Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[CH:9][N:10]=2.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20].Cl.[OH-].[K+]>N1C=CC=CC=1.O>[CH2:19]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[CH:9][N:10]=2)=[O:23])[CH3:20]
Reactant: Nc1ccc2ncc(-c3ccc(O)cc3)nc2n1
Reactant: CCN=C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc2ncc(-c3ccc(O)cc3)nc2n1
Temperature: 75 °C

Procedure:
0.50 g of 4-(6-aminopyrido[2,3-b]pyrazin-3-yl)phenol (2.10 mmol) were initially charged in 5.0 ml of pyridine. 183 μl of ethyl isocyanate (2.31 mmol) were added dropwise at room temperature and the mixture was heated to 70-80° C. for 2 h. Thereafter, another 183 μl of ethyl isocyanate were added and the mixture was heated to 70-80° C. for a further 2 h. Once the reaction had ended, the reaction mixture was added to ice-water and neutralized with 1N hydrochloric acid. The precipitated product was filtered off with suction and dried. The product which had been filtered was partly dissolved in ethanol and admixed with 52 mg of potassium hydroxide (0.93 mmol), dissolved in water. The mixture was heated to 40° C. for approx. 1 h. Thereafter, the reaction solution was neutralized with 1N hydrochloric acid and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25]1([CH:31]=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C@H:31]([OH:32])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C#CC(C)(C)C
Reactant: O=CC1CCCCC1
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C=C[C@@H](O)C1CCCCC1
Yield: 80 %

Procedure:
The product was prepared by General procedure S using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.55 mL (1.1 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 61 μL (0.50 mmol) cyclohexane-carboxaldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 80% yield (78 mg, 0.40 mmol). [α]D20=−27.7 (c=0.13, CHCl3, 96% ee); 1H NMR (CDCl3, 500 MHz): δ 0.92-0.97 (m, 2H), 1.01 (s, 9H), 1.11-1.26 (m, 4H), 1.41 (m, 1H), 1.64 (m, 2H), 1.73 (m, 2H), 1.86 (br d, 1H, J=12.6 Hz), 3.75 (t, 1H, J=7.0 Hz), 5.35 (dd, 1H, J=15.6, 7.5 Hz), and 5.62 (d, 1H, J=15.7 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 26.1, 26.2, 26.6, 28.76, 28.84, 29.6, 32.9, 43.8, 77.9, 126.2, and 143.9 ppm; IR (neat): 3351, 2953, 2926, 2853, 1655, 1473, 1450, 1387, 1362, 1305, 1260, and 1204 cm−1; HRMS-CI m/z 195.1743 [(M−H)+; calcd for C13H23O: 195.1749].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:40][CH2:39][CH2:38][C@@H:34]1[C:35]([OH:37])=[O:36]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:40][CH2:39][CH2:38][CH:34]3[C:35]([OH:37])=[O:36])[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCC3C(=O)O)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with (D)-proline. A yellow solid 100 was obtained (0.0366 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)O)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)[C:29]([OH:31])=[O:30].C(N1C=CN=C1)([N:36]1C=CN=C1)=O>ClCCl.N.CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[O:26][C:20](=[O:21])[NH:19]2)[C:5]([F:8])=[N:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:31][C:29](=[O:30])[NH:36][C@@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1cccc(F)c1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cccc(F)c2)O1
Product: O=C1N[C@H](c2cccc(F)c2)[C@@H](c2cc(Br)cnc2F)O1
Temperature: 25 °C
Yield: 9.2 %
Yield: 13.55 %

Procedure:
To a 25 mL round bottom flask was added tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(3-fluorophenyl)-2-hydroxyethylcarbamate (223 mg, 0.520 mmol) in dichloromethane (4 mL). To this solution was added trifluoroacetic acid (1.014 mL, 13.16 mmol) and the reaction was allowed to stir over night at room temperature. The reaction solvent was then evaporated in vacuo. The crude reaction mixture was then dissolved in 5 mL of 2N ammonia in methanol and stirred for 5 min. The solvent was then evaporated in vacuo and the crude residue was diluted with dry tetrahydrofuran (4 mL) and carbonyldiimidazole (168 mg, 1.039 mmol) was added and the reaction was stirred at room temperature for 1 hr. The reaction solvent was then evaporated in vacuo and the crude solid was purified by silica gel chromatography 10% EtOAc/90% Hexanes to 30% EtOAc/70% Hexanes affording (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (25 mg, 0.070 mmol, 13.55% yield) and (4R,5R)-5-(5-bromo-2-fluoropyridin-3-yl)-4-(3-fluorophenyl)oxazolidin-2-one (17 mg, 0.048 mmol, 9.2% yield) as an inseparable mixture. 1H-NMR (CDCl3, 400 MHz) δ 8.33 (d, J=2.3, 1H), 7.47-7.41 (m, 1H), 7.19-7.11 (m, 3H), 5.64 (s, 1H), 5.36 (d, J=5.0, 1H), 5.00 (d, J=5.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.09 min. Mass=355.09 (MH)+.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1([C:43]2[CH:48]=[CH:47]C(O)=[CH:45][CH:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:44][C:43]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:48][CH:47]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccc(-c5ccccc5)cc4)c(C)c3C)c2cc1OC
Yield: 44.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-phenylphenol (39 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (36 mg, yield 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:23]4([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
1-(4-Fluorophenyl)-5-iodo-1H-indazole (2.0 g, 5.9 mmol) was dissolved in dry THF (30 mL), cooled to −78° C., and treated with nBuLi (4 mL, 1.6 M in hexanes, 6.5 mmol). After 1 h, cyclohexanone (919 uL, 8.88 mmol) was added all at once and the reaction was allowed to warm to rt. The crude reaction was extracted from water using EtOAc and the combined organic layers were dried with MgSO4, concentrated in vacuo, filtered, and chromatographed on a SiO2 MPLC column using 25% EtOAc in hexanes. Obtained 700 mg (38%) of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexanol. MS found: (M+H)+=311.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].[C:36](=[S:38])=[S:37].CN(C)C=O>O>[ClH:1].[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:4]3[C:3]4[N:35]=[C:36]([SH:38])[S:37][C:2]=4[N:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: S=C=S
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncnc5sc(S)nc45)CC3)nc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of 7 parts of 6-chloro-N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]-4,5-pyrimidinediamine, 2.1 parts of carbon disulfide and 90 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from ethanol. The product was filtered off and dried in vacuo overnight at 120° C., yielding 2.3 parts (29%) of 7-[[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]amino]-thiazolo[5,4-d]pyrimidine-2-thiol monohydrochloride; mp. 226.5° C. (compound 148).
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])[CH:13]=2)[CH:8]=[CH:7]1.O.CN([CH:30]=[O:31])C>>[CH:30]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([CH2:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)[NH:6][CH:7]=1)=[O:31]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(Cc2ccc3cc[nH]c3c2)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cc3cccc(C(=O)O)c3)ccc12
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
(I-8): 3 ml anhydrous DMF was cooled in ice-water bath, then 50 μl POCl3 was added, the solution was stirred about 15 minutes, then 32 mg of methyl 3-(1H-indol-6-ylmethyl)benzoate in 2 ml DMF was added. The mixture was heated to 40° C. for 3 hours. After cooling to room temperature, the mixture was treated by cold water, following the general procedure above, the target compound was purified as a brown solid. Mass calculated for C17H13NO3: 279; LCMS: 280.6 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.87 (1H, s), 8.24 (1H, d, J=3.0 Hz), 7.99 (1H, s), 7.80 (1H, d, J=7.3 Hz), 7.76 (1H, d, J=7.9 Hz), 7.52 (1H, d, J=7.9 Hz), 7.41 (1H, t, J=7.9 Hz), 7.34 (1H, s), 7.12 (1H, d, J=7.3 Hz), 4.12 (2H, s).
Reaction SMILES: C(O[CH2:4][CH2:5][CH2:6][C:7]1(O)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2)C.C(OC(=O)C)(=O)C.[IH:30].II>>[I:30][CH2:4][CH2:5][CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2
Reactant: I
Reactant: CCOCCCC1(O)c2ccccc2C=Cc2ccccc21
Agent: II
Solvent: CC(=O)OC(C)=O
Product: ICCCC1c2ccccc2C=Cc2ccccc21
Temperature: 65 °C

Procedure:
A solution of 9.25 g. (0.0314 mole) of 5-(3-ethoxypropyl)-5-hydroxy-dibenzo[a,d]cycloheptene prepared as above in 45 ml. of acetic anhydride is heated on the steam-bath for 90 minutes then cooled to 65°C. A stream of nitrogen is passed through the solution while 30 ml. of hydriodic acid (sp. gr., 1.5) is added in portions, keeping the temperature below 90°C. The solution develops a dark brown iodine color during the addition. The solution is heated to 80°C. for 30 minutes, then cooled and poured into ice-water. The brown oil that separates is extracted into benzene and the extract washed with water, dilute sodium thiosulfate solution and finally with water. Evaporation of the benzene gives the product 5-(3-iodopropyl)-5H-dibenzo[a,d]cycloheptene as a yellow oil. A sample gives a precipitate with alcoholic silver nitrate solution.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][C:15]#[N:16].C(OCC)(=O)C>C(O)C>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH:14]([C:2](=[O:3])[CH3:1])[C:15]#[N:16]
Reactant: N#CCc1cc(Cl)cc(Cl)c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)C(C#N)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 8 h

Procedure:
To a solution of NaOEt (from 0.68 g of sodium) in ethanol (20 ml) was added 2,3,5-trichlorophenylacetonitrile (5 g) and ethyl acetate (4.43 ml). The mixture was heated under reflux, under nitrogen for 2.5 hours. The mixture was left standing at room temperature overnight. The mixture was then concentrated and the residue was dissolved in water. The aqueous phase was washed with ether, acidified with concentrated H2SO4 and extracted with ether. The extracts were bulked, dried (MgSO4) and evaporated, 2.59 g, mp. 134°-135° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:22][N:23]=[C:24]=[O:25].C(OC(C)C)(C)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:24]([NH:23][CH3:22])=[O:25])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CN=C=O
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(OCCNC(=O)NC)c2C1
Reaction time: 1 h

Procedure:
1.45 g (5 mmol) cf 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were initially introduced into 20 ml of toluene. The reaction was catalyzed using 3 drops of triethylamine, and 0.325 ml (5.5 mmol) of methyl isocyanate was then added dropwise. The mixture was stirred for 1 h at +25° C. The mixture was evaporated, and the residue obtained was stirred with hot diisopropyl ether. The mixture was cooled, and the product was filtered off under suction.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CC(C)C

Procedure:
Keep 13β-ethyl-17β-hydroxy-gon-4-en-3-one (6 g.) with isovaleroyl chloride (7.2 g.) in pyridine at room temperature for 20 hours. Add aqueous sodium bicarbonate and extract the product with ether. Wash, dry and evaporate the extracts and purify the residue by chromatography upon neutral alumina. Distill at 200°-230°/.01 mm. and crystallize from hexane to obtain the title compound, m.p. 82°- 89°; ultraviolet absorption peak at 240 mμ (ε15,650); infrared absorption peaks at 5.76, 5.99, 6.18 μ.
Reaction SMILES: [C:1](O[C@@H](C1C(C)=CC2N=C(N3CCN(C)C(C4C=C5C(=CC=4)N(C)N=C5)C3=O)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)([CH3:3])[CH3:2].[C:45]([O:49][C@@H:50]([C:56]1[C:80]([CH3:81])=[CH:79][C:59]2[N:60]=[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH:65]([C:69]4[CH:70]=[C:71]5[C:75](=[CH:76][CH:77]=4)[N:74]([CH3:78])[N:73]=[CH:72]5)[CH2:64]3)[S:62][C:58]=2[C:57]=1[C:82]1[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][CH:83]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])([CH3:48])([CH3:47])[CH3:46].COC(OC)(C)C.C=O>CC(C)=O>[C:45]([O:49][C@@H:50]([C:56]1[C:80]([CH3:81])=[CH:79][C:59]2[N:60]=[C:61]([N:63]3[CH2:68][CH2:67][N:66]([CH:1]([CH3:3])[CH3:2])[CH:65]([C:69]4[CH:70]=[C:71]5[C:75](=[CH:76][CH:77]=4)[N:74]([CH3:78])[N:73]=[CH:72]5)[CH2:64]3)[S:62][C:58]=2[C:57]=1[C:82]1[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][CH:83]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])([CH3:46])([CH3:47])[CH3:48]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: C=O
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1

Procedure:
(2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(4-isopropyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (16 mg) was prepared in a similar manner as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate, and acetone and 2,2-dimethoxypropane instead of (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid and formaldehyde. LCMS-ESI+: calc'd for C37H45ClN5O3S: 674.3 (M+H+); Found: 674.3 (M+H+).
Reaction SMILES: C1COC2(N)N(C(NC3C=CC4OC(CO)=CC=4C=3)=NC=C2F)O1.[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([C:42](OC)=[O:43])=[CH:36]3)=[N:30][CH:31]=1.CC(C[AlH]CC(C)C)C>>[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([CH2:42][OH:43])=[CH:36]3)=[N:30][CH:31]=1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Agent: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Product: OCc1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine was reduced with DIBALH to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.81 (d, 1H, J=4.2 Hz), 7.23 (d, 1H, J=1.8 Hz), 7.28-7.23 (m, 2H), 7.19 (t, 1H, J=2.4 Hz), 7.12 (dd, 1H, J=1.8 and 9.0 Hz), 7.07 (t, 1H, J=8.4 Hz), 6.52 (ddd, 1H, J=1.2 and 8.1 Hz), 6.30 (s, 1H), 4.71 (s, 2H); 19F NMR (CD3OD): −47971; LCMS: ret. time: 15.36 min.; purity: 100%; MS (m/e): 366 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23]O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.Cl.[NH2:32][OH:33].C(=O)(O)[O-].[K+]>O>[CH3:27][Si:2]([CH3:28])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22]/[CH:23]=[N:32]/[OH:33])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: NO
Reactant: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(C/C=N/O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05 mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2 h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (1E)-3-[4-(7-[2-(trimethyl-silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal oxime as a semisolid residue (50 mg, 80%). LC/MS (M+H): m/z=415.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>C(O)(=O)C>[Cl:22][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: Clc1ccc2ccccc2n1
Solvent: CC(=O)O
Product: O=C(O)c1cc(Nc2ccc3ccccc3n2)ccc1Cl

Procedure:
A solution of 2-chloro-quinoline (0.50 g, 3.1 mmol) and 5-amino-2-chloro-benzoic acid (0.53 g, 3.1 mmol) in acetic acid (10 mL) was heated at 100° C. for 2 h. Acetic acid was removed and the residue triturated in ethyl acetate. The title compound was obtained as a white solid (0.55 g, 59%) after the filtration. MS (ES+): m/z 299 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[N:8][C:6]=2[N:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].[C:37](#[N:39])[CH3:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:7][C:2]1[N:3]=[CH:4][C:38]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]3[S:10][C:9]([C:26]4[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=4)=[N:8][C:6]=3[N:7]=2)=[CH:37][N:39]=1
Reactant: CC#N
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cccc(-c2nc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)c1

Procedure:
4-(5-Chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27, 3-acetamido-phenyl boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 90° C. for 10 minutes. Water was added and the solution was filtered. The aqueous layer was dried and combined with 5-pyrimidine-2-amine boronic acid (1.2 eq) and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) and slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 150° C. for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was purified by reverse phase silica gel chromatography to yield 140.