Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[C:15]1([C:25](OCC)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([C:25]([CH2:13][C:12]#[N:14])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccc2ccccc12
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 2.50 M of n-butyllithium in hexane (49.9 mL, 125 mmol) in tetrahydrofuran (49.9 mL) cooled to −78° C. is added acetonitrile (6.52 mL, 125 mmol) drop-wise. The resulting cloudy mixture is stirred for 30 min. Ethyl α-napthoate (8.87 mL, 49.9 mmol) is added drop-wise and the reaction mixture is stirred at −78° C. for 2 hr. The reaction is warmed to room temperature, quenched with acetic acid (50 ml) and partitioned between ethyl acetate and water. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The crude material is purified by column chromatography (eluent: 5-15% CH2Cl2/methanol) to provide 1-naphthoylacetonitrile (6.99 g, yield 72%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=8.7 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.90 (t, J=8.1 Hz, 2H), 7.71-7.64 (m, 1H), 7.57 (dt, J=15.5, 7.2 Hz, 2H), 4.21 (s, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:39](=[O:41])[CH3:40])[C@@:29]2([CH3:42])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:43][Si:44](OS(C(F)(F)F)(=O)=O)([CH3:46])[CH3:45].N1C(C)=CC=CC=1C>>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:44]([CH3:46])([CH3:45])[CH3:43])[C@@H:30]([O:38][C:39](=[O:41])[CH3:40])[C@@:29]2([CH3:42])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CC(=O)O[C@@H]1[C@H](O[Si](C)(C)C)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)-12-acetoxyspirostan-11-ol was silylated with trimethylsilyltrifiate and 2,6-lutidine in methylene chlodde according to the procedure described in Tetrahadron Letters, 1981, 22, 3455.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.O=[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCC1=CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: OCCCC1CCN(Cc2ccccc2)CC1
Yield: 68.9 %

Procedure:
6.48 g of 1-benzyl-4-hydroxypropyl-1,2,5,6-tetrahydropyridine was dissolved in 60 ml of methanol, 88 mg of PtO2 was added, and atmosphere was replaced with hydrogen. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated, to give 4.50 g (19.3 mmol, 68.9%) of the title compound as a yellow oil.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][C:9]([CH3:11])=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:9]1([CH3:11])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1
Reactant: OCCNCCO
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)OCCN1CCO
Temperature: 37 °C
Reaction time: 20 h
Yield: 74.8 %

Procedure:
A mixture of 526 g (5.0 moles) of diethanolamine, 581 g (10 moles) of acetone and 690 g (5.0 moles) of anhydrous potassium carbonate are allowed to stir for 20 hours. During the first two hours the solution temperature gradually increases to a maximum of 37° C. The mixture is filtered and the collected solid is washed with 500 ml of acetone. The filtrate and wash are combined, the solvent distilled off under reduced pressure, and the residue distilled under reduced pressure. There is obtained 543 g (75%) of a colorless liquid, b.p. 89°-92°/8 mm, nD26 1.4614, neutralization equivalent 144.5 (calculated 145.2).
Reaction SMILES: [F:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].[Li+].[OH-]>CCO.O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:2]([F:1])([F:4])[CH3:3])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:31])([F:32])[F:30])[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(R)-4-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (530 mg, 1.16 mmol) was dissolved in EtOH (5 mL). Then LiOH (835 mg, 34.8 mmol, 30.0 eq.) in 2 mL water was added to the mixture. The mixture was heated to 80° C. and stirred for 15 h. Solvent was removed. DCM was added and filtrated. The filtrate was concentrated and purified by silica gel chromatography using DCM/methanol (10/1) to give the title compound (200 mg, 40%) as a slight yellow solid. EDI-MS (M-NH2): 415.2. HPLC: 99.36%. 1H NMR (400 MHz, CD3OD) δ 8.13 (t, 1H), 8.02 (d, 1H), 7.86 (s, 1H), 7.58 (dd, 1H), 7.48 (d, 1H), 4.45-4.41 (m, 1H), 3.85-3.72 (m, 2H), 2.14-2012 (m, 2H), 1.89-1.86 (m, 2H), 1.74-1.68 (m, 4H), 1.51-1.32 (m, 7H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].F[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:35]1([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=3)[CH2:4][CH2:3]2)[C:36]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Fc1cccc2ccccc12
Reactant: OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(N3CCC(Oc4cccc5ccccc45)CC3)c3ccccc3n2)cc1

Procedure:
Equimolar quantities of 4-(4-hydroxypiperidinyl)-2-phenylquinazoline, sodium hydride and 1-fluoronaphthalene are heated in dimethylformamide to prepare the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Solvent: CCO
Product: Nc1ccc(CCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 86 h
Yield: 100.3 %

Procedure:
In ethanol (100 ml) was dissolved 1-[2-(4-nitro-phenyl)ethyl]piperidine (24.8 g), and to the mixture was added dried 10% palladium on carbon(1.24 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 86 hours. The palladium was filtered off, and the filtrate was concentrated to give 1-[2-(4-aminophenyl)ethyl]-piperidine (21.7 g) as pale brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH:12]1([CH:17]([OH:20])[CH:18]=[CH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([C:17](=[O:20])[CH2:18][CH2:19][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCc1cc(Br)ccc1OC
Reactant: C=CC(O)C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1cc(CCC(=O)C2CCCC2)ccc1OC
Temperature: 140 °C
Yield: 47.2 %

Procedure:
A mixture of bromide (1.3 g, 6.02 mmol, from step 1), 1-Cyclopentyl-2-propen-1-ol (1.14 g, 9.07 mmol), dichlorobis(triphenylphosphine)palladium (II) (85 mg, 0.12 mmol), sodium bicarbonate (0.61 g, 7.25 mmol) in N-methylpyrrolidinone (12 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. The oil was purifed by silica gel chromatography to give the title compound as a yellow oil (0.74 g, 47%). 1H NMR (CDCl3): δ ?1.17 (t, 3H, J=7.6 Hz), 1.54-1.80 (m, 9H), 1.17 (q, 2H, J=7.6 Hz), 2.73 (m, 2H), 2.84 (m, 2H), 3.80 (s, 3H), 6.75 (d, 1H, J=8.0 Hz), 6.97 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][NH:17][N:16]=1)=O>C(O)(=O)C>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:13]([C:15]3[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][NH:17][N:16]=3)=[N:12][C:3]=2[CH:4]=1
Reactant: COc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1OC
Solvent: CC(=O)O
Product: COc1cc2nc(-c3n[nH]cc3[N+](=O)[O-])[nH]c2cc1OC
Temperature: 140 °C
Yield: 94 %

Procedure:
To a solution of EDC (4.81 g 25 mmol), HOBt (3.40 g, 25 mmol) and triethylamine (4.67 g, 46 mmol) in DMF (100 ml) was added 4-nitro-1H-pyrazole-3-carboxylic acid (3.63 g, 23.09 mmol) and 4,5-dimethoxy-benzene-1,2-diamine dihydrochloride (5.06 g, 20.99 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between EtOAc (50 ml) and saturated aqueous NaHCO3 (50 ml). A precipitate was formed and removed by filtration. The filtrate was washed with water followed by diethyl ether and then azeotroped with MeOH and toluene to yield 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 36%). 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 7.65 mmol) was dissolved in acetic acid (150 ml) and refluxed at 140° C. for 5 hours. The solution was left to cool and the solvent removed in vacuo. The resulting solid was partitioned between EtOAc (25 ml) and brine (25 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield 5,6-dimethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazol (2.08 g, 94%).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[NH:49][N:48]=[N:47][N:40]=3)=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 1000 mg (1.79 mmol) of methyl 4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoate in 10 ml of toluene is mixed with 2851 mg (24.7 mmol) of trimethylsilyl azide and 618 mg (2.47 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 h. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by chromatography on a silica gel column (mobile phase: cyclohexane/ethyl acetate 2:1→1:2). 648 mg (1.08 mmol, 60% of theory) of a colorless oil are obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2].O.[Li+].[OH-]>C1COCC1>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(Nc4ccccc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Nc1ncc(C#N)c(-c2c[nH]c3ncc(Nc4ccccc4)cc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
2-(isopropylamino)-4-(5-(phenylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (0.083 g, 0.158 mmol) was stirred in THF (7 mL) and water (1.5 mL) and treated with LiOH.H20 (0.066 g, 1.60 mmol, 10.0 Eq) and allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography (50% EtOAc/Petroleum ether) to yield the product as a yellow solid (29 mg, 50%)
Reaction SMILES: [CH2:1]([O:3][NH2:4])[CH3:2].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=O)[CH3:6].Cl.C([O-])(O)=O.[Na+]>CO.O>[CH2:1]([O:3][N:4]=[C:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)(=[O:15])=[O:16])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Reactant: CCON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCON=C(C)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
0.42 g of a 40% strength aqueous O-ethylhydroxylamine solution was added to a solution of 0.4 g (1.3 mmol) of the compound from Example 1 in 20 ml of methanol. Using 10% strength hydrochloric acid, the mixture was acidified to pH 4, and the solution was then stirred at 20-25° C. for about 18 hours. The reaction solution was poured into water and adjusted to pH 8 using NaHCO3. The mixture was then extracted with methyl tert-butyl ether (MtBE), and the combined organic phases were washed with water and dried. Removal of the solvent gave 0.4 g of the title compound as a viscous oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-2-methyl benzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, 3-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-methylbenzenesulfonamide (percentage yield: 90%), was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:8])=[CH:4][N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2ccc(Cl)nc2)cc1
Yield: 97.6 %

Procedure:
A solution of 6-chloronicotinic acid (473 mg, 3 mmol), 4-methoxybenzylamine (412 mg, 3 mmol), 1-(3-dimethlaminopropyl)-3-ethylcarbodiimide hydrochloride (700 mg, 3.6 mmol) and HOBt (200 mg)) in DMF (15 ml) was stirred at room temperature for 3 h. Water (100 ml) was added. The solution was extracted with ethyl acetate (150 ml×2), washed with saturated K2CO3 solution (100 ml) and water (200 ml). Organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the desired product (810 mg, 97%). HPLC (6 minute gradient) tR=3.12 min; MS m/z 275.00, 276.95 (M+H]+
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>C(O)(=O)C>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:1](=[O:7])[CH:2]=[CH:3][C:4]1=[O:6]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCCCCO
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1CCCCCCO

Procedure:
One mole equivalent of maleic anhydride and one mole equivalent of 6-amino hexanol are dissolved in anhydrous acetic acid and the solution is heated under reflux for eight hours. The acetic acid is distilled off in a rotary evaporator. The residue is dissolved in diethyl ether and washed once with 1 N NaOH, and twice with water. After drying over MgSO4 and evaporating the diethyl ether, the residue is crystallized from isopropyl ether to produce N-(6-hydroxyhexyl) maleimide.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1([S:14](Cl)(=[O:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][NH:7][S:14]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:16])=[O:15]
Reactant: NCc1ccco1
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: O=S(=O)(NCc1ccco1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a stirred solution of furfurylamine (0.319 g, 3.3 mmol) in pyridine (5 mL) at 0° C. was slowly added cyclohexanesulfonyl chloride (0.500 g, 2.7 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the product (0.325 g, 49%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, 1H, J=1.8, 0.9 Hz), 6.35 (dd, 1H, J=3.3, 2.1 Hz), 6.30 (d, 1H, J=3.0 Hz), 4.43 (m, 1H), 4.32 (d, 2H, J=5.7 Hz), 2.75 (tt, 1H, J=12.0, 3.3 Hz), 2.15-2.05 (m, 2H), 1.95-1.80 (m, 2H), 1.70 (m, 1H), 1.60-1.40 (m, 2H), 1.30-1.10 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[C:25]([OH:28])([CH3:27])[CH3:26])[N:19]([CH3:29])[C:18]=4[CH:30]=3)[C:10](=[O:31])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)=O.CCO.CC#N>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([C@@H:22]5[CH2:24][C@@H:23]5[C:25]([OH:28])([CH3:27])[CH3:26])[N:19]([CH3:29])[C:18]=4[CH:30]=3)[C:10](=[O:31])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Agent: O=C=O
Solvent: CC#N
Solvent: CCO
Product: Cn1c([C@@H]2C[C@@H]2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Yield: 32.5 %

Procedure:
(1RS,2SR)-4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (0.830 g) was resolved by a preparative SFC (CHIRALPAK AYH, CO2/EtOH/CH3CN=600/200/200) to give a white solid (355 mg, >99% ee). This solid was recrystallized from IPA to give the title compound (270 mg) as a white solid.
Reaction SMILES: [CH:1]([CH:3]1[C:8](=O)[C:7](C2CCCC2)=[C:6](OC)[CH2:5][CH2:4]1)=O.C(=O)(O)O.[NH2:21][C:22](N)=[NH:23]>CN(C=O)C>[NH:21]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:1]=[N:23][CH2:22]1
Reactant: N=C(N)N
Reactant: COC1=C(C2CCCC2)C(=O)C(C=O)CC1
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: C1=NCNc2ccccc21
Temperature: 150 °C
Yield: 148.4 %

Procedure:
A mixture of 6-formyl-2-cyclopentyl-3-methoxycyclohex-2-en-1-one (2.0 g, 10.2 mmol) and guanidine carbonate (4.6 g) in DMF (30 mL) was heated at 150° C. for 4 hours. The solvent was removed under reduced pressure and to the residue ice-cold water was added. The product was extracted with ethyl acetate (3×50 mL). The combined organic extract was washed with water and brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to give 2.0 g of crude dihydroquinazoline. The dihydroquinazoline was aromatized to the title compound by heating in nitrobenzene at 150° C. in the presence of 10% Pd-C. To a solution of dihydroquinazoline (2.0 g, 8.2 mmol) in nitrobenzene (20 mL), 200 mg of 10% Pd-C was added, and the reaction mixture was heated at 150° C. for 3 days. The Pd-C was removed by filtration. The filtrate was concentrated, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as an off-white solid (1 g, 50% yield), mp 181–183° C.; 1H NMR (CDCl3): δ 1.6–2.2 (complex, 8H, 4×CH2), 3.9 (s, 3H, OCH3), 4.27 (t, 1H, CH), 5.02 (brs, 2H, NH2), 7.02 (d, 1H, Ar-H, J=9 Hz), 7.54 (d, 1H, Ar-H, J=9 Hz), 8.87 (s, 1H, Ar-H); MS m/z 244.07, C14H17N3O (M++1).