Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[F:13][CH:14]([F:34])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:32]=[C:31]([NH2:33])[NH:30][N:29]=3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(O)(=O)C>[F:34][CH:14]([F:13])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[C:32]4[C:3]([OH:10])([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5](=[O:7])[NH:33][C:31]=4[NH:30][N:29]=3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: Nc1cc(C2CCN(c3ccc(OC(F)F)cc3)CC2)n[nH]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccc(OC(F)F)cc4)CC3)n[nH]c2N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
Ethyl trifluoroacetoacetate (5.64 mL, 38.5 mmol) was added to a solution of 3-{1-[4-(difluoromethoxy)phenyl]piperidin-4-yl}-1H-pyrazol-5-amine (2.97 g, 9.63 mmol) produced in Reference Example 72 in acetic acid (52 mL), and the mixture was stirred at 60° C. for 3 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure, followed by azeotropy with toluene twice. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: hexane/ethyl acetate=100/0-0/100 (gradient)] and further purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-40/60 (gradient)] to obtain the title compound (1.84 g, yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: O=C(NN1CCCCC1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e 316.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:39][C:40]([NH:42][C@@H:43]([CH2:61][CH:62]2[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)[C@@H:44]([O:56][Si](C)(C)C)[CH2:45][NH:46][C:47](=[O:55])[O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])=O)=CC=1)([O-])=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:40]([NH:42][C@@H:43]([CH2:61][CH:62]3[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]3)[C@@H:44]([OH:56])[CH2:45][NH:46][C:47](=[O:55])[O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])=[O:39])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOC(=O)NC[C@H](O[Si](C)(C)C)[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)CNC(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (33.0 mg, 0.10 mmol) in CH2Cl2 (2 mL), DIEA (39 mg, 0.30 mmol) was added, followed by the solution of 2-(trimethylsilyl)ethyl (2S,3S)-3-(4-nitrophenoxycarbonylamino)-4-cyclohexyl-2-(trimethylsilyloxy)butylcarbamate in CH2Cl2 (0.8 mL, 0.2 mmol) prepared in the previous step. The resulting yellow solution was stirred at rt for 30 min, and completion of reaction was confirmed by LC-MS. Solvent was removed under vacuum, and the residue was purified by preparative HPLC to give 2-(trimethylsilyl)ethyl (2S,3S)-3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexyl-2-hydroxybutylcarbamate (25.8 mg, 38%); MS m/z 686 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][O:20][C:19]2[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1ccc(O)cc1)Nc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A mixture of compound 7a (496 mg, 2 mmol), K2CO3 (553 mg, 4 mmol), and KI (66 mg, 0.4 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (440 mg, 4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc (3:1) to provide the intermediate 7b (100 mg, 0.3 mmol, 16% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.30 (broad s, 1H), 7.56-7.46 (m, 4H), 6.94-6.87 (m, 2H), 6.87-6.80 (m, 2H), 4.57 (s, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:17])[CH:13]=[C:14]([CH:15]=[CH2:16])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:17][C:12]1[CH:13]=[C:14]([CH:15]=[CH2:16])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([C:3]#[N:4])[CH3:18])[N:7]=2
Reactant: C=Cc1cc(Cl)cc2nn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: C=Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-vinyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (50 mg) described in Example 59 above and 4-trifluoromethylthiobenzoyl chloride (0.05 mL), the title compound was isolated as a white solid (65 mg, 73%). Rf=0.5 (1:1 EA/heptane). MS (ES): M/Z [M+H]=466. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.41 (d, J=13.4 Hz, 1H), 5.50 (d, J=11.5 Hz, 1H), 5.57 (d, J=13.4 Hz, 1H), 6.45 (d, J=17.6 Hz, 1H), 6.91 (dd, J=17.6, 11.3 Hz, 1H), 7.51 (s, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.3 Hz, 2H), 8.03 (s, 1H) and 8.96 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[N:8]=1.[NH3:31]>CN(C)C=O>[F:1][C:2]([F:30])([F:29])[CH2:3][N:4]=[C:5]([NH2:31])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[N:8]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1CCSCc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CN(C)C=O
Product: NC(=NCC(F)(F)F)Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)-thioureido]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (6.8 g.), dimethylformamide (30 ml.), saturated ethanolic ammonia (5 ml.) and yellow mercuric oxide (6.5 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue triturated with ether and filtered to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.6 g.), m.p. 167°-168° after crystallisation from ethanol.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH3:21])[C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:22][Li]>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH3:21])[C:18]([OH:20])([CH3:22])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [Li]C
Product: CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)(C)O

Procedure:
The ketone of Example 8 is reacted with methyl lithium by the method of Example 17 to give the title compound.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:5](=[N:1][C:2]#[N:3])[S:6][CH3:7])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Solvent: CCO
Product: CSC(=NC#N)NCCCCc1csc(NC(=N)N)n1
Reaction time: 8 h

Procedure:
To a solution of 2-guanidino-4-(4-aminobutyl)thiazole (0.8 g.) in ethanol (10 ml.) was added dimethyl (cyanoimido)dithiocarbonate (0.6 g.). The mixture was stirred overnight. The white precipitate was filtered off and recrystallized from acetonitrile to give 2-guanidino-4-[4-(3-cyano-2-methylisothioureido)butyl]thiazole, m.p. 178°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH2:12])=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH:12][CH:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: NC(=O)c1sc2ccc(F)cc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC=C(c1ccccc1)c1ccccc1)c1sc2ccc(F)cc2c1O
Yield: 82.1 %

Procedure:
To a solution of 5-fluoro-3-hydroxybenzo[b]-thiophene-2-carboxamide (400 mg, 1.89 mmol) in hot toluene (35 ml) were added diphenylacetaldehyde (577 mg, 2.84 mmol) and p-toluenesulfonic acid monohydrate (25 mg). The reaction mixture was stirred at reflux temperature for 2 hours with azeotropic removal of water, cooled, and evaporated under diminished pressure. The solid obtained was recrystallized from diethyl ether-hexane to yield 604 mg (82%) of 5-fluoro-3-hydroxy-N-(2,2-diphenylethenyl)benzo[b]thiophene-2-carboxamide, m.p. 186°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[CH:7].[F:11][C:12]1[C:13](I)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])/[C:15]/2=[CH:22]\[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28]>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.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[C:7][C:13]1[C:12]([F:11])=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:22]/[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])/[C:16](=[O:21])[NH:17]2
Reactant: C#CC(C)(C)NC(=O)OC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C)(C)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, (1,1-dimethyl-2-propynyl)-carbamic acid methyl ester (47.7 mg, 0.34 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:32]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CCN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-morpholinoethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:10][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([NH:25][O:26]C5CCCCO5)=[O:24])[CH:16]=4)[O:11]3)[CH2:8]2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:10][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([NH:25][OH:26])=[O:24])[CH:16]=4)[O:11]3)[CH2:8]2)=[CH:33][CH:34]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2)NO
Yield: 66.8 %

Procedure:
(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (260 mg, 0.56 mmol) in DCM (10 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (143 mg, hydrochloride salt) as as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:17]=[N:18][C:19]([N:26]2[CH2:29][CH:28](OS(C)(=O)=O)[CH2:27]2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]>C(#N)C>[Cl:15][C:16]1[CH:17]=[N:18][C:19]([N:26]2[CH2:29][CH:28]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:27]2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Temperature: 180 °C

Procedure:
To a solution of 3-Fluorophenol (0.005 ml, 0.056 mmole) in acetonitrile (1 ml), potassium carbonate (10 mg, 0.0728 mmol) were added followed by the addition of methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (20 mg, 0.062 mmol). The reaction mixture was heated at 150° C. under microwave irradiation for 10 min (2 cycle of 5 min each) then at 180° C. for 5 min. After solvent evaporation the obtained residue was purified by SPE-Si (10 g) eluting with mixture cyclohexane/ethyl acetate from 95/5 to 90/10. Collected fractions, after solvent evaporation, afforded the title compound D77 (10 mg)
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:32])[C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:5]1.Cl.[NH2:34][OH:35]>CO.Cl>[ClH:1].[CH3:2][N:3]([CH3:32])[C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26](/[C:29](=[N:34]/[OH:35])/[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:5]1
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Reactant: NO
Agent: Cl
Solvent: CO
Product: C/C(=N\O)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a solution of (81.3) (12 mg, 0.026 mmol) and hydroxylamine hydrochloride (7.11 mg, 0.102 mmol) in MeOH (3 ml) was added 2 drops of HCl (2N) by a 1-ml syringe to reach pH about 3 and the mixture was stirred in a sealed tube at 85° C. for 3 h. The mixture was evaporated to dryness and the residue was purified by preparative acid HPLC (gradient eluent NB from 20/80 to 95/5. mobile phase A: TFA/CH3CN 0.05%; mobile phase B: TFA/H2O 0.05%). The desired fractions were collected, evaporated by BUCHI under 30 mbar at 40° C. to remove CH3CN. The remained solution was lyophilized to afford the title compound (8.1 mg, yield 65.4%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1>C(Cl)Cl.C(C(O)=O)(F)(F)F>[CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CCCCN(CC2CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCCCN(CC2CC2)C1=O

Procedure:
A solution of tert-butyl [3-(cyclopropylmethyl)-2-oxo-1,3-diazepan-1-yl]acetate (240 mg, 0.85 mmol) in CH2Cl2 (5 mL) and CF3CO2H (2 mL) was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo and the residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a clear oil. MS: m/z=227 (M+1).
Reaction SMILES: OC[CH:3]([NH:14][C:15](=[O:21])[O:16][C:17](C)(C)C)[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.O1CCCC1.CC(C)([O-])C.[K+]>C(OCC)(=O)C>[O:8]1[C:7]2([CH2:6][CH2:5][CH:4]([CH:3]3[CH2:17][O:16][C:15](=[O:21])[NH:14]3)[CH2:13][CH2:12]2)[O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC(CO)C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(C2CCC3(CC2)OCCO3)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 250 mL round bottom flask was charged with tert-butyl (2-hydroxy-1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)carbamate (1.5 g, 4.98 mmol), prepared in the previous step, and tetrahydrofuran (100 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (670 mg, 5.97 mmol) was added. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to the product as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CSC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([CH2:6][OH:7])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1c(F)cc(Br)cc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.10 mmol) in THF (100 mL) was added BH3.DMS (20.03 mL, 211 mmol) dropwise at rt. The resulting mixture was stirred at 60° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was quenched by MeOH. The solvent was removed in vacuo to yield a white solid of (4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield), which was used in the next step without further purification: ES-LCMS m/z 222.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH:9]=1)[NH2:8].[Br:13][C:14]1[CH:21]=[C:20]([F:22])[C:17]([CH2:18]N)=[C:16]([F:23])[CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:13][C:14]1[CH:21]=[C:20]([F:22])[C:17]([CH2:18][NH:8][C:7]2[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N+:10]([O-:12])=[O:11])=[C:16]([F:23])[CH:15]=1
Reactant: NCc1c(F)cc(Br)cc1F
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(NCc2c(F)cc(Br)cc2F)c1
Temperature: 140 °C
Yield: 80.4 %

Procedure:
A mixture of 5-methoxy-2-nitroaniline (513 mg, 3 mmol), 4-bromo-2,6-difluorobenzyl amine (616 g, 3 mmol), DIPEA (1.55 mL, 9 mmol) and acetonitrile (10 mL) was heated to 130-150° Celsius for 16 h. The mixture was then cooled to RT and concentrated to dryness. To the residue was added H2O (100 mL) and the resulting solid was collected by filtration and dried to afford the title compound (900 mg, 80.1%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[O:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: c1ccc(CN2CCN(c3ccccc3-c3ncco3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: c1ccc(N2CCNCC2)c(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A mixture of 4-benzyl-1-(2-oxazol-2-ylphenyl)piperazine (0.906 g, 2.84 mmol) and 10% palladium on carbon (1 g) in 20 mL of methanol was stirred under a hydrogen atmosphere (1 atm) at room temperature for 4 hours. The mixture was filtered and concentrated by rotary evaporation to give 1-(2-oxazol-2-ylphenyl)piperazine (0.480 g, 2.1 mmol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClC(Cl)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH:25]([CH3:27])[CH3:26])[C:35](=[O:37])[CH3:36])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(C)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1)C(C)C
Reaction time: 72 h

Procedure:
{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-isopropyl-amine was diluted to 0.20 M with anhydrous dichloroethane, then delivered to an 8 mL vial via pipette (0.20 mmol). To the amine solution was added base (0.4 M triethylamine in dichloroethane, 0.40 mmol). Acetyl chloride was diluted to 0.20 M with dichloroethane, and added at rt (0.2 mmol). The reaction was shaken three days, with the temperature ramped from 50° C. to 85° C. An additional 0.20 mmol of acetyl chloride was added after the second day. Polyamine scavenging resin was added (0.5 mmol). The solution was shaken overnight at room temperature, and filtered into an 8 mL vial. The reaction was concentrated via HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). N-{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-N-isopropyl-acetamide was isolated in 100% purity @ 254 nm, LCMS (APCI): 423 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH2:8][C@@H:9]([C:11]2[C:12]([CH3:21])=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[O:15][CH2:14]3)[OH:10])[CH2:5]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31](Cl)(=[O:33])=[O:32])=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][S:31]([NH:2][CH2:3][CH:4]2[CH2:7][N:6]([CH2:8][C@H:9]([OH:10])[C:11]3[C:12]([CH3:21])=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[O:15][CH2:14]4)[CH2:5]2)(=[O:32])=[O:33])=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Reactant: Cc1c([C@@H](O)CN2CC(CN)C2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CC(CNS(=O)(=O)Cc3ccc(C#N)cc3)C2)ccc2c1COC2=O

Procedure:
(R)-1-(4-Cyanophenyl)-N-((1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)azetidin-3-yl)methyl)methanesulfonamide was prepared in a similar fashion to that described for the synthesis of EXAMPLE 14 starting from (R)-5-(2-(3-(aminomethyl)azetidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 12] and (4-cyanophenyl)methanesulfonyl chloride.