Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc2scc(CBr)c2c(=O)[nH]1
Yield: 50 %

Procedure:
A mixture of ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in U.S. Pat. No. 4,054,656 (1.00 g, 4.20 mmol), N-bromosuccinimide (784 mg, 4.41 mmol), 2,2′-azo-bis-isobutyronitrile (68.9 mg, 0.420 mmol) and carbon tetrachloride (30 mL) was heated under reflux for 3 hr. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The organic layer was washed with water (×3) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained crude crystals were recrystallized from ethyl acetate to give ethyl 5-(bromomethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate (662 mg, 50%) as a pale-yellow powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:9][C:10]=1[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[C:15]([O:14][C:12]([NH:11][C:10]1[S:9][C:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:7][C:6]=1[C:4]([OH:5])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 103.8 %

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-phenyl-thiazole-4-carboxylic acid ethyl ester (151 mg, 0.43 mmol) in a THF/ethanol mixture (3 ml; 2:1) was cooled to 0° C. and treated with lithium hydroxide (1.3 ml; 1N aqueous solution). After 15 min, the cooling bath was removed and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was acidified with HCl (1.3 ml, 1N aqueous solution) and extracted with dichloromethane (2×10 ml). The combined organic layers were dried and the solvent was evaporated to yield the product as off-white solid (143 mg, 100%) which was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[CH:23]=[O:24])=[C:18]([CH3:26])[CH:17]=2)=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[N:10]1.[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[CH2:23][OH:24])=[C:18]([CH3:26])[CH:17]=2)=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[N:10]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a 0° C. solution of 2-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-propionaldehyde (753 mg, 1.74 mmol) in THF (17 mL) and MeOH (3 mL) is added sodium borohydride (198 mg, 5.23 mmol) portionwise. The reaction mixture is warmed to room temperature. After 2 h, the reaction is concentrated under reduced pressure and the residue is partitioned between Et2O (100 mL) and 1N HCl (30 mL). The aqueous layer is extracted with Et2O (100 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 30% EtOAc/Hex) to yield the title compound (715 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.43-7.40 (m, 2H), 7.33-7.28 (m, 1H), 7.04 (d, 1H, J=8.4 Hz), 6.64-6.58 (m, 2H), 4.79 (s, 2H), 3.68-3.63 (m, 2H), 3.14-3.16 (m, 1H), 2.99 (sept, 1H, J=7.0 Hz), 2.28 (s, 3H), 1.30 (d, 3H, J=7.0 Hz), 1.21 (d, 6H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[Br:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2cccc(Br)c2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Br)c2C(=O)N2CCC[C@@H]12

Procedure:
9.2 g (0.038 mol) of 6-bromoisatoic acid anhydride and 4.6 g (0.040 mol) of L-proline in 55 ml of dimethyl sulphoxide are heated at 70° for 1 hour, the solvent is removed in a high vacuum and the oil obtained is heated at 170° for 15 minutes. The crude product is purified by chromatography on silica gel using a mixture of chloroform and methanol (20:1) as the elution agent. There is obtained (S)-6-bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione which melts at 221°-224° after recrystallization from chloroform/hexane.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1.[Br:20][Si](C)(C)C>C(#N)CC.C(OCC)(=O)C>[Br:20][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Br
Reactant: Fc1cccc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: Fc1cccc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 100 °C
Yield: 100.6 %

Procedure:
4-Chloro-2-(2-chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (3.05 g, 10.1 mmol) was suspended in propionitrile (60 mL) under an atmosphere of nitrogen and bromotrimethylsilane (4.0 mL, 30.0 mmol) was added. The reaction mixture was heated at 100° C. overnight. The resultant mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a beige solid (3.5 g, 100% yield). This was used directly in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 9.46 (d, J=2.5 Hz, 1H), 8.21 (d, J=3.4 Hz, 1H), 7.85-7.77 (m, 1H), 7.74-7.64 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(OCC)C.[CH3:15][NH2:16]>O>[CH3:15][NH:16][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: N#Cc1cnccc1Cl
Solvent: O
Solvent: CCOCC
Product: CNc1ccncc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
4-Chloronicotinonitrile (45.0 g, 324 mmol) was suspended in water (250 mL) and 41% aqueous methylamine solution (250 mL). The resultant mixture was heated, with stirring, at 90° C. for 1 hour before the mixture was cooled to room temperature and extracted with ethyl acetate (×2). The combined organic layers were washed with water, followed by brine then dried (MgSO4) and evaporated to provide a residue. Trituration of the residue with diethyl ether gave the title compound (40.4 g, 93%) as a white solid. 1H NMR (CDCl3) 2.98 (3H, d, J=5.1 Hz), 5.20 (1H, br s), 6.53 (1H, d, J=6.13 Hz), 8.35 (1H, d, J=6.13 Hz), 8.43 (1H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:20])=[CH:9][C:10]([NH:12][CH2:13][C@@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:6]=2[O:5][C:4]1=[O:21])[CH3:2].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>>[CH2:1]([N:3]1[C:7]2[C:8]([F:20])=[CH:9][C:10]([N:12]3[CH2:13][C@H:14]([C:15]([O:17][CH3:18])=[O:16])[O:19][C:22]3=[O:23])=[CH:11][C:6]=2[O:5][C:4]1=[O:21])[CH3:2]
Reactant: CCn1c(=O)oc2cc(NC[C@@H](O)C(=O)OC)cc(F)c21
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21

Procedure:
Prepared from methyl (2R)-3-[(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate (Step 3, 1.01 g, 3.39 mmol) and 1,1′-carbonyldiimidazole (0.549 g, 3.39 mmol) according to the method of EXAMPLE 86, Step 9 (1.10 g, 99%); MS for C14H13FN2O6 m/z 325 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11]
Reactant: CCOC(=O)CNC
Reactant: Cc1cccc(Cl)c1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(Cl)c1N1C(=O)CN(C)C1=S
Yield: 55.7 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 9.2 g of 2-chloro-6-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (7.1 g) as an orange solid (7.1 g), m.p. 142°-145° C. Anal. Calcd. for. C11H11N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.96; H, 4.26; N, 10.97. Mass spectrum (El, M.+) m/z 254.
Reaction SMILES: [NH:1]([C:8](=O)[CH2:9][C:10]1[N:11]=[C:12]([S:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[S:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O1CCCC1>[NH:1]([CH2:8][CH2:9][C:10]1[N:11]=[C:12]([S:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[S:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Sc1nc(CC(=O)Nc2ccccc2)cs1)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Sc1nc(CCNc2ccccc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a suspension of 2-{[4-(2-anilino-2-oxoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (2.9 g) obtained in Example 488-1 in tetrahydrofuran (30 mL) was added 1 mol/L borane-tetrahydrofuran complex (24 ml), and the mixture was stirred at room temperature overnight. Methanol was gradually added to the reaction mixture, and the mixture was stirred at room temperature overnight. The resin was collected by filtration, washed three times with methanol, and vacuum dried to give the title pale-brown resin (2.4 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:16]=1[CH:17]=[N:18][CH:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21]>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:17]([NH:18][C@@H:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21])[C:16]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:15]=2[F:14])=[CH:3][CH:4]=1
Reactant: CC(C)CC(CO)N=Cc1ccc(F)cc1F
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Reaction time: 1 h

Procedure:
To a solution of 1,4-dibromobenzene (24.5 g, 100 mmol, 5eq) in dry ether (200 mL) under nitrogen atmosphere at −30° C., nBuLi (64.75 mL, 1.6 M solution in hexanes, 5 eq) was added and the reaction mixture was stirred for 1 h. A solution of 2-[(2,4-difluorobenzylidene)-amino]-4-methylpentan-1-ol (5 g, 20 mmol) in dry ether was added slowly at −30° C. After stirring for 4 h, the reaction was quenched with water. The ether layer was washed with saturated solution of NaCl, and dried over MgSO4. The solvent was removed under reduced pressure and the crude was flash chromatographed on 500 cm3 of silica gel using 8:2 hexanes:EtOAc as an eluant to yield (2S)-2-{(S)-[(4-bromophenyl)-(2,4-difluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1ccccc1CBr
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1c(C)nc2c(Br)cc(N3CCOCC3)cc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.7 g, 2.364 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added in 1-(bromomethyl)-2-methylbenzene (0.525 g, 2.84 mmol) and potassium carbonate (0.980 g, 7.09 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.726 g, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.43 (s, 3H) 2.54 (s, 3H) 3.00-3.14 (m, 4H) 3.78-3.90 (m, 4H) 5.22 (s, 2H) 6.44 (d, J=7.83 Hz, 1H) 6.53 (d, J=2.02 Hz, 1H) 7.02-7.12 (m, 1H) 7.15 (d, J=2.02 Hz, 1H) 7.18-7.27 (m, 2H); MS (ES+) m/e 400.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH2:27][OH:28])=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:28][CH2:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:16]1=[N:17][O:18][C:14]([CH:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[C:15]1[CH2:26][CH2:25]2)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (Preparation 27D, 0.046 g, 0.118 mmol) in dichloromethane (2.0 mL) at room temperature was added triethylamine (0.049 mL, 0.354 mmol) followed by methanesulfonyl chloride (0.014 mL, 0.177 mmol). The reaction mixture was stirred for 1 h at room temperature, concentrated under reduced pressure to yield (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc([N+](=O)[O-])cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (4 mL) and 4-nitrobenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-nitrobenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[O:10]2)=[CH:5][CH:4]=1.[H-].[Na+].C(S)C.Cl>CN(C)C=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[O:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2OC3(CCN(C)CC3)c3ccccc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CN1CCC2(CC1)OC(c1ccc(O)cc1)c1ccccc12
Temperature: 0 °C

Procedure:
A mixture of 1.0 g. of 1,3-dihydro-3-p-methoxyphenyl-1'-methylspiro[isobenzofuran-1,4'-piperidine] (Example 12), 1.0 g. of a 57% sodium hydride dispersion, and dimethylformamide is stirred under nitrogen. To the stirring mixture is rapidly added 2.0 ml. of ethanethiol. The mixture is refluxed under nitrogen for 4 hours, cooled, poured into ice-water, and acidified with 1N hydrochloric acid. The product is collected, dried, and dissolved in boiling dimethyl sulfoxide, and the solution is filtered. Upon cooling small colorless crystals, m.p. 273° dec., separate.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1.[C:26](O)(=[O:29])[CH2:27][OH:28]>>[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:27](=[O:28])[CH2:26][OH:29])[CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1
Reactant: O=C(O)CO
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
The HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (300 mg) was reacted with glycolic acid via General Procedure B to give 306 mg of 1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)[CH:34]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Product: CN1CCN(c2cc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCN4)ccn2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 2-(4-Methylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester using Suzuki coupling conditions as described in Scheme 1.
Reaction SMILES: [OH:1][C:2]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[CH:9][CH:10]=1.[CH2:29]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[CH2:29])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: CCCC(O)(CCC)CCc1cccc(C(=O)CCNC(=O)OC(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(CCNC(=O)OC(C)(C)C)c1cccc(CCC(O)(CCC)CCC)c1
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosponium bromide in THF is added KOBu-t (1 M in THF, 6.1 mmol) at room temperature. After stirring for 30 mins, tert-butyl 3-(3-(3-hydroxy-3-propylhexyl)phenyl)-3-oxopropylcarbamate is added. The resulting mixture is stirred at room temperature for 18 h. The reaction is quenched by the addition of AcOH. The mixture is filtered and concentrated under reduced pressure. Purification by flash chromatography (15 to 50% EtOAc-hexanes gradient) gives tert-butyl 3-(3-(3-hydroxy-3-propylhexyl)phenyl)but-3-enylcarbamate.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[CH2:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:13]=2)[CH2:8][CH2:9][NH:10]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-nitro-1,2,3,4-tetrahydro-isoquinoline (38 g, 0.21 mol) and 10% Pd/C (5 g) in MeOH (400 mL) was stirred under an atmosphere of hydrogen at rt for 16 h and then filtered through Celite. Removal of solvent gave 1,2,3,4-tetrahydroisoquinolin-7-amine as a pink solid in quantitative yield. MS: 149.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=O)[CH2:6][CH2:5]2.[NH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])N>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:8]([CH3:15])([CH3:14])[C:7]3[NH:17][C:19]4[C:26]([C:6]=3[CH2:5][C:4]=2[CH:3]=1)=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=4
Reactant: N#Cc1cccc(NN)c1
Reactant: COc1cc2c(cc1Cl)CCC(=O)C2(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Cl)Cc1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound I1-1, 4.45 g, 16.5 mmol) and 3-hydrazinobenzonitrile (2.63 g, 1.2 eq.) were dissolved in TFA (91 mL), and stirred at 90° C. for 3 hours. According to the concentration under reduced pressure, TFA was removed and the residues were added with saturated aqueous solution of NaHCO3, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration. The filtrate was concentrated under reduced pressure to obtain the target compound as a mixture with 11-3 (red powder, 6.46 g).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10]>O1CCOCC1.O>[NH:1]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 10 g (0.086 mol) of valine and 3.4 g (0.086 mol) of NaDH in 250 ml of dioxan: H2O (2:1) mixture was slowly added 20.5 g (0.094 mol) of ditertbutylcarbonate at 0° C. with vigorous stirring. The reaction mixture was then stirred for another hour at room temperature, dioxan was removed under reduced pressure, and BOC-Val-OH was obtained by acidifying the mixture to a pH of 2-3. The raw product consisting of 18 g of viscous oil was obtained after evaporating the solvent from the ethyl acetate extracts.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]=1.[I:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C[O-].[Na+].[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([I:14])=[CH:16][CH:17]=3)=[C:5]2[C:4](=[O:13])[N:3]=1
Reactant: NCC1=C2C(=O)N=C(N)N=C2N=C1
Reactant: O=Cc1ccc(I)cc1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC1=NC(=O)C2=C(CNCc3ccc(I)cc3)C=NC2=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
In 40 ml of dry methanol were suspended 126 mg of 2-amino-5-aminomethylpyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride) and 116 mg of p-iodobenzaldehyde. After addition of 1 N methanolic sodium methoxide, the mixture was stirred at room temperature for 30 min. To this mixture was added 76 mg of sodium borohydride and the reaction was conducted at room temperature for 15 min. The reaction was then terminated by addition of 500 mg silica gel. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to give 121 mg of the desired compound.