Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[OH-].[Na+].[Si:5]([O:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO>[Si:5]([O:12][CH:13]1[CH:17]2[C@@H:16]([O:18]2)[C:15](=[O:1])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)[C@@H]2OC12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Hydrogen peroxide (4.5 mL, 46.3 mmol, 30% wt. % solution in water) and 1N NaOH (46 μL, 0.046 mmol) were added to a solution of enone 2 (2.5 g, 11.5 mmol) in MeOH (30 mL) at 0° C. After stirring 1.5 h at 0° C. the mixture was concentrated in vacuo, washed with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the above titled compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1([C:18]([F:21])([F:20])[F:19])[O:7][C:6]([CH2:9][CH2:10][C:11]#[N:12])([F:8])[C:5]([CH2:14][CH2:15][C:16]#[N:17])([F:13])[O:4]1.N.[H][H]>[Co].[Cr].[Co].O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1([C:18]([F:19])([F:20])[F:21])[O:4][C:5]([CH2:14][CH2:15][CH2:16][NH2:17])([F:13])[C:6]([CH2:9][CH2:10][CH2:11][NH2:12])([F:8])[O:7]1
Reactant: N#CCCC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)CCC#N
Reactant: [H][H]
Agent: [Co]
Agent: [Cr]
Agent: N
Solvent: C1CCOC1
Product: NCCCC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)CCCN
Temperature: 110 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
In a 1400 ml Hastelloy-C Shaker tube was charged the 2,2-bis(trifluoromethyl)-4,5-di(2-cyanoethyl)-4,5-difluoro-1,3-dioxolane of Example 43 (56.3 g, 0.16 mole), tetrahydrofuran (320 ml) and Raney-Cobalt catalyst (14.4 g). The tube was sealed and cool-evacuated. Ammonia (64 g, 3.765 mole) was transferred into the tube and the tube was pressurized with hydrogen gas to 500 psi. The tube was then heated to 110° C. and the hydrogen pressure was adjusted to 1500 psi. The heating was continued for 18 hrs at this temperature. After the tube was cooled, the product mixture was filtered to remove the catalyst, and solvent was removed in vacuo. The residue was d.:stilled to give the desired product 46 g (80% yield) as a clear, colorless, viscous liquid, Bp. 80° C./0.06 mmHg. H-1 NMR (CDCl3): 3.02 (m, 4H), 2.30 (m, 4H), 1.97 (m, 4H), 1.50 (s, br, --NH2); F-19 NMR (CDCl3): -80.5 (m, 6F), [-108.8 (m, br, trans), -110.6 (m, br cis) (2F total)].
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH2:22]([NH:24][C:25]([NH:21][C:17]1[CH:16]=[C:15]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:20]=[CH:19][N:18]=1)=[O:26])[CH3:23]
Reactant: CCN=C=O
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1cc(-c2sc(CC)nc2-c2cccc(C)c2)ccn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 46.5 %

Procedure:
To A solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.50 g, 1.7 mmol) in N,N-dimethylacetamide (10 mL) was added ethyl isocyanate (0.20 mL, 2.5 mmol) and the reaction mixture was stirred at 80° C. for 20 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure. The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (0.29 g, yield 47%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CCCCCC.C([Li])CCC.Cl[P:21]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>O1CCCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([P:21]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(P(Cl)c2ccc(C)cc2)cc1
Reactant: Cc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(P(c2ccc(C)cc2)c2cccc(C)n2)cc1
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
After dissolving 2-bromo-6-methylpyridine (23.5 mmol) in 40 ml of tetrahydrofuran, the mixture was cooled in a dry ice-ethanol bath, 1.59 M hexane solution of n-butyllithium (23.5 mmol) was added dropwise while stirring, and stirring was continued for 10 minutes to obtain a reaction mixture. To the obtained reaction mixture there was added chlorobis(4-methylphenyl)phosphine (17.5 mmol) dissolved in 40 ml of tetrahydrofuran, and stirring was continued at room temperature for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, purification was performed twice by silica gel column chromatography (developing solution: hexane/ethyl acetate=5/1, 9/1), to obtain 2.68 g of bis(4-methylphenyl)(6-methyl-2-pyridyl)phosphine (50% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:24])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:24])=[CH:33][C:34]#[N:35])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2OC)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(OC)c2OC)c1
Yield: 97.6 %

Procedure:
(3,5-Dimethoxyphenyl)-(2,3,4-trimethoxyphenyl)methanone (1.15 g, 3.46 mmol), cyanomethylphosphonic acid diethyl ester (1.09 ml, 6.92 mmol) in anhydrous THF (8 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 6.92 ml, 6.92 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give 3-(3,5-dimethoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-acrylonitrile as a pink oil (1.20 g, 98%): 1HNMR (DMSO-d6) δ 7.00-6.84 (m, 2H, Ar), 6.62-6.59 (m, 1H, Ar), 6.45 (d, J=2 Hz, 2H, Ar), 6.01 (s, 0.51H, double bond proton), 3.87-3.44 (multiple singlets, 15H, 5OCH3); 13C NMR (CDCl3) δ 160.9, 160.8, 160.7, 160.2, 155.5, 155.4, 152.5, 151.8, 142.7, 142.6, 141.4, 140.5, 126.2, 125.8, 125.4, 124.1, 118.0, 117.8, 107.2, 107.0, 105.7, 102.0, 101.9, 96.8, 96.6, 61.1, 61.0, 60.9, 56.2, 55.7, 55.6; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.53; H, 5.84; N, 3.88.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]([C:48]3[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=3)=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccncc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide and isolated as light-red solid. MS(m/e): 402.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: CC(C)(C)N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-bromopyridine-2-sulfonyl chloride (2.7 g, 10 mmol) in DCM (100 mL) was cooled to 0° C. and treated with tert-BuNH2 (5.5 mL, 52 mmol). The resulting mixture was stirred at rt for 48 h. Water (50 mL) was added and the DCM layer were separated, dried and concentrated to obtain compound 32a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.75 (d, J=2.3 Hz, 1H), 8.03 (dd, J=8.2, 2.3 Hz, 1H), 7.90-7.94 (m, 1H), 5.02-5.07 (m, 1H), 1.23 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:13]=2[CH2:12][NH:11]1.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:26][S:23]([N:11]1[CH2:12][C:13]2[C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:10]1)(=[O:25])=[O:24]
Reactant: COC(=O)c1cccc2c1CNC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc2c1CN(S(C)(=O)=O)C2
Yield: 51.4 %

Procedure:
DIEA (0.438 g, 3.39 mmol) was added to a solution of methyl isoindoline-4-carboxylate (0.5 g, 2.82 mmol) and mesyl chloride (0.36 g, 3.1 mmol) in DCM (10 mL). After 12 h the mixture was concentrated and the residue purified by silica gel chromatography to afford methyl 2-(methylsulfonyl)isoindoline-4-carboxylate (0.37 g 52%) as an off white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:13]2[N:14]=[C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1.[OH:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([NH:8][C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[C:30]3[CH:29]=[CH:28][C:27](=[O:26])[NH:32][CH:31]=3)=[N:10][CH:11]=2)[N:14]=1
Reactant: OB(O)c1ccc(O)nc1
Reactant: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Cl)n2n1
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: O
Solvent: C1COCCO1
Product: O=c1ccc(-c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)c[nH]1
Temperature: 120 °C
Yield: 2.2 %

Procedure:
A glass microwave reaction vessel was charged with N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine (Example 27, Step 1, 40 mg, 0.11 mmol), 6-hydroxypyridin-3-ylboronic acid (19 mg, 0.13 mmol, Combi-Blocks, Inc.), Pd(PPh3)4 (13 mg, 0.01 mmol) and 2 M Na2CO3 (aq., 0.17 mL, 0.34 mmol) in dioxane (1.00 mL). The reaction was stirred and heated in a microwave at 120° C. for 20 min. H2O was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 3′-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-3,4′-bipyridin-6(1 H)-one (1 mg, 2.40 μmol, 2% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 416.9 (M+1). 1H NMR (400 MHz, MeOH-d4) δ ppm 8.82 (s, 1 H), 8.30 (d, J=5.09 Hz, 1 H), 7.96 (d, J=9.39 Hz, 1 H), 7.74 (dd, J=9.59, 2.54 Hz, 1 H), 7.55-7.64 (m, 2 H), 7.37 (d, J=5.09 Hz, 1 H), 7.24 (s, 1 H), 6.69 (d, J=9.39 Hz, 1 H), 6.44 (d, J=9.39 Hz, 1 H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:18]1([C:25]([OH:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]1)#[N:17].[CH2:28]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)C1C=CN=CC=1)C>C(Cl)Cl>[C:16]([C:18]1([C:25]([O:27][C:43]2[CH:44]=[CH:45][C:40]([C:37]3[CH:36]=[CH:35][C:34]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=3)=[CH:41][CH:42]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]1)#[N:17]
Reactant: CCCCCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC1CCCC(C#N)(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ccc(OC(=O)C3(C#N)CCCC(C)C3)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 23 g of dicyclohexylcarbodiimide in 50 ml of CH2Cl2 is added at room temperature to a mixture of 16 g of 1-cyano-3-methyl-cyclohexanecarboxylic acid, 25 g of 4'-hexylbiphenyl-4-ol, 1.2 g of 4-diethylaminopyridine and 200 ml of methylene chloride, and the mixture is stirred for 2 hours. Customary working up and separation by column chromatography (silica gel/toluene) and recrystallization gives the pure product 4'-hexylbiphenyl-4-yl 1-cyano-3-methylcyclohex-anecarboxylate, m.p. 51°.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O.NN>C(O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH2:13])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: C=CCN1CCN(CCCN)CC1
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
To a solution of N-[3-(4-allyl-1-piperazinyl)propyl]phthalimide (35.6 g) in ethanol (400 ml) was added 100% hydrazine hydrate (14.3 g). The resulting mixture was refluxed with stirring for 2.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with ethanol. The filtrate and washing were combined and evaporated under reduced pressure. The residual oil was subjected to column chromatigraphy (aluminum oxide), eluting with a mixture of chloroform and methanol (10:1). The fractions containing the object compound were collected and then evaporated under reduced pressure to give an oil of 3-(4-allyl-1-piperazinyl)propylamine (18.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH:24]=O)([O-:14])=[O:13].Cl>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:24]/[C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=4)[NH:20][CH:19]=3)/[O:8][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccc([N+](=O)[O-])cc23)Oc2cc(O)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.400 g, 2.7 mmol) and 5-nitro-1H-indole-3-carboxaldehyde (0.56 g, 2.9 mmol) in ethanol (5.0 mL) was added with concentrated hydrochloric acid (1.0 mL), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain (Z)-6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.77 g, 90%).
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Cl:42][C:43]1[CH:49]=[C:48]([Cl:50])[C:47]([O:51][CH3:52])=[CH:46][C:44]=1[NH2:45]>>[Cl:42][C:43]1[CH:49]=[C:48]([Cl:50])[C:47]([O:51][CH3:52])=[CH:46][C:44]=1[NH:45][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=2)[N:30]=[CH:29][N:28]=1
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3cc(OC)c(Cl)cc3Cl)c2cc1N

Procedure:
Starting material: N4-(2,4-dichloro-5-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting material was 4-chloro-7-methoxy-6-nitro-quinazoline and 2,4-dichloro-5-methoxyaniline; other starting materials were prepared as example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8](O)[CH3:9])[CH:5]=[CH:4][N:3]=1.CCN(S(F)(F)[F:17])CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([F:17])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(O)c1ccnc(Cl)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)c1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-(2-Chloropyridin-4-yl)ethan-1-ol (115 g, 729 mmol, 1.00 equiv) and dichloromethane (3300 mL) were added to a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. DAST (144 g, 893 mmol, 1.25 equiv) was added dropwise with stirring at −78° C. in 30 min. The resulting solution was stirred overnight at room temperature. The reaction was then slowly quenched by the addition of water (1000 mL). The resulting solution was extracted with dichloromethane (3×1000 mL). The combined organic layer was washed with brine (3×1000 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel column (1:10 ethyl acetate/petroleum ether) to afford 2-chloro-4-(1-fluoroethyl)pyridine as light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]Br.O>ClCCl.[Fe]>[Br:12][C:7]1[C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1cc(C)ccc1O
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(Br)c1O
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
To a solution of 21.5 g (0.143 mol) of 28 in 40 mL of dry dichloromethane, 0.3 g of iron turnings was added. A solution of 10.7 mL (34.2 g, 0.215 mol) of bromine in 100 mL of dichloromethane was added dropwise with vigorous stirring for 20 min. This mixture was refluxed for 30 min, and then 300 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of dichloromethane. The combined organic extracts were washed with saturated aqueous Na2SO3, dried over K2CO3, and then evaporated to dryness. Drying the residue in vacuum gave 15.7 g (48%) of 29 (bp 105-115° C./1 mm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[N+](CC)([O-])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:6]([F:19])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC[N+](=O)[O-]
Product: COC(=O)c1cc(Br)cc2c1c(F)cn2C(C)C
Temperature: 25 °C
Reaction time: 0.16 h
Yield: 20.7 %

Procedure:
To a 20 ml vial was added methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (50.0 mg, 0.169 mmol), (selectfluor) 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (78 mg, 0.219 mmol) followed with a magnetic stir bar and nitroethane (2 ml). The vial was capped and the reaction stirred at room temperature. Reaction progress was monitored by LCMS. After reaction completion the reaction solvent was removed in-vacuo. The residue was dissolved with DCM (1.4 ml). The DCM solution was charged onto an analogix Si35 SF10-8 gram column. The compound was eluted with EtOAc/Hexanes, 5-15%, 20 min. The desired product and side MW629 co-eluted. The mixture was dissolved with DMSO (1 ml) and purified by reverse phase HPLC using a Gemini 5μ 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient. The desired product eluted at 6.8 minutes and the side product MW 629 at 9.5 minutes. The desired fractions were concentrated to a residue. LCMS and NMR support the desired structure and analytical HPLC showed 100% purity. The product, methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (11 mg, 0.035 mmol, 20.53% yield), was obtained as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (t, J=1.77 Hz, 1H), 7.78 (d, J=1.77 Hz, 1H), 7.47 (d, J=2.53 Hz, 1H), 4.76-4.84 (m, J=1.64, 6.65, 6.65, 13.36 Hz, 1H), 3.96 (s, 3H), 1.50 (d, 6H). MS(ES)[M+H]+315.1.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH3:55][C:56]([O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([CH3:58])[CH3:57]>CN(C)C(=O)C>[CH3:58][C:56]([O:59][CH:60]1[CH2:61][CH2:62][N:63]([C:4]([C:3]2[CH:7]=[C:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)[CH:9]=[CH:10][CH:2]=2)=[O:6])[CH2:64][CH2:65]1)([CH3:55])[CH3:57]
Reactant: CC(C)(C)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Reaction time: 0.08 h

Procedure:
To 20 ml vial was added 3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid (1b) (50 mg, 0.178 mmol). To this was added N,N-dimethylacetamide (2 mL) and triethylamine (70 μL, 0.445 mmol). This mixture was allowed to stir for 5 mins before addition of O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate, this solution was also allowed to stir for a further 5 minutes. A solution of 4-[(2-methylpropan-2-yl)oxy]piperidine hydrochloride (35 mg, 0.178 mmol) in N,N-dimethylacetamide (1 mL) and triethylamine (25 μl, 0.179 mmol) was then added and the reaction left to stir at ambient temperature for 2 hours before being purified by preparative HPLC to afford the desired compound; m/z (LC-MS, ESI+), RT=1.74 (M+H 420.4).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][O:11][C:12]1([CH3:15])[CH2:14][CH2:13]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([C:4]1[CH:5]=[C:6]([C:16]#[C:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][O:11][C:12]1([CH3:15])[CH2:13][CH2:14]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(COC3(C)CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1COC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution methyl {4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate (Compound 140, 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded of the title compound as a colorless solid.