Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].FC(F)(F)S(OC1[CH:21]=[C:22]2[C:26](=[C:27]([Cl:30])[C:28]=1[Cl:29])[C:25](=[O:31])[C:24]([CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)([CH3:32])[CH2:23]2)(=O)=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:29][C:28]1[C:27]([Cl:30])=[C:26]2[C:22]([CH2:23][C:24]([CH2:33][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)([CH3:32])[C:25]2=[O:31])=[CH:21][C:3]=1[CH2:2][C:1]([OH:9])=[O:8]
Reactant: CC1(CC2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(CC2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Diethyl malonate (18.3 g., 0.114 mole) is added with stirring under nitrogen at 10°-15° C. to a suspension of sodium hydride (56% in mineral oil, 4.89 g., 0.114 mole) in dry dimethylformamide (85 ml.). The reaction mixture is stirred for 1 hour at room temperature, cooled to 5° C. and then 6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl trifluoromethanesulfonate (18.8 g., 0.0426 mole dissolved in dry toluene (20 ml.) is added over 1 hour at 5°-7° C. After stirring at room temperature for 18 hours, the reaction mixture is poured into ice water (1000 ml.) and extracted with ether (4×150 ml.) and the with methylene chloride (2×50 ml.). The combined organic extracts are washed three times with water and concentrated under vacuum. The residual oil is dissolved in ethanol (150 ml.) and added to a solution of 20 g. of sodium hydroxide in water (150 ml.). The mixture is refluxed for 3 hours, cooled and the ethanol removed under vacuum. The residue is diluted with water, extracted with hexane and then acidified with hydrochloric acid. The gum that separates is extracted with ether. The combined etheral extracts are washed with water and then extracted repeatedly with dilute sodium bicarbonate. The combined aqueous extracts are acidified with hydrochloric acid and extracted with ether. The ether extracts are washed with brine, dried over magnesium sulfate an concentrated under vacuum to obtain the crude (6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid, 9.3 g., m.p. 145.5°-148° C., in 62% yield. Recrystallization from butyl chloride affords material which melts at 149°-151° C.
Reaction SMILES: [OH:1][C:2]([CH3:40])([CH3:39])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]([CH3:40])([CH3:39])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:22])=[O:23])[CH:19]=[CH:20][C:12]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(C)(C)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)COc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of 4-(2-(2-hydroxy-2-methylpropoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (600 mg, 0.585 mmol) in DCM (5 mL) was added TFA (1.4 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by prep HPLC purification to obtain 4-(2-(2-hydroxy-2-methylpropoxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (120 mg, 26.0%) as a white solid. m/z (ESI) 461.8 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.50 (s, 1H), 7.38-7.24 (m, 2H), 7.20 (d, J=4.6 Hz, 1H), 7.16-6.95 (m, 4H), 6.76 (d, J=4.3 Hz, 1H), 6.23-6.00 (m, 1H), 4.46 (s, 1H), 4.31 (d, J=3.9 Hz, 2H), 3.61-3.58 (m, 4H), 0.83 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+]>O1CCCC1>[CH3:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[B:17]([OH:18])[OH:16]
Reactant: Cc1cc(F)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1B(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
2-Bromo-5-fluorotoluene (52.0 mmol, 10 g) in 400 ml of tetrahydrofuran was cooled to −78° C. and n-butyllithium (2.5 M, 58.2 mmol) was added. The solution was stirred for 20 minutes, trimethoxy borane (3 eq, 0.16 mol) was added, and the reaction was allowed to warm to room temperature overnight. Sodium hydroxide (60 ml of 1.25 M) was added and the reaction was stirred for 30 minutes. The tetrahydrofuran was removed in vacuo. The remaining aqueous layer was diluted and extracted with diethyl ether. The aqueous layer was adjusted to pH 3 with 2N HCl and extracted with ethyl acetate, which was dried (MgSO4) and concentrated in vacuo to give 6.57 g (81%) of a colorless solid: MS(FAB) m/e (rel. intensity) 154(48), 136(100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=2[O:27]C(=O)C)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=2[OH:27])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(Nc2ccc(Cl)cc2)c(Cl)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2ccc(Cl)cc2)c(Cl)c1)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[3-Chloro-4-(4-chloro-phenylamino)-phenyl]-2-acetoxy-5-nitro-benzamide (155 mg) was dissolved in a 1:1 mixture of THF and water (12 ml) and LiOH.H2O (64 mg) was added. After stirring at room temperature for 2 hours the solvents were evaporated and water was added to the residue. Filtration, acidification of the filtrate and filtration of the precipitate gave a residue which was flash-chromatographed (EtOAc; 1:3) to provide N-[3-Chloro-4-(4-chloro-phenylamino)-phenyl]-2-hydroxy-5-nitro-benzamide as a curry coloured powder (70 mg). Mp. >219° C. (dec.).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1.[ClH:14].N([O-])=O.[Na+]>O>[Cl:14][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: Cl
Reactant: CCOC(=O)c1sc(N)nc1CC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1sc(Cl)nc1CC
Reaction time: 0.5 h

Procedure:
Ethyl 2-chloro-3-oxo-pentanoate is prepared from ethyl 3-oxo-pentanoate and sulfuryl chloride utilizing the procedure of Bankowski et al, Rocz. Chem., Volume 49, Page 1899 (1971). A mixture of 9.2 g (0.0515 mole) of ethyl 2-chloro-3-oxo-pentanoate, 3.92 g (0.0515 mole) of thiourea and 30 ml. of ethanol was held at reflux for 17 hours. Ethanol was removed under reduced pressure and the residue was treated with 300 ml. of saturated sodium bicarbonate solution. The solid precipitate was collected to give 11.2 g of white solid, m.p. 165°-170° C. which recrystallized from ethanol to give 7.7 g (75%) of ethyl 2-amino-4-ethyl-5-thiazolecarboxylate as colorless prisms, m.p. 177°-179° C. To a solution of 7.0 g (0.0349 mole) of ethyl 2-amino-4-ethyl-5-thiazolecarboxylate and 0.2 g of CaSO4 in 60 ml. of concentrated HCl was added dropwise a solution of NaNO2 in 20 ml. of water in such a way that the reaction temperature did not exceed 30° C. The reaction mixture was stirred for 30 minutes and poured into a solution of 3.5 g (0.035 mole) of cuprous chloride in 30 ml. of 6 N HCl. The resulting dark blue solution was stirred for 30 minutes and extracted with ether. The ether solution was dried and concentrated under reduced pressure. The residue was Kugelrohr distilled at 2 mm. to give 4.35 g of yellow liquid which was chromatographed on silica gel to give 4.0 g (52%) of the desired product as colorless liquid, nD25 =1.5189.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[S:6].[C:7]([NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])(=N)[NH2:8].C[N:23](C=O)C>>[NH2:19][C:18]1[C:13]([C:11]([N:10]=[CH:7][NH:8][NH:23][C:5]2[S:6][CH2:2][CH2:3][N:4]=2)=[O:12])=[N:14][C:15]([Cl:21])=[C:16]([NH2:20])[N:17]=1
Reactant: N=C(N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)C=O
Reactant: S=C=NCCCl
Product: Nc1nc(N)c(C(=O)N=CNNC2=NCCS2)nc1Cl
Reaction time: 2 h

Procedure:
2-Chloroethylisothiocyanate (670 mg., 0.0055 mole) is added to a warm (40° C.) solution of N-amidino 3,5-diamino-6-chloro-2-pyrazinecarboxamide (1.15 g., 0.005 mole) in DMF (30 ml.) with stirring. After 2 hours, the solid precipitate is collected, washed with H2 0 and dried to give 3,5-diamino-6-chloro-N-[(2-thiazolinylamino)aminomethylene]-2-pyrazinecarboxamide., m.p. 252°-254° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15](N)[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Cc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
4-chloro-3-nitro-quinoline is reacted with isobutyl amine in the presence of triethylamine (TEA) at between −10 and +15° C. in toluene, while excluding moisture. After washing and phase separation, the organic solution is ready for the next step.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49]N(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH:43]([CH3:49])[C:44]([O:46][CH3:47])=[O:45])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetate (Example 127, Step C) was azetroped with toluene 3× and then dissolved in THF (14 mL) under Ar and the mixture was cooled to −78° C. HMPA (236 μL, 1.356 mmol) and LHMDS (1.0M in THF) (1356 μL, 1.356 mmol) were added under Ar at −78° C. The mixture was stirred at −78° C. for 30 min. The mixture color turned light yellow. Then iodomethane (110 μL, 1.763 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature. The mixture was quenched with sat. NH4Cl and the layers were separated. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2×50 g stacked VersaPak I-style, Spherical, Supelco, Bellenfonte, Pa.; eluent: 20 to 30% MtBE in hexanes) to give the title compound as the less polar, major diastereomer. The retention time of the less polar diastereomer is 0.871 min (80-100% MeCN +0.1% TFA in water +0.1% TFA, over 1 minute). The retention time of the more polar diastereomer is 0.841 min (80 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 1 minute).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]1([CH3:36])[C@H:14]([NH:15][C:16]2[C:17]3[N:18]([CH:25]=[C:26]([C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH:27]=3)[N:19]=[CH:20][C:21]=2[C:22]([NH2:24])=[O:23])[CH2:13][CH2:12][NH:11][CH2:10]1.[NH2:37][C:38](=[O:42])[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:37][C:38](=[O:42])[C:39]([N:11]1[CH2:12][CH2:13][C@@H:14]([NH:15][C:16]2[C:17]3[N:18]([CH:25]=[C:26]([C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH:27]=3)[N:19]=[CH:20][C:21]=2[C:22]([NH2:24])=[O:23])[C:9]([CH3:36])([CH3:8])[CH2:10]1)=[O:40]
Reactant: NC(=O)C(=O)O
Reactant: COc1ccc(-c2cc3c(N[C@@H]4CCNCC4(C)C)c(C(N)=O)cnn3c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(N[C@@H]4CCN(C(=O)C(N)=O)CC4(C)C)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To solution of (R)-4-(3,3-dimethylpiperidin-4-ylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt (20 mg, 0.039 mmol), 2-amino-2-oxoacetic acid (4.20 mg, 0.047 mmol) and HATU (22.43 mg, 0.059 mmol) in DMF (0.3 mL) was added triethylamine (0.022 mL, 0.157 mmol) and the resulting mixture was stirred at rt overnight. The mixture was quenched with 0.3 mL of MeOH, diluted with MeOH, filtered and was purified via preparative reverse phase HPLC. The fraction containing the major product was concentrated under vacuum to afford the title compound as a tan solid (10 mg, 0.015 mmol, 38%). HPLC (Method B) retention time=2.88 min. LCMS (m+1)=466.3. 1H NMR (400 MHz, METHANOL-d4) δ 8.59 (t, J=2.2 Hz, 1H), 8.24 (dt, J=8.7, 2.8 Hz, 1H), 8.21 (s, 1H), 8.03 (t, J=2.0 Hz, 1H), 7.31 (dd, J=5.7, 1.8 Hz, 1H), 7.05 (dd, J=8.5, 2.3 Hz, 1H), 4.46-4.30 (m, 2H), 4.07-4.00 (m, 4H), 3.78 (dd, J=13.8, 1.7 Hz, 1H), 3.68-3.51 (m, 1H), 3.21-3.08 (m, 1H), 2.23 (dt, J=13.6, 4.0 Hz, 1H), 2.04-1.75 (m, 1H), 1.22-1.06 (m, 6H).
Reaction SMILES: Br[C:2]1[C:3]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([Sn](CCCC)(CCCC)CCCC)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43].O1CCOCC1>C(OCC)(=O)C.[F-].[K+].[Cu]Cl>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][C:3]2[C:2]([C:39]3[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[C:41]([O:42][CH3:43])[CH:40]=3)=[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[N:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=3)[N:6]=[CH:5][N:4]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)c(OC)c1
Reactant: CSc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Br)nc1
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(SC)cn2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A mixture of N-{5-bromo-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (100 mg), 3,4-dimethoxyphenyltributyltin (220 mg), bis(triphenylphsophine)palladium (II) chloride (26 mg), copper (I) chloride (11 mg), a few crystals of 2,6-di-tert-butylcrezol and dioxane (5 ml) is refluxed for 1.5 hour. After cooling, the reaction solution is diluted with ethyl acetate and aqueous potassium fluoride solution, and the mixture is stirred at room temperature for 30 minutes. The insoluble materials are removed by filtration, and the filtrate is acidified with 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by preparative thin layer chromatography (solvent; chloroform/ethyl acetate=3:1), and recrystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-{5-(3,4-dimethoxyphenyl)-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]-pyrimidin-4-yl}benzenesulfonamide (82 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=1.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.CO.[O:28]1[CH2:33][CH2:32][O:31][CH2:30]C1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][NH:16][C:33](=[O:28])[CH:32]([C:10]2[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:15])=[CH:8][CH:9]=2)[O:31][CH3:30])=[CH:19][CH:20]=1)#[N:23]
Reactant: C1COCCO1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: N#Cc1ccc(CN)cc1
Solvent: CO
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCCCN(C)C)cc1

Procedure:
4-[3-(Dimethylamino)propoxy]benzaldehyde was reacted according to general procedure A using methanol/dioxane as a solvent. The product of this reaction was subsequently coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-[4-(3-dimethylamino-propoxy)-phenyl]-2-methoxy-acetamide. Colorless solid. MS 382.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3]=1[C:12]#[N:13].[CH3:14][N:15]=[C:16]=[O:17]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:14][NH:15][C:16]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3]=1[C:12]#[N:13])=[O:17]
Reactant: CN=C=O
Reactant: N#Cc1c(N2CCCC2)nsc1N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Nc1snc(N2CCCC2)c1C#N
Yield: 82.1 %

Procedure:
A mixture of 16.0 g of 5-amino-4-cyano-3-(1-pyrrolidinyl)isothiazole, 25 drops of dibutyltin diacetate and 5.4 g of methyl isocyanate in 90 ml of tetrahydrofuran was heated under reflux for about 56 hours. Small increments of methyl isocyanate (3 ml at 27 hours and 2 ml at 40 hours) and dibutyltin diacetate (10 drops at 32 hours and 5 drops at 40 hours) were added during the reflux period. A solid that had formed was isolated by filtration. The filtrate was concentrated under reduced pressure to obtain a second crop. A total of 17.0 g of 1-methyl-3-(4-cyano-3-(1-pyrrolidinyl)-5-isothiazolyl)urea, m.p. 239°, was obtained. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.076 mmol), β-alanine (896 mg, 10.1 mmol) and NaOMe solution (15 mL, 7.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 3 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 29 mg of the title compound as a pale yellow solid. MS: (+) m/z 521.34 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
4-Fluorobenzonitrile (204.2 g), pyrazole (138.6 g, 1.22 eq) and potassium carbonate (281.5 g, 1.22 eq) in DMF (1110 ml) were heated at 120° C. for 7 hours. The suspension was cooled to 25° C. and water (2920 ml) added. The reaction was extracted with MTBE (3×1460 ml) and the combined extracts were washed with water (3×1460 ml) and saturated aqueous sodium chloride (1460 ml). The organic phase was concentrated at atmospheric pressure until the pot temperature rose to 65° C. Heptane (1700 ml) was added over 30 minutes at 60-65° C., and then a further 300 ml of distillate was collected. The solution was stirred at 60-65° C. for 15 minutes and then cooled to <5° C. The slurry was filtered and washed with heptane (2×200 ml), and dried under vacuum to constant weight to give the title compound as a solid (245.3 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:33]2[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Reactant: OB(O)c1cccnc1F
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: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A suspension of tert-butyl({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (206 mg), (2-fluoropyridin-3-yl)boronic acid (80 mg), sodium carbonate (119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 87 mg, 41%).