Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:31][NH:32][C:33]([C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)=[O:34]>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:36]5[CH2:37][CH2:38][CH2:39][C@H:35]5[C:33]([NH:32][CH3:31])=[O:34])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:25])[CH3:26]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Reactant: CNC(=O)[C@@H]1CCCN1
Product: CNC(=O)[C@@H]1CCCN1c1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2

Procedure:
Following the procedures of Example 388, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate and (S)—N-methylpyrrolidine-2-carboxamide were reacted to give 405. M/z 423.2, calc. 422.22. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.74 (d, J=4.3, 1H), 5.95 (p, J=6.7, 2H), 4.58-4.41 (m, 4H), 4.35 (d, J=8.5, 1H), 3.67-3.57 (m, 1H), 3.41-3.33 (m, 1H), 2.57 (d, J=4.6, 3H), 2.15 (dd, J=10.8, 7.7, 1H), 1.94 (d, J=6.6, 3H), 1.47 (dd, J=6.6, 2.4, 6H)
Reaction SMILES: Cl.Cl[C:3]1[CH:21]=CC=C[C:4]=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:38][N:39]([C:41]([NH:43][CH:44]2[CH2:46][CH2:21][CH2:3][CH2:4][CH2:47]2)=[O:42])[CH2:40]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].ClC1C=CC=C(C(OO)=[O:36])C=1.O>ClCCl>[O:36]=[S:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:1])([F:26])[F:27])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Sc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2S(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
The compound (46 mg) prepared in step (d) of Example 133 was dissolved in dichloromethane (1 ml). m-Chloroperbenzoic acid (19 mg) was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous MgSO41 and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (n-hexane:ethyl acetate=1:4) to give 4-[10-oxo-9-(2,2,2-trifluoroethylcarbamoyl)-9,10-dihydro-10λ4-thioxanthen-9-yl]butyl bromide (38 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1.IC1C=C2C(=CC=1)C(=O)[NH:36]C(=O)C2=COC.NCC1C=CC(C2C=CC=CN=2)=C(O)C=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:36]=1)[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: NCc1ccc(-c2ccccn2)c(O)c1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccn2)c(O)c1
Yield: 57 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (98 mg, 0.30 mmol) and 5-Aminomethyl-2-pyridin-2-yl-phenol (60 mg, 0.30 mmol) in 57% yield: MS (ESI): 498.1 (M+1)+1.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8](Cl)[CH:7]=[C:6]([Cl:11])[N:5]=1>C(O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:2][CH3:1])[CH:7]=[C:6]([Cl:11])[N:5]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: CN
Solvent: CCO
Product: CNc1cc(Cl)nc(Cl)c1
Temperature: 57.5 °C
Reaction time: 0.17 h

Procedure:
An 8M solution of methylamine in ethanol (5 ml; 40 mmol) was added drop wise to a stirred solution of 2,4,6-trichloropyridine (5 g; 27.4 mmol) in absolute ethanol (50 ml). After heating to 55-60° C. for 24 hr, the mixture was cooled to rt and concentrated. After adding water (50 ml) to the residue, the resulting suspension was filtered and the white filter cake was washed with water (3×10 ml). After air drying, the solid was suspended in dichloromethane (25 ml) and stirred for 10 minutes. Filtration, rinsing with dichloromethane and drying afforded 2.45 g (51%) of A1.6 as a white solid. HPLC (A): 95%, ret. time=1.16 min., LC/MS (M+H)+=177.00 (178.99).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].O[Li].O>C1COCC1.O>[C:17]([O:16][C:14]([NH:13][C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[C:3]([OH:21])=[O:2])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H](CCCCCC(C)=O)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.5 h

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-8-oxononanoic acid methyl ester (1 eq.) was dissolved in a 1:1 mixture of THF and water at RT and LiOH hydrate (1.2 eq.) was added and the mixture was stirred for 30 min. The mixture was partitioned between 0.1M HCl and DCM, separated and the organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure. The colourless oil A1 obtained was used in the next step without purification. MS (ES) C14H25NO5 requires: 287, found: 288 (M+H)+.
Reaction SMILES: [N:1]1([C:13](=[O:14])[C:12]2[N:10]([CH3:11])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])C.C[N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH2:28][CH3:29])[CH:22]=[N:21][C:20]=2[N:19]([CH3:30])[C:17]1=[O:18]>>[NH:1]1[C:13](=[O:14])[C:12]2[N:10]([CH3:11])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4].[CH3:30][N:19]1[C:20]2[N:21]=[CH:22][N:23]([CH2:27][CH2:28][CH3:29])[C:24]=2[C:25](=[O:26])[NH:16][C:17]1=[O:18]
Reactant: CCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Product: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: Cn1cnc2c1c(=O)[nH]c(=O)n2C

Procedure:
The 1,3-methyl-7-alkylxanthine was thus converted to the corresponding 3-methyl-7-alkylxanthine. The results of the conversion reaction are shown in FIG. 2. It is seen that in using either of the substrates (caffeine or 1,3-dimethyl-7-propylxanthine) the transformant strain having pCA32A, i.e., P. putida IF-3-9C-21/pCA32A, produces the corresponding conversion product (theobromine or 3-methyl-7-propylxanthine, respectively) in an amount about 2 to 4 times that produced by P. putida IF-3-9C-21.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)[N:46](Br)[C:44](=O)C1.[C-]#N.[Na+]>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:7]1[C:2]([CH2:1][C:44]#[N:46])=[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccccc2)cccc1-c1ccc2ccccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1c(-c2ccccc2)cccc1-c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
A solution of 2-(2-methyl-1,1′-biphenyl-3-yl)naphthalene (2.0 g, 6.8 mmol) and 200 mg of benzoyl peroxide was refluxed, then NBS (1.21 g, 6.8 mmol) was added. The reaction mixture was refluxed overnight, diluted with methylene chloride, washed with water and dried over MgSO4. Removal of solvent under reduced pressure gave a crude product. The crude product was dissolved in 20 mL of DMF and sodium cyanide (0.65 g, 13 mmol) was added. The reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water and dried over MgSO4. Removal of solvent under reduced pressure gave a crude product that was purified by silica gel chromatography eluting with 0.4% ethyl acetate/hexanes to give 1.15 g of (3-naphthalen-2-yl-biphenyl-2-yl)-acetonitrile: 1H NMR (CDCl3): δ 3.43 (s, 2H), 7.30-7.60 (m, 11H), 7.80-7.95 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:44]=[CH:43][C:21](/[CH:22]=[CH:23]/[C:24]3[C:32]4[C:27](=[CH:28][C:29]([CH:33]=O)=[CH:30][CH:31]=4)[N:26]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1>>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]3[C:32]4[C:27](=[CH:28][C:29](/[CH:33]=[C:3]5/[C:2](=[O:10])[NH:1][C:9]6[C:4]/5=[CH:5][CH:6]=[CH:7][CH:8]=6)=[CH:30][CH:31]=4)[N:26]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[N:25]=3)=[CH:43][CH:44]=2)[CH2:13][CH2:12]1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccc(CN3CCOCC3)cc2)c2ccc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccc(CN3CCOCC3)cc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21

Procedure:
According to the method of A57B, oxindole (39 mg, 0.29 mmol) was reacted (E)-3-(4-(morpholinomethyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (116 mg, 0.25 mmol) to give the title compound as a yellow solid upon silica gel purification (95:5 CH2Cl2/MeOH) (95 mg, 64%). MS ESI 593.5 [M+H]+, calcd for [C35H40N4O3Si+H]+ 593.3
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (1.5 g), 4-chlorothiophenol (1.63 g) and potassium carbonate (1.56 g) in toluene (15 ml) was stirred at 70° C. for 5 hours. Ethyl acetate and water were added, and the organic layer was separated, washed with water, dried and evaporated to dryness. The residue was washed with toluene to give yellow crystals of 3'-(4-chlorophenylthio)-4'-nitroacetophenone (1.9 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)=[O:4].[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=4[CH:16]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)NC(=O)CO2
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2c(c1)NC(=O)CO2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-acetamide (Example 155a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 185-187° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@@:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=4)[CH2:11]3)[C:9](=[O:23])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]>CCOC(C)=O.[Pd]>[O:23]=[C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[C@:10]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=1)[CH2:11]2.[ClH:1].[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]
Reactant: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Product: Cl
Reaction time: 16 h

Procedure:
To a solution of methyl(2R)-4′-chloro-6′-oxo-1,3,6′,7′-tetrahydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxylate (860 mg, 2.61 mmol) and triethylamine (364 μL, 2.61 mmol) in 10 mL of EtOAc was added 2.6 g of 10% palladium on carbon. The reaction was placed under 50 psi of H2 and shaken on a Parr hydrogenation apparatus. After 16 h, the reaction was backfilled with nitrogen, filtered through Celite® and concentrated in vacuo to afford the title compound as a mixture with 1 equivalent of triethylamine hydrochloride. MS: m/z=296.1 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:42])/[C:11](/[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:12]/[C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](OC)=[O:30])=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:42])[C:11]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:12][C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([NH:2][OH:3])=[O:30])=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)C=Cc1ccc(CNC(=O)c2ccc(/C=C(/C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(/C=C/c1ccc(CNC(=O)c2ccc(C=C(C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Hydroxylamine hydrochloride (0.5 g, 7.2 mmol) in methanol (2 mL) was mixed with KOH (0.4 g, 7.2 mmol) in methanol (2 mL) at 0° C., and sonicated for 2 minutes and the white precipitate formed was filtered. The filtrate was added to methyl 3(4-((4-(1E)-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-enyl)benzamido)methyl)phenyl)acrylate (0.20 g, 0.4 mmol) in DCM (1.5 mL) and the mixture stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The ethyl acetate layers were washed with water (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a crude compound, which was triturated with DCM (15 mL) to obtain a solid which was filtered and washed with DCM (5 mL) to afford the title compound (0.050 g, 25% yield). 1H NMR (DMSO-d6) δ (ppm): 0.51-052 (2H, m, —CH2), 0.63-0.65 (2H, m, —CH2), 2.74-2.75 (1H, m, —CH), 4.43-4.44 (2H, d, CH2), 6.39-6.43 (1H, d, ═CH), 7.05-7.07 (2H, d, Ar—H), 7.16-7.22 (4H, m, Ar—H), 7.29-7.32 (3H, m, Ar—H and ═CH), 7.40-7.44 (1H, d, ═CH), 7.49-7.51 (2H, d, Ar—H), 7.68-7.70 (2H, d, Ar—H), 7.89-7.90 (1H, d, —NH), 9.00 (2H, m, NH and OH), 10.73 (1H, s, NH), MS m/z: 498.1 (M+−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:21][C:28](=[O:29])[C:27]4[C:26]([F:25])=[CH:34][CH:33]=[CH:32][C:31]=4[F:35])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]aniline (0.31 g) in THF (10 mL) was added 2,6-difluorobenzoyl chloride (0.18 g). The reaction was kept stirring at rt for 0.5 h and worked up with sat. NaHCO3 solution (8 mL). After extraction with EtOAc (2×10 mL), drying with Na2SO4, and concentration, the crude mixture was purified through silica gel column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide as a yellow solid (0.42 g, 95%). ESIMS (M+H)+=480.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][SH:26])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1>C(Cl)Cl>[ClH:10].[ClH:10].[CH2:1]([NH:7][C:8](=[SH:26][CH2:25][CH2:24][CH2:23][N:19]1[CH2:20][CH2:21][CH2:22][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:28][CH:27]=2)[CH2:17][CH2:18]1)[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: SCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCCCN=C=O
Solvent: ClCCl
Product: CCCCCCNC(O)=[SH]CCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Product: Cl
Yield: 77.6 %

Procedure:
The procedure described in Example 2 was followed, using 1.3 g of n-hexyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)homopiperazin-1-yl]propanethiol and 75 ml of methylene chloride, to give 1.3 g (33% of theory) of N-(n-hexyl)-S-{3-[4-(4-chlorobenzyl)homopiperazin-1-yl]propyl}thiocarbamate dihydrochloride as a tan powder, M.p. 183°-187° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:23]=2[N:22]=1)[CH2:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][CH:18]([CH3:20])[CH3:19])[S:15][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:49])[C:42]([OH:44])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.ClCl>CN(C)C=O>[Cl:30][C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21]([C@@H:9]([NH:8][C:42](=[O:44])[C:41]3[CH:45]=[CH:46][C:47]([C:48]([N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:49])=[C:39]([CH3:38])[CH:40]=3)[CH2:10][CH2:11][C:12]3[N:13]=[C:14]([NH:17][CH:18]([CH3:20])[CH3:19])[S:15][CH:16]=3)=[N:22][C:23]=2[CH:29]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(C)Nc1nc(CC[C@H](NC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CC(C)NC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](CCc2csc(NC(C)C)n2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 45 %

Procedure:
Prepared analogously to Example 17 from N-(tert-butoxycarbonyl)-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(2-isopropylaminothiazol-4-yl)propylamine] and trifluoroacetic acid and subsequent reaction with 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, and diisopropylamine in dimethylformamide. Yield: 45%; C29H33ClN6O2 (565.139); mass spectrum: (M+H)+=565/567 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:18]2[CH:9]1[C:10]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[C:13]([O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:31]1C=CC=C1CC(O)=O.[CH3:40][CH2:41][O:42]CC>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:10]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH:12]=2)[CH2:17][C@H:18]1[S:31][C:41](=[O:42])[CH3:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2CC2C1N2C(=O)OC(C)(C)C
Reactant: CCOCC
Reactant: O=C(O)Cc1cccs1
Product: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2C[C@@H](SC(C)=O)[C@@H]1NC(=O)OC(C)(C)C

Procedure:
5-tert-Butoxycarbonyloxy-7,7-diethyl-1a,2,7,7a-tetrahydro-1-aza-cyclopropa[b]naphthalene-1-carboxylic acid tert-butyl ester (218 mg, 0.52 mmol) and the thiolacetic acid (2 mL) was stirred at r.t for over night. The mixture was diluted with Et2O (50 mL), washed with H2O, NaHCO3 (3×), H2O, brine, dried over MgSO4. The residu was purified by a flash chromatrgraphy (10% AcOEt/Hex) (234 mg, 91%). 1H NMR (CDCl3): 7.05-6.95 (3H, m, Har), 4.80 (1H, d, J=10.5 Hz, NH), 4.15-4.00 (2H, m, CHCH), 3.17 (1H, dd J=5 Hz and 17 Hz, PhCHH), 2.97 (1H, dd, J=12 Hz and 17 Hz, PhCHH), 2.40 (3H, s, SCOCH3), 1.86 (1H, m), 1.70 (2H, m), 1.60-1.55 (11H, m), 1.47 (9H, s, t-butyl), 0.89 (3H, t, J=7.5 Hz, CH3), 0.71 (3H, t, J=7.5 Hz, CH3).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>CN(C)C=O>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: N#Cc1ccc(F)cc1CBr
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 100 °C
Reaction time: 14 h
Yield: 22.8 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-4-fluorobenzonitrile (0.29 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-19:1). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (34 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[F:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[F:22][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:38]2[CH:37]=[CH:36][N:35]=[C:34]([F:33])[CH:39]=2)[N:11]=1)=[CH:3][C:2]([C:29]1[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1ccnc(F)c1
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2ccnc(F)c2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in method BB12 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[N+]=[N-].C(OCC)(=O)C>CO.CCCCCC.[Pd]>[NH2:1][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Yield: 97.6 %

Procedure:
A solution of 4.05 g (17.9 mmol) of 4-azido-1-(tert-butoxycarbonyl)piperidine from Step A in 50 mL of methanol was hydrogenated with 350 mg of 10% Pd/C under a hydrogen balloon for 16 h when the reaction was complete by TLC (10% ethyl acetate in hexane). The catalyst was filtered off and the volatiles removed in vacuo to give 3.5 g of title compound which was used directly in subsequent reactions.