Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40].CC(C)([O-])C.[Na+].C(P(C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[C:25]([F:33])[CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=2)[CH:12]=[C:13]([NH:40][C:39]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:36]([F:35])([F:48])[F:49])[CH:38]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 47 %

Procedure:
A mixture of 2-(3′-fluoro-5-trifluoromethanesulfonyloxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (48 mg, 0.10 mmol), 3,5-bis-(trifluoromethyl)aniline (18 μL, 0.12 mmol), sodium tert-butoxide (9.8 mg, 0.10 mmol), Pd(OAc)2 (2.5 mg, 0.01 mmol), 2-(di-tert-butylphosphino-1,1′-binaphthyl (3.5 mg, 0.01 mmol) and toluene (1 mL) was stirred under microwave irradiation at 130° C. for 3×10 min. The mixture was diluted with toluene (9 mL), washed with 1M HCl (2×10 mL) and brine (10 mL), dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (Et2O-petroleum ether) to afford the title product as a colourless powder (28 mg, 44%). RT=4.97 min.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1
Reactant: Cc1nnc(-c2cc3c(Br)coc3cn2)o1
Reactant: OB(O)c1ccccc1Cl
Product: Cc1nnc(-c2cc3c(-c4ccccc4Cl)coc3cn2)o1
Yield: 21 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole and using (2-chlorophenyl)boronic acid instead of (4-fluorophenyl)boronic acid, the title compound (yield 21%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH2:21][CH2:22][N:23]=2)=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].ClCCl.CO>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[O:20][CH2:21][CH2:22][N:23]=4)=[CH:17][CH:18]=3)[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(C2=NCCO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(C4=NCCO4)cc3)cn2c1

Procedure:
Subsequently, 2-amino-5-iodopyridine (88 mg) and 2-bromo-1-[4-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]-1-ethanone mg) were dissolved in ethanol (7 mL), and sodium hydrogencarbonate (34 mg) was added to the solution, followed by refluxing for 13 hours. Dichloromethane-methanol solution was added to the reaction mixture, and the mixture was washed with water and saturated saline, followed by drying over sodium sulfate anhydrate. The solvent was evaporated, and the residue was subjected to silica gel chromatography. Fractions eluted by dichloromethane-methanol (100:5) were concentrated under reduced pressure, to thereby yield the title compound (89 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1F
Temperature: 90 °C

Procedure:
To a solution of 2.5 g (27.0 mmol) of 2-fluoro-4-iodobenzoic acid (Compound B) in 11 mL (8.6 g, 187.5 mmol) of ethanol was added 0.3 mL of c. sulfuric acid. The reaction mixture was heated to reflux in an oil bath (90° C.) for 1.75 hours, fitted with a short path distillation apparatus, distilled and then allowed to cool to ambient temperature. The reaction mixture was extracted and partitioned between pentane and water and the layers were separated. The aqueous phase was washed with pentane and the organic phases were combined. The combined organic phase was washed sequentially with sat. NaHCO3 (aq.) solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[O:15])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:34][C:35]([F:40])([F:39])[C@@H:36]1[CH2:38][O:37]1>O1CCCC1.CN1CCCC1=O.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]([CH2:38][C@H:36]([OH:37])[C:35]([F:40])([F:39])[F:34])[C:12](=[O:15])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:10]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CN(C[C@H](O)C(F)(F)F)C1=O
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a pre-cooled −30° C. solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate (described in Intermediate 11, step B, 56 mg, 0.172 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 0.8 mL) was added lithium bis(trimethylsilyl)amide (0.22 mL, 0.22 mmol, 1 M in THF) and the mixture was stirred at −30° C. for 30 min. (2S)-2-(Trifluoromethyl)oxirane (19 mg, 0.172 mmol) was added and the resulting mixture was stirred at −30° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→90% ethyl acetate/hexane) afforded the title compound. MS: m/z=461.2 (M+Na).
Reaction SMILES: Cl.[CH3:2][C@@:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1>C(O)CCC>[CH2:2]([O:9][C:8]([C@:3]1([CH3:2])[CH2:7][CH2:6][CH2:5][NH:4]1)=[O:10])[CH2:3][CH2:7][CH3:6]
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)[C@]1(C)CCCN1
Temperature: 60 °C

Procedure:
Concentrated HCl (2 ml) is added to a suspension of (S)-2-methyl-pyrrolidine-2-carboxylic acid (2 g) in butan-1-ol (50 ml) which is heated at 60° C. for 18 hours then at reflux for 4 days. The reaction mixture is evaporated, partitioned between saturated aqueous NaHCO3 and CH2Cl2, extracted 3×CH2Cl2, dried over Na2SO4 and evaporated. The isolated oil is then kugelrohr distilled at 10 mbar to give the title compound as a clear colorless oil from the fraction distilling at an oven temperature of 100-120° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:12])[CH:10]=[CH2:11]>C(Cl)(Cl)Cl>[O:6]=[C:5]([NH:12][CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: C=CCN
Reactant: O=C1CCCC(=O)O1
Solvent: ClC(Cl)Cl
Product: C=CCNC(=O)CCCC(=O)O

Procedure:
A functional monomer was prepared in the following manner, and was used in Example 15 to introduce activated ester groups on the backbone of the polymer. Glutaric anhydride, 20 g (0.175 mole), was dissolved in 100 ml chloroform. The glutaric anhydride solution was cooled to <10° C. using an ice bath. Allyl amine, 10 g (0.177 mole), was dissolved in 50 ml chloroform and added to the cooled solution of glutaric anhydride with stirring. The addition rate of allyl amine was adjusted to keep the reaction temperature <10° C. After the allyl amine addition was completed, the reaction solution was allowed to come to room temperature while stirring overnight. After removing the solvent, the 5-oxo-6-aza-8-nonenoic acid isolated amounted to 31.4 g (105% crude) with a dual DSC melting point of 35.1° C. and 44.9° C. NMR analysis at 300 MHz was consistent with the desired product: 1H NMR (CDCl3) amide proton 6.19 (b, 1H), vinyl protons 5.13, 5.81 (m, 3H), methylene adjacent to amide N 3.85 (m, 2H), methylenes adjacent to carbonyls 2.29, 2.39 (t; 4H), and central methylene 1.9. (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]2[O:30][CH2:31][O:32][C:25]=12.Cl[CH2:34][C:35]#[N:36]>>[C:35]([CH2:34][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]5[O:30][CH2:31][O:32][C:25]=45)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:18][CH2:19]1)#[N:36]
Reactant: N#CCCl
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCN(CC#N)CC1

Procedure:
Using an analogous procedure to that described in Example 12, 6-methoxy-4-(2,3-methylenedioxyanilino)-7-(3-piperazin-1-ylpropoxy)quinazoline was reacted with 2-chloroacetonitrile to give the title compound as a solid; NMR Spectrum: (DMSOd6) 2.1 (m, 2H), 2.45–2.7 (m, 11H), 3.5 (s, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.0 (s, 2H), 6.7 (d, 1H), 6.9 (t, 1H), 7.0 (m, 2H), 7.75 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([C:15](=[O:25])[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1Cl)=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].[H-].[Na+].O>C(COC)OC>[CH2:1]([O:3][C:4]([C:5]1[C:15](=[O:25])[C:16]2[C:17](=[CH:18][C:19]([F:23])=[C:20]([F:22])[CH:21]=2)[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Yield: 90 %

Procedure:
2-(2-Chloro-4,5-difluorobenzoyl)-3-(4-fluoroanilino)-2-propenoic acid ethyl ester (11.0 g, 28.7 mmol) was dissolved in dimethoxyethane (200 ml) and cooled to 0°. Sodium hydride (1.65 g of a 50% suspension in mineral oil, 34.5 mmol) was added portionwise, and the mixture was heated to reflux for 3 hours. The reaction mixture was then poured into water (2 l) and the title product was collected by filtration (8.96 g, 25.8 mmol, 90% yield).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([NH:17][C:18]([C:20]1[C:25]([CH3:26])=[C:24]([Cl:27])[CH:23]=[CH:22][N:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:28](OC)(=[O:30])[CH3:29].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C.O>[C:13]([NH:17][C:18]([C:20]1[C:25]([CH2:26][C:28](=[O:30])[CH3:29])=[C:24]([Cl:27])[CH:23]=[CH:22][N:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1c(Cl)ccnc1C(=O)NC(C)(C)C
Reactant: COC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(=O)Cc1c(Cl)ccnc1C(=O)NC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 28 mL, 70 mmol) is added dropwise to diisopropylamine (10 mL, 70 mmol) in THF (100 mL) at −78° C. After 1 h at −78° C. and 15 min at 0° C. the reaction mixture is cooled to −50° C. and N-tert-butyl-4-chloro-3-methyl-pyridine-2-carboxamide (5.7 g, 25 mmol) in THF (50 mL) is added dropwise and stirring is continued for 30 min at −40° C. Methyl acetate (2.2 mL, 28 mmol) is added and stirring is continued for 30 min at −40° C. Saturated NH4Cl (2 mL), water (6 mL) and ethyl acetate are added and the organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-10% EtOAc/cyclohexane) to furnish 4-chloro-3-(2-oxo-propyl)-pyridine-2-carboxylic acid tert-butylamide (3.7 g, 55%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Si]([O:32][CH2:33][CH2:34][C:35]1[C:36]([F:53])=[C:37]([CH:50]=[CH:51][CH:52]=1)[CH2:38][N:39]1[CH2:49][CH2:48][C:42]2([O:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.[CH:54]([C:57]1[N:62]=[C:61]([C:63](O)=[O:64])[CH:60]=[CH:59][CH:58]=1)([CH3:56])[CH3:55].C(N(CC)CC)C>CN(C=O)C>[F:53][C:36]1[C:35]([CH2:34][CH2:33][OH:32])=[CH:52][CH:51]=[CH:50][C:37]=1[CH2:38][N:39]1[CH2:40][CH2:41][C:42]2([O:47][CH2:46][CH2:45][N:44]([C:63]([C:61]3[CH:60]=[CH:59][CH:58]=[C:57]([CH:54]([CH3:56])[CH3:55])[N:62]=3)=[O:64])[CH2:43]2)[CH2:48][CH2:49]1
Reactant: CC(C)c1cccc(C(=O)O)n1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.20 g) was added to a solution of 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.17 g), 6-isopropylpicolinic acid (example 85, step d) (0.07 g) and triethylamine (0.22 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The residue was dissolved in THF (10 mL) and a solution of TBAF in THF (1M, 0.8 mL) was added. The resulting mixture was stirred for 2 h and the solvent evaporated. Purification was by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (50 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.2 g.
Reaction SMILES: C(N(CC)CC)C.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl[C:23]1[N:24]=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1>C1(C)C=CC=CC=1>[C:29]1([C:26]2[N:25]=[N:24][C:23]([N:12]3[CH2:13][C@@H:8]4[CH2:14][C@H:11]3[CH2:10][N:9]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:28][CH:27]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(-c2ccccc2)nn1
Temperature: 100 °C
Yield: 49.2 %

Procedure:
Triethylamine (20 mL) was added to a suspension of t-butyl(S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.43 g, 17.3 mmol, Aldrich Chemical Company) and 3-chloro-6-phenylpyridazine (3.30 g, 17.3 mmol, Aldrich Chemical Company) in toluene (50 mL), and the mixture was heated under nitrogen at 100° C. for 7 days. The dark mixture was cooled to room temperature, and the resulting precipitate was isolated by filtration, washed with toluene (15 mL) and dried under vacuum to provide the title compound as an off-white solid (3.00 g). The filtrate was concentrated, and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate, to provide additional product (0.41 g, total yield 3.41 g, 56%): MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][C:10]=2[CH3:18])=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:16])=[CH:11][C:10]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc(Sc2ccc(F)cc2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Sc1ccc(F)cc1
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (2.82 g, white solid) from 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanone (2.71 g, 10.4 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.89 g, 15.6 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]([F:22])([CH:7]([O:11][C:12](=[O:21])[C:13]([F:20])([F:19])[CH:14]([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].FC(F)([CH:41]([OH:45])[CH:42]([CH3:44])[CH3:43])C(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)=O>>[F:1][C:2]([F:22])([CH:7]([O:11][C:12](=[O:21])[C:13]([F:19])([F:20])[CH:14]([O:18][C:41](=[O:45])[C:42]([CH3:44])=[CH2:43])[CH:15]([CH3:16])[CH3:17])[CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC(C)C(O)C(F)(F)C(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: COC(=O)C(F)(F)C(OC(=O)C(F)(F)C(O)C(C)C)C(C)C
Product: C=C(C)C(=O)OC(C(C)C)C(F)(F)C(=O)OC(C(C)C)C(F)(F)C(=O)OC
Yield: 49 %

Procedure:
Reaction was conducted by the same procedure as Example 11 aside from using methyl 2,2-difluoro-3-(2,2-difluoro-3-hydroxy-4-methylpentanoyloxy)-4-methylpentanoate in Example 11-1 instead of 2,2,3,3,4,4,5,5-octafluoropentyl 2,2-difluoro-3-hydroxy-4-methylpentanoate in Example 11-3. Subsequent purification was conducted by silica gel column chromatography instead of vacuum distillation. The target compound, methyl 2,2-difluoro-3-(2,2-difluoro-3-methacryloyloxy-4-methylpentanoyloxy)-4-methylpentanoate was obtained in a yield of 49%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[CH2:36][N:11]2[C:12]3[C:17]([C:18]([C:19]4[C:20](=[O:35])[O:21][C:22](=O)[C:23]=4[C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)=[C:10]2[CH2:9][CH2:8]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(=O)C.[OH-].[Na+].Cl.C[N:41](C)C=O>N>[OH:4][CH2:5][CH2:6][CH:7]1[CH2:36][N:11]2[C:12]3[C:17]([C:18]([C:19]4[C:20](=[O:35])[NH:41][C:22](=[O:21])[C:23]=4[C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)=[C:10]2[CH2:9][CH2:8]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CC(=O)OCCC1CCc2c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc3n2C1
Reactant: CN(C)C=O
Agent: Cl
Agent: N
Agent: [Na+]
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(CCO)CC4)C(=O)NC2=O)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 200 mg of 3-[7-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione in 2 ml of dimethylformamide and 1 ml of 33% aqueous ammonia was heated to 140° C. Then, 1 ml of a 2M solution of sodium hydroxide was added to the cooled solution and the mixture was stirred for 2 hours. The mixture was acidified with 2M hydrochloric acid and evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was dried. The solvent was evaporated and the solid obtained was triturated with ethyl acetate to give 115 mg of 3-[6,7,8,9-tetrahydro-7-(2-hydroxyethyl)pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 236°-238° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:3][CH2:2]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCN(c2ncccn2)CC1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 15 step i) using 2-piperazin-1-ylpyrimidine (3.0 g) and sulfamide (1.2 g) in dioxane (30 mL) to give the subtitle compound as a white solid. Yield: 2.06 g.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([OH:9])=[CH:11][N:12]2[CH3:22])=[CH:17][CH:16]=1
Reactant: Cn1cc(OC(=O)c2ccccc2)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cn1cc(O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinol-3-yl benzoate (1 0 g), piperidine (3.7 ml) and dichloromethane (200 ml) was stirred at ambient temperature for 2 days under nitrogen. The solvent was removed by distillation at 50°. The resultant solid was triturated with diethyl ether 100 ml), collected and washed with diethyl ether (2×100 ml) to give the novel compound 7-fluoro-3-hydroxy-1 -methyl-4-quinolone, m.p. 283°-285°.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:11]2[NH:12][N:13]=[CH:14][N:15]=2)[CH:5]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].O>C(O)(=O)C>[Cl:18][CH2:19][C:20]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][C:6]=1[C:11]1[NH:12][N:13]=[CH:14][N:15]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(OC(F)(F)F)cc1-c1ncn[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)Nc1ccc(OC(F)(F)F)cc1-c1ncn[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a cooled solution of 4-trifluoromethoxy-2-(2H-[1,2,4]triazol-3-yl)-phenylamine (3.00 g, 12.3 mmol) in acetic acid (62 mL) was added dropwise chloroacetyl chloride (1.96 mL, 24.6 mmol). The resulting light brown suspension was stirred for 20 h at ambient temperature and was then poured into water (246 mL) and stirred for another 3 h. The precipitate was filtered off and washed with water. Drying in vacuo afforded the title compound (3.22 g, 82%) as an off-white solid. MS: m/e=323.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12](Br)[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[C:32]([Si:36]([CH3:42])([CH3:41])[O:37][CH2:38][C:39]#[CH:40])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(#N)C.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.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([C:40]#[C:39][CH2:38][O:37][Si:36]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:41])[CH3:42])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(Br)n1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCC#Cc1nc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cs1
Temperature: 100 °C
Yield: 16 %

Procedure:
Under argon, 500 mg (0.916 mmol) of 2-amino-4-(2-bromo-1,3-thiazol-4-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)pyridine-3,5-dicarbonitrile and 0.186 ml (0.916 mmol) of tert-butyl(dimethyl)(prop-2-yn-1-yloxy)silane were initially charged in 10 ml of acetonitrile, and 105 mg (0.092 mmol) of tetrakis(triphenylphosphine)palladium(0), 35 mg (0.183 mmol) of copper(I) iodide and 0.255 ml (1.832 mmol) of triethylamine were added in succession. The mixture was then heated under reflux at 100° C. for 4 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC. This gave 239 mg of the target compound in a purity of 38% (yield: 16%). The batch obtained in this manner contained the desilylated compound in a proportion of 62%. The mixture was used without further purification for the subsequent hydrogenation.