Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:21]([OH:23])=O)=[C:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].O>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:7]2[N:8]=[C:9]3[C:21](=[O:23])[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH2:14][CH2:13][C:10]3=[C:11]([OH:12])[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(O)c(CCc3ccccc3)c(C(=O)O)nc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(O)c3c(nc21)C(=O)c1ccccc1CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
12.4 g. of 1-ethyl-4-hydroxy-5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (0.04 mol.) and 150 g. of polyphosphoric acid are heated at 200°-210° (bath temperature) with stirring for 30 minutes. After the mixture has cooled to room temperature 300 ml. of water are added slowly with stirring until the polyphosphoric acid is completely dissolved. The remaining 1-ethyl-5,6-dihydro-4-hydroxybenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-b]pyridin-11(1H)-one is dissolved in chloroform, the extract is washed twice with water, dried with Na2SO4 and then evaporated in vacuo, yield: 9 g. (77%); m.p. 190°-192°. Recrystallization from ethanol raises the m.p. to 195°-197°.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)=[O:17])[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.[OH-].[Na+]>Cl>[NH2:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)=[O:17])[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C(=O)Cc2ccnc(N)c2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
2-(2-tert-Butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (50.0 g, 0.153 mol) was added to 2N-hydrochloric acid (260 mL) and the mixture was stirred at 100° C. for 2 hrs. The reaction mixture was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried and concentrated. The crude crystals were washed with isopropyl ether to give the title compound (29.1 g, yield 84%).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=O.Cl.[CH2:19]([NH2:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC.CCOC(C)=O>[CH2:19]([NH:21][C:15]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:13][C:14]=2[CH:1]=1)=[O:17])[CH3:20]
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 0 °C
Reaction time: 15 h

Procedure:
5.8 ml (3.3 eq.) of DIEAA is added dropwise to a solution of 2.43 g (10 mmoles) of 10H-phenothiazine-2-carboxylic acid, 1.79 g (2.2 eq.) of ethylamine hydrochloride and 4.17 g (1.1 eq.) of HBTU in 50 ml of DMF, cooled down to 0° C. The reaction mixture is stirred for 15 hours at 23° C., and then poured into a mixture of 100 ml of a saturated solution of NaHCO3 and 100 ml of AcOEt. After stirring for a few minutes, the precipitate formed is removed by filtration and the filtrate is decanted. The organic phase is successively washed with water, a 1M solution of citric acid and salt water. The organic solution is dried over sodium sulphate, filtered and concentrated to dryness under vacuum. The solid obtained is suspended in Et2O, triturated and filtered. A beige solid is obtained with a quantitative yield. Melting point: 150-151° C.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[C:24]([CH3:35])=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[C:24]=3[CH3:35])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1c(O)cccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(O)c3C)CC2)c(OC)nc1C
Yield: 54 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxy-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6]
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde (22.25 g, 0.11 mole) in methanol at rt was added NaBH4, (2.07 g, 0.055 mole) stirred at rt for 2 hr. The reaction was quenched with H2O, and concentrated. The residue was diluted with diethyl ether, washed with 1 N HCl, brine, dried over MgSO4, and concentrated. 3-Bromo-5-fluorobenzyl alcohol was obtained as a colorless oil was collected (14.6 g, 65%). 1H NMR (DMSO-d6) δ 4.50 (m, 2H), 5.44(t, 3H, J=5.93 Hz), 7.16 (dd, 1H, J=1.09, 8.79 Hz), 7.36(s, 1H), 7.38 (dd, 1H, J=2.99, 6.15 Hz); Anal. Calc. For C7H6Br2FO: C, 41.01; H, 2.95. Found: C, 41.30; H, 3.01.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(O)(=O)C.N([O-])=O.[Na+]>O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:1]([O-:4])=[O:2])=[CH:18][C:17]=2[F:23])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(F)ccc2F)cc1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2cc(F)c([N+](=O)[O-])cc2F)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A stirred solution of 20 mL (0.427 mole) of 90% nitric acid (fuming) in 170 mL of water was cooled in an ice-water bath, and 22.0 grams (0.077 mole) of N-(4-methylphenylsulfonyl)-2,5-difluoroaniline was added. To this mixture was added 170 mL of acetic acid and then 0.5 gram (0.008 mole) of sodium nitrite. Upon completion of the addition, the reaction mixture was warmed to 90° C., where it stirred for about 2.5 hours. The reaction mixture was then cooled and poured into cold water. The resultant precipitate was collected by filtration and dried, yielding about 25 grams of N-(4-methylphenylsulfonyl)-2,5-difluoro-4-nitroaniline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:16]1[CH2:17][NH:14][CH2:15]1
Reactant: Fc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cccc(OC2CNC2)c1
Yield: 67 %

Procedure:
A solution of 2.50 g of 1-benzhydryl-3-(3-fluoro-phenoxy)-azetidine in 10 mL of THF was added to a suspension of 10% Pd/C in methanol. Ammonium formate (4.6 g) were added portion wise and the reaction was heated under reflux for 3 h. The mixture was cooled, filtered through celite, and the filtrate was concentrated. The residue was triturated with CH2Cl2 and filtered. The filtrate was concentrated to give 0.840 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[CH2:37][C:38]#[N:39])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH3:41][C:42]([CH3:46])([CH3:45])[CH:43]=O.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[C:37]([C:38]#[N:39])=[CH:41][C:42]([CH3:46])([CH3:45])[CH3:43])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Reactant: CC(C)(C)C=O
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)C=C(C#N)C(=O)N1CCCC(n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Temperature: 30 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
Into a 50-mL round-bottom flask, was placed N-(4-[4-amino-1-[1-(2-cyanoacetyl)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-4-(trifluoromethyl)benzamide (130 mg, 0.24 mmol, 1.00 equiv), 2,2-dimethylpropanal (2 mL), piperidine (1 mL), and methanol (30 mL). The resulting solution was stirred for 24 h at 30° C. in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1 to give 40 mg (27%) of N-[4-(4-amino-1-[1-[2-cyano-2-(2,2-dimethylpropylidene)acetyl]piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-4-(trifluoromethyl)benzamide as a white solid. MS (ESI, pos. ion) m/z: 617 (M+1), 1HNMR (300 MHz, CDCl3, ppm), 8.364 (1H, s), 8.212 (1H, s), 8.086˜8.059 (2H, t), 7.929˜7.901 (2H, d, J=8.4), 7.827˜7.800 (2H, d, J=8.1), 7.742˜7.715 (2H, d, J=8.1), 6.963 (1H, s), 6.3 (2H, s), 5.031˜4.934 (1H, m),4.8˜3.05 (4H, m), 2.738˜2.067 (5H, m), 1.274 (9H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:17][C@@H:18]([C@@H:26]1[C@@:30]2([CH3:47])[CH2:31][CH2:32][C@@:33]34[CH2:39][C@:38]53[CH2:40][CH2:41][C@H:42]([OH:46])[C:43]([CH3:45])([CH3:44])[C@@H:37]5[CH2:36][CH2:35][C@H:34]4[C@:29]2([CH3:48])[CH2:28][CH2:27]1)[CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([CH3:24])[CH3:23]>O1CCOCC1>[CH3:17][C@@H:18]([C@@H:26]1[C@@:30]2([CH3:47])[CH2:31][CH2:32][C@@:33]34[CH2:39][C@:38]53[CH2:40][CH2:41][C@H:42]([OH:46])[C:43]([CH3:45])([CH3:44])[C@@H:37]5[CH2:36][CH2:35][C@H:34]4[C@:29]2([CH3:48])[CH2:28][CH2:27]1)[CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([CH3:23])[CH3:24].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O-:10])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)=C(C)CC[C@@H](C)[C@H]1CC[C@@]2(C)[C@@H]3CC[C@H]4C(C)(C)[C@@H](O)CC[C@@]45C[C@@]35CC[C@]12C
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C([O-])c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To p-nitrobenzoic acid (1 g, 0.006 mole) dissolved in dioxane (20 ml) was added thionyl chloride (3 ml, 7 equivalents) and the mixture was stirred at 60° C. for 2 hours. The resulting mixture was evaporated under reduced pressure, then dioxane (20 ml) and pyridine (3 ml) were added to the resulting residue. Cyclobranol (2 g, 0.0045 mole) was added to the solution and the mixture was stirred at 60° C. for 2 hours to complete the reaction. The mixture was evaporated under reduced pressure, and the residue was extracted with chloroform (30 ml). The extract was washed successively with 3% aqueous sodium carbonate, water, and saturated brine, dried, and evaporated to dryness under reduced pressure. The crude crystals were washed with ethanol (50 ml), and recrystallized from ethyl acetate, giving cyclobranol-p-nitrobenzoate (2.28 g) in a 90% yield. m.p. 244°-245° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([F:19])[CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:13]=[C:12]([F:11])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,5-difluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 292-293° C.). MS(ES+) m/z 246 ([M+1]+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[H-].[Na+].[CH3:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>C1COCC1>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]4=[N:28][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Chloroethanesulfonyl chloride (19.5 mL) was added dropwise to a mixture of NaH (60%, 12.5 g) in THF (100 mL) at 0° C. in an ice bath. After being stirred at 0° C. for 10 min, a solution of 3-[4-(4-methylphenoxy)phenyl]pyridin-2-amine (17.2 g) in THF (100 mL) was added dropwise to the mixture at 0° C. The ice-bath was removed and the mixture was stirred at room temperature under N2 for 14 hr. The mixture was quenched with EtOH at 0° C. and water was added dropwise to the mixture at 0° C. The mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration, and washed with water and EtOAc to give the title compound (8.68 g) as colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:14]1([CH3:20])C=CC=C[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].B1(C2CC2)OC(=O)CN(C)CC(=O)O1>O>[CH:20]1([C:2]2[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Agent: CN1CC(=O)OB(C2CC2)OC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=[N+]([O-])c1cc(C2CC2)cc([N+](=O)[O-])c1
Yield: 64 %

Procedure:
In a 250 mL round bottom flask to a solution of 3-bromo 1,5-dinitrobenzene (2.1 g, 8.50 mmol) in toluene (90 mL) tricyclohexylphosphine (0.72 g, 2.55 mmol), Cs2CO3 (16.58 g, 51 mmol), cyclopropylboronic acid MIDA ester (2.35 g, 11.90 mmol) and 10 ml de-ionized water were added and the solution was degassed with nitrogen for 30 minutes. To the above solution Pd (OAc)2 (0.29 g, 1.28 mmol) was added under nitrogen and the reaction mixture was refluxed for 12 hours. LC MS analysis of the crude reaction indicated the completion of the reaction. The crude reaction mixture was filtered on celite pad and the volatiles were removed under reduced pressure. The dark brown oil was worked-up with 2×100 mL ethyl acetate and water (100 mL), dried on MgSO4 and ethyl acetate was evaporated under reduced pressure. The crude reaction mixture was separated by column chromatography to give Compound 8 in 64% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(OC(C)(C)C)=O)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@H:20]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:19]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@H:20]([O:29][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:33])[CH3:32])[CH2:19]2)[CH:4]=[C:5]([C:16]#[N:17])[CH:6]=1
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Yield: 79.3 %

Procedure:
Methyl ((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (242 mg, 0.354 mmol) was treated with TFA (25% in 1,2-dichloroethane, 4 mL, 12.98 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10), the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-20% ethyl acetate/dichloromethane). Methyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (135 mg) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[NH:20][C@H:19]5[CH2:24][CH2:25][CH2:26][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:40]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[N:20]([CH3:40])[C@H:19]5[CH2:24][CH2:25][CH2:26][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: C[C@H]1CC[C@H](Cn2c(N3CC(=O)N[C@H]4CCC[C@@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@H]2CCC[C@@H]21
Reaction time: 1 h

Procedure:
4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (282 mg, 0.559 mmol) was taken up in DMF (5595 μl), and sodium hydride (22.38 mg, 0.559 mmol) and iodomethane (87 μl, 1.399 mmol) were added. The mixture was stirred for 1 hour, quenched via the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-20% MeOH/DCM) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a brown foam. MS ESI calc'd. for C28H32ClN7O [M+H]+ 518. found 518.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:20]([O:23]CC=C)[CH:21]=[CH2:22].C(C1C=C(Br)C=C(F)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[F:9][C:4]1[C:5]2[O:8][CH:21]([CH2:20][OH:23])[CH2:22][C:6]=2[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C=CCOCC=C
Reactant: Oc1ccc(Br)cc1F
Agent: C=CCc1cc(Br)cc(F)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: C=CCBr
Solvent: Cc1cc(C)cc(C)c1
Product: OCC1Cc2cc(Br)cc(F)c2O1
Yield: 70 %

Procedure:
Treatment of 4-bromo-2-fluorophenol (25.0 g, 130.9 mmol) with potassium carbonate (72.35 g, 523.53 mmol) and allyl bromide (19.00 g, 157.06 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-4-bromo-6-fluorophenol. Treatment of 2-allyl-4-bromo-6-fluorophenol (25.6 g, 110.8 mmol) with 3-chloroperoxybenzoic acid (57.36 g, 332.38 mmol, 77%) followed by potassium carbonate (38.28 g, 277.0 mmol) generally according to the procedure described for Intermediate 9 afforded 19.1 g (70%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (18.61 g, 75.3 mmol) with p-toluenesulfonyl chloride (17.22 g, 90.34 mmol) generally according to the procedure described for Intermediate 10 gave 22.6 g (75%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.25 mmol) and 2-methylphenylboronic acid (0.254 g, 1.87 mmol) generally according to the procedure described for Intermediate 35 afforded 0.282 g, (55%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (99%) of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.30 g, 3.0 mmol) according to the procedure described in Example 154 afforded 0.038 g (22%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]amine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38](OC(=O)CN)(C)(C)C.Cl.C(OC(=O)[C@H](C)N)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C@@H:23]([CH3:38])[C:24]([OH:26])=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Agent: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)N[C@@H](C)C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, L-alanine tert-butyl ester hydrochloride was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[CH3:13].[CH2:16]([C:18]1[S:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:17]>C(O)C.Cl.C(O)(C)C>[OH:1][CH:2]([CH2:14][OH:15])[CH2:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH2:8][CH2:24][C:23]([C:21]2[S:22][C:18]([CH2:16][CH3:17])=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[O:25])=[CH:6][C:5]=1[CH3:13]
Reactant: Cc1cc(C=O)cc(C)c1CC(O)CO
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(CC(O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
A solution of 4-(2,3-dihydroxy-propyl)-3,5-dimethyl-benzaldehyde (64 mg, 0.308 mmol) and 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (50 mg, 0.218 mmol) in ethanol (2 mL) and 5 N HCl in isopropanol (0.5 mL) is stirred at rt for 5 days. The solvent is removed in vacuo and the residue is separated by prep. HPLC. Product containing fractions are treated with sat. aq. NaHCO3 and 3 M aq. NaOH (5 mL). The mixture is stirred at rt for 1 h, then extracted with DCM. The solvent of the organic extract is removed. The residue is dissolved in THF:methanol 1:1 (5 mL) and is treated with Pd/C. The slurry is stirred at it for 16 h under 1.5 bar of H2. The mixture is filtered over celite and the filtrate is evaporated to give 3-[4-(2,3-dihydroxy-propyl)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (20 mg) as a colourless oil, LC-MS: tR=1.04 min, [M+1]+=423.28.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:9]=[C:10](Cl)C=O)([O-:5])=[O:4].S(=O)(=O)(O)O>O1CCOCC1>[N+:3]([C:6]1[CH:7]=[C:8]([C:9]#[CH:10])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])([O-:5])=[O:4]
Reactant: O=CC(Cl)=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C#Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
To 50 ml of a rapidly stirred 0.5 m sodium hydroxide solution maintained at 60°C was rapidly added a solution containing 4.0 g (15.5 mmoles) of 3,4-dinitro-α-chlorocinnamaldehyde dissolved in 10 ml of dioxane. The mixture was stirred for 5 minutes, at which time the solution was cooled and neutralized with 1N sulfuric acid. The reaction mixture was extracted into methylene chloride, and the combined extracts washed with several portions of water. The methylene chloride solution was reduced in volume to 25 ml and filtered through a 1 × 3 inch dry column of silica gel, eluting with methylene chloride. Evaporation of the eluate yielded 1.2 g (40% yield) of 3,4-dinitroethynyl benzene as a light brown oil.