Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].CC1(C)[O:34][C@H:33]([CH2:35][O:36][NH2:37])[CH2:32][O:31]1>>[OH:34][C@@H:33]([CH2:32][OH:31])[CH2:35][O:36][NH:37][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CC1(C)OC[C@@H](CON)O1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@@H](O)CO)c(=O)n(C)c1=O

Procedure:
Example 37 was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with (S)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (See, Bailey et al., J. Med. Chem., 34, 1991, 51-65), followed by acid hydrolysis of the resulting material. 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 2H) 6.79 (t, J=8.0 Hz, 1H) 3.89 (m, 3H) 3.66 (m, 1H) 3.55 (m, 1H) 3.31 (s, 3H) 3.02 (s, 3H). [M+H] calc'd for C16H18FIN4O6, 509; found, 509.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH:5]([C:7]1[C:15]2[O:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]([CH3:25])=[C:9]([NH:26][C:27](=[O:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:8]=1[CH3:34])=[O:6]>O>[OH:6][CH:5]([C:7]1[C:15]2[O:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]([CH3:25])=[C:9]([NH:26][C:27](=[O:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:8]=1[CH3:34])[CH2:1][CH3:2]
Reactant: CC[Mg]Cl
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: O
Product: CCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To ethylmagnesium chloride (2.0 M THF solution, 5.0 mL, 10.0 mmol) was added N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (0.7 g, 1.72 mmol) obtained in Example 20 at 0° C. and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with water and 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 264 mg (yield: 35%) of the title compound as a low polarity isomer. Melting point: 145-146° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cccc(CC)c2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cccc(CC)c2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
7-Ethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (76.6 g, 0.24 mol was dissolved in 450 mL dichloromethane and cooled to 0° C. Trifluoroacetic acid (150.0 mL, 1.96 mol) was added within 30 min. and after an additional 45 min. the reaction mixture was concentrated at a rotary evaporator. The residue was dissolved in 300 mL dichloromethane and poured cautiously onto 500 mL saturated aq. sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was suspended in 400 mL n-hexane and put in an ultrasonic bath for 15 min. The suspension was filtered and the filter cake was washed with 100 mL n-hexane. This procedure was repeated to give the desired product as a light brown solid (40.2 g, 76.6%). EI-MS: m/e=217.1 ([M])
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH:18](O)[CH3:19])=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[N:6][CH:7]=1.FC1C=C(B(O)O)C=NC=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:43]([CH:18]([C:9]1[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH3:19])=[N+:44]=[N-:45]
Reactant: CC(O)c1ccc2cccnc2c1-c1cncc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: OB(O)c1cncc(F)c1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[8-(5-fluoropyridin-3-yl)quinolin-7-yl]ethanol (0.135 g, 0.503 mmol) (prepared in analogy to Example 7 step 1-4, using 5-fluoropyridin-3-ylboronic acid instead of (2-fluorophenypboronic acid as starting material) in methylene chloride (3 mL) was added triethylamine (0.105 mL, 0.755 mmol), followed by methanesulfonyl chloride (0.0487 mL, 0.629 mmol). After stirring at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (2 mL) and treated with sodium azide (0.164 g, 2.52 mmol) at room temperature overnight. After diluting with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate and then evaporated to dryness. The crude product was used in the next step. LCMS calculated for C16H13FN5(M+H)+: m/z=294.1; found: 294.0.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[CH3:10][O:11][NH2:12]>CO>[CH3:10][O:11][N:12]=[C:5]1[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]1
Reactant: CON
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CO
Product: CON=C1CCNCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 3.84 g (25.00 mmol) 4-piperdinone hydrochloride and 2.51 g (30.00 mmol) O-methylhydroxylamine hydrochloride in 50 mL of MeOH was stirred for 8 hours at 60° C. and then evaporated down in vacuo. The residue was stirred with saturated aqueous potassium carbonate solution and the aqueous phase was extracted with DCM. The combined organic phases were dried over sodium sulfate, evaporated down in vacuo, and dried. Yield: 2.80 g (87% of theoretical); C6H12N2O (M=128.172); calc.: molpeak (M+H)+: 129; found: molpeak (M+H)+: 129; HPLC-MS: 1.44 minutes (method C).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH3:11][SiH:12]([CH3:17])[O:13][SiH:14]([CH3:16])[CH3:15].[CH4:18]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:5]1([NH:4][CH2:1][CH2:2][CH2:3][Si:12]([CH3:17])([CH3:11])[O:13][Si:14]([CH2:18][CH2:2][CH2:1][NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:16])[CH3:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CCNc1ccccc1
Reactant: C[SiH](C)O[SiH](C)C
Reactant: C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: C[Si](C)(CCCNc1ccccc1)O[Si](C)(C)CCCNc1ccccc1

Procedure:
N-allylaniline (0.200 mole) and 1,1,3,3-tetramethyldisiloxane (0.100 mole) are introduced along with 0.05 g hexachloroplatinic acid into a 100 ml cylindrical glass reactor equipped with reflux condenser, nitrogen inlet, and stir bar. The contents of the reaction are heated and maintained while stirring, at approximately 70° C., for a period of ten hours. The IR spectrum of the resulting viscous oil shows no peaks corresponding to Si-H, indicating completion of the reaction. The crude product is mixed with carbon black and stirred overnight at room temperature. The product is filtered through silica gel and the filter cake washed with toluene. Volatile fractions are removed by stripping under vacuum at 150° C. to give a slightly colored oil. The oil is further purified by vacuum distillation at <1 torr at 223°-230° C. The yield of 1,3-bis(N-phenyl-3-aminopropyl)-1,1,3,3-tetramethyldisiloxane is virtually quantitative.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:9]=1)[C:5]#[N:6].[Cl:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[C:21]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:9]=2)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#Cc1cc(Cl)nc(NCc2cccc(F)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Temperature: 110 °C
Yield: 46.5 %

Procedure:
To a degassed suspension of 2-chloro-6-(3-fluorobenzylamino) isonicotinonitrile (150 mg, 0.573 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (151 mg, 0.860 mmol) in DME (5 ml) was added Na2CO3 (1.433 ml, 2M, 2.87 mmol) and Pd(Ph3P)4 (66.2 mg, 0.057 mmol). The reaction mixture was capped and heated to 110° C. in an oil bath for 2 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to give 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (95 mg, 47%). LCMS (m/z): 357.0 (MH+), retention time=1.09 min
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].C(O)(=O)C.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>CO>[C:16]([O:15][C:11]([NH:12][N:13]=[CH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C=NNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 100 %

Procedure:
Pivaldehyde (52.1 g, 454 mmoles, ca. 75% solution in t-butanol) was dissolved in 120 mL methanol in a 1 L, 3-necked round bottom flask with reflux condenser, thermometer, and addition funnel. Glacial acetic acid (1 mL) was added followed by controlled addition of t-butyl carbazate (50 g, 378 mmoles), without removal of heat of the reaction. The mixture was stirred for 4 hours, while monitoring by TLC. Upon completion of the reaction, the solvent was removed in vacuo, the residue was taken up in pentane, and the pentane was evaporated. The resultant oil crystallized upon standing to provide N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester (75.7 g, 93%). Rf=0.42 (2:1 hexanes:ethyl acetate, 1% acetic acid); 1H NMR (400 MHz, CDCl3) δ 7.6 (br s, 1H), 7.1 (s, 1H), 1.5 (s, 9H), 1.1 (s, 9H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[N:4]=[CH:3]1.[C:12]1([NH:22]C(=O)C)C2CCCCC=2C=CC=1.Cl.NC1C2CCCCC=2C(C#N)=CC=1>>[NH2:11][C:10]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]([C:12]#[N:22])=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1cccc2c1CCCC2
Reactant: Cn1cnc2c(N)cccc21
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: Cn1cnc2c(N)ccc(C#N)c21

Procedure:
The title compound was prepared from compound 9A by procedures analogous to those described in Experiment 2 (2A to 2D).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:37]([CH:34]3[CH2:35][CH2:36][N:31]([CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)[CH2:32][CH2:33]3)=[O:38])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C3CCOCC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a white solid. MS m/e: 544.2 [M]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8](C#N)[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].[N:25]1C=CC=C[CH:26]=1>>[C:26]([C:23]1[CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=[CH:18][C:19]=1[C:20]([NH:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:8]=1)=[O:21])#[N:25]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred solution of 16.3 gm. (0.1 mole) of 5-nitroanthranilonitrile in 100 ml. of dry pyridine is added 18.56 gm. (0.1 mole) of p-nitrobenzoyl chloride. The reaction mixture is refluxed for 3 hours. The pyridine is distilled in vacuo. The oily residue is poured into 600 ml. of water and is distilled in vacuo. The oily residue is poured into 600 ml. of water and the precipitate removed by filtration. The precipitate is boiled with 1500 ml. of ethanol. The insoluble material is removed by filtration. There is obtained 21.57 gm. of yellow solid that melts at 195°-196°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[N:4][CH:3]=1.O.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:18])=[N:4][CH:3]=1
Reactant: C=CCn1c(=O)ccc2ncc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)ccc2ncc(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (1.683 g, 8.25 mmol) was dissolved in 1,4-dioxane (100 ml) and water (50 ml) was added. The solution was cooled to 0° C. and sodium periodate (5.29 g, 24.75 mmol) was added, followed by osmium tetroxide (9 mL of 4% aqueous solution). The stirred mixture was allowed to warm to rt, then stirred at rt for 1 h. The mixture was then treated with a further 100 ml of water and sodium periodate (10.58 g, 49.5 mmol) and stirred at rt for 1 h. The mixture was evaporated to approximately 50 ml and the residue was extracted with 20% methanol in DCM (3×300 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (mainly as the methyl hemiacetal) as an off-white solid (1.531 g, 90%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16](I)[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.C[CH2:31][N:32](C(C)C)C(C)C.CN.C(Cl)Cl>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16]([NH:32][CH3:31])[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)c(I)c1C#N)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CCCCO
Solvent: ClCCl
Product: CNc1c(F)c(Nc2cc(C3CC3)[nH]n2)nc(N[C@@H](C)c2ccc(F)cc2)c1C#N
Temperature: 185 °C
Yield: 51.4 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile (Example 134, 0.10 g, 0.19 mmol) and DIEA (0.03 g, 0.25 mol) in n-BuOH (1.5 ml) was added methylamine (2.0 M in THF, 1.9 mmol). The reaction was then heated to 185° C. under microwave conditions (1 hour×2 cycles). The reaction was then cooled to room temperature, DCM (10 ml) was added, and washed with 10% aqueous Na2S2O3. The organic layer was then dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.04 g, 49%). 1H NMR (400 MHz, CD3OD) δ 7.35 (br s, 2H), 7.04-7.00 (m, 2H), 5.95 (br s, 1H), 5.14 (br s, 1H), 3.15 (d, J=2.7 Hz, 3H), 1.87-1.82 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.94 (m, 2H), 0.65-0.63 (m, 2H). MS: Calcd.: 409. Found: [M+H]+ 410.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]2=[O:22].[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][N:29]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:22])[C:6]([C:19]([OH:21])=[O:20])=[CH:7][N:8]3[C:14]3[S:15][CH:16]=[CH:17][N:18]=3)=[CH:3][C:2]=2[F:1])[CH2:28]1)[CH3:24]
Reactant: O=C(O)c1cn(-c2nccs2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nccs4)c3c2F)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To 1.0 g (3.06 mmol) of the 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.46 g of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.39 g of 3-[(ethylamino)methyl]pyrrolidine. The reaction was warmed to 60° C. for one hour and was then taken to room temperature and stirred overnight. The solids were filtered and washed with ether to give 0.32 g of 7-[3[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-3-quinolinecarboxylic acid, mp 200°-207° (dec).
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH2:17][C:18]([NH2:20])=[O:19])=[C:8]2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([CH3:21])=[C:9]2[CH2:17][C:18]([NH2:20])=[O:19])[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2C1CCCCC1
Yield: 46 %

Procedure:
1-Cyclohexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (300 mg, 1.0 mmol) was reacted with 40 mg (1.0 mmol) of 60% NaH/mineral oil and then 0.143 mL (1.0 mmol) of ethyl 4-bromobutyrate as described in Example 50, Part D to give a product that was chromatographed on silica gel (eluted with 2% MeOH/methylene chloride) to give 190 mg (46% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 92-94(° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol; available from Sigma-Aldrich #706620) and 4-(Trifluoromethyl)phenol (0.86 g, 5.34 mmol) in dry tetrahydrofuran (10 ml), Triphenylphosphine (1.54 g, 5.87 mmol) and diisopropyl azodicarboxylate (1.15 ml, 5.87 mmol) were added. The reaction mixture was stirred at room temperature for 2 days. Solvents were evaporated in vacuo and the residue was loaded on SPE-Si (25 g) cartridge and purified eluting with a mixture petroleum ether/ethylacetate (from 100/0 to 80/20). Collected fractions gave, after evaporation, the title compound (D34) (1.8 g).
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[N+:25]([O-])=O)([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:4]([CH:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1[NH2:25])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Yield: 109.5 %

Procedure:
α-(2-Propenyl)-[2-(2-nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (50.49 g; 0.102 mole) was dissolved in methanol (350 ml) under argon at room temperature. Powdered stannous chloride dihydrate (119.67 g; 0.53 mole; 5.2 eq.) was added followed by concentrated hydrochloric acid (155 ml with stirring. Celite, ethyl acetate, and saturated potassium carbonate solution were added with stirring (the potassium carbonate was added portionwise). The suspension was filtered through a Celite pad (rinsed three times with ethyl acetate), rotary evaporated, and suction-filtered. The collected white solid was rinsed with 10% methanol:water and dried giving 51.97 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C-:17]#[N:18].[Na+].S(=O)(O)[O-].[Na+]>CCOCC.O>[C:17]([CH:6]([OH:7])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)#[N:18]
Reactant: [C-]#N
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-3-phenoxybenzaldehyde (0.39 g, 1.8 mmol) in 25 ml of ether is added 25 ml of water followed by sodium cyanide (0.149 g, 3.04 mmol). The mixture is stirred vigorously while a solution of sodium bisulfite (0.257 g, 2.47 mmol) in 15 ml of water is added over about 5 minutes. The reaction mixture is stirred for two hours. The organic phase is separated, washed with water, dried over calcium sulfate and solvent evaporated to give α-cyano-4-fluoro-3-phenoxybenzyl alcohol.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[I:12]Cl>C(O)(=O)C>[I:12][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[I:12][C:3]1[C:2]([OH:11])=[CH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: ClI
Reactant: Oc1ccc2c(c1)CCCC2
Solvent: CC(=O)O
Product: Oc1cc2c(cc1I)CCCC2
Product: Oc1ccc2c(c1I)CCCC2
Temperature: 100 °C

Procedure:
A 4.45 g solution of 5,6,7,8-tetrahydro-2-naphthol was dissolved in 25 ml of glacial acetic acid, mixed with 5.85 g of iodine monochloride and heated under reflux at 100° C. for 2 hours. After reaction, the reaction mixture was poured onto 100 ml of ice water and extracted with ethyl acetate. The extract was washed sequentially with an aqueous solution of sodium thiosulfate (hypo), water and saturated aqueous NaCl solution, dried with anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using an eluting agent comprising a mixture (1:2) of methylene chloride and cyclohexane to provide white crystals each comprising 2.11 g of 1-iodo-5,6,7,8-tetrahydro-2-naphthol and 2.84 g of 3-iodo-5,6,7,8-tetrahydro-2-naphthol having the following physical properties.