Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]([NH2:27])=[O:26].O>O1CCCC1>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH2:24][C:25]([NH2:27])=[O:26])[C:11]3=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2cc(OCc3ccc(F)cc3)ccc21
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
A mixture of 5-(4-fluoro-benzyloxy)-isoindole-1,3-dione (100 mg, 0.37 mmol), sodium hydride (55% in mineral oil, 18 mg, 0.42 mmol) and 2-bromoacetamide (61 mg, 0.44 mmol) in dry tetrahydrofuran (5 mL) at 0° C. was stirred at room temperature for 3 h and then heated at 50° C. for 1 h. After cooling to 0° C., water (2 mL) was added and the product extracted with ethyl acetate. The organic extracts were then washed with brine and dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, heptane-CH2Cl2 2:3 then CH2Cl2— 2N NH3-MeOH 99:1: to 4:1) to afford the title compound (78 mg, 65%) as a white solid.
Reaction SMILES: [F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH3:28])[O:21][C:20]([CH3:30])([CH3:29])[CH:19]=[C:18]2[CH:31]([CH3:33])[CH3:32])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.C1COCC1>[F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH3:28])[O:21][C:20]([CH3:30])([CH3:29])[CH:19]=[C:18]2[CH:31]([CH3:32])[CH3:33])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C(C)C)=CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl (2E,4E,6E)-6-fluoro-7-(4-isopropyl-2,2-dimethyl-7-propoxy-2H-chromen-6-yl)-3-methyl-octa-2,4,6-trienoate (Compound 112, 73 mg, 0.16 mmo) in ethanol and THF was hydrolyzed with NaOH to yield the title compound as a yellow solid after recrystallized from acetonitrile.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][C:19]=1[CH3:44]>O1CCCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][C:19]=1[CH3:44]
Reactant: Cc1cc(C(=C(C=CC=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)c(C)c1)c1ccc(F)c(C)c1)c1nnnn1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A solution of the dianion of ethyl acetoacetate (1.42 mL, 11.1 mmoles) in dry tetrahydrofuran (15 mL) was generated as described in Example 10 using 450 mg (11.3 mmoles) of NaH (60% in mineral oil) and 4.5 mL (11.1 mmoles) of 2.5M n-BuLi in hexane at 0° C. under argon. The orange dianion solution, after being chilled to -78° C., was transferred via a cannula into a tetrahydrofuran (15 mL) solution containing 5,5-bis(4-fluoro-3-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (2.12 g, 5.6 mmoles) at -78° C. The reaction mixture was stirred at -78° C. for 15 minutes. Analytical TLC eluted once with 50% (v/v) ethyl acetate in hexanes showed a major product at Rf =0.16. The reaction mixture was diluted with 20 mL of 1N HCl and the organic residues were extracted with ethyl acetate (30 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give a pale syrup. The crude product was chromatographed on a silica gel column eluted with 35% (v/v) ethyl acetate in hexanes to give 1.39 g (48.7%) of the title compound. MS (CI): m/e=511 for (M+H)+ ;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:13]N(N=O)C(N)=O.[OH-].[K+]>COCCOC.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:13])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1
Yield: 149.5 %

Procedure:
1.00 grams (6 millimoles) of m-nitrobenzoic acid and 2.4 grams (2.4 millimoles) of N-methyl,N-nitrosourea were dissolved in 25 milliliters of a 5:1 mixture of 1,2-dimethoxyethane and water. 40 milliliters of 0.6 N potassium hydroxide was added in a dropwise manner while the mixture was held at 0°C. in an ice bath. The solution was extracted with ether (4×50 milliliters) and the water layer (pH 10) was saved. The ether layer was dried (MgSO4) and workup gave 0.65 grams of methyl m-nitrobenzoate, melting point 71°-72°C. The water layer gave 0.25 grams of unreacted acid. Yield, based on consumed acid, was approximately 85 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]2[CH2:17][O:16]2)[CH2:10][C:11]([O:13]C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:17][N:19]([CH3:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:16][C:11](=[O:13])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC(c1ccc(Cl)c(Cl)c1)C1CO1
Reactant: CNc1ccccc1
Solvent: OCC(F)(F)F
Product: CN(CC1OC(=O)CC1c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 23 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Treat a solution of the product of step 2 (368 mg, 1.34 mmol) in 2,2,2 trifluoroethanol (1 mL) with N-methyl aniline (217 μL, 2.01 mmol, 1.5 eq) and stir for 6 h at 23° C. followed by 6 h at 80° C. Cool to 23° C., concentrate in vacuo and purify by silica gel chromatography (column: 3.5×12 cm; eluant: hexane:EtOAc (4:1)) to provide 446 mg (1.3 mmol, 97%) of 4-(3,4-dichlorophenyl)-dihydro-5-[(methylphenylamino)methyl]-2(3H)-furanone as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])=[C:6]([CH2:8][C:9](O)=O)[CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-:37].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:13][C:14]3[C:15]([CH3:22])=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][C:19]=3[C:9](=[O:37])[CH2:8][C:6]=2[CH:7]=1
Reactant: [OH-]
Reactant: COc1cccc(CCc2ccc(Br)cc2CC(=O)O)c1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1C)CCc1ccc(Br)cc1CC2=O
Temperature: 90 °C
Yield: 55 %

Procedure:
To a stirred suspension of 5-bromo-2-[2-(3-methoxy-2-methyl-phenyl)-ethyl]-phenylacetic acid (11) (4.38 g; 12.06 mmol) in toluene (20 mL), was added phosphorous pentoxide (6.0 g; 42.2 mmol). The mixture was heated at 90° C. for 16 hours. The mixture was cooled, treated with 1.0 N solution of sodium hydroxide and extracted with chloroform. The extracts were combined, dried over Na2SO4, and evaporated. The resultant residue was chromatograped on silica gel using hexane and ethyl acetate (4:1) to give compound 12 as colorless crystals, 2.40 g; 55% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[N:10][N:11]=1
Reactant: COc1ccc2c(-c3ccc(C)c(C)c3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc(C)c(C)c3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(3,4-dimethylphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:33]([NH:40][C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: -5 °C
Yield: 95.9 %

Procedure:
Into a 500 mL round bottomed flask equipped with a magnetic stirrer was added N-(tert-butoxycarbonyl)-L-isoleucine (22.53 g, 97.39 mmol, 1.0 eq) and THF (300 mL). The solution was stirred until homogeneous, cooled to -5° C., and treated with N-ethylmorpholine (14.23 mL, 12.88 g, 112.0 mmol, 1.15 eq). The solution was stirred at -5° C. for 20 min, and isobutyl chloroformate (13.24 mL, 13.90 g, 102 mmol, 1.05 eq) was added dropwise over 10 min. After stirring at -5° C. for 30 min, benzylamine (12.24 mL, 12.0 g, 112.0 mmol, 1.15 eq) was added dropwise over 10 min. After the addition was complete, the flask was removed from the cold bath and the solution was stirred at 22° C. for 2.5 hrs. The solution was concentrated to a residue, and partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was extracted with ethyl ether (2×100 mL) and discarded. The organic extracts were combined, washed with 1N HCl (5×50 mL), 1N NaOH (3×50 mL), satd. aq NaCl (50 mL), and dried (MgSO4). The solution was concentrated in vacuo to provide 29.93 g (96%) of N-(tert-butoxycarbonyl)-L-Isoleucine benzylamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L3) according to the general procedure M. Obtained as an orange oil (238 mg).
Reaction SMILES: I[C:2](=[CH2:16])[CH2:3][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[OH:5].[OH-].[Na+].Cl>CN(C)C=O>[C:6]1([CH:4]([CH2:3][C:2]#[CH:16])[OH:5])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: C=C(I)CC(O)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCC(O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.00 Grams of 2-iodoallyl-α-naphthylcarbinol were disolved in 50 g of dimethylformamide, and 1.23 g of sodium hydroxide in a flake form were added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed the reaction mixture was neutralized with concentrated hydrochloric acid, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was subjected to extraction with toluene and washed with a 7% sodium carbonate aqueous solution, and then the toluene was distilled off under reduced pressure to give 2.78 g of α-naphthylpropargylcarbinol; nD25 =1.549, FI-MS m/e 196(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])C)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:27]2[CH:22]([C:23]3([CH3:29])[O:28][CH:26]2[CH2:25][CH2:24]3)[C:21](=[O:30])[CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:13][O:15][C:19]3[CH:27]4[CH:22]([C:23]5([CH3:29])[O:28][CH:26]4[CH2:25][CH2:24]5)[C:21](=[O:30])[CH:20]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: CC12CCC(O1)C1C(Cl)=CC(=O)C12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC12CCC(O1)C1C(OCc3cnc(-c4ccc(Cl)cc4)s3)=CC(=O)C12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
To a solution of 1-[2-(4-chloro-phenyl)-thiazol-5-yl]ethanol (264 mg, 1.1 mmol) in tetrahydrofuran (5 ml) is added in one portion the sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol). The reaction mixture is stirred for five minutes at room temperature and 5-Chloro-1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (219 mg, 1.1 mmol) is added in one-portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 5-[2-(4-chloro-phenyl)-thiazol-5-ylmethoxy]-1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (410 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH2:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][NH:25][C:35]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[S:20][C:18]=2[N:19]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[C:21]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:15][N:13]([CH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:21]#[N:22])(=[O:31])=[O:30])[CH3:14]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc(C#N)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3-cyanobenzenesulphonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (4 mg, 13%) as a white solid. MS (ESI+) for C19H19N3O3S m/z 370 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[CH3:32]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[CH3:32])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1coc(-c2ccc(N)c(C)c2)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2C)nc1Cl
Yield: 50.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.12 g, 0.69 mmol), thionyl chloride (4 mL), methyl 4-amino-3-methylphenyl)-1,3-oxazole-4-carboxylate obtained in Example (109e) (0.23 g, 0.95 mmol) and pyridine (5 mL), to obtain 135 mg of the title compound as a light brown solid (50%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]2[C:15]3[N:11]([C:12]([C:24]4[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=4)=[C:13]4[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:14]4=3)[CH2:10][CH2:9][CH:8]=2)[S:5][CH:6]=1>[Pt].C(O)C.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]2[C:15]3[N:11]([C:12]([C:24]4[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=4)=[C:13]4[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:14]4=3)[CH2:10][CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: Cn1ccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(Cl)cs2)n1
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3c2nc(Cl)cs2)n1
Reaction time: 168 h

Procedure:
A suspension of 10-(4-chlorothiazol-2-yl)-1,3-dimethyl-5-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (25 mg, 0.058 mmol) and 10% platinum on carbon (12 mg, 6.15 μmol) in ethanol (2.2 ml) and THF (6.6 ml) was stirred under an atmosphere of hydrogen for 7 days. The mixture was filtered and the residue rinsed thoroughly with ethanol and the combined filtrates evaporated under vacuum. Purification by chromatography on silica, eluting with 80% EtOAc/hexane afforded a crude material which was triturated with diethyl ether to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([O:50][Si](C(C)C)(C(C)C)C(C)C)[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1>>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([OH:50])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)[Si](Oc1cc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)ccc1Cl)(C(C)C)C(C)C
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(O)c4)c4ccccc43)cn12
Yield: 76 %

Procedure:
The title compound (193 mg, 76%) was prepared starting from Intermediate E (155 mg, 0.427 mmol) and [5-tert-butyl-2-(4-chloro-3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 260 mg, 0.436 mmol), using analogous procedures to those described in Example 50. LCMS (Method 5): Rt 3.54 min, m/z 655.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.82-2.26 (11H, m), 2.31-2.39 (1H, m), 3.10-3.17 (1H, m), 3.99 (1H, d, J=8.1 Hz), 4.78-4.86 (1H, m), 5.37-5.42 (1H, m), 6.33 (1H, s), 6.89-6.95 (1H, br d), 7.07-7.12 (2H, m), 7.24-7.38 (5H, m), 7.42 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=9.8 Hz), 8.12 (1H, s), 8.25 (1H, br d), 10.64 (1H, v br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@@H:5]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:6][NH:7][C:8](=[O:21])[CH2:9][NH:10]C(OCC1C=CC=CC=1)=O)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[C@@H:5]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:25])[CH2:6][NH:7][C:8](=[O:21])[CH2:9][NH2:10])[CH3:2]
Reactant: CCOC(=O)[C@H](CNC(=O)CNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Reaction time: 4 h

Procedure:
Protected amine 3-5 (0.47 g, 1.01 mmol) was dissolved in 10 mL EtOH, 10% Pd/C (94 mg) was added, and the reaction was stirred under an H2 balloon. After 4 h, additional 10% Pd/C was added (94 mg), and the reaction was continued for 3 d. The mixture was filtered through Celite, concentrated, and azeotroped with CHCl3, providing amine 3-6 as a gum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C>[C:12]1([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: BrCCCOCCOCCCc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(CCCOCCOCCCNCc2ccccc2)cc1
Reaction time: 4.5 h
Yield: 78.8 %

Procedure:
[3-[2-(3-Bromopropoxy)ethoxy]propyl]benzene (3.01 g) was added dropwise over 5 min to benzylamine (5.35 g) at 120° under nitrogen. The solution was stirred at 130° for 4.5 h, cooled, diluted with ethyl acetate (200 ml) and washed with 2N hydrochloric acid (150 ml). The aqueous phase was re-extracted with ethyl acetate (2×100 ml) and the combined organic phases washed with 8% sodium bicarbonate solution (200 ml), dried and evaporated in vacuo to give the title compound (2.58 g) as an oil. T.l.c. (System E 40:10:1) Rf 0.49
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CCOC(C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:9])[N:6]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)CC1
Temperature: 120 °C

Procedure:
2-Amino-3,5-dibromopyrazine (1.26 g, 5.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.64 g, 25 mmol) were placed in a dry RBF and heated with stirring to 120° C. under dry nitrogen. Molten mixture was stirred at this temperature for 6 h and cooled to room temperature. The resulting slurry was diluted with EtOAc (20 mL) and stirred for 20 min. Amine salts were removed by filtration and washed with EtOAc (3×5 mL). Filtrate was washed with pH 4 buffer (35 mL) and brine (35 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 7:3) gives the title compound I-3r as an off white solid (1.64 g, 92% yield).