Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OB1C2CCCC1CCC2.C[Li].[CH3:14][O:15][C:16]([C:18]1[C:19]([NH2:29])=[C:20]([Cl:28])[CH:21]=[C:22]2[C:26]=1[NH:25][N:24]=[C:23]2Br)=[O:17]>O1CCCC1.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Pd+2]>[CH3:14][O:15][C:16]([C:18]1[C:19]([NH2:29])=[C:20]([Cl:28])[CH:21]=[C:22]2[C:26]=1[NH:25][N:24]=[C:23]2[CH3:1])=[O:17]
Reactant: COB1C2CCCC1CCC2
Reactant: COC(=O)c1c(N)c(Cl)cc2c(Br)n[nH]c12
Agent: [Pd+2]
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1c(N)c(Cl)cc2c(C)n[nH]c12
Yield: 66 %

Procedure:
To a solution of 899 mg (5.91 mmol) of 9-methoxy-9-bora-bicyclo[3.3.1]nonane in 5 mL of anhydrous tetrahydrofuran is added dropwise 3.71 mL (5.91 mmol) of a solution 1N of methyl lithium in diethylether. After few minutes of stirring, a mixture of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 39, and 104 mg (0.15 mmol) of bis(triphenylphosphine) palladiumI(II) dichloride in 10 mL of anhydrous tetrahydrofuran is added. The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes. After filtration over Celite and concentration in vacuo, the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) to afford 470 mg of product (66%) as a pale yellowish solid; LC/MS:240/242 (M+H)+.
Reaction SMILES: [CH2:1]([S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16]C)=[O:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(CSCCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(CSCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of methyl 3-(phenethylthiomethyl)benzoate (1.15 g, 4.02 mmol) in THF (4 mL) and MeOH (4.00 mL) was added 1 N aqueous NaOH solution (6 mL). The resulting mixture was stirred at rt for overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with 1 N HCl solution. The solid was filtered and vacuum dried to give the desired product (1.05 g, 95%) as a white solid. 1H NMR (DMSO-d6) δ 13.07 (s, 1H), 7.93 (s, 1H), 7.83-7.81 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.29-7.25 (m, 2H), 7.20-7.17 (m, 3H), 3.84 (s, 2H), 2.91-2.78 (m, 2H), 2.63-2.59 (m, 2H). MS (ESI): 273.1 (M+H)+.
Reaction SMILES: [Li].[CH2:2]([N:9]1[CH2:17][C@H:16]2[C@H:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:14][C:15]2=[O:18])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].O>O1CCCC1.C(OCC)(=O)C>[CH2:2]([N:9]1[CH2:17][C@H:16]2[C@H:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:14][C@H:15]2[OH:18])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: [BH4-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
4.0 cm3 of a 1M solution of lithium tri-sec-butylboro-hyride in tetrahydrofuran is added over 5 minutes to a solution, cooled to 0° C., of 1.3 g of (3aR,7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone in 6.0 cm3 of tetrahydrofuran. After stirring for 3 hours at 0° C., 0.5 cm3 of the 1M solution of borohydride is again added to the reaction mixture. After 1 hour at 0° C., followed by the addition of 50 cm3 of water and 50 cm3 of ethyl acetate, the organic phase is decanted, washed with 20 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm3 of diisopropyl oxide, the crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR,4R,7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of white crystals; melting point 154° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(diethyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M28) (0.53 g, 0.827 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (210 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[O:14])[CH:3]=1.[CH3:24][S:25](C)=O>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([S:25][CH3:24])=[CH:21][CH:22]=2)=[O:14])[CH:3]=1
Reactant: CS(C)=O
Reactant: CCOc1nc(C(=O)NCc2ccc(Cl)nc2)cc(N)c1C#N
Product: CCOc1nc(C(=O)NCc2ccc(SC)nc2)cc(N)c1C#N

Procedure:
A solution of Example 185 (70 mg, 0.21 mmol) and sodium methylthiolate (32 mg, 0.46 mmol) in dimethyl sulfoxide (0.8 mL) was heated to 90° C. for 12 h., extracted with ethyl acetate (5 mL), and washed with H2O (2×5 mL). The organic layer was concentrated in vacuo and purified by silica gel chromatography (50-100% ethyl acetate in hexanes) providing the title compound as an off white solid (42 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.98-9.15 (m, 1H), 8.32-8.44 (m, 1H), 7.57 (dd, J=8.31, 2.20 Hz, 1H), 7.32 (s, 2H), 7.25 (dd, J=8.31, 0.85 Hz, 1H), 7.06 (s, 1H), 4.49 (q, J=7.12 Hz, 2H), 4.41 (d, J=6.44 Hz, 2H), 2.48 (s, 3H), and 1.31 (t, J=7.12 Hz, 3H); MS (ESI) m/e positive ion 344 [M+H]+; negative ion 342 [M−H]−.
Reaction SMILES: C(OC([N:8]1[C@@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:22]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH2:31][NH:32][CH2:33][CH2:34][C:29]=2[C:28](=[O:35])[O:27]1)[CH:23]([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[OH:21][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([C:18]([N:32]3[CH2:33][CH2:34][C:29]4[C:28](=[O:35])[O:27][C:26]([CH2:22][CH:23]([CH3:24])[CH3:25])([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]=4[CH2:31]3)=[O:20])[NH:8][CH2:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@@H]1C(=O)O
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@H]1Cc3ccc(O)cc3CN1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a solution of (R)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (102 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and the crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes). The purified fractions were re-dissolved in dichloromethane (5 mL), cooled to 0° C. and stirred with TFA (1 mL) for 5 hours at room temperature. The reaction mixture was concentrated to dryness, re-dissolved in dichloromethane (20 mL), washed with sat. NaHCO3 solution (5 mL), brine (5 mL), dried (MgSO4), and concentrated to provide 5-((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (55 mg, 67%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.58-1.88 (m, 2H), 2.25-2.54 (m, 5H), 2.65-2.97 (m, 2H), 3.52 (d, J=6.40 Hz, 1H), 3.75-3.95 (m, 2H), 3.98-4.11 (m, 3H), 4.56-4.86 (m, 1H), 6.51 (s, 1H), 6.59-6.73 (m, 1H), 6.95 (t, J=8.48 Hz, 1H), 7.28-7.45 (m, 5H); MS m/z 447 (M+H)+.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)=[CH:5]OCC.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[C:3](=[O:20])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:5]=2)=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(C)c1
Reactant: Nc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Yield: 101 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 1 g (3.78 mmol) of 3-ethoxy-2-(4-methoxy-3-methyl-benzoyl)-acrylic acid methyl ester, 0.214 g (3.78 mmol) of aniline, and 20 mL of diphenyl ether to yield 1.12 g of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([CH2:23][O:24][P:25]([OH:28])([OH:27])=[O:26])[CH2:12][C@H:11]([OH:29])[C@@H:10]1[NH:30]CC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[NH2:30][C@@H:10]1[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@@H:13]([CH2:23][O:24][P:25]([OH:28])([OH:27])=[O:26])[CH2:12][C@@H:11]1[OH:29]
Reactant: O=P(O)(O)OC[C@H]1C[C@H](O)[C@H](NCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COP(=O)(O)O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 40 mg of the compound of step 1.3 (0.068 mmol) in MeOH (2 mL) was added 10% Pd on carbon catalyst (10 mg) and the mixture was vigorously stirred under a hydrogen atmosphere (1 atm) at room temperature for 4 h. After filtration and lyophilization, the titled compound was obtained as a colorless solid (16 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH:31]([F:33])[F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH:31]([F:33])[F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(F)F)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OCC(F)F)nc1Cl
Yield: 69.7 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2,2-difluoroethoxy)piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (122a) (0.24 g, 0.48 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (8 mL) to obtain 0.16 g of the title compound as a colorless solid (71%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:25]2[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=2[CH3:34])O1.C(OCC)(=O)C>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:34][C:26]1[CH:25]=[CH:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][C:27]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccc2cc[nH]c2c1
Yield: 64.8 %

Procedure:
6-Bromo-1H-indole (203 mg, 1.04 mmol) and potassium carbonate (287 mg, 2.08 mmol) was dissolved in a DMF/water (4:1, 2.5 mL) mixture solution, and the gas included in the mixture solution was removed using ultrasonic wave and nitrogen gas. After sequentially adding 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborolane (300 mg, 1.14 mmol) and Pd(dppf)Cl2 (85 mg, 0.10 mmol), the mixture was stirred at room temperature in a sealed reactor. 2 hours later, after adding ethyl acetate and water, the reaction solution was filtered through a diatomite pad. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried with anhydrous magnesium sulfate and then concentrated. Purification of the residue by chromatography (silica gel, EA:Hx=1:4) yielded 6-(2-methyl-5-nitrophenyl)-1H-indole (170 mg) as brown solid.
Reaction SMILES: [C:1]12(CS(O)(=O)=O)[C:8]([CH3:10])(C)[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C1(C)C=CC=CC=1>[CH:16]1[CH:10]=[CH:8][C:1]2[C:7](=[CH:6][CH:5]=[CH:4][C:2]=2[OH:3])[CH:17]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cccc2ccccc12
Temperature: 25 °C

Procedure:
The compound of the above formula (48) and 221.1 mg (0.9 mmol) of (±)-10-camphorsulfonic acid were dissolved in 150 ml of toluene and refluxed for 30 minutes. After the obtained solution was left to be cooled to room temperature, this solution was added to 100 ml of a toluene solution containing 4.5 g (27.3 mmol) of p-toluenesulfonic acid heated at 90° C. and refluxed for 4 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a naphthol compound represented by the following formula (49) as 3.7 g (8.2 mmol, yield of 45%) of a yellow solid.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][C:20]1[NH:21][C:22](=O)[C:23]2[CH:28]=[N:27][N:26]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[C:24]=2[N:25]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][C:20]1[NH:21][C:22](=[S:2])[C:23]2[CH:28]=[N:27][N:26]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[C:24]=2[N:25]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1cnn2C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: S=c1[nH]c(Cc2cccc(Cl)c2)nc2c1cnn2C1CCCC1
Temperature: 0 °C

Procedure:
50 mg (0.23 mmol, 1.5 equiv.) of diphosphorus pentasulfide are added to a solution of 50 mg (0.15 mmol) of 6-(3-chlorobenzyl)-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 1) in 1 ml of pyridine at room temperature, and the mixture is then stirred under reflux overnight. After cooling, the reaction solution is mixed with 10 ml of ice-cold 2.5% strength sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH4+].[OH-].[C:11](OC(=O)C)(=[O:13])[CH3:12]>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:11](=[O:13])[CH3:12])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)ccn1
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)Nc1cc(Br)ccn1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromopyridin-2-amine (12.0 g, 69.4 mmol) in acetic anhydride (240 mL) was added DMAP (0.0847 g, 0.694 mmol). The reaction mixture was allowed to stir at 140° C. for 3 h and then allowed to cool to rt. Ice water was added and the pH of the mixture was adjusted to 8.5 by the addition of concentrated NH4OH. The solid which precipitated was filtered, washed with cold water and hexanes, and dried to give N-(4-bromopyridin-2-yl)acetamide (13.3 g) as a white solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][C:34]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])([CH3:39])[C:35]([O:37]C)=[O:36]>>[CH3:33][C:34]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:61][CH:62]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])([CH3:39])[C:35]([OH:37])=[O:36]
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C(C)(C)C(=O)OC)C4)cc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C(C)(C)C(=O)O)C4)cc2)cc1
Yield: 77 %

Procedure:
The compound of example 525 was prepared analogous to compound of example 98 by hydrolysis of compound of example 524.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[CH2:17]Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][CH:24]=[CH:23][N:22]=1>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:20]=[C:21]2[C:26]([Br:27])=[CH:25][CH:24]=[CH:23][N:22]2[CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: O=C(CBr)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Temperature: 78 °C
Reaction time: 8 h
Yield: 153.7 %

Procedure:
(S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (1.771 g, 5.4 mmol), 2-amino-3-bromo-pyridine (0.9412 g, 5.4 mmol), and ethanol (20 mL) were combined under nitrogen. The reaction mixture was heated to 78° C. and stirred overnight. The sample was concentrated and saturated sodium bicarbonate (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The ethyl acetate extracts were dried over magnesium sulfate and filtered. The crude material was adsorbed onto silica gel and purified by flash chromatography (40 g SiO2, 0-100% ethyl acetate in hexanes) to give (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.869 g, 8.3 mmol, 2.2 mmol, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35](=[O:67])[N:36]([NH:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:37]([C@H:41]([NH:45][CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[CH2:42][C:43]#[CH:44])=[N:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:45]([C@@H:41]([C:37]1[N:36]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:35](=[O:67])[C:34]2[C:39](=[CH:40][C:31]([Cl:30])=[CH:32][CH:33]=2)[N:38]=1)[CH2:42][C:43]#[CH:44])[CH2:46][CH2:47][CH2:48][N:49]1[C:50](=[O:59])[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:57]1=[O:58])=[O:7]
Reactant: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Reactant: O=C(O)c1cccc(Cl)c1F
Agent: Cn1cc[n+](C)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN1C(=O)c2ccccc2C1=O)C(=O)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 3-chloro-2-fluoro-benzoic acid (3.2 g, 18.3 mmol) of in acetonitrile (30 ml) was added 2-chloro-1,3-dimethylimidazolium chloride (DMC) (3.3 g, 19.5 mmol), followed by diisopropylethyl amine (6.8 ml, 39 mmol). The resulted solution was stirred at room temperature for 10 min, then transferred into flask containing (R)-2-{3-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (6.1 g) in a 2.5M solution of diisopropylethyl amine in acetonitrile (30 ml). The reaction mixture was stirred at room temperature and the reaction progress was monitored by HPLC/MS. Upon completion, a saturated solution of sodium carbonate (100 ml) was added. The organic layers were collected and the aqueous layer was washed with EtOAc (2×50 ml). The combined organic layers were washed with brine (100 ml) and dried over sodium sulfate. The solvent was removed and residue was separated on silica gel column to afford 3-chloro-N-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)propyl]-2-fluoro-benzamide as off-white solid (7.6 g, 96%). M.p. 130-132° C. LCMS: m/e 682 [M+H]. 1H NMR (CDCl3): δ 8.09 (m, 1H), 7.71 (m, 3H), 7.46 (m, 1H), 7.35 (m, 2H), 7.29 (m, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 7.03 (m, 1H), 6.90 (m, 1H), 6.82 (m, 1H), 6.68 (m, 1H), 6.50 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.51 (m, 1H), 3.38 (m, 1H), 3.26 (m, 1H), 3.06 (m, 1H), 2.88 (m, 1H), 2.01 (s, 1H), 1.80 (m, 1H), 1.54 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:24][CH2:25]1
Reactant: IC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(C4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[C:3]=1[NH2:4].[CH2:23]([N:30]=[C:31]=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1C=CC=CC=1>C1COCC1>[CH2:23]([NH:30][C:31]([NH:4][C:3]1[C:5]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCN=C=O
Reactant: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2N)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCNC(=O)Nc1c(F)cc(F)cc1CCc1ccc(CC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of the product from step (d) (4.5 g) in THF (50 ml) was stirred at room temperature and heptyl isocyanate (5.5 g containing 36 mole % benzene, prepared by the method described in Organic Syntheses, Collective Volume 3, p.846) and N,N-dimethylaminopyridine (750 mg) were added. The mixture was stirred at room temperature for ca 60 hours, then evaporated under reduced pressure to give an oil which was flash chromatographed through a silica column using ether/hexane (2:1 v/v). The eluate was evaporated under reduced pressure and the residue crystallised from hexane and triturated with methanol to give 4.5 g of material. The latter was flash chromatographed through a silica column using ether/hexane (2:1 v/v) and then freeze-dried from dioxan to give 5.3 g of the desired product, mp 105°-107° C.