Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.75 g, 1.73 mmol) (from example 137, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.073 g, 1.82 mmol) dissolved in water (1 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.115 mL, 1.88 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Trans-methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (658 mg, 95%) was isolated as an off-white solid. MS m/z 403 (M+H)+
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl.Cl.[CH3:49][Si:50]([CH3:77])([CH3:76])[CH2:51][CH2:52][O:53][CH2:54][N:55]1[C:59]2[N:60]=[CH:61][N:62]=[C:63]([C:64]3[CH:65]=[N:66][N:67]([C:69]4([CH2:73][C:74]#[N:75])[CH2:72][NH:71][CH2:70]4)[CH:68]=3)[C:58]=2[CH:57]=[CH:56]1.Cl[C:79]1[N:80]=[CH:81][C:82]([C:85]([O:87][CH3:88])=[O:86])=[N:83][CH:84]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:74]([CH2:73][C:69]1([N:67]2[CH:68]=[C:64]([C:63]3[C:58]4[CH:57]=[CH:56][N:55]([CH2:54][O:53][CH2:52][CH2:51][Si:50]([CH3:76])([CH3:49])[CH3:77])[C:59]=4[N:60]=[CH:61][N:62]=3)[CH:65]=[N:66]2)[CH2:70][N:71]([C:79]2[N:80]=[CH:81][C:82]([C:85]([O:87][CH3:88])=[O:86])=[N:83][CH:84]=2)[CH2:72]1)#[N:75]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.065 g, 0.10 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.50 g, 1.0 mmol), methyl 5-chloropyrazine-2-carboxylate (0.18 g, 1.0 mmol) (Ark Pharm, Inc., Cat. #: AK-23920), and cesium carbonate (1.0 g, 3.1 mmol) in toluene (15.0 mL) under nitrogen, followed by palladium acetate (0.023 g, 0.10 mmol). The reaction mixture was stirred at 120° C. for 3 h. After cooled to r.t., the reaction mixture was filtered through a pad of celite, washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethane (0-70%) to afford the desired product (0.31 g, 55%). LCMS (M+H)+: m/z=546.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:16])[C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CN(Cc2ccccc2)CC(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a −78° C. solution of 1-benzyl-3-methyl-piperidin-4-one (4.06 g, 20 mmol) in anhydrous THF (20 mL) was added lithium hexamethyldisilazide (21 mL, 21 mmol of a 1.0 M solution THF). After being stirred at −78° C. for 30 min, a solution of iodomethane (1.31 mL, 21 mmol) in THF (5 mL) was added into the reaction mixture. The resultant solution was stirred at 25° C. for 2 h and quenched with water. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography (hexane/EtOAc) to provide 1.37 g (31.5% yield) of 1-benzyl-3,5-dimethyl-piperidin-4-one.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=3)=[C:2]([CH3:1])[S:6][C:5]=2[CH:7]=1
Reactant: Cc1sc2cc(O)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: BrCCCCBr
Product: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 27.1, 2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene as colorless oil, MS: 443 (MH+, 1Br).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[F:34])[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=2)(=O)=O)=CC=1.[CH3:45][O-].[Na+]>CO>[F:34][C:25]1[CH:26]=[C:27]([NH:30][C:31](=[O:33])[CH3:32])[CH:28]=[CH:29][C:24]=1[O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:16][CH:15]=[C:14]([CH2:13][CH2:12][O:11][CH3:45])[C:22]=12
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCOS(=O)(=O)c2ccc(C)cc2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCc1c[nH]c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Temperature: 45 °C
Reaction time: 8 h

Procedure:
150 mg (0.24 mmol) of 2-{4-[4-(acetylamino)-2-fluorophenoxy]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl 4-methylbenzenesulfonate are dissolved in 6 ml of methanol. 0.17 ml (0.94 mmol) of a 5.4M sodium methoxide solution is added, and the mixture is stirred at 45° C. overnight. The reaction solution is partitioned between 1N aqueous sodium hydroxide solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. The solvent is removed under reduced pressure. The product obtained is reacted without further purification.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(N)CCN.O>COCC(O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: NCCCN
Solvent: O
Solvent: COCC(C)O
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 105 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Thebaine (4.0 g dry basis, 13 mmol) is placed in a mixture of 1-methoxy-2-propanol (13.0 g) and 1,3-propanediamine (1.6 g, 22 mmol, 1.66 equiv) and is heated at 105° C. A solution of p-toluenesulfonylhydrazide (4.8 g, 26 mmol, 2.0 equiv) in 1,3-propanediamine (9.6 g, 130 mmol, 9.96 equiv) is added in portions to the thebaine mixture at such a rate that the batch temperature is maintained in the range 105 to 110° C. The reaction mixture is held at 105 to 110° C. for 1 hour then cooled to room temperature and water (24 g) is added while maintaining the batch temperature at ≦30° C. The resulting slurry is stirred, further cooled to ˜2° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.80 g, 94.3% yield; 99.0 area % purity by HPLC)
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][NH:14][CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]3)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][N:14]([C:35]4[N:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]3)=[CH:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3ccc(F)s3)CNCC2CS1)c1ccccc1
Reactant: Clc1ncccn1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=NC2(c3ccc(F)s3)CN(c3ncccn3)CC2CS1)c1ccccc1
Yield: 69.4 %

Procedure:
To a stirred mixture of N-[7a-(5-fluoro-2-thienyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (127 mg, 0.351 mmol) in 1,4-dioxane (7.0 mL) is added diisopropylethylamine (0.184 mL, 1.05 mmol) and 2-chloropyrimidine (402 mg, 3.51 mmol). The solution is heated to reflux for 2 hours then is cooled, diluted with ethyl acetate, (60 mL) and washed with dilute sodium bicarbonate (30 mL, prepared from saturated sodium bicarbonate (15 mL) and water (15 mL), water (30 mL) and brine (30 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel chromatography eluting with dichloromethane/methanol (gradient from 99:1 to 96:4) to give after concentration a residue which is further purified by silica gel chromatography eluting with hexanes/ethyl acetate (gradient from 60:40 to 30:70) to give the title compound (107 mg, 69%). ES/MS (m/e): 440 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:13](=[O:15])[NH2:14])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16](OC)(=O)C>C([O-])([O-])OCC>[OH:15][C:13]1[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]2[N:1]=[CH:16][N:14]=1
Reactant: COC(C)=O
Reactant: NC(=O)n1ncc(-c2ccccc2)c1N
Agent: CCOC([O-])[O-]
Product: Oc1ncnc2c(-c3ccccc3)cnn12
Reaction time: 13 h

Procedure:
A mixture of 3-amino-2-carbamoyl-4-phenylpyrazole (4.8 g) and ethyl orthoformate (30 ml) is stirred at 100°-110° C. for 13 hours, and thereto is added methanol acetate. The precipitate is separated by filtration, washed with methanol or ethyl acetate, and dried to give the title compound (2.08 g).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH2:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[NH2:45]>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:45][CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH:39]1[NH:46][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1N
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(Cl)cccc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(NC3CCCCC3N)cccc2s1
Temperature: 25 °C

Procedure:
tert-Butyl (3R)-3-[[5-(4-chloro-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (200 mg, 0.36 mmol, 1.00 equiv), cyclohexane-1,2-diamine (112.9 mg, 0.99 mmol, 3.00 equiv), NaOBu-t (63.4 mg, 0.66 mmol, 2.00 equiv), tris(dibenzylideneacetone)dipalladium (30.2 mg, 0.03 mmol, 0.10 equiv) and O-biphenyl(t-Bu)2P (11.8 mg, 0.04 mmol, 0.12 equiv) in toluene (12.0 mL) were dissolved in dioxane (2 mL) and heated to reflux for 18 h. The mixture was cooled to room temperature and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with a mixture of 6-50% ethyl acetate in petroleum ether (15:1-2:1) to provide the title compound as a yellow solid. MS, m/z:[M+H]+ (ESI): 639.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.[OH-].[Na+]>C(#N)C>[Br:22][C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cnc(Br)c(Cl)n1
Reaction time: 3 h

Procedure:
A mixture of 2-[6-chloro-2-pyrazinyl]-(1S,4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo-[2.2.1]-heptane (10.6 g, 34.1 mmol), N-bromosuccinimide (6.06 g, 34.1 mmol) and acetonitrile (100 ml) was stirred for 3 hours. Aqueous sodium hydroxide (200 ml, 1 M) was added and the acetonitrile was evaporated. The mixture was extracted with ethyl acetate (2×200 ml). Chromatography on silica gel with ethyl acetate: petroleum (1:1) gave the title compound as free base. Yield 10.44 g (79%).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][N:18]([C:30]([C:27]5[CH:28]=[CH:29][O:25][N:26]=5)=[O:31])[CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-4, 100 mg, 0.30 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 52 mg, 0.46 mmol, 1.5 equiv), DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) and HATU (175 mg, 0.46 mmol, 1.5 equiv) were added to anhydrous acetonitrile (3 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 8-5 as a white solid. MS m/z (M+H): calculated=422.2188; observed=422.2201. 1H NMR δ (ppm)(CHCl3-d): 8.42 (1H, dd, J=7.77, 1.64 Hz), 7.12 (1H, dd, J=8.03, 1.54 Hz), 7.01 (1H, dd, J=8.02, 4.63 Hz), 6.76 (1H, d, J=1.64 Hz), 6.43 (1H, d, J=13.40 Hz), 4.32 (1H, dd, J=12.00, 8.94 Hz), 4.19 (1H, dd, J=12.14, 2.21 Hz), 4.15-4.08 (1H, m), 4.08 (1H, t, J=8.61 Hz), 4.01-3.85 (1H, m), 3.64 (2H, s), 3.49 (3H, d, J=2.90 Hz), 3.22-3.05 (1H, m), 3.06-2.98 (1H, m), 2.85-2.70 (1H, m), 1.02 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[N:30]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:30]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (100 mg, 0.24 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (33 μL, 0.36 mmol), and the mixture was stirred at room temperature for 4 hr. Cyclopropanecarbonyl chloride (15 μL, 0.17 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (150 mL), washed with 1N hydrochloric acid (15 mL), 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), fractions containing the object product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, hexane and diisopropyl ether to give the title compound (108 mg, 92%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23].O>C(Cl)Cl>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:23])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-benzyl-piperazine (1.97 ml) and NEt3 (1.9 ml) in DCM (100 ml) was added n-butyl chloroformate (1.47 ml). The mixture was stirred at RT for 2 h. Water was added, the org. phase separated, dried (Na2SO4) and evaporated off to give 3.13 g of a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH2:2][CH3:3].O1CCCC1.BrC[CH2:20][CH2:21][CH2:22][C:23]#[N:24].[H-].[Na+]>O.C(OCC)(=O)C.CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:2][CH3:3]
Reactant: N#CCCCCBr
Reactant: CCCc1c(O)ccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCC#N)ccc(Cl)c1Cl
Temperature: 65 °C
Reaction time: 72 h

Procedure:
To a solution of 37.1 g. of 2-propyl-3,4-dichlorophenol in 400 ml. of dry tetrahydrofuran and 25 ml. of hexamethylphosphoramide were added 32 ml. of 5-bromovaleronitrile. Sodium hydride (7.2 g. of a 60% dispersion in mineral oil) was added and the reaction was stirred for about three days at 65° C. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The solution was evaporated and ethyl acetate and water were added. The layers were separated and the ethyl acetate was washed several times with dilute hydrochlorid acid. The organic layer was filtered through sodium sulfate and evaporated to provide the desired nitrile intermediate. NMR.
Reaction SMILES: CN(C)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C([O-])(=O)C.[Na+]>ClCCCl>[C:3]([C:19]1[NH:18][CH:22]=[CH:21][CH:20]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: CN(C)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N-dimethylbenzamide (48.0 g, 0.32 mol) in 1,2-dichloroethane (500 mL) was added oxalyl chloride (48.0 g, 0.38 mol). The reaction mixture was stirred for 24 hours at room temperature. To the reaction mixture was then added pyrrole (22.0 g, 0.33 mol). The reaction mixture was again stirred for 24 hours at room temperature. Aqueous sodium acetate (20%, 200 mL) was added to the reaction mixture and vigorous stirring was continued for 24 hours at room temperature. The organic layer was filtered through a silica gel column and concentrated under reduced pressure to yield 2-benzoylpyrrole which was used without further purification. Yield 43.0 g (80%), mp 76°-77° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.O.[Pd]>[C:28]([O:27][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[CH2:23][CH2:22]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCNCC2)CC1
Yield: 101.6 %

Procedure:
To a solution of 1-(1-benzyloxycarbonyl-4-piperidinylmethyl)-4-(t-butoxycarbonylamino)piperidine (10.0 g) in ethanol (100 ml) and water (10 ml) is added a 10% palladium-on-carbon (1.2 g), and the mixture is reduced at a room temperature under at a moderate pressure (3.0 kg/cm2). After the consumption and disappearance of the starting compound is confirmed (about 2 hours thereafter), the catalyst is removed by filtration. The filtrate is evaporated under reduced pressure to give crude 4-(t-butoxycarbonylamino)-1-(4-piperidinyl-methyl)piperidine (about 7 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16](OC)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1ccccc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of methyl (2-benzyloxyphenyl)acetate (935 mg) in tetrahydrofuran (9.4 ml) was added sodium borohydride (600 mg) and the suspension was heated to 45° C. A mixture of methanol (3 ml) and tetrahydrofuran (6 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and quenched by 1 N aqueous hydrochloric acid solution. The organic layer was washed with brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [eluting with ethyl acetate - n-hexane (1:1)] to afford 2-(2-benzyloxyphenyl)ethanol (764 mg).
Reaction SMILES: [Li][CH3:2].[CH3:3][C:4]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=1[C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[OH:12][C:8]1([CH3:2])[CH2:7][C:6]([CH3:13])([CH3:14])[C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([CH3:3])[C:9]1([CH3:10])[CH3:11]
Reactant: COC(=O)C1=C(C)C(C)(C)C(=O)CC1(C)C
Reactant: [Li]C
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)C(C)(C)C(C)(O)CC1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of CeCl3 (1.51 equiv.) in THF (75 ml) was stirred at room temp for 1 hour. The suspension was cooled down to −78° C., MeLi (1.50 equiv., 1.46M in Et2O) was slowly added over 10 minutes, followed by the addition of a solution of (2a) (20.31 mmol) in THF (15 ml). After 30 minutes, the mixture was allowed to warm to 0° C. and quenched by adding NH4Cl and ice. The mixture was extracted with Et2O and the organic layers were washed with water, saturated bicarbonate solution, and brine. After drying with MgSO4, the solution was concentrated and distilled (125° C., 0.1 mbar). Yield 99%.