Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:19](OCC)=[O:20]>>[C:8]1([N:6]2[C:4](=[O:5])[N:3]([C:2]([F:14])([F:15])[F:1])[C:19](=[O:20])[O:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NC(F)(F)F)N(O)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1on(-c2ccccc2)c(=O)n1C(F)(F)F
Reaction time: 0.5 h

Procedure:
1-Trifluoromethyl-3-phenyl-3-hydroxyurea (11 grams; 0.05 mol) is dissolved in a cooled (10°C) 2N aqueous sodium hydroxide solution (35 ml). Ethyl chloroformate (6 ml; 0.06 mol) is added dropwise at 10° to 15°C with stirring. Stirring is continued for a period of about 1/2 hour after the addition is completed resulting in the formation of a precipitate. The precipitate is recovered by filtration, washed with water and dried to yield 2-phenyl-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([F:21])[CH:23]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(F)c1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
4.00 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine are placed in 15 ml dimethylformamide, then first 4.50 ml diisopropylethylamine, then 2.50 ml 3-fluoro-aniline are added. The reaction mixture is stirred for 7 hours at 120° C., and after cooling evaporated down. The residue is extracted with dichloromethane and water, the organic phase is washed with saturated sodium chloride solution, dried and evaporated to dryness. The residue is purified by chromatography (NP_MPLC, Biotage cartridge (4*15 cm)). 2.60 g of the product are obtained as a powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)O>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:5][CH:6]([Cl:3])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(C2CCCCC2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
25 ml of thionyl chloride are added dropwise to a solution of 20.4 g of methyl-(para-cyclohexylphenyl)-carbinol in 100 ml of benzene and 3 ml of pyridine, and the mixture then refluxed for 5 hours. It is then poured on to ice, the aqueous mixture is extracted with ether, and the ethereal solution washed with sodium bicarbonate solution and water. When the solution is dried and the ether evaporated, α-methyl-para-cyclohexyl-benzyl chloride is obtained in the form of a dark viscous liquid which is processed directly.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:31]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4([C:27]5[CH:26]=[N:25][N:24]([CH3:28])[C:23]=5[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[O:16]4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][C:3]=2[O:29][CH3:30])[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1C1CC1
Temperature: 120 °C

Procedure:
To a microwave vial was added (4-bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (70 mg, 0.15 mmol), cyclopropylboronic acid (26 mg, 0.30 mmol), Fibre cat (49 mg, 0.0075 mmol), DMF (0.7 mL), and K2CO3 (150 μL of 3.0 M, 0.45 mmol). The vial was purged with nitrogen and was heated at 120° C. for 2 hours. The reaction was filtered and purified by HPLC (20-99%) MeOH:H2O. ESI-MS m/z calc. 429.2, found 430.4 (M+1)+. Retention time: 2.95 minutes (4 min run).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29]C(C)=CC=O.Cl.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[CH3:28][C:23]([CH3:24])=[CH:22][CH2:21][N:7]([C@H:1]1[CH2:2][CH2:3][C@H:4]([CH3:29])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: CC(C)=CC=O
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2-enal and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([O:16][CH3:17])[CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(Cl)ccc1O
Product: CCOC(=O)COc1ccc(Cl)cc1OC

Procedure:
The subtitle compound was prepared by the method of example 1 step (iv) using ethyl bromoacetate and 4-chloro-2-methoxyphenol Yield 2.7 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccccc1Cl
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 5.26 mL (40 mMol) 2-(2-chlorophenyl)ethanol and 8.36 mL (60 mMol) triethylamine in 100 mL tetrahydrofuran were added dropwise 3.25 mL (42 mMol) methanesulfonyl chloride with cooling. The reaction mixture was stirred 4 hours at ambient and was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed sequentially with water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 9.22 gm (98.3%) of the title compound as a yellow oil. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14]CN(CC)CC2)=[O:7])=[CH:4][C:3]=1[Cl:19].[CH3:20][NH:21][CH:22](NC)CN>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:14][N:21]([CH3:22])[CH3:20])=[O:7])=[CH:4][C:3]=1[Cl:19]
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Reactant: CNC(CN)NC
Product: CN(C)CCNC(=O)c1ccc(N)c(Cl)c1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 15 mmol scale utilising 2,2-Dimethyaminoethylamine (Aldrich; 1.455 g, 16.5 mmol), as a white solid (1.45 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=N[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[NH:9][C@H:10]([C:15]([NH:43][CH2:38][C:37]#[N:36])=[O:17])[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)NCC#N
Reaction time: 18 h

Procedure:
To a solution of N-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}-L-leucine from step 3 (76 mg, 0.17 mmol), HATU (146 mg, 0.38 mmol), aminoacetonitrile hydrochloride (52 mg, 0.56 mmol) in DMF (1.1 mL) cooled to −10° C., was added N,N-diisopropylethylamine (0.13 mL, 0.75 mmol). The reaction was allowed to proceed at room temperature for 18 h and it was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography using EtOAc and hexane as eluant to give the title compound as a colorless gum.
Reaction SMILES: [Cl-:1].[CH2:2]1[C:10]2[N+:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.N1CCCC1>C(O)(C)C>[Cl-:1].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[C:2]2[C:10]3[N+:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[CH:13]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: c1cc[n+]2c(c1)CCC2
Agent: [Cl-]
Solvent: C1CCNC1
Solvent: CC(C)O
Product: Cn1cc(C=C2CC[n+]3ccccc32)c2ccccc21
Temperature: 80 °C

Procedure:
1.55 g of 2,3-dihydro-1H-indolizinium chloride and 1.59 g of 1-methylindole-3-carboxaldehyde were suspended in 15 ml of isopropanol, in a 50 ml three-necked flask. The reaction mixture was heated at 80° C. and then 820 μl of pyrrolidine were introduced. The reaction mixture was immediately cooled to ambient temperature. The precipitate was filtered off, and washed with 2 times 30 ml of isopropanol before being dried under a strong vacuum in the presence of P2O5, until a constant weight was obtained. 2.59 g of orange powder were recovered. The analyses (NMR) (d6-DMSO) and mass spectrometry ESI+M/Z=261) were in conformity with the expected structure.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCC#C[C@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC#C[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 19 h
Yield: 57.3 %

Procedure:
To a stirred solution of 25.2 (0.050 g, 0.10 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 19 hours. The reaction mixture was then concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 25 (28 mg, 56% yield) as a colorless oil. MS ESI (neg.) m/e: 487.1 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([CH:18]([CH3:20])[CH3:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([CH:18]([CH3:20])[CH3:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C(C)C)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cc(C(=O)O)n(-c2ncccc2Cl)n1
Yield: 100.2 %

Procedure:
A mixture of 1.07 g of ethyl 1-(3-chloro-2-pyridinyl)-3-isopropyl-1H-pyrazole-5-carboxylate, 15 ml of methanol and 15 ml of a 2N aqueous sodium hydroxide solution was heated to reflux for 1.5 hours. After the reaction mixture was allowed to cool, water was poured and the mixture was washed with methyl t-butyl ether two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl t-butyl ether three times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.97 g of 1-(3-chloro-2-pyridinyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][C@@H:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1>O>[Si:10]([O:19][C@@H:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: O=C1C[C@H](O)CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.02 g of imidazole and 1.58 g of t-butyldimethylchlorosilane were added to a dimethylformamide (5 ml) solution of 1.01 g of (S)-4-hydroxy-2-pyrrolidone, and stirred overnight at room temperature. Water was added to the reaction liquid, and stirred with cooling with ice.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 736.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 2.4 g, 60 mmol) in DMF (100 ml) was added dropwise at an ice bath temperature a solution of pyrrole (3.35 g, 50 mmol) in DMF (5 ml). The mixture was stirred for 30 minutes at room temperature and cooled again. To the mixture was added dropwise a solution of benzenesulfonylchloride (9.7 g, 5.5 mmol) in DMF (3 ml). The mixture was stirred for 30 minutes at room temperature and poured into ice-water, and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crystal was washed with hexane to give 1-benzenesulfonylpyrrole (8.4 g). Yield: 81%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 90.6 %

Procedure:
2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005) (1.25 g, 4.80 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (1.30 g, 6.28 mmol, 130 M %). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5006) (1.68 g, 4.35 mmol, 91% yield). M.p. 154-155° C. 1H-NMR (200 MHz, CD2Cl2): δ 7.52 (m, 1H, H4′), 7.25 (m, 1H, H4″), 7.19 (dd, J=7.8, 1.0 Hz, 1H, H5), 7.13-7.00 (m, 3H, H3′,5′,6), 6.81 (m, 2H, H3″5″), 6.72 (dd, J=7.8, 1.0 Hz, H7), 5.33 (s, 2H, CH2PhF2), 4.00 (s, 3H, OCH3).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.B(O)(O)O.O>C1(C)C(C)=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2noc3ccccc23)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1ccc(N=Cc2ccc(-c3noc4ccccc34)cc2)cc1
Temperature: 60 °C

Procedure:
22.32 g of 3-(p-formylphenyl)-1,2-benzisoxazole, 14.03 g of p-chloroaniline and 0.5 g of boric acid in 160 ml of xylene are refluxed for 2 hours, the water formed being distilled off. The mixture is cooled to 60° C., 500 ml of methanol are added and the resulting mixture is further cooled to -10° C. The product which has precipitated is filtered off with suction, washed with 100 ml of cold methanol and dried. This gives 32 g (96.2% of theory) of compound (102) in the form of pale yellow crystals which melt at 164° to 165° C. After recrystallising twice from toluene, pale yellow crystals with a melting point of 164.5° to 165° C. are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6](C)=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OCC1OC=CC(=O)C=1OCC1C=CC=CC=1>>[CH3:1][O:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Agent: O=c1ccoc(CO)c1OCc1ccccc1
Product: COCc1occc(=O)c1OCc1ccccc1
Yield: 100 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4( 1H)-one using 2-hydroxymethyl-3-benzyloxy-pyran-4( 1 H)-one (2.32 g, 10 mmol, 1 eq.) yielded the title compound as an orange oil (2.5 g, ˜100%). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product as a bright yellow oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=CC=1CC(OC)=O)(=[O:4])=[O:3].C([N:20]=[C:21]=[O:22])CCC.C(=O)([O-])[O-].[K+].[K+].Cl>C(C(C)=O)C>[CH2:5]([S:2]([NH:1][C:21]([NH2:20])=[O:22])(=[O:3])=[O:4])[CH2:10][CH2:9][CH3:8]
Reactant: CCCCN=C=O
Reactant: COC(=O)Cc1ccccc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCS(=O)(=O)NC(N)=O
Temperature: 0 °C
Yield: 135 %

Procedure:
A mixture of 22.9 g methyl o-aminosulfonylbenzeneacetate, 13.5 g n-butyl isocyanate, 15.2 g potassium carbonate and 250 ml methyl ethyl ketone was stirred and refluxed for three hours. The reaction mixture was cooled, poured into 1250 g of ice-water, and acidified to pH 1.5 with concentrated HCl. The product was filtered, washed and dried. The crude product was recrystallized from 1-chlorobutane to yield 24.3 g of purified N-(n-butyl)sulfonylurea derivative of methyl o-isocyanatosulfonylbenzeneacetate, m.p. 164°-166° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])[C:26]([Cl:40])=[CH:25][N:24]=1>>[Cl:40][C:26]1[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.050 g, 49%). MP: 106-125° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.17 (s, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 6.63 (s, 1H), 6.50 (d, 1H, J=8.6 Hz), 6.34-6.28 (m, 2H), 5.54 (br s, 1H), 5.26 (br s, 1H), 4.46 (t, 1H, J=8.3 Hz), 3.86 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.41 (m, 2H), 3.32 (s, 6H), 3.07 (s, 1H), 3.05-2.98 (m, 1H), 2.88-2.78 (m, 9H), 2.52 (d, 1H, J=8.1 Hz), 2.26 (d, 1H, J=9.1 Hz), 1.65 (d, 1H, J=9.1 Hz). MS: 557.46 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:19])[CH3:18])=[C:15]3[N:10]([C:11]([S:20][CH3:21])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.C(O[CH:27](OC(C)(C)C)[N:28]([CH3:30])[CH3:29])(C)(C)C>>[CH3:27][N:28]([CH3:30])/[CH:29]=[CH:18]/[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][N:12]=[C:11]2[S:20][CH3:21])=[O:19]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CSc1nccc2c(C(C)=O)c(-c3ccc(F)cc3)nn12
Product: CSc1nccc2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nn12
Temperature: 120 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To 1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone (1.24 g, 4.12 mmol) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (15 mL) and the mixture heated to 120° C. for 1 hour. The reaction was allowed to cool to room temperature and stirred for 16 hours. The mixture was diluted with hexanes. The precipitate was collected by filtration and air dried to yield (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one (880 mg, 60%). 1H NMR (DMSO): δ 8.03 (d, 1H), 7.72–7.82 (m, 3H), 7.57 (d, 1H), 7.37 (t, 2H), 5.08 (d, 1H), 3.04 (bs, 3H), 2.71 (s, 3H), 2.52 (bs, 3H). MS m/z 357 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[F:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[F:20])[O:21][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Nc1cc(O)ccc1F
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
To a solution of 3-cyano-4-fluoronitrobenzene (9.36 g, 56.3 mmol) and 3-amino-4-fluorophenol (7.16 g, 56.3 mmol) in N,N-dimethylformamide (150 ml) was added potassium carbonate (11.7 g, 84.5 mmol), and the mixture was stirred at room temperature for 4 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 5% Aqueous sodium hydrogen carbonate solution (300 mL) was added to the residue, and the mixture was extracted with ethyl acetate (270 mL)/tetrahydrofuran (30 mL). The aqueous layer was extracted with ethyl acetate (270 mL)/tetrahydrofuran (30 mL), and the combined organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (15.6 g, quantitative) as a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1N.Cl.N([O-])=O.[Na+].[Cu][C:20]#[N:21]>O.C(Cl)(Cl)Cl>[C:20]([C:5]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13])#[N:21]
Reactant: COC(=O)c1cccc(OC)c1N
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(OC)c1C#N
Reaction time: 0.5 h

Procedure:
A suspension of methyl-2-amino-3-methoxybenzoate (Intermediate 36, 2.27 g, 12.5 mmol) in water (10 mL) and con. HCl (2 mL) was cooled to 0 deg. C. and a solution of sodium nitrite (1.04 g, 15 mmol) in water (10 mL) was added dropwise. The resulting solution was stirred cold for 30 min. then added to a suspension of copper(I)cyanide (3.4 g, 38 mmol) in water (100 mL). The resulting suspension was heated at 60 deg. C. for 3 h, cooled, chloroform was added and the mixture was filtered through celite. The organic layer was dried (MgSO4), the solvent was evaporated and the residue was flash chromatographed eluting with 0-50% hexane-ethyl acetate affording Intermediate 37 (0.56 g, 23.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.99 (s, 6 H), 7.20 (d, J=8.35 Hz, 1 H), 7.61 (t, J=8.13 Hz, 1 H), 7.68 (d, J=7.47 Hz, 1 H).