Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:5].C(O)(=O)C>CO.[Pt](=O)=O.[Rh]>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH3:5]
Reactant: COC[C@H](C)Oc1ccncc1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: COC[C@H](C)OC1CCNCC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 16.1 %

Procedure:
(S)-4-(1-methoxypropan-2-yloxy)pyridine (91) (15 g, 89.71 mmol) and Platinum(IV) oxide in MeOH (50 mL) were stirred under an atmosphere of hydrogen at 50 bar and 80° C. for 16 hours. Analysis indicated no reaction, so 20 ml of acetic acid was added and the temperature increased to 100° C. and pressure increased to 80 bar for another 18 hrs, Still very little reaction observed. An aliquot of 5% Rhodium on alumina was added and the mixture heated overnight at 100° C., 80 bar. GCMS-2 indicated more product formation so reaction put back on at 100° C. again as the impurity peak doesn't seem to be increasing. GCMS-3 indicated more product formation so reaction put back on at 100° C. again for 48 hours as the impurity peak doesn't seem to be increasing. GCMS-4 indicated more product formation so reaction put back on at 100° C. again for 48 hours as the impurity peak doesn't seem to be increasing. GCMS-5 showed just a trace of SM with the main peak being product with the impurity slightly increased. The reaction was filtered and the solvent evaporated, the reaction was quenched with 2M NaOH (75 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a yellow liquid. The crude product was purified by distillation at 0.89 mBar, collecting fractions that distilled at 70° C. to afford the desired compound as a colourless liquid (2.500 g, 16.08% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.14 (3H, d), 1.47-1.37 (2H, m), 1.94-1.83 (2H, m), 2.62-2.56 (2H, m), 3.10-3.06 (2H, m), 3.30-3.26 (1H, m), 3.40-3.36 (4H, m), 3.50-3.44 (1H, m), 3.75-3.66 (1H, m); NH missing.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-amine (7-3, 0.500 g, 1.68 mmol) in THF (8.4 mL) was added triethylamine (0.510 g, 5.03 mmol) followed by isonicotinoyl chloride hydrochloride (0.750 g, 4.21 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure and added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in toluene to give N-{4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-yl}isonicotinamide (0.17 g) as yellow solids in 25% yield: 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J=6.0 Hz, 2 H), 8.42 (d, J=1.0 Hz, 1 H), 8.28 (d, J=1.0 Hz, 1 H), 8.13 (m, 1 H), 7.67 (d, J=6.0 Hz, 2 H), 6.84 (s, 1 H), 6.68 (s, 2 H), 1.98 (s, 6 H). ESI-MS: m/z 403.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].Cl.[Al+3].[Cl-].[Cl-].[Cl-]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(Br)cc1O
Reaction time: 2 h

Procedure:
3-Bromo-phenol (10.0 g, 57.8 mmol) was dissolved in 10 ml of pyridine and 10 ml of acetic anhydride and stirred overnight at RT. The mixture was then poured into water, and 1 M HCl was added until reaching a neutral pH value. Extraction with AcOEt furnished a crude product, which was treated with AlCl3 (13.25 g, 100 mmol) at 140° C. After 2 h, the mixture was poured into water and extracted with diethyl ether. The crude residue was purified by column chromatography (eluent:hexane/AcOEt 70:30) to give 1-(4-bromo-2-hydroxy-phenyl)-ethanone (10.1 g) as a red solid.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([NH:45][C:46]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][C:29]=1[F:34])=[S:47])=[O:44]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-difluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 68%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].B1C2CCCC1CCC2.[OH:20][C:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=2)[O:23][C:22]=1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:35]([O:49][CH3:50])[CH:34]=1>O1CCCC1.[OH-].[Na+]>[OH:20][C:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:28]=2)[O:23][C:22]=1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:35]([O:49][CH3:50])[CH:34]=1
Reactant: COc1cc(-c2oc3ccc(I)cc3c(=O)c2O)cc(OC)c1OCc1ccccc1
Reactant: C=CCCCCCCCC
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc2oc(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)c(O)c(=O)c2c1
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a stirring solution of 1-decene (0.189 g, 1.3 mmol, 1.4 eq) in tetrahydrofuran (2 ml) under argon was added 9-BBN in tetrahydrofuran (0.5M, 2.8 ml, 1.4 mmol, 1.5 eq). The reaction was stirred for 8 hours then 3-hydroxy-6-iodo-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 56 (0.501 g, 0.9 mmol) in tetrahydrofuran (5 ml), 3M NaOH solution (1.26 ml) and dichloropalladium(dppf) (0.021 g, 0.03 mmol, 0.03 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether and acidified (6 M HCl). The organic layer was collected and the aqueous layer extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give a red oil. This was passed through a short plug of silica, eluting with ethyl acetate to give 3-hydroxy-6-decyl-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 58(0.369 g, 72%) as a red oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1.CCOC(C)=O>CS(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][CH2:13]1
Reactant: Clc1ccccn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Temperature: 140 °C
Yield: 0 %

Procedure:
A solution of 2-chloropyridine (0.83 ml, 8.81 mmol), tert-butyl piperidine-4-ylcarbamate (1.85 g, 9.24 mmol) and TEA (0.98 mL, 9.69 mmol) in DMSO (5 mL) was heated at 120° C. for 4 h 45 mins and then warmed to 140° C. for 2 days. EtOAc was added and the organic phase was washed with water then brine before evaporating to dryness. The residue was purified on a Biotage Horizion HPFC system eluting with 20% EtOAc in petroleum ether (40-60° C.) to give the title compound (0.65 mg, 27%). 1H NMR (500 MHz, CDCl3): 8.19 (s, 1H), 7.48 (dd, 1H), 6.67 (d, 1H), 6.61 (t, 1H), 4.49 (bs, 1H), 4.21 (d, 2H), 3.70 (bs, 1H), 2.99 (t, 2H), 2.05 (d, 2H), 1.59-1.38 (m, 11H). 13C NMR (CDCl3): 159.5, 155.4, 148.2, 137.7, 113.3, 107.5, 79.6, 48.4, 44.6, 32.3, 28.7; Mass Spectrum: M+H 278.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:28]([NH2:30])[CH3:29]>O>[CH2:28]([NH:30][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:29]
Reactant: CCN
Reactant: Oc1ccc2ccccc2c1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: CCNc1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
288 parts of β-naphthol, 6 parts of diphenyl phosphite and 115 parts of ethylamine gas are heated at 230° C in a pressure autoclave for 10 hours. The pressure is 35 atmospheres. The mixture is added to 2,000 parts of water and the batch is stirred for 30 minutes at 70° - 80° C. The lower oily phase is separated off and distilled. 314 parts of N-ethyl-β-naphthylamine boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 92% of theory.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([O:61][Si](C(C)(C)C)(C)C)[CH:57]=4)[CH:52]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[C:52]4[C:53](=[CH:54][CH:55]=[C:56]([OH:61])[CH:57]=4)[CH:58]=[CH:59][CH:60]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4cccc5ccc(O)cc45)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (73 mg, 0.07 mmol) in CH2Cl2 (2 mL) was added a solution of p-toluenesulfonic acid in methanol (2 mL, 10% solution). The flask was capped and the mixture stirred 4 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) to afford 44.2 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-4-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Rf =0.23). (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(O)(C)C>C(OC(=O)C)(=O)C>[N+:11]([C:8]1[CH:7]=[C:4]([CH:5]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])([O-:13])=[O:12]
Reactant: Cc1ccncc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(C=Cc2ccncc2)cc(O)c1O

Procedure:
A solution containing 2.0 g (0.011 mole) of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.23 g (0.024 mole) of 4-picoline in 9.0 ml of acetic anhydride was refluxed for 1 h. About 15 ml of isopropanol was then added and the solution was cooled to 0° C. where upon the diacetyl-derivative of the desired product crystallized. After filtration the product was suspended in 100 ml of 0.5N hydrochloric acid and refluxed for 1.5 h. After cooling the precipitate was filtered, washed with water and acetone and dried. Yield 1.89 g (67%), m.p. above 350° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)#[N:17]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)=[O:23])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: Cc1c(-c2ccc(C(=O)c3ccc(C#N)cc3)s2)noc1C(F)(F)F
Yield: 36 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 4-cyanobenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (130 mg, 36%). 1H NMR (CDCl3) 2.42 (d, J=1.3, 3H), 7.62 (d, J=4.0, 1 H), 7.67 (d, J=4.0, 1H), 7.85 (d, J=8.3, 1H), 7.98 (d, J=7.9, 1H). 13C NMR 8.0, 114.9, 116.3, 118.7 (q, J=271), 118.0, 129.1, 129.8, 132.7, 135.3, 137.6, 141.1, 144.6, ˜155 (q, obscured due to baseline noise), 157.7, 186.4. 19F NMR −63.1. LC/MS 7.08 min, [M+1]+ 363.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH:16]=[CH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)([CH3:4])[CH3:3].[Cl:28]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)(=O)C.O>[Cl:28][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])[NH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)NCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)NCCOc1ccccc1CCCc1cccc2[nH]cc(Cl)c12
Yield: 74.7 %

Procedure:
A solution of 4.74 g of the product of Example 9 in 43 ml of acetic acid was added with stirring under an inert atmosphere to 2.17 g of N-chlorosuccinimide over 40 minutes and the mixture was diluted with water and iced. The mixture was made alkaline by addition of 32% sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 3.76 g of N-[2-{2-(3-[3-chloro-1H-indol-4-yl]-propyl)-phenoxy}-ethyl]-2-methyl-2-propanamine.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>O1CCCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:7]
Reactant: CCNCC
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1cccc(CCl)c1
Yield: 89.4 %

Procedure:
A sohtion of 3-(chloromethyl)benzoyl chloride (50 g, 264 mmol) in 200 ml of tetrahydrofuran was poured into a solution of diethylamine (607 mmol, 44.4 g, 63.1 ml) in 450 ml of rapidly stirring water. After 10 m, the mixture was extracted with 100 ml of ether and the extract was dried over MgSO4 and concentrated under recuced pressure affording 53.23 g (236 mmol, 89% yield) of the product as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16]O)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][Br:22])[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12
Reactant: N#CC1=C(CO)Nc2n[nH]cc2C1c1ccccc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CC1=C(CBr)Nc2n[nH]cc2C1c1ccccc1Cl
Yield: 36.9 %

Procedure:
4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[methyl(2-pyridinylmethyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 35) (527 mg, 1.12 mmol) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue was azeotroped from toluene. The residue was dissolved in a saturated aqueous solution of sodium hydrogen carbonate (3 ml) and the pH was adjusted to pH 4 with aqueous citric acid solution (10%w/v). The aqueous phase was extracted with ethyl acetate (×2) and the combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a yellow oil (456 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:18]=1
Reactant: COC(=O)C1CCNC(Cc2ccc(Cl)cc2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 110.2 %

Procedure:
To a solution of methyl 2-(4-chlorobenzyl)piperidine-4-carboxylate (3.72 g, 13.2 mmol) and DIPEA (4.85 mL, 27.78 mmol) in DCM (100 mL) was added methyl chloroformate (1.431 mL, 18.48 mmol) in DCM (50 mL) over 30 minutes. The reaction solution was stirred overnight (16 h). The organic phase was washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (4.74 g, 110%) as a yellow oil. MS m/z 326, 328 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:22]([F:25])=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([C:29]([NH:1][C:2]2[CH:3]=[C:4]([C:22]([F:25])=[CH:23][N:24]=2)[C:5]([NH:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=2)[CH3:9])=[O:6])=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(NC(=O)c1cc(N)ncc1F)c1ccc(OCC(F)(F)F)nc1
Product: CC(NC(=O)c1cc(NC(=O)C2CC2)ncc1F)c1ccc(OCC(F)(F)F)nc1
Yield: 11 %

Procedure:
The title compound is prepared in 11% yield (4.4 mg) from 2-amino-5-fluoro-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (34 mg, 0.095 mmol, Step-1, single enantiomer) and cyclopropanecarbonyl chloride (20 mg, 0.19 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1>>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[F:30])[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccc(F)c(Cl)c3)CC1)O2

Procedure:
Compound 142 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(bromomethyl)-2-chloro-1-fluorobenzene and conditions outlined in procedure V. LCMS: 444 [M+H]; Rt=1.04 min.