Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH3:7][CH2:8][CH:9](O)[CH2:10][CH3:11].OS(O)(=O)=O>O>[C:1]([O:6][CH:9]([CH2:10][CH3:11])[CH2:8][CH3:7])(=[O:5])[C@H:2]([CH3:4])[OH:3]
Reactant: C[C@H](O)C(=O)O
Reactant: CCC(O)CC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(CC)OC(=O)[C@H](C)O

Procedure:
A mixture of 180 g of L-lactic acid, 528 g of 3-pentanol and 1 ml of conc. H2SO4 was refluxed in a Dean-Stark apparatus, until no more water formed (ca. 3 hours). The mixture was washed with water, NaHCO3 solution and brine, dried (MgSO4) and distilled to yield the title compound, boiling point 79°-81° C. at 15 mm of Hg.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][C:23]([F:22])([F:33])[F:34])[CH:26]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2C)nc1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: CCc1cnc(N(CCc2ccc(O)c(C)c2C)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]pyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: [Cl-:1].S(Cl)(Cl)=O.[F:6][C:7]1([F:19])[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16](O)=O)=[CH:15][C:9]=2[O:8]1>>[Cl:1][CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[O:11][C:7]([F:19])([F:6])[O:8][C:9]=2[CH:15]=1
Reactant: [Cl-]
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Solvent: O=S(Cl)Cl
Product: FC1(F)Oc2ccc(CCl)cc2O1

Procedure:
The starting material, 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid, is commercially available from Saltigo (an affiliate of the Lanxess Corporation). Reduction of the carboxyls acid moiety in 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl2), provides 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole, which is subsequently converted to 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile using sodium cyanide. Treatment of 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile with base and 1-bromo-2-chloroethane provides 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile. The nitrile moiety in 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile is converted to a carboxylic acid using base to give 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].[H-].[Na+].I[CH3:54]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37]([N:40]([S:41]([CH3:44])(=[O:43])=[O:42])[CH3:54])=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:11][CH2:12][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][CH2:15]1)=[O:8]
Reactant: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(N(C)S(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of sulfonamide 203 (23 mg, 31 μmol) in THF (2 mL) is treated with sodium hydride (2 mg, 46 μmol, 60% dispersion in mineral oil) at 0° C. After warming to RT and stirring 0.5 h, iodomethane (10 μL, 0.15 mmol) is added via syringe and the reaction stirred 2 h. Analysis by LC/MS at this juncture revealed the reaction is only 40% complete. Hence more sodium hydride (6 mg, 0.15 mmol, 60% dispersion in mineral oil) is added, followed after 0.5 h by iodomethane (30 μL, 0.46 mmol). After a further 16 h at RT, the reaction is diluted with water (10 mL) and extracted into EtOAc (3×15 mL). The combined EtOAc phases are dried (Na2SO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][C:11]2([C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)[C:10]1=[O:24])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[CH2:13][CH2:12][C:11]2([C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)[C:10]1=[O:24]
Reactant: O=C1N(OCc2ccccc2)CCC12CCOc1ccc(F)cc12
Agent: [Pd]
Solvent: CO
Product: O=C1N(O)CCC12CCOc1ccc(F)cc12
Reaction time: 18 h

Procedure:
A solution of 1'-benzyloxy-2,3-dihydro-6-fluorospiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one (1.4 g) in methanol (75 mL) containing 10% palladium on carbon (300 mg) was stirred vigorously under hydrogen gas (1 atm). After 18 hours, more palladium on carbon (300 mg) was added, and the mixture was then filtered after being stirred under hydrogen gas for a further 20 minutes. The filtrate was concentrated in vacuo, and the residue purified by silica gel chromatography, eluting with ethyl acetate, to afford the title compound as a white crystalline solid, 780 mg, m.p. 208°-209° C.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36](O)=[O:37]>>[CH3:30][C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:37]
Reactant: Cc1ccsc1C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: Cc1ccsc1C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3-methyl-2-thiophenecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3-methyl-2-thiophenecarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 488 (M-H)-.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH:4]=[CH:5][CH2:6][OH:7].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=1>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:7][CH2:6][CH:5]=[CH:4][CH2:3][OH:8])=[CH:12][C:13]=1[CH3:18]
Reactant: Cc1cc(CBr)ccc1F
Reactant: OCC=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(COCC=CCO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a suspension of NaH (1.0 g, 60% oil dispersion) in 80 mL THF was slowly added but-2-ene-1,4-diol (2.0 g, 22 mmol) as a solution in 5 mL THF at room temperature. To this mixture was added dropwise 4-bromomethyl-1-fluoro-2-methyl-benzene (5.0 g, 24 mmol) and the resulting stirred for 8 h at room temperature. The reaction was quenched by the slow addition of 50 mL of saturated NH4Cl and the mixture extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (2×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 2.3 g of the title compound as a light yellow oil.
Reaction SMILES: Cl.C([N:9]([CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[C:18]([OH:22])[C:19]([Cl:21])=[CH:20][C:12]=2[CH2:11]1)C1C=CC=CC=1.[H][H]>ClC1C=CC=CC=1.CO.[Pd]>[ClH:21].[Cl:21][C:19]1[C:18]([OH:22])=[CH:17][C:13]2[CH2:14][CH2:15][CH2:16][CH:10]([NH:9][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:11][C:12]=2[CH:20]=1
Reactant: Oc1cc2c(cc1Cl)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CO
Product: Oc1cc2c(cc1Cl)CC(NC[C@H](O)COc1ccccc1)CCC2
Yield: 150 %

Procedure:
A mixture of (2S)-1-[N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride (121 mg) and 10% Pd/C (50% wet, 18 mg) in chlorobenzene (1.8 ml) and MeOH (0.4 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour and filtered. The filtrate was evaporated in vacuo, and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol) over silica gel (2.0 g). The eluate was treated with 4N hydrogen chloride in ethyl acetate and evaporated in vacuo. The residue was triturated in diisopropyl ether, and the precipitated powder was collected by filtration to afford (2S)-1-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5-H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (74 mg, 75%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:11].Cl[CH2:20][Li].BrCCl.C([Li])CCC>CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH3:11])[CH2:20][O:18]1
Reactant: CC(C(=O)c1ccc(F)cc1F)c1ncccn1
Reactant: [Li]CCl
Agent: ClCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(c1ncccn1)C1(c2ccc(F)cc2F)CO1

Procedure:
Treatment of the product of part (ii) (3.10 g) with chloromethyllithium (prepared from bromochloromethane (1.78 g) and a 1.6M solution of n-butyllithium in hexane (8.20 ml)) according to the method of Example 11(iii) gave the title compound as a gun (2.25 g), which was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34]Br)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:34]=1[C:33](=[O:36])[C:32]1[CH:31]=[CH:30][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:38][CH:37]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(NS(C)(=O)=O)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-(methylsulfonylamino)phenacyl bromide*.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].O>CN(C=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=1)[CH2:28][O:24][CH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1)#[N:33]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COCc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (144.5 mg) in DMF (3 mL) was added 60% sodium hydride (36.9 mg) at 0° C., and the mixture was stirred for 30 min. 3-(Bromomethyl)benzonitrile (90 mg) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (162 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18](I)=[C:19]([C@@H:21]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:22])[N:20]=2)[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:19]([C@@H:21]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:22])[N:20]=2)[CH:17]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1-c1cncc(F)c1

Procedure:
A solution of 5-fluoropyridin-3-ylboronic acid (0.096 g, 0.68 mmol), (S)-benzyl 1-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)ethylcarbamate (0.200 g, 0.455 mmol), sodium carbonate (0.145 g, 1.366 mmol), and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, 1:1 complex with DCM (0.019 g, 0.023 mmol) in dioxane (2.53 mL) and water (0.50 mL) was stirred at 110° C. under microwave irradiation for 2 h. Purification by MPLC (eluted with a gradient of 10-60% EtOAc in hexanes) afforded crude (S)-benzyl 1-(6-fluoro-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-2-yl)ethylcarbamate as an off-white foam. LC-MS (ESI) m/z 409.1 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NC1CCCCC1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NC1CCCCC1
Yield: 86.1 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.442 mmol) and cyclohexylamine (50 mg, 0.51 mmol) to give 160 mg of the title compound (86%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 bs, 1H), 7.86 (d, 1H, J=7.6 Hz), 7.21 (s, 1H), 7.15 (s, 1H), 5.03~5.18 (m, 1H), 3.43~3.60 (m, 1H), 3.03 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.76 (dm, 1H, J=17.1 Hz), 2.36 (dd, 1H, J=16.2, 4.5 Hz), 2.28 (dd, 1H, J=16.2, 11.7 Hz), 1.98 (dm, 1H, J=13.5 Hz), 1.50~1.86 (m, 5H), 1.03~1.36 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C[Si]([N:12]=[C:13]=[O:14])(C)C>C(O)(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:13]([NH2:12])=[O:14])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: CN1CCN(C(N)=O)CC1
Reaction time: 8 h
Yield: 121.1 %

Procedure:
To a stirred solution of 1-methylpiperazine (1.66 mL, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution stirred overnight. The volatiles were removed in vacuo to give 4-methyl-piperazine-1-carboxylic acid amide (2.6 g, quant.) as an oil which slowly crystallised on standing; 1H-NMR (300 MHz, CDCl3) 4.62 (2H, s), 3.40 (4H, t), 2.39 (4H, t), 2.29 (3H, s); m/z (ES+) 143 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-])=[O:2].[ClH:13]>CO.[Pd]>[ClH:13].[OH:2][NH:1][C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: ONc1ccc(B(O)O)cc1

Procedure:
Employing the procedure of Example II, 1.1 gms of 4-nitrophenylboronic acid was hydrogenated at 42 psi in 50 ml of methanol containing 0.7 ml of conc. HCl on a Parr shaker hydrogenation apparatus for 3 hours using palladium on carbon as catalyst. After filtering, the filtrate was concentrated yielding 0.91 gms of a white-powdery solid having a melting point of 200°-205° C. (decomposition).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[N:15]=[C:16]([O:19][CH3:20])[S:17][CH:18]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[N:15]=[C:16]([O:19][CH3:20])[S:17][CH:18]=4)[C:12]=3[N:35]3[CH2:36][CH2:37][C@H:33]([N:32]([CH3:38])[CH3:31])[CH2:34]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: COc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2F)cs1
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2N2CC[C@H](N(C)C)C2)cs1
Temperature: 90 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
2-Cyclopropyl-7-fluoro-6-(2-methoxy-1,3-thiazol-4-yl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-179) (120 mg, 0.36 mmol) was dissolved in dimethyl sulfoxide (2.4 ml), then at room temperature, triethylamine (76 μl, 0.55 mmol) and (3S)-3-(dimethylamino)pyrrolidine (56 μl, 0.44 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 18 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC, in which, as the mobile layer, chloroform:methanol=9:1 was first used and then chloroform:7 N ammonia-containing methanol solution=97:3 was used, thereby obtaining a roughly-purified product (17 mg). This was washed with diisopropyl ether to obtain the entitled compound (6.5 mg, 4.2%) as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>C1(C)C=CC=CC=1>[OH:27][C:25]([CH3:28])([CH3:26])[CH2:24][NH:23][C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4]
Reactant: CC(C)(O)CN
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCC(C)(C)O)nn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
A mixture of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol), 1-amino-2-methyl-propan-2-ol (39 mg, 0.43 mmol) and TBD (15 mg, 0.11 mmol) in toluene (0.5 mL) was stirred for 15 h at room temperature under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 5% methanol in dichloromethane) to afford the title compound (90 mg, 69%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>CS(C)=O.O.CCOCC>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: Fc1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 84.4 %

Procedure:
To 14.7 g (0.1 mol) 5-methoxyindole in 100 ml DMSO were added 32.6 ml (0.3 mol) 1-bromo-4-fluorobenzene, 1.06 g (0.04 mol) 18-crown-6 and 10.92 g (60 mmol) KF on alox. The suspension was heated to 120° C. for 48 h. Additional 21.7 ml (0.2 mol) 1-bromo-4-fluorobenzene, 1.06 g (0.04 mol) 18-crown-6 and 10.92 g (60 mmol) KF on alox were added, and the mixture was stirred at 130° C. for 20 h. At RT, ether and water were added, the phases were separated and the inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. The residue was triturated in ethanol to yield 25.5 g (84%) 1-(4-Bromo-phenyl)-5-methoxy-1H-indole as light brown solid, mp 90-91° C., MS: 301 (M, 1Br).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34][O:35][C:36]1[CH:37]=[N:38][C:39](S(C)(=O)=O)=[N:40][CH:41]=1>O1CCCC1.CC(N(C)C)=O.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:39]3[N:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][N:38]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1cnc(S(C)(=O)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1cnc(OCCOc2nn(C)c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2-c2ccc(C)cc2)nc1
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2) (250 mg) in tetrahydrofuran (20 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 47 mg) and the mixture was stirred for 5 minutes. To the mixture was added a solution of 5-methoxy-2-methylsulphonylpyrimidine (Aktual. Probl. Razvit. Nauchn. Issled. Molodykh Uch. Spets. Vil'nyus. Gosuniv. im. V. Kapsukasa, Mater. Konf. Molodykh Uch. Spets. Estestv. Khim. Fak. (1980), 87-90. Editor(s): Grigonis, I. Publisher: Vil'nyus. Gos. Univ. im. V. Kapsukasa, Vilnius, USSR.) (160 mg) in dimethylacetamide (2 ml) and the reaction was stirred for a further 16 hrs. The reaction was diluted with water (100 ml) and extracted with ethyl acetate (100 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with dichloromethane: ether:hexane (10:2.5:1) to yield the title compound as a white solid (190 mg).
Reaction SMILES: [OH-].[Na+].C(N[CH2:7][C:8]1[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)(=O)C.[C:17]([O:21][C:22]([N:24]=[N+]=[N-])=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22]([NH:24][CH2:7][C:8]1[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)NCc1ccc(CC(=O)O)s1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.3 ml of a 2 N aqueous sodium hydroxide solution is added to a solution of 0.6 g of 2-(5-acetylaminomethyl-2-thienyl)-acetic acid in 5 ml of dioxane. The mixture is stirred for 12 hours at 55°-60° C. and cooled to 25° C., 0.2 ml of tert.-butoxycarbonyl azide is added, the mixture is stirred for 16 hours at room temperature and 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid is isolated in accordance with the process described above.