Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.Cl.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>COCCOC>[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[N:14]=[CH:13][CH:12]=3)[N:7]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN)cc4)ccc3=O)ccnc2c1
Temperature: 85 °C

Procedure:
A suspension of 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (1250 mg, 3768 μmol), (4-aminomethylphenyl)boronic acid, hydrochloride (1412 mg, 7536 μmol), Na2CO3 (7536 μL, 15071 μmol) [2M], and [1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) complex with dichloromethane (276 mg, 377 μmol) in DME (2 mL) was sparged with argon for 5 minutes then heated to 85° C. for 4 hours. The reaction was then partitioned between DCM (50 mL) and 1 M NaOH (20 mL). The organic was dried over MgSO4, concentrated onto dry silica (10 g) then purified on silica (40 g) eluting with 0>5% MeOH/DCM. The product was isolated as an off white solid from ACN. MS (ESI pos. ion) m/z: 403 (MH+); calc'd for C23H22N4O3: 402. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 2 H) 3.87 (s, 3 H) 4.67 (s, 4 H) 6.95 (d, J=5.28 Hz, 1 H) 7.01 (dd, J=9.00, 2.54 Hz, 1 H) 7.08 (d, J=9.78 Hz, 1 H) 7.27 (d, J=2.35 Hz, 1 H) 7.41 (d, J=8.22 Hz, 2 H) 7.78 (d, J=8.41 Hz, 2 H) 7.90 (d, J=9.19 Hz, 1 H) 8.03 (d, J=9.78 Hz, 1 H) 8.62 (d, J=5.28 Hz, 1 H).
Reaction SMILES: C([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:27])=[S:26])=[CH:14][CH:13]=2)(C)(C)C.C(N(CC)CC)C.ClC(O[CH2:45][CH:46]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=O.O>Cl.C(OCC)(=O)C>[CH:48]1[C:47]2[CH:46]([CH2:45][O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]3[N:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:11](=[O:28])[C:12]4[C:17]([C:18]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][C:15]([C:25]([NH2:27])=[S:26])=[CH:14][CH:13]=4)[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]=2[CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Tert-butyl[6-(aminothiocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.26 g, 7 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in tetrahydrofuran (20 ml). To the obtained mixture were added triethylamine (2.0 ml, 14 mmol) and 9-fluorenylmethyl chloroformate (2.72 g, 10.5 mmol) and the mixture was stirred with heating at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.21 g, 78.1%) as an amorphous.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:6][C:7]=1[CH2:8]C.[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:18]([C:19]1[CH:27]=[CH:26][C:24]([O:25][CH2:2][C:3]2[N:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:6][C:7]=2[CH3:8])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1nc(CCl)c(CC)o1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(C=O)cc2OC)c(C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
A mixture of ethyl (2E)-3-(4-chloromethyl-5-ethyl-1,3-oxazol-2-yl)-2-propenoate (11.62 g), vanillin (7.70 g), potassium carbonate (6.99 g) and N,N-dimethylformamide (200 mL) was stirred at room temperature for 15 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of ethyl (2E)-3-{4[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (12.15 g, yield 70%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:25]2[C:20](=[C:21]([O:26][CH2:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][CH:17]=[C:16]2[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:42])([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cccc2c(OCC(=O)N3CCC[C@@H]3C(=O)OC(C)(C)C)cccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cccc2c(OCC(=O)N3CCC[C@@H]3C(=O)O)cccc12
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of 290 mg (0.5 mmol) (R)-1-[[5-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 230 mg (98%) of the title compound as a white powder. MS m/e (%): 493 (M+Na+, 45), 488 (M+NH4+, 37), 471 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](I)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7](Br)[CH:6]=1)[CH3:2].C(OC(=O)[C:22]1[CH:27]=[C:26](Br)[C:25]([O:29][CH2:30][O:31]C)=[C:24](Br)[CH:23]=1)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:22]2[CH:27]=[CH:26][C:25]3[O:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][CH2:30][O:31][C:26]=3[CH:27]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(I)c1
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(Br)c1
Product: CCOC(=O)c1cc(-c2ccc3c(c2)OCO3)c(OCOC)c(-c2ccc3c(c2)OCO3)c1

Procedure:
3,5-Bis-(3,4-methylenedioxyphenyl)-4-methoxymethoxybenzoic acid ethyl ester was prepared as a white solid (3.1 g, 42.4%) in a similar manner to Step 1 of Example 143 from a 2:1 mixture of 3-bromo-4-methoxymethoxy-5-iodobenzoic acid ethyl ester and 3,5-dibromo-4-methoxymethoxybenzoic acid ethyl ester. There also yielded 780 mg of the monoarylated product. 1H NMR (CDCl3) δ 1.37 (t, J=8.18 Hz, 3H); 2.80 (s, 3H); 4.36 (quartet, J=8.18 Hz, 2H); 4.46 (s, 2H); 6.00 (s, 4H); 6.87 (d, J=8.18 Hz, 2H); 7.05 (dd, J=8.18 Hz, 1.63 Hz, 2H); 7.11 (d, J=1.23 Hz, 2H); 7.95 (s, 2H).
Reaction SMILES: S(Cl)(Cl)=O.O[C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].CN(C)C=O.[ClH:22]>C1(C)C=CC=CC=1.O>[Cl:22][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: Cl
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)[C@H](Cl)Cc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Thionyl chloride (43.8 g, 368.4 mmol) was added dropwise to a solution of 20.4 g (122.8 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S)) in 200 ml of toluene, and the mixture was stirred at 40° C. for 2 hours. To that solution was added 1.8 g (24.6 mmol) of dimethylformamide, and the mixture was stirred at 40° C. for 24 hours. This reaction mixture was cooled and, while maintaining the temperature at 20° C., 70 ml of water was added dropwise and, after about an hour of stirring, extracted with 200 ml of toluene. Water (70 ml) was added to the organic phase and, after pH adjustment to 9.0 with a 30% aqueous solution of sodium hydroxide, the organic phase was removed by phase separation. To the aqueous phase obtained was added 200 ml of toluene, the pH was adjusted to 1.0 with 35% aqueous hydrochloric acid, and the aqueous phase was removed by phase separation. The toluene was distilled off under reduced pressure from the thus-obtained toluene phase to give 21.6 g (116.8 mmol, yield 95%) of (2R)-2-chloro-3-phenylpropionic acid. The optical purity of the product as determined by the same method as in Example 12 was 99.5% ee (R) (rate of configurational inversion 99.5%).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:48][CH3:49])=[C:31]([C:36]([CH2:39][S:40]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:48][CH3:49])=[C:31]([C:36]([CH2:39][S:40]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCCC2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)N2CCCC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-methoxy-6-(pyrrolidin-1-ylsulphonylmethyl)benzoate (Intermediate 150) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[S:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:41][C:40]3[N:36]([CH3:35])[N:37]=[C:38]([CH3:57])[C:39]=3[CH:43]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2sc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc12
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (120 mg, 0.240 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole (212 mg, 0.481 mmol) and tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.120 mmol) in toluene (3 mL) was heated to 120° C. in a Biotage Initiator microwave for 30 minutes. The mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (89 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.73 (m, 5H), 1.83-1.97 (m, 3H), 2.35 (s, 3H), 3.78-3.79 (m, 1H), 3.86 (s, 3H), 4.26-4.27 (m, 1H), 4.43 (d, J=4.88 Hz, 2H), 7.02-7.04 (m, 1H), 7.81-7.82 (m, 2H), 8.51 (s, 1H), 9.16 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H23FN6OS, 415. found, 415.
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2([CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[C:3]1=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2([CH2:5][CH2:6][NH:7][CH2:8]2)[C:3]1=[O:24]
Reactant: CN1CC(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccccc2)C2(CCNC2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 7-methyl-6-oxo-9-phenyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (diastereomer 1, step 1) (488.3 mg, 1.48 mmol) in DCM (10 mL) was treated with TFA (2.3 mL, 29.6 mmol). The reaction mixture was stirred at room temperature for 5 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with a saturated sodium bicarbonate solution. The organic portion was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound which was used in the next step without further purification;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[C:14]1([CH3:26])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:23]1[CH2:24][CH2:25][N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:26])[CH2:21][CH2:22]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: Cc1ccccc1N1CCNCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(N1CCN(c3ccccc3C)CC1)C2

Procedure:
3.6 g of 6-methoxy-2-tetralone are dissolved together with 3.9 g of N-(o-tolyl)-piperazine in 50 ml of acetic acid, 1 g of a 10% palladium on charcoal catalyst is added and hydrogenation effected. When the take-up of hydrogen ceases, the catalyst is filtered off, the solvent evaporated and the residue chromatographed on Kieselgel in manner analogous to that described in Example 1. The title compound is obtained as a compact residue. M.P. 286°-288° [Hydrochloride salt form].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:19])[CH2:11][NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:7]=[CH:8][CH:9]=1.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21].C1CCN2C(=NCCC2)CC1>>[CH3:17][CH:16]([S:13]([NH:12][CH2:11][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][NH:1][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])[CH:5]=1)[CH3:19])(=[O:15])=[O:14])[CH3:18]
Reactant: CC(CNS(=O)(=O)C(C)C)c1cccc(CCN)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1cccc(CCNS(=O)(=O)C(C)C)c1
Yield: 54 %

Procedure:
Scheme Va, step C: {2-[3-(2-Aminoethyl)phenyl]propyl}[(methylethyl)sulfonyl]amine (0.57 g, 2 mmol), isopropylsulfonyl chloride (0.24 mL, 2.1 mmol) and DBU (0.33 mL, 2.2 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the final title compound, [(methylethyl)sulfonyl]{2-[3-(2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]propyl}amine, (0.422 g, 54%) as a white crystalline solid. Electron spray M.S. 391 (M*+H). Analysis for C17H30N2O4S2:
Reaction SMILES: [C:1]1([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[OH2:18]>[Fe]>[C:1]1([CH2:11][C:12](=[O:18])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: CC(=Cc1cccc2ccccc12)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: CC(=O)Cc1cccc2ccccc12
Temperature: 85 °C
Yield: 91 %

Procedure:
A mixture of 1-naphthyl-2-nitropropene (taken directly from the synthesis of the last paragraph without purification, 10.4 g, 0.8 mol), iron powder (320.0 g, 5.8 g-atoms), ferric chloride hexahydrate (0.8 g) and water (800 mL) was mechanically stirred and heated to 85° C. Hydrochloric acid (37% aqueous, 120 mL, 1.2 mol) was then added dropwise over 5 hours while the temperature was maintained at 85-90° C. The mixture was filtered, the filtrate was extracted with methylene chloride (100 mL), and the residual solids were extracted with methylene chloride (2×200 mL). The combined organic extracts were washed with water, dried over MgSO4 and evaporated to give 139.6 g of 1-naphthylacetone that was shown by gas-liquid chromatography to be approximately 95% pure (91% yield). Further purification was achieved by recrystallization from methanol at -78° C. 1H NMR 2.10 (s, 3 H), 4.11 (s, 2 H), 7.4 (m, 4 H), 7.8 (m, 3 H).
Reaction SMILES: [CH3:1][CH:2]([N:6]1[CH:10]=[C:9](C)[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7]1)[C:3]([OH:5])=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].N>>[CH2:18]([N:20]([CH2:21][CH3:22])[C:3](=[O:5])[CH:2]([CH3:1])[N:6]1[CH:10]=[CH:9][C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:19]
Reactant: CCNCC
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Agent: N
Product: CCN(CC)C(=O)C(C)n1ccc(-c2ccccc2)n1

Procedure:
Following the procedure of Example 68, but substituting α-methyl-3-phenylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid, and diethylamine for aqueous ammonia there was obtained N,N-diethyl-α-methyl-3-phenylpyrazole-1-acetamide having a boiling point of 178°/0.2 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[OH:16].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1.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>[NH2:8][C:5]1[N:4]=[CH:3][C:2]([C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([F:9])[CH:11]=2)=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: OB(O)c1ccc(O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc(O)c(F)c2)cn1
Temperature: 120 °C

Procedure:
A mixture of 5-bromopyrimidin-2-amine (3.3 g, 19 mmol), (3-fluoro-4-hydroxyphenyl)boronic acid (2.7 g, 17 mmol), tetrakis(triphenylphosphine)palladium (0.6 g, 0.5 mmol), sodium carbonate (18.3 g, 172 mmol) in ethanol (15 mL), water (5 mL) and toluene (15 mL) was heated at 120° C. for 3 h. The volatiles were removed under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated to obtain the desired product which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([CH3:34])=[N:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:18][CH:17]=3)[C:14]=2[CH3:15])[CH:7]=[CH:8][CH:9]=1)=[O:3].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH:45][C:25]([NH:24][CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[C:14]([CH3:15])=[C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:2]([NH2:1])=[O:3])[C:11]([CH3:34])=[N:12]3)=[CH:21][CH:20]=2)=[O:33])(=[O:43])=[O:44])=[CH:40][CH:41]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1cccc(C(N)=O)c1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(Cl)cc3)cc2)c(C)c1-c1cccc(C(N)=O)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-(4-{4-[3-(aminocarbonyl)phenyl]-3,5-dimethyl-1H-pyrazol-1-yl}phenyl)ethylcarbamate (step 6 of example 72) and 4-chlorobenzensulfonamide: MS (ESI) m/z 552 [M+H]+, 550 [M−H]−, 1H-NMR (CDCl3) δ 7.92-7.80 (4H, m), 7.58-7.47 (4H, m), 7.29-7.18 (4H, m), 6.33 (1H, br.s), 3.47 (2H, t, J=6.1 Hz), 2.86 (2H, t, J=6.1 Hz), 2.23 (6H, s).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH:12]=[CH2:13]>C(O)C.[I-].[Na+]>[CH2:1]([NH:8][CH2:13][CH2:12][CH:11]=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCBr
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCNCc1ccccc1
Temperature: 75 °C
Yield: 84413.4 %

Procedure:
To a solution of benzylamine (100 mL, 0.9 mol) and 4-bromobut-1-ene (25 g, 0.18 mmol) in ethanol (250 mL) was added sodium iodide (1.0 g, 6.7 mmol). The reaction mixture was degassed via argon bubbling for 20 min then heated to 75° C. for 4 h. After cooling, the reaction mixture was diluted with dichloromethane (1 L) and 1M KOH (500 mL) was added. The two phases were separated and the aqueous layer was further extracted with dichloromethane (3×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, ethyl acetate to 10:1 ethyl acetate/triethylamine) provided N-benzylbut-3-en-1-amine (24.5 g, 84%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.31-7.28 (m, 3H), 7.24-7.21 (m, 2H), 5.82-5.72 (m, 1H), 5.10-5.00 (m, 2H), 3.77 (s, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.29-2.23 (m, 2H), 1.36 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:42](Cl)(=[O:44])=[O:43])[CH2:35][CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[O:32][CH2:33][CH2:34][CH2:35]2)(=[O:43])=[O:44]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1cccc2c1OCCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2c1OCCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. chromane-8-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.