Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1)(=O)[CH3:8].O>O1CCCC1.C(OCC)(=O)C>[CH2:7]([NH:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:8]
Reactant: COc1ccc(CCNC(C)=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCNCCc1ccc(OC)c(OC)c1

Procedure:
To a suspension of 0.98 g of lithium aluminum hydride in 50 ml of dried tetrahydrofuran (THF), a solution of 3 g of N-acetylhomoveratrylamin in 25 ml of THF was added dropwise with stirring. After heating for 3 hours under reflux, the reaction mixture was cooled with ice and gradually added dropwise under violent stirring with a solvent mixture composed of 10 ml of water and 10 ml of THF. Insoluble matter was filtered off and the filtrate was concentrated. The residue obtained was dissolved in 50 ml of ethyl acetate, washed twice with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, N-ethyl-homoveratrylamine was obtained as oily product. The yield was 2.3 g.
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C@H:6]([CH3:13])[CH2:7][C:8]([O:10]CC)=[O:9])([CH3:3])[CH3:2].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH:17]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[O:5][C@H:6]([CH3:13])[CH2:7][C:8]([OH:10])=[O:9])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C[C@@H](C)O[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](O[C@H](C)CC(=O)O)(C(C)C)C(C)C

Procedure:
0.0755 mol (21.78 g) of the product from stage 1 is stirred at 60° C. for 5 days in 1.51 liters of a 0.01 molar lithium hydroxide solution in a tetrahydrofuran/water 1:1 mixture. The mixture is acidified with aqueous citric acid and the product is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH:21]([CH2:25]Br)[C:22]([NH2:24])=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]([C:22]([NH2:24])=[O:23])[CH2:25]1
Reactant: NC(=O)C(Br)CBr
Reactant: COc1ccccc1NCCNCc1ccccc1
Product: COc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1

Procedure:
In a manner similar to Preparation 1, react N-(2-methoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine (15.4 g, 60.2 mmol) with 2,3-dibromopropanamide (27.7 g, 0.12 mol) to give the title compound.
Reaction SMILES: C(NCCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCC.[C:38]([O:61][CH2:62][CH2:63][OH:64])(=[O:60])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]CCCCCCCCCC.[C:65](OC[C:86]([CH2:91][OH:92])([CH2:89][OH:90])CO)(=[O:83])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]/[CH:73]=[CH:74]\[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82].[CH2:93]([OH:111])CCCCCCCCCCCCCCCCC.C(O)(=[O:130])CCCCCCC/C=C\CCCCCCCC>>[CH2:38]([OH:60])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].[CH2:65]([OH:83])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82].[CH:44]1[CH:43]=[CH:42][C:41](/[CH:40]=[CH:39]/[CH2:38][O:61][C@@H:62]2[O:130][C@H:86]([CH2:89][OH:90])[C@@H:91]([OH:92])[C@H:93]([OH:111])[C@H:63]2[OH:64])=[CH:46][CH:45]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO)(CO)CO
Agent: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCO
Product: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Details of the (A), (B) and (C) components in Table 1, Table 1-2, Table 2, and Table-3 are as follows: (A) Component A-1: Pentaerythritol stearate (average ester replacement degree 45% by equivalent), A-2: Long chain fatty acid polyamide polyamine (MW=3,000 to 4,000); obtained by dropwise adding epichlorohydrin (1/3 mole ratio) to a compound obtained by reaction of polyethylene imine (MW=1,000) and Lunac S-40 (1/7 mole ratio) manufactured by Kao Corporation, A-3: Distearylamine, A-4: Ethylene glycol monobehenate, A-5: Pentaerythritol monooleate (average ester replacement degree 45% by equivalent), A-6: Stearyl alcohol PO adduct (PO=10 mole), A-7: Oleic acid, A-8: Beef tallow, A-9: Cured castor oil, A-10: Lauryl alcohol EO Adduct (EO=15 mole), A-11: Stearyl alcohol EO/PO adduct (EO 24/PO 18 random adduct), A-12: KB-115 (manufactured by Kao Corporation) (main component: fatty acid polyhydric alcohol ester), A-13: Rosin (Hartall R-WW, manufactured by Harima Chemicals, Inc.), A-14: Alkyl ketene dimer obtained by de-hydrochloric acid reaction, in the presence of ternary amine catalyst, of fatty acid chloride obtained by the reaction of phosphoric acid trichloride with Lunac S-40 (manufactured by Kao Corporation), A-15: Alkenyl succinic acid anhydride obtained by addition reaction of Dialen 168 manufactured by Mitsubishi Chemical Industries Ltd. and maleic anhydride at 3/2 mole ratio, and A-16: Methylpolysiloxane (KF96A-1000, manufactured by Shin-Etsu Silicone Co., Ltd.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:22][S:23][CH2:24][CH2:25][C:26](O)=[O:27])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:50]([O:54][C:55](=[O:76])[C@H:56]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1)([CH3:53])([CH3:52])[CH3:51]>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:50]([O:54][C:55](=[O:76])[C@H:56]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:26](=[O:27])[CH2:25][CH2:24][S:23][CH2:22][CH:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:61][CH:60]=1)([CH3:52])([CH3:53])[CH3:51]
Reactant: O=C(O)CCSCC(COC(=O)CCCCCCCCCCCc1ccccc1)OC(=O)CCCCCCCCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(COC(=O)CCCCCCCCCCCc2ccccc2)OC(=O)CCCCCCCCCCCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 6,7-bis(12-phenyldodecanoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 34 (200 mg) and 4-aminobenzoyl-glutamic acid di-t-butyl ester (108 mg) in pyridine (6 ml), phosphorus trichloride (4 drops) was added drop by drop, followed by stirring at room temperature for 1 hour. After the solvent was concentrated, the residue was purified by silica gel column (n-hexane:ethyl acetate=2:1) to yield the title compound (282 mg, yield 93%) as a colorless oily substance.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21](Cl)=[N:22][CH:23]=1>CO.C(O)CCC>[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][CH2:4][CH:3]([OH:2])[CH2:13][N:14]([CH3:16])[CH3:15])=[CH:7][CH:8]=2)=[N:22][CH:23]=1
Reactant: Clc1ncc(Br)c(Nc2ccc3c(c2)CCC3)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Br)c(Nc3ccc4c(c3)CCC4)n2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 89, 156 mg, 0.56 mmol) in methanol (2 ml) was added to a solution of 5-bromo-2-chloro-4-(indan-5-ylamino)pyrimidine (Method 15, 200 mg, 0.62 mmol) in n-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica.(1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (117 mg, 42%). NMR: 2.03 (m, 2H), 2.18 (s, 6H), 2.32 (m, 2H), 2.83 (m, 4H), 3.80 (m, 3H), 4.76 (d, 1H), 6.70 (d, 2H), 7.17 (m, 1H), 7.23 (m, 1H), 7.41 (m, 3H), 8.10 (s, 1H), 8.35 (s, 1H), 9.03 (s, 1H); MS (MH+): 498.4, 500.4.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (2.5 g, 12.4 mmol), 3-(trifluoromethyl)benzyl bromide (1.7 ml, 11.3 mmol) and diisoproylethylamine (2.9 ml, 16.9 mmol) in dichloromethane (25 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (32 ml) was added and the reaction mixture was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; 5-10% ammonia in methanol (7 M)/dichloromethane) to yield D6 (1.9 g, 60%) as a solid. C13H12F3N2 requires 258. Found 259 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:25]=[C:24]([C:26]([NH2:28])=[O:27])[O:23][N:22]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:25]=[C:24]([C:26]([NH2:28])=[O:27])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1ccn2Cc1ccc(-c2cc(C(N)=O)on2)cc1
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
To a mixture of 4-methylindole (20 mg, 0.15 mmol) in THF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 30 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 35 mg, 0.125 mmol) in THF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The THF was evaporated and the residue was taken up in DMF (2 mL). The reaction mixture was stirred at room temperature for 8 days, then H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (16-20% acetone/CH2Cl2) to give 3-[4-(4-methyl-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (6 mg, 14%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (br. s., 1H), 7.97 (br. s., 1H), 7.81 (d, J=8.2 Hz, 2H), 7.43-7.56 (m, 2H), 7.17-7.34 (m, 3H), 6.91-7.03 (m, 1H), 6.80 (d, J=6.9 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.47 (s, 2H), 2.45 (s, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[N+:1]([O-:4])=[O:2])(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 64 %

Procedure:
A mixed acid was prepared by adding fuming nitric acid (1 mL), which was added 3 times as divided portions, to concentrated sulfuric acid (6 mL) under ice cooling, and added portionwise with 4-acetamidobenzaldehyde (1.91 g, 11.7 mmol). After the addition, the reaction mixture was immediately poured onto ice, and the solids were collected by filtration. The solids were sufficiently washed with cold water, dried, purified by silica gel column chromatography (developing solvent: CH2Cl2), and then recrystallized from water to obtain the target compound as pale yellow needlelike solid (1.57 g, yield: 64%).
Reaction SMILES: [F:1][C:2]([F:28])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[N:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[F:28][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:18][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([N:52]=[N+:53]=[N-:54])=[O:24])=[CH:21][CH:20]=3)=[N:16][N:15]=2)=[CH:12][CH:13]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoic acid (217 mg, 0.54 mmol) in isopropanol (5.4 mL) was added triethylamine (0.09 mL, 0.65 mmol) and diphenyl phosphorazidate (0.13 mL, 0.60 mmol) and the reaction was stirred at room temperature for 16 hours. The white precipitate that had formed was filtered and dried in a vacuum oven to provide 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoyl azide as a white solid (145 mg, 63%): mp 140° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 8.32 (m, 4H), 8.24-8.17 (m, 2H), 7.68 (d, J=8.9 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −85.25, −86.89; ESIMS m/z 426 ([M+H]+).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (2.17 g), 2-fluoro-5-hexylbenzonitrile (1.23 4), anhydrous aluminum chloride (0.88 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.11 g of desired compound (refractive index: 1.5608).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:20]=[N:21][NH:22][CH:23]=3)[CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH3:7].[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[NH:20][N:21]=[N:22][CH:23]=3)[CH:14]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2c[nH]nn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2cnn[nH]2)c1
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To a solution of 3-hexyl-6-methyl-6-[3-(1H-1,2,3-triazol-4-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 40, 2.88 mmol) in tetrahydrofuran (25 ml) at 0° C. was added lithium aluminium hydride (5.8 ml, 5.76 mmol, 1.0M in THF) dropwise over a few minutes. The mixture was stirred at room temperature for 2 hours and then quenched by the cautious addition of 2N sodium hydroxide (3 ml) at 0° C. Ethyl acetate (15 ml) was then added and the mixture was stirred rapidly for 30 minutes and then filtered through celite washing with ethyl acetate. The solvent was evaporated in vacuo and the crude residue was purified by silica column chromatography eluting with hexane:ethyl acetate (1:1) then ethyl acetate:methanol:ammonia solution (0.880) (95:5:1) to afford the title compound (301 mg, 32% over 2 steps) as a colourless oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].[BH4-].[Na+].[CH3:40][OH:41]>ClCCl.C(O)(=O)C>[F:32][C:33]([F:37])([F:36])[C:40]([OH:4])=[O:41].[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CO
Reactant: NCC(F)(F)F
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCC(F)(F)F)c4)cc23)CC1
Product: O=C(O)C(F)(F)F
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.09 mmol) and 2,2,2-trifluoroethylamine (78 μL, 0.55 mmol) in dichloromethane (2 mL) and methanol (1 mL) was added 2 drops of acetic acid. The mixture was then stirred overnight. Sodium borohydride (20.8 mg, 0.55 mmol) was then added and the mixture was stirred for 30 min. The resulting mixture was concentrated and dissolved in dimethyl sulfoxide followed by purification by Gilson Preparatory HPLC to give 29.4 mg of the title compound (62.5%).
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11](C)([CH3:20])[CH2:12]C=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1OCC1CC1)\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.ClCCl.[C:38](#N)[CH3:39]>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:12])([CH3:20])[CH2:29][C:30]([O:31][CH2:32][CH:33]3[CH2:39][CH2:38]3)=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][CH:8]=1)\[CH3:6])/[CH:3]=[O:4]
Reactant: CC#N
Reactant: C/C(=C(\F)CO)c1cc2c(cc1OCC1CC1)C(C)(C)CC=C2C(C)C
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: C/C(=C(\F)C=O)c1ccc2c(c1)C(C(C)C)=C(OCC1CC1)CC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4-dimethyl-6-(cyclopropyl)methoxy-1-isopropyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-54, 0.025 g, 0.070 mmol), tetrapropylammonium perruthenate (0.012 g, 0.038 mmol) and 4-methylmorpholine N-oxide (0.022 g, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)[C:14]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9 %

Procedure:
To 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-pyrazolo[3,4d]pyrimidin4-ylamine (Compound 9) (4.2 g, 95 mmol) in acetone (200 mL) was added HCl (5N, 50 mL) dropwise. Stir at room temperature for 24 hrs. Evaporate the acetone and basify with NaOH (5N, 60 mL). Extract with EtOAc (3×200 mL). Dry, filter and evaporate to leave a solid which was triturated with EtOAc: Et2O (1:20) and filtered to give 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone as a cream solid (3.4 g, 90%), m.pt. 203-205° C.1H NMR (400 MHz, d6-DMSO) 8.28 (1H, s), 7.66 (2H, m), 7.44 (2H, m), 7.08-7.20 (5H, m), 6.1-7.3 (2H, bs), 5.26 (1H, m), 2.71 (2H, m), 2.41 (4H, m), 2.24 (2H, m) HPLC: Tr=15.43 mins, 95%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH2:23][C:24]#[N:25])=O>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]2[CH:12]=[C:23]([C:24]#[N:25])[O:22][C:15]=2[CH:16]=1
Reactant: COc1ccc(C=O)c(OCC#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(C#N)oc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 49.4 %

Procedure:
Potassium carbonate (15.1 g) and molecular sieves 4A (3 g) were added to a DMF solution (100 ml) of (2-formyl-5-methoxyphenyl)oxyacetonitrile (10.4 g), which was stirred at 100° C. for 10 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the entitled compound (4.65 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([OH:16])=O)=[O:10])=[CH:4][CH:3]=1.C(Cl)Cl.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH:38]1[CH2:40][CH2:39]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([NH:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)=[O:16])=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)Nc1ccc(N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC2CC2)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round-bottomed flask was charged 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoic acid (70 mg, 0.26 mmol), DCM (1 ml), and DMF (1 ml). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (74 mg, 0.39 mmol) was then added. The reaction mixture was stirred for 10 min before (aminomethyl)cyclopropane (27 μl, 0.31 mmol) was introduced. The reaction mixture was stirred at RT under N2 for 16 h. The reaction was partitioned between DCM (15 ml) and brine (10 mL). The aqueous layer was back exacted with DCM (3×10 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH in CH2Cl2, to provide N3-(6-aminopyridin-3-yl)-N1-(cyclopropylmethyl)-4-methylisophthalamide as an off-white solid. m/z: 325.2 (M+1).