Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[N:8]=[C:7]([S:11][CH3:12])[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[Na].[C:15](Cl)(=[O:17])[CH3:16]>O1CCCC1>[C:15]([N:8]1[C:7]([S:11][CH3:12])=[N:6][C:5](=[O:13])[N:4]([CH:1]([CH3:3])[CH3:2])[C:9]1=[O:10])(=[O:17])[CH3:16]
Reactant: CSc1nc(=O)n(C(C)C)c(=O)[nH]1
Reactant: CC(=O)Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CSc1nc(=O)n(C(C)C)c(=O)n1C(C)=O

Procedure:
To 9.0 parts sodium 3-isopropyl-6-methylthio-s-triazine-2,4(1H,3H)-dione prepared as in Example 10 in 100 parts tetrahydrofuran can be added 3.1 parts acetyl chloride. The reaction can be refluxed for 5 hours and the solvent evaporated. Methylene chloride can be added to the residue and the solution can be washed with 1N sodium hydroxide and brine. After drying and evaporation of the solvent, the residue can be recrystallized from chlorobutane.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCCCC1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(OCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (5.02 g, 36.3 mmol) and chloroethyl piperidine (7.36 g, 39.96 mmol) in 30 ml of DMF, 5 g of K2CO3 was added. The reaction was stirred at 80° C. overnight. After cooling the mixture was quenched with water then extracted in CHCl3. The organic layer was separated, dried over Na2SO4, filtered and concentrated. 2-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-ethanol (4.58 g, 18.4 mmol) was isolated as a brown oil; Yield 51%; MS: 250.3 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.[CH3:24][CH2:25][N:26](C(C)C)C(C)C.BrCC#N>>[C:25]([CH2:24][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH:4]=1)#[N:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(=O)CN(Cc1cc(CN)ccn1)C(=O)OC(C)(C)C
Agent: N#CCBr
Product: CN(C)C(=O)CN(Cc1cc(CNCC#N)ccn1)C(=O)OC(C)(C)C

Procedure:
General Procedure T from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-[(dimethylcarbamoyl)methyl]carbamate (1.0 equiv.), DIPEA (2.0 equiv.) and bromoacetonitrile (1.1 equiv.). Purification by preparative TLC (10% MeOH and 1% NH4OH in DCM) gave the title product as light yellow oil. 1H NMR (300 MHz, methanol-d4): δ ppm 8.42 (d, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 4.58 (m, 2H), 4.19 (m, 2H), 3.93 (s, 2H), 3.65 (s, 2H), 2.98 (m, 6H), 1.42 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:17](=[O:19])[NH2:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=[O:31])[CH3:30].S([O-])(O)(=O)=O.[Na+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:17](=[O:19])[NH2:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:28][C:29](=[O:31])[CH3:30])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Temperature: 90 °C
Yield: 73.6 %

Procedure:
To a mixture of [(S)-1-carbamoyl-2-(4-hydroxyphenyl)ethyl]-carbamic acid tert-butyl ester (3.00 g, 10.7 mmol) and potassium carbonate (7.40 g, 53.5 mmol) in N,N-dimethylformamide (50 ml) were added subsequently chloroacetone (1.02 ml, 12.8 mmol) and tetrabutylammonium iodide (197 mg, 0.54 mmol). The reaction mixture was heated to 90° C. for 16 h and cooled to room temperature. It was diluted with water (100 ml) and acidified with a 10% solution of sodium hydrogensulphate to pH 2. Ethyl acetate (300 ml) was added. The phases were separated. The organic layer was washed with water (3×150 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give 2.65 g of {(S)-1-carbamoyl-2-[4-(2-oxopropoxy)phenyl]ethyl}carbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1>>[S:9]1[CH:13]=[CH:12][C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)=[CH:10]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2ccsc2)CCC1
Yield: 72 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 3-thiophene boronic acid according to the general procedure described for the Suzuki coupling. The product was purified by automated flash chromatography using gradient elution (0 to 50% ethyl acetate/hexanes). A yellow solid was isolated after collection of fractions and recrystallized from hexanes and ethyl acetate to give 0.086 g of colorless needles (72%). 1H NMR (CDCl3, 300 MHz): δ 2.13 (quintet, J=6.3 Hz, 2H), 2.47 (t, J=6.3 Hz, 2H), 2.76 (dd, J=6.3, 1.2 Hz, 2H), 6.39 (t, J=1.2 Hz, 1H), 7.31-7.36 (m, 2H), 7.55 (dd, J=2.7, 1.5 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 22.6, 27.8, 37.4, 123.8, 124.9, 125.0, 126.6, 140.5, 153.3, 199.9. LCMS (ESI): mass calcd for (C10H10OS) m/z 178.05; measured [M+H]+: m/z 179.04.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][S:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(N)CN
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(N)CNS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 14.97 g (0.196 mol) of 1,2-diamino-2-methyl-propane in 300 ml of chloroform and 80 ml pyridine at 0° C. was added 10 g (0.057 mol) of benzenesulfonyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to reach room temperature. The mixture was evaporated to dryness in vacuo and the residue was partitioned between water and chloroform. Evaporation of the chloroform gave 10.3 g (79%) of semisolid. The product was identified by NMR and IR spectroscopy and elemental analysis.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[N:15]=1)=[O:36]
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
A mixture of 2-[6-(aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.40 g, 1.0 mmol) and potassium carbonate (0.43 g, 3.1 mmol) was stirred at room temperature for 20 minutes. Successively, N,N-dimethylcarbamoyl chloride (0.47 g, 4.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 hrs. The precipitates were filtered, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (40:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.24 g, 68%) as white crystals.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[CH2:8]([NH:12][N:13]=[CH:14][NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH3:11].Cl.[C:26]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35]([CH2:39][C:40](=[O:42])[NH2:41])=[C:34](O)[CH:33]=[CH:32]2)(=[NH:28])[NH2:27].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[CH2:8]([NH:12][N:13]=[CH:14][NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][C:34]2[CH:33]=[CH:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:26](=[NH:27])[NH2:28])[CH:30]=3)[C:35]=2[CH2:39][C:40](=[O:42])[NH2:41])=[O:21])=[CH:23][CH:24]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNN=CNc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCNN=CNc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 107 %

Procedure:
30 Milliliters of 20% hydrous pyridine was added to 1.6 g of 4-n-butylaminoiminomethylaminobenzoic acid.hydrochloride, 1.5 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.33 g of DCC and 65.5 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 4 days at room temperature. Then, the precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of DMF, and the solution was added dropwise to a mixed liquid of 300 ml of acetone and 200 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 30 ml of methanol and 2.1 ml of concentrated hydrochloric acid, and the solution was added dropwise to 250 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration, and to the collected precipitate were added 9 ml of methanol, 7 ml of ethanol and 6 ml of 2-propanol, followed by stirring for 1 hour under cooling with ice. The precipitate was collected by filtration and washed with a small amount of acetone to obtain 1.68 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([O:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:3]=1[NH:18][C:19]([CH:21]1[O:26][C:25]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=2[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22]1)=[O:20].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.FC(B[CH2:77][N:78]1[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]1)(F)F.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:87]([O:86][C:84]([N:81]1[CH2:82][CH2:83][N:78]([CH2:77][C:2]2[CH:7]=[C:6]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:5]([O:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:3]=2[NH:18][C:19]([CH:21]2[O:26][C:25]3[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=3[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22]2)=[O:20])[CH2:79][CH2:80]1)=[O:85])([CH3:90])([CH3:89])[CH3:88]
Reactant: CC(C)(C)OC(=O)N1CCN(CBC(F)(F)F)CC1
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2Br)Oc2ccc(C#N)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2CN2CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of ethyl 2-(2-bromo-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (53.0 mg, 0.092 mmol), Pd(OAc)2 (0.6 mg, 0.003 mmol), X-Phos (2.6 mg, 0.006 mmol), tert-butyl 4-(trifluoromethylboranylmethyl)piperazine-1-carboxylate (25.0 mg, 0.09 mmol) and Cs2CO3 (90 mg, 0.28 mmol) in THF/water (10:1, 400 μL) under N2 atmosphere was heated under microwave irradiation at 100° C. for 1 h. The reaction was filtered and purified by HPLC (10-99% CH3CN/water) to provide ethyl 2-(2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (15.0 mg, 24% yield). LC/MS m/z 692.5 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12](F)=[CH:11][N:10]=1>CN(C)C=O>[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=1
Reactant: Fc1cnc(Cl)nc1-c1ccc(Cl)cc1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Cl)ncc2OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.948 ml cyclopropanemethanol in 13 ml dimethylformamide was added 0.468 g sodium hydride 55% in mineral oil and the reaction mixture was stirred at room temperature for 15 min. The resulting solution was added drop wise to a solution of 2.586 g 2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine at 0° C. and the mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=10:90 to 80:20 to yield 2.50 g of the title compound as white solid. MS (EI): 295.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:45]=[CH:44][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:19][CH:20]=3)[C@@H:14]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[CH2:13][C@@:12]2([CH2:40][CH:41]([CH3:43])[CH3:42])[C:33]([O:35]C(C)(C)C)=[O:34])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:45]=[CH:44][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:19][CH:20]=3)[C@@H:14]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[CH2:13][C@@:12]2([CH2:40][CH:41]([CH3:42])[CH3:43])[C:33]([OH:35])=[O:34])=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2csc(-c3ccccc3)n2)N1C(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cnccn2)[C@H](c2csc(-c3ccccc3)n2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1 and purified by reverse phase HPLC to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(C)C)=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=[N:14]1.O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[CH:15]=[N:14]1
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Then, 3.5 g (9.7 mmol) of 2-[2-fluoro-4-chloro-5-isopropoxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 10 ml of concentrated sulfuric acid under ice cooling, and the solution was warmed to room temperature. After ten minutes, about 100 ml of water was added to the reaction mixture. The deposited crystals were collected by filtration, and then washed twice with 20 ml of water and once with 10 ml of hexane in this order. The crystals thus obtained were recrystallized from isopropanol, which afforded 3.2 g (9.9 mmol) of 2-[2-fluoro-4-chloro-5-hydroxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one.
Reaction SMILES: [Na].[Na].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:8].[CH3:23][O:24][C:25]([C:27]1([CH:37]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:31](=[CH2:32])[CH:30]([CH2:33][CH2:34][Cl:35])[C:29](=[O:36])[NH:28]1)=[O:26].FC(F)(F)C(=O)C.C(=O)(O)[O-].[Na+].OOS([O-])=O.[K+]>C(#N)C.O>[CH3:23][O:24][C:25]([C:27]1([CH:37]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[NH:28][C:29](=[O:36])[CH:30]([CH2:33][CH2:34][Cl:35])[C:31]21[O:8][CH2:32]2)=[O:26]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: C=C1C(CCCl)C(=O)NC1(C(=O)OC)C(O[Si](C)(C)C(C)(C)C)C1CCCCC1
Agent: CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])OO
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C(CCCl)C12CO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
An aqueous ethylenediaminetetraacetic acid disodium solution (1.04 ml, 4×10−4 M) was added to a stirred solution of 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-4-(2-chloro-ethyl)-3-methylene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (71 mg, 0.16 mmol, 1.0 equiv) in acetonitrile (2.6 ml) and the reaction mixture was cooled to 0° C. Trifluoroacetone (0.6 ml) was added via a precooled syringe. A mixture of sodium bicarbonate (0.313 g, 3.72 mmol, 23.25 equiv) and Oxone (0.738 g, 1.2 mmol, 7.5 equiv) was added. The reaction mixture was stirred for 4 h at 0° C. Water (20 ml) was added and the resultant mixture was extracted with dichloromethane (100 ml). The organic layer was separated, dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. Purification of the residue by flash column chromatography (15% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) provided 4-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-7-(2-chloro-ethyl)-6-oxo-1-oxa-5-aza-spiro[2.4]heptane-4-carboxylic acid methyl ester (53 mg, 72%).
Reaction SMILES: C(OC([N:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][CH:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:16]2=[O:20])[CH2:12]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:15]1[CH2:14][CH:13]2[CH:17]([CH2:18][CH2:19][NH:11][CH2:12]2)[C:16]1=[O:20]
Reactant: O=C1C(c2ccccc2F)CC2CN(C(=O)OCc3ccccc3)CCC12
Agent: [Pd]
Solvent: CO
Product: O=C1C(c2ccccc2F)CC2CNCCC12
Temperature: 25 °C
Reaction time: 96 h
Yield: 195.3 %

Procedure:
After then dissolving 50 mg of the 3-benzyloxycarbonyl-8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonane in 30 ml of methanol, 100 mg of 10% palladium-carbon was added and the mixture was stirred for 4 days at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was distilled off under reduced pressure to obtain 62 mg of 8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:4]=3)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCn2cccn2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCn2cccn2)cc1

Procedure:
250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with pyrazole to yield 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.0 (M)+.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1([S:10](Cl)(=[O:12])=[O:11])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1>C1COCC1>[CH3:1][NH:2][S:10]([C:4]1([Cl:3])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1)(=[O:12])=[O:11]
Reactant: CN
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Solvent: C1CCOC1
Product: CNS(=O)(=O)C1(Cl)NC(Cl)=CS1
Reaction time: 0.5 h

Procedure:
21 g of a 30% strength aqueous methylamine solution were added dropwise at approx. -75° C. in the course of 45 minutes to 25.25 g (0.1 mol) of 2,4-dichloro-thiazole-sulphonyl chloride from Example 1 in 250 ml of THF, the cold bath was then removed and the temperature was subsequently allowed to rise to room temperature, the mixture was subsequently stirred for 30 minutes, the resulting suspension was evaporated under a waterpump vacuum, and the residue was stirred with 300 ml of water. The solid was filtered off with suction and chromatographed on silica gel (eluent toluene/EtOH 15:1) in order to remove small amounts of starting material and product which is substituted in the 2-position.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:19])(=[O:30])=[O:29])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cc(F)cc(F)c32)c(C)c1

Procedure:
(5.7 mg, 33%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 2,4,6-trimethylphenylsulfonyl chloride (13.1 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][N:16]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCC(=O)Cl
Reactant: C1CC(N2CCC(Oc3nc4c(s3)CNCC4)CC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Yield: 71.5 %

Procedure:
A solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (1.3 grams, 4 mmol, obtained in above step) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (30 mL) was cooled to 0° C. Propionylchloride (0.4 mL, 5 mmol) in dichloromethane (5 mL) was added drop wise over a period of 15 minutes and stirred the reaction for 30 minutes. Reaction mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (1.0 gram).