Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=[O:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:30]1[C:31]2[C:38]([CH3:39])=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>C(Cl)Cl>[CH3:28][N:2]([CH3:1])[C:3](=[O:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16][N:17]([C:30]3[C:31]4[C:38]([CH3:39])=[CH:37][NH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3ccccc3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1c[nH]c2ncnc(N3CCC(Cc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 120 °C
Yield: 81 %

Procedure:
3-(4-benzylpiperidine-4-carboxamido)phenyl dimethylcarbamate (0.140 g, 0.336 mmol) from step B, 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.056 g, 0.336 mmol), N,N-diisopropylethylamine (0.175 mL, 1.00 mmol), and isopropanol (5 mL) were combined and heated at 120° C. overnight in a pressure vessel. The reaction was diluted with CH2Cl2, washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was taken up in hot ethanol/H2O. Upon cooling, the product precipitated out of solution to give the title compound in 81% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 108.1 %

Procedure:
In a 50 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 1 g, 1.62 mmol), tert-butyl 2-bromoacetate (316 mg, 240 μL, 1.62 mmol) and cesium carbonate (634 mg, 1.95 mmol) were combined with dry dimethyl formamide (10 mL) to give a white suspension. The tube was capped and heated at 50° C. After 10 min, the reaction mixture was cooled down to room temperature, poured into water and extracted with ethyl acetate (2×). The combined ethyl acetate layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 2-tert-butoxy-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as light yellow solid (1280 mg), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].[N:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:3][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:43][CH2:42][CH2:41][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:33])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:34])[CH3:1]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCCN1CCOCC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
200 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to a stirred mixture of 0.044 mL 2-Morpholin-4-ylethylamine, 0.174 mL diisopropylethylamine, and 1 mL DMF at 0° C. 1.1 mL of 0.45M hydroxybenzotriazol-benzotriazoltetramethyluronium hexafluorophosphate in DMF was added. The mixture was warmed to 20° C. with stirring for 18 h, diluted with 30 mL ethyl acetate, washed two times with 20 mL of 10% sodium carbonate, washed with 20 mL brine, and dried with sodium sulfate. The solvents were removed by evaporation to give the title compound as an oil; 240 mg.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[H-].[Na+].[Br:13][C:14](Br)([F:16])[F:15].ClCCl>CN(C)C=O>[Br:13][C:14]([F:16])([F:15])[S:10][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: Sc1nc2ncccc2s1
Reactant: FC(F)(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(Br)Sc1nc2ncccc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
A solution of thiazolo[4,5-b]pyridine-2-thiol (2.0 g, 12 mol) in N,N-dimethylformamide is added dropwise to a mixture of sodium hydride (0.96 g, 0.024 mol) in N,N-dimethylformamide over 30 minutes. The resultant reaction mixture is treated with a solution of dibromodifluoromethane (2.52 g) in N,N-dimethylformamide, stirred at room temperature for 24 hours, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and dichloromethane followed by azeotropic removal of N,N-dimethylformamide (toluene) affords an oil. The oil is further purified by column chromatography using silica gel and a 20:1 ethyl acetate/hexanes solution to give the title product as a light yellow liquid (0.61 g, 17% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[O:7]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)=[N:8]1.CN(C)C=[O:25]>>[CH3:1][C@@:2]([OH:4])([CH2:5][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:9]2[C:10]3[S:14][CH:13]=[CH:12][C:11]=3[O:7][N:8]=2)[CH:16]=1)[CH2:3][OH:25]
Reactant: CC(C)(C)[O-]
Reactant: Oc1cccc(-c2noc3ccsc23)c1
Reactant: CN(C)C=O
Agent: [K+]
Product: C[C@](O)(CO)COc1cccc(-c2noc3ccsc23)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
Add potassium t-butoxide (14.2 g, 0.126 mol) in small portions under nitrogen to a stirred solution of 3-thieno[2,3-d]isoxazol-3-yl-phenol (example 1, 27.5 g, 0.126 mol) and dimethylformamide (200 mL). After 10 min. add (2R)-(+)-2-methylglycidyl-4-nitrobenzoate (10.0 g, 0.0.0422 mol, Aldrich Chemical Company) and rinse through with dimethylformamide (50 mL). Heat to 50° C. and stir for two hours. Pour into ice water (1200 mL) and extract with ethyl acetate (add ammonium chloride to aid separation). Separate the organic phase, dry (Na2SO4), filter and concentrate in vacuo. Purify the residue by flash chromatography over silica gel, elute with 4-7% methanol in dichloromethane and concentrate the desired fractions. Purify again by preparative chromatography (silica gel, elute with 3-5% methanol in dichloromethane) to give a tan solid (6.8 g, 53% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[C:12]([CH3:20])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([B:21]([OH:26])[OH:22])=[CH:16][CH:17]=2)[C:12]([CH3:20])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nn(COCc2ccccc2)c2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nn(COCc2ccccc2)c2ccc(B(O)O)cc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
To a −78° C. stirred solution of the compound from step A (0.72 g, 2.18 mmol) in anhydrous toluene/THF (5 mL/3 mL) under nitrogen was added triisopropyl borate (0.53 g, 2.83 mmol) and then butyl lithium (2.5 M in hexanes, 1.22 mL, 3.05 mmol) slowly over about 10 min. After 10 min the dry ice bath was removed and stirring was continued for 20 min. The mixture was cooled at −78° C. and triisopropyl borate (0.32 g, 1.71 mmol) and butyl lithium (2.5 M in hexanes, 0.85 mL, 2.14 mmol) were added. The dry ice bath was removed and the mixture was allowed to warm to ambient temperature and was stirred for additional 20 min before quenching with a saturated solution of sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (50 mL×2). The extracts were dried and contracted to give a solid. The solid was triturated with ethyl acetate/hexane (1:1) and dried to give the title compound (0.47 g, 81%).
Reaction SMILES: [Si]([O:18][CH2:19][CH:20]1[CH2:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)([CH3:26])[C:23]([C:38]([O:40][CH3:41])=[O:39])=[CH:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2([CH3:26])[C:23]([C:38]([O:40][CH3:41])=[O:39])=[CH:22][CH2:21][CH:20]([CH2:19][OH:18])[CH2:25]2)=[CH:28][C:29]=1[C:34]([F:35])([F:36])[F:37]
Reactant: COC(=O)C1=CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 17.5 h
Yield: 94.1 %

Procedure:
A solution of methyl (4RS,6RS)-4-((tert-butyl-diphenylsilyloxy)methyl)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-6-methylcyclohex-1-enecarboxylate (495 mg, 0.823 mmol) in THF (5 mL) was treated at rt with acetic acid (0.118 mL, 2.058 mmol), followed by tetrabutylammonium fluoride (1.0 M in THF, 1.235 mL, 1.235 mmol). The resulting solution was stirred for 17.5 h. After this time, the solution was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 20-50% ethyl acetate-hexane, to provide methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate as a colorless gum (281 mg, 94%). Mass spectrum m/z 363.0 (M+H+). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.2 Hz, 1 H), 7.39 (d, J=8.6 Hz, 1 H), 7.32 (dd, J=8.6, 2.2 Hz, 17 H), 7.28 (dd, J=5.4, 2.5 Hz, 1 H), 3.64 (s, 3 H), 3.42 (m, 2 H), 2.45 (m, 1 H), 2.00 (m, 1 H), 1.76 (m, 1 H), 1.65 (s, 3 H), 1.53 (m, 2 H), 1.42 (br. s, 1 H).
Reaction SMILES: [N:1]([CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1I)[CH2:5][CH3:6])=[N+:2]=[N-:3].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[N:1]([CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][CH3:6])=[N+:2]=[N-:3]
Reactant: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1I
Reactant: OB(O)c1ccccc1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1-c1ccccc1
Temperature: 100 °C
Yield: 54 %

Procedure:
To a mixture of 2-(1-azidopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.11 g, 0.29 mmol) and phenylboronic acid (42.9 mg, 0.352 mmol) in 1,4-dioxane (2 mL) was added a 1M solution of sodium carbonate (37.3 mg, 0.352 mmol) in water (0.35 mL) and tetrakis(triphenylphosphine)palladium (0) (16.9 mg, 0.0147 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to provide the desired product (50 mg, 53.4%). LCMS calculated for C18H18N5O (M+H)+: m/z=320.2. Found: 320.3.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]=1.Br.C(N(CC)CC)C>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ccc(I)cn1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (420 mg, 1.5 mmol) and 2-amino-5-iodopyridine (330 mg, 1.5 mmol) in ethanol (6.7 mL) containing hydrobromic acid (48%, 84 μL, 0.75 mmol) and triethylamine (105 μL, 0.75 mmol) was heated under reflux under argon overnight. After cooling to room temperature, the mixture was evaporated and poured onto hydrochloric acid (0.5 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (170 mg, 28%) which was obtained as a light yellow solid. MS: m/e=402.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C@@:19]1([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([NH:18][C@@:19]2([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: OCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(N)C1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@](C)(Nc2nc(N3CCOCC3)nc(Cl)c2CCO)C1
Temperature: 130 °C
Reaction time: 60 h
Yield: 129.3 %

Procedure:
To a solution of 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]ethanol (Preparation 1) (7.8 g, 28.0 mmol) and tert-butyl(3S)-3-amino-3-methylpyrrolidine-1-carboxylate (Preparation 4) (8.4 g, 42.1 mmol) in NMP (58 mL) was added DIPEA (18.1 g, 140 mmol) at 15° C. and the resulting mixture was stirred at 130° C. for 60 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×5), dried over Na2SO4, filtered and concentrated to give 16 g of a brown gum. The crude product was purified by silica gel column chromatography eluting with a gradient of petroleum ether/EtOAc (20:1 to 8:1) to give the title compound (9.1 g, 73%) as a light yellow solid. m/z (APCI+) for C20H32N5O4Cl 442.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C@H:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:18]([CH3:20])[NH2:19])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>ClCCl>[CH3:20][C@H:18]([NH:19][C:39]([C:35]1[O:34][CH:38]=[CH:37][CH:36]=1)=[O:40])[C@@H:17]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[N:8]=[CH:9]2
Reactant: O=C(Cl)c1ccco1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccncc2)c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
(αS,βR)-β{[1-(4-Pyridyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (64.3 mg, 0.19 mmol) is dissolved in 7.1 mL of dichloromethane. Triethylamine (0.062 mL, 0.45 mmol) and 2-furoylchloride (24.3 mg, 0.19 mmol) are added. After 4 h stirring at r.t. the reaction mixture is diluted with dichloromethane, washed with water and brine and dried over Na2SO4. The reaction mixture is filtered, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 53.7 mg (65.6%) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[NH3:18].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:18])=[N:13]2)[CH:7]=1
Reactant: FCC1(c2cc(Br)ccc2F)COCC(=S)N1
Reactant: N
Solvent: CO
Product: NC1=NC(CF)(c2cc(Br)ccc2F)COC1

Procedure:
A solution of 6.14 g (18.05 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-fluoromethyl-morpholine-3-thione in 77 ml 7M NH3/MeOH was stirred at rt for 15 h. The mixture was evaporated and purified chromatographed on silica gel (DCM/1-5% MeOH followed by DCM/MeOH/aqueous NH3 95:4.5:0.5) to give the desired product as yellowish resin.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[F-].[K+].Br[CH2:18]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH3:14][O:13][C:10]1[C:11]2[O:12][CH2:18][O:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: BrCBr
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Agent: [F-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Methyl 3,4-dihydroxy-5-methoxybenzoate(48 g, 240 mmol) prepared in Step 2 was dissolved in dimethylformamide(1.2 l), potassium fluoride (42 g, 720 mmol) and dibromomethane(42.0 g, 480 mmol) were added thereto, and the mixture was heated while stirring for 8 hours at 80° C. The reaction solution was cooled down to room temperature and the excess solvent was removed. The residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and then subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3, v/v) to give methyl 7-methoxybenzo [3,4-d]1,3-dioxolan-5-carboxylate(30 g, Yield 59%) as a white solid.
Reaction SMILES: FC1C=C2C(=CC=1)NC(=O)C2.N1C=CN=C1C(N)=O.[NH2:20][CH2:21][C@@H:22]([OH:30])[CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(#N)C.O1CCCC1>[NH2:20][CH2:21][C@H:22]([OH:30])[CH2:23][N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: NC[C@@H](O)CN1CCOCC1
Agent: NC(=O)c1ncc[nH]1
Agent: O=C1Cc2cc(F)ccc2N1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: NC[C@H](O)CN1CCOCC1
Temperature: 60 °C

Procedure:
A 0.25 L flask fitted with a thermometer, condenser, magnetic stirring, and nitrogen inlet was charged with 4.92 g 5-Fluorooxindole, 7.0 g Imidazole amide, 15.5 g (R)-1-Amino-3-(4-morpholinyl)-2-propanol, 9.78 g Triethylamine and 88 ml Tetrahydrofuran. The mixture was heated to 60° C. for 16.5 hours. The reaction is cooled to ambient temperature and filtered. The solids obtained are slurried (3) three successive times in acetonitrile at 11 ml/g, dried in vacuo for 3.6 g (25.25%). [HPLC, Hypersil BDS, C-18, 5μ, (6:4), Acetonitrile:0.1M Ammonium Chloride, PHA-571437=4.05 min.] H1NMR (DMSO): δ10.86 (1H,bs); 7.75 (1H,d); 7.70 (1H,s); 7.50 (1H,m); 6.88 (2H,m); 4.72 (1H,bs); 3.78 (1H,bs); 3.56 (4H,m); 3.32 (6H,m); 3.15 (1H,m); 2.43 (8H,bm).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([O:20]CC)=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([OH:20])=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(C3CC3)cc(C(=O)O)c12

Procedure:
To a solution of ethyl 6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (278 mg, 0.922 mmol) in ethanol (30 mL) was added sodium hydroxide (3.69 mL, 3.69 mmol) and the contents heated at reflux for 2 hours. The solvent was removed in vacuo, the residue dissolved in 20 mL of water, and acidifed by addition of acetic acid. The contents were extracted with EtOAc (4×30 ml). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was collected as 233 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.12 (m, 4 H), 1.69 (s, 9 H), 2.22-2.41 (m, 3 H), 2.52 (s, 3 H), 7.45 (s, 3 H). LCMS(ES) [M+H]+ 274.2
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[N:19]1([CH2:17][N:9]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: Fc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc2c(c1)c(-c1ccccc1)nn2CN1CCCCC1
Yield: 61.5 %

Procedure:
3-Phenyl-5-fluoroindazole (2.12 g), paraformaldehyde (0.33 g), piperidine (1 g) and 1N aqueous sodium hydroxide solution (1 ml) were added to ethanol (30 ml) followed by heating under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in benzene, washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 1.9 g of 1-piperidinomethyl-3-phenyl-5-fluoroindazole having a melting point between 82°-84° C after recrystallization from methanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH:19]([OH:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[H-].[Na+].Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:21][CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:20])[N:11]2[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2cnccc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3cnccc3n2)CC1
Yield: 80.6 %

Procedure:
Following the procedure of Example 4 but starting with 2-(1,6-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (1.7 g.) in anhydrous tetrahydrofuran (17 cc.), sodium hydride (50% dispersion in mineral oil) (0.58 g.), 1-chlorocarbonyl-4-methylpiperazine (0.5 g.) in anhydrous tetrahydrofuran (5 cc.) and hexamethylphosphotriamide (4.5 cc.), a product (1.3 g.), melting at 215° C., is obtained. After washing with diisopropyl ether (30 cc.), this product is dissolved in methylene chloride (40 cc.). After filtration, the solution is concentrated to dryness to yield 3-(4-methylpiperazin-1-yl)carbonyloxy-2-(1,6-naphthyridin-2-yl)isoindolin-1-one (1 g.) melting at 215° C.