Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.Cl>[OH:3][CH:1]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:2]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)O)cc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 4-(4-acetyl-2-methoxy-5-nitrophenoxy)butyrate (5.06 g) in methanol (300 cm3) was cooled with stirring at 0° C. under argon. Sodium borohydride (640 mg) was added portionwise and the resulting solution stirred at 40° C. overnight. Further sodium borohydride (500 mg) was added as TLC analysis indicated that starting material remained. After a further 3 h TLC analysis indicated that the reaction was complete. The reaction was cooled, acidified with dilute (1M) hydrochloric acid and evaporated to dryness. The residue was dissolved in ethyl acetate (250 cm3) washed with dilute aqueous acid and brine, dried over magnesium sulphate and filtered. The solvent was evaporated to leave a yellow oil which solidified on standing. After recrystallisation from methanol/diethyl ether, methyl 4-[4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyrate was obtained as yellow needles (5.04 g, ˜100%). 1H NMR (CDCl3) δ 1.52 (3H, d, J=8.3 Hz. MeCHO). 2.18 (2H, m, CCH2C), 2.53 (2H, t, J=6.5 Hz, CH2CO), 3.71 (3H, s, OMe). 3.95 (3H, s, OMe), 4.13 (2H, t, J=7.3 Hz, CH2O), 5.52 (1H, q, J=8.2 Hz, CHOH), 7.29 (1H, s, aromatic) and 7.57 (1H, s, aromatic).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.II.[Cl:15][C:16]1[C:21]([CH:22]=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:24][C:25](=[O:27])[CH3:26].[NH4+].[Cl-]>C1COCC1>[Cl:15][C:16]1[C:21]([CH:22]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=2)[OH:23])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:24][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)Nc1cccc(C=O)c1Cl
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Temperature: 32.5 °C
Reaction time: 2.5 h
Yield: 74.5 %

Procedure:
A solution of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (0.165 mol) in THF (30 ml) was added dropwise under N2 flow to a suspension of Mg (0.181 mol) and a crystal of I2 in THF (20 ml). The mixture was stirred at 30-35° C. for 2.5 hours and then cooled to 10° C. The mixture was added dropwise at 5° C. under N2 flow to a solution of N-(2-chloro-3-formylphenyl)acetamide (0.0788 mol) in THF (500 ml). The mixture was stirred at RT for 3 hours, poured out into ice and NH4Cl, and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 98.5/1.5). The pure fractions were collected and the solvent was evaporated, yielding 22.2 g (74%) of (±)-N-[2-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]hydroxymethyl]phenyl]acetamide (interm. 25).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[NH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1>>[CH2:2]([N:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: O=C1CCCNC1
Product: CCCCN1CCCC(=O)C1

Procedure:
In a manner similar to Preparation 1, react 1-iodobutane with 3-piperidinone to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH3:18])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C(#N)C>[C:51]([NH:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH3:18])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:53])[CH3:52]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)Cc4ccc(C(=O)c5ccc(N)cc5)n4C)c3Cl)c2n1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(=O)c2ccc(CC(=O)N(C)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)n2C)cc1
Reaction time: 2 h
Yield: 50 %

Procedure:
Compound 56 (0.033 g, 0.056 mmol) was dissolved in 5 mL acetonitrile. To this was added diisopropylethylamine (0.032 mL, 0.184 mmol) and acetyl chloride (0.05 mL, 0.703 mmol). The reaction was allowed to stir for 2 hours then was quenched with the addition of ˜2 ml of methanol. The solvents were evaporated and the residue purified via reverse phase chromatography eluting with a gradient of acetonitrile:water 10-90%.The proper fractions were isolated and the solvents were lyophilized to yield the product (0.021 g, 0.028 mmol) as an off-white powder. 1H NMR (CDCl3): δ 8.61 (d, 1H), 7.84-7.47 (m, 9H), 7.37 (d, 1H), 6.55 (d, 1H), 5.86 (d, 1H), 5.60 (s, 2H), 3.84 (s, 3H), 3.53 (m, 2H), 3.28 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H); MS: M+1=629.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13](OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:21].[OH-].[Na+].[C:24]([OH:27])(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([OH:27])(=[O:26])[CH3:25].[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([NH2:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
In an autoclave were charged 2.44 g of (S)-1-(benzyloxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine (7.38 mmol), and 15.7 g of 40% by weight aqueous ammonia (50 equivalent), which was heated to 80° C. whereby an internal pressure of 8 barr was observed. After allowing the reaction for 16 hrs, the reaction mixture was cooled to room temperature, followed by addition of a 30% by weight aqueous sodium hydroxide solution to adjust the pH to 13, and then ammonia was removed by distillation under reduced pressure. The residue was extracted with 15 mL of ethyl acetate three times, and the organic layers were combined. After washing with 3 mL of a saturated brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave a yellow oily material. When 10 mL of ethyl acetate, and 354 mg of acetic acid (0.8 equivalent) were added sequentially thereto, a crystal was precipitated. After stirring at 5° C. for 30 min, the crystal was filtrated under reduced pressure, which was washed with 10 mL of ethyl acetate, and thereafter vacuum drying was carried out to give a white crystal of 1.1684 g (yield: 56%, purity: 100% by weight, optical purity: 100% e.e.)
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[C:20]1=[O:29])[CH2:26]2>>[C:1]([O:18][C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[C:20]1=[O:29])[CH2:28]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: O=C1C2CC3CC(C2)CC1(O)C3
Product: C=CC(=O)OC12CC3CC(CC(C3)C1=O)C2
Yield: 94 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-hydroxyadamantane-2-one was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-acryloyloxyadamantane-2-one (yield: 94%, white solid) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17][CH2:18]O>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(O)c1

Procedure:
3-Hydroxyphenylacetic acid (5 g, 32.9 mmol) and sulfuric acid (1 mL) were stirred in EtOH (100 mL) at 70° C. for 1 hour. The mixture was worked-up to give the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:8])=[C:4]([CH3:17])[CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[C:19]([C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:8])=[C:4]([CH3:17])[CH:3]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)sc1C(=O)NCc1cccnc1
Solvent: CN(C)C=O
Product: Cc1cc(C#N)sc1C(=O)NCc1cccnc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A mixture of 5-bromo-3-methyl-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide (1.92 g, 6.17 mmol) and copper cyanide (2.21 g, 24.68 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred under nitrogen atmosphere at 150° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature, and partitioned between ethyl acetate (200 mL) and 14% aqueous ammonium hydroxide solution (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and combined organic layer was washed with water (2×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 7% methanol in dichloromethane to afford the title compound as an off-white solid (0.72 g, 45%): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.57 (s, 1H), 7.71 (dd, J=7.8, 7.8 Hz, 1H), 7.39 (s, 1H), 7.30 (m, 1H), 6.31 (br s, 1H), 4.63 (d, J=5.9 Hz, 2H), 2.50 (s, 3H); MS (ES+) m/z 258.2 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:33]=[CH:32][C:15]3[N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][C:21]([O:23]CC)=[O:22])[CH:17]=[N:18][C:14]=3[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)=[NH:3]>Cl>[NH2:3][C:2]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:33]=[CH:32][C:15]3[N:16]([CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[N:18][C:14]=3[CH:13]=2)=[O:10])=[CH:34][CH:35]=1)=[NH:1]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc(NC(=N)N)cc3)ccc21
Agent: Cl
Product: N=C(N)Nc1ccc(C(=O)Nc2ccc3c(c2)ncn3C(CC(=O)O)c2ccccc2)cc1

Procedure:
A solution of ethyl 3-{5-[(4-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (4.0 mg, 8.5 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 72 hours. The solution was then evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=2.95 min, MH+ 443].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]#[N:25])[CH:23]=[C:18]3[N:17]([CH2:26][CH3:27])[C:16]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:26]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]#[N:25])[CH:23]=2)[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:28])[CH3:27]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(C#N)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C#N)cc21
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (500 mg) and 10% Pd—C (71.8 mg) in EtOAc (50 mL) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (90 mg) as a white solid.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH:12]([NH:20]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])([O-:3])=[O:2].N1CCCCC1>CC#N>[N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH:12]([NH2:20])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[O:9])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)C(COC(=O)CCCO[N+](=O)[O-])NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)C(N)COC(=O)CCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69.8 %

Procedure:
To a solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate 1.26 g, 2.45 mmol) in CH3CN (15 ml), piperidine (1.21 ml, 12.2 mmol) was added in the dark, the reaction was stirred at room temperature for 25 min. Then the mixture was concentrated to a small volume and diluted with EtOAc (80 ml) and washed with 5% aqueous NaHPO4. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH 98:2 as eluent) yielding the title compound (0.500 g, 70%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:15]1([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 600 mg, 3.00 mmol) in dry DCM (10 ml) was added cyclobutanone (CAS number 1191-95-3; 248 μl, 3.30 mmol), acetic acid (257 μl, 4.49 mmol) and molecular sieves. The reaction was then stirred at room temperature for 1 hour. To this was then added sodium triacetoxyborohydride (952 mg, 4.49 mmol) and the reaction was allowed to stir at room temperature for 17 hours. The reaction was basified by the addition of 2M NaOH (aq) and the organics were extracted DCM, filtered through a hydrophobic frit and concentrated in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]3[C:15](=[O:28])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=4[F:27])[CH2:17][CH2:18][CH2:19][C:13]=3[C:12]([C:29]([F:32])([F:31])[F:30])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]3[C:15](=[O:28])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=4[F:27])[CH2:17][CH:18]=[CH:19][C:13]=3[C:12]([C:29]([F:31])([F:30])[F:32])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2F)CCC3)ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2F)CC=C3)ccc1F

Procedure:
1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one prepared by the same methods as shown in Example 40 (0.50 g, 0.90 mmol), N-bromosuccinimide (0.19 g, 1.08 mmol), and AIBN (9.0 mg) were refluxed with 50 mL of CCl4 under N2 for 2 h. The reaction mixture was cooled and filtered through Celite. The filtrate was concentrated to a brown solid. It was then dissolved in 20 mL of THF and 1,8-diazabicyclo[5,4, 0]unden-7-ene (DBU, 0.14 mL) was added. The mixture was refluxed for 12 h. The solvent was removed. It was dissolved in EtOAc and washed with water and brine, dried over MgSO4 and concentrated. Flash chromatography on silica gel with 15% EtOAc in hexane gave 0.21 g of 1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-6,7-dihydropyrazolo-[3,4-c]azepin-8-one. The title compound was then prepared from 1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-6,7-dihydropyrazolo-[3,4-c]azepin-8-one by the same methods shown in Example 40. LRMS (ES+): 603.2, (M+H)+. 1H NMR (CDCl3) 7.82 (d, 1H), 7.73 (m, 2H), 7.54-7.35 (m, 4H), 7.09 (dd, 4H), 6.46 (m, 1H), 4.34 (s, 2H), 4.32 (d, 2H), 3.86 (bs, 2H), 3.59 (m, 2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:32][C:33]([F:46])([F:45])[C:34]1[CH:35]=[C:36](/[CH:40]=[CH:41]/[C:42](Cl)=[O:43])[CH:37]=[CH:38][CH:39]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[C:42](=[O:43])/[CH:41]=[CH:40]/[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:45])([F:46])[F:32])[CH:35]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Reactant: O=C(Cl)/C=C/c1cccc(C(F)(F)F)c1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)/C=C/c2cccc(C(F)(F)F)c2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure E using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and (2E)-3-[3-(trifluoromethyl)phenyl]acryloyl chloride. HPLC, Rt: 6.6 min (purity: 87.4%).
Reaction SMILES: [Cl:1][C:2]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].C(=[NH:78])(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:78][C:13]1[CH:12]=[C:11]([CH3:16])[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([Cl:1])[N:14]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)OC(C)(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(N)nc(Cl)c1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
tert-butyl 2,6-dichloro-4-methylnicotinate (10.5 g, 40.1 mmol, 1 equiv), Pd2(dba)3 (1.84 g, 2.01 mmol, 0.05 equiv), xantphos (2.32 g, 4.01 mmol, 0.1 equiv), and Cs2CO3 slurried in dioxane (deoxygenated by bubbling nitrogen through it for 10 min) added. Benzophenone imine (8.0 mL, 48.1 mmol, 1.2 equiv) added and the mixture was heated at 90° C. for 1 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was taken up in MeOH (200 mL) and NaOAc (9.87, 120 mmol, equiv) and hydroxlamine hydrochloride (5.57 g, 80 mmol, 2 equiv) was added. After 30 min, the reaction was added to 1 N NaOH and extracted with DCM (×2). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-30% EtOAc/hex) to afford tert-butyl 6-amino-2-chloro-4-methylnicotinate (7.5 g, 77%). 1H NMR (400 MHz, CDCl3) δ 6.22 (d, J=0.8 Hz, 1H), 4.58 (br. s., 2H), 2.27 (d, J=0.8 Hz, 3H), 1.60 (s, 9H); LCMS (ESI, M+1): 243.1.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Sodium hydroxide (25 mg) was added to a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D46) (204 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoic acid (E19) (127 mg) as a white needle crystal. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.62 (2H, t), 3.06 (2H, t), 4.89 (1H, m), 6.98 (1H, dd), 7.25 (1H, d), 7.45 (1H, d), 7.91 (1H, dd), 8.19 (1H, dd), 8.35 (1H, d), 11.10 (1H, s), 12.14 (1H, br s). δF (DMSO-d6, 376 MHz): −118.9. MS (ES): C22H19ClFN3O4 requires 443; found 444.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]2[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[CH2:19]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:19]2)=[N:30][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(F)cc4)ccc3C#N)C2)nc1
Temperature: 120 °C

Procedure:
60 mg (0.26 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 77 mg (0.31 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) and 0.225 ml (1.29 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 99 mg (50% of theory) of the product were obtained in solid form.
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].[CH:25]([C:27]1[C:36]2[O:37][C:38]3([C:48]([CH3:50])([CH3:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]3[CH3:51])[CH:39]=[N:40][C:35]=2[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)=O>ClCCl>[CH3:4][O:3][C:1]([CH:5]=[CH:25][C:27]1[C:36]2[O:37][C:38]3([C:48]([CH3:50])([CH3:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]3[CH3:51])[CH:39]=[N:40][C:35]=2[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)=[O:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Solvent: ClCCl
Product: COC(=O)C=Cc1cc2ccccc2c2c1OC1(C=N2)N(C)c2ccccc2C1(C)C

Procedure:
0.34 g (1 mmol) of carbomethoxymethylene triphenylphosphorane and 0.36 g (1 mmol) of the compound of Example 1 are heated to reflux in 20 ml of dichloromethane for 18 hours. The solvent is evaporated off. The product is purified on a silica column (80/20 pentane/ethyl acetate eluent).