CH:34]=[CH:33][C:32]2[C:31]3[C:26](=[CH:27][C:28](I)=[CH:29][CH:30]=3)[C:25]([CH3:37])([CH3:36])[C:24]=2[CH:23]=1>>[Br:21][C:22]1[CH:23]=[C:24]2[C:32]([C:31]3[CH:30]=[CH:29][C:28]([C:8]4[CH:20]=[CH:19][C:11]5[O:12][C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=6[C:10]=5[CH:9]=4)=[CH:27][C:26]=3[C:25]2([CH3:37])[CH3:36])=[CH:33][CH:34]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(I)cc21
Reactant: Brc1ccc(-c2ccc3oc4ccccc4c3c2)cc1
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccc4oc5ccccc5c4c3)cc21

Procedure:
2-(7-bromo-9,9-dimethylfluoren-2-yl)dibenzofuran was synthesized in the same manner as in the synthesis of 2-(4-bromophenyl)dibenzofuran except that 2-bromo-7-iodo-9,9-dimethylfluorene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][N:11]([C:24]([C:23]4[CH:27]=[C:19]([S:16]([CH3:15])(=[O:17])=[O:18])[CH:20]=[CH:21][C:22]=4[O:28][C@@H:29]([CH3:34])[C:30]([F:32])([F:33])[F:31])=[O:25])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: Clc1ccc2sc3c(c2c1)CCNC3
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(sc3ccc(Cl)cc23)C1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 1 using 6-chloro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine [29078-50-0] and 5-methylsulfonyl-2-[((S)-2,2,2-trifluoro-1-methylethyl)oxy]benzoic acid [845616-82-2]. MS (m/e): 518.1 (M+H+).