Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.[CH3:32][N:33](C=O)C>COCCOC.C([O-])(O)=O.[Na+].[C-]#N.[Zn+2].[C-]#N.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>[C:32]([C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1)#[N:33]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Reactant: CN(C)C=O
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: [C-]#N
Solvent: COCCOC
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C#N)n3)cccc2s1
Temperature: 130 °C

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (237 mg, 0.519 mmol, Example 7(d)), zinc cyanide (32 mg, 0.27 mmol) and Pd(PPh3)4 (47 mg, 0.04 mmol, Aldrich) in DMF (1.0 mL) and 1,2-dimethoxyethane (1.0 mL) was heated at 130° C. in a microwave synthesizer for 20 min. The reaction mixture was cooled to room temperature, diluted with saturated aqueous solution of NaHCO3 (10 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (gradient 35-80% EtOAc/hexane) gave the title compound as a light-yellow solid. MS (ESI, pos. ion.) m/z: 456 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10]I)[C@H:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:22].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[N:29]([CH2:10][C@H:9]1[N:6]([CH2:5][C:4]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:3]=2[O:2][CH3:1])[C:7](=[O:22])[C@H:8]1[NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CI)c(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CN=[N+]=[N-])c(OC)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 6 ml of N,N-dimethylformamide are added 740 mg of cis-1(2,4-dimethoxybenzyl)-4-iodomethyl-3-phenylacetamido-2-oxoazetidine and 146 mg of sodium azide and the mixture is stirred for 4 days at room temperature. The solvent is distilled off in vacuo, and ethyl acetate and water are added to the residue. The ethyl acetate layer is separated, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off in vacuo. To the residue, ether is added and the precipitated crystals are collected by filtration to give cis-4-azidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine, m.p. 110°-111° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[OH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccccc1O
Product: O=C(O)c1ccncc1NCc1ccccc1O
Yield: 2 %

Procedure:
The title compound was prepared in 2% yield from 2-(aminomethyl)phenol and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.30 (br s, 1H), 9.67 (s, 1H), 8.20 (s, 1H), 7.79 (d, 1H, J=4.9 Hz), 7.54 (d, 1H, J=4.9 Hz), 7.20 (d, 1H, J=7.0 Hz), 7.09 (t, 1H, J=7.6 Hz), 6.84 (d, 1H, J=8.1), 6.84 (dd, 1H, J=7.4 Hz), 4.44 (s, 2H). [M+H] calc'd for C13H12N2O3, 245; found 245.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[NH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:21][CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Reactant: NC1CCc2ccccc21
Solvent: CCO
Product: O[C@H](CNC1CCc2ccccc21)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 1-aminoindane and ethanol essentially as described above in Example 96. Purity by LC/MS=100%, [M+H]+=416.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:47]=[CH:46][C:33]([C:34]([NH:36][C:37]2[CH:38]=[C:39](B(O)O)[CH:40]=[N:41][CH:42]=2)=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:39]2[CH:38]=[C:37]([NH:36][C:34](=[O:35])[C:33]3[CH:46]=[CH:47][C:30]([OH:29])=[CH:31][CH:32]=3)[CH:42]=[N:41][CH:40]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: O=C(Nc1cncc(B(O)O)c1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(NC(=O)c4ccc(O)cc4)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (5-(4-hydroxybenzamido)pyridin-3-yl)boronic acid (88 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 227 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by reverse phase using SP1® Purification System to give 29 mg (21% yield) of the title compound as a white solid. Purity 96%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:17][NH:18][O:19][CH3:20]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:18]([CH2:17][C:16]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:14]([F:13])[CH:15]=2)[O:19][CH3:20])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(C)c(F)c1
Product: CON(Cc1ccc(C)c(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 100 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-fluoro-4-methyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (100% yield): mp 131° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 2.25 (3H, broad s, CH3), 3.69 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.39 (1H, s, CH), 7.0-7.03 (2H, m, aromatics), 7.13 (1H, m, aromatic). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.51; H, 5.60; N, 4.24.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][F:23])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH2:22][F:23])=[O:34])=[CH:19][CH:20]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(SCF)cc2)OC1(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(S(=O)CF)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-(4-fluoromethylsulfanyl-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.67 g, 7.158 mmol) in DCM (250 mL) is cooled to −78° C. followed by addition of solution of m-CPBA (1.59 g, 7.158 mmol) in DCM (25 mL). Reaction mixture is allowed to stir −78° C. for 20 minutes. After completion of the reaction mixture is quenched with aqueous bicarbonate solution and extracted with DCM. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography (40 g column) using 78% ethyl acetate in hexane as an eluent to afford title compound (1.88 g) as colorless oil. 1H-NMR (400 MHz, DMSO): δ 1.42 (s, 9H), 1.50 (s, 3H), 1.62 (s, 3H), 383-.388 (m, 1H), 4.46-4.58 (m, 1.5H), 4.75-4.84 (m, 1.5H), 5.17 (d, J=7.2 Hz, 1H), 5.25-5.27 (dd, J=1.12 Hz, J=8.8 Hz, 0.5H), 5.37-5.39 (m, 0.5H), 5.51-5.54 (dd, J=2.44 Hz, J=8.84 Hz, 0.5H), 5.63-5.64 (m, 0.5H), 7.70-7.77 (m, 4H). LC-MS (m/z): M+H=390.4.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1I.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17]
Reactant: Cc1cccc(I)c1Br
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C#CC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with bis(triphenylphosphine)palladium(II)chloride (0.042 g, 0.060 mmol) and copper(I) iodide (0.023 g, 0.120 mmol) under nitrogen atmosphere. THF (4.6 mL) was added, followed by 2-bromo-1-iodo-3-methylbenzene (0.594 g, 2 mmol), triethylamine (2.3 mL, 16.50 mmol) and 3,3-dimethylbutyne (0.251 mL, 2.040 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was filtered through a plug of silica gel and the plug was rinsed with Et2O. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (0-2% EtOAc/hexanes). 2-Bromo-1-(3,3-dimethylbut-1-ynyl)-3-methylbenzene was obtained as a light-yellow clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:36](O)=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:39]([O:46][CH2:47][CH2:48][NH:49][CH:50]([CH3:52])[CH3:51])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:36]([N:49]([CH2:48][CH2:47][O:46][Si:39]([C:42]([CH3:44])([CH3:43])[CH3:45])([CH3:40])[CH3:41])[CH:50]([CH3:51])[CH3:52])=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[C:24]([C:32]([F:34])([F:33])[F:35])[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-N-(2-((tert-butyl-dimethylsilyl)oxy)ethyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (463) was synthesized from 5-(benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (462) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (245).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)OCC[O:9]2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(CCCN3CCc4ccccc4C3)OCCO2)cc1
Agent: Cl
Solvent: CO
Product: O=C(CCCN1CCc2ccccc2C1)c1ccc(F)cc1
Yield: 106.5 %

Procedure:
Dioxolane 4A (2.75 g, 6.0 mmol) and 1 M HCl (15 mL) were stirred in MeOH (50 mL) at RT for 3 days. After concentration in vacuo the residue was extracted with EtOAc (400 mL) and 1 M NaOH (100 mL), then H2O (2×50 mL), and brine (25 mL). The solution was dried (Na2SO4), filtered, and concentrated to yield ketone 11A (1.9 g, quant.) as a yellow solid. 13C NMR(300 MHz, CDCl3, δ): 198.60, 165.59 (d, J=254 Hz), 134.85, 134.38, 133.56, 131.65 (d, J=9 Hz), 128.61, 126.56, 126.08, 125.56, 115.52 (d, J=22 Hz), 57.36, 56.08, 50.87, 36.14, 29.12, 21.79.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH+:8]([O-:19])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: [O-][NH+]1C=Cc2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.6 %

Procedure:
To 5-chloro-1H-pyrrolo[2,3-b]pyridine (10.0 g, 65.6 mmol) in EtOAc (70 mL) at 0° C. was added dropwise over 15 h a solution of m-chloroperbenzoic acid (57%, 17.9 g, 104 mmol) in EtOAc (80 mL). The reaction mixture was stirred for 20 h at RT. Then, the mixture was cooled to −40° C. and the solids were filtered off and rinsed with cold EtOAc. The solid was taken up in water (70 mL) and treated dropwise with 30% aq. K2CO3 until pH was 11. The solution was warmed for 30 min, cooled to 0° C., filtered and dried in vacuo. Analysis (NMR) indicated the presence of m-chloroperbenzoic acid. The solid was taken up in 10% MeOH in DCM and washed with 30% aq. K2CO3 until all m-chlorobenzoic acid was removed. The organic layer was dried over Na2SO4, filtered and concentrated to provide 2.61 g (24% yield) of 5-chloro-1H-pyrrolo[2,3-b]pyridine-N-oxide (C). The combined mother liquors were concentrated. Flash chromatography (5% MeOH-DCM) provided and additional 1.49 g (13% yield) contaminated with ˜10% of the benzoic acid. LC/MS (M+H+) 168.76.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][NH2:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9].[F:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>C(#N)C>[F:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][NH:16][C:34]([NH:33][C:24]3[CH:25]=[CH:26][C:27]([N:28]4[CH2:29][CH:30]([OH:32])[CH2:31]4)=[C:22]([F:21])[CH:23]=3)=[O:35])=[CH:13][C:12]([C:17]([F:20])([F:18])[F:19])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1ccc(F)c(F)c1
Agent: Cl
Solvent: CC#N
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1ccc(F)c(F)c1)Nc1ccc(N2CC(O)C2)c(F)c1
Yield: 87.9 %

Procedure:
To a stirred solution of ((1-(3,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (75 mg, 0.239 mmol, 1.0 eq) in acetonitrile (5.5 mL) was added TEA (0.13 mL, 0.96 mmol, 4.0 eq.) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (73 mg, 0.244 mmol, 1.02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (4:1) as eluent) to get 1-((1-(3,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (102 mg, 88%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:4]=1[C:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[N:8]1)=[O:6]>CCO.[Pd]>[CH3:1][NH:2][C:3]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:4]=1[C:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[N:8]1)=[O:6]
Reactant: CNc1ccc([N+](=O)[O-])cc1C(=O)n1nc(O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(N)cc1C(=O)n1nc(O)c2ccccc21
Reaction time: 16 h

Procedure:
To 1.1 g. of 1-(2-methylamino-5-nitrobenzoyl)-1H-indazol-3-ol, prepared in Example 14, suspended in 200 ml of absolute EtOH was added 200 mg of 5% Pd/C and the mixture was hydrogenated at 50 psi for 16 hours. The catalyst was filtered off, washed with hot EtOH and the filtrate was diluted with H2O and concentrated to small volume. The precipitate was collected, washed with cold 95% EtOH and dried; yield of dark-yellow amorphous powder 0.65 g. (65.4%); m.p. 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccncc1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccncc4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 4-bromomethyl-pyridine gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[S:11][C:12]([CH3:19])=[CH:13][C:14]=1[S:15](Cl)(=[O:17])=[O:16]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:14]1[CH:13]=[C:12]([CH3:19])[S:11][C:10]=1[CH3:9])(=[O:17])=[O:16]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1cc(S(=O)(=O)Nc2onc(C)c2Br)c(C)s1
Yield: 55 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dimethylthiophene-3-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 2,5-dimethylthiophene-3-sulphonyl chloride in 55% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 77-80° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>C(#N)C>[CH3:33][N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]2=3)=[O:3])[CH2:28][CH2:29]1
Reactant: CN1CCC(N)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(NC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
Amounts of 3.2 gm (0.012 mol) of 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2.1 gm (0.02 mol) of sodium carbonate were refluxed in 100 ml of acetonitrile together with 2.3 ml (0.02 mol) of 4-amino-1-methyl-piperidine for 15 minutes under stirring. The mixture was filtered while hot, and the filtrate was purified over a silica gel column [eluant: acetonitrile; followed by methylene chloride/ethyl acetate/cyclohexane/methanol/ammonia (175:75:23:23:3)]. The desired fraction was concentrated by evaporation in vacuo, and the residue was recrystallized from 50% aqueous acetonitrile.
Reaction SMILES: [P:1]([O:13]C[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].P(O[CH2:42][C@H:43]1[O:47][C@@H:46]([N:48]2[C:58]3[N:57]=[C:55]([NH2:56])[NH:54][C:52](=O)[C:51]=3[N:50]=[CH:49]2)[CH2:45][C@@H:44]1[OH:59])(OP(OP(O)(O)=O)(O)=O)(=O)O.OP(=O)(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)OP(=O)(OP(=O)(O)O)O>>[CH:55]1[N:57]=[C:58]2[N:48]([C@@H:46]3[O:47][C@H:43]([CH2:42][O:12][P:9]([O:8][P:5]([O:4][P:1]([OH:13])([OH:3])=[O:2])([OH:7])=[O:6])([OH:11])=[O:10])[C@@H:44]([OH:59])[CH2:45]3)[CH:49]=[N:50][C:51]2=[C:52]([NH2:54])[N:56]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1

Procedure:
3.75 microliter 6.6 mM mix of dCTP, dGTP and dTTP
Reaction SMILES: [CH3:1][O:2][C:3]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)([O:5][CH3:6])[CH3:4].[Li]CCCC.C(Br)(Br)(Br)[Br:18]>C1COCC1>[Br:18][C:9]1[S:8][C:7]([C:3]([O:5][CH3:6])([O:2][CH3:1])[CH3:4])=[N:11][CH:10]=1
Reactant: COC(C)(OC)c1nccs1
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(C)(OC)c1ncc(Br)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of 2-(1,1-dimethoxyethyl)-1,3-thiazole (40 g, 0.23 mol) in THF (600 ml) was added n-BuLi (100 ml, 0.25 mol) dropwise at −78° C. After stirring for 1 h at −78° C., a solution of CBr4 (300 g, 0.9 mol) in THF (300 ml) was added drop-wise. The reaction mixture was stirred for another 1 h at −78° C., and then was quenched by the addition of sat. aq. NH4Cl and was extracted with ethyl acetate (150 ml×3). The organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column (eluted by petroleum ether/EtOAc=10:1) to afforded 25 g of 5-bromo-2-(1,1-dimethoxyethyl)-1,3-thiazole as solid (43%). 1H-NMR (CDCl3 400 MHz) δ 7.81 (s, 1H, Ar—H), 3.23 (s, 6H, —OCH3), 1.72 (s, 3H, —CH3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[C:11](=O)(OC)[O:12]C.C[O-].[Na+]>CO>[Br:10][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:11](=[O:12])[O:9][CH2:8][C:7]=2[CH:6]=1
Reactant: COC(=O)OC
Reactant: Nc1ncc(Br)cc1CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ncc(Br)cc2CO1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a stirred solution of 2-amino-5-bromo-3-(hydroxymethyl)pyridine (3.0 g, 15 mmole) in methanol (30 mL) was added dimethyl carbonate (5 mL, 60 mmole) and sodium methoxide (25 wt % solution in methanol, 4 mL, 17.4 mmole). The reaction was heated at reflux for 18 hr, cooled to RT, and concentrated to dryness. The remaining residue was triturated with saturated aqueous NH4Cl (50 mL), filtered, washed with cold H2O (50 mL), and dried under vacuum to give the title compound (1.75 g, 51%) as a beige solid: LCMS (ES) m/e 229.0 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 5.31 (s, 2H).