Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH3:21][C:22]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]2[C:23]=1[CH:24]=[CH:25][C-:26]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li+]>CCOCC>[CH3:31][C:28]1[CH:29]=[CH:30][C:22]([CH3:21])=[C:23]2[C:27]=1[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:25][CH:24]2[Si:7]([CH3:17])([CH3:18])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16]
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Reactant: Cc1ccc(C)c2c1cc[c-]2-c1ccccc1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccccc3)c3c(C)ccc(C)c32)C(C)=C1C
Reaction time: 25 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (4,7-dimethyl-1-phenylindenide) (5.53 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 25 hours, and was then evaporated under vacuum. The residue was extracted with pentane (3×40 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a thick oil. Yield 9.07 g (100%). 1H NMR(C6D6): δ 7.41 (d, 2H), 7.19 (m, 2H), 6.97 (s, 3H), 6.45 (d, 1H), 3.78, (s, 1H), 2.86 (br s, 1H), 2.30 (s, 3H), 2.13 (s, 3H), 1.96 (s, 3H), 1.89 (s, 3H), 1.78 (s, 3H), 1.77 (s, 3H), −0.04 (s, 3H), −0.32 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20](OC(C)(C)C)=O)[CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O.[CH3:34][S:35]([CH:38]=C)(=[O:37])=[O:36]>C(Cl)Cl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH2:15][CH2:14]1
Reactant: COc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
1,1-Dimethylethyl 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine-1-carboxylate (0.7 g, 2.0 mmol) was taken up in 20 mL of DCM and treated with 7 mL of TFA. The mixture stirred for 1 h and was then reduced in vacuo. The solids were transferred to a 50 mL sealed tube and taken up in 20 mL of dioxane. TEA (0.58 g, 5.75 mmol) was added followed by ethenyl methyl sulfone (0.51 g, 4.79 mmol). The mixture was heated to 30° C. for 24 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step B (0.7 g, 1.88 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.56 (s, 1H), 3.86 (s, 3H), 3.33-3.42 (m, 4H), 3.26 (t, J=6.68 Hz, 2H), 2.99 (s, 3H), 2.87 (t, J=6.59 Hz, 2H), 2.74-2.81 (m, 2H), 2.67-2.74 (m, 2H), 2.20 (s, 3H), 1.81-1.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1[CH2:27][S:28]C1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.C[S-].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:28][CH3:27])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (1.54 g) in THF (50 mL) was added sodium methanethiolate (0.39 g). The mixture was allowed to warm to room temperature and stirring continued for 2 h. Saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated to give the subtitle compound as a pale yellow solid. Yield: 1.51 g.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][N:11]([CH3:21])[CH:12]([C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[CH3:13]>O1CCCC1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:10][N:11]([CH3:21])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])=[CH:16][CH:15]=1)[CH3:13]
Reactant: Cc1ccccc1Br
Reactant: CC(c1ccc(Br)cc1)N(C)C
Agent: [Pd]
Agent: [Mg]
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(C)N(C)C)cc1
Reaction time: 5 h
Yield: 97.2 %

Procedure:
A solution of the Grignard reagent prepared from 344 mg of magnesium and 2.27 g of 2-bromotoluene in 15 mL of tetrahydrofuran was added dropwise to a suspension of 2 g of (±)-1-dimethylamino-1-(4-bromophenyl)-ethane and 158 g of tetrakisphenylphosphine-palladium in 10 mL of tetrahydrofuran. The addition was effected at room temperature and under an argon atmosphere. After completion of the addition the mixture was heated to boiling for a further 5 hours and then evaporated under reduced pressure. The residue was then treated with 50 mL of ether and 50 mL of saturated ammonium chloride solution and the aqueous phase was separated. The aqueous phase was extracted twice with 50 mL of ether. The combined organic extracts were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica gel while eluting with methylene chloride/methanol 9:1. There was obtained 2.04 g (96%) of (±)-4'-[1-(dimethylamino)ethyl]-2-methylbiphenyl as a yellow oil.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.C(Cl)(Cl)Cl>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCOCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCOCC2)c2ccccc21

Procedure:
The product obtained from Example 20 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as a crystalline white solid, m.p. 168°-2/3° C. (hexane-chloroform). High Res. Mass Spec. Calcd. for C22H25N3O4 : 396.1923 (M+H). Found: 396.1922.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:14][C:15](=[O:17])[CH3:16])[CH2:8]2)(=[O:3])[CH3:2].[Br:18]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:18])[CH2:10][CH:9]([NH:14][C:15](=[O:17])[CH3:16])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CC(NC(C)=O)C2
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1Br)CC(NC(C)=O)C2
Yield: 77 %

Procedure:
A solution of N-(5-acetylamino-indan-2-yl)-acetamide (9.8 g, 42 mmol) and bromine (8.5 g, 53 mmol) in acetic acid (200 mL) was stirred at room temperature for 3 h. After evaporation of the solvent, the syrupy residue was dissolved in ether and washed with water. The organic layer was washed with aqueous sodium bisulfite and dried over magnesium sulfate. The solvent was concentrated and the resulting solid collected by filtration (10 g, 77% yield).
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:3]([N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:33]([NH:40][C:41](=[O:51])[NH:42][C@H:43]([CH2:48][CH:49]=[CH2:50])[CH2:44][C:45](O)=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:14]([N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:45](=[O:46])[CH2:44][CH:43]([NH:42][C:41]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:51])[CH2:48][CH:49]=[CH2:50])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:26][CH:27]=1)=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2(50 ml) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCl (1.17 g, 7.3 mmol, 1.2 eq), HOBt (0.93 g, 7.3 mmol, 1.2 eq), DIEA (2.13 mL, 12.2 mmol 2.4 eq) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 687 (M+H), 709 (M+Na)
Reaction SMILES: [CH3:1][N:2]([CH2:22][CH2:23][OH:24])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][N:2]([CH2:22][CH2:23][O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(C)CCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(C)CCOC(=O)c1ccccc1

Procedure:
N-methyl-N-(2-benzoyloxyethyl)oleamide was prepared by the procedure of example 1 from 34 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)oleamide and 14 gms. (0.1 mole) of benzoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([C:20]2[CH:21]=[C:22]([CH:29]=O)[N:23]([CH2:25][CH2:26][CH2:27][F:28])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.Cl.[NH2:34][OH:35]>O1CCCC1>[NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([C:20]2[CH:21]=[C:22]([CH:29]=[N:34][OH:35])[N:23]([CH2:25][CH2:26][CH2:27][F:28])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CN1C(=O)C(c2cccc(-c3cccnc3F)c2)(c2cc(C=O)n(CCCF)c2)N=C1N
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CN1C(=O)C(c2cccc(-c3cccnc3F)c2)(c2cc(C=NO)n(CCCF)c2)N=C1N
Temperature: 45 °C

Procedure:
A solution of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde in dry tetrahydrofuran was treated with 1.1 equivalent of hydroxylamine hydrochloride, warmed to 45° C. for 2 hours and concentrated in vacuo. The resultant residue was dissolved in chloroform, washed with water, dried over sodium sulfate and concentrated in vacuo. This residue was purified by HPLC (CN bonded stationary phase, gradient 30% to 60% of (20% MeOH/methylene chloride) and hexane to afford the title compound as a white amorphous solid, mp 119-123° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(COCc2ccccc2)n1Cc1ccc2c(c1)OCO2

Procedure:
To a solution (2.5 ml) of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) in THF was added sodium hydride (26 mg) at 0° C. with stirring. The mixture was stirred at room temperature for 10 min., benzylbromide (71 μl) was added, and the mixture was further stirred for 2 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (210 mg) as colorless crystals.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:6][CH:5]=1>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][C:11]([OH:1])=[O:12])=[CH:6][CH:5]=1
Reactant: O=CCCc1ccc(Cl)s1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Silver nitrate (117 mg, 0.69 mmol) in 1 mL of H2O is added to 1.36 mL of 1N NaOH at 0° C. and stirred for 5 minutes. To the brown suspension is added 3-(5-chloro-thiophen-2-yl)-propionaldehyde (60 mg, 0.34 mmol) and the resulting mixture is allowed to warm to room temperature over 2 hours. The precipitate is filtered and washed with hot water (2×). The combined aqueous layers are acidified with 6 N HCl and extracted with EtOAc (2×). The combined organic layers are washed with water (2×), then dried over MgSO4, filtered and concentrated in vacuo to give the title compound (50 mg, 0.26 mmol) as a beige solid. The crude material can be used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ6.72 (d, 1H), 6.60 (d, 1H), 3.07 (t, 2H), 2.71 (t, 2H).
Reaction SMILES: [N:1]1([C:8]2[N:16]3[C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][O:19][C:14]4=[C:15]3[C:10](=[CH:11][CH:12]=[C:13]4[C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:33](N)([NH2:36])(=[O:35])=[O:34]>N1C=CC=CC=1.CO>[CH3:32][C:27]1[C:26]([C:13]2[C:14]3[O:19][CH2:18][C@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:16]4[C:8]([N:1]5[CH2:7][CH2:6][CH2:5][N:4]([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:3][CH2:2]5)=[N:9][C:10]([C:15]=34)=[CH:11][CH:12]=2)=[C:30]([CH3:31])[O:29][N:28]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: NS(N)(=O)=O
Solvent: CO
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1ccc2nc(N3CCCN(S(N)(=O)=O)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 120 °C
Yield: 77 %

Procedure:
(4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (5.8 mg, 0.013 mmol) and sulfamide (7.8 mg, 0.081 mmol) were dissolved in pyridine (0.71 mL) and the solution was heated at 120° C. for 3 min in a microwave. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (5.1 mg, 74%). LCMS calc. for C24H27N7O4S (M+H)+: m/z=510.2. found: 509.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1>CO.[Rh]>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: [Rh]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
(R)-tert-butyl 1-(4-hydroxyphenyl)ethylcarbamate (described in the literature: WO 2007035154 (A1)) (100 mg, 0.4214 mmol) was dissolved in methanol (5 mL). A methanolic (5 mL) solution of rhodium on alumina (10 Wt %, 10 mg) was added. The reaction mixture was place under a hydrogen atmosphere and stir at room temperature for 18 hours. The rhodium catalyst was filtered off and the mother liquors were concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (62 mg, 61% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:35][C:24]([F:23])([F:34])[C:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:26]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cn3nc(C(F)(F)F)c4c3CCCC4)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.1 %

Procedure:
(S)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (23 mg, 0.086 mmol) was dissolved in DCM (5 mL) and thionyl chloride (51 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) to this was added 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (25 mg, 0.086 mmol) followed by potassium carbonate (24 mg, 0.172 mmol). The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative basic HPLC gave the title compound (1.2 mg, 2.7 μmol, 2.9%). MS (ESI): m/z [M+H]+ 442.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=O)=[CH:4][C:3]=1[Cl:13].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:12])=[CH:4][C:3]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1nc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.4 %

Procedure:
A mixture of 6-amino-5-chloro-2-(methyloxy)-3-pyridinecarboxylic acid (Y. Hirokawa et al., Bioorg. Med. Chem. Lett., 1998, 12, 1551–1554, 500 mg, 2.47 mmol) and 1,1′-carbonyldiimidazole (440 mg, 2.71 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 45 min. A solution of 1,1-dimethylethyl 4-(aminomethyl)-1-piperidinecarboxylate (529 mg, 2.47 mmol) in N,N-dimethylformamide (5 ml) was added and the resulting mixture was stirred at room temperature for 5 h. The mixture was poured into water (200 ml) and extracted with ethyl acetate/toluene (2:1, 200 ml×3). The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was chromatographed on a column of silica gel eluting with methanol/dichloromethane (1:25) to give 703 mg (71%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[NH2:26][C:27]1[C:28]([CH3:34])=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1.Cl.N1C=CC=CC=1.C(OCCO)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:24]#[N:25])=[C:28]([CH3:34])[CH:29]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCOCC1
Reactant: Cc1cc(O)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3ccc(O)cc3C)c(C#N)cnc2cc1OCCCN1CCOCC1
Yield: 61.8 %

Procedure:
A mixture of 0.3 g of 4chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile derivative, 0.12 g of 4amino-m-cresol, 0.1 g of pyridine hydrochloride and 4 ml of 2-ethoxy ethanol was stirred under nitrogen at reflux temperature for 1.5 hr. The mixture was cooled and added to the mixture of ethyl acetate and saturated solution of sodium bicarbonate, stirred for 15 minutes. Following separation of layers, the organic layer was dried over anhydrous sodium sulfate, filtered and filtrate was evaporated to yield dark oil. The oil was purified by silica gel flash chromatography utilizing a gradient of methylene chloride/methanol (95:5 to 90:10 ) to give 0.23 g of the title compound as a tan solid, mp120-126 C; mass spectrum (electrospray, m/e):M+H 449.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[O:28])([CH3:25])([CH3:24])[CH3:23].O>C1(C)C=CC=CC=1.O1CCCC1>[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][C:12]1=[O:11])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: O=C1CCc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCN1C(=O)CCc2ccccc21
Temperature: 25 °C

Procedure:
0.5M Potassium bis-(trimethylsilyl)-amide in toluene (10 ml) was added dropwise at −30° C. in an argon atmosphere to a stirred solution of 2-oxo-1,2,3,4-tetrahydroquinoline (735 mg) in tetrahydrofuran (50 ml). After further cooling to −50° C. a solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (1.5 g) in tetrahydrofuran (10 ml) was added slowly. Subsequently the temperature was allowed to raise to room temperature followed by heating at 50-60° C. for 48 hours. Ice and water were added and the mixture was extracted twice with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate/hexane (1:1) as eluent gave the desired compound as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:24]C(OCC)=O)=[N:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(O)(C)C.[OH-].[K+]>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH:16]([CH3:17])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:30])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:23][N:22]=1
Reactant: CCOC(=O)Nc1ccc(C(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(c1ccc(N)nc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 84.6 %

Procedure:
A solution of the product of Example 21 (70 mg) in isopropanol (4 ml) containing 50% aqueous potassium hydroxide (4 drops) was heated under reflux for 4 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with ethyl acetate. The combined organic extracts were washed with water and dried (MgSO4). Evaporation of the solvent gave the title compound as an amorphous foam, (49 mg).