Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC[N:22]=[C:23]=[N:24][CH2:25][CH2:26][CH2:27]N(C)C.[N:31]#CN.C(O)(C(F)(F)F)=O.BrC#N>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:23]([N:24]1[CH2:25][CH:26]([NH:31][C:17]([C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:13]([CH3:14])[CH2:15][CH3:16])=[O:19])[CH2:27]1)#[N:22]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: N#CN
Agent: CN(C)c1ccncc1
Agent: N#CBr
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CN(C#N)C1

Procedure:
Following general procedure 9, to a stirred solution of the amine (56) (172 mg, 1 equiv.), N-carbobenzyloxy-L-isoleucine (265 mg, 1 equiv.) and EDCI (192 mg, 1 equiv.) in CH2Cl2 (5 mL) was added DMAP (24 mg, 0.2 equiv.). The resultant mixture was stirred at rt for 16 h. The mixture was then diluted with EtOAc and washed successively with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 30% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired coupled product. The N-Boc group of the coupled product was then converted to the cyanamide (N—CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 25% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired solid benzyl (1S,2S)-1-{[(1-cyano-3-azetidinyl)amino]carbonyl}-2-methylbutylcarbamate (57).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=c1ccc(Br)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 209.9 %

Procedure:
Into a one-neck round-bottom flask were added 5-bromo-1H-pyridin-2-one (696 mg, 4.00 mmol), phenylboronic acid (975 mg, 8.00 mmol), cupric acetate (1450 mg, 8.00 mmol), triethylamine (1120 μl, 8.00 mmol), pyridine (647 μl, 8.00 mmol), 4 Å molecular sieves (1056 mg) and methylene chloride (24 ml). The flask was loosely capped and the above mixture was stirred at rt in the atmosphere of air for 20 h. The mixture was filtered through a celite pad, washed with CH2Cl2. After concentration in vacuo, a green oil (2100 mg) was obtained, which was then purified by chromatography on silica gel (64 g) eluting with 1000 ml 20%, 2000 ml 40% and 1000 ml 50% EtOAc/hexane to obtain the title compound as a light-yellow wax-like material. 1H NMR (CDCl3, 400 MHz): δ=5.59 (d, 1H, J=9.6 Hz), 7.35-7.38 (m, 2H), 7.41-7.46 (m, 2H), 7.49-7.52 (m, 3H). MS(ES+): m/z 250.06/252.02 (100/97) [MH+]. HPLC: tR=2.71 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]2[N:10]=[C:11]([NH:15][C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][CH3:24])[S:12][C:13]=2[CH3:14])=[C:5]([CH2:7][CH3:8])[N:6]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([NH:15][C:11]2[S:12][C:13]([CH3:14])=[C:9]([C:4]3[S:3][C:2]([NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6][C:5]=3[CH2:7][CH3:8])[N:10]=2)[CH:21]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1nc(N)sc1-c1nc(Nc2cc(Cl)ccc2OC)sc1C
Solvent: ClCCl
Product: CCc1nc(NC(=O)C(C)(C)C)sc1-c1nc(Nc2cc(Cl)ccc2OC)sc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a suspension of 16z (0.50 g, 1.1 mmol) in DCM (55 mL) was added TEA (395 μL, 2.84 mmol). Pivaloyl chloride (174 μL, 1.42 mmol) was then added to the suspension in one portion and the reaction mixture was stirred at room temperature for 10 min at which time TLC indicated reaction completion. The reaction mixture was washed with cold water and extracted with DCM (2×). The organic layer was dried over anhydrous sodium sulfate and filtered and DCM was removed in vacuo. The resulting solid was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 eluent) to yield 17z as a light orange powder (0.34 g, 66%). Mp decomposition at 192° C. 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J=2.8 Hz, 1H), 7.13 (dd, J=8.8 Hz, 2.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 2.79 (q, J=7.6 Hz, 2H), 2.30 (s, 3H), 1.39 (s, 9H), 1.34 (t, J=7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 178.6, 164.6, 164.2, 163.8, 162.2, 149.1, 144.9, 128.9, 125.5, 120.5, 113.8, 112.3, 104.9, 56.3, 40.1, 26.7, 21.4, 13.5, 12.2. HRMS m/z (ESI) calcd. for C21H25ClN4O2S2 (M+H)+ 465.1180. Found 465.1181.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+](N[C:19]1[NH:20][CH:21]=[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:23](=[O:25])[N:24]=1)([O-])=O>N1C=CC=CC=1>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[C:23](=[O:25])[N:24]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC1CCCc2cccnc21
Reactant: Cc1ccc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2c[nH]c(NCCCC3CCCc4cccnc43)nc2=O)cn1
Yield: 26.4 %

Procedure:
A solution of 3-(5,6,7,8-tetrahydroquinol-8-yl)-propylamine (0.75 g, 0.0038 mole) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4(1H)-pyrimidone (0.99 g, 0.0037 mole) in pyridine (1 ml) was refluxed for 8 hr and evaporated to dryness. The residue was chromatographed on silica in 10% MeOH/CHCl3 then dissolved in hot CHCl3, filtered, and the product precipitated with petroleum ether 40°-60° C. to give the title compound (0.38 g), m.p. 75°-80° C.
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][F:13].[NH2:14][C:15]1[CH:19]=[CH:18][N:17](C)[N:16]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[F:13][CH2:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=1[O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1
Reactant: CS(=O)(=O)c1cccc(CF)c1F
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: CS(=O)(=O)c1cccc(CF)c1Oc1ccc2ncnc(Nc3cc[nH]n3)c2c1

Procedure:
The compound of Example 157 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-fluoro-1-(fluoromethyl)-3-(methylsulfonyl)benzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:10][C:9]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:2]([C:6]1[S:10][C:9]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH:7]=1)=[O:1]
Reactant: NS(=O)(=O)c1cc2cc(C3OCCO3)sc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1cc2cc(C=O)sc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
5-(2-Dioxolanyl)thieno[2,3-b]thiophene-2sulfonamide (2.59 g, 8.89 mmol) was suspended in acetone and p-toluenesulfonic acid (2.50 g, 13.1 mmol) was added. The mixture was stirred at room temperature for one hour at which time a solution was obtained. Water (2.0 mL) was added and stirring continued for 3 hours. A saturated solution of sodium bicarbonate (30 mL) was added dropwise, followed by the slow addition of water (40 mL). The resulting solution or mixture was seeded with a few crystals of product and the acetone was evaporated in vacuo. The crystals were collected, washed with water and dried in vacuo to give 2.10 g of 5-formylthieno[2,3-b]thiophene-2-sulfonamide, m.p. 188°-189° C. This product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1ccc(-c2cccc(S(=O)(=O)Cl)c2)cc1
Product: Cc1ccc(-c2cccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)c2)cc1
Yield: 93.5 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from [3-(4-methylphenyl)phenyl sulfonyl chloride (14.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.05 mmol) yielding 18.3 mg (19%) of the title compound. MS (ESI+) calcd for C20H17N5O2S 391.110296, found 391.110156.
Reaction SMILES: [Ca].Cl[C:3]([N:5]([C@@H:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:19])[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].[C:30]([OH:34])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:3]([N:5]([C@@H:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:19])[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7]1)=[O:4])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)O
Reactant: C[C@H](c1cccc2ccccc12)N(C(=O)Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Ca]
Product: C[C@H](c1cccc2ccccc12)N(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 14.9 g of triphosgene dissolved in 400 ml of methylene chloride was added dropwise a solution containing 25.68 g of tert-butyl(R)-3-[1-(naphthalen-1-yl)ethylamino]pyrrolidine-1-carboxylate (the compound obtained in the above-mentioned Reference example 1.005 (1)) and 31.5 ml of triethylamine in 100 ml of methylene chloride at −20° C. Further, 7.5 g of triphosgene was added to the same, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1→2:1) to obtain 10.63 g of tert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate and 9.22 g of tert-butyl(R)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate shown in the following Reference example Table, respectively. (2) To 18.52 g of tert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate was added 1.0 liter of tert-butanol, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated, and then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 9.24 g of tert-butyl(S)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate (the following Reference example 1.006(a)).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2ccccc2)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.1 g) as starting compound was reacted and treated in the same manner as in Example 1 using benzoyl chloride (0.50 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.15 g) to give 4-amino-N-(1-(3-benzoylaminopropyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=1>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH3:14])=[CH:17][CH:18]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNc1ccc(-c2ccc3cc(OC)ccc3n2)cc1

Procedure:
4-(6-Methoxyquinolin-2-yl)-N-methylaniline T523 was prepared using general procedure A from 2-chloro-6-methoxyquinoline (39 mg, 0.2 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (46 mg, 0.2 mmol). T523 was obtained as a brown solid (27 mg, 51%). NMR (400 MHz, CDCl3): δ 8.03-7.99 (m, 4H), 7.75 (d, J=8.4 Hz, 1H), 7.33 (dd, J=9.2, 2.8 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 6.71 (m, 2H), 3.92 (s, 3H), 2.89 (s, 3H); MS (ESI): 235 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]([CH3:40])[CH3:39])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]([CH3:39])[CH3:40])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)cc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-butyl-6-(isopropyl carbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.CCOCC>[CH2:18]([O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: c1ccc(COc2cccc3c2CCCC3)cc1
Yield: 99.1 %

Procedure:
5,6,7,8-tetrahydro-1-naphthol (5.9 g, 39 mM) was added to a suspension of potassium carbonate (8.3 g, 60 mM) in acetone (100 ml) and heated under reflux for 0.5 hour. Benzyl bromide (7.5 g, 43.8 mM) was then added and the mixture was heated under reflux for a further 3 days with stirring. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure to give an oil. This oil was dissolved in ether, washed with water, dried (sodium sulphate) and evaporated to giving an oil which was distilled under high vacuum to give the benzyl ether (3) (9.4 g, b.p. 170°-176° C. at 0.8 mm Hg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:10][C:2]1=2.Cl.O=C1CC2C(=CC=C(/C=C/C(O)=O)C=2)N1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][NH:43][CH3:44])=[CH:34]1.CC1NC2C(C=1CNC)=CC=CC=2>>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]([N:43]([CH3:44])[CH2:42][C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]([CH3:32])[CH:34]=3)=[O:15])=[CH:10][C:2]1=2
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCCN2
Reactant: CNCc1cn(C)c2ccccc12
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)OCCN2
Yield: 83.3 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (0.11 g, 0.53 mmole), from Preparation 7, for the (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 1-methyl-3-(methylaminomethyl) indole (0.10 g, 0.59 mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the title compound (0.16 g, 82%) was prepared as a light yellow solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:58])[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:57])[C@H:22]([NH:36][C:37]([N:39]3[CH2:44][CH2:43][CH:42]([N:45]4[CH2:51][CH2:50][C:49]5[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=5[NH:47][C:46]4=[O:56])[CH2:41][CH2:40]3)=[O:38])[CH2:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:27]([NH2:34])=[C:26]([Cl:35])[CH:25]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C.Cl>O.C1COCC1>[NH2:34][C:27]1[C:28]([C:30]([F:32])([F:31])[F:33])=[CH:29][C:24]([CH2:23][C@@H:22]([NH:36][C:37]([N:39]2[CH2:40][CH2:41][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:43][CH2:44]2)=[O:38])[C:21]([N:18]2[CH2:17][CH2:16][CH:15]([CH:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:7]([OH:58])=[O:6])[CH2:10][CH2:11]3)[CH2:20][CH2:19]2)=[O:57])=[CH:25][C:26]=1[Cl:35]
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)NC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20.1 mg (0.47 mmol) lithium hydroxide hydrate in 10 mL water was added to a solution of 250 mg (0.32 mmol) ethyl[1′-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4′-bipiperidinyl-1-yl]-acetate (Example 7.5) in 5 mL THF and the reaction mixture was stirred for 2 h at RT. 0.5 mL 1 M HCl were added, the substance precipitated was filtered off and dried at 50° C. The crude product was purified by HPLC.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[O:7][C:6]([CH2:17][F:18])([CH2:15][F:16])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][C:6]([CH2:15][F:16])([CH2:17][F:18])[CH2:5][C@H:4]2[NH2:1]
Reactant: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2ccc(F)cc21
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CC(CF)(CF)Oc2ccc(F)cc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of Example 65B (54.1 mmol) in THF (190 mL) was cooled to <5° C. To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (12.1 mL, 81.0 mmol) followed by diphenylphosphoryl azide (15.2 mL, 70.3 mmol), keeping the temperature ≦5° C. (no exotherm). After stirring for 2 hours at ≦5° C., the reaction mixture was warmed to ambient temperature and stirred for 14 hours. The reaction mixture was diluted with MTBE (250 mL), washed with 2N NaOH (2×125 mL), brine (50 mL), 2N HCl (2×125 mL), and brine (50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated, giving (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman (14.6 g, >100%) as a dark oil. The crude (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman in MeOH (300 mL) was added to 5% Pd—C (4.38 g) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 3 hours at 50° C. and 30 psi H2. Upon cooling, the reaction mixture was filtered through a nylon membrane and concentrated. The resulting residue was used without further purification. MS (DCI) m/z 232 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.O.C(OCC)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(OC)cc3s2)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(O)cc3s2)C1
Reaction time: 2.25 h

Procedure:
A solution of (S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-methoxybenzo[d]thiazol-2-amine (1.22 g, 3.43 mmol) in dichloromethane (25 ml) under nitrogen atmosphere was treated with boron tribromide (1M in dichloromethane, 7.5 ml) at 0° C. Stirring was continued for 10 min at 0° C. and for 135 min at ambient temperature. The reaction mixture was carefully diluted with water (50 ml), ethyl acetate (200 ml) and treated with solid sodium bicarbonate (until no further gas development was observed). The mixture was stirred until phases became clear. The separated organic phase was washed with saturated sodium bicarbonate solution (2×75 ml), water (75 ml), brine (75 ml) and dried over sodium sulfate. Concentration in vacuo afforded crude (S)-2-(1-(ethylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-ol which was used in the next step without further purification. Yield: 1.15 g. ES/MS m/z 342.0 (MH+), Rt=1.86 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[F:25][C:26]([F:31])([F:30])[S:27][CH2:28]Cl.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:28][S:27][C:26]([F:31])([F:30])[F:25])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: FC(F)(F)SCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CSC(F)(F)F)CC3)c(F)cc2c1=O
Yield: 33.7 %

Procedure:
3.3 g (10 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 90° in 50 ml of dimethylformamide with 4 g (27 mmol) of trifluoromethylthiomethyl chloride, 2.1 g of triethylamine, 1.7 g of potassium iodide and 0.2 g of tetrabutylammonium iodide for 16 hours. The solution is poured into 50 ml of water and the precipitate is filtered off with suction and boiled up with methanol. 1.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoromethylthiomethyl-1-piperazinyl)-3-quinolinecarboxylic acid of melting point 247°-250° (with decomposition) are obtained.