Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:19][C:20]([CH3:22])=[CH2:21])[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]([CH3:23])[CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:20](=[CH2:21])[CH2:19][N:8]([C:6]1[CH:5]=[C:4]([CH3:23])[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)[N:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1
Reactant: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 85 °C
Yield: 59.9 %

Procedure:
To a degassed solution of (6-chloro-4-methyl-pyridin-2-yl)-(2-methyl-allyl)-(4-trifluoromethyl-phenyl)-amine (340 mg, 1.0 mmol), 4-trifluoromethylbenzeneboronic acid (230 mg, 1.2 mmol), 2N Na2CO3 (1.5 mL) in DME (10 mL) was added tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) under argon. The mixture was heated to 85° C. for 4 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% methylene chloride in methylene chloride) to give the product as a white solid (270 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.91 Hz, 2H), 7.69 (d, J=8.29 Hz, 2H), 7.59 (d, J=8.67 Hz, 2H), 7.39 (d, J=8.67 Hz, 2H), 7.11 (s, 1H), 6.66 (s, 1H), 4.86 (s, 2H), 4.70 (s, 2H), 2.30 (s, 3H), 1.81 (s, 3H). MS m/e 451.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:30]C1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:29])=[O:30])=[CH:26][CH:27]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
A solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 4, (450 mg, 1.12 mmol) in CH2Cl2 (10 mL) was added dropwise to a suspension of hydroxy(tosyloxy)iodobenzene (439 mg, 1.12 mmol) in CH2Cl2 (15 mL) and the mixture was stirred until a clear solution was obtained (about 1 hour). The reaction mixture was then washed with water and dried with MgSO4. Removal of solvent in vacuo provided the corresponding sulfoxide (yield: 485 mg, about 100%). 1H NMR (300 MHz, CDCl3) δ 2.72 (s, 3H), 5.40 (s, 2H), 6.90 (m, 2H), 7.15 (m, 3H), 7.33 (m, 3H), 7.57 (m, 3H), 7.71 (m, 1H), 7.86 (s, 1H). MS (DCI/NH3) m/z 419 (M+H)+, 436 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH3:25])=[N:4][N:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]3[CH3:25])=[N:4][N:3]=2)=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(-c2ccc(C#N)cc2)c2ccccc12
Yield: 94.4 %

Procedure:
Heat a mixture of (S)-tert-butyl 4-(4-chlorophthalazin-1-yl)-3-methylpiperazine-1-carboxylate (4.0 g, 11.0 mmol), 4-cyanophenylboronic acid (2.43 g, 16.5 mmol), cesium carbonate (14.4 g, 44.1 mmol), and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (J. Org. Chem. 2007, 72, 5104-5112) (75.4 mg, 0.11 mmol) in 1,4-dioxane (80 mL) and water (20 mL) at 90° C. overnight. Partition the reaction mixture between water and CH2Cl2. Extract the aqueous layer with CH2Cl2. Dry the combined organic layer over Na2SO4 and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 20% EtOAc in CH2Cl2) to provide the title compound as a light orange foam (4.46 g, 94%). ES/MS m/z 430.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14]O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][Cl:18])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1nccc2c(CO)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1nccc2c(CCl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-iso-Propyl-5-hydroxymethylisoquinoline (6.5 g) was dissolved in 50 ml of chloroform and 6.5 ml of phosphorus oxychloride was added dropwise under ice cooling. The mixture was stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction mixture, and it was made weakly alkaline with potassium carbonate. The chloroform layer was washed in water, and dried. The solvent was distilled off under reduced pressure to afford 7.1 g of 1-isopropyl-5-chloromethylisoquinoline as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:28]3[CH2:30][CH2:29]3)=[C:21]([O:23][C:24]([F:27])([F:26])[CH3:25])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:28]3[CH2:30][CH2:29]3)=[C:21]([O:23][C:24]([F:27])([F:26])[CH3:25])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(OC(C)(F)F)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)Oc1cc(Oc2cc(F)c(C(=O)O)cc2Cl)cnc1C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
To a solution of tert-butyl 5-chloro-4-(6-cyclopropyl-5-(1,1-difluoroethoxy)pyridin-3-yloxy)-2-fluorobenzoate (Preparation 270, 260 mg, 0.59 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (440 μL, 5.86 mmol). The reaction mixture was stirred over 48 hours at room temperature then concentrated in vacuo and the crude residue azeotroped with methanol (2×25 mL). The crude material was purified by silica gel column chromatography eluting with 50% ethyl acetate in heptane to afford the title compound as a white solid (200 mg, 96%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[C:16]([N+:24]([O-:26])=[O:25])[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:13]1[CH2:14][CH2:15][N:11]([CH3:10])[C:12]1=[C:16]([N+:24]([O-:26])=[O:25])[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccccc2)C1=C(Sc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.71 g of benzoyl chloride was added to 1.26 g of 1B and 0.63 g of triethylamine in 25 ml of methylene chloride at 0°-20°. After stirring overnight at room temperature, the solvent was stripped. The solid residue was triturated with ice-cold methanol and then filtered to give 2, as a yellow solid, m.p.: 175°-178°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[C:25]([CH3:32])[CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH3:34]OC1C=C2C(=CC=1OC)N=CN=C2N1CCC(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)NC2=O)CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[C:25]([CH3:32])[CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:34])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5c(C)cccc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cccc(C)c5n(C)c4=O)CC3)c2cc1OC
Yield: 61 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of 3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline (Compound 101) obtained in Reference Example 12 was used in place of Compound 24. As a result, 185.2 mg (yield: 61%) of Compound 59 was obtained as white crystals.
Reaction SMILES: N.[F:2][C:3]1[CH:4]=[C:5]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][CH2:42][F:43])[C:15]1([N:19]=[C:18]([N:20](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:17]([CH3:35])=[N:16]1)[C:7]1([CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]1)[CH2:6]2>C1(C)C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][CH2:42][F:43])[C:15]1([N:19]=[C:18]([NH2:20])[C:17]([CH3:35])=[N:16]1)[C:7]1([CH2:8][CH2:9][CH:10]([O:13][CH3:14])[CH2:11][CH2:12]1)[CH2:6]2
Reactant: COC1CCC2(CC1)Cc1cc(F)c(OCCCF)cc1C21N=C(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Agent: N
Solvent: Cc1ccccc1
Product: COC1CCC2(CC1)Cc1cc(F)c(OCCCF)cc1C21N=C(C)C(N)=N1
Temperature: 85 °C
Yield: 9.9 %

Procedure:
Methanolic ammonia (7 M, 1.89 mL, 13.2 mmol) and toluene (2 mL) was added to di-tert-butyl [5′-fluoro-6′-(3-fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-yl]imidodicarbonate (Intermediate 16, 260 mg, 0.44 mmol). The mixture was transferred to a MW vial which was capped and heated to 85° C. for a week. The mixture was concentrated and partitioned between EtOAc and 2 M citric acid. The phases were separated and the organic phase was discarded. The aqueous phase was basified by addition of 50% aq. NaOH solution to pH 12 and then extracted with EtOAc. The combined organic phases were treated with charcoal, filtered through diatomaceous earth and concentrated. Purification of the residue by preparative HPLC afforded the title compound (17 mg, 10% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.83-0.95 (m, 1 H) 1.07-1.26 (m, 2 H) 1.33-1.49 (m, 3 H) 1.76-1.85 (m, 2 H) 1.97-2.11 (m, 2 H) 2.13-2.19 (m, 3 H) 2.82-2.99 (m, 3 H) 3.18 (s, 3 H) 3.90-4.01 (m, 2 H) 4.51 (t, 1 H) 4.61 (t, 1 H) 6.26 (d, 1 H) 6.53 (s, 2 H) 7.13 (d, 1 H); MS (ES+) m/z 392 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[C:5]([NH:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][NH:32][CH2:31][C:30]4=[O:35])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]>C1COCC1.O>[ClH:1].[C:2]([C:4]1[C:5]([NH:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][NH:32][CH2:31][C:30]4=[O:35])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCNCC4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCNCC4=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Concentrated hydrochloric acid (0.31 ml) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 121, 250 mg, 0.371 mmol) in THF (10 ml) and water (2 ml) at room temperature. After stirring for 18 h at room temperature the reaction mixture was evaporated. The residue was purified by reversed phase HPLC (RP 2) to give the title compound.
Reaction SMILES: [C:1]([C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].N>C(O)C.[Ni].O>[NH2:2][CH2:1][CH:3]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccccc2)CC1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(CN)c2ccccc2)CC1
Reaction time: 5.5 h

Procedure:
tert-butyl 4-[cyano(phenyl)methylene]piperidine-1-carboxylate (1.18 g, 3.95 mmol) in ethanol (15 ml) was saturated with NH3 at ambient temperature and Raney nickel (1 ml, 3.95 mmol) in water was added. The reaction was placed on a Parr reactor under H2 pressure (48 psi) for 19 hours. The reaction mixture was then re-saturated with NH3 and additional Raney nickel (1 ml, 3.95 mmol) was added before placing back on the Parr reactor for an additional 5.5 hours. The reaction mixture was filtered through Celite, washing with EtOH, and concentrated in vacuo. The product was carried on without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].C1COCC1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1F>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[O:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2Br)C1
Reaction time: 1 h

Procedure:
To a solution of Boc-3-hydroxyazetidine (1.50 g, 8.67 mmol) in DMF (9.1 mL) was added 1 M potassium tert-butoxide in THF (9.96 mL, 9.96 mmol) followed by 1-bromo-2,4-difluorobenzene (2.50 g, 13.0 mmol). After a period of 1 h at 50° C., the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18]O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C(Cl)(Cl)Cl>ClCCl>[Br:40][CH2:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCCC1)Nc1ccccc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1ccccc1CCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-cyclohexyl-N-[2-(2-hydroxyethyl)phenyl]acetamide (780 mg) in dichloromethane (20 mL) were added triphenylphosphine (938 mg) and carbon tetrabromide (1.12 g) at room teperature. The solution was stirred at room temperature for 1 hour. Chloroform was added and the solution was washed in turn with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=7:3) to give the title compound (450 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O.[CH3:23][N:24](C)[CH:25]=O.C(N(CC)C(C)C)(C)C.CNC>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([N:24]([CH3:25])[CH3:23])=[O:14]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC(Cc1nc2ccccc2s1)C(=O)O
Agent: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(Cc1nc2ccccc2s1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 80 %

Procedure:
The 3-(benzo[d]thiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (0.15 g, 0.465 mmol) was combined with N,N,N′,N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.21 g, 0.558 mmol), N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (120 μl, 0.92 mmol) and the 2 M dimethylamine in THF (1.0 mL). The reaction was stirred for 2 h., partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as a semisolid. The product was purified by Flash chromatography on a silica gel column eluting hexane:ethyl acetate gradient to give tert-butyl 3-(benzo[d]thiazol-2-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.13 g, 80%). Analytical LCMS (M+H)+: m/z=350.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30]Cl)(=[O:24])[CH3:23]>CS(C)=O>[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:24])[CH3:23]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a stirring suspension of 7-benzyl-3-methylxanthine (25.6 g, 100 mmol) (which had been prepared as described for CT22404 of Example 18) in dimethylsulfoxide (200 ml) was added 95% sodium hydride (3.2 g, 133 mmol) in portions over 10 minutes. After stirring for 30 minutes, (R)-5-acetoxy-1-chlorohexane (19.63 g, 110 mmol) was added neat. After heating at 70-80° C. for 6 hours, the reaction mixture was quenched by addition of water (500 ml) and extracted with ethyl acetate (3×150 ml). The combined extracts were washed with water (150 ml), saturated aqueous sodium chloride solution (150 ml) and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was purified by flash chromatography on silica gel eluting with 20% hexane/ethyl according to give (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (33.7 g).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[OH:10][C:11]1[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[F:20][C:21]1[C:26](O)=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31]>C(Cl)Cl.O>[OH:10][C:11]1[C:12]([C:17]([O:19][C:26]2[C:25]([F:28])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=2[F:20])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1ncccc1O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ncccc1O
Reaction time: 12 h

Procedure:
At 20-25° C. 13 g of N,N′-diisopropylcarbodiimide (DIC) were added dropwise to a solution of 14 g of 3-hydroxypyridine-2-carboxylic acid and 18.5 g of pentafluorophenol in 700 ml of CH2Cl2. After the reaction had ended (about 40 min), the solution was allowed to stand at 20-25° C. for about 12 hours. The solvent was removed, and the residue formed was then taken up in water and the solution was extracted with CH2Cl2. The organic phase gave, after drying and removal of the solvent, 29 g of the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCCC1>[CH3:12][C:11]1[N:7]([CH2:6][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[CH:9][CH:10]=1
Reactant: Cc1ccnn1C
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccnn1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of n-butyllithium (25 mL, 2.5M) in tetrahydrofuran (30 mL) was added 1,5-dimethyl-1H-pyrazole (5.0 g) in tetrahydrofuran (20 mL) dropwise via syringe. After 1 hour, cyclohexanone (5.1 g) in tetrahydrofuran (20 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was quenched by the addition of saturated ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with additional ethyl acetate (twice). The combined organics were dried over Na2SO4, filtered, and concentrated to provide the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[CH2:27][N:28]=[C:29]=[S:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:39]=1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[CH2:27][NH:28][C:29]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[N:39]=2)=[S:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:35][CH:34]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OCc2cccc(CN=C=S)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Product: COc1ccc(C(OCc2cccc(CNC(=S)NCc3cccc(CO[Si](C)(C)C(C)(C)C)n3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 110.4 %

Procedure:
To a solution of 3-(4,4′-dimethoxytrityloxymethyl)benzyl isothiocyanate (21) (332 mg, 0.69 mmol) in CDCl3 (4.6 mL) was added a solution of 2-aminomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (3) (63.10 mg, 0.39 mmol) in CDCl3 (3 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The reaction mixture was refluxed for 5 hours. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=3:1 to 2:1) to give N-[3-(4,4′-dimethoxytrityloxymethyl)benzyl]-N′-{[6-(tert-butyldimethylsilyloxymethyl)pyridin-2-yl]methyl}thiourea (22) (316 mg, 62%) as a yellow oil.