Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]2([C:42]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=3[CH2:43][NH2:44])[N:36]([C:45]3[C:46]4[CH:53](CC)[CH2:52][CH2:51][C:47]=4[N:48]=[CH:49][N:50]=3)[CH2:35]2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:56][C:57]([CH3:59])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N)(C)C>ClCCCl>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]2([C:42]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=3[CH2:43][NH:44][CH:57]([CH3:59])[CH3:56])[N:36]([C:45]3[C:46]4[CH:53]([CH2:2][CH3:3])[CH2:52][CH2:51][C:47]=4[N:48]=[CH:49][N:50]=3)[CH2:35]2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)=O
Reactant: CCC1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)N
Solvent: ClCCCl
Product: CCC1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(C)C)cccc43)c21
Reaction time: 1 h
Yield: 18 %

Procedure:
(1′-Benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine tris(2,2,2-trifluoroacetate) (606 mg, 0.762 mmol) was stirred in a solution of acetone (0.280 mL, 3.81 mmol) and DCE (5 mL) for 15 minutes. NaBH(OAc)3 (323 mg, 1.52 mmol) was added in one portion and resulted in vigorous evolution of gas. After 1 hour at room temperature, LCMS suggested complete conversion to the desired isopropylamine. The reaction was concentrated and partitioned between EtOAc and 10% aqueous K2CO3. The organic was washed with brine, dried over Na2SO4 and concentrated to a crude residue. The racemic crude was purified by silica gel chromatography (gradient: 5-100% (80 DCM: 19 MeOH: 1 NH4OH)/DCM). Purification provided N-((1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (68 mg, 0.137 mmol, 18.0% yield) as an oil. 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.27-7.33 (m, 5H), 7.24 (m, 1H), 7.18 (t, 1H), 6.96 (d, 1H), 3.95 (m, 411), 3.54 (s, 2H), 3.27 (m, 1H), 2.84-2.99 (m, 5H), 2.63 (dt, 1H), 2.03-2.31 (m, 4H), 1.86 (m, 1H), 1.70 (dd, 2H), 1.42 (m, 2H), 1.15-1.119 (m, 7H), 0.78 (t, 3H). MS (APCI+) [M+H]: 496.3. Separation of isomers was conducted by preparative HPLC using a Chiralpak AD-H column (4.6×100 mm) The compound was eluted with 25% methanol/water (0.1% TEA additive) at 3 mL/min and 120 bars.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Br:17][C:18]1[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].Cl>N1C=CC=CC=1>[Br:17][C:18]1[CH:19]=[C:20]([S:26]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Br
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5.0 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 5.2 g of 3-bromo-4-methoxy-benzene-sulfonyl chloride was stirred for 3 hours with 20 ml of pyridine. The resulting, red colored suspension was poured into 300 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 300 ml of ethanol and 200 ml of 2N sodium hydroxide solution. After the addition of 4.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 4.4 g of 3-bromo-4-methoxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide separated as yellow crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [C:1]([O:4][C:5]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH:7]=[CH2:8])[CH3:6])(=[O:3])[CH3:2].[Cl:15][O-].[Ca+2].Cl[O-].O.C(=O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:6])([CH2:9][CH2:10][CH:11]([Cl:15])[C:12]([CH3:14])=[CH2:13])[CH:7]=[CH2:8])(=[O:3])[CH3:2]
Reactant: [O-]Cl
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: O=C=O
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: C=CC(C)(CCC(Cl)C(=C)C)OC(C)=O
Temperature: 10 °C
Reaction time: 1 h
Yield: 177.7 %

Procedure:
A stirred mixture of linalyl acetate (39 g, 0.2 mol), 65% calcium hypochlorite (22 g, 0.1 mol), water (70 mL) and dichloromethane (700 mL) was cooled to 10° C. and solid carbon dioxide was added until an exotherm was no longer observed upon addition. After stirring for an additional 1 h at 10° C., the organic layer was separated and washed successively with a solution containing 5% sodium bicarbonate and 1% sodium bisulfite (100 mL), and then with brine (100 mL). The organic layer was dried, the solvent evaporated, and the residue distilled to yield 41 g of 3-acetoxy-6-chloro-3,7-dimethyl-1,7-octadiene, bp 75°-80° C. (0.5 mm). IR (film) 1740, 1370, 1250, 920 cm-1. NMR (CDCl3) δ1.53 (3H, s), 1.8 (3H, bs), 1.8-2.4 (2H, m), 4.33 (1H, m), 4.84-5.33 (4H, complex) 6.0 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.ClC1N=C(N2CCOCC2)C2SC=CC=2N=1.C(OC(C1SC=C(C)C=1N)=O)C.[Li]CCCC.[I:51]I>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:5]2[S:10][C:9]([I:51])=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: II
Reactant: Cc1csc2c(N3CCOCC3)nc(Cl)nc12
Agent: CCOC(=O)c1scc(C)c1N
Agent: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: -40 °C
Reaction time: 0.83 h
Yield: 84 %

Procedure:
To a solution of 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (3.0 g, 11.1 mmol; prepared according to the procedure for the synthesis of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine but commencing with 3-amino-4-methyl-thiophene-2-carboxylic acid ethyl ester) in THF (60 mL) at −78° C. was added n-BuLi (8.9 mL, 2.5 M in Et2O). The resulting slurry was warmed to −40° C. and stirred 50 min. The reaction mixture was then cooled to −78° C. and a solution of I2 (5.6 g, 22.2 mmol) in THF (30 mL) was added. The solution was warmed to room temperature and stirred 5 h. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous Na2S2O3, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (3.8 g, 84% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:7][CH:8]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26].C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:16][C:15]1[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[N:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1csc(Nc2ncccc2OCc2ccccc2)n1)Nc1ccccc1
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Crude 4-(2-aminoethyl)-N-(3-(benzyloxy)pyridin-2-yl)thiazol-2-amine (Example 134, Step A; 0.25 g, 0.766 mmol) was dissolved in DMF (10 mL), and 1-isocyanatobenzene (0.182 g, 1.53 mmol) was added. The reaction mixture was stirred for 2 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 2:3 hexane:ethyl acetate to afford the title compound (0.122 g, 35.8% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 2.75 (t, 2H), 3.42 (q, 2H), 5.27 (s, 2H), 6.19 (t, 1H), 6.70 (s, 1H), 6.86-6.91 (m, 2H), 7.20 (t, 2H), 7.34-7.43 (m, 6H), 7.58 (d, 2H), 7.87 (d, 1H), 8.48 (s, 1H), 9.94 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[N:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[N:8][CH:9]=2)[S:1][CH:2]=1
Reactant: BrBr
Reactant: c1cc2cnncc2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1csc2cnncc12
Temperature: 90 °C
Yield: 28.5 %

Procedure:
A solution of thieno[2,3-d]pyridazine (468.0 mg, 3.437 mmol) and sodium acetate (879.2 mg, 10.50 mmol) in acetic acid (14 mL) was charged with bromine (0.55 mL, 11 mmol) and then irradiated under microwave heating at 90° C. for 3 h. The reaction mixture was concentrated in vacuo. Purification by ISCO chromatography (1 to 15% methanol:dichloromethane) afforded 210.6 mg (27%) of the title compound as a pink solid. 1H NMR (400 MHz, DMSO-d6): δ 9.96 (d, J=1.52 Hz, 1H), 9.53 (d, J=1.52 Hz, 1H), 8.51 (s, 1H); MS (ESI): 214.97, 216.92 [M+H]+; HPLC tR=2.68 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([C:7]1[CH:8]=[C:9]([NH:13]C(CC2C=CN3C=2CSC3C2C=NC=CC=2)=O)[CH:10]=[CH:11][CH:12]=1)=[O:6].CC1C=C(C(=O)C2C=CC=C([N+]([O-])=O)C=2)C=CC=1.Cl>C(O)C>[NH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:5]([C:4]1[CH:31]=[CH:32][CH:33]=[C:2]([CH3:1])[CH:3]=1)=[O:6]
Reactant: Cc1cccc(C(=O)c2cccc(NC(=O)Cc3ccn4c3CSC4c3cccnc3)c2)c1
Agent: Cc1cccc(C(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
The 3-amino-3'-methylbenzophenone may be prepared as follows: stannous chloride in the dihydrate form(19 g) is added, at a temperature between 40° and 80° C., to a suspension of 3'-methyl-3-nitrobenzophenone (6.8 g) in a mixture of ethanol (80 cc) and concentrated hydrochloric acid (30 cc), in the course of 10 minutes. The solution obtained is heated at a temperature in the vicinity of 85° C. for 3 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is suspended in distilled water (300 cc). An aqueous 10N sodium hydroxide solution (100 cc) is added, at a temperature in the vicinity of 20° C., with stirring, to the suspension obtained and extraction is carried out 3 times with diethyl ether (550 cc in total). The ether extracts are combined, washed twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. 3-Amino-3'-methylbenzophenone (5.7 g) in the form of yellow crystals, m.p. 110° C., is thereby obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12](I)=[C:8]3[N:7]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:24]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)#[CH:25]>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:25]#[C:24][C:26]4[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=4)=[C:8]3[N:7]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Reactant: C#Cc1cnc(N)nc1
Product: Nc1ncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-iodo-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7 step 4) (215 mg, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2 step 2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (59 mg, 28%). MS (ISP) 421.1 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:26][CH2:27][CH2:28][CH2:29]I>CCOC(C)=O.CCCCCC>[Cl:26][CH2:27][CH2:28][CH2:29][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:14])([F:15])[F:1])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: ClCCCI
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)C(CCCCl)c1ccc(OC(F)(F)F)cc1
Yield: 10.1 %

Procedure:
Step AAK (1): 2-(4-(Trifluoromethoxy)phenyl)acetic acid (3.54 g, 16.1 mmol) was deprotonated with NaHMDS (2.0 M in THF, 18.1 mL, 36.2 mmol) and reacted with 1-chloro-3-iodopropane (3.62 g, 17.7 mmol) using a procedure analogous to Step AC (1) to afford after purification by silica gel column chromatography (25-50% EtOAc/hexane), 5-chloro-2-(4-(trifluoromethoxy)phenyl)pentanoic acid (0.48 g, 1.62 mmol, 10% yield) as a pale-yellow oil. LC-MS (M−H)− 295.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[NH:16][NH2:17]
Reactant: NN
Reactant: Fc1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Solvent: CCO
Solvent: O
Product: NNc1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
470 g (1.87 mol) of 3,5-dichloro-2,4-difluorobenzotrifluoride are initially introduced in 1000 ml of ethanol, 142 g (2.84 mol) of hydrazine hydrate are metered in, and the mixture is subsequently heated to reflux for 3 hours. The solvent is then removed by distillation under reduced pressure, and the residue is stirred into 1000 ml of cold water. After 30 minutes, the solid product is filtered off with suction and dried in a circulation dryer. 445 g (90% of theory) of 2,6-dichloro-3-fluoro-4-trifluoromethyl-phenylhydrazine of melting point 50° to 51° C. are obtained.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[O:15][CH2:14]1.[CH2:16]([C:20](C)=[O:21])C(C)C>>[OH:21][CH2:20][CH2:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:14][CH2:13][OH:15])=[O:11])=[CH:3][CH:4]=1
Reactant: CC(=O)CC(C)C
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1CO1
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Terephthalic acid (0.25 mole), the catalyst of Example II (0.5g), and methyl isobutyl ketone (250 ml) is charged to an autoclave and heated to about 150°C. A slight stoichiometric excess of ethylene oxide is added to the autoclave. A slight exotherm is observed. After about one hour, the reaction mixture is removed from the autoclave, cleaned, and filtered. Upon cooling, a good yield of bis(2-hydroxyethyl)terephthalate is obtained in the form of a precipitate.
Reaction SMILES: C(OC1C=C(C=CC=1)CN(C1C=CC(C#N)=CC=1)N1C=NN=C1)C1C=CC=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][N:41]2[CH:45]=[N:44][N:43]=[CH:42]2)=[CH:36][CH:35]=1)#[N:33].[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[F:63])[CH2:58]Br)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.CCOC(C)=O>[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[F:63])[CH2:58][N:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][CH:38]=1)[N:41]1[CH:42]=[N:43][N:44]=[CH:45]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Agent: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Yield: 56.1 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using NaH (60% dispersion in oil, 0.20 g, 5.0 mmol), 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (0.926 g, 5.0 mmol) and 3-benzoyloxy-4-fluorobenzyl bromide (1.55 g, 5.0 mmol) in anhydrous DMF (20 mL) to give 4-[(3-benzoyloxy-4-fluorobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as a white solid (1.16 g, 56%) after chromatography [SiO2, EtOAc (100%)]; δH (400 MHz, CDCl3) 4.91 (s, 2H), 6.67 (AA′BB′, 2H), 7.07 (ddd, J=8.2, 4.3, 2.0, 1H), 7.18 (dd, J=9.4, 8.6, 1H), 7.24 (dd, J=7.0, 2.3, 1H), 7.49-7.56 (m, 2H), 7.58 (AA′BB′, 2H), 7.62-7.70 (m, 1H), 8.15-8.20 (m, 2H), 8.21 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 414.2 (100, [M+H]+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28](O)=[O:29])[CH:19]=1>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:28]([C:20]1[CH:19]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:21]=1)=[O:29]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4,6-bis(trifluoromethyl)-2-pyridinecarboxylic acid (Bionet Research) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown oil (66%). MS (ESI): m/z=440.12 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.C(NC(C)C)(C)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[C:16]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1cc(Br)co1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: O=Cc1cc(C#Cc2ccccc2)co1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.6 %

Procedure:
A solid mixture of 4-bromo-2-furaldehyde (1.50 g, 8.57 mmol), PdCl2(PhCN)2 (197 mg, 0.514 mmol) and CuI (65.0 mg, 0.343 mmol) was flushed under an argon stream for 1 minute (min). A solution of HP(t-butyl)3BF4 (298 mg, 1.03 mmol) and diisopropylamine (1.80 mL, 12.9 mmol) in dioxane (9 mL) was added to the solid mixture followed by phenylacetylene (1.13 mL, 10.3 mmol). The reaction was allowed to stir at room temperature (rt) under an atmosphere of argon for 15 hours (h) before being filtered through a plug of silica gel with ethyl acetate (EtOAc). The solution was then concentrated in vacuo and chromatographed over silica gel to give 4-phenylethynyl-furan-2-carbaldehyde as a colorless oil (1.54 g, 92%). Rf=0.35 (1:9 heptane/EtOAc); 1H NMR (400 MHz, CDCl3) δ ppm 9.68 (d, J=0.5 Hz, 1 H) 7.90 (s, 1 H) 7.48-7.55 (m, 2 H) 7.35-7.40 (m, 3 H) 7.33 (d, J=0.7 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.FC1C(C2=CCOCCC2)=CC=CN=1>C1COCC1.[Pd]>[F:1][C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1C1=CCCOCC1
Agent: [Pd]
Agent: Fc1ncccc1C1=CCOCCC1
Solvent: C1CCOC1
Product: Fc1ncccc1C1CCCOCC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Palladium (0.20 g, 0.0188 mmol, 10% wt. on activated carbon) was added to a stirred solution of an approximately 7:3 mixture of (E)-2-fluoro-3-(2,3,6,7-tetrahydrooxepin-4-yl)pyridine:(E)-2-fluoro-3-(2,5,6,7-tetrahydrooxepin-4-yl)pyridine (0.75 g, 3.88 mmol) in THF (15 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 4.5 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give 2-fluoro-3-(oxepan-4-yl)pyridine. MS (ESI, pos. ion) m/z: 196.1 (M+1).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (163 mg, 1.45 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (300 mg, 1.03 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 70° C. for 14 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 120 mg, 33%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1

Procedure:
4-Hydroxyphenylacetic acid (50 g, 0.32 m) in 300 ml of glacial acetic acid was cooled to 10°, at which temperature 100 ml of nitric acid was slowly added. The mixture was allowed to reach room temperature, then was poured into 1 l of water. The separated solid was washed with water and recrystallized from ethanol to give 35 g of 4-hydroxy-3-nitrophenyl acetic acid, m.p. 144°-146°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([O:10][C:11]([N:13]1[CH:18]([C@@H:19]([OH:33])[C@@H:20]([NH:29][C:30](=[O:32])[CH3:31])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:14]1[CH3:40])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:33])[C@@H:20]([NH:29][C:30](=[O:32])[CH3:31])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:2][CH2:3][CH2:4][CH3:5])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:14]1[CH3:40])=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CCCCBr
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)C1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cccc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 102.5 %

Procedure:
Add 1-bromobutane (6 μL, 55.6 μmol) to a solution of 5-[2-(S)-acetylamino-1-(S)-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (25 mg, 50.5 μmol) and cesium carbonate (33 mg, 1.01 mmol) in N,N-dimethylformamide (250 μL). Heat to 60° C. for 3 hours. Dilute with ethyl acetate, wash with water, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 85:15 ethyl acetate:dichloromethane) to give the title compound (28.5 mg, 80%).