Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].[NH3:37]>CN(C)C=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])=[N:12][C:13]([NH2:37])=[N:14][CH:15]=1)=[O:9]
Reactant: N
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1Br
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(N)nc1-c1ccccc1Br
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of 0.42 g (0.7 mmol) 4-(2-bromo-phenyl)-2-methylsulfonyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 30 ml N,N-dimethylformamide a stream of NH3 was introduced during 10 Min. The reaction solution was stirred for 4 hrs. The solvent was evaporated and the residue distributed between 20 ml CH2Cl2 and 20 ml H2O. The aqueous phase was extracted twice with 30 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 140:10:1) to give 0.29 g (77%) 2-amino-4-(2-bromo-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a white foam, MS (ISP): 535.1, 533.1 (M+H+).
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][CH2:21][OH:22]>ClCCl>[OH:22][CH2:21][CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: OCCS
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: O=C1c2c(O)cccc2C(SCCO)c2cccc(O)c21
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (100 mg) was dissolved in dichloromethane (7 ml) and 2-mercaptoethanol (0.03 ml) was added. The solution was stirred at room temperature for 7 hours, during which time the light brown solution became pale green. Removal of the solvent and recrystallisation of the residue from a hexane/chloroform mixture (5:1) gave 10-(2-hydroxyethylthio)-1,8-dihydroxy-9-anthrone (89 mg, 90%) as pale yellow needles, melting point 146°-147° C. (Found: C 63.1, H 4.75, S 10.7; C16H14O4S requires C 63.55, H 4.7, S 10.6%).
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([C@@H:28](O)[CH2:29][CH2:30][CH2:31][CH3:32])[C:6]([NH:8][CH:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]([CH3:26])[C:10]2=[O:27])=[O:7])[CH2:3][CH2:2]1.NC1N=C(C2C=CC=CN=2)C2C=CC=CC=2N(C)C1=O>>[O:7]=[C:6]([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]([CH3:26])[C:10]1=[O:27])[C@H:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCC[C@H](O)[C@@H](CC1CC1)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(C)C1=O
Agent: CN1C(=O)C(N)N=C(c2ccccn2)c2ccccc21
Product: CCCCC[C@@H](CC1CC1)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(C)C1=O

Procedure:
(±)-3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one was made from 1 and 3-amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one (G. Semple et al Synth. Commun. 1996, 26, 721) according to step 1 in Example 1. MS (ESI): 449 (M+H), 471 (M+Na), 447 (M−H). This diastereomeric mixture was submitted to chiral separation on a Chiralpak AD column with 10-15% i-propanol/hexane. The 2nd eluting peak was converted to Example 10 by the same procedures of steps 2 and 3 in Example 1. MS (ESI): 433.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27](Cl)[CH3:28])=[N:25][CH:26]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=3)[CH3:28])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ccc(Cl)cn1
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(Cl)cn2)nc2nc(N)sc12
Yield: 30 %

Procedure:
The title compound was prepared by general method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (823 mg, 2.75 mmol) and 5-chloro-2-[(1R)-1-chloroethyl]pyridine (<4.4 mmol). Purification by flash column chromatography (eluent DCM: methanol gradient) yielded 350 mg (30% yield) of the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:11])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14].CS(N(C)N(S(C)(=O)=O)C(OC)=O)(=O)=O>>[CH3:1][S:2]([N:5]([CH3:11])[N:6]([S:7]([CH3:10])(=[O:8])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])=[O:4]
Reactant: CCOC(=O)Cl
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Agent: COC(=O)N(N(C)S(C)(=O)=O)S(C)(=O)=O
Product: CCOC(=O)N(N(C)S(C)(=O)=O)S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-2-(ethoxycarbonyl)-1-methylhydrazine (compound 7) was prepared from 1,2-bis(methylsulfonyl)-1-methylhydrazine and ethyl chloroformate using a procedure similar to that described for compound 6. The recrystallization solvent was ether-petroleum ether. Yield was 51.0%, and the Mp was approximately 89-90° C. 1H NMR (CDCl3): δ 4.4 (2H, q, OCH2), 3.5, 3.3 and 3.1 (9H, 3s, 2 CH3SO2 and NCH3), 1.4 (3H, t, OCCH3).
Reaction SMILES: C([C:5]1([O:18][CH2:19][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:21])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(C)(C)C.C(C1(O)C2C=CC=CC=2C2C1=CC=CC=2)(C)(C)C.COC(=O)[C@H](CO)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH:7]1[C:6]2[CH:5]([O:18][CH2:19][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C1(OC[C@H](N)C(=O)O)c2ccccc2-c2ccccc21
Agent: CC(C)(C)C1(O)c2ccccc2-c2ccccc21
Agent: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: N[C@@H](COC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
O-(9-t-butyl-9H-fluoren-9-yl)-L-serine: from 9-t-butyl-9H-fluoren-9-ol (Example 1x) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:20]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:20]=1
Reactant: Cc1c(OCC(=O)OC(C)C)ccc(F)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(OCC(=O)O)ccc(F)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[3-(3-fluorophenyl)-5-hydroxy-phenyl]methylamino]-2-methyl-phenoxy]acetate (90 mg, 0.2 mmol, 1 eq) in a mixture of MeOH (3 mL) and THF (3 mL) was added NaOH (1 M aqueous solution, 3 mL, 3 mmol) and the reaction was stirred at room temperature for 3 h. The MeOH and THF were removed under reduced pressure and the aqueous phase was acidified to pH 3-6 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as yellow oil (30 mg, 37%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@H]2CCCC[C@@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@H]2CCCC[C@@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (823 mg) in 2-propanol (15 mL) were added 4-{[(1S,2S)-2-hydroxycyclohexyl]amino}thiazol-2(5H)-one (780 mg) and piperidinium acetate (360 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/heptane to give the title compound (645 mg).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([OH:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>CCOCC>[C:13]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:6]([OH:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC(O)C(C)CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)C(O)CC=C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A mixture of 3,7-dimethyl-4-hydroxy-6-octen-1-ol (5.06 g, 29 mmole), acetic anhydride (3.06 g, 30 mmole), pyridine (4.75 g, 60 mmole) and ether (100 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (200 ml) and washed with saturated cupric sulfate solution (2×100 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene as a colorless oil (2.27 g, 45%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]#[N:16].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH3:13])[C:4](=[O:14])[C:3]([C:15]#[N:16])=[C:2]2[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: Cn1c(=O)c(C#N)c(Cl)c2cc(Cl)ccc21
Solvent: ClCCl
Product: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of Compound 70 (0.8 g, 3.16 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (819 mg, 9.50 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was then removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 950 mg (99%) of yellow solids. M.P. 223° C. 1H NMR (DMSO-d6): δ 2.92 (m, 4H), 3.48 (m, 4H), 3.55 (s, 3H), 7.60 (d, J=8.8 Hz, 1H), 7.77 (m, 2H). EIMS m/z 303 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][OH:15])=[N:9]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:6]([CH:16]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[O:15])=[N:9]1
Reactant: Cc1cc(CO)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(C=O)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Yield: 61.5 %

Procedure:
A solution of alcohol 4 (0.57 g, 1.3 mmol) and 0.5 M Dess-Martin periodinane (9.05 mL, 4.1 mmol) in CH2Cl2 (25 mL) was stirred under N2 atmosphere at RT for 3 h. The reaction mixture was quenched with a 10% aqueous solution of Na2S2O3 (10 mL) and extracted with more CH2Cl2 (10 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and the volatiles were removed in vacuo. The residue was purified by MPLC (5 g SiO2 cartridge, eluent 70% iso-hexane—30% CH2Cl2) to give aldehyde 5 0.3 g (64%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[C:11]=2[CH3:20])=[CH:6][CH2:5]1)([CH3:3])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([OH:17])=[O:16])[C:11]=2[CH3:20])=[CH:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1noc(C2=CCC(C(C)C)CC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)noc1C1=CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [ethyl 5-(4-isopropylcyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxylate] (92 mg, 0.332 mmol) in THF (5 mL) and MeOH (3 mL) was added 2M sodium hydroxide (aq) (0.166 mL, 0.332 mmol) and the mixture was stirred at room temperature for 2 hrs. The resulting mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was washed with EtOAc, acidified with 2M HCl (aq) and extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:35])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC(Cl)(Cl)Cl)=[O:28])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OP([O-])(O)=O.[K+]>O1CCCC1.[Zn]>[C:1]([NH:8][CH2:9][C:10](=[O:35])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)O
Yield: 93.1 %

Procedure:
This compound was prepared from the product of 14b (1.38 g; 2.5 mmol) in tetrahydrofuran (25 mL) following the procedure in Example 12c and using the same quantities of 1 M KH2PO4 solution and zinc powder. Following work-up, 1.0 g (93%) product was obtained (pale yellow oil).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:21](=[O:22])[CH:20]3[C:15](=[CH:16][CH2:17][CH2:18][CH2:19]3)[C:14]2=[O:23])=[CH:8][C:7]=1[S:24][C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1>CN(C)C=O.C(Cl)CCl>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:21](=[O:22])[CH:20]3[C:15](=[CH:16][CH2:17][CH2:18][CH2:19]3)[C:14]2=[O:23])=[CH:8][C:7]=1[S:24][C:25]1([C:28]([Cl:3])=[O:29])[CH2:27][CH2:26]1
Reactant: O=S(Cl)Cl
Reactant: O=C1C2=CCCCC2C(=O)N1c1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1C2=CCCCC2C(=O)N1c1cc(SC2(C(=O)Cl)CC2)c(Cl)cc1F
Temperature: 25 °C

Procedure:
While stirring at room temperature, 3 ml of thionyl chloride are added to a solution of 1 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid and one drop of dimethylformamide in 40 ml of ethylene chloride and the reaction mixture is then heated under reflux for 3 hours. Concentration of the reaction mixture by evaporation yields 1 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid chloride in the form of an oil.
Reaction SMILES: C(=O)([O-])[O-].FC(F)(F)C(O)=O.[CH:12]([C:15]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][NH2:27])[CH2:22][CH2:21]2)[O:17][N:16]=1)([CH3:14])[CH3:13].[Cl:28][C:29]1[C:34]([CH:35]=O)=[C:33](Cl)[N:32]=[CH:31][N:30]=1>C(#N)C>[Cl:28][C:29]1[N:30]=[CH:31][N:32]=[C:33]2[N:26]([CH:23]3[CH2:24][CH2:25][N:20]([C:18]4[O:17][N:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[N:19]=4)[CH2:21][CH2:22]3)[N:27]=[CH:35][C:34]=12
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC(C)c1noc(N2CCC(NN)CC2)n1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1noc(N2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 140 °C
Yield: 19.8 %

Procedure:
SiliaBond Carbonate (Silicycle, Quebec City, Canada; 0.69 mmol/g loading; 395 mg, 0.27 mmol) was added to a mixture of [1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-hydrazine trifluoroacetic acid salt (from Step 4; 185 mg, 0.55 mmol) and 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 81 mg, 0.45 mmol) in anhydrous acetonitrile (3 mL). The reaction mixture was heated in a Biotage Optimizer microwave at 140° C. for 5 min. The resin was filtered off and washed with acetonitrile. The solvent was evaporated and the residue was purified on a silica column (ISCO 12 g) eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (31 mg, 20%). Mass spectrum (ES) MH+=348.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:15][CH2:16][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:18][CH2:19][N:20]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][CH2:22]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CCN(CC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 10 h
Yield: 91.9 %

Procedure:
To a solution of compound (18) (6.84 g, 15.53 mmol) in dry MeCN (150 ml) were added N,N′-diisopropylethyl amine (13.52 ml, 10.03 g, 77.63 mmol) and tert-butyl bromoacetate (4.82 ml, 6.36 g, 32.61 mmol). The reaction mixture was slowly heated to 60° C., and stirred for 10 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in a Na2CO3 solution (100 ml). The aqueous layer was extracted with CH2Cl2 (3×100 ml), and the combined extract was washed with brine and dried over MgSO4 to obtain a concentrated white oil. The oil was recrystallized from Et2O to provide compound (19) as a white solid (9.55 g, 92% yield). 1H NMR (500 MHz, CDCl3): δ 7.26-7.19 (m, 10H), 5.04 (s, 4H), 3.34-3.05 (m, 12H), 2.9-2.6 (m, 8H), 1.35 (s, 18H); 13C NMR (125 MHz, CDCl3): δ 170.4, 156.3, 136.7, 128.3, 127.8, 127.7, 80.8, 66.8, 55.8, 54.2, 46.9, 46.5, 28.1; HRMS (FAB) calculated for C36H53N4O8: 669.3863 [(M+H)+], measured value: 669.3860 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(CC)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
To a solution of ethyl 7—(4-ethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (430 mg) in ethanol (20 ml) was added 1N sodium hydroxide (4.0 ml) at room temperature, and the mixture was stirred for 24 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated to give crystals, which were collected by filtration to give 7—(4-ethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (328 mg) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][OH:7].Cl[C:11]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][N:12]=1.CC(O)=O>CN(C=O)C>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][O:7][C:11]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][N:12]=1
Reactant: COC(CO)OC
Reactant: CCOc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOc1ccnc(OCC(OC)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 60% NaH/mineral oil (2.55 g, 63.96 mmol) in anhydrous DMF (70 mL) at 0° C. under nitrogen atmosphere was slowly added glycolaldehyde dimethyl acetal (Aldrich, 5.65 g, 53.3 mmol). The mixture was stirred at ambient temperature for 1 hour and then transferred to a solution of the product from step (a) (8.05 g, 50.76 mmol) in anhydrous DMF (70 mL) at -55° C. over 15 minutes. The mixture was allowed to warm to -20° C. over 2 hours and then neutralized with AcOH. Solvent was evaporated in vacuo and the residue partitioned between H2O and CH2Cl2. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried (Na2SO4) and evaporated in vacuo. The residue was flash chromatographed (EtOAc/hexanes, 1:4) to give the desired product (7.92 g, 69%) as a colourless oil: 1H NMR (CDCl3): δ 1.37 (t, J=7.0 Hz, 3H), 3.44 (s, 6H), 4.36-4.43 (m, 4H), 4.78 (t, J=5.0 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H); MS m/z229 (M=1, 13%), 197 (100%). Anal Calcd. for C10H16N2O4 : C, 52.62; H, 7.07; N, 12.27. Found: C, 52.45; H, 7.01; N, 12.26.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCCCC=1.[N+:26]([O-:31])([N+]([O-])=O)=[O:27].O>C(O)(=O)C>[N+:26]([C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:31])=[O:27]
Reactant: O=C(O)c1ccc2oc(Br)c(-c3ccccc3)c2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: O
Solvent: C1=CCCCC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 55 °C

Procedure:
A mixture of 20 g (0.063 mole) of 2-bromo-3-phenyl-5-benzofurancarboxylic acid and 1.25 1 of acetic acid is stirred and heated to 55° C. To this mixture is added 7.7 g (0.094 mole) of cyclohexene. To this mixture is added dropwise 8.7 g (0.094 mole) of dinitrogen tetroxide in 25 ml of acetic acid. After 5 hours the mixture is poured into cold water and the solid product is collected. Recrystallization from aqueous ethanol followed by recrystallization from a benzene-ethanol mixture provides 2-nitro-3-phenyl-5-benzofurancarboxylic acid, m.p. 271°-273° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:10]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=2)(=[O:14])=[O:13])=[CH:16][C:17]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COC(=O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (60 mg), 3 mL of 2N NaOH and 3 mL of methanol was stirred at room temperature overnight. To the reaction mixture was added slowly 2M HCl until white solid precipitated. Filtration followed by vacuum drying afforded 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylic acid as a white solid. MS: (M+H)/z=382.0.