Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([C@H:6]([CH3:8])[OH:7])[NH2:5].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CO>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([C@H:6]([CH3:8])[OH:7])[NH:5][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H](N)[C@H](C)O
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](NC(=O)c1ccccc1)[C@H](C)O
Temperature: 12 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A crude D-threonine methyl ester (39.49 g) was dissolved in 300 mL of methanol and than transferred to the 1 L 3-neck round bottom flask equipped with a thermocouple, magnetic stirrer and cooling ice bath. A solution was chilled to 12° C., and a total of 64.1 g (0.63 mol, 3 eq.) was added to the flask and then cooled to −10° C. A total of 30.9 g (0.21 mol) of benzoyl chloride was added to the solution and resulting mixture stirred at 0° C. for 1 hour. After this period of time the solvent was removed on rotovap to yield a viscous semi-solid. A total of 300 mL of cold water was added to the residue and organic material was extracted with ethyl acetate (2×300 mL). The organic phase was separated, washed with brine (200 mL) and dried over sodium sulfate. The solvent was removed on rotovap to yield 52.02 g (104%) of a clear yellow oil with Rf=0.39 in EtOAc/hexane=6:4). Obtained oil was crystallized from 200 mL of ether to give a white solid, which was filtered off, washed with hexane (2×100 mL) and dried under suction. An additional drying in a vacuum desiccator yielded 42.35 g (84.7% yield in 2 steps).
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][P:25]([OH:28])([OH:27])=[O:26])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:29])[CH2:11]3)[CH:8]=[N:9][C:4]2=[C:3]([NH2:30])[N:2]=1.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)[OH:32].P(OC[C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(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>>[P:17]([O:16][CH2:15][C@H:13]1[O:14][C@@H:10]([N:7]2[C:5]3[N:6]=[CH:1][N:2]=[C:3]([NH2:30])[C:4]=3[N:9]=[CH:8]2)[C@H:11]([OH:32])[C@@H:12]1[OH:29])([O:20][P:21]([O:24][P:25]([OH:28])([OH:27])=[O:26])([OH:23])=[O:22])(=[O:19])[OH:18]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
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
Agent: 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
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
10 μL 25 mM dNTPs (25 mM each dATP, dCTP, dGTP, dTTP)
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9][C:10]1[C:11]2[NH:27][CH:26]=[CH:25][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=1.C1C(=O)N([Cl:36])C(=O)C1>C(Cl)Cl>[Cl:36][C:25]1[C:12]2[N:13]=[C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[C:10]([S:9][C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:28])[C:11]=2[NH:27][CH:26]=1
Reactant: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c(Cl)c[nH]c23)c(C)c1
Yield: 104.8 %

Procedure:
To a solution of 4-(4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (10 mg, 0.02 mmol) in CH2Cl2 (5 mL) was added NCS (2.8 mg, 0.02 mmol) and the resolution mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product (8.8 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH:13]=O.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH2:13][NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: CC(=O)NCc1ccc(Cl)c(C=O)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of N-(4-chloro-3-formyl-benzyl)-acetamide (382 mg, 1.81 mmol) and cyclopropylamine (0.194 mL, 2.71 mmol) in MeOH (18 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (102 mg, 2.71 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. EtOAc (50 mL) was added, and the resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (371 mg, 81%). LC-MS: tR=0.53 min; ES+: 253.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]2[CH3:19])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]2[CH3:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.6 g, 5.9 mmol) in tetrahydrofuran (6 mL)/methanol (5 mL) was added 4N aqueous sodium hydroxide solution (9 mL), and the mixture was stirred at 60° C. for 1 hr. Tetrahydrofuran and methanol were evaporated under reduced pressure. 6N Aqueous hydrochloric acid solution was added to the residue with stirring, and the precipitated solid was collected by filtration. The filtrate was washed with water and ethyl acetate/hexane (1/5), and dried under reduced pressure to give the title compound (1.1 g, 79%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[O:24]1CCC[CH2:25]1>>[F:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]2[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:25](=[O:24])[NH:1][C:2]=2[CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1F
Product: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
1,1-Dimethylethyl 4-[(2-amino-4-fluoro-5-methylphenyl)amino]-1-piperidinecarboxylate (D28) (0.88 mmol, 284 mg) in tetrahydrofuran (30 mL) was treated with N,N′-carbonyldiimidazole (0.88 mmol, 141 mg, 1 eq) under argon at room temperature and was stirred at room temperature overnight. The reaction mixture was then concentrated under vacuum and the residue dissolved in THF (5 ml) and stirred for 3 h then heated at 45° C. for 45 min, then N,N′-carbonyldiimidazole (0.44 mmol, 70 mg, 0.5 eq) was added and allowed to react for 40 min. The mixture was concentrated, partitioned between 10% Na2CO3 aqueous solution and ethyl acetate. Organics were dried on MgSO4, concentrated and chromatographed (EtOAc/pet ether) to give the title compound (0.68 mmol, 239 mg, 77% yield). M−H=348.3.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])=[N:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:11]2[S:20][N:21]=[C:22]([CH3:23])[C:10]=12
Reactant: CCCCOC(=O)c1nc(-c2ccccn2)c2snc(C)c2c1O
Reactant: NCC(=O)O
Product: Cc1nsc2c(-c3ccccn3)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-pyridin-2-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 345.2 (M+1).
Reaction SMILES: CN(C)C=O.C(OC(=O)C)(=O)C.[N:13]([CH2:22][C:23]([OH:25])=[O:24])([CH2:18][C:19]([OH:21])=O)[CH2:14][C:15]([OH:17])=[O:16]>N1C=CC=CC=1>[O:24]=[C:23]1[O:25][C:19](=[O:21])[CH2:18][N:13]([CH2:14][C:15]([OH:17])=[O:16])[CH2:22]1
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)CN1CC(=O)OC(=O)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask is charged with dimethylformamide 72 g, acetic anhydride 25 g, pyridine 2 g, and nitrilotriacetic acid 38.2 g and the suspension is nitrogen purged for several minutes. The flask is stoppered and the mixture is stirred at room temperature for 3 days. A small amount of unreacted NTA is filtered out. The bulk of the solvent 79 ml is removed in vacuo at a bath temperature of 60°-70° C. The resulting viscous solution is twice roto-vacued after two successive additions of 40 ml dimethylformamide.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][CH:8]([OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)=[O:4].[CH2:19]([C:23]1[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:20][C:21]#[CH:22]>>[Si:26]([O:25][C:24]1[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=1[CH2:19][CH2:20][C:21]#[C:22][C:11]1[CH:10]=[C:9]([CH:8]([OH:16])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:18])([F:17])[F:1])[CH:14]=[CH:13][CH:12]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: O=C(NCCC(O)c1cccc(I)c1)C(F)(F)F
Reactant: C#CCCc1ccccc1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CCC#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of the iodide (2,2,2-trifluoro-N-(3-hydroxy-3-(3-iodophenyl)propyl)acetamide) with (2-(but-3-ynyl)phenoxy)(tert-butyl)dimethylsilane yielded N-(3-(3-(4-(2-(tert-butyldimethylsilyloxy)phenyl)but-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as brown oil. Yield (0.220 g, 41%): 1H NMR (400 MHz, DMSO-d6) δ 9.36 (bs, 1H), 7.26-7.31 (m, 4H), 7.19-7.21 (m, 1H), 7.11 (t, J=6.0 Hz, 1H), 6.96 (t, J=6.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.39 (d, J=4.4 Hz, 1H), 4.53-4.56 (m, 1H), 3.22-3.24 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 1.75-1.81 (m, 2H), 1.0 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:12])[CH:10]=[CH2:11].[N+:23](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-:24]>C(OCC)(=O)C>[CH2:29]([O:28][C:26]([C:25]1[CH2:11][CH:10]([C:9](=[O:12])[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:3][C:2]=2[F:1])[NH:24][N:23]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CC(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NNC(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Temperature: 60 °C

Procedure:
To N-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-yl)-acrylamide (4.47 g) in ethyl acetate (150 ml) was added ethyl diazoacetate (1.5 equiv.) and the mixture heated at 60° C. for 24 hours. Evaporated and then columned: eluant 10-100 EtOAc in hexane. Collected 5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.67 g)
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][N:5]([CH2:34][C:35]([O:37]C)=[O:36])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=[C:8]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:7]=1.[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=[C:8]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:7]=1)[CH2:34][C:35]([OH:37])=[O:36])([OH:39])=[O:2]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 31.3 %

Procedure:
A solution of 0.205 g (0.373 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycine methyl ester and 1.5 ml (1.5 mmol) of 1.0N NaOH in 10 ml of methanol was stirred at reflux for 30 minutes. The solvent was removed under reduced pressure and the residue was acidified with 0.18 ml of acetic acid, the product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid. Recrystallization from methanol-water gave 61 mg (mp 110°-114°) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])([OH:10])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)O)NC(=O)OC(C)(C)C
Yield: 47 %

Procedure:
A solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(tertiarybutoxycarbonylamino)pentanoyl]oxyhexadecanamide (100 mg) in methanol (2 ml) was hydrogenated over 10% palladium on carbon (20 mg) under atmospheric pressure of hydrogen for 3.5 hours at room temperature. Then, the catalyst was filtered off with celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate (0.5 ml) and n-hexane (1 ml) to give (3S)-3-[(2S)-5-carboxy-2-(tertiarybutoxycarbonylamino)-pentanoyl]oxyhexadecanamide (40 mg).
Reaction SMILES: [P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:2].Br[CH2:26][C:27](=[O:33])[C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30]>>[P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:26][C:27](=[O:33])[C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])[N:6]=1)=[O:2]
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)n[nH]c2c1
Reactant: CCC(C)(C)C(=O)CBr
Product: CCC(C)(C)C(=O)Cn1nc(C(OP(=O)(OC)OC)=C2CCCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared from cyclopentylidene(6-methoxy-1H-indazol-3-yl)methyl dimethyl phosphate from Step B Example 6 and 1-Bromo-3,3-dimethylpentan-2-one from Step A Example 4 using the procedure described in Method I Step C of Example 1 followed by RP-HPLC purification using 35˜100% MeCN gradient without TFA. It was obtained as a colorless solid after lyophilization. LC-MS: 3.70 min. (m/Z=339.2, 465.2, 487.1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:27])[CH2:17]2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[C@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)[C:19]3=[O:27])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: BrCc1cccnc1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C1N(Cc2cccnc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 78 starting from 3-bromomethyl-pyridine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C29H27ClN2O2: 470, observed (M+H)+: 471.2 1HNMR (400 MHz, MeOD-d4) δppm 2.25 (dd, J=8.59, 1.77 Hz, 2 H) 3.31 (br. s., 1 H) 5.28 (d, J=3.03 Hz, 2 H) 6.12 (d, J=7.58 Hz, 1 H) 6.71-6.85 (m, 1 H) 7.03 (d, J=8.08 Hz, 1 H) 7.12-7.19 (m, 1 H) 7.21-7.29 (m, 2 H) 7.30-7.39 (m, 2 H) 7.86-7.99 (m, 1 H) 8.40 (d, J=8.59 Hz, 1 H) 8.74 (d, J=5.31 Hz, 1 H) 8.84 (s, 1 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:34][C:35]1[C:39]([Cl:40])=[C:38]([CH2:41][OH:42])[S:37][N:36]=1.[C:43](O)(=[S:45])[CH3:44]>C(OCC)(=O)C.C1COCC1>[C:43]([O:42][CH2:41][C:38]1[S:37][N:36]=[C:35]([Cl:34])[C:39]=1[Cl:40])(=[S:45])[CH3:44]
Reactant: OCc1snc(Cl)c1Cl
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=S)OCc1snc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a THF (50 ml) solution of 2.85 g (10.9 mmol) of triphenylphosphine was added, under ice-cooling, 2.2 g (10.9 mmol) of diisopropyl azodicarboxylate, followed by stirring for 30 minutes. To the solution was added a THF (5 ml) solution of 1.0 g (5.43 mmol) of (3,4-dichloroisothiazol-5-yl)methanol and 0.83 g (10.9 mmol) of thioacetic acid, followed by stirring at room temperature for 5 hours, to give rise to a reaction. After the completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 0.42 g (yield: 32%) of (3,4-dichloroisothiazol-5-yl)methyl thioacetate as a light red oily substance (refractive index: 1.5855).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([O:14]C(C)(C)C)=O)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][C:32](C(Cl)=O)=[CH:31][CH:30]=1.C(OCC)(=O)C>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12](=[O:14])[C:32]3[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(Cl)ccc2C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
165 mg (0.56 mmol) of 8-chloro-4-t-butoxycarbonyl-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of trifluoroacetic acid, and the obtained solution was stirred at room temperature for 2 hours. The solvent was evaporated and the obtained crude product was dissolved in dichloromethane. 0.24 ml (1.68 mmol) of triethylamine and 0.085 ml (0.67 mmol) of 4-chlorobenzoyl chloride were added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was washed with hexane/ethyl acetate (1/1) to obtain the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1.C(N(CC)C(C)C)(C)C.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][C:40]=1[C:47]([F:50])([F:49])[F:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)C.O.C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH:28][CH2:43][C:42]4[CH:45]=[CH:46][C:39]([F:38])=[C:40]([C:47]([F:50])([F:48])[F:49])[CH:41]=4)[CH2:24][CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(N)CC3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ncnc2sc(NC(=O)N3CCC(NCc4ccc(F)c(C(F)(F)F)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
A suspension of the trifluoroacetic acid salt of 4-amino-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (1.82 g, 4.30 mmol) in methanol was treated with N,N-diisopropylethylamine (1.5 mL, 6.50 mmol), 4-fluoro-3-(trifluoromethyl)benzaldehyde (1.3 mL, 6.50 mmol) and toluene. The resulting mixture was stirred at 25° C. for 1 h and was then concentrated in vacuo. This procedure was repeated until the reaction mixture became homogenous when dissolved in toluene. After the final concentration to remove toluene, the reaction mixture was diluted with dichloroethane (100 mL) and then was treated with acetic acid (0.26 g) and sodium triacetoxyborohydride (2.73 g, 13 mmol). The resulting reaction mixture was allowed to stir at 25° C. overnight. At this time, the reaction mixture was poured into water and extracted into ethyl acetate. The organics were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 1:1 ethyl acetate/hexanes) afforded a colorless oil. The oil was dissolved in diethyl ether and then was concentrated in vacuo to afford 4-(4-fluoro-3-trifluoromethyl-benzylamino)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (530 mg, 25%) as a white, foamy solid; ES-HRMS m/e calcd for C20H20F4N6O2S (M+H)+ 485.1378, found 485.1378.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:12]([C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[O:18][C:19]1[C:24]([N:25]=[C:26]=[S:27])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]>ClCCCl>[C:12]([C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[O:18][C:19]1[C:24]([NH:25][C:26]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[S:27])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Solvent: ClCCCl
Product: CC(C)(C)c1cccc(NC(=S)Nc2cccnc2Oc2ccccc2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
To a solution of 3-tert-butylaniline (104 mg, 0.70 mmol) in DCE (3 mL) was slowly added 1c (100 mg, 0.35 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture was dissolved in methanol and filtered through an SCX cartridge and concentrated to afford 97a (158 mg, quantitative) as a yellow oil. This material was carried to the next step without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:26]([F:29])([F:28])[F:27])[O:16][N:15]=[C:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:26]([F:27])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]([NH:2][OH:3])=[NH:22])=[C:19]([CH3:25])[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: NO
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C#N
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=N)NO
Temperature: 85 °C

Procedure:
Hydroxylamine hydrochloride (0.27 g) was added to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzonitrile (1.1 g) (Example I4) and triethylamine (0.65 ml) in ethanol (30 ml). The reaction mixture was heated to 85° C. for 20 hours. The reaction mixture was allowed to cool to ambient temperature before adding more hydroxylamine hydrochloride (0.078 g). The reaction mixture was again heated to 85° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. A1 of Table A (0.84 g) as a white solid.