Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Br:15].[CH2:17](Br)[CH:18]=[CH2:19]>>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([O:16][CH2:19][CH:18]=[CH2:17])=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: COc1cc(O)ccc1Br
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(Br)c(OC)c1
Reaction time: 8 h

Procedure:
To a stirred mixture of K2CO3 (3.45 g, 0.025 mol), and 3-methoxy-4-bromo-phenol (6.09 g, 0.030 mol) at ambient temperature under argon is added allyl bromide (3.60 g, 0.030 mol). The resulting mixture is heated and stirred overnight. The mixture is filtered and the filtrate is concentrated on the rotovap. The residue is partitioned between Et2O and H2O. The Et2O layer is separated and extracted with 2×70 ml 5% NaOH, washed with brine, dried (MgSO4) and filtered. Evaporation on the rotovap followed by flash chromatography (EtOAc-hexane 1:9) gives 5.93 (81%) of the title compound. Rf-0.41 (EtOAc-hexane 25:75) HNMR (CDCl3) d 7.38 (d, 1H), 6.38 (dd, 1H) 6.1-5.9 (m, 1H), 5.41 (d, 1H), 5.29 (d, 1H), 4.51-4.48 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[C:13]([CH3:16])([OH:15])[CH3:14].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:12]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[C:9]([F:11])[CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[C:13]([OH:15])([CH3:16])[CH3:14])=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cc(F)cc21)C(C)(C)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cc(F)cc21)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound 3-(4-amino-6-fluoro-1H-indol-1-yl)-3-(4-chlorophenyl)-2-methylpentan-2-ol (176 mg, 0.489 mmol) and NMM (145 mg, 1.467 mmol) in DCM (10.0 mL) was added methanesulfonyl chloride (112 mg, 0.978 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (50 mL). The organic layers was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by Prep-TLC (eluent: ethyl acetate/petroleum=4:1) to obtain the title compound. LC/MS m/z=438.9 [M+H]+. 1H NMR (400 MHz, MeOD) δ 8.02 (s, 1H), 7.57-7.25 (m, 4H), 6.86 (dd, J=10.9, 2.1 Hz, 1H), 6.74 (d, J=3.6 Hz, 1H), 5.85 (d, J=11.1 Hz, 1H), 3.00 (s, 3H), 2.84-2.73 (m, 1H), 2.61-2.47 (m, 1H), 1.31 (s, 3H), 1.27 (s, 3H), 0.64 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][C@H:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:4][CH2:3][CH2:2][N:11]1[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C@H:6]1[CH3:5]
Reactant: OCCBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCO
Temperature: 25 °C
Yield: 57.3 %

Procedure:
2-Bromoethanol (1.1 mL, 15 mmol) was added to a mixture of tert-butyl (3R)-3-methylpiperazine-1-carboxylate (2.0 g, 10 mmol, Aldrich) and potassium carbonate (4.1 g, 30 mmol) in acetonitrile (35 mL). The mixture was heated to reflux for 10 hours, cooled to room temperature, filtered and concentrated. Flash column chromatography, eluting with a gradient from 0-10% ethyl acetate/hexanes, afforded product as a colorless oil (1.40 g, 57%). 1H NMR (300 MHz, CDCl3): δ 3.70-2.85 (m, 5H), 2.80 (ddd, 1H), 2.59-2.46 (m, 1H), 2.39-2.20 (m, 2H), 1.75-1.55 (m, 2H), 1.46 (s, 9H), 1.04 (d, 3H); LCMS (M+H)+: 245.2.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:18])([F:17])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)[OH:8]>ClCCl>[F:5][C:6]([F:17])([F:18])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[OH:8]
Reactant: COc1ccccc1C(O)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 56 h
Yield: 107.3 %

Procedure:
Boron tribromide (10 ml) (1M soln in DCM) was added to a solution of 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol (1.5 g) in dichloromethane (20 ml). The reaction mixture was stirred at room temperature under a atmosphere of nitrogen for 56 hrs. The mixture was then partitioned between DCM (100 ml) and 1N HCl (100 ml), organics washed with water (100 ml), dried over magnesium sulfate, filtered and solvent removed in vacuuo to afford the title compound as a clear yellow oil (1.5 g). 1H NMR (CDCl3): δ 3.50 (bs, 1H), 5.25 (m, 1H), 6.73 (bs, 1H), 7.00 (m, 2H), 7.32 (d, J=2.56 Hz, 1H), 7.45 (m, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:36][CH3:37])[CH:12]=2)[CH2:6]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 140 °C
Yield: 50.2 %

Procedure:
N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 109 mg, 0.63 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 300 mg, 0.60 mmol), DIPEA (0.386 mL, 2.22 mmol) and DMA (4 mL) was sealed into a microwave tube and heated to 140° C. for 1 h in the microwave reactor. After cooling, to r.t., the mixture was part-purified by ion exchange chromatography, using an SCX column. The column was first washed with CH3OH and then the desired product was eluted from the column using 0.7M methanolic ammonia. Clean fractions were concentrated in vacuo to give an orange gum. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (140 mg, 50%) as an orange solid; 1H NMR (CDCl3): 1.90-1.98 (2H, m), 2.05-2.12 (2H, m), 2.20 (6H, s), 3.15-3.23 (1H, m), 3.28 (2H, t), 3.69 (2H, dd), 3.96 (3H, s), 4.18 (4H, dt), 6.03 (1H, s), 6.87 (1H, d), 7.35 (1H, s), 7.97 (1H, s), 8.31 (1H, d), 9.02 (1H, s); m/z: ES+ MH+ 465.61.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[C:12]#[CH:13]>>[CH2:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH2:16][CH2:15]1)[C:12]#[CH:13]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)Oc1ccccc1
Product: C#CCC1CCN(C(=O)Oc2ccccc2)CC1

Procedure:
Phenyl chloroformate (6.2 g, 40.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.65 g, 13.4 mmol) according to general procedure 1. Yield=0.600 g, 34%. m/z MH+=244.08. HPLC rt=10.3 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([OH:33])=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O[N:35]1[C:39]2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.O1CCCC1>CN(C)C=O>[CH3:39][NH:35][C:31](=[O:33])[CH2:30][CH:27]1[CH2:28][CH2:29][CH:24]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9]2)[CH2:25][CH2:26]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CC(=O)O)CC1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)CC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 60 °C
Yield: 26.2 %

Procedure:
A mixture of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetic acid (0.094 g, 0.21 mmol), 1-hydroxy-7-azabenzotriazole (0.044 g, 0.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.082 g, 0.43 mmol), 2M methylamine in tetrahydrofuran (2.13 mL, 4.26 mmol) and N,N-dimethylformamide (1.50 mL) was heated at 60° C. overnight. The mixture was allowed to cool to ambient temperature and purified by preparative RP-HPLC to yield N1-methyl-2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetamide (0.025 g, 0.055 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.24(s, 1H), 7.42(d, 2H), 7.38 (t, 2H), 7.16(t, 1H), 7.07(m, 5H), 5.82(br, 2H), 5.62(br, 1H), 4.70(m, 1H), 2.83 (d, 3H), 2.36-1.70(m, 11H); MS: MH+ 456; TLC (ethyl acetate) Rf 0.34; RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.32 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]([CH3:8])[CH3:7].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:17]([O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([CH2:5][N:6]([CH3:8])[CH3:7])[CH:3]=1)[CH3:18]
Reactant: CN(C)Cc1cccc(Br)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(CN(C)C)c1
Yield: 66.7 %

Procedure:
A mixture of (3-bromo-benzyl)-dimethyl-amine (1.10 g), ethyl acrylate (0.8 ml; 7.7 mmol), tri-o-tolyl-phosphane (156 mg; 0.53 mmol), Pd(OAc)2 (40 mg; 0.16 mmol) and NEt3 (1.4 ml; 10 mmol) is heated under reflux for 8 h. The reaction mixture is evaporated and the residue is subjected to flash chromatography on silica gel eluting with CH2Cl2/MeOH (95:5) to give the compound (800 mg).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:28])[C:18]=1[CH3:29])(=O)C.Cl.C(=O)([O-])O.[Na+]>CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:28])[C:18]=1[CH3:29]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCO)=C(C)C1=O
Reaction time: 12 h
Yield: 96.3 %

Procedure:
To a solution of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (4.4 g) in methanol (200 ml) is added concentrated hydrochloric acid (0.1 ml) and the mixture is kept standing at room temperature for 12 hours. To the reaction mixture is added sodium hydrogen carbonate (0.2 g), and the solvent is distilled off. The residue is dissolved in dichloromethane and the insoluble materials are filtered off. Dichloromethane is distilled off to thereby leave crude crystals. Recrystallization from hexane-ether (3:1) gives 6-(12-hydroxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (3.8 g) as orange-yellow needles. Melting point: 63° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](O)=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1.Cl.[CH3:23][O:24][NH2:25]>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:25][O:24][CH3:23])=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in analogy to step (c) of example 1. 1H NMR (CD3OD) δ: 8.80 (s, 1H), 8.33 (s, 1H), 7.64 (d, 1H, J=3.0 Hz), 7.24-7.27 (m, 1H), 6.96-7.08 (m, 2H), 6.74 (d, 1H, J=3.0 Hz), 5.62 (s, 2H) 3.85 (s, 3H). LCMS (API-ES, M+H+): 318.0. HRMS calcd for C16H14F2N3O2. (M+H) 318.1054, found 318.1045. Anal. (C16H13F2N3O2) C, H, N. HPLC: 99.6% purity.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@@H:10]([O:12]C(C)=O)[C@H:9]([O:16][C:17]([CH3:19])=[O:18])[C@@H:8]([O:20][C:21]([CH3:23])=[O:22])[C@H:7]1[O:24][C:25]([CH3:27])=[O:26])=[O:3].C(N)C1C=CC=CC=1>C1COCC1>[C:17]([O:16][C@@H:9]1[C@@H:8]([O:20][C:21](=[O:22])[CH3:23])[C@@H:7]([O:24][C:25](=[O:26])[CH3:27])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]1[OH:12])(=[O:18])[CH3:19]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The synthesis of compound 9 is illustrated in FIG. 6. 20 g (51.24 mmol) of β-D-galactosepentaacetate 1 was dissolved in 150 ml THF and 6.7 ml (61.49 mmol) of benzylamine was added with a dropping funnel. The reaction was stirred for 18 h at room temperature to give 2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 2.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[CH3:4][O:5][C:6]([C:8]1([C:13]([O:15]C)=[O:14])[CH2:10][CH:9]1[CH:11]=[CH2:12])=[O:7].COC(=O)CC(OC)=O.BrC/C=C/CBr.[OH-].[K+]>CO>[CH3:4][O:5][C:6]([C:8]1([C:13]([OH:15])=[O:14])[CH2:10][CH:9]1[CH:11]=[CH2:12])=[O:7]
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Agent: BrC/C=C/CBr
Agent: [Ca+2]
Agent: [Cl-]
Solvent: COC(=O)CC(=O)OC
Solvent: CO
Product: C=CC1CC1(C(=O)O)C(=O)OC
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
In a 100-ml two-necked flask with thermometer, magnet stirrer and CaCl2 tube, 36.8 g (0.2 mole) of 2-vinylcyclopropane-1,1-dicarboxylic acid dimethyl ester, which is accessible from malonic acid dimethyl ester and trans-1,4-dibromobut-2-ene (cf. U.S. Pat. No. 4,713,478 and U.S. Pat. No. 4,713,479) were dissolved in 65 ml of methanol and cooled to ca. 5° C. with ice water. 13.3 g (0.2 mole) of KOH were added portionwise to the mixture, so that the temperature did not rise above 15° C. To complete the reaction, stirring was carried out for a further 12 h and the mixture was then concentrated at a rotation evaporator in vacuum (50 mbar) at 50° C. The obtained oil (ca. 43 g) was dissolved in 50 ml of water and adjusted to about pH 2-3 with conc. hydrochloric acid accompanied by cooling. The organic phase was taken up in 100 ml of diethyl ether, the aqueous phase extracted twice more each time with 100 ml of diethyl ether and the combined ether phases dried over anhydrous Na2SO4. The solution was stabilized with 0.01 g of hydroquinone monomethyl ether, concentrated in vacuum and dried in fine vacuum. 28.2 g (83% yield) of a colourless liquid were obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24]C(OC(C)(C)C)=O)[CH2:21][C@H:20]([C:32]([OH:34])=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:35].CCCCCC>O1CCOCC1>[ClH:35].[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH2:24])[CH2:21][C@H:20]([C:32]([OH:34])=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (4.7 g, 10.1 mmol) (see Starting Material 1 above) in dioxane (25 mL), HCl (4M in dioxane, 25 mL, 100 mmol) is added and the reaction mixture is stirred for 16 h at RT. Hexane (50 mL) is added and the crystals are filtered off, washed with hexane and dried in vacuo to afford the title compound as a white solid. MS: 367.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.48 min.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[CH:19]=[N:20][NH:21][CH:22]=4)=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[C:26]1C=C2C(=CC=1)NCC2.BrCC1C=CC(C(C)(C)C)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(C(OC(C)(C)C)=O)C=2)O1>[Pd]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[CH:22]=[N:21][NH:20][CH:19]=4)=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[CH:23][CH:24]=1)([CH3:26])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CN2CCc3cc(-c4cn[nH]c4)ccc32)cc1
Reactant: Brc1ccc2c(c1)CCN2
Agent: [Pd]
Agent: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(CN2CCc3cc(-c4cn[nH]c4)ccc32)cc1

Procedure:
1-(4-Isopropylbenzyl)-5-(1H-pyrazol-4-yl)indoline, 50 can be prepared by alkylation of 5-bromoindoline, 22 with 1-(bromomethyl)-4-(tert-butyl)benzene using the conditions described in Example 7, part 1 followed by palladium catalyzed coupling of the alkylation product with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, 10 followed by hydrolysis using the reaction conditions described in Example 8.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13]/[N:14]=[C:15](/[C:23](=[O:25])[CH3:24])\[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O[C@@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:19]([O:18][C:16](=[O:17])/[C:15](=[N:14]\[O:13][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)/[C:23](=[O:25])[CH3:24])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](O/N=C(/C(C)=O)C(=O)OC(C)(C)C)CC1

Procedure:
A solution of diethyl azodicarboxylate (1.62 ml) in tetrahydrofuran (5 ml) was added dropwise to a solution of tert-butyl (Z)-2-hydroxyimino-3-oxobutyrate (1.6 g), methyl cis-4-hydroxycyclohexanecarboxylate (1.9 g) and triphenylphosphine (2.7 g) in tetrahydrofuran (20 ml) over 15 min at room temperature. The mixture was stirred for 18h, then the solvent removed under reduced pressure. The residue was chromatographed on silica to give the title compound (0.93 g, 33%) as a colourless liquid. νmax (film) 2950, 1730, and 1690 cm-1. δH (CDCl3) 1.47-1.64 (3H, m), 1.53 (9H, s), 1.56 (3H, d, J 5.3 Hz), 2.05 (2H, m), 2.17 (2H, m), 2.35 (1H, m), 2.37 (3H, s), 3.69 (3H, s), and 4.24 (1H, tt, J 4.1, 10.0 Hz), δC (CDCl3) 25.2, 26.3 (2C), 28.1 (3C), 29.9 (2C), 41.6, 51.7, 82.9, 84.0, 160.6, 175.5, and 193.0. [Mass spectrum +ve ion (ammonia) MH+ (328), MNH4+ (345)].
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([C@@H:15]3[CH2:17][C@@H:16]3[F:18])=[O:14])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[CH3:19][C:20]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=[C:22]([C:35]([O:37][CH3:38])=[O:36])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:18][C@H:16]1[CH2:17][C@H:15]1[C:13]([NH:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:25]3[C:20]([CH3:19])=[CH:21][C:22]([C:35]([O:37][CH3:38])=[O:36])=[N:23][CH:24]=3)[N:3]=[CH:4]2)=[CH:9][N:8]=1)=[O:14]
Reactant: O=C(Nc1cc2cnc(Cl)cc2cn1)[C@@H]1C[C@@H]1F
Reactant: COC(=O)c1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(-c2cc3cnc(NC(=O)[C@@H]4C[C@@H]4F)cc3cn2)cn1
Temperature: 130 °C
Yield: 52.4 %

Procedure:
A mixture of (1S,2S)-N-(7-chloro-2,6-naphthyridin-3-yl)-2-fluorocyclopropanecarboxamide (100 mg, 0.376 mmol), methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (156 mg, 0.565 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (26.6 mg, 0.038 mmol) and saturated aqueous sodium carbonate solution (0.1 mL) in acetonitrile (1 mL) was heated under microwave irradiation (Biotage) at 130° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-100% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow solid (75 mg, 52%), which was used in the next step without further purification.
Reaction SMILES: C1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:13]#[N:14])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11])C=CC=CC=1>S(=O)(=O)(O)O>[C:15]1([CH:7]([C:13]#[N:14])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C:10](=[O:12])[CH3:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC(=O)CC(c1ccccc1)C(C#N)c1ccccc1

Procedure:
Thirty grams of 1-2 diphenyl 4-oxo pentane carbonitrile obtained in the course of the first stage are dissolved in the hot state in 270 ml of alcohol at 95° GL. Then 90 ml of concentrated sulphuric acid are added. The reaction mixture is heated under reflux for 6 hours. After cooling it is extracted at least 4 times with 200-100-100-100 ml of CH2Cl2 -- ether (50:50), until almost complete decolorization of the aqueous phase has occured.
Reaction SMILES: [N-]=C=O.[C:4]1([CH3:17])[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH2:16])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.N[C:20]1[S:21][C:22]([Br:25])=[CH:23][N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:25][C:22]1[S:21][C:20]([NH:16][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:17])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:15])=[N:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)NC(N)=O)cc1
Reactant: Nc1ncc(Br)s1
Agent: Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of toluene-4-sulfonylurea isocyanate (2.6 g, 13 mmol) in CH2Cl2 (10 ml) was added slowly to a mixture containing 2-amino-5-bromothiazole hydrochloride (3.4 g, 13 mmol) and triethylamine (5.4 ml, 39 mmol) in CH2Cl2 (60 ml) under an argon atmosphere and stirred overnight at rt. The reaction mixture was concentrated under reduce pressure, diluted with ethyl acetate and washed with NaHCO3 (half sat. 3×), 5% KHSO4/10% K2SO4, water, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. Recrystallization from MeOH/water yielded a beige solid: 2.8 g (58%), MS: m/e 376.1 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:33])[S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][N:23]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]3)(=[O:18])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH3:33])[S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][N:23]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]3)(=[O:18])=[O:17])[CH2:12][CH2:13]1
Reactant: COC(=O)N1CCc2c(cccc2S(=O)(=O)N(C)CC2CCN(Cc3ccccc3)CC2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)N1CCc2c(cccc2S(=O)(=O)N(C)CC2CCNCC2)C1

Procedure:
A mixture of 5.6 g of the product obtained in Step C, 3.7 g of ammonium formate and 0.56 g of 10% Pd/C in 120 ml of methanol is refluxed for 3 hours, then filtered over Celite and evaporated to dryness, enabling the expected product to be isolated.