Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]([NH:7][CH:8]1[CH:12]([O:13][CH2:14][CH3:15])[O:11][C:10](=[O:16])[CH2:9]1)=[O:6])C=C.C(=O)=O.[C:20]1([C:30]([NH:32][CH:33]2[C:40](=[O:41])[N:39]3[CH:42](C(O)=O)[CH2:43][CH2:44][CH:38]3[CH2:37][CH:36]=[CH:35][CH2:34]2)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[CH2:14]([O:13][CH:12]1[CH:8]([NH:7][C:5]([C@H:42]2[N:39]3[C:40](=[O:41])[C@@H:33]([NH:32][C:30]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][N:21]=4)=[O:31])[CH2:34][CH:35]=[CH:36][CH2:37][C@@H:38]3[CH2:44][CH2:43]2)=[O:6])[CH2:9][C:10](=[O:16])[O:11]1)[CH3:15]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Reactant: O=C(NC1CC=CCC2CCC(C(=O)O)N2C1=O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Product: CCOC1OC(=O)CC1NC(=O)[C@@H]1CC[C@H]2CC=CC[C@H](NC(=O)c3nccc4ccccc34)C(=O)N21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of N-allyloxycarbonyl-4-amino-5-ethoxy-2-oxotetrahydrofuran (1.83 g, 8.0 mmol) in dichloromethane (30 mL) is added N, N-dimethylbarbituric acid (2.98 g, 47.8 mmol) and tetrakispalladium(0)triphenyl phosphine (0.85 g, 1.9 mmol). The resulting mixture immediately produces CO2 and is allowed to stir at room temperature for 15 minutes after gas evolution has ceased. To this mixture is added 6-[(Isoquinoline-1-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 14, (1.2 g, 3.15 mmol), hydroxybenztriazole (1.0 g, 18.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.4 g, 18.5 mmol). The reaction mixture is allowed to stir for 2 hours at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layers are combined and washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and concentrated in vacuo. The residue is purified over silica (ethyl acetate) to afford 1.42 g (89% yield) of the desired product as a yellow foam. 1H NMR (300 MHz, CDCl3): δ 9.50 (m,1H), 9.02 (d, J=7.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 7.83 (m, 3H), 7.69–7.41 (m, 3H), 5.84 (m, 1H), 5.70 (m, 1H), 5.49 (m, 2H), 4.71 (m, 2H), 4.26 (m, 1H), 3.90 (m, 1H), 3.71 (m, 1H), 3.17–2.95 (m, 2H), 2.80 (m, 1H), 2.51=2.30 (m, 4H), 2.14 (m,1H), 1.90 (m, 2H), 1.31 (t, J=7.0 HZ, 3H). 13C NMR (CDCl3): δ 173.8, 171.9, 171.0, 165.7, 147.8, 140.8, 137.6, 133.4, 132.4, 132.2, 132.0, 130.7, 130.4, 128.8, 127.7, 127.6, 127.2, 126.0, 124.8, 101.6, 66.0, 61.0, 58.9, 50.3, 48.4, 34.9, 33.5, 33.0, 32.6, 36.6, 15.2. ESI MS-507.15 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:39])[NH:6]2>Cl.O1CCOCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:39])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
tert-Butyl 4-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]piperidine-1-carboxylate [285 mg (containing 13.5% triphenylphospine oxide), 0.49 mmol] was dissolved in 4M hydrogen chloride in dioxane (5 ml) and stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the solid suspended in methylene chloride and filtered off. The solid was dissolved in methanol and absorbed onto an Isolute SCX column which was washed through with methanol and then the product eluted with 7N ammonia in methanol. Concentration of the fractions gave 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (185 mg, 86%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:10]([C:11]2[S:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28]Cl)[CH:20]=3)=[N:14][N:15]=2)=[N:9][O:8][N:7]=1)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCO>O>[N:33]1([CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][C:17]([NH:16][C:13]3[S:12][C:11]([C:10]4[C:6]([NH2:5])=[N:7][O:8][N:9]=4)=[N:15][N:14]=3)=[O:30])[CH:24]=[CH:23][CH:22]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: O=C(Cc1cccc(OCCCCl)c1)Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: Nc1nonc1-c1nnc(NC(=O)Cc2cccc(OCCCN3CCNCC3)c2)s1

Procedure:
N-Trifluoroacetyl-4-(5-(3-(3-chloro-propoxy)-phenylacetyl)amino-[1,3,4]thiadiazol-2-yl)-furazan-3-ylamine (0.05 g, 0.1 mmol), piperazine (0.035 g, 0.4 mmol) and EtOH (0.3 mL) were heated by microwave irradiation at 120° C. for 2×10 minutes. The reaction was diluted with water and purified by preparative HPLC. Yield: 0.03 g (33%). 1H-NMR (MeOD) δ 7.25 (t, 1H), 6.90–6.95 (m, 2H), 6.85 (d, 1H), 4.12 (t, 2H), 3.82 (s, 2H), 3.3.10–3.15 (m, 6H), 3.00 (t, 3H), 2.10–2.15 (m, 3H). LCMS 445.2 (M+1), HPLC Method B Rt 1.6 minutes.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:7]=3[C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:4]=1.[Cl:29]N1C(=O)CCC1=O.C(O)C>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:6]([N:5]([C:18]4[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=4)[N:4]=[C:3]3[CH:2]([F:1])[F:28])=[C:7]2[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc2c(c1)CCc1c(C(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(ccc3c(C(F)F)nn(-c4ccc(S(N)(=O)=O)cc4)c32)c1Cl
Temperature: 50 °C

Procedure:
4-[3-(Difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (1.0 g, 1.23 mmol) from Step 2 was suspended in chloroform (100 ml), and N-chlorosuccinimide (NCS) (329 mg, 1.23 mmol) was added. The reaction was heated to 50° C. for 16 hours. At this point, ethanol (20 ml) was added to dissolve the suspended reagents. The reaction was again heated to 50° C. for 24 hours. At this time, an additional equivalent of NCS (329 mg) was added, and the reaction was heated to 50° C. for an additional 4 days. Upon cooling, a precipitate which had formed was collected. This solid was pure 4-[6-chloro-3-(difluoromethyl)-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (350 mg, 65%): 1H NMR (acetone d6) δ=4.0 (s, 3H), 7.2 (t, 1H, j=54.0 Hz), 7.3 (d, 1H j=9.3 Hz), 7.6 (d, 1H j=9.3 Hz), 7.9 (d, 2H j=8.7 Hz), 8.0 (d, 1H j=9.3 Hz), 8.1 (d, 1H j=9.3 Hz), 8.2 (d, 2H j=8.7 Hz); 19F NMR (acetone d6) δ-113.5 ppm (d, 2F).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.[O-:24]O.C1(C(C)C)C=CC=CC=1>CN(C=O)C>[CH3:23][C:17]1[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]([CH2:13][S@@:12]([C:10]2[NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][C:7]=3[N:9]=2)=[O:24])=[N:15][CH:16]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Reactant: [O-]O
Solvent: CN(C)C=O
Solvent: CC(C)c1ccccc1
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2n1
Temperature: 20 °C

Procedure:
A solution in DMF (6 volumes) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]imidazo[4,5-b]pyridine (100 mg, 0.303 mmol) is added under stirring at 20° C., immediately followed by cumene hydroperoxide (80%, 65 μL, 0.352 mmol)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[C:13](=[O:14])C(=O)[NH:11][C:10]=13)[NH:7][N:6]=[CH:5]2.[OH:16]O.Cl>[OH-].[Na+]>[NH2:11][C:10]1[C:9]([C:13]([OH:14])=[O:16])=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[CH3:1]
Reactant: OO
Reactant: Cc1cc2cn[nH]c2c2c1NC(=O)C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1,6-dihydro-pyrrolo[2,3-g]indazole-7,8-dione (23 g, 114.3 mmol) in 4N aqueous sodium hydroxide solution (160 ml) at ambient temperature, was added dropwise 30% aqueous hydrogen peroxide solution (27 ml) maintaining the temperature <30° C. with external cooling. The resulting reaction mixture was stirred at ambient temperature for 2 hours. According to TLC, the reaction was complete after 2 hours. The pH was adjusted to pH 3.5 by addition of concentrated hydrochloric acid. The resulting brown suspension was filtered and the filtercake washed with cold water and dried in vacuo at 50° C. to afford the desired product as brown solid. LC/MS: 192 (M+H)+.
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:19]([F:22])([F:21])[F:20])[C:7]([N:9]1[CH2:16][C:15]([F:18])([F:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.C(SCC(C(F)(F)F)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([C:19]([F:22])([F:20])[F:21])[C:7]([N:9]1[CH2:16][C:15]([F:17])([F:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(C(=O)N1CC(F)(F)C[C@H]1C(=O)O)C(F)(F)F
Agent: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)O)C(F)(F)F
Product: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)C(CS)C(F)(F)F

Procedure:
By substituting 1-(3-acetylthio-2-trifluoromethylpropanoyl)-4,4-difluoro-L-proline for the 1-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline in the procedure of Example 4, 1-(3-mercapto-2-trifluoromethylpropanoyl)-4,4-difluoro-L-proline is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:28]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:12]([OH:28])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)=O
Reactant: COc1ccc(COC(C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Product: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 87 %

Procedure:
Following the general procedure of the oxidation of aldehydes to carboxylic acids of Description 13, (3R/S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethyl-4-oxobutyl (3-chloropropyl)sulfonate (14b) (3.1 g, 7.9 mmol) dissolved in 40 mL of acetone was reacted with 3.9 mL of Jones-reagent (2.0 M in water). After work-up, 2.8 g (87% yield) of the title compound (14) was obtained as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (13).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C(=O)(O)[O-].[Na+]>>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(-c2cccnc2)c(CCCCCCO)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2cccnc2)c(CCCCCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.36 ml) is combined with 3-(6-hydroxyhexyl)-1methyl-2-(3-pyridyl)indole (1.37 g) at 0°. The mixture is then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate is added and the mixture is extracted with dichloromethane. The extract is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude chloride, 3-(6-chlorohexyl)-1-methyl-2-(3-pyridyl)indole. 3-(6-Chlorohexyl)-1-methyl-2-(3-pyridyl)indole (0.5 g) is combined with dimethyl malonate (792 mg), potassium carbonate (790 mg) and dimethylformamide (11.6 ml) and the mixture is heated at 80°-90° for 18 hours under nitrogen. The mixture is poured into ice water (80 ml), and acidified with 1N NCl and washed with ether. The aqueous layer is adjusted to pH 6 and extracted with ether which is then dried over anhydrous magnesium sulfate and concentrated to yield 3-[7,7-(bis-methoxycarbonyl)heptyl]-1-methyl-2 -(3-pyridyl)indole.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[CH3:35][NH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Product: CN[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 99.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.89 min, m/z=459.0 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=3)[C:20](=[O:31])[C:19]=2[CH:18]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:23]3[CH:24]=[CH:25][C:26]4[C:27]5[C:19](=[CH:18][C:17]([Br:16])=[CH:29][CH:28]=5)[C:20](=[O:31])[C:21]=4[CH:22]=3)[CH2:11]2)[CH2:15]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4c(c3)C(=O)c3cc(Br)ccc3-4)CC2C1
Temperature: 85 °C
Reaction time: 9 h
Yield: 75.5 %

Procedure:
A mixture of 3-Boc-3,7-diazabicyclo[3.3.0]octane (2.12 g, 10.0 mmol; see WO 0181347), 2,7-dibromofluoren-9-one (6.76 g, 20.0 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium (0) (Pd2 dba3; 185 mg, 0.202 mmol; Strem), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 310 mg, 0.498 mmol; Strem) and sodium tert-butoxide (1.4 g, 14.6 mmol; Aldrich) in 100 mL toluene was warmed to 85° C. and stirred for 9 h. The reaction mixture was cooled to ambient temperature and filtered through diatomaceous earth, rinsing with dichloromethane. After concentrating the solution under reduced pressure, the residue was purified by column chromatography (silica gel, 10-60% EtOAc/hexanes) to give the title compound (3.54 g, 7.55 mmol, 75% yield). MS (DCI/NH3): m/z 469, 471 (M+1)+.
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=O)CC.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].C1C=CC(CCBr)=CC=1>>[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20](=[O:25])[C:19]2=[O:26]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: BrCCc1ccccc1
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCc1ccccc1

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using 5-methyl isatin (purchased from Fisher Scientific) and 2-phenethyl bromide (purchased from Fisher Scientific).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][C:16]#[N:17]>CO>[ClH:7].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][C:16]([NH:2][OH:3])=[NH:17]
Reactant: NO
Reactant: N#CNc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(NO)Nc1c(Cl)cccc1Cl
Reaction time: 3 h

Procedure:
A solution of 34.7 g (0.5 mol) of hydroxylamine hydrochloride in methanol and a solution of 27 g (0.5 mol) of sodium methylate in methanol is mixed whilst cooling by means of an ice bath. The NaCl is filtered off and the filtered solution is introduced into a 2,000 ml Erlenmeyer flask with magnetic stirring and cooling by means of an ice bath. A solution of 39.6 g (0.21 mol) of 2,6-dichlorophenyl-cyanamide in CH3OH is run into the preceding solution and the mixture is stirred at ambient temperature (15°-25° C.) overnight. A small amount of insoluble matter is filtered off. To the methanol solution is added twice its volume of distilled water. An insoluble material is filtered off and discarded. The filtrate is placed in a freezer for 3 hours and an insoluble material is filtered off and discarded. The filtrate is evaporated to dryness. The residue is taken up in 1,000 ml of water and the medium is rendered acid with concentrated HCl. An insoluble material is filtered off and discarded. The liquid phase is washed with ether and the pH is brought to 8 with NaOH, taking care not to exceed this value. The mixture is extracted with ether. The ether is dried over MgSO4 and the hydrochloride of the product is precipitated from the ether by bubbling-in HCl gas.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(OCC)C>[CH2:33]([O:32][C:30]([NH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: N[C@@H]1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H]1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.6 %

Procedure:
To a solution of (±) cis 1-amino-2-(4-benzylphenoxymethyl)cyclopentane (0.9 g, 3.20 mmol) in dry diethyl ether (100 ml) containing triethylamine (0.89 ml, 6.4 mmol) was added ethyl chloroformate (0.40 ml, 4.16 mmol) under argon. After stirring at room temperature for 2.5 h the reaction was quenched with ice water and the pH of the aqueous layer was adjusted to 7 by addition of dilute hydrochloric acid. The organic layer was separated and the aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a pale yellow oil (1.16 g) which was used in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C(O)C>O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(Cc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 120 g. of ethyl 4-(4-methoxybenzyl)benzoate, 500 ml. of 2N sodium hydroxide solution and 250 ml. of ethanol was heated at reflux for two hours. The reaction mixture was cooled, diluted with water and extracted with ether. The aqueous layer was acidified with hydrochloric acid and the precipitate which formed was collected and dried to give 100 g. of 4-(4-methoxybenzyl)benzoic acid, m.p. 152°-153° C. when recrystallized from aqueous ethanol.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[F:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.O1CCCC1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:18]2[C:17]([F:20])=[C:16]([F:21])[C:15]([F:22])=[C:14]([F:23])[C:13]=2[F:12])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
In a mixture solvent of 500 mL of ethyl acetate and 150 mL of tetrahydrofuran were dissolved 50 g of 4-vinylbenzoic acid and 62.1 g of pentafluorophenol, and the solution was ice-cooled. To the solution was added 69.65 g of dicyclohexylcarbodiimide, and the mixture was stirred under ice-cooling for 1 hour and then at room temperature for 1 hour. Precipitated dicyclohexylurea was filtered off and the filtrate was concentrated under a reduced pressure. To the residue was added 150 mL of hexane, and precipitated dicyclohexylurea was filtered off. Then, the filtrate was concentrated under a reduced pressure to give 99 g of pentafluorophenyl 4-vinylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.COC1C=CC(C[N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][N:36]=4)=[C:28]3[C:27]([CH3:42])=[N:26]2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([NH:41][C:38]3[CH:37]=[N:36][C:35]([O:34][C:33]4[CH:32]=[CH:31][N:30]=[C:29]5[NH:25][N:26]=[C:27]([CH3:42])[C:28]=45)=[N:40][CH:39]=3)=[O:17])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ncc(N)cn4)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Product: Cc1n[nH]c2nccc(Oc3ncc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cn3)c12
Yield: 4.6 %

Procedure:
Prepared by 2-step process (Example 19, Step D and Example 13 Step D) from 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.103 g, 0.442 mmol obtained from Example 19, step C), and 2-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrimidin-5-amine (0.04 g, 0.110 mmol). The crude material was purified by preparative TLC (1.0 mm thickness, EtOAc) to afford 2.3 mg (9%) of the desired product. LRMS M+1 (459.0) observed. 1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 9.04 (s, 2H), 8.51 (br s, 1H), 8.40 (m, 1H), 8.27 (m, 1H), 7.59 (m, 2H), 7.23 (m, 2H), 6.94 (m, 1H), 2.50 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A175) and methoxy-acetyl chloride the title compound was obtained as colorless solid.