Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:5]2[CH:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.Cl>O1CCOCC1>[CH3:10][CH:6]1[C:5]2[CH:11]=[C:12]([CH3:13])[C:2]([N:1]3[CH:16]=[CH:20][CH:19]=[CH:18]3)=[CH:3][C:4]=2[O:8][C:7]1=[O:9]
Reactant: COC1CCC(OC)O1
Reactant: Cc1cc2c(cc1N)OC(=O)C2C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-n1cccc1)OC(=O)C2C
Temperature: 25 °C

Procedure:
1.8 g of 6-amino-3,5-dimethylbenzofuran-2-(3H)-one are dissolved in 20 ml of dioxane and, while stirring at room temperature, 2 ml of 2,5-dimethoxytetrahydrofuran and 1.4 ml of 37% strength hydrochloric acid are added. After 30 minutes the aqueous phase is removed and the organic phase is concentrated to dryness by evaporation in vacuo. The residue is chromatographed over silica gel with methylene chloride. The resulting pale-yellow oil crystallises from butyl oxide. In this manner 3,5-dimethyl-6-(pyrrol-1-yl)-benzofuran-2(3H)-one having a melting point of 61°-63° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.[OH:15][CH:16]=[C:17]([O:24][CH3:25])[C:18](OCCC)=O.O>C(Cl)(Cl)Cl>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:17]([O:24][CH3:25])[C:16](=[O:15])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOC(=O)C(=CO)OC
Reactant: CCCCCCCSc1nnc(N)s1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCSc1nn2c(=O)c(OC)cnc2s1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A mixture of 4.7 g of 2-amino-5-heptylthio-1,3,4-thiadiazole, 3.3 g of propyl 3-hydroxy-2-methoxy-2-propenoate and 12 g of polyphosphoric acid was heated to 130°~135° C. and stirred for 30 minutes. After cooling, water and chloroform were added to the mixture and extraction was carried out. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent. Thus 4.0 g of 2-heptylthio-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 68°~71° C. Yield 64%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:31]=[N:30][C:14]3[N:15]=[C:16]([NH:19][C:20]4[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:29])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:31]=[N:30][C:14]3[N:15]=[C:16]([NH:19][C:20]4[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:29])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4N)ncc3c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of 6-(3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.24 mmol) in ethanol (5 mL) and water (5 mL) was added iron powder (110 mg, 1.92 mmol) and ammonium chloride (100 mg, 1.920 mmol). The mixture was stirred at 100° C. for 1 hour, cooled to RT, filtered and concentrated. The residue was purified by Preparative HPLC to afford N1-(6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-6-methylbenzene-1,2-diamine (29.5 mg, 32%) as a yellow solid. MS (ES+) C22H21N5O2 requires: 387. Found: 388 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.30, 9.21 (br, br, 2H), 8.95 (s, 1H), 8.60 (d, 1H, J=3.0 Hz), 6.96-6.92 (m, 3H), 6.63 (d, 1H, J=5.5 Hz), 6.55 (t, 1H, J=2.0 Hz), 6.50-6.48 (m, 1H), 4.79 (s, 2H), 3.84 (s, 6H), 2.08 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][C:32]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:33]=1[CH2:34]Cl.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:32]=3[CH3:31])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c(C)c1
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (1.0 g, 7.24 mmoles) and 2,4,6-trimethylbenzyl chloride (339 mg, 1.5 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (61 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (s, 1 H), 10.07 (s, 1 H), 6.77 (s, 2 H), 4.99 (s, 2 H), 4.59 (t, J=12.00 Hz, 1 H), 4.08-4.14 (m, 2 H), 2.21-2.29 (m, 8 H), 2.14-2.20 (m, 4 H), 1.77 (d, J=12.63 Hz, 2 H), 1.52-1.64 (m, 3 H), 1.27 (q, J=12.88 Hz, 2 H), 1.05-1.17 (m, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[OH:15][C:16]1[C:25]([CH3:26])=[CH:24][C:19]([C:20]([NH:22]O)=[NH:21])=[CH:18][C:17]=1[CH3:27]>>[CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]2[O:13][N:22]=[C:20]([C:19]3[CH:24]=[C:25]([CH3:26])[C:16]([OH:15])=[C:17]([CH3:27])[CH:18]=3)[N:21]=2)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Reactant: Cc1sc(C(=O)O)c(C)c1CC(C)C
Product: Cc1cc(-c2noc(-c3sc(C)c(CC(C)C)c3C)n2)cc(C)c1O

Procedure:
4-[5-(4-Isobutyl-3,5-dimethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol is prepared from 4-isobutyl-3,5-dimethyl-thiophene-2-carboxylic acid and 4,N-dihydroxy-3,5-dimethyl-benzamidine in analogy to Example 21; LC-MS: tR=1.20 min, [M+1]=357.35; 1H NMR (D6-DMSO): δ 8.91 (s, 1H), 7.60 (s, 2H), 2.53 (s, 3H), 2.44-2.40 (m, 5H), 2.23 (s, 6H), 1.81-1.72 (m, 1H), 0.89 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[C:69]([C:73]1[CH:78]=[CH:77][C:76]([C@@H:79]([NH3+:81])[CH3:80])=[CH:75][CH:74]=1)([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[C:69]([C:73]1[CH:74]=[CH:75][C:76]([C@@H:79]([NH:81][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:80])=[CH:77][CH:78]=1)([CH3:72])([CH3:70])[CH3:71]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H]([NH3+])c1ccc(C(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
To a mixture of 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (100 mg) in DMF (2 mL) was added DIEA (116 μL) and HATU (88 mg). The mixture was stirred for 5 min, and then (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride (49 mg) was added. The reaction mixture was stirred at rt for 30 min. The completion of the reaction was monitored by anal. HPLC. The solvent was removed in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10→100%) to obtain the title compound (120 mg). ESI-MS (m/z): 559 [M+H-tBu]+, 615 [M+H]+, 637 [M+Na]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:25]2[CH:26]=[CH:27][C:28]([Cl:40])=[C:29]3[C:33]=2[N:32]([CH3:34])[N:31]=[C:30]3[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:4][CH:3]=1.[CH3:41][NH:42][CH2:43][CH2:44][OH:45]>CC(N(C)C)=O>[Cl:40][C:28]1[CH:27]=[CH:26][C:25]([C:5]2[C:6]([C@@H:8]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:9][C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)=[N:7][C:2]([N:42]([CH2:43][CH2:44][OH:45])[CH3:41])=[CH:3][CH:4]=2)=[C:33]2[C:29]=1[C:30]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[N:31][N:32]2[CH3:34]
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Reactant: CNCCO
Solvent: CC(=O)N(C)C
Product: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)C(F)(F)F)n1
Temperature: 150 °C

Procedure:
To a solution of (S)—N-(1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide (57D, 50 mg, 0.08 mmol) in DMA (1 mL) was added 2-(methylamino)ethanol (64.5 μL, 0.803 mmol). The reaction mixture was heated to 150° C. for 2 hours. The crude mixture was concentrated in vacuo and used without further purification. MS (m/z) 661.16 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6](OC)=[O:7])=[CH:4][C:3]2[S:10][CH:11]=[CH:12][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:7][CH2:6][C:5]1[S:1][C:2]2[CH:12]=[CH:11][S:10][C:3]=2[CH:4]=1
Reactant: COC(=O)c1cc2sccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc2sccc2s1

Procedure:
2,3-Dibromothiophene (1) is converted to 3-Bromothiophene-2-carboxaldehyde (2) through a series of reactions with n-butyl lithium yielding 2-litho-3-bromothiophene, followed by N-formylpiperidine and 3N HCl. This 3-bromothiophene-2-carboxaldehyde (2) is then placed in toluene solution containing ethylene glycol to which is added pyridinium tosylate yielding 3-bromo-2-(2-dioxolanyl)thiophene (3). This 3-bromo-2-(2-dioxolanyl)thiophene (3) is then reacted with n-butyllithium followed by sulfur, then by methyl bromoacetate, to yield methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4). This methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) is next dissolved in acetone and p-toluenesulfonic acid monohydrate is added in catalytic amount yielding methyl 3-(2-formylthiophene-3-yl)-3-thiapropionate (5). This methyl 3-(2-formylthiophene-3-yl)3-thiapropionate (5) is then treated in solution with piperidinium acetate yielding methyl thieno[3,2-b]thiophene-2-carboxylate (6). This methyl thieno[3,2-b]thiophene-2-carboxylate (6) is then placed in solution with lithium aluminum hydride yielding 2-hydroxymethylthieno[3,2-b]-thiophene (7). This 2-hydroxymethylthieno[3,2-b]-thiophene (7) is then added to a suspension of pyridinium chlorochromate in methylene chloride and yields thieno[3,2-b]thiophene-2-carboxaldehyde (8). This thieno[3,2-b]thiophene-2-carboxaldehyde (8) is then mixed with ethylene glycol, pyridinium tosylate and benzene yielding 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9) is then reacted with n-butyllithium after which SO2 is bubbled onto the surface and N-chlorosuccinimide and NH4OH are added separately at the appropriate time. This series of steps yields 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10). This 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10) may then be reacted with p-toluenesulfonic acid monohydrate in acetone to yield 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11). The 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) is then reacted with an appropriate amine yielding the intermediate iminium salt (12) which may then be reduced with NaBH4 or NaCNBH3 to give the desired 5-substituted thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[F:14])[N:6]=1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:3][CH:4]=2)=[C:8]([F:14])[CH:9]=1
Reactant: CC(C)(N)CO
Reactant: Fc1cc(Br)ccc1-c1csc(Br)n1
Product: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2F)cs1
Temperature: 175 °C
Yield: 19.7 %

Procedure:
2-Bromo-4-(4-bromo-2-fluorophenyl)-1,3-thiazole (1.5 g, 4.4 mmol), prepared in the previous step, and 2-amino-2-methyl-1-propanol (2.5 mL, 26.7 mmol) were placed in a sealed tube and heated to 175° C. overnight. The reaction was concentrated under reduced pressure. The residue was purified on silica gel using a stepwise gradient of 5-40% ethyl acetate:hexane to give 2-{[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (0.3 g, 22%), MS (ES) m/z 346 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([CH2:19][CH:20]=[CH2:21])([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:5][CH:6]=[CH2:7]>CO.[Pd]>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:9])=[O:10])([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH3:7]
Reactant: C=CCC(CC=C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide (326 mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psi pressure for 4 hours. At the end, the reaction mixture was filtered and methanol was removed. The resulting solid was crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9 Hz, 2H), 7.76 (d,J=9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=2)O1>>[CH:12]1([C:4]2[N:3]=[C:2]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 48.3 %

Procedure:
Following general procedure G, 4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.245 g, 0.98 mmol) was reacted with methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.284 g, 0.98 mmol) to afford crude product (0.179 g) as an oil. MW=378.39. 1H NMR (CDCl3, 500 MHz) δ 7.26-7.22 (m, 4H), 7.16 (s, 1H), 4.13 (s, 2H), 3.70 (s, 1H), 3.62 (s, 2H), 3.42 (quin, J=8.2 Hz, 1H), 2.15-2.07 (m, 2H), 2.00-1.80 (m, 4H), 1.76-1.65 (m, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[S:7]([O-:10])([O-:9])=[O:8].[Na+:11].[Na+].O>COC(C)(C)C>[CH2:2]([S:7]([O-:10])(=[O:9])=[O:8])[CH2:3][CH2:4][CH:5]=[CH2:6].[Na+:11]
Reactant: O=S([O-])[O-]
Reactant: C=CCCCBr
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C=CCCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-Bromo-1-pentene (199.74 g), sodium sulfite (202.67 g), and water (650 ml) were mixed at room temperature. Under reflux, the solution was stirred for 19 hours. After cooling to room temperature, t-butyl methyl ether was added thereto. The aqueous layer separated was concentrated and dehydrated azeotropically with toluene. Thus, sodium 4-pentene-1-sulfonate (1) containing inorganic substances (387.51 g) was obtained as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:28]>>[CH:15]1([N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][C:27]#[N:28])=[CH:31][CH:32]=3)=[N:24][CH:25]=2)=[O:19])[CH2:16][CH2:17]1
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Product: N#CCc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and (4-cyanomethylphenyl)boronic acid following a procedure analogous to that described in Intermediate 6. LC (method 4): tR=0.85 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=1.Br[CH2:25][C:26]([CH3:28])=[CH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:27][C:26]([CH3:28])=[CH2:25])[CH:12]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=C(C)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
N-(3-Methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (34 mg, 0.11 mmol), 3-bromo-2-methylprop-1-ene (11 μl, 0.11 mmol), cesium carbonate (69 mg, 0.21 mmol) and DMA (210 μL) were combined in a vial and stirred at 100° C. for 1.25 hours. The reaction mixture was diluted with EtOAc, washed with aqueous sodium bicarbonate, then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude N-(3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine as a yellow oil. MS ESI calcd. for C19H19F3N5 [M+H]+ 374. found 374.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C.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>[CH3:9][C:4]1[N:3]=[C:2]([C:17]#[C:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2ccccc2)n1
Temperature: 0 °C
Yield: 46.7 %

Procedure:
To a solution of Cul (10 mg, 50 μmol) in triethylamine (5 ml) were added (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) and (PPh3)2PdCl2 (36 mg, 50 μmol). The reaction mixture was cooled to 0° C. and phenylacetylene (176 μl, 1.60 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated under reflux for 14 h. The solvent was evaporated and the crude residue was purified by flash chromatography (hexane/ethyl acetate 4:1) to yield 105 mg (0.50 mmol, 47%) of (6-methyl-2-phenylethynyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: C([O:4][C@@:5]1([CH2:36][CH3:37])[C:33]2[CH:32]=[C:31]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:20](=[O:26])[NH:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:34])[C:9]=2[CH2:8][O:7][C:6]1=[O:35])(=O)C.NN.Cl>CO>[CH2:27]([N:19]1[C:18]2=[C:13]3[CH2:12][N:11]4[C:31](=[CH:32][C:33]5[C@:5]([CH2:36][CH3:37])([OH:4])[C:6](=[O:35])[O:7][CH2:8][C:9]=5[C:10]4=[O:34])[C:14]3=[N:15][C:16]3[C:17]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[NH:21][C:20]1=[O:26])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN1C(=O)Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CCCCN1C(=O)Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of (9S)-9-acetoxy-1-butyl-9-ethyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-2,10,13(3H,9H,15H)-trione (11.5 mg, 0.023 mmol) in MeOH (3 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl). The mixture was warmed to room temperature and stirred for 1 hr. Aqueous 1 N HCl solution was added dropwise to acidify the reaction mixture and the mixture was stirred for 1 hr. at room temperature. After concentrated under reduced pressure, the obtaining residue was extracted with CH2Cl2 (20 ml×3). The combined CH2Cl2 solution was washed with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=30/1) to give pure product (6.1 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[Sn](C)(C)C.[OH:22][CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=2)[CH2:25]1>O1CCOCC1.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[C:33]1[CH:32]=[CH:31][C:30]([N:26]2[CH2:25][C@H:24]([CH2:23][OH:22])[O:28][C:27]2=[O:29])=[CH:35][CH:34]=1
Reactant: CC(=O)NCC1CC(c2ccc([Sn](C)(C)C)c(F)c2)=NO1
Reactant: O=C1O[C@H](CO)CN1c1ccc(I)cc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CC(=O)NCC1CC(c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3)c(F)c2)=NO1
Temperature: 90 °C
Reaction time: 16 h
Yield: 0.9 %

Procedure:
N-({3-[3-Fluoro-4-(trimethylstannyl)phenyl]-4,5-dihydroisoxazol-5-yl]methyl}acetamide (600 mg, 1.5 mmol), (5S)-5-(hydroxymethyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (319 mg, 1.0 mmol) and 2-trifurylphosphine (23 mg, 0.1 mmol) were dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture placed under an atmosphere of argon. Tris(dibenzylidineacetone)dipalladium (0) chloroform adduct (52 mg, 0.05 mmol) was added and the reaction mixture stirred for 16 hours at 90° C. Silica gel (0.5 g) was added and the mixture concentrated in vacuo. Purification by column chromatography (10 g silica gel bond elut: 0% to 5% methanoydichloromethane) yielded an off white solid. This was dissolved in dimethylsulphoxide (0.5 ml) and purified by reverse phase preparative HPLC using a gradient from 20% acetonitrile/water to 70% acetonitrile/water to give 3.7 mg of the desired compound.
Reaction SMILES: [CH:1]1([C:7](=[O:27])[CH:8]=[CH:9][CH:10]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH:11]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[CH:1]1([C:7](=[O:27])[CH2:8][CH2:9][CH:10]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH:11]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CCC1CCC2(OCCO2)C1CCCCCCCO)C1CCCCC1
Yield: 69.6 %

Procedure:
A solution of 7-(3-cyclohexyl-3-oxoprop-1-enyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (2.0 g.) in ethanol (50 ml.) was catalytically reduced with hydrogen at a pressure of 7 kg/cm2 and in the presence of a 5% palladium on charcoal catalyst (0.5 g.) at room temperature for 3 hours. The catalyst was then filtered off and the ethanol evaporated off from the filtrate, to give 7-(3-cyclohexyl-3-oxopropyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (1.4 g.), νmax 3450 cm-1, 1700 cm-1, 1040 cm-1.