Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=2)=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 82%).
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Si:14]([O:21][CH2:22][C@@H:23]([N:25]1[C:29]2[N:30]=[CH:31][N:32]=[CH:33][C:28]=2[C:27]([C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([N:42]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:41]=2)=[O:35])=[CH:26]1)[CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O.[OH-].[Na+]>C1COCC1>[NH2:42][C:40]1[CH:41]=[C:36]([C:34]([C:27]2[C:28]3[CH:33]=[N:32][CH:31]=[N:30][C:29]=3[N:25]([C@@H:23]([CH3:24])[CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:26]=2)=[O:35])[CH:37]=[N:38][CH:39]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Aqueous citric acid (120 mL, 2.0 M) was added to {7-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}{5-[(diphenylmethylene)amino]pyridin-3-yl}methanone (63.2 g, 110 mmol) (see Preparation 24) in THF (274 mL) and the mixture was stirred at room temperature for 17 hours. The mixture was cooled to 0°, water (200 mL) added and the mixture was basified using sodium hydroxide (28 g). The mixture was extracted with ethyl acetate (150 mL) then the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine (600 mL), dried over sodium sulfate and evaporated in vacuo to afford the title compound as a semi-solid in quantitative yield, 45.2 g.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([OH:32])=O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1.[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH:38]1[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=2[O:40][CH2:39]1)[CH3:34]>CCOC(C)=O>[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([N:43]3[C:42]4[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH:38]3[CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:48])=[O:32])[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1
Reactant: CCOC(=O)CC1COc2ccccc2N1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 75 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
T3P (50% solution in EtOAc, 132.4 g, 0.208 mol) was added to 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (22.1 g, 0.114 mol), ethyl-2-(3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (23.0 g, 0.104 mol) and TEA (57.9 mL, 0.416 mol) in EtOAc (139 mL) at rt. The resulting mixture was stirred at 75° C. for 16 h. The resulting solution was diluted with 800 mL of EtOAc and washed with aq. sat. NaHCO3 solution (300 mL), 0.5 M HCl solution (300 mL) and brine (300 mL). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by re-crystallization from MeOH to afford the title compound (14.5 g, 35%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCCCCC(=O)O
Reaction time: 2 h
Yield: 100.7 %

Procedure:
Ethyl 5-(2-((tert-butoxycarbonylamino)methyl)-5-fluorophenoxy)pentanoate (Example 16; 1.6 mmol) was dissolved in a mixture of THF (6 ml), methanol (6 ml) and water (6 ml). Sodium hydroxide (5.0 mmol) was added and stirred for 2 h. The organic solvent was removed under vacuum, and the aqueous residue was acidified with 1 N HCl to pH=3. The mixture was extracted with ethyl acetate, and the organic phase was removed under vacuum to afford the title compound (0.55 gr) that was used as such in the next step (Example 5.1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:11][CH2:12][C:13]#[CH:14])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH:11][CH2:12][C:13]#[CH:14])=[N:4][C:5]([S:9]([CH3:10])=[O:23])=[N:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCNc1nc(SC)nc(Cl)c1Br
Solvent: ClCCl
Product: C#CCNc1nc(S(C)=O)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a stirring solution of 5-bromo-6-chloro-2-(methylthio)-N-(prop-2-ynyl)pyrimidine-4-amine (intermediate 29) (5.45 mmol) in 6 ml of DCM, 1.34 g (6 mmol) of m-chloroperbenzoic acid (77%) (Aldrich) in 8 ml of DCM were added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed several times with cold DCM and dried. 1.52 g (90.5%) of 5-bromo-6-chloro-2-(methylsulfinyl)-N-(prop-2-ynyl)pyrimidine-4-amine were obtained as a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]([CH3:45])[C:40]([O:42]CC)=[O:41])[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:23][C:22]([F:25])([F:24])[CH2:21][NH:20][C:18]([NH:17][C:13]1[CH:12]=[C:11]([C:8]2[N:5]3[N:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][N:37]([CH:39]([CH3:45])[C:40]([OH:42])=[O:41])[CH:38]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1)=[O:19]
Reactant: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.206 g, 0.556 mmol, Example 30, Step 3), ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate (0.18 g, 0.61 mmol), tetrakis(triphenylphosphine)palladium(0) (32.1 mg, 0.00278 mmol) and K3PO4 (0.30 g, 1.4 mmol) in 1,4-dioxane (3.0 mL) and water (2.0 mL) was heated at 100° C. under an atmosphere of nitrogen for 3 h. After cooling, the reaction mixture was adjusted to pH=4, extracted with ethyl acetate (3×30 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product without further purification. LCMS (M+H)+: m/z=474.1.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([CH3:12])=[CH:7]2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(N)ccc(F)c2cn1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)ccc(F)c2cn1

Procedure:
Prepared from 8-fluoro-3-methylisoquinolin-5-amine (Description 76) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 378 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][NH:24][CH3:25])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][N:24]([CH3:25])[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CNCc1cccc(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CN(C)CC(=O)c2ccc3ccccc3c2)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of α-bromo-2′-acetonaphthone (386.2 g, 1.57 mol) in dichloromethane (2.5 L) at 0° C. was added Compound 3 (249.1 g, 1.65 mol) in 30 min, followed by the addition of triethylamine (220.7 mL, 1.57 mmol) in 45 min. After stirring at 0° C. for 40 min, the reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was then washed with water (2×) and the aqueous layer was re-extracted with dichloromethane (2×). The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The ketone, Compound 4, was obtained as a reddish oil (513.3 g, quantitative), was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ 8.50 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.92 (d, 8.0 Hz, 1H), 7.88-7.85 (m, 2H), 7.60-7.54 (m, 2H), 7.26-7.23 (m, 1H), 6.97-6.94 (m, 2H), 6.82 (dd, J=8.0, 2.5 Hz, 1H), 3.88 (s, 2H), 3.75 (s, 3H), 3.69 (s, 2H), 2.42 (s, 3H); ESI MS m/z 320 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:8]=[C:9]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:10]2[S:15][C:14]([CH:16]=O)=[CH:13][C:11]=2[N:12]=1>>[Cl:6][C:7]1[N:8]=[C:9]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:10]2[S:15][C:14]([CH2:16][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:13][C:11]=2[N:12]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCN
Product: COCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
Reaction of 2-methoxyethylamine with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methoxy-ethyl)-amine, which was reacted with 1-isopropyl-4-piperidone using the standard reductive amination conditions to yield (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isopropyl-piperidin-4-yl)-(2-methoxyethyl)amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6].[C:15]([Mg]Cl)#[CH:16]>C1COCC1>[OH:6][CH:5]([C:4]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:15]#[CH:16]
Reactant: C#C[Mg]Cl
Reactant: COc1cc(OC)c(OC)cc1C=O
Solvent: C1CCOC1
Product: C#CC(O)c1cc(OC)c(OC)cc1OC

Procedure:
3-Hydroxy-3-(2,4,5-trimethoxyphenyl)-1-propyne was prepared according to Method A above from 2,4,5-trimethoxybenzaldehyde (0.784 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 548 mg, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)N[C@@H](C)COCCCc1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCCCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-isopropyl-N—[(S)-1-methyl-2-(3-phenyl-propoxy)-ethyl]-amine as described for example 1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:59]([CH3:61])[CH3:60])[C:14]([N:16]1[C@H:21]([C:22]2[NH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([C:37]3[CH:38]=[CH:39][C:40]5[N:44]=[C:43]([C@@H:45]6[CH2:50][C@@H:49]7[C@@H:47]([CH2:48]7)[N:46]6C(OC(C)(C)C)=O)[NH:42][C:41]=5[CH:58]=3)[CH:31]=[CH:30]4)=[CH:25][N:26]=2)[CH2:20][C@@H:19]2[C@H:17]1[CH2:18]2)=[O:15])=[O:11]>C(Cl)Cl>[C@@H:47]12[CH2:48][C@@H:49]1[CH2:50][C@@H:45]([C:43]1[NH:42][C:41]3[CH:58]=[C:37]([C:32]4[CH:33]=[C:34]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:24]4[NH:23][C:22]([C@@H:21]6[CH2:20][C@@H:19]7[C@@H:17]([CH2:18]7)[N:16]6[C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[CH:59]([CH3:61])[CH3:60])=[N:26][CH:25]=4)[CH:36]=[CH:35]5)[CH:38]=[CH:39][C:40]=3[N:44]=1)[NH:46]2
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)ccc3c2)[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6)[nH]c5c4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
TFA (2 mL) was added to a solution of (1R,3S,5R)-tert-butyl 3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (226 mg, 0.310 mmol) in DCM (5 mL) and the reaction was stirred for 2 h at room temperature. The solution was concentrated under vacuum and the residue was taken in MeOH (10 mL) and filtered through a Strata XC MCX cartridge and washed with methanol (25 mL). The compound was released from the cartridge by washing the column with a solution of 2M of ammonia/methanol (10 mL) and concentrated under reduced pressure to give a methyl(S)-1-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (131 mg, 0.208 mmol) as tan solid. LC-MS retention time 1.235 min; m/z 630.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.16 (s, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.3, 6.3 Hz, 2H), 7.87 (s, 1H), 7.78-7.85 (m, 2H), 7.60-7.69 (m, 2H), 7.44 (s, 1H), 5.20 (dd, J=8.8, 4.8 Hz, 1H), 4.62 (d, J=6.8 Hz, 1H), 4.28 (dd, J=9.8, 7.8
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:12].C[O:20][C:21]([C:23]1[C:28]([C:29](OC)=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1)=O.[H-].[Na+].Cl>O1CCCC1.CCOCC.CO>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[C:7](=[O:12])[C:8]2[C:21]([OH:20])=[C:23]3[C:28]([CH:27]=[CH:26][CH:25]=[N:24]3)=[C:29]([OH:30])[C:9]=2[C:10]1=[O:11]
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: COc1ccc(CN2C(=O)CCC2=O)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2C(=O)c3c(c(O)c4ncccc4c3O)C2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To 1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6 mmol) and pyridine-2,3-dicarboxylic acid dimethyl ester (1.13 g, 5.8 mmol) dissolved in tetrahydrofuran (60 ml) and methanol (7.0 ml) was added a 60% dispersion of sodium hydride in mineral oil (NaH, 492 mg, 12.3 mmol). The reaction mixture was warmed to 80° C. and kept at 80° C. with stirring overnight. The reaction mixture was placed in an ice bath and titrated to a pH of 4 with 1 M HCl. 200 ml of ether was added and the resulting yellow solid was collected by filtration. The solid was washed twice with ether, twice with water, and dried under high vacuum with heating to provide 7-(2,4-dimethoxy-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 300 (1.1 g, 52%). 1H NMR (d-DMSO) δ 10.8 (broad, 2H), 9.0 (d, 1H), 8.67 (d, 1H), 7.72 (m, 1H), 6.90 (d, 1H), 6.5 (d, 1H), 6.38 (dd, 1H), 4.58 (s, 2H), 3.76 (s, 3H), 3.66 (s, 3H). MS: 382.1 (M+1)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:62](=[NH:75])([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>O1CCOCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:63]1([C:62](=[N:75][C:2]2[CH:11]=[CH:10][C:9]3[C:8]([CH3:13])([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CC1(O)CCCc2nc(Cl)ccc21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(O)CCCc2nc(N=C(c3ccccc3)c3ccccc3)ccc21
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-methyl-5,6,7,8-tetrahydroquinolin-5-ol (306 mg, 1.55 mmol), Xantphos (107 mg, 0.185 mmol), tris(dibenzylideneacetone)dipalladium(0) (71 mg, 0.077 mmol), cesium carbonate (1.01 g, 3.09 mmol), and benzophenone imine (0.272 mL, 1.63 mmol) in 1,4-dioxane (10 ml) under an argon atmosphere was heated at 100° C. in an oil bath for 6 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 mL), saturated aqueous sodium bicarbonate solution (10 mL), and brine (20 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-80% ethyl acetate/hexanes linear gradient) to afford 2-[(diphenylmethylidene)amino]-5-methyl-5,6,7,8-tetrahydroquinolin-5-ol. MS ESI calc'd. for C23H23N2O [M+H]+ 343. found 343.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>C1COCC1>[C:10]([NH:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([C:16]([NH:15][CH2:13][CH3:14])=[O:17])[C:5](=[O:8])[N:4]=1)(=[O:12])[CH3:11]
Reactant: CCN=C=O
Reactant: CC(=O)Nc1nc(O)ncc1F
Solvent: C1CCOC1
Product: CCNC(=O)n1cc(F)c(NC(C)=O)nc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a suspension of N-(5-fluoro-2-hydroxypyrimidin-4-yl)acetamide (as prepared in U.S. Pat. No. 3,309,359; 0.25 g, 1.46 mmol) in dry THF (5 mL) was added ethyl isocyanate (0.127 mL, 1.61 mmol), and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, and the solid residue was suspended in Et2O (10 mL). The suspension was suction filtered and washed with Et2O (2×10 mL). The resulting solid was dried in vacuo to yield 4-acetamido-N-ethyl-5-fluoro-2-oxopyrimidine-1(2H)-carboxamide (0.350 g, 99%) as a white solid: mp 233-235° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.01 (s, 1H), 8.62 (d, J=7.0 Hz, 1H), 3.40-3.27 (m, 2H), 2.30 (s, 3H), 1.15 (t, J=7.2 Hz, 3H); ESIMS m/z 241
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([O:13][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-4A) (253 mg, 0.9 mmol) in DCM (6 mL) at 0° C. was added triethylamine (0.25 mL, 1.8 mmol) followed by dropwise addition of methanesulfonyl chloride (95 μL, 1.3 mmol). After stirring 2 hours at room temperature the reaction mixture was concentrated under reduced pressure and the resulting solid was extracted with Et2O (2×20 mL). The combined extracts were washed sequentially with 1% aqueous citric acid and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (I-29) as a colorless oil. MS m/z 382.1 (M+23)+.
Reaction SMILES: O.O=C1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=2[S:5](=[O:17])(=[O:16])[NH:4]1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=1[S:5](=[O:17])(=[O:16])[NH2:4]
Reactant: O=C1Nc2ccc(C(=O)O)cc2S(=O)(=O)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(C(=O)O)cc1S(N)(=O)=O

Procedure:
A suspension of 3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide monohydrate (10 g) in a mixture of concentrated sulfuric acid (150 mL) and water (150 mL) was refluxed until complete dissolution of the starting material (1-2 h). The resulting solution was placed on an ice bath and supplemented dropwise with a 20% aqueous solution of NaOH under stirring and cooling until pH 1-2. The precipitate was collected by filtration, washed with water and dried (yield: 6.6 g); m.p.: 214-219° C.