Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[N:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]3[O:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23][C:11]=23)=[CH:4][CH:3]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>>[CH2:26]([N:8]([CH2:9][C:10]1[CH:15]=[N:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]2[O:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23][C:11]=12)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ncc(CNc2ccc(F)cc2)c2c1OC(C)(C)OC2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)c1ncc(CN(Cc2ccccc2)c2ccc(F)cc2)c2c1OC(C)(C)OC2

Procedure:
Methyl 5-((benzyl(4-fluorophenyl)amino)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate 25a was prepared from methyl 5-((4-fluorophenylamino)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (21a) (120 mg, 0.3 mmol), benzaldehyde (100 uL, 1.0 mmol) and sodium cyanoborohydride (28 mg, 0.45 mmol) according to the procedure described in Example 24. MS-ESI m/z 437 [MH]+.
Reaction SMILES: FC1C(O[C:9]([C:11]2[N:12]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)=[O:10])=C(F)C(F)=C(F)C=1F.S(=O)(=O)(O)O.[NH2:32][CH2:33][C:34]#[N:35].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:33]([CH2:34][NH:35][C:9]([C:11]1[N:12]([CH2:19][CH:20]2[CH2:21][CH2:22]2)[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)=[O:10])#[N:32]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc([N+](=O)[O-])cn1CC1CC1
Reactant: N#CCN
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCNC(=O)c1cc([N+](=O)[O-])cn1CC1CC1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of compound 278 (3.6 g, 9.57 mmol), aminoacetonitrile bisulfate (2.94 g, 19.12 mmol) and N,N-diisopropylethyl-amine (3.5 ml) in DMF (60 ml) was stirred under Ar at 55° C. for 16 h. After evaporation of solvent, the residue was separated by chromatography on silica gel eluted by CHCl3-ethyl acetate (10:1) to give g of compound 279. MS (ESI) 247.12 (M−H+). H1-NMR (DMSO-d6) 9.16 (t, 1H), 8.26 ((d, 1H), 7.49 (d, 1H), 4.28 (d, 2H), 4.23 (d, 2H), 1.30–1.28 (m, 1H), 0.50–0.46 (m, 2H), 0.41−0.38 (m, 2H).
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1.[Cl:35][C:36]1[N:41]=[C:40](Cl)[C:39]([F:43])=[CH:38][N:37]=1>>[Cl:35][C:36]1[N:41]=[C:40]([NH:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[C:39]([F:43])=[CH:38][N:37]=1
Reactant: NCc1cccnc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Fc1cnc(Cl)nc1NCc1cccnc1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-pyridylmethylamine (162 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) reacted to give 5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 43%). 1H NMR (CD3OD): δ 4.71 (s, 2H), 6.38 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 6.88 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J=8.1 Hz, 1H), 7.14 (t, J=2.4 Hz, 1H), 7.37 (dd, J=4.8 and 7.8 Hz, 1H), 7.73 (d, J=3.6 Hz, 1H), 7.87 (dt, J=2.1 and 7.5 Hz, 1H), 8.39 (dd, J=1.2 and 7.8 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −170.99; LCMS: ret. time: 8.82 min.; purity: 92.90%; MS (m/e): 312.05 (MH+).
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.Cl.[CH2:15]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CO>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[CH:28][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC(Nc1ccc(OCc3ccccc3)cc1)C2
Yield: 68.3 %

Procedure:
A solution of 977 mg (S.54 mmol, Aldrich) of 6-methoxy-2-tetralone, 1.30 g (5.54 mmol, Aldrich) of 4-benzyloxyaniline hydrochloride and 174 mg (2.77 mmol, Aldrich) of NaBH3CN in 30 ml of MeOH was stirred at 25° C. over 3A molecular sieves for 1.75 hour. The mixture was filtered, saturated NaHCO3 was added and this was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo. Purification via flash chromatography (silica gel, 1:8 EtOAc/petroleum ether) afforded 1.36 g (69%) of title compound as a deep red oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1>>[CH3:24][O:23][C:21]([C:18]1[S:17][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:20][CH:19]=1)=[O:22]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: COC(=O)c1cnc(Br)s1
Product: COC(=O)c1cnc(C#Cc2c(-c3ccccc3)noc2C)s1
Yield: 86 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using methyl 2-bromothiazole-5-carboxylate instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 139 mg, 86%) which was obtained as a light yellow solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:26]([F:29])([F:28])[F:27].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:26]([F:27])([F:28])[F:29])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:30])([F:1])[F:31])[CH:20]=1)=[O:41]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1cccc(-c2c(-c3ccccc3C(F)(F)F)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(-c3ccccc3C(F)(F)F)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from {3-[3-(2-trifluoromethylphenyl)-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chlorophenyl isocyanate in substantially the same manner as described in Example 65; off-white solid: mp 230-232° C.; MS (EI) m/z 587(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=O)[NH:15][N:16]=2)[N:13]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:14]1[N:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.0 g, 2.8 mmol) in phosphorus oxychloride (10 mL) was stirred at 130° C. for 6 h. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with CH2Cl2, the resulting solution washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g (100%) of the title compound as an off-white solid. HPLC/MS (method A): retention time=3.52 min, (M+H)+=375.0.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2[CH:11]=CC=C[C:9]=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[C:44]3=[N:45][CH:46]=[C:47]([S:48]([N:51]4[CH2:54][CH2:53][C@H:52]4[C:55](O)=[O:56])(=[O:50])=[O:49])[N:43]3[C@:42]([CH3:71])([CH2:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]4[CH:66]=[N:67][CH:68]=[N:69][CH:70]=4)=[CH:61][CH:60]=3)[C:41]2=[O:72])[CH:36]=[C:37]([Cl:39])[CH:38]=1.C(N)(C)C.[NH4+].[Cl-]>C(Cl)Cl>[CH:10]([NH:6][C:55]([C@@H:52]1[CH2:53][CH2:54][N:51]1[S:48]([C:47]1[N:43]2[C@:42]([CH3:71])([CH2:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]4[CH:70]=[N:69][CH:68]=[N:67][CH:66]=4)=[CH:61][CH:60]=3)[C:41](=[O:72])[N:40]([C:35]3[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=3)[C:44]2=[N:45][CH:46]=1)(=[O:50])=[O:49])=[O:56])([CH3:11])[CH3:9]
Reactant: C[C@@]1(Cc2ccc(-c3cncnc3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CC[C@H]3C(=O)O)n21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)[C@@H]1CCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 18 h

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium tetrafluoroborate (0.016 g), (i-Pr)2EtN (0.013 mL) and (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-azetidine-2-carboxylic acid (0.023 g, 0.04 mmol) were combined in CH2Cl2 (2 mL) at room temperature. Isopropyl amine (0.0064 mL) was then added and the reaction was stirred for 18 h. The reaction was diluted with CH2Cl2 and poured into saturated aqueous NH4Cl.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)#[N:8].O.[OH-].[K+]>CCOCC>[NH2:8][CH2:7][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)[CH2:16][CH2:17]1
Reactant: N#CCCCN1CCN(c2ncccn2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: NCCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold mixture of lithium aluminum hydride (2.0 g; 5.26 mmol) and anhydrous ether (240 ml) kept at a temperature of -54° C., there was dropwise added a solution of 1-(3-cyanopropyl)-4-(2-pyrimidinyl)piperazine (8 g; 3.46 mmol) in anhydrous ether (80 ml), and the resultant mixture was kept at the same temperature as above for 1.5 hours, followed by dropwise addition of water (2 ml), a 15% aqueous potassium hydroxide solution (2 ml) and water (6 ml) in order. The reaction mixture was stirred at room temperature for 2 hours, subjected to filtration with celite and washed with chloroform. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 1-(4-aminobutyl)-4-(2-pyrimidinyl)-piperazine. IR νmaxFilm (cm--1): 3100-3600, 1580, 1540.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])C.[Br-].[CH:14]1([Zn+])[CH2:17][CH2:16][CH2:15]1.C1(C2C(C(O)=O)=CC=CC=2)CCCC1>>[CH:14]1([C:8]2[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: [Zn+]C1CCC1
Agent: O=C(O)c1ccccc1C1CCCC1
Agent: [Br-]
Product: O=C(O)c1cccc(C2CCC2)n1

Procedure:
This intermediate was prepared from ethyl-6-bromo-2-pyridinecarboxylate and cyclobutylzinc bromide in two steps according to the preparation of 6-cyclopentyl-benzoic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:24][C:13]1[N:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:15]2[C:11]([N:12]=1)=[C:10]([NH2:23])[N:9]=[C:8]([O:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[N:16]=2
Reactant: Nc1nc(OCC2CCCO2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Nc1nc(OCC2CCCO2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 1 °C
Reaction time: 0.5 h

Procedure:
2-[(Tetrahydro-2-furanylmethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.7202 g) was dissolved in chloroform (15 mL) and cooled to ˜1° C. before N-bromosuccinimide (1.056 g) was added keeping the reaction temperature below 2° C. The reaction mixture was then stirred at ˜1° C. for 30 minutes before allowing to warm to room temperature were upon the reaction mixture was stirred for 3 hours. The reaction mixture was then stood overnight at room temperature before being partitioned between water (50 mL) and the organic phase separated using a hydrophobic frit. The organic phase was evaporated under reduced pressure to give a brown gum which was purified using silica chromatography (ISCO) eluting with 0-100% ethyl acetate: cyclohexane. This gave the title compound as a white foam solid (1.3748 g).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:28][C:9]1[C:10]([F:27])=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][C:5]1[N:24]([CH2:25][CH3:1])[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:16])[C:14]=1[CH:13]=2
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(CC)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reaction time: 2 h
Yield: 85.1 %

Procedure:
16 g of ethylamine are added, in the course of 5 minutes, at between 10° and 15° C., to a stirred suspension of 13.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 135 cm3 of ethanol, the temperature is allowed to rise to about 20° C., 0.5 g of DBU is added and the mixture is heated, with stirring, for 2 hours at a temperature close to 75° C. After cooling to a temperature close to 20° C., the precipitate is drained and washed with twice 100 cm3 of ethanol and twice 100 cm3 of diethyl ether. 10.4 g of 8-chloro-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 300°-301° C., which is used for the subsequent steps without further purification.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1>O1CCCC1>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: O=C(Oc1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
4-Benzoyloxy-4'-benzoylbiphenyl [compound (11)] in Example 12 was added to an alkali-containing tetrahydrofuran followed by stirring at room temperature for several hours. After completion of the reaction, the tetrahydrofuran solution was concentrated to obtain 4-hydroxy-4'-benzoylbiphenyl [compound (31)]. The results are shown in Table 8.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([CH3:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[O:9])=[C:6]([C:22]([F:25])([F:24])[F:23])[N:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34]1[C:35]([CH:40]=O)=[N:36][CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:26]([O:33][C:34]1[C:35]([CH:40]2[NH:1][C:2]3[CH:3]=[CH:4][N:5]=[C:6]([C:22]([F:25])([F:24])[F:23])[C:7]=3[C:8](=[O:9])[N:10]2[CH:11]([CH3:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[N:36][CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(Cc1ccc(F)c(F)c1)NC(=O)c1c(N)ccnc1C(F)(F)F
Reactant: O=Cc1ncccc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(F)c(F)c1)N1C(=O)c2c(ccnc2C(F)(F)F)NC1c1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
4-amino-N-(1-(3,4-difluorophenyl)propan-2-yl)-2-(trifluoromethyl)nicotinamide (3.61 g, 10.05 mmol) and 3-(benzyloxy)picolinaldehyde (2.57 g, 12.1 mmol) were combined along with a catalytic amount of 4-toluenesulfonic acid (0.03 g, 0.20 mmol) in anhydrous toluene (150 mL). This was heated at reflux overnight in a round bottom flask fitted with a Dean-Stark trap. The resultant dark solution was cooled to room temperature, concentrated in vacuo to a dark brown oil. This oil was purified by silica gel column chromatography using 30% acetone/hexanes as eluant to provide the product diastereomers as an oil (4.61 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (m, 1H), 8.0 (m, 1H), 7.3-7.6 (m, 7H), 5.15 (d, 2H), 3.0 (dd, 1H), 2.8 (m, 1H), 1.25 (d, 3H). MS m/z 555.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1[S:9][C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:4].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[CH2:56][N:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:19][N:2]([CH3:1])[C:3]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:51]3[CH2:55][CH2:54][CH2:53][C@H:52]3[CH2:56][N:57]3[CH2:61][CH2:60][CH2:59][CH2:58]3)=[O:16])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CN(C)C(=O)c1ccc(-c2ccc(C(=O)O)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1
Yield: 81 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 10% DMF/dichloromethane using 4-(5-dimethylcarbamoyl-thiophen-2-yl)-benzoic acid (88 mg, 0.32 mmol), EDC-HCl (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol), DIEA (0.14 mL, 0.80 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (46 mg, 0.30 mmol) to give the title compound (100 mg, 81% yield). MS (ES+) 412.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 102 mg of 4-ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.94 (t, 3H, J=7.6 Hz), 2.38 (q, 2H, J=15.2 Hz, 7.6 Hz), 6.94 (d, 2H, J=6.8 Hz), 7.16 (m, 2H), 7.23 (m, 1H), 7.30 (m, 4H), 8.60 (b, 2H), 9.73 (b, 1H). MS: m/z 401.1 (M++1).
Reaction SMILES: [O-2].[O-2].[O-2].[Al+3].[Al+3].[N+:6]([O-:9])([OH:8])=[O:7].O=[Ce:11]=O>[N+]([O-])([O-])=O.[Pd+2].[N+]([O-])([O-])=O.[Pd]>[N+:6]([O-:9])([O-:8])=[O:7].[Ce+3:11].[N+:6]([O-:9])([O-:8])=[O:7].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=[Ce]=O
Agent: [Pd+2]
Agent: [Pd]
Agent: O=[N+]([O-])[O-]
Product: [Ce+3]

Procedure:
A quantity of 700 grams of gamma alumina powder having a surface area of 150 square meters per gram (150 m2 /g) was impregnated with an aqueous palladium nitrate solution containing 31.9 grams of palladium. All 31.9 grams of palladium were impregnated. The palladium containing alumina, a nitric acid stabilized colloidal dispersion of ceria containing 300 grams CeO2 (Note: The average CeO2 particle size is about 100 angstrom. This is not bulk ceria.), cerium nitrate crystals in an amount sufficient to form 500 grams CeO2,lanthanum nitrate crystals in an amount sufficient to form 100 grams La2O3, barium acetate crystals in an amount sufficient to form 60 grams BaO, zirconium acetate solution in an amount sufficient to form 140 grams ZrO2 and 500 grams of co-formed ceria-zirconia powder (surface area 50 m2 /g containing 20 wt % CeO2) were ballmilled with acetic acid to form a slurry. The slurry was further mixed with 70 grams of pre-milled NiO particles in water to form a washcoat layering slurry containing about 48 percent by weight of solids. A monolith support of cordierite containing about 400 flow passages per square inch of cross section was dipped into the washcoat slurry. The excess was blown off the monolith by compressed air. The resultant catalyzed monolith after being calcined at 450° C. contained 55 g/ft3 palladium, 0.7 g/in3 alumina, 0.8 g/in3CeO2, 0.1 g/in3La2O3, 0.14 g/in3ZrO2, 0.06 g/in3BaO, 0.5 g/in3 ceria-zirconia composite and 0.07 g/in3NiO.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[C:24]1([P:30](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][P:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:31])[CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc2[nH]nc(C=Cc3ccccc3)c2c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: O=P(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 70 mg of 3-styryl-1H-indazol-5-ol, 300 mg of imidazole and of 273 μl of diphenylphosphinyl chloride in 15 ml of dichloromethane is stirred at ambient temperature. After stirring for approximately 90 minutes, the medium is treated with 30 ml of distilled water. The aqueous phase is extracted twice with 30 ml of dichloromethane and the organic phases are then dried over magnesium sulfate, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude is taken up with ethyl acetate. The solid is filtered through sintered glass, and rinsed with ethyl ether. The filtrate is concentrated under reduced pressure in a rotary evaporator, and purified by flash chromatography on silica 35-70 μm. Eluent: cyclohexane/ethyl acetate gradient of 80:20 to 70:30. 143 mg of a yellow solid are collected. This compound is purified by preparative LC/MS to obtain 47.3 mg of diphenylphosphinic acid 3-((E)-styryl)-1H-indazol-5-yl ester.
Reaction SMILES: [CH2:1]([O:6][CH:7]([C:9]1[CH2:11][CH:10]=1)C)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:12]C(COCCCCCC)=C.C(OCC1CC=1)CCCCC>>[Br:12][C:10]([CH2:9][CH2:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH2:11]
Reactant: C=C(Br)COCCCCCC
Reactant: CCCCCOC(C)C1=CC1
Agent: CCCCCCOCC1=CC1
Product: C=C(Br)CCOCCCCC

Procedure:
This olefin was converted to 1-pentyloxyethyl-cyclopropene in the same manner that 2-bromo-3-hexyloxypropene was converted to 1-hexyloxymethyl-cyclopropene.
Reaction SMILES: O1CCN([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)CC1.[CH2:49]([OH:51])[CH3:50]>>[CH2:49]([O:51][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]2[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=3)[CH:32]=[CH:31][N:30]=2)[CH:8]=1)[CH3:50]
Reactant: CCO
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CCOc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 14, using ethanol in place of morpholine. 1H-NMR (300 MHz, DMSO, ppm): δ 12.49 (s, 1H), 9.57 (m, 1H), 8.98-8.96 (m, 1H), 8.41-8.38 (m, 2H), 7.88-7.54 (m, 10H), 7.16-7.10 (m, 2H), 4.63 (m, 2H), 4.14-4.12 (m, 2H), 3.88 (s, 2H), 2.60-2.58 (m, 2H), 1.37-1.35 (t, J=3 Hz, 3H). MS (ES, m/z): 638 [M+H]+.