Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:21])[C:7]=2[C:22]=1[O:23][CH3:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[C:2]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:21])[C:7]=2[C:22]=1[O:23][CH3:24])([OH:26])=[O:1]
Reactant: COc1cc(C)cc2c1Sc1ccc(CO)c(OC)c1C(=O)OC2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)cc2c1Sc1ccc(C(=O)O)c(OC)c1C(=O)OC2

Procedure:
560 mg (1.62 mmol) of the compound from Example VI are stirred overnight at 25° C. with 9.13 g (24.3 mmol) of pyridinium dichromate in 20 ml of dimethylformamide. The mixture is poured into water and washed with ether, the ether phase is washed with water and dried over sodium sulphate and, after concentrating in vacuo, the residue is chromatographed on silica gel using methylene chloride/ethanol 10:1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[CH:15][C:14]([C:17]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:20]4[CH:21]=[CH:22][C:23]5[N:24]([C:25]([CH3:28])=[N:26][N:27]=5)[C:19]=4[CH:18]=3)=[N:13]2)[CH2:9]1.C([O-])([O-])=O.[K+].[K+].[C:44](#[N:47])[CH:45]=[CH2:46].N12CCCN=C1CCCCC2>CC#N.CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:29]1[C:20]2[CH:21]=[CH:22][C:23]3[N:24]([C:25]([CH3:28])=[N:26][N:27]=3)[C:19]=2[CH:18]=[C:17]1[C:14]1[CH:15]=[CH:16][N:12]([CH:10]2[CH2:9][N:8]([CH2:46][CH2:45][C:44]#[N:47])[CH2:11]2)[N:13]=1
Reactant: C=CC#N
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5CN(CCC#N)C5)n4)n3Cc3cccc(Cl)c3)n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-(1-Azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine trifluoroacetate salt (19 mg, 0.025 mmol, prepared as in Example 156) in MeCN (1.0 mL) was treated with K2CO3 (34 mg, 0.25 mmol) and 2-propenenitrile (3.3 μL, 0.050 mmol, Aldrich). The reaction was stirred at room temperature for 2 hours and then was heated at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and additional 2-propenenitrile (3.3 μL, 0.050 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.7 μL, 0.025 mmol, Aldrich) were added. After stirring at room temperature for 3 days, the reaction was diluted with MeOH (2 mL) and MeCN (2 mL) and was purified via preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[N:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[N:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c2nccnc12
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1ccc(N)c2nccnc12
Temperature: 70 °C
Yield: 99.9 %

Procedure:
Compound 468A (0.200 g, 1.00 mmol) was suspended in acetic acid (5.0 mL) and iron powder (325 mesh, 0.112 g, 2.00 mmol) was added. The reaction was then heated at 70° C. for 20 min and then cooled to 22° C. The reaction was filtered through Celite, rinsing with ethyl acetate. The ethyl acetate rinse was collected and washed with sat. aq. K2CO3. The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organic layers were dried over anhydrous magnesium sulfate. Concentration in vacuo gave 0.170 g (100%) of compound 468B as a yellow solid. HPLC: 88% at 1.677 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 171.29 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
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: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccc(Cl)cc3)ccc2C1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
To a mixture of 6-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2 g, 5.25 mmol) and 4-chlorophenyl boronic acid (1.17 g, 7.5 mmol)in toluene (20 ml) was added a 2M sodium carbonate solution (7.5 ml). The reaction mixture was stirred under a nitrogen atmosphere, then tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. After allowing to cool the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. Purification by flash chromatography using hexane/ethyl acetate as eluant gave the title compound as an oil (0.7 g, 39%); δH (CDCl3) 1.5 (9H, s, C(CH3)3), 2.89 (2H, t, J 8.3 Hz, CH2), 3.68 (2H, t, J 8.3 Hz, CH2), 4.61 (2H, s, CH2), and 7.15-7.5 (7H, m, ArH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].C1C=CC2N(O)N=[N:18]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:18])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-benzoic acid (1.2 eq), the amine derivative (1 eq), HOBt (1.2 eq), DIEA (1.2 eq) and EDCI.HCl (1.2 eq) were dissolved in dry DMF (0.15 M), under argon. The mixture was stirred at room temperature overnight. DMF is evaporated and saturated NaHCO3 solution was added. Product was extracted with EtOAc, dried over Na2SO4, filtered and evaporated. The crude was purified on reverse phase (H2O 1% TFA/MeCN 1% TFA 100/0, 0/100). MeCN was evaporated. The product was suspended in H2O and basified with saturated NaHCO3 solution until pH=8-9. The aqueous layer was extracted three times with AcOEt. The organic layer was evaporated to give the final compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni].CO>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: Nc1cccc(S(N)(=O)=O)c1
Reaction time: 4 h
Yield: 92.8 %

Procedure:
3-Nitro-benzenesulfonamide (1.46 g, 7.2 mmol) was hydrogenated over Raney nickel (0.3 g) in methanol at 50° C. and 70 psi for 4 h, then catalyst was filtered out, washed with warm methanol, combined filtrates were evaporated to give 1.15 g (93%) of 3-amino-benzenesulfonamide as colorless solid.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[F:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][OH:34])=N)=[CH:29][CH:28]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:34][N:33]=[C:31]([C:30]4[CH:35]=[CH:36][C:27]([F:26])=[CH:28][CH:29]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)c1ccc(F)cc1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccc(F)cc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 4-fluoro-N-hydroxy-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.87 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([CH2:33][CH2:34][OH:35])[CH:32]=1)[CH2:5][N:6]1[CH2:29][CH2:28][C:9]2([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]3[N:18]=[C:19]([C:22]4[CH:27]=CC=C[CH:23]=4)[S:20][CH:21]=3)=[O:16])[CH2:10]2)[CH2:8][CH2:7]1.N.[CH3:37]O>>[C:22]([C:19]1[S:20][CH:21]=[C:17]([C:15]([N:11]2[CH2:10][C:9]3([CH2:28][CH2:29][N:6]([CH2:5][C:4]4[CH:30]=[C:31]([CH2:33][CH2:34][OH:35])[CH:32]=[C:2]([F:1])[CH:3]=4)[CH2:7][CH2:8]3)[O:14][CH2:13][CH2:12]2)=[O:16])[N:18]=1)([CH3:37])([CH3:23])[CH3:27]
Reactant: CO
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Agent: N
Product: CC(C)(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2,2,2-trifluoro-1-(9-(3-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone (example 41, step d) (0.21 g) in methanol (3 mL) was added to ammonia (35% aqueous solution, 15 mL) and the reaction mixture stirred at 20° C. for 1 hour. The mixture was evaporated to dryness under reduced pressure and the residue azeotroped three times with acetonitrile. The residue was dissolved in DMF (7 mL) and treated with 2-tert-butylthiazole-4-carboxylic acid (0.096 g) followed by triethylamine (0.290 mL) and then HATU (0.257 g) and the resultant mixture stirred at 20° C. for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.22 g.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C([C:43](OO)=[O:44])C=1.CO.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([O:44][CH3:43])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A suspension of 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 96 (15 mg, 0.030 mmol) in CH2Cl2 (1 mL) was treated with mCPBA (70%, 8.94 mg, 0.036 mmol). After 30 min, methanol (0.050 mL 1.2 mmol) and triethylamine (0.020 mL, 0.14 mmol) were added and the resultant mixture was heated to 40° C. overnight. The reaction was concentrated in vacuo and purified by chromatography to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(2-methoxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea. (8.6 mg, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.90 (s, 1H), 7.20 (d, J=12.3 Hz, 1H), 6.00 (s, 1H), 4.02 (s, 3H), 3.63 (s, 3H), 2.09 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 481.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[CH:4]=1)#[N:2].[Cl-].[NH4+].[N-:15]=[N+:16]=[N-:17].[Na+].[OH-].[Na+]>CN(C=O)C.O>[CH3:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1]2[NH:17][N:16]=[N:15][N:2]=2)=[CH:4]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(C#N)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2nnn[nH]2)c2ccccc21
Reaction time: 26 h
Yield: 19.5 %

Procedure:
3-Cyano(1-methyl-1H-indole) (J. Med. Chem. 199, 34, 147) (0.500 g, 3.21 mmol) was dissolved in dry DMF (4 ml) and treated with ammonium chloride (0.214 g, 4.01 mmol) and sodium azide (0.260 g, 4.01 mmol). The mixture was then heated to reflux with stirring. After 26 h, the reaction mixture was allowed to cool and was evaporated under reduced pressure to give a brown oil. Water (15 ml) was added to this residue whereupon it solidified. The mixture was made strongly basic with sodium hydroxide solution and then extracted with diethyl ether. The aqueous layer was then treated with activated charcoal and heated on a water bath for 10 minutes. The mixture was then filtered and the filtrate acidified with 5M HCl to pH4. The resulting brown precipitate was then filtered off and dried in vacuo to give the title compound (0.125 g, 20%) as a pale brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:33][CH3:34])=[C:17]3[N:22]([CH:23]=2)[CH:21]=[CH:20][CH:19]=[C:18]3[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][C:36](=[O:39])[C:37]#[CH:38]>>[C:36]([C:37]1[CH:38]=[C:23]2[N:22]3[C:17](=[C:18]([CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])[CH:19]=[CH:20][C:21]=13)[C:16]([CH2:33][CH3:34])=[C:15]2[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)(=[O:39])[CH3:35]
Reactant: C#CC(C)=O
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO[Si](C)(C)C(C)(C)C)c12
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3ccc(CO[Si](C)(C)C(C)(C)C)c1n32
Yield: 70 %

Procedure:
2-(4-Benzyloxyphenyl)-8-(tert-butyldimethylsilanyloxymethyl)-1-ethylindolizine was reacted with 3-butyn-2-one by the general synthetic principles outlined in example 73, step 1, to afford 4-acetyl-2-(4-benzyloxyphenyl)-7-(tert-butyldimethylsilanyloxymethyl)-1-ethylpyrrolo[2,1,5-cd]indolizine as a brown oil in 70% yield. 1H--NMR (DMSO-d6, 200 MHz) δ: 0.13 (s, 6 H); 0.89 (s, 9 H); 1.37 (t, 3 H); 2.64 (s, 3 H); 3.18 (q, 2 H); 5.20 (s, 2 H); 5.32 (s, 2 H); 7.12-7.54 (m, 7 H); 7.73 (d, 2 H); 7.94 (d, 1 H); 8.18 (s, 1 H); 8.34 (d, 1 H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=O)=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N.Cl.[CH:50]12[NH:57][CH:54]([CH2:55][CH2:56]1)[CH2:53][O:52][CH2:51]2.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH:54]12[N:57]([C:19]([C:16]3[N:8]4[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:6]([C:5]5[O:1][CH:2]=[N:3][CH:4]=5)[C:7]4=[N:18][CH:17]=3)=[O:21])[CH:50]([CH2:56][CH2:55]1)[CH2:51][O:52][CH2:53]2
Reactant: C1CC2COCC1N2
Reactant: O=C(O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12)N1C2CCC1COC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a mixture of 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (80 g), triethylamine (113 mL) and DMF (2000 mL) were added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (127 g) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (42.3 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate solution at 0° C. The obtained solid was collected by filtration, and washed with saturated aqueous sodium bicarbonate solution, water, ethanol and methyl tert-butyl ether to give the title compound (104 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C(N(CC)CC)C>CN(C=O)C.O>[NH2:12][C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[C:8]=2[N:9]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2nnn(CC(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.5 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (2 mL) was treated with 2-bromoacetophenone (100 mg, 0.5 mmol) and triethylamine (105 μL, 0.75 mmol), stirred at room temperature for 3 days, diluted with water (100 mL) and filtered. The resulting solid was purified by chromatography [SiO2; Hexane:EtOAc, (3:1 to 1:1)] to give the title compound (20 mg, 13%) as a yellow solid.
Reaction SMILES: [N:1](CCC(OCC)=O)=[C:2]=[O:3].[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16]N)[CH3:12].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N:1]([CH:15]([CH3:16])[C:14]([O:13][CH2:11][CH3:12])=[O:18])=[C:2]=[O:3]
Reactant: CCOC(=O)CCN
Reactant: CCOC(=O)CCN=C=O
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N=C=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The solution of ethyl 3-isocyanatopropionate in toluene used in the above process can be prepared as follows: A mixture of 15.36 g of β-alanine ethyl ester in 600 ml of toluene is dissolved by heating to 90° C. Then 63 ml of a 20% solution of phosgene in toluene are added over 10 minutes under argon and at a temperature of 90°-95° C. Stirring at ca. 90° C. for 16 hours gives the desired solution of ethyl isocyanatopropionate, which is used direct in the above reaction.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl>O>[CH3:13][N:12]([CH3:14])[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: C1CNCCN1
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: Cl
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)ccc1N1CCNCC1
Reaction time: 1 h

Procedure:
264 Grams of 4-chloro-3-dimethylsulfamoylbenzoic acid (1.0 mole) and 345 g of anhydrous piperazine were heated at 130° C., while stirring, for 1 hour. Subsequently the reaction mixture was dissolved in 2 l of water and the pH value was adjusted to 7 with 5N HCl. After having stood over night, the crystalline precipitate was suction-filtered, washed with water and tetrahydrofurane and recrystallized from water.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[C:45]([CH3:49])[N:46]=[N:47][CH:48]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[CH:44]=[C:45]([CH3:49])[N:46]=[N:47][CH:48]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cnn1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnnc(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-(4-chloro-3,5-dimethyl-phenyl)-3-methyl-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.09 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:17]([O:18]C(=O)C)[C@@H:16]([CH2:22][O:23]C(=O)C)[O:15][C@@H:7]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C@@H:6]1[N:27]=[N+:28]=[N-:29])(=O)C>C[O-].[Na+]>[N:27]([C@@H:6]1[C@@H:5]([OH:4])[C@@H:17]([OH:18])[C@@H:16]([CH2:22][OH:23])[O:15][C@H:7]1[O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:14])[CH3:12])=[N+:28]=[N-:29]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: C[Si](C)(C)CCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1N=[N+]=[N-]
Yield: 93.9 %

Procedure:
Compound 23 (4.88 g, 11.3 mmol) was stirred in methanolic NaOMe (0.04M, 50 ml) for 90 min. The mixture was decationised with Amberlite IR-120(H+) resin, filtered and evaporated to dryness to give 24 (3.24 g, 94%), [α]D25 +8.5° (c 0.8, MeOH), m.p. 158°-161° C. (ether-heptane).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([C@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH:1]1([CH2:7][C@H:8]([C@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
Methyl (2R,3R)-2-cyclohexylmethyl-3-hydroxyhexanoate (3.44 g, 14.2 mmol) is dissolved in 3:1:1 THF-MeOH-H2O (35 mL). To this is added lithium hydroxide monohydrate (1.79 g, 42.6 mmol). The reaction mixture is stirred for 18 h at 25° C. and the mixture is then extracted with ether. The aqueous layer is acidified with solid sodium bisulfate and then extracted with two 250-mL portions of ether. The combined organics are washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to afford (2R,3R)-2-cyclohexylmethyl-3-hydroxyhexanoic acid as a solid (3.05 g, 96% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[N+:33](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[NH2:33][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (46.52 g, 105.5 mmol) and 4-nitrobenzoyl chloride (23.55 g, 126.9 mmol) in methylene chloride (260 mL) was added N,N-diisopropylethyl amine (55.17 mL, 316.7 mmol). The mixture was stirred at rt for 15 h. Yellow precipitates were collected by filtration, washed with ethyl acetate, and dried to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 2.70-2.78 (m, 4H), 2.96-3.02 (m, 1H), 3.81-3.86 (m, 1H), 4.41 (d, J=4.8 Hz, 2H), 7.37 (d, J=5.2 Hz, 1H), 7.44-7.48 (m, 1H), 7.51-7.55 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.88-7.96 (m, 5H), 8.16-8.19 (m, 2H), 8.26-8.29 (m, 2H), 8.33 (d, J=8.8 Hz, 1H), 8.54 (s, 1H); MS (ES+): m/z 590 [MH+]; HPLC: tR=4.37 min (OpenLynx, polar—5 min).