Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[Br:31][C:32]1[CH:37]=[CH:36][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40]O)=[CH:34][CH:33]=1>C1C=CC=CC=1.O.C(OCC)(=O)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40][O:30][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(Br)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.500 g, 2.10 mmol) and (E)-3-(4-bromophenyl)-but-2-en-1-ol (0.454 g, 2.0 mmol) in dry benzene (20 ml), the mixture warmed to room temperature, and stirred for 2.5 days. The resulting mixture was diluted with water and ethyl acetate (50 ml each), the aqueous layer collected and further extracted with ethyl acetate (50 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica gel (20% ethyl acetate in n-heptane eluent) to give (E)-(S)-ethyl 3-{4-[3-(4-bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate as an oil; 0.780 g (87%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][OH:26])[CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:25]([C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([CH:2]=[O:1])[CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:26]
Reactant: CC(C)CN(CCCOc1cc(CO)cc(CO)c1)C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)CN(CCCOc1cc(C=O)cc(C=O)c1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
tert-Butyl (3-(3,5-bis(hydroxymethyl)phenoxy)propyl)(isobutyl)carbamate (0.29 g, 0.78 mmol) and CH2Cl2 (20 mL) were added to a round-bottom flask. To the solution was added PCC (0.42 g, 1.94 mmol) and the reaction was stirred for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (90% hexanes/EtOAc) afforded the desired product (0.15 g, 20% 3 steps) as a white semi-solid which was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Brc1cccc(N2CCCC2)n1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cccc(N4CCCC4)n2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-6-pyrrolidin-1-yl-pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](N)[CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].CI>OS(O)(=O)=O.CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:6])[C:9](=[O:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Br)ccn1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1ccc(Br)cc1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
A solution of 4-bromopyridin-2-amine (600 mg, 3.5 mmol) in a mixture of 2M H2SO4 (20 mL) and 2M Na2NO2 (10 mL) was stirred at 0-5° C. for 2 h. The reaction mixture was extracted with CH2Cl2, and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was used in next step without further purification. The crude product 15a, potassium carbonate (3.6 mmol) and methyl iodide (3.7 mmol) were refluxed in acetone (100 mL) in a sealed tube for 4 h. The reaction mixture was cooled, and potassium carbonate was filtered off. The acetone was evaporated off and a small amount of water was added to the residue. This solution was extracted with CH2Cl2. The organic layer was dried, concentrated and purified with column chromatography to afforded 17a (355 mg, 57%). 1H NMR (CDCl3,): δ 3.49 (s, 3H), 6.31 (d, J=6.0 Hz, 1H), 6.82 (s, 1H), 7.14 (d, J=6.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:19])[C:16](=[S:18])[S-:17].C[NH2+]C>C(=S)=S>[CH3:14][N:15]([CH3:19])[C:16](=[S:17])[S:18][CH:7]([CH2:8][N+:9]([O-:11])=[O:10])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: COc1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1

Procedure:
As in Example 17, reaction of p-methoxy-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave p-methoxy-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 86° C.-89° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: NCC1C=C(NC(=O)N(CCC2C=CC(C(NC3C=C4C(=CC=3)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C4)C(O)=O)=CC=2)C)C=CC=1S(CC)(=O)=O.[C:57]([O:61][C:62]([N:64]([C:105]([O:107][C:108]([CH3:111])([CH3:110])[CH3:109])=[O:106])[C:65]1[C:74]2[C:69](=[CH:70][C:71]([NH:75][CH:76]([C:80]3[CH:85]=[CH:84][C:83]([CH2:86][CH2:87][O:88][C:89](=[O:104])[NH:90][C:91]4[CH:96]=[CH:95][C:94]([S:97]([CH2:100][CH3:101])(=[O:99])=[O:98])=[C:93]([C:102]#[N:103])[CH:92]=4)=[CH:82][CH:81]=3)[C:77]([OH:79])=[O:78])=[CH:72][CH:73]=2)[CH:68]=[CH:67][N:66]=1)=[O:63])([CH3:60])([CH3:59])[CH3:58]>>[NH2:103][CH2:102][C:93]1[CH:92]=[C:91]([NH:90][C:89]([O:88][CH2:87][CH2:86][C:83]2[CH:84]=[CH:85][C:80]([CH:76]([NH:75][C:71]3[CH:70]=[C:69]4[C:74](=[CH:73][CH:72]=3)[C:65]([N:64]([C:105]([O:107][C:108]([CH3:109])([CH3:111])[CH3:110])=[O:106])[C:62]([O:61][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:63])=[N:66][CH:67]=[CH:68]4)[C:77]([OH:79])=[O:78])=[CH:81][CH:82]=2)=[O:104])[CH:96]=[CH:95][C:94]=1[S:97]([CH2:100][CH3:101])(=[O:99])=[O:98]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1C#N
Agent: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN
Reaction time: 15 h
Yield: 165.3 %

Procedure:
Using a procedure analogous to that used to prepare 25E, 26C (374 mg, 0.21 mmol) was hydrogenated for 15 h to give 26D (270 mg, 72%) as a yellow glass. MS (ESI) m/z 777.93 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[N:26]1([C:31](N)=[NH:32])C=CC=N1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:31]([NH2:32])=[NH:26])[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:23][CH:24]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(N)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (300 mg, 0.876 mmol), pyrazole-1-carboxamidine hydrochloride (0.128 g, 0.876 mmol.) and triethylamine (0.122 mL, 0.876 mmol) in DMF (2 mL) was stirred at rt for 3 hours. The precipitate was collected by filtration and washed with ether to afford the expected product. 1H NMR (DMSO-d6): δ 10.02 (1H, s), 7.93 (1H, s), 7.82 (2H, m), 7.70 (1H, s), 7.60(2H, br), 7.28 (2H, m), 5.20 (2H, s), 3.95 (2H, m), 3.38 (1H, m), 3.15 (2H, m), 2.09 (2H, m), 1.66 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:23]1[C:31]2[N:30]=[CH:29][NH:28][C:27]=2[C:26](=[O:32])[NH:25]/[C:24]/1=[N:33]\[NH2:34])[CH2:19][CH2:20][CH2:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[O:32]=[C:26]1[NH:25]/[C:24](=[N:33]\[NH:34][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[N:9]2)/[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:31]2[N:30]=[CH:29][NH:28][C:27]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)CCCn1cc(-c2ccccc2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCn1/c(=N/NC(=O)CCCn2cc(-c3ccccc3)cn2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of 4-(4-phenyl-1H-pyrazol-1-yl)butanoic acid (190 mg, 0.825 mmol), (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (195.0 mg, 0.825 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (401 mg, 0.908 mmol) and triethyl amine (0.23 ml, 1.65 mmol) in DMF (10 ml) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with water and then brine. The organic phase was dried over Na2SO4, filtered and concentrated to yield the desired product (369 mg, 99.7% yield) as yellowish oil. LCMS calculated for C23H29N8O2 (M+H): 449.2. Found: 449.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[N-:11]=[N+:12]=[N-:13].[Na+].[CH3:15]OC(OC)OC>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:15]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cnnn2)nc1
Temperature: 25 °C

Procedure:
The title compound was synthesized using 5-nitropyridin-2-amine (1 g, 6.97 mmol), sodium azide (0.68 g, 10.5 mmol), trimethylorthoformate (1.2 g, 11.2 mmol) and acetic acid (14 mL) and stirred at room temperature over night. The reaction was heated to 120° C. reflux for 7 hours. The reaction was cooled down to room temperature, concentrated to take off acetic acid. Ice water (50 mL) was added, extracted with ethyl acetate (50 mL), second wash with sodium hydroxide (1N, 20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 50 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 30% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH2:31])[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH:31][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c2ncccc12

Procedure:
A mixture of 6-bromo-9H-purine (0.0712 g, 0.358 mmol), 1-[8-(3-fluorophenyl)-5-methylquinolin-7-yl]ethanamine (0.050 g, 0.18 mmol), and N,N-diisopropylethylamine (0.0623 mL, 0.358 mmol) in ethanol (0.6 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product. LCMS calculated for C23H20FN6 (M+H)+: m/z=399.2; Found: 399.0.
Reaction SMILES: O[C:2]1[C:3]([O:9][S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:4]([I:8])[CH:5]=[CH:6][CH:7]=1.[C:20]1([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(#N)C.C(O)(=O)C>O>[S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([O-:12])(=[O:11])=[O:9].[CH2:27]([O:26][C:20]1[CH:21]=[CH:22][C:23]([I+:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[CH:24][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: CCCCCCCCOc1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCCCCCOc1ccc([I+]c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 40 °C

Procedure:
22.2 g (or 0.057 mol) of hydroxytosyloxyiodobenzene, 9 g (or 0.04 mol) of n-octyl phenyl ether, 5 ml of acetonitrile and 1.5 ml of acetic acid were charged into a 250 ml Erlenmeyer flask equipped with a magnetic stirrer bar. This mixture was stirred and was heated to a temperature of 40° C. for 2 hours, 30 minutes. 1.5 ml of glacial acetic acid was then added and the mixture was then maintained for 5 hours at 40° C. The reaction mixture was permitted to cool and 150 ml of water were added while stirring vigorously. This mixture was then stirred for 12 hours at room temperature and was then separated. The organic phase was washed several times with water, until a yellow precipitate appeared. This solid was recovered by filtration, was washed with 50 ml of ether and was then dried under vacuum at a temperature of 45° C.
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[CH3:26])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:12])=[O:11])(O)O.[C:27](=[O:30])([O-])[O-].[Na+].[Na+].[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:25][C:22]1[C:21]([CH3:26])=[C:20]([N:13]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[S:10]([C:5]2[C:4]([C:36]3[CH:37]=[CH:38][C:33]([C:39]4[CH:25]=[CH:22][CH:21]=[C:20]([O:30][CH3:27])[N:13]=4)=[CH:34][CH:35]=3)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:12])=[O:11])[O:24][N:23]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2cccc(OC)n2)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To 230 mg (0.87 mmol) of compound B, and 280 mg (0.73 mmol) of 2-Borono-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide in a mixture of 5.5 mL of degassed toluene and 3.7 mL of degassed ethanol, was added 84 mg (0.072 mmol) of tetrakis(triphenylphosphine) palladium(0) and 3.2 mL of degassed 2N aqueous sodium carbonate. The mixture was stirred at 85° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and then brine, dried (magnesium sulfate) and evaporated. Flash chromatography (50 mm×6"; 30% to 40% to 50% ethyl acetate/hexane) afforded 172 mg of an oily-solid residue (45%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:18]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH3:19]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH2:18][CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: CCc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1CC
Yield: 71.6 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2-ethylaniline (1.85 ml, 15 mmol) and 1,4-dioxan (10 ml) were stirred at room temperature overnight then heated at reflux for 30 minutes. The solvent was evaporated, the residue converted to free base and recrystallised from aqueous ethanol to give 3-butyryl-4-(2-ethylphenylamino)-8-methylquinoline (2.38 g), m.p. 117°-119°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH2:20](OCC)[CH3:21].[C:25]1([Mg]CC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-]>O>[C:14]1([C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=2[NH2:1])=[CH:20][CH2:21][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC[Mg]c1ccccc1
Reactant: CCOCC
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Agent: [Cl-]
Solvent: O
Product: Nc1c(C(=CCc2ccccc2)c2ccccc2)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
(2-Amino-3-trifluoromethyl-phenyl)-phenyl-methanone (0.26 g, 1.0 mmol) was taken into diethyl ether (20 mL) and phenyl ethyl magnesium chloride (1.5 mL, 1.5 mmol, 1.0 M solution in diethyl ether) was added dropwise and stirred at room temperature for 1 hour. The reaction was poured into water/saturated ammonium chloride solution and extracted with diethyl ether. The combined organics was dried over MgSO4 and concentrated. The material was purified via column chromatography using 0˜10% ethyl actetate in hexane as the eluent to yield 0.08 g (22%) of 2-(1,3-diphenyl-propenyl)-6-trifluoromethyl-phenylamine as an oil. MS ESI (m/z) 354.3 ([M+H]+);
Reaction SMILES: CN(C=O)C.O=P(Cl)(Cl)[Cl:8].[OH:11][C:12]1[CH:17]=[C:16](O)[N:15]=[CH:14][N:13]=1.CC(C)=O.[CH2:23]([Cl:25])Cl>>[Cl:8][C:16]1[C:17]([CH:12]=[O:11])=[C:23]([Cl:25])[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(O)ncn1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=Cc1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Charge DMF (8.9 mL, 1.3 eq) in a round bottom flask and cool to 0° C. Add POCl3 (32.6 mL, 4.0 eq) to the reaction drop wise at 0° C. Stir the reaction mass at 0° C. for 1 h. Charge 4,6-dihydroxy pyrimidine (10.0 g, 1.0 eq) to the reaction mass and allowed it to come to room temperature slowly. Reflux the reaction mass for 4 h and monitor the reaction by TLC (10% acetone in DCM). Concentrate the reaction mass under vacuum and pour the concentrated reaction mass over crushed ice. Extract the product with diethyl ether and wash with saturated aq. sodium chloride. Dry the organic layer over anhydrous sodium sulfate and concentrate it under vacuum to get pale yellow solid as product (6.2 g, 40%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a solution of 128 (0.55 g; 1.46 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added aqueous sodium hydroxide (20 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as a gray solid (0.39 g).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:7][CH2:6][CH:5]([C:8]([CH3:10])=[CH2:9])[C:4]=1[CH2:11]Cl.[C:13](=[O:15])=[O:14].Cl.[Na]>O1CCCC1.CCOCC>[C:8]([CH:5]1[CH2:6][CH2:7][C:3]([CH3:2])([C:13]([OH:15])=[O:14])[C:4]1=[CH2:11])([CH3:10])=[CH2:9]
Reactant: C=C(C)C1CCC(C)=C1CCl
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C1CCC(C)(C(=O)O)C1=C
Temperature: -10 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
75 ml of dry tetrahydrofuran and 23 g of magnesium shavings are added to a round flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. Without stirring there is added thereto slowly (within 4 hours) a solution of 112.4 g of 1-methyl-2-chloromethyl-3-(prop-1-en-2-yl)-cyclopent-1-ene in 100 ml of tetrahydrofuran. The mixture is brought to 60°-65° for 1 hour and then cooled to -10°. A carbon dioxide stream is conducted through the solution, which is cooled to -10° C. The amount of carbon dioxide introduced is weighed; it amounts to 29.5 g. The mixture is left to stand at room temperature overnight. The mixture is then cooled to 10° C. and decomposed with 300 ml of a 10% hydrochloric acid solution. The acid solution is extracted with ether, the organic acid formed is taken up as the sodium salt (treatment with 10% sodium hydroxide) from the ether into the aqueous phase, which is washed with ether. After acidifying with 10% orthophosphoric acid, the mixture is extracted with ether and the etherial solution is dried over sodium sulphate. The solvent is evaporated and there are obtained 78.2 g (yield: 66%) of crude 3-isopropenyl-2-methylene-1-methyl-cyclopentanecarboxylic acid, which are recrystallized with hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH2:29]>C(O)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:29][CH3:28])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: CN
Solvent: CCO
Product: CNCCc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (500 mg, 1.29 mmol, Example 56, Step D) in 29% methylamine in ethanol solution (6 mL) was stirred at room temperature overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was triturated with diethyl ether to give 410 mg (99%) of the desired product as a white foam: mp 65-68° C.; MS(APCI+): m/z 323.1 (MH+); Anal. Calcd for C20H22N2O2.0.5H2O: C, 72.48; H, 7.00; N, 8.45. Found: C, 72.21; H, 6.85; N, 8.34.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]([N:12]([C:25](=[O:28])[CH2:26][CH3:27])[C:13]1[C:18]([I:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[S:21](O)(=[O:23])=[O:22])[CH2:10][CH3:11].P(Cl)(Cl)(Cl)(Cl)[Cl:30].CCOCC>ClCCl>[O:8]=[C:9]([N:12]([C:25](=[O:28])[CH2:26][CH3:27])[C:13]1[C:18]([I:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[S:21]([Cl:30])(=[O:23])=[O:22])[CH2:10][CH3:11]
Reactant: CCC(=O)N(C(=O)CC)c1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)N(C(=O)CC)c1c(I)cc(Br)cc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 32.5 g (55 mmol) of the N,N-diethylethanamine salt of 2-[bis(1-oxopropyl)amino]-5-bromo-3-iodobenzenesulphonic acid in dichloromethane are added portionwise, at 0° C. under nitrogen, 16.8 g (82.4 mmol) of phosphorus pentachloride. The mixture is allowed to warm to room temperature and is heated for 4 hours at the reflux temperature. 200 ml of ether are poured in, the mixture is filtered and the filtrate is concentrated. The residue is purified by chromatography on a column of florisil™ eluting with an ether/hexane mixture (2/8). The product is recrystallized from an ether/pentane mixture. 12 g of product are obtained in the form of white crystals.