Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])CC1C2C(=CC=CC=2)NC=1)=[O:7])([CH3:4])[CH3:3].[NH2:23][C@H:24]([C:29]([N:31]([CH3:43])[C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].ClC(OCC(C)C)=O.CN1CCOCC1>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:40][C:32]1[NH:31][C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH:33]=1)=[O:7])([CH3:1])[CH3:3].[NH2:23][C@H:24]([C:29]([N:31]([CH3:43])[C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[C@H](N)C(=O)N(C)[C@@H](Cc1ccccc1)C(N)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Yield: 78 %

Procedure:
Condensation of Boc-trp-OH (1.81 g.) and H-Leu-MePhe-NH2 and H-Leu-Mephe-NH2 (mixture of isomers) hydrochloride salt (1.95 g.) by the mixed anhydride method using isobutyl chloroformate (813 mg.) and N-methylmorpholine (two 685 mg. portions) in tetrahydrofuran (35 ml.) at -20° C. for 20 min. and then at room temperature briefly, isolation by ethyl acetate extraction, and purification by filtration through silica gel with ethyl acetate gave Boc-trp-Leu-MePhe-NH2 and Boc-trp-Leu-Mephe-NH2 (mixture of isomers) as white foam (2.70 g., 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH2:13])=[C:9]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[NH:8][C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH:13][C:30]([C:27]3[CH:26]=[C:25]([CH2:24][C:23]4[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:22]=4[F:21])[O:29][N:28]=3)=[O:31])=[C:9]([Si:14]([CH2:15][CH3:16])([CH2:19][CH3:20])[CH2:17][CH3:18])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.128 g; 0.413 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.104 g; 0.434 mmol), HATU (N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.165 g: 0.434 mmol) and N,N-diisopropylethylamine (0.108 mL; 0.619 mmol) in DMF (3 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The crude material was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) to give 0.108 g (49%) of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:18])=[CH:5][CH:4]=1.[CH3:19]I>CO>[CH3:19][N:11]1[C:12]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:9]([C:6]2[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=2)[C:10]1=[O:18]
Reactant: CI
Reactant: O=c1[nH]c2cccnc2n1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)n(-c2ccncc2)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
5.7 g of sodium hydroxide pastilles were added to a suspension of 15 g of the product of Step B in 700 ml of methanol and complete dissolution occured after a few minutes. The mixture was stirred at room temperature for an hour and after the addition of 45.6 g of methyl iodide thereto, the mixture was stirred at room temperature for another 6 hours. The mixture stood overnight and was then filtered to remove hydroiodide of product melting at 275°-285° C. The filtrate was evaporated to dryness and the combined residue and hydroiodide were dissolved in water. The solution was made alkaline by addition of 30% sodium hydroxide solution and was then extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated to dryness and the residue was crystallized from 95% ethanol to obtain 4 g (25% yield) of 1-methyl-3-(4-pyridyl)-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one in the form of a pale crystalline powder melting at 211°-213° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>>[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[O:27])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Product: COc1cc2c(cc1OC)CN(C(=O)Cc1ccc(OC(C)=O)cc1)CC2

Procedure:
Using the procedure described in Example 12, 15.0 g of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline was reacted with 4-acetoxyphenylacetyl chloride to give 13.0 g of N-(4-acetoxyphenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+].C(N1C2C=CC=CC=2C2C1=CC=CC=2)CCCCCC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:26]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCCCCCn1c2ccccc2c2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1c2ccccc2c2ccccc21

Procedure:
N-Dodecyl carbazole was prepared from carbazole (66 g, 0.40 mol), 1-bromododecane (100 g, 0.41 mol, commercially available from Aldrich, Milwaukee, Wis.), benzyltriethyl ammonium chloride (4.48 g, 0.02 mol), toluene (400 ml), and sodium hydroxide (200 g of 50% aqueous solution) according to the procedure described for N-heptylcarbazole
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=5)[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:38]([CH2:40][NH2:41])[OH:39]>CS(C)=O>[OH:39][CH2:38][CH2:40][NH:41][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=5)[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: COc1ccc(Cn2nnc(-c3cccc(OCc4csc5c(C(=O)NCCO)cnc(N)c45)c3)n2)cc1
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.10 mmol) (from Example 28 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The precipitate was filtered and dried to give 4-amino-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide. (Yield 18.0 mg, 35%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([C:2]3[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=3)[CH2:26][CH2:27]2)=[CH:28][CH:29]=1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(Cc3ccc(F)cc3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-(4-fluorobenzyl)piperidine. MS (+ESI) m/z 385 (MH+).
Reaction SMILES: BrCC(=O)C[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]CCCCCC(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC=CC=1.C([SiH](CC)CC)C>ClCCl>[Br:18][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C(CBr)CCCCCCCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: BrCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
1-Bromo-9-phenylnonan-2-one--A solution of 6-bromohexanoyl chloride (49.7 g, 0.233mol) in dry dichloromethane (40 ml) was added dropwise over 5 minutes to a suspension of aluminium chloride (31.0 g, 0.233 mol) in dry dichloromethane (100 ml), keeping the temperature between 20° C.-23° C. The mixture was stirred for 30 minutes at room temperature to give a yellow solution. Benzene (18.2 g, 0.233 mol) in dry dichloromethane (30 ml) was added and stirred for 20 hours at room temperature. Triethylsilane (59.9 g, 0.515 mol) was added over 10 minutes, maintaining the temperature between 25° C.-35° C. The solution was stirred for 60 minutes at room temperature. This was then poured onto ice/water (200g). A partial separation was achieved and the organic layer was washed with brine and water several times until the pH of the solution was neutral. The organic solution was dried (MgSO4) and evaporated under reduced pressure to a yellow oil. This was distilled under reduced pressure at 90° C.-110° C./0.5 mbar to give colourless oils. The relevant fractions were combined and purified by flash chromatography on silica gel using hexane to give 6-bromo-1-phenylhexane as a colourless oil (18.33 g, 33%).
Reaction SMILES: [CH:1]1([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][CH:8]=[C:2]12.[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)#[CH:14]>C1(C)C(C)=CC=CC=1>[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:6]2[N:3]3[CH2:4][CH2:5][CH:1]([C:9]([O:11][CH3:12])=[O:10])[C:2]3=[CH:8][CH:7]=2)=[O:20])=[CH:17][CH:16]=1)#[CH:14]
Reactant: COC(=O)C1CCn2cccc21
Reactant: C#Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1C
Product: C#Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)OC)cc1

Procedure:
A solution of methyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (2.50 g, 0.015 mole) in dry xylene (100 ml) containing the acid chloride of 4-ethynylbenzoic acid [4.40 g, 0.026 mole; L. E. Salisbury, J. Org. Chem., 43, 4987 (1978)] was heated at reflux temperature for 12 hours. The solvent was removed in vacuo and the residue was purified by chromatography on alumina (200 g) using hexane/ethyl acetate (95:5) as the eluting solvent to give methyl 5-(4-ethynylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, m.p. 113°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O>>[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(C)cc23)cc(OC)c1OC
Yield: 33 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-methylindole-3-carboxaldehyde (1.59 g) except that the reaction solution was concentrated under reduced pressure, that the residue was purified by silica gel column chromatography, and that the obtained crude crystals were recrystallized from a mixed solvent of ethyl acetate and hexane, to give Compound 20 (1.16 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]([C:19]1[O:20][C:21]2[C:27]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([Cl:32])[CH:25]=[CH:24][C:22]=2[N:23]=1)([CH3:18])([CH3:17])[CH3:16].O>O1CCCC1>[C:15]([C:19]1[O:20][C:21]2[C:27]([S:28]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)(=[O:30])=[O:29])=[C:26]([Cl:32])[CH:25]=[CH:24][C:22]=2[N:23]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
1.62 ml (11.68 mmol; 1.2 eq) of triethylamine followed by 1.20 ml (10.71 mmol; 1.1 eq) of 1-methylpiperazine were added to a solution of 3.0 g (9.73 mmol; 1.0 eq) of 2-tert-butyl-6-chlorobenzooxazole-7-sulfonyl chloride in 45 ml of tetrahydrofuran. The reaction medium was stirred at ambient temperature for 2 hours. Water was added and the reaction medium was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 3.57 g of 2-tert-butyl-6-chloro-7-(4-methylpiperazine-1-sulfonyl)benzooxazole were obtained in the form of a tacky brown foam. Yield=98%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].F[C:14]1[CH:15]=[C:16]([Br:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:14]1[CH:15]=[C:16]([Br:24])[CH:17]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:19]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Product: FC(F)(F)c1cc(Br)cc(OCc2ccc3ccccc3c2)c1
Yield: 80 %

Procedure:
Using the procedure described in the first paragraph of Note e. below Table IV in Example 15, 2-naphthalenemethanol was reacted with 3-fluoro-5-trifluoromethylbromobenzene to give 3-(naphth-2-ylmethoxy)-5-trifluoromethylbromobenzene (80%), m.p. 68°-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:16]
Reactant: CNC1CCCCC1
Reactant: COc1ccc(N)c(CO)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N)c(CN(C)C2CCCCC2)c1

Procedure:
2-Amino-N-cyclohexyl-5-methoxy-N-methyl-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and N-methyl-cyclohexylamine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride): 3240 cm-1NH2 ; 3400 cm-1NH2 ; 2780 cm-1N-methyl; 2830 cm-1OCH3 ; 2850 cm-1 aliphatic hydrocarbon; 2930 cm-1 aliphatic hydrocarbon; 1500 cm-1C=C; 1510 cm-1C=C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].O=C(Cl)[O:12][C:13](Cl)(Cl)[Cl:14].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:14][C:13]([O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)Oc1ccc(Cl)c(Cl)c1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
3,4-Dichlorophenol (2.35 g) was dissolved in anhydrous dichloromethane (50 ml) at room temperature under an atmosphere of argon. The mixture was cooled to −30° C. and diphosgene (3.92 g) and N,N-Diisopropylethylamine (2.51 ml) were added slowly in the order specified. The resulting solution was then stirred at 0° C. for 3 hours, then at room temperature for 18 hours and finally at reflux for 2 hours. The solution volume was measured and used accordingly.
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH2:29])[C:11]2O[C:15]([C:17]([OH:19])=[O:18])=[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13](=[O:28])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][NH2:31]>CO>[C:1]1([S:7]([CH:10]([NH2:29])[C:11]2[N:31]([CH3:30])[C:15]([C:17]([OH:19])=[O:18])=[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13](=[O:28])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Reactant: CN
Solvent: CO
Product: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.08 %

Procedure:
To a stirred solution of 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01) (640.0 mg, 1.54 mmol) in MeOH (5.0 mL) was added methylamine (2 M in methanol, 2.0 mL) at room temperature and the mixture was stirred for 6 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure to get the crude compound. It was then purified using normal column chromatography to get 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01) (430.0 mg, 65.08%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O>[C:16]1([CH2:15][N:12]2[CH:13]=[CH:14][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[N:11]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(Nc2ccn(Cc3ccccc3)n2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(Nc2ccn(Cc3ccccc3)n2)cc1

Procedure:
The title pyrazole of Example 3 (6.3 g) was heated on a steam bath in a mixture of aqueous HBr (48%, 200 ml) and glacial acetic acid (25 ml) for 6 hours. The reaction mixture was cooled, poured into water, neutralised with sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried and evaporated to give after chromatography the title compound, 1.0 g, mp 114°-116° (from cyclohexane/ethyl acetate).
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[CH2:29][O:28]C(C)(C)[O:26][CH2:25][C:24]=2[CH:32]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O1CCCC1.O>[O:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:29][OH:28])=[C:24]([CH2:25][OH:26])[CH:32]=1)[Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC1(C)OCc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](OCc1ccc(CO)c(CO)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.175 g (13.825 mM) of tert-butyl-(7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocyclohepten-2-yl)methoxydiphenylsilane in 50 ml of tetrahydrofuran-water (4:1) was added 2 ml of trifluoroacetic acid with ice-cooling and the mixture was stirred at room temperature for 4 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]2[C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][O:19][C:15]=2[C:14]=1[CH2:26][CH2:27][CH3:28])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:26]([C:14]1[C:15]2[O:19][N:18]=[C:17]([C:20]([F:21])([F:23])[F:22])[C:16]=2[CH:24]=[CH:25][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:27][CH3:28]
Reactant: CCCc1c(CCCCO[Si](C)(C)C(C)(C)C)ccc2c(C(F)(F)F)noc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(CCCCO)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole, from this Example step 3, (2.8 g, 6.7 mmol) in dry THF (75 mL) was added tetrabutylammonium fluoride (1.0M 10.1 mL, 10.1 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 was added and the mixture was extracted with ethyl acetate 3 times. Combined organic extracts were washed with brine and dried over Na2SO4. The solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate and hexane (20:80) to give the title compound.
Reaction SMILES: [C:1]12([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)[C:18]=3[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[C:18]=3[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCCSc1c(C(=O)NC23CC4CC(CC(C4)C2)C3)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC23CC4CC(CC(C4)C2)C3)cnn1-c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
Methyl 4-[4-(1-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (143 mg, 0.32 mmol) (Intermediate #3) was dissolved in methanol and treated at ambient temperature with 2M aqueous sodium hydroxide solution. The mixture was stirred at ambient for 18 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the title compound as a white solid (132 mg, 94%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH3:2].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1>>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)=[C:5]([CH:10]=1)[CH2:4][N:3]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1)[CH2:1][CH3:2]
Reactant: CCNCc1cc(Br)ccc1OCC1CC1
Reactant: N#Cc1ccc(Cl)nc1
Product: CCN(Cc1cc(Br)ccc1OCC1CC1)c1ccc(C#N)cn1

Procedure:
The title compound was prepared by reacting N-ethyl-5-bromo-2-cyclopropylmethoxybenzylamine (reference example 13) and 2-chloro-5-cyanopyridine using a similar method to that of reference example 18.