Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][S-:11].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: C[S-]
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(F)cc(Br)c1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
50.0 g of 1-bromo-3,5-difluorobenzene and 18.2 g sodium methanethiolate were stirred at 150° C. for 15 min in 300 ml of anhydrous DMF. Subsequently, the mixture was cooled to room temperature, poured onto 1 l of saturated aqueous ammonium chloride solution and extracted three times with 200 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 48.5 g of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [CH3:1]/[C:2](/N)=[CH:3]\[C:4]#[N:5].Cl.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][NH2:16].[OH-].[Na+]>Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:5])[N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:8])[N:16]=1
Reactant: Cc1ccccc1NN
Reactant: C/C(N)=C\C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(N)n(-c2ccccc2C)n1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
3-Aminocrotonitrile (2.00 g, 24.4 mmol) was added to a stirred solution of (2-methylphenyl)hydrazine hydrochloride (3.67 g, 23.1 mmol) in 1 M hydrochloric acid (20 mL). The reaction was heated (100° C.) for 18 h and then cooled to rt. The solution was adjusted to pH>12 using 1 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3×20 mL), and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 25-50% ethyl acetate/hexane afforded 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (3.97 g, 87%) as an orange oil. 1H NMR (300 MHz, acetone-d6) δ 7.29 (m, 4H), 5.32 (s, 1H), 2.12 (s, 3H), 2.08 (s, 3H); ES-MS m/z 188.2 (MH+), HPLC RT (min) 0.79.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[C:18]([CH3:19])=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]=O>>[F:12][C:13]1[C:18]([CH3:19])=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: CCc1nc(I)cn1CCN
Reactant: Cc1c(F)ccc(CCC=O)c1F
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(F)c(C)c1F

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (334.0 mg; 1.260 mmol) and 3-(2,4-difluoro-3-methyl-phenyl)-propionaldehyde (232.7 mg; 1.260 mmol) afforded 8-[2-(2,4-difluoro-3-methyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C@@H:11]([CH3:19])[CH2:10]1)=[O:7])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:37]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:41][CH:40]=1)=[O:38]>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([N:8]([C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:41][CH:40]=2)=[O:38])[C@@H:11]([CH3:19])[CH2:10]1)=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a solution of 2-{(4-chlorophenyl)[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate (170 mg, 0.45 mmol, 1 equ.) in methylene chloride (2.0 mL) at room temperature was added diisopropylethylamine (127 uL, 0.73 mmol, 1.60 equ.) followed by methyl 5-[4-(chlorocarbonyl)phenyl]-2,2-dimethylpentanoate (196 mg, 0.73 mmol, 1.60 equ.). The reaction was stirred over night at room temperature. The mixture was concentrated, then poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered dried and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane 25/75 to 1:1 gradient) to afford the pure methyl 5-(4-{[(2S,4R)-4-[[(acetyloxy)acetyl](4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoate (110 mg, 40%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].[K+].Cl[CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:23]=[C:22]([S:34][CH2:35][CH3:36])[N:21]2[CH:37]=1>CN(C=O)C>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[C:24]1[N:23]=[C:22]([S:34][CH2:35][CH3:36])[N:21]2[CH:37]=[C:18]([CH2:17][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:19]=[C:20]2[CH:25]=1
Reactant: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CCl)cn12
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)cn12
Reaction time: 16 h

Procedure:
102 mg (1.17 mmol) of morpholine are introduced into 7 ml of DMF at 0° C., and 236 mg (0.78 mmol) of triethylamine and a catalytic amount of potassium iodide are added. A solution of 290 mg of 2-(chloromethyl)-7-(2,4-dichlorophenyl)-5-(ethylsulphanyl)imidazo[1,2-c]pyrimidine (Example 91A) in DMF is then slowly added dropwise. The mixture is allowed to reach RT and is stirred at this temperature for a further 16 h. Purification of the crude product by preparative HPLC and drying under high vacuum result in 214 mg (43% of theory) of product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[C:25]2[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=2)[NH:32][C:31]1=[O:37]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 73.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (50 mg, 73.1%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([C:9]2[C:10](=O)[NH:11][N:12]=[C:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]([F:8])=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:22])=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]=1[C:4]1[C:5]([F:8])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)ccc(Cl)c2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2c(F)ccc(Cl)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
1.33 g of 4-(3-chloro-2,6-difluorophenyl)-5-(4-chlorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.33 g of 3-chloro-4-(3-chloro-2,6-difluorophenyl)-5-(4-chlorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (x) of the present invention).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:9]=2[CH:10]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8](/[CH:11]=[C:12](/[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)\[CH3:13])[C:9]=2[CH:10]=1
Reactant: CN1CCc2c(c3cc(Cl)c(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: C/C(=C\n1c2c(c3cc(Cl)c(Cl)cc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-(7,8-dichloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (500 mg, 1.2 mmol) in thionylchloride (5 mL) and stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (5 mL) and the solution was stirred at RT for 5 min. Powdered KOH (482 mg, 8.5 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, formate salt) δ (ppm): 8.60 (d, 2H), 7.70 (d, 2H), 7.65 (s, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 4.0 (s, 2H), 3.20 (t, 2H), 2.98 (t, 2H), 2.80 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [CH2:1]([CH:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH2:8][CH:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: C=CCCC1C=CCC2=C1C(=O)c1ccccc1C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC1CCCC2=C1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A 5.0 g. sample of 1,4-dihydro-1-(3-butenyl)anthraquinone (6a, R = H) was dissolved in 100 ml. of ethyl acetate. The solution was then hydrogenatd using 0.2 g. 10% Pd/C catalyst. After the absorption of three equivalents of hydrogen, the mixture was filtered to remove the catalyst. It was then stirred at room temperature overnight while exposed to air to oxidize the hydroquinone. After removal of the solvent, the residue was recrystallized from methanol to give 4.2 g. product (83% yield). The gas chromatographic retention time, infrared spectrum, and nmr spectrum of this sample were identical with those of an authentic sample.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][C:23]2=O)=[CH:19][CH:18]=1.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](=[CH:19][CH:18]=1)[CH2:21][CH:22]=[C:23]2[C:8]1[CH:7]=[CH:6][CH:5]=[C:2]([O:3][CH3:4])[C:1]=1[O:9][CH3:10]
Reactant: O=C1CCc2ccc(Cl)cc21
Reactant: COc1ccccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2=CCc3ccc(Cl)cc32)c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, 45.9 ml of veratrole (49.78 g, 360.1 mol) are dissolved in 240 ml of THF and, at −78° C., 236.2 ml of a 1.6 M solution of n-butyllithium in THF (377.7 mol) are added drop wise. The reaction mixture is warmed to 0° C. and stirred at this temperature for 3 h. The mixture is cooled to −60° C., and 30.0 g of the compound from Example 16A (180.1 mol) dissolved in 150 ml of THF are added drop wise. The reaction mixture is warmed to room temperature over the course of 3 h and then acidified with 1 N hydrochloric acid and extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator. The residue is is purified by filtration through silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). The crude product [6-chloro-1-(2,3-dimethoxyphenyl)indan-1-ol] is dissolved in 1 l of dichloromethane and, after addition of 75 mg of 4-toluenesulphonic acid monohydrate (0.39 mol), stirred at RT for. 16 h. The reaction solution is washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1). 10.5 g (20% of theory) of the title compound are obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]2[CH3:26].B(Br)(Br)Br.C1CCCCC=1>>[CH3:26][C@H:5]1[C:4]2[C:13](=[CH:14][CH:15]=[CH:2][CH:3]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:16]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C[C@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared in the same manner as 4-[(S)-8-fluoro-6-methyl-6H-phenanthridine-5-sulfonyl]-phenol (example 8) using boron tribromide (1 M solution in dichloromethane) and cyclohexene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:36])[C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[NH2:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]([C@@H:18]2[C@H:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:36][C:37](=[O:38])[NH:19]2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc([C@@H](N)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2NC(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 1.0 g (2.06 mmol) of rel-(1S,2R)-1,2-bis(3'-benzyloxy-4'-methoxyphenyl)-2-aminoethanol, 334 mg (2.05 mmol) of carbonyldiimidazole, 20 ml of toluene.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:22]=[C:23]([C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:14]=1.[CH3:33]O>>[CH3:33][O:29][C:28](=[O:30])[C:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:15]2[CH:14]=[C:13]([NH:12][CH2:11][CH2:10][C:4]3[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=3[Cl:2])[N:18]=[C:17]([O:19][CH3:20])[N:16]=2)[CH:22]=1)([CH3:32])[CH3:31]
Reactant: CO
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: Cl
Product: COC(=O)C(C)(C)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid (81.46 μL, 4M solution in 1,4-dioxane, 0.33 mmol) is added to a stirred solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [100 mg, 0.22 mmol, Example 49(b)] in MeOH (8 mL), and the reaction mixture is stirred overnight at 65° C. The reaction is cooled to room temperature and concentrated in vacuo. The residue is purified by chromatography to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (34 mg, Example 79). LCMS: RT=2.79 minutes; MS: 475 (M+H); 1H NMR (300 MHz, CDCl3): □7.98 (1H, s), 7.88 (1H, b), 7.42 (3H, d, J=2 Hz), 7.2 (2H, s), 6.4 (1H, s), 5.08 (1H, b), 4.05 (3H, s), 3.7 (2H, b), 3.65 (3H, s), 3.1 (2H, t, J=2 Hz), 1.65 (6H, s).
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[CH2:3][O:4][C:5]([NH:7][C:8]([NH2:10])=[S:9])=[O:6].[C:13]([NH:16][CH:17]([C:23](=O)[CH2:24]Br)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14].CN(C)C1C=CC=CC=1>C(O)C>[C:13]([NH:16][CH:17]([C:23]1[N:10]=[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:11])[Cl:12])=[O:6])[S:9][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CBr
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2.51 g of N-(β,β,β-trichloroethoxycarbonyl)thiourea and 2.66 g. of ethyl α-acetamido-β-oxo-γ-bromobutyrate in 50 ml. of ethanol is added 1.8 g. of N,N-dimethylaniline. The mixture is stirred for 24 hours at room temperature, and condensed under reduced pressure. The residue is dissolved in 30 ml. chloroform and the solution is washed with 3 N-HCl, water, and dried. The solid matter which is obtained by removal of chloroform is purified by silica gel chromatography to give ethyl α-acetamido-2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-ylacetate. 1.43 g. Melting point: 161.9° C.
Reaction SMILES: [C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20]([NH:22][O:23]C4CCCCO4)=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20]([NH:22][OH:23])=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NO)ccc3O2)C1
Yield: 97 %

Procedure:
(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (35 mg, 0.088 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (0.4 ml) as described in Example 30, Step C, giving (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (27 mg, hydrochloride salt) as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[C:28](B(O)O)=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>O1CCOCC1.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>[Cl:18][C:19]1[C:28]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cc2ccccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-c2cc3ccccc3nc2Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.55 g, 2.18 mmol), 2-chloroquinolin-3-ylboronic acid (0.90 g, 4.35 mmol, Aldrich, St. Louis, Mo.) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol, Strem Chemicals, Inc., Newburyport, Mass.) in dioxane (3 mL) and water (1 mL) was sealed and purged with argon for several minutes. The reaction mixture was stirred at 90° C. for 6 h and then allowed to cool to room temperature. The organic phase was taken and the solvents removed under vacuum. Purification of the crude reaction mixture by silica gel chromatography (0 to 3% MeOH/CH2Cl2) provided the title compound as an orange solid. m/z (ESI, +ve ion) 380 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]1[CH:34]=[C:33]([CH2:35][CH2:36]OS(C)(=O)=O)[CH:32]=[N:31]1>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:36][CH2:35][C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(CCOS(C)(=O)=O)cn1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1cc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cn1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
To a solution of 1.00 gm (3.422 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 50 mL acetonitrile were added 1.04 gm (7.53 mMol) potassium carbonate followed by 1.26 gm (6.16 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane and the reaction mixture was heated to reflux for 18 hours. To the reaction mixture were then added 0.021 gm (0.171 mMol) 4-dimethylaminopyridine and reflux was continued for 36 additional hours. The reaction mixture was cooled to room temperature and then partitioned between dichloromethane and water. The aqueous phase was extracted well with dichloromethane. All of the organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 2.5% methanol in dichloromethane containing 0.5% ammonium hydroxide. Fractions shown to contain product were concentrated under reduced pressure to give 0.610 gm (44%) of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]([CH2:12][CH2:13][N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])=[N:10][N:11]=2)=[CH:3][CH:2]=1.[CH3:25]C(C)([O-])C.[K+].IC>>[CH3:25][N:10]1[C:9]([CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[N:8][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCc1nnc(-c2ccncc2)[nH]1
Agent: [K+]
Solvent: CI
Product: Cn1nc(-c2ccncc2)nc1CCN1C(=O)c2ccccc2C1=O

Procedure:
The product was obtained starting from 2-(2-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)ethyl)isoindoline-1,3-dione (300 mg, 752 μmol) according to the method described in example 8, step 1 using 1.3 equivalents of potassium tert-butoxide and iodomethane with a reaction time of 16 h and after purification by flash chromatography (using silica gel and a MeOH/ethyl acetate gradient) as white solid (114.9 mg, 345 μmol, 45.9%). MS: M=334.1 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]([C:14]#[N:15])=[N:8][C:7]2[N:6]=[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:4][C:3]1=2.[OH-].[Na+].C([OH:36])C.O>C(Cl)Cl>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]([C:14]([NH2:15])=[O:36])=[N:8][C:7]2[N:6]=[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:4][C:3]1=2
Reactant: CCO
Reactant: CCCn1c(C#N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCn1c(C(N)=O)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A mixture of 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile (40 mg, 0.0934 mmol), NaOH (6 mg, 0.140 mmol) and Ethanol:water (3:1) (2 ml) were stirred at 50° C. for 18 hours. Reaction mixture was cooled and organic volatiles were evaporated and the residue obtained was dissolved in DCM (10 ml) and washed with brine (10 ml). Organic layer was dried over Na2SO4 and evaporated to obtain pure 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylic acid amide (32 mg, 78%) as an off white solid.