Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][O:6][C@@H:5](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@@H:4]1[NH2:19].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:19][C@@H:4]1[C@@H:3]([O:2][CH3:1])[C@@H:8]([CH3:9])[CH2:7][O:6][C@H:5]1/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A mixture of (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-amine (5.2 mg), N-(tert-butoxycarbonyl)glycine (10.1 mg), 4-dimethylaminopyridine (7.0 mg), and dicyclohexylcarbodiimide (12.0 mg) in dichloromethane (0.5 ml) was stirred for 2 hours at room temperature. The reaction was quenched by addition of water. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography (ethylacetate as an eluent) gave (2S,3R,4S,5S)-3-[[(tert-butoxycarbonylamino)acetyl]amino]-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran (6.3 mg, y. 79%).
Reaction SMILES: [CH3:1][CH:2]([CH2:17]S(C1C=CC=CC=1)(=O)=O)[CH2:3][CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O.[OH-].[K+].O.CS(C)=O>C1(C)C=CC=CC=1>[CH3:17][CH:2]1[CH2:3][C:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=2)=[CH:1]1
Reactant: CC(CC1CCCCCCCCCCC1=O)CS(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1C=C2CCCCCCCCCC=C2C1
Yield: 85.6 %

Procedure:
11.35 g (0.03 mole) of 2-(2-methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 11.0 g (0.197 mole) of powdered KOH in 30 ml of toluene were first heated to reflux during 30 min., in a reaction vessel fitted with a water separator. After addition of 6 ml of DMSO, the reaction mixture was further heated at 110°, for 12 hours. After the treatments of extraction, washing, drying and distillation (0.05 Torr--bath temperature: 150°) described in Example 1, there were isolated 5.61 g (86% yield) of the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:12]2=[CH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=[O:26])[C:23](Cl)=[O:24].Cl.[CH3:29][CH2:30][O:31]CC>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:21][CH2:20][C:12]2=[C:13]([C:22](=[O:26])[C:23]([O:31][CH2:30][CH3:29])=[O:24])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(CN2CCc3cc4ccccc4n3CC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)c1c2n(c3ccccc13)CCN(Cc1ccccc1)CC2

Procedure:
(Chart D, Step 1): A round bottom flask is charged with 3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (1.17 g, 4.23 mmol) and ethyl ether (21 mL). The yellow homogeneous solution is cooled with an ice bath for 10 minutes. Oxalyl chloride (0.37 mL, 4.23 mmol) is added drop-wise. A yellow precipitate is observed, turning into a gel. After 10 minutes of stirring the ether is removed under reduced pressure. Ethanol (21 mL) is quickly added to the yellow residue and a nitrogen stream is established on the surface of the reaction to remove excess HCl. Using a syringe, triethylamine (1.30 mL, 9.31 mmol) is added dropwise forming HCl gas which is carried away by the nitrogen stream. After the triethylamine addition is complete, the flask is adapted with a reflux condenser, and the reaction is heated to reflux for two hours. The reaction is then cooled and concentrated to 2.79 g of a yellow solid. The crude solid is purified on silica gel using a gradient from 25% to 50% ethyl acetate/heptane as the eluent to give 1.293 grams of ethyl 2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-2-oxoacetate as a yellow solid. Anal. Calculated for C23H24N2O3: C, 73.38; H, 6.43; N, 7.44. Found; C, 73.02; H, 6.55; N, 7.38.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH3:13][NH:14][CH3:15].Cl>>[CH3:13][N:14]([CH3:15])[CH:4]([CH2:3][CH2:2][CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCBr
Reactant: CNC
Agent: Cl
Product: C=CCCCCCC(CCC)N(C)C
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of 96.49 g of undecylenyl bromide and 314.0 ml of dimethylamine is agitated for 48 hours at 20° C. At the end of the reaction, the pH is brought to 2 by a hydrochloric acid solution (10%). The amine is extracted with methylene chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].C(C1C(N2CCOCC2=O)=CC=CC=1S(N[C@H](C(N1CCO[C@H](C)C1)=O)CNC(C1SC(Cl)=CC=1)=O)(=O)=O)C.CCN(C(C)C)C(C)C.[Cl:70][C:71]1[CH:72]=[C:73]([C:79]2[C:80]([CH2:89][CH3:90])=[C:81]([S:85](Cl)(=[O:87])=[O:86])[CH:82]=[CH:83][CH:84]=2)[C:74](=[O:78])[N:75]([CH3:77])[CH:76]=1>C(Cl)Cl.O1CCOCC1.C(Cl)Cl>[Cl:70][C:71]1[CH:72]=[C:73]([C:79]2[C:80]([CH2:89][CH3:90])=[C:81]([S:85]([NH:1][C@H:2]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]3[S:8][C:9]([Cl:12])=[CH:10][CH:11]=3)=[O:6])(=[O:86])=[O:87])[CH:82]=[CH:83][CH:84]=2)[C:74](=[O:78])[N:75]([CH3:77])[CH:76]=1
Reactant: C[C@H]1COCCN1C(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Reactant: CCc1c(-c2cc(Cl)cn(C)c2=O)cccc1S(=O)(=O)Cl
Agent: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCO[C@H](C)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1c(-c2cc(Cl)cn(C)c2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCOC[C@@H]1C
Reaction time: 2 h

Procedure:
5-Chloro-thiophene-2-carboxylic acid [(S)-2-amino-3-((S)-3-methyl-morpholin-4-yl)-3-oxo-propyl]-amide, Intermediate 3 (78 mg, 0.235 mmol) was dissolved in 3 ml DCM/1,4-Dioxane (1:1) and DIPEA (164 μl, 0.94 mmol). Intermediate 65 (82 mg, 0.235 mmol) in 1.5 ml DCM was slowly added and the reaction was stirred for 2 h. Then the solution was evaporated to dryness and purified by prep. HPLC. After lyophilization the title compound is obtained as colorless, amorphous solid.
Reaction SMILES: [CH3:1][Al](C)C.[C:5]([C:8]1[N:9]=[C:10]([Cl:17])[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:7])[CH3:6]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:17][C:10]1[S:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:5]([OH:7])([CH3:1])[CH3:6])[N:9]=1
Reactant: COC(=O)c1sc(Cl)nc1C(C)=O
Reactant: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1sc(Cl)nc1C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A solution of 5.6 ml (11.2 mmol) 2N AlMe3 in toluene was added to a dry ice-acetone bath of 1.14 g (5.2 mol) of methyl 4-acetyl-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 212) in 20 ml dry CH2Cl2. The mixture was allowed to warm to room temperature slowly before being quenched with MeOH. After stirring at room temperature overnight, the mixture was diluted with 1N HCl and stirred 15 min before being diluted with water and extracted twice with EtOAc. The EtOAc was washed with brine, dried (MgSO4) and concentrated to give an oil that was purified by chromatography (50% hexanes in CH2Cl2 with gradient elution to 100% CH2Cl2) affording 720 mg of product as an oil. NMR (CDCl3): 1.5 (s, 6H), 3.8 (s, 3H), 5.7 (s, broad, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:36])[CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.O.NN>C(O)C>[NH2:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:37])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:36]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 99.3 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-2-methylquinoline (3.98 g), hydrazine monohydrate (0.72 ml) and ethanol (40 ml) was heated under reflux for 1 hour. The precipitate was removed by vacuum filtration and the filtrate was evaporated in vacuo. The residue was dissolved with dichloromethane and the precipitate was removed by vacuum filtration. The filtrate was evaporated in vacuo to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (2.99 g) as a yellow amorphous powder.
Reaction SMILES: O=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)=[N:3]1.[C:27](=[O:30])([O-])[O-].[K+].[K+].[C:33]1(C)C=CC(S(OC)(=O)=O)=CC=1.[N+](C1C=CC=CC=1)([O-])=O>>[O:10]=[C:9]1[C:5]2=[C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[N:3]([CH3:2])[C:27](=[O:30])[C:6]2=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)[N:8]1[CH3:33]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1cccc(-c2nc(=O)c3c(-c4cccc(C#N)c4)nc(=O)c2=3)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1C(=O)C2=C(c3cccc(C#N)c3)N(C)C(=O)C2=C1c1cccc(C#N)c1

Procedure:
6.8 Parts of 1,4-diketo-3,6-di-(3'-cyanophenyl)pyrrolo-[3,4-c]-pyrrole, 6 parts of anhydrous potassium carbonate and 16 parts of methyl p-toluenesulfonate are heated at 200°-205° C. in 100 parts of dry nitrobenzene for 2 hours, with stirring. After the suspension has been cooled, the dye formed is filtered off and washed with nitrobenzene, acetone and finally with hot water. After drying, 5.5 parts of 1,4-diketo-2,5-dimethyl-3,6-di-(3'-cyanophenyl)-pyrrolo-[3,4-c]-pyrrole [formula (X)] are obtained in the form of brown-red crystals. After being finely divided, the dye gives red shades in PVC and varnishes, with good fastness to light and migration. ##STR14##
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3].[CH3:14][O:15][CH2:16][C:17](OC)=[O:18]>C(OC)(C)(C)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C@H:2]([NH:1][C:17](=[O:18])[CH2:16][O:15][CH3:14])[CH3:3]
Reactant: COCC(=O)OC
Reactant: CC(N)c1ccc2ccccc2c1
Solvent: COC(C)(C)C
Product: COCC(=O)N[C@H](C)c1ccc2ccccc2c1
Yield: 34.8 %

Procedure:
39 g (0.23 mol) of racemic 1-amino-1-(β-naphthyl)ethane were dissolved in 200 ml of methyl tert-butyl ether. The solution was treated with 29.5 g (0.25 mol) of methyl methoxyacetate, the reaction was started by adding 0.5 g of lipase (approximately 1,000 U/mg, Pseudomonas spec. DSM 8246), and the batch was mixed during the reaction on a vibrating table. After the reaction rate had reached 50% (check by means of gas chromatography), which was the case after approximately 48 hours, the enzyme was filtered off. The filtrate was concentrated and the concentrate taken up in dilute hydrochloric acid (300 ml) and diethyl ether (300 ml). After the ether phase had been separated off, the acid phase was re-extracted using diethyl ether. After the ether phases had been combined, dried and concentrated, 18.7 g (0.08 mol) of (R)-N-[1-(β-naphthyl)ethyl]methoxyacetamide were obtained. After addition of sodium hydroxide solution until the pH is alkaline, it was possible to extract (S)-1-amino-1-(β-naphthyl)ethane from the aqueous phase with diethyl ether. Drying and evaporation of the organic phase gave 15 g of (0.09 mol) of (S)-1-amino-1-(β-naphthyl)ethane. After reaction to give the trifluoroacetamide, the enantiomeric excess (=ee) was determined on a chiral GC column (20 m Chiralolex B-Ph) as 89.5%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][N:30]3[CH2:31][CH2:32][C@H:28]([F:27])[CH2:29]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: F[C@H]1CCNC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CC[C@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and (S)-3-fluoropyrrolidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=0.984 min, m/z=517; 1H NMR (CDCl3) 1.43 (d, 3H), 1.84-2.09 (m, 4H), 2.11-2.29 (m, 5H), 2.61 (m, 1H), 2.71-2.87 (m, 3H), 4.96 (s, 1H), 5.13 (s, 1H), 5.53 (m, 1H), 6.71 (d, 2H), 6.98 (t, 2H), 7.18 (m, 3H), 7.20 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.FC(F)(F)C(O)=O.[CH:31]([C:34]1[S:35][CH:36]=[C:37]([C:39]([N:41]2[CH2:46][C:45]3([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[O:44][CH2:43][CH2:42]2)=[O:40])[N:38]=1)([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][N:49]1[CH2:50][CH2:51][C:45]2([O:44][CH2:43][CH2:42][N:41]([C:39]([C:37]3[N:38]=[C:34]([CH:31]([CH3:32])[CH3:33])[S:35][CH:36]=3)=[O:40])[CH2:46]2)[CH2:47][CH2:48]1)[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)OCC(F)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)CO[Si](C)(C)C(C)(C)C)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-(2-(tert-butyldimethylsilyloxy)-1-fluoroethyl)benzaldehyde (example 39, step d) (0.329 g) in MeOH (4 mL) was treated with acetic acid (0.055 mL) followed by (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.408 g) and stirred at room temperature for 5 minutes. The solution was cooled in an ice-water bath, treated with sodium triacetoxyborohydride (0.309 g), stirred in ice-water for 135 minutes, then removed from the cooling bath and stirred at room temperature for a further 65 minutes. The solution was cooled back down in ice-water, treated with more sodium triacetoxyborohydride (0.310 g) and stirred in ice-water for 75 minutes. More sodium triacetoxyborohydride (0.312 g) was added and the mixture was stirred for 70 minutes. More sodium triacetoxyborohydride (0.619 g) was added and the mixture was stirred overnight, allowing the cooling bath to slowly expire. The next day, more sodium triacetoxyborohydride (0.307 g) was added and the mixture was stirred for 70 minutes. More acetic acid (0.055 mL) was added and the mixture was stirred for 80 minutes. The mixture was warmed to 40° C. and stirred at that temperature for 25 minutes, then it was concentrated onto flash silica in vacuo. The residue was purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a sticky white solid. Yield 0.344 g.
Reaction SMILES: [CH3:1]/[C:2](/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[N:3]\[NH:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6].[C:19](OC(=O)C)(=[O:21])[CH3:20].C1OC=NN1>>[CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([C:19](=[O:21])[CH3:20])[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[O:6]1
Reactant: C/C(=N\NC(=O)c1ccncc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: C1=NNCO1
Product: CC(=O)N1N=C(c2ccncc2)OC1(C)c1ccccc1
Yield: 75 %

Procedure:
The title compound was prepared from the isonicotinoylhydrazone of acetophenone and acetic anhydride, using the General Structural Outline for Oxadiazoline Synthesis in 75% yield, mp 79-81° C.; IR ν □1667, 1628, 1597, 1551, 1329, 1311, 1258, 1216, 1199, 1157, 1084, 1062, 1028, 989, 956, 892, 830, 767, 722□cm−1; 1H NMR (300 Mhz) δ □8.7 (2H, d, J=6 cps), 7.7 (2H, d, J=6 cps), 7.5-7.3 (5H, m), 2.3 (3H, s), 2.2 (3H, s); 13C NMR δ 166, 153, 151, 138, 132, 129, 127, 125, 121, 102, 22.5, 22.7.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:11](=[O:21])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[C:5]2=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O.Cl>CN1C(=O)CCC1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]([C:10]1[C:5]2[C:6](=[N:7][C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:3][CH:4]=2)[NH:8][CH:9]=1)=[O:21]
Reactant: C1CCNC1
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c2nc(Cl)ccc12
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2nc(N3CCCC3)ccc12

Procedure:
A solution of 1-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,3-difluoro-phenyl)-ethanone (100 mg, 0.29 mmol) and pyrrolidine (1 mL) in NMP (2 mL) was heated in a sealed tube with microwave at 220° C. for 15 min. The solution was poured into water and 0.5N HCl was added to precipitate the product. The crude product was collected by filtration, washed with water, and dried on the pump for direct use (80 mg, 0.23 mmol, 79%). MS (ES+): m/e=342.2 (M+H); LC: 2.92 min.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20]Cl>CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH3:20])=[O:13])[C:8]=2[C:15]([F:17])([F:18])[F:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: CO
Product: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (Intermediate I-5D, 0.500 g, 1.94 mmol) in dichloromethane (5 mL) and methanol (1 mL) at room temperature was added trimethyldiazomethane (2.0 M in ether) (1.17 mL, 2.33 mmol) slowly over 10 min. During the addition, the solution remained colorless and the evolution of gas nitrogen was noted. Toward the end of the addition, the bubbling ceased and the solution became pale yellow. The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (40 mL) and washed with brine (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (0.509 g, 1.88 mmol, 97% yield) as a yellow oil. The product had an HPLC with a ret. time=2.52 min. (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 4.05 (s, 3H), 7.50-7.64 (m, 3H), and 7.70 (d, J=7.48 Hz, 2H).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.BrC[CH2:11][CH2:12][OH:13].COCCN1CCNCC1>>[OH:13][CH2:12][CH2:11][CH2:1][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: OCCCBr
Reactant: O=CN1CCNCC1
Agent: COCCN1CCNCC1
Product: OCCCN1CCNCC1

Procedure:
The title compound was prepared from formylpiperazine and 3-bromo-1-propanol in the same manner as in Preparation Example 1(5) to (7).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:26]([OH:27])=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]=[O:36].C(NC(C)C)(C)C>ClCCl>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([C:18]3[C:26]([OH:27])=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)([CH2:35][OH:36])[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc2c(c1)C(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Reactant: C=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one (1.61 g, 3.60 mmol) and para-formaldehyde (0.43 g, 14.6 mmol) in dichloromethane (60.0 mL) was added diisopropylamine (7.20 mmol). After stirring at ambient temperature for 3 h, the reaction was quenched with saturated aqueous ammonium chloride (60.0 mL). The organic layer was separated and washed with water (3×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexanes (20-60%) to afford the title compound (1.07 g, 63%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 10.09 (br, 1H), 7.37-7.16 (m, 12H), 6.99 (s, 1H), 6.87 (d, 1H), 6.62 (s, 1H) 6.54 (s, 1H), 6.37 (d, 1H), 5.87 (d, 2H), 4.45 (ABq, 2H), 2.33 (s, 3H); MS (ES+) m/z 480.4 (M+1).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25](O)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>>[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:26]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C27H24N4O, 420.52; m/z found, 421.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: Clc1ccc(CNCc2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: N#CCCCBr
Product: N#CCCCN(Cc1ccc(Cl)c(Cl)c1)Cc1ccc(Cl)c(Cl)c1

Procedure:
Using a procedure analogous to Example 6, Bis-(3,4-dichlorobenzyl)amine (2.71 g, 8.09 mM) was reacted with 4-bromobutyronitrile (0.81 ml) to give the title compound as an oil 1.97 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[N:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[N:26])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C#N)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 73.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-cyanophenol (31 mg, 0.26 mmol) to give the title compound (44 mg, 73%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).