Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[OH:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N+:12]2([O-:47])[CH2:13][CH2:14][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=3)([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:41])([F:39])[F:40])=[CH:35][CH:36]=3)[OH:19])[CH2:16][CH2:17]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(C[N+]2([O-])CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a stirred solution of 0.5 gram (0.0008 mole) of N-[4-(2-propen-1yloxy)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (Compound 42, prepared in Example 5) in 10 mL of chloroform was added 0.3 gram (0.0008 mole) of 50% 3-chloroperoxybenzoic acid. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 2 hours. After this time the reaction mixture was washed, first, with an aqueous solution saturated with sodium bicarbonate, and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of ethyl acetate and hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure to a residue. The residue was concentrated further under high vacuum, yielding about 0.2 gram of N-[4-(2-propen-1-yloxy)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27](B(O)O)=[CH:26][CH:25]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:27]4[C:28]([CH3:30])=[N:29][C:24]([Cl:23])=[CH:25][CH:26]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: Cc1nc(Cl)ccc1B(O)O
Product: Cc1nc(Cl)ccc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 6-chloro-2-methylpyridine-3-boronic acid following a procedure analogous to that described for Intermediate 15. LC (method 6): tR=1.41 min; Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5].[NH2:9][C:10]1[N:15]=[C:14](Cl)[C:13]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:25][C:26]#[N:27])[CH:21]=[CH:22][C:23]=2[F:24])=[C:12]([CH3:28])[N:11]=1>C(O)CCC>[NH2:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5])[C:13]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:25][C:26]#[N:27])[CH:21]=[CH:22][C:23]=2[F:24])=[C:12]([CH3:28])[N:11]=1
Reactant: CCC[C@H](N)CCO
Reactant: Cc1nc(N)nc(Cl)c1Cc1cc(CC#N)ccc1F
Solvent: CCCCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1cc(CC#N)ccc1F
Reaction time: 2 h

Procedure:
(S)-3-Aminohexan-1-ol (101 mg) was added to a stirred solution of the product from step (iv) (100 mg) in butan-1-ol (2 mL). The reaction was performed in a microwave, at 180° C. for 2 h. The solvent was removed and the crude product was purified using chromatography, to give the subtitle compound, 70 mg.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[OH-].[K+].[CH3:20]O>O>[CH3:20][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[C:4]([C:14]([OH:16])=[O:15])=[CH:3][CH:2]=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(C)ccc1-c1ccccc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 5 h

Procedure:
Methyl 4-methylbiphenyl-2-carboxylate (10.0 g, 44.2 mmol, 1 eq), 0.5 N KOH in methanol (265.5 ml, 133 mmol, 3 eq), and water (50 mL) were mixed and refluxed under N2. After 5 hours, the solvent was removed in ml and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL), the organic layers collected, dried (MgSO4) and the solvent removed in y3=to yield 8.71 g of a white solid; m.p. 140.0°-145.0° NMR (206 MHz, DMSO-d6 δ 7.72 (d, 1H, J=7 Hz); 7.56 (t, 1H, J=7 Hz); 7.45 (d, 1H, J=7 Hz); 7.40 (t, 1H, J=7 Hz); 7.25 (9, 411); 2.36 (s, 3H). Anal. Calcd. for C14H12O2; C, 79.23; H, 5.70. Found: C, 79.22; H, 5.47.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH:16]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1)[CH:17]=O>C(O)(C)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:16]([C:19]4([C:22]5[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=5)[CH2:20][CH2:21]4)=[CH:17][N:14]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(C(Cl)C=O)CC2)cc1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc(C2(c3cnc4ncc(-c5ccc(F)cc5)nn34)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine (20.1 mg, 0.106 mmol) and chloro[1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (53 mg, 0.24 mmol) in isopropyl alcohol (0.6 mL) was heated to 90° C. overnight. After cooling, the mixture was diluted with methanol and was purified by mass-guided RP-HPLC to afford the desired product. LCMS: (M+H)=361.1.
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[O:14]([CH2:13][C:10]1[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc(COc2ccccc2)nc1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(COc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
To a diethyl ether (250 mL) solution of 5-bromo-2-phenoxymethyl-pyridine (4.40 g, 16.6 mmol) described in Manufacturing Example 54-1-3 was added n-butyl lithium (2.55 M n-hexane solution, 8.46 mL, 21.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 40 minutes at −78° C. N,N-dimethylformamide (1.93 mL, 25.0 mmol) was then added dropwise thereto and stirred for 20 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (1.00 g, 28.3%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[C:9]([CH3:44])=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:30][CH2:29]5)=[N:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:14]=2)[C:9]([CH3:44])=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 81.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (186 mg. 0.277 mmol) was alkylated using (S)-2-methyloxirane (32 mg, 0.554 mmol), DIPEA (72 mg, 0.554 mmol) and ethanol (4 mL) to get 157 mg (82% yield) of the titled compound. MS: m/z=694.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[CH2:8]([SH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Na+].[Na+].II>C(OCC)C.O>[CH2:8]([S:15][S:7][C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCS
Reactant: Cc1occc1S
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCSSc1ccoc1C
Reaction time: 0.33 h

Procedure:
0.57 Grams (0.0050 moles) of 2-methyl-3-furanthiol and 1.32 grams (0.01 moles) of n-heptylmercaptan are dissolved in 12 ml of diethyl ether. 0.8 Grams (0.0075 moles) of sodium carbonate dissolved in 8 ml water is added to the reaction mass. Over a period of 20 minutes, a solution of 1.9 grams (0.0075 moles) of iodine dissolved in 6 ml diethyl ether is added to the reaction mass with stirring until the iodine color remains. The reaction mass is then stirred over a period of 35 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:11][C:10]2[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1.[OH-].[Na+].[O-:18][Mn](=O)(=O)=O.[K+]>O>[CH3:13][N:8]1[C:9](=[O:12])[C:10]2[NH:11][C:3]([C:2]([OH:18])=[O:1])=[N:4][C:5]=2[N:6]([CH3:15])[C:7]1=[O:14]
Reactant: Cn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)c2[nH]c(C(=O)O)nc2n(C)c1=O
Temperature: 5 °C
Reaction time: 4 h

Procedure:
5.00 g (24.0 mmol) 8-Hydroxymethyl-1,3-dimethyl-3,7-dihydro-purine-2,6-dione were suspended in 15 mL water. 16.8 mL (33.6 mmol) of a 2 N NaOH-solution were added. The resulting mixture was cooled to 5° C. At that temperature a solution of 5.05 g (32.2 mmol) KMnO4 in 86 mL water was added. After stirring at room temperature for 4 h the reaction mixture was filtered over Celite. After addition of activated carbon the filtrate was again filtered over Celite. The filtrate was concentrated to a volume of 200 mL and 5 mL of conc. HCl-solution were added. After standing at 4° C. for 16 h the crystaline product was filtered off, washed twice with cold water and acetone and dried under reduced pressure at 40° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](Br)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C1COCC1.[Cu]I.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>[C:1]([O:4][C:5]1[C:6]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cccnc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
2-Bromopyridin-3-yl acetate (10 g, 46 mmol) was dissolved in THF (80 mL) and triethylamine (32 ml, 231 mmol), ethynyltrimethylsilane (19.5 ml, 139 mmol), and CuI (0.44 g, 23 mmol) were added. The mixture was degassed with argon for 15 minutes, then PdCl2(PPh3)2 (1.6 g, 2.3 mmol) was added and the mixture was stirred under argon at ambient temperature for 18 hours. The reaction was concentrated in vacuo, dissolved in 25% EtOAc in hexanes, filtered and purified over silica gel (25% ethyl acetate/hexanes) to afford 2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate (9.7 g, 41 mmol).
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1C)[CH3:16]>>[CH2:18]([N:17]([CH2:15][CH3:16])[C:25]1[CH:20]=[CH:21][C:22]([C:10]([C:5]2[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=2[C:7]([OH:9])=[O:8])=[O:11])=[CH:23][CH:24]=1)[CH3:19]
Reactant: CCn1c(C)cc2ccccc21
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
Homophthalic anhydride (I) can be reacted mol-for-mol with a compound such as 1-ethyl-2-methylindole (T) in the presence of a catalyst, as previously disclosed, to yield keto-acid (II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:19](O)=[O:20].[CH3:22][O:23][C:24](=[O:42])[C@H:25]([NH2:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=2)=[CH:29][CH:28]=1>>[CH3:22][O:23][C:24](=[O:42])[C@H:25]([NH:41][C:19]([C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:20])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reactant: COC(=O)[C@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Product: COC(=O)[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1OC
Yield: 76.1 %

Procedure:
3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (223 mg) was prepared from 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (141 mg, 0.5 mmol) and-2-(R)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (155 mg, 0.5 mmol) following the general procedure A.
Reaction SMILES: [NH2:1][CH:2]1[CH2:23][C:5]2[N:6]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>ClCCl>[C:13]([C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)[C:5]3[CH2:23][CH:2]([NH:1][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])[CH2:3][C:4]=3[C:12]=2[CH:11]=1)#[N:14]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)NC1Cc2c(n(Cc3cccc(F)n3)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-2-amino-4-(6-fluoro-pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (70 mg, 0.23 mmol) and diisopropylethylamine (0.35 mmol, 61 μL) in dichloromethane (1 mL) add N,N-dimethylcarbamoyl chloride (0.35 mmol, 32 μL) and stir at room temperature overnight. Load the solution on silica gel and purify by column chromatography (0-100% ethyl acetate/dichloromethane) to obtain the title compound. LCMS 378.1 (M+1).
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of cyclobutanemethanol (11.0 mL, 116 mmol) in CH2Cl2 (35 mL) and pyridine (35 mL) was added DMAP (0.71 g, 5.81 mmol) followed by p-toluenesulfonyl chloride (22.1 g, 116 mmol). This mixture was allowed to stir at ambient temperature for 16 hours then was quenched with 5% aqueous HCl (40 mL) and diluted with CH2Cl2 (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, eluted with 75% hexanes in EtOAc) to give the title compound (24.7 g, 103 mmol, 89% yield). MS (DCI/NH3) m/z 258 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:18]2[NH:23][C:22](=[O:24])[NH:21][C:20]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])=[CH:27][CH:26]=3)=[C:19]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]=1[O:10]C(OC)=O)[CH3:2].[OH-].[Na+].Cl.O>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:18]2[NH:23][C:22](=[O:24])[NH:21][C:20]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])=[CH:29][CH:30]=3)=[C:19]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:10])[CH3:2]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(NC(=O)OC)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1OC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(NC(=O)OC)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 28 °C
Reaction time: 4 h
Yield: 44.6 %

Procedure:
To a mixture of the intermediate from Step 1 (60 mg, 0.107 mmol) in ethanol (2 mL) was added sodium hydroxide aqueous solution (2 mL, 1.25 mol/L) at 0° C., and the mixture was stirred at 28° C. for 4 h. The reaction mixture was adjusted to pH=5 with diluted hydrochloric acid. The mixture was poured into water (20 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, evaporated, and purified by preparative HPLC to give Compound 83 (24.1 mg, yield 44.6%). 1H NMR (DMSO-d6400 MHz): δ 10.28 (s, 1H), 9.70 (s, 1H), 8.64 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.19 (s, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.07-7.00 (m, 3H), 6.84 (d, J=7.2 Hz, 2H), 5.16 (d, J=2.8 Hz, 1H), 4.06-4.01 (m, 2H), 3.65 (s, 3H), 1.35-1.31 (m, 3H); MS (ESI): m/z 505.0 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.C(N(CC)CC)C>C(O)(C)C>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 82 °C

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82° C. for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35° C. to remove the tetrahydropyranyl group to yield (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>CN(C=O)C>[N:1]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Temperature: 95 °C

Procedure:
A solution of imidazole (13.6 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (8.0 g, 60% dispersion in oil) in dry DMF (250 ml) at ambient temperature under nitrogen for 2.5 hours. A slurry of N-(4-bromobutyl)phthalimide (53.6 g) in dry DMF (80 ml) was added and the mixture heated at 95° C. for 16 hours. The solvent was evaporated off under vacuum and the residue was extracted with hot toluene. The combined toluene extracts were evaporated to dryness and the residue triturated with ether and dried to give N-[4-(imidazol-1-yl)butyl]phthalimide, m.p. 76°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24]O)[N:22]=1)=[CH:5]2.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:50]I>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][I:50])[N:22]=1)=[CH:5]2
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Reaction time: 8 h
Yield: 39.9 %

Procedure:
The compound obtained in Example 13 (3.7 g, 10.2 mmol) was dissolved in tetrahydrofuran (100 ml). Imidazole (2.1 g, 30.6 mmol), triphenylphosphine (4.0 g, 15.3 mmol) and iodine (3.9 g, 15.3 mmol) were added, and stirred for 8 h at 0° C.˜room temperature. After completion of the reaction, ethyl acetate (100 ml) was added, and the reaction mixture was washed with water (100 ml×2). The organic layer was concentrated and the residue was purified by column chromatography to give the title compound (2.0 g, 4.07 mmol, Yield 40%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9].[CH3:10][C:11](=[O:18])[C:12](=[N:16]O)[C:13](=O)[CH3:14]>C(#N)C>[CH3:14][C:13]1[NH:9][C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])=[N:16][C:12]=1[C:11](=[O:18])[CH3:10]
Reactant: Cc1cnccc1CN
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CC(=O)c1nc(-c2ccncc2C)[nH]c1C
Temperature: -10 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
A mixture consisting of 7.1 g (0.058 mole) of 3-methyl-4-pyridylmethylamine, 6.25 g (0.051 mole) of 2,3,4-pentanetrione 3-oxime, and 125 ml of acetonitrile was stirred at the reflux temperature for five hours. After cooling at -10° C., a precipitate formed. This was collected, washed with a little cold acetonitrile, and dried. Recrystallization from a mixture of chloroform and hexane gave 4.5 g of the desired product, mp 185°-187° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:16][C:11]=2[N:10]([CH3:23])[C:9]1=[O:24].CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1>[CH3:23][N:10]1[C:11]2[CH:16]=[C:15]3[C:14](=[CH:13][C:12]=2[N:8]([CH3:7])[C:9]1=[O:24])[C:20](=[O:22])[CH2:19][CH2:18][CH2:17]3
Reactant: Cn1c(=O)n(C)c2cc(CCCC(=O)O)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C)c2cc3c(cc21)CCCC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Oxalyl chloride (7.0 ml, 81 mmol) was added by portions to a solution of 4-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)butanoic acid (20 g, 81 mmol) obtained in Reference Example 136 and dimethylformamide (1 ml) in tetrahydrofuran under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated, the reaction residue was dissolved in nitroethane, and aluminum chloride (21.6 g, 162 mmol) was added by portions under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice (500 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give the title compound as colorless crystals (18.0 g).