Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([OH:48])=O)#N.CCN(C(C)C)C(C)C>C(#N)C>[C:17]([C:51]1[CH:43]=[CH:44][C:45]([C:46]([NH:1][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=2)=[O:48])=[CH:49][CH:50]=1)#[N:18]
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Temperature: 80 °C

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (step b) (30 mg, 0.138 mmol) in 1.0 mL acetonitrile was added HATU (104 mg, 0.273 mmol), 3-cyano benzoic acid (30 mg, 0.203 mmol) and DIPEA (48.0 ul). The reaction mixture was heated to 80° C. for five hours. Cooled the reaction mixture and light yellow precipitate was filtered, washed with acetonitrile to yield 4-cyano-N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide. The crude product was further dissolved in 1.0 mL ethanol, added hydantoin (10 mg, 0.01 mmol) and pipperdine (9.5 ul). The reaction was heated to 80° C. for three hours. Cooled the reaction mixture and precipitate was filtered, washed with ethanol to yield 7 mg (40% yield, two steps) (Z)-4-cyano-N-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzamide. LCMS (M+1=429)
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.CN(C(ON1N=[N:30][C:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:39](N(CC)C(C)C)(C)[CH3:40]>CN(C=O)C>[ClH:1].[N:29]12[CH2:28][CH2:27][CH:26]([CH2:39][CH2:40]1)[C@H:25]([NH:30][C:12]([C:3]1[S:4][C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[C:2]=1[Cl:1])=[O:14])[CH2:24]2
Reactant: O=C(O)c1sc2cc(F)ccc2c1Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1sc2cc(F)ccc2c1Cl

Procedure:
158 mg (0.69 mmol) of 3-chloro-6-fluoro-1-benzothiophene-2-carboxylic acid, 124 mg (0.62 mmol) of S-3-aminoquinuclidine dihydrochloride, 284.2 mg (0.75 mmol) of HATU, 289.8 mg (2.24 mmol) of N,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 4M HCl in dioxane and methanol and then reconcentrated. 190.5 mg (81.5% of theory) of the title compound are obtained. The analytical data correspond to those of the enantiomeric compound from example 56.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1.[CH3:29]C(C)([O-])C.[K+].IC.C(OCC)(=O)C>O1CCOCC1>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2]([NH:1][CH3:29])=[N:3][CH:4]=[C:5]([Br:28])[N:6]=2)[CH2:9][C@@H:10]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNc1ncc(Br)nc1N1CCN(C(=O)OC(C)(C)C)[C@@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 309.9 %

Procedure:
To a solution of 2-amino-5-bromo-3-[(S)4-Boc-3-benzylpiperazinyl]pyrazine 108 (140 mg, 0.313 mmol) in anhydrous dioxane (3 mL) was added a 1 M solution of potassium t-butoxide (0.34 mL, 0.34 mmol). The reaction mixture was stirred at room temperature for 10 minutes and iodomethane (89 mg, 0.627 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-[(S)-4-Boc-3-benzylpiperazinyl]-5-bromo-2-methylaminopyrazine 111 (45 mg, 0.97 mmol).
Reaction SMILES: [CH2:1]([S:8][CH:9]([S:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:10][C@@H:11]([C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:21])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH2:32]([S:31][CH:9]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][C@@H:11]([C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:21][S:40]([CH3:39])(=[O:42])=[O:41])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O[C@@H](COCc1ccccc1)[C@H](CC(SCc1ccccc1)SCc1ccccc1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@@H](COCc1ccccc1)[C@H](CC(SCc1ccccc1)SCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-di-O-benzyl-2-deoxy-L-threo-pentose dibenzyl dithioacetal (61.4 g, 113 mmol) in dry pyridine (700 ml) was added methanesulphonyl chloride (19.4 g, 169 mmol) in dry pyridine (200 ml) dropwise, with stirring, at 0° C. The temperature of the mixture was raised to room temperature and stirring continued for 18 hours. The pyridine was then removed in vacuo and the residue dissolved in dichloromethane. The dichloromethane extracts were then successively washed with 2M hydrochloric acid, 1M sodium carbonate and water, dried (magnesium sulphate) and evaporated to give the title product as a thick viscous syrup. A sample of this was crystallised from hexane-ethyl acetate to give the title product as white crystals, m.p 82°-83° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: N#CC1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: N#C[C@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O

Procedure:
1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (23 g) obtained in Step D of Example 103 was resolved by HPLC (column: CHIRALPAK IC, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=200/800) to give the title compound (11 g: a longer retention time).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:27]([OH:29])[CH3:28])[C:14]([NH:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[O:26][C:14]([C@H:13]([NH:12][C:6]3[C:7]4[CH:11]=[CH:10][S:9][C:8]=4[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C@@H:27]([OH:29])[CH3:28])=[N:16][N:17]=2)=[CH:24][CH:23]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.53 g, 1.29 mmol) in THF (90 mL) was added PS-BEMP (1.76 g, 3.87 mmol, ˜2.2 mmol g) and p-TsCl (265 mg, 1.39 mmol) at room temperature. The mixture was stirred at room temperature for 8 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-0)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (139 mg, 27%) and the dehydration product 4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (8 mg, 2%). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.03 (dd, J=5.3, 8.8 Hz, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.32 (t, J=8.8 Hz, 2H), 6.83 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.20 (dd, J=4.7, 8.4 Hz, 1H), 4.78 (b, 1H), 4.63 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.11 (dd, J=5.3, 8.6 Hz, 2H), 7.96 (d, J=5.6 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.6 Hz, 2H), 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>[H][H].O=[Pt]=O>[OH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[CH2:10][N:1]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])[CH2:6][CH2:5][N:4]([CH2:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])[CH2:3][CH2:2]1
Reactant: C1CNCCNCCN1
Reactant: [H][H]
Reactant: O=Cc1ccccc1O
Agent: O=[Pt]=O
Product: Oc1ccccc1CN1CCN(Cc2ccccc2O)CCN(Cc2ccccc2O)CC1

Procedure:
From 1,4,7-triazacyclononane, salicylaldehyde and H2/PtO2.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@@H:4]([C:17]([OH:19])=[O:18])[CH2:3]1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.CCOC(C)=O.CCCCCC>[Si:29]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@@H:4]([C:17]([OH:19])=[O:18])[CH2:3]1)([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a mixture of cis4-hydroxy-N-benzyloxycarbonyl-D-proline (18.74 g) and imidazole (11.56 g) in DMF (100 mL) was added TBDMSCl (23.36 g) at 5° C. After stirring at room temperature for 16 hours, the reaction mixture was diluted with EtOAc-hexane (1:1, 600 mL), washed with 1N HCl, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was dissolved in MeOH-THF (3:1, 400 mL). To the solution was added an aqueous solution (100 mL) of K2CO3 (9.77 g) at 5° C., and the mixture was stirred at the same temperature for 1 hour. The organic solvent was evaporated, and the residue was adjusted to pH 2 by the addition of 3N HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography to give cis-4-(tert-butyldimethylsilyloxy)-N-benzyloxycarbonyl-D-proline (23.99 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[NH:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)NC(=O)CN(CC1CC1)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CN(CC1CC1)C2
Yield: 38.4 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-cyclopropylmethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (150 mg, 0.57 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (162 mg, 0.48 mmol) were coupled to provide N-(1R,2R)-{2-[5-chloro-2-(4-cyclopropylmethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (104 mg, 38%) as a tan solid following preparative tlc on silica gel (10% MeOH-DCM); 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.86 (d, J=8 Hz, 1H), 3.86 (s, 3H), 3.82 (m, 2H), 3.68 (s, 2H), 3.32 (s, 3H), 3.22 (s, 2H), 2.88 (m, 3H), 2.41 (m, 3H), 1.97 (m, 2H), 1.63 (m, 2H), 1.37 (m, 2H), 0.87 (m, 1H), 0.48 (m, 2H), 0.14 (m, 2H); MS (m/e) 564 (M+1); mp 97° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](I)[CH3:23]>CC(C)=O.ClCCl>[CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH2:22][CH3:23])=[O:10])[N:5]=[N:4][N:3]=1
Reactant: CCI
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Under a nitrogen atmosphere, 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (89.7 g, 0.44 mol) was dissolved in acetone (1 L) and cesium carbonate (214.7 g, 0.66 mol) was added with vigorous stirring. Ethyl iodide (70.3 ml, 0.88 mol) was added dropwise and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature and filtered. The acetone was removed in vacuo to yield a yellow solid which was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate (200 ml). The organic fraction was dried (Na2SO4), filtered, and concentrated to yield 92.7 g of ethyl 2-(5-methyl-1H-tetrazol-1-yl)benzoate as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13].[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13]
Reactant: COc1nc(C)nc(N)n1
Reactant: COCCOc1ccccc1S(=O)(=O)N=C=O
Solvent: C1COCCO1
Product: COCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1

Procedure:
9.0 g of 2-methoxyethoxy-phenylsulfonyl isocyanate and 4.9 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are refluxed in 60 ml of absolute dioxane for 3 hours. The mixture is treated with activated carbon, filtrated and evaporated to 1/5 of the original volume. After addition of ether 13.0 g of N-(2-methoxyethoxy-phenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea crystallise therefrom, m.p. 134°-138° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[Cl:21][C:15]([CH:13]1[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[O:17]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid (21.25 mmol, 5 g) in dichloromethane (60 ml) under a nitrogen atmosphere were added N,N-dimethylformamide (1.063 mmol, 0.083 ml) and oxalyl chloride (2M solution in dichloromethane, 25.00 mmol, 12.5 ml). After stirring at room temperature for two hours the reaction mixture was concentrated in vacuo to give 5.53 gram of crude benzyl 3-(chlorocarbonyl)azetidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([OH:15])CO)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].I([O-])(=O)(=O)=O.[Na+]>O.C(OCC)C>[OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[O:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(CC(O)CO)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1ccc(CC=O)cc1
Reaction time: 2 h

Procedure:
A biphasic mixture of 3-[4-(1-hydroxy-1-methylethyl)phenyl]propane-1,2-diol (5.44 g, 25.9 mmol) in water (85 mL) and diethyl ether (170 mL) was charged with sodium periodate (11.07 g, 51.7 mmol) and stirred vigorously for two hours. The reaction mixture was then partitioned between diethyl ether (50 mL) and saturated aqueous sodium thiosulfate (50 mL), and the layers were separated. The aqueous layer was extracted with diethyl ether (2×100 mL), and the combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated. To remove water left over, the concentrated material was dissolved in dichloromethane (70 mL), washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4].CCN(CC)CC.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][O:16][S:26]([CH3:29])(=[O:28])=[O:27])[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(CO)co1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-methanol (500 mg, 2.05 mmol) in dry CH2Cl2 (10.0 mL) was treated at 0° C. with Et3N (0.37 mL, 2.65 mmol) followed by DMAP (25 mg, 0.20 mmol) and Ms-Cl (0.20 mL, 2.54 mmol). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.50. LC-MS-conditions 02: tR=1.05 min; [M+H]+=322.25.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]23[CH2:17][CH:16]([CH2:18]2)[C:15](=[O:19])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:13]3=[O:20])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitropenyl)-3-azabicyclo[3.1.1]heptane-2,4 -dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 2.96 g of n-pentyl iodide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation, the product is obtained having a melting point of 75°-79°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([C:14]3=[O:21])[CH2:12]1)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]12[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH:14]3[OH:21])[CH2:20]1)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC12CC3CC(C1)C(=O)C(C3)C2)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC12CC3CC(C1)C(O)C(C3)C2)OCc1ccccc1
Reaction time: 2 h
Yield: 53.2 %

Procedure:
865 mg of (4-Oxo-adamantan-1-yl)-carbamic acid benzyl ester (12) were dissolved in 15 mL of THF and 109 mg of sodium borohydride were added at 0° C. Stirring was continued for 2 h, then the reaction mixture was acidified by addition of 2M HCl. The reaction mixture was extracted three times with ethyl acetate and the combined organic layer was dried over sodium sulphate and evaporated. The resulting oil was subjected to HPLC separation to give 463 mg of the desired product as a cis/trans mixture along with 119 mg of the cis derivative (13a) and 10 mg of the trans derivative (13b). 13a: Rt=1.37 min (Method 3). Detected mass: 302.3 (M+H+). 13b: Rt=1.39 min (Method 3). Detected mass: 302.3 (M+H+);
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([C:20]1[N:21]=[C:22]([CH3:32])[S:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:19].[Cu][C:34]#[N:35].O.C(OCC)(=O)C>CN1CCCC1=O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[S:23][C:22]([CH3:32])=[N:21][C:20]=2[C:18]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH2:11][C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[C:34]#[N:35])=[O:19])=[CH:26][CH:27]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2Br)c(-c2ccc(F)cc2)s1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2C#N)c(-c2ccc(F)cc2)s1

Procedure:
To (RS)-1-[2-(3-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E81 (270 mg, 0.53 mmol) in N-methyl-pyrrolidinone (8 ml) was added copper(I)cyanide (96 mg, 1.06 mmol) and the mixture stirred under argon at reflux for 6 h. The reaction mixture was cooled, poured into water (80 ml) and ethyl acetate (50 ml) and then filtered through kieselguhr. The filtrate was separated and the aqueous phase extracted with ethyl acetate (2×). The combined organics were washed with water (4×50 ml), dried and the solvent removed in vacuo. Chromatography (silica gel) afforded the title compound as a white amorphous solid (94 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.[OH-].[Na+]>CN(C)C=O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:40]([CH:37]4[CH2:39][CH2:38]4)=[O:41])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F)Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 39 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (21.3 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.030 ml) and cyclopropanecarbonyl chloride (0.010 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring for 1 hr. To the reaction mixture were added a 1 N aqueous solution of sodium hydroxide (1.0 ml) and methanol (1.0 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.6 mg, 39%) as white powder.