Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]=1[C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1)=[O:4].[OH-].[Na+]>CO>[C:16]([N:8]1[C:9]([C:10]2[CH:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1-c1cc(C)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2c(C(=O)O)cnn2C(C)(C)C)no1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of 1-tert-butyl-5-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester (7.37 g, 26.59 mmol) in methanol (17.7 mL, 1.5M) cooled to 0° C. was treated dropwise with a 4N aqueous sodium hydroxide solution (13.3 mL, 53.15 mmol). The reaction was allowed to slowly warm to 25° C. The reaction was stirred at 25° C. over-night. At this time, the reaction was concentrated in vacuo to remove methanol. The residue was diluted with water (150 mL) and was then extracted with dichloromethane (3×150 mL). These organics were discarded. The aqueous layer was then acidified to pH=1 with a 2N aqueous hydrochloric acid solution. This solution was extracted with a 90/10 dichloromethane/methanol solution (3×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (5.42 g, 82%) as a brown solid. The material was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C.ClCCl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]#[N:13])=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: N#Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cccn1CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 g (40.0 mmol) Potassium carbonate is added to a solution of 1.70 ml (20.0 mmol) pyrrole-2-carbonitrile and 8.34 g (30.0 mmol) 2,4′-dibromoacetophenone in 40 ml DMF. The resulting suspension is stirred for 1 hour at room temperature. The reaction mixture is diluted with dichloromethane and filtered with suction. The residue is washed with dichloromethane. The filtrate is evaporated and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carbonitrile as light orange solid; HPLC/MS 2.80 (B), [M+H] 289/291.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 6-bromohexanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 4.02 (q, 2H), 3.97 (t, 2H), 3.91 (s, 3H), 2.39 (t, 2H), 1.67 (m, 2H), 1.57 (m, 2H), 1.46 (m, 2H), 1.15 (t, 3H); MS (ESI): 494.9.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].CCN(CC)CC>C(Cl)Cl>[CH3:9][S:10]([O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](C)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)COS(C)(=O)=O
Yield: 102.1 %

Procedure:
A solution of methyl 3-hydroxy-2-(S)-methylpropanoate (35 g, 295 mmol) in 830 mL of CH2Cl2, under N2 atmosphere, was cooled to -60° C. With rapid stirring, methanesulfonyl chloride (24 mL, 310 mmol) was added, followed by Et3N (50 mL, 354 mmol) over 90 s. As the addition ended, a heavy white precipitate formed which stopped the magnetic stirring. The cold bath was removed and the reaction allowed to reach r.t. The reaction mixture was poured into aq 25% NH4OAc. After separation, the organic phase was dried over MgSO4 and evaporated to give the title compound as a colorless oil (59.1 g, 102%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[C:27]([C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)=[N:26][N:25]=[N:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[C:27]4[NH:23][N:24]=[N:25][N:26]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccccc1-c1nnn[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccccc4-c4nnn[nH]4)c23)c1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 523 mg (3.0 mmol) of 2-(tetrazol-5-yl)-benzaldehyde (Step 61.1) to form 4-(3-chloro-phenylamino)-3{[2-(tetrazol-5-yl)-phenyl]-methyleneamino}-1H-pyrazolo[3,4-d]pyrimidine. The above intermediate is reduced in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H and the reaction mixture is hydrolyzed analogously. The DMEU solution is poured into water, adjusted to pH=3 with 1 N HCl and extracted with ethyl acetate. The organic phase yields, after washing 10× with water and 1× with brine, drying (Na2SO4), concentration by evaporation and digestion in diethyl ether, 4-(3-chloro-phenylamino)-3-[2-(tetrazol-5-yl)-benzylamino]-1H-pyrazolo-[3,4-d]pyrimidine; TLC: Rf=0.19 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=7.7; FAB-MS: (M+H)+=419.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH3:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:27][C:24]2[N:25]=[CH:26][N:22]([CH2:21][C:20]3[CH:28]=[CH:29][C:17]([CH3:16])=[CH:18][CH:19]=3)[N:23]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Cc1ccc(Cn2cnc(N)n2)cc1
Product: COc1cc(Nc2ncn(Cc3ccc(C)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(4-methyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=60%). MS ISP (m/e): 375.4 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]3[C:25]=2[C:24](SC)=[N:23][CH:22]=[N:21]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]=1[F:47])[NH2:43]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]3[C:25]=2[C:24]([NH:43][C:42]2[CH:44]=[CH:45][C:46]([F:47])=[C:40]([Cl:39])[CH:41]=2)=[N:23][CH:22]=[N:21]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CSc1ncnn2ccc(COCC3CN(C(=O)OC(C)(C)C)CCO3)c12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(COCc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A solution of 2-(4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, 0.15 mmol) in CH2Cl2 (3 mL) was cooled to 0 C. and treated with a solution of mCPBA (56 mg, 0.32 mmol) in CH2Cl2 (2 mL). The reaction was stirred for 15 minutes at 0 C. then warmed to room temperature. To this solution was added 3-chloro-4-fluoroaniline and stirred at room temperature for one hour. The resulting orange solution was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3, then saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. Preparative reverse-phase HPLC afforded the desired compound (30 mg, 41%). HPLC tR=4.383 min (YMC S5 ODS 4.6×50 mm, 10–90% aqueous methanol, 4 min gradient, monitored at 220 nm). LC/MS (M+H)=492.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:27]([CH3:32])=[CH:28][C:29](=[O:31])[CH3:30]>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:33])[C:27]=1[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)C=C(C)NCc1ccccc1C
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3C)C(C)=C1C(C)=O)C2=O

Procedure:
The title compound 71 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (60 mg, 0.24 mmol) and enamine 72 (45 mg, 0.22 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 71 as a yellow solid. (Yield 36 mg, 34%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]OS(=O)(=O)OC.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:20]([CH3:23])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCCc2nc3cccnc3[nH]2)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(CCCOCc2ccccc2)nc2cccnc21

Procedure:
Under an argon atmosphere, to a solution of 2-[3-(benzyloxy)propyl]-3H-imidazo[4,5-b]pyridine (2 g) in DMF (40 mL) was added 60% sodium hydride (0.299 g), and the mixture was stirred under ice-cooling for 30 min. Then, dimethylsulfuric acid (0.75 mL) was added, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture was added methanol (5 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:22]([N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1.O.NN.Cl>CCO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:22]([NH2:24])[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1
Reactant: CC(c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl) isoindoline-1,3-dione (1.2 g, 2.52 mmol in EtOH (40 mL) was added hydrazine hydrate (0.8 mL, 16.4 mmol) at 25° C. The reaction mixture was stirred for overnight at 25° C. The reaction mixture was acidified with 5 N hydrochloric acid and concentrated in vacuo. Water was added to residue and extracted with EtOAc. Aq. layer was basified with aq. NaOH solution and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanamine: LC-MS (ESI) m/z 345.96 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:13]1([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][O:1][C:5]=3[CH:6]=2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Oc1ccc2ncoc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1nc2ccc(OCC3CC3)cc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of 1,3-benzoxazol-6-ol (2.31 g), (bromomethyl)cyclopropane (3.46 g), potassium carbonate (3.54 g) and DMF (25 mL) was stirred at 60° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.88 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)[NH2:37]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:37][C:36]5[CH:38]=[CH:39][C:40]([N:41]6[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]6)=[C:34]([F:33])[CH:35]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)c(F)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to the compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline with yield 52.4 mg (41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (br. s., 6H) 1.99 (s, 2H) 2.22 (s, 3H) 2.40-2.51 (m, 4H) 2.98 (br. s., 4H) 3.97 (s, 3H) 4.22 (t, 2H) 4.79 (m, 1H) 7.03 (t, J=9.35 Hz, 1H) 7.45 (dd, J=8.72, 1.64 Hz, 1H) 7.54-7.78 (m, 3H) 8.04 (s, 1H) 8.28 (s, 1H) 8.36 (d, J=8.34 Hz, 1H) 10.11 (s, 1H). [M+H] calc'd for C32H37F2N8O3, 639. found 639.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH:36]1([NH:35][S:32]([C:28]2[CH:27]=[C:26]([NH:25][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=5)=[N:9][C:10]=34)=[O:22])[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH2:38][CH2:37]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 548.1 [(M−H)−]; mp 244° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:13][CH2:14][CH:15]=[CH2:16])[N:5]=CC1C=CC=CC=1.Cl.O>C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:13][CH2:14][CH:15]=[CH2:16])[NH2:5]
Reactant: C=CCCC(N=Cc1ccccc1)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C=CCCC(N)C(=O)OC
Reaction time: 2 h

Procedure:
Dissolve N-(phenylmethylene)-2-(3-butenyl)glycine methy ester (25 g) in ethyl ether (400 mL) and stir with 1N hydrochloric acid (150 mL) and water (150 mL). Place under an argon atmosphere and stir for 2 hours. Separate the aqueous phase and adjust to pH 9, extract into chloroform, dry and evaporate the solvent in vacuo to give the title compound as a light oil (4.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.C([Li])(C)(C)C.[OH-].[Na+]>C1COCC1.O>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=2)[N:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(B(O)O)cc2)no1
Temperature: -100 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
A solution of 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (1.0 g) in dry THF (8 ml) containing triisopropylborate (3.5 ml, 2.82 g) was cooled to -100° C. under nitrogen, and treated cautiously with tert-butyllithium (8.82 ml, 1.7M solution). The temperature was maintained between -90° C. and -105° C. during addition. The mixture was stirred at -100° C. for 20 mins after complete addition, and then allowed to warm to -30° C. The mixture was treated slowly with water (5 ml) and allowed to warm to room temperature, 2N sodium hydroxide (50 ml) was added and the basic aqueous layer washed with dichloromethane (2×50 ml). The aqueous layer was acidified with 2N hydrochloric acid (60 ml) and extracted with dichloromethane (4×50 ml, containing 20% methanol). The combined, dried extracts were concentrated in vacuo to give the title compound as a pale yellow solid (500 mg). m.p . 266°-268° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([NH2:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](=[S:40])[NH2:30])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1CCN(C(=O)N2CC(C(N)=O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: N#CC1CCN(C(=O)N2CC(C(N)=S)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1

Procedure:
1.50 g (3.53 mmol) of the compound from Example 116A and 786 mg (1.94 mmol) of Lawesson reagent were reacted according to the General Method 10A. Yield: 1.34 mg (39% of theory, 45% pure)
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc(F)c2)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium bicarbonate, and 100 mg of 3-fluorobenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 120 mg of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.58 (s, 6H), 3.08 (s, 3H), 7.05 (m, 3H), 7.33 (m, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H). IR (cm−1): 3020, 1697, 1620, 1403, 1318, 1149, 958, 768. MS (FAB): 361 (m+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])C(O)=O)=[CH:7][C:6]=1OC)(=[O:3])[CH3:2].[C:22](=O)=[O:23]>[Cu].N1C2C(=CC=CC=2)C=CC=1>[C:15]([NH:14][CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH2:2][O:23][CH3:22])=[CH:19][CH:18]=1)(=[O:17])[CH3:16]
Reactant: COc1cc(C=C(NC(C)=O)C(=O)O)ccc1OC(C)=O
Reactant: O=C=O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: COCC(=O)Oc1ccc(C=CNC(C)=O)cc1

Procedure:
18.0 g (0.06 mol) of 4-acetoxy-α-acetylamino-3-methoxycinnamic acid are heated with 30 ml of quinoline and 1.2 g of copper powder to 160°-170° C. for 3 hours, in the course of which carbon dioxide is evolved. Thereafter, the quinoline is distilled off under reduced pressure and the residual mass is taken up in ethyl acetate. After filtering off the copper powder, the ethyl acetate solution is extracted with 25 ml of 1 N hydrochloric acid and is then washed with water and subsequently with sodium bicarbonate solution. The organic phase is dried over sodium sulphate and thereafter the solvent is removed by distillation under reduced pressure. The resulting oil yields 4-(2-acetylaminovinyl)-2-methoxy-acetoxybenzene, of melting point 169°-170° C., from ethyl acetate.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].[NH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14]1.[BH4-].[Na+].O>CO>[ClH:11].[CH3:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([NH:12][CH2:9][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[OH:8])[CH2:14]2)=[CH:19][CH:18]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: COc1ccc2c(c1)CC(N)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Temperature: 4 °C
Yield: 20 %

Procedure:
An amount of 3.53 g of phenylglyoxal is reacted under stirring at room temperature for 3 hours with 5 g of 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride in 100 ml of methanol in the presence of 0.9 g of sodium borohydride. After cooling to 4° C., 4,3 g of sodium borohydride are added and the reacting mixture is left under stirring at room temperature for a night. After addition of 20 ml of water, the solution is stirred at room temperature for 15 minutes, then it is evaporated to dryness. The residue is dissolved in 300 ml of ethyl acetate and 60 ml of water; after filtration, the organic phase is separated, dried over magnesium sulfate, filtered and evaporated to dryness. The oil thus obtained is purified by flash-chromatography by using a mixture ethyl acetate/methanol 8/2 as eluant to obtain the 2-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride. Yield: 20% of the theoretical value.