Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][CH:17]([CH2:34][OH:35])[CH2:18][C:19]([CH3:33])([CH3:32])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:21].[C:36]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:36]([NH:46][C@H:47]([C:51]([O:35][CH2:34][CH:17]([OH:16])[CH2:18][C:19]([CH3:32])([CH3:33])[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)=[O:21])=[O:52])[CH:48]([CH3:50])[CH3:49])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]
Reactant: COc1ccc(COC(=O)C(C)(C)CC(O)CO)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)CC(O)COC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a mixture of DCC (14.8 g, 72 mmol), DMAP (0.88 g, 7.2 mmol) and 4-methoxybenzyl 4,5-dihydroxy-2,2-dimethyl-valerate (20.3 g, 72 mmol) in CH2Cl2 (400 mL) at 0° C., was added dropwise a solution of N-CBz-L-valine (16.2 g, 65 mmol) in CH2Cl2 (100 ml). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH2Cl2), to give 22.4 g 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]12[CH2:25][CH:24]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:26])[C:16](=[O:27])[CH:15]1[CH:11]([CH2:12][CH:13]([O:28][C:29]3[C:38]4[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=4)[N:32]=[C:31]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]([CH3:50])[CH3:49])[N:43]=4)[CH:30]=3)[CH2:14]1)[C:10](=[O:51])[NH:9]2)=[O:7])C.C(O)(=O)C>O.CO.C1COCC1>[CH:48]([C:44]1[N:43]=[C:42]([C:31]2[CH:30]=[C:29]([O:28][CH:13]3[CH2:12][CH:11]4[CH:15]([C:16](=[O:27])[N:17]([CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]5[C:8]([C:6]([OH:7])=[O:5])([NH:9][C:10]4=[O:51])[CH2:25]5)[CH2:14]3)[C:38]3[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=3)[N:32]=2)[CH:47]=[CH:46][CH:45]=1)([CH3:50])[CH3:49]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4cccc(C(C)C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C(C)C)n3)nc2c1C
Temperature: 55 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A solution LiOH (40 mg) in water (1.5 mL) was added to a solution of 17-[2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (112, 220 mg, 0.33 mmol) in a mixture of MeOH (3 mL) and THF (1 mL). The resulting solution was successively heated to 55° C. for 3 h, then stirred at room temperature for 5 h. Then, the pH of the reaction mixture was adjusted to pH 6 with acetic acid and water (3 mL) was added. The resulting solution was extracted with CHCl3. Then, the organic layer was dried (Na2SO4), filtered and evaporated to give 200 mg (95%) of the title compound 113 as a white powder: m/z=641 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[Li].O/[N:21]=[C:22](/[C:24]1[CH:41]=[CH:40][C:27]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]2)=[CH:26][CH:25]=1)\[NH2:23].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([C:5]1[C:6]([C:16]2[O:18][N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:29]4[CH2:30][CH:31]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:32]4)=[CH:40][CH:41]=3)[N:21]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C(=O)O)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-butyl-5-phenylisoxazole-3-carboxylic acid, lithium salt (0.132 g, 0.523 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 0.160 g, 0.523 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.100 g, 0.523 mmol), and HOBt (0.080 g, 0.523 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 60 min and then heated at 60° C. overnight. The solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 1% methanol in dichloromethane to give tert-butyl 1-(4-(5-(4-butyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.156 g) as a pale yellow solid. The ester intermediate was >99% pure by HPLC with a ret. time=3.40 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=515.0.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([C:20]2[N:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:6]([Cl:38])[CH:5]=1.[OH-].[Li+]>C(Cl)Cl.CCCCCCC>[Cl:38][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([C:20]1[N:21]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[N:22]=[C:23]2[C:28]=1[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]2)[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:12])[C:3]([OH:39])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)N(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-{3-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-3-cyclohexyl-ureido}-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 24 h at 60° C. to give the title compound as off-white solid. MS: m/e=559.3 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[N+:24]([O-:26])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.[BH4-].[Li+].O.Cl.[OH-].[Na+]>O1CCCC1>[F:23][C:19]1[C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=C(Cc1cccc(F)c1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
N-(1-Benzylpiperidin-4-yl)-2-(3-fluoro-2-nitrophenyl)acetamide (2.19 g, 5.90 mmol) was dissolved in tetrahydrofuran (40 ml). Mixture was warmed to 60° C. Chlorotrimethylsilane (2.7 ml, 21.27 mmol) was added to the mixture followed by lithium borohydride (7.2 ml, 14.40 mmol). Mixture was held at 60° C. for 2 hours with stirring. Reaction was quenched with 2 mL methanol. Water (4.0 ml, 222 mmol) was added to the mixture followed by concentrated hydrochloric acid (4.0 ml, 47.4 mmol). Mixture was warmed to reflux and held with stirring for 3 hours. Mixture was cooled to room temperature. Reaction was made basic with 5 mL 10N sodium hydroxide. Mixture stirred at room temperature for 15 minutes. Reaction layers were partitioned and the aqueous phase was discarded. Organic phase was concentrated by roto-vap. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound as grey oil in 38% yield. MS (M+H)+=358.4.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][CH:24]1[N:29]([CH3:30])[CH2:28][CH2:27][N:26]([C:31]2[N:36]=[CH:35][C:34]([C:37](OC)=[O:38])=[CH:33][N:32]=2)[CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:37]([C:34]3[CH:33]=[N:32][C:31]([N:26]4[CH2:27][CH2:28][N:29]([CH3:30])[CH:24]([CH3:23])[CH2:25]4)=[N:36][CH:35]=3)=[O:38])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN(C)C(C)C2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
Trimethylaluminium (2M in toluene, 1.31 ml, 2.62 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (260 mg, 1.05 mmol) and methyl 2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate (263 mg, 1.05 mmol) in toluene (5.26 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was poured into methanol (50 mL) and acidified with HCl (2M aqueous solution, to obtain a clear freely stirring solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane. Fractions containing product were evaporated to dryness to give material that was still impure. The residue was repurified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (175 mg, 36%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1.CCCCCC.C(Cl)Cl>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=[S:23])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)CCCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: NC(=S)CCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
To a solution of 4-(4-bromophenyl)butyramide (1.653 g, 6.827 mmol) in toluene (35 mL) was added Lawesson's reagent (1.381 g, 3.414 mmol). The reaction was refluxed overnight, cooled to room temperature, and concentrated yielding an orange oil. Flash chromatography of this oil (1:1 hexane:methylene chloride with 1% acetic acid) yielded 4-(4-bromophenyl) thiobutyramide as off-white needles (0.196 g): mp 104°-105° C. 1H NMR (DMSO-d6) 300 mHz δ9.33 (br s, 1H), 9.12 (br s, 1H), 7.44 (d, J=8.11 Hz, 2H), 7.14 (d, J=8.48 H z, 2H), 2.56-2.41 (m, 4H), 1.95-1.85 (m, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1
Reactant: O=C1CCNCC1Cc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The amine (7.0 g, 23 mmol) from Example 102 and sodium carbonate (4.88 g, 46 mmol) were slurried in ethanol (50 ml). Benzyl bromide was added and the reaction was stirred for 18 hours at 25° C. The reaction was filtered and concentrated. The residue was partitioned between water and dichloromethane. The dichloromethane layer was dried (MgSO4), filtered, and concentrated to yield a crude yellow residue which was chromatographed on a silica gel column eluted initially with dichloromethane followed by methanol/dichloromethane (1:99). The title compound was eluted as a pale yellow oil (7.2 g, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]1(C)C=CC=C[C:13]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C=C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1)=[CH2:13]
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1ccc(NC(C)=O)nc1
Temperature: 85 °C
Yield: 1924.4 %

Procedure:
A solution of of N-(5-bromo-pyridin-2-yl)-acetamide (4.30 g, 20 mmol) in acetonitrile (15 ml) and triethylamine (5.04 ml) was treated with palladium acetate (45 mg, 0.2 mmol) and tri-o-tolylphosphine (203 mg, 0.66 mmol). The mixture was placed in a pressure reactor under 50 psig of ethylene pressure and heated at 85° C. for 66 hours. The reaction mixture was cooled, vented, and partitioned between phosphate buffer (0.1 M, pH 6.6) and ethyl acetate. The aqueous phase was extracted with ethyl acetate twice more. The combined ethyl acetate extracts were washed with additional phosphate buffer, brine and dried over sodium sulfate. The extracts were filtered and evaporated to afford 2.06 g (63%) of the title product as a flaky crystalline residue. Recrystallization from ethyl acetate/cyclohexane gave colorless flakes. mp 120-121° C. 1H NMR (CDCl3): δ=8.55 (br, 1 H); 8.24 (d, 1 H); 8.15 (d, 1 H); 7.76 (d of d, 1H); 6.64 (d of d, 1 H); 5.73 (d, 1 H); 5.28 (d, 1 H); 2.19 (s, 3 H). MS (Cl): m/z=163 (M+H+).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH:6]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:5]1.C(O)C>O>[OH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH:6]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:5]1
Reactant: O=C1CC(N2CCCC2)CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CC(N2CCCC2)CCc2ccccc21
Temperature: 10 °C
Yield: 97.8 %

Procedure:
5.75 g of sodium borohydride were slowly added to a solution of 11.5 g of the product of Step A in 11 5 ml of ethanol and 11.5 ml of water cooled to 10° C and the mixture was stirred for an hour at 20° C. The ethanol was evaporated and 100 ml of water were added. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 11.35 g of 5ξ-hydroxy-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2ccnc(F)c2)nc2c(C=O)cnn12)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
To tert-butyl cyclopropyl(5-(2-fluoropyridin-4-yl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (320 mg, 0.82 mmol) in methylene chloride (3 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were removed by rotary evaporation and 1N NaOH was added to the residue to make basic. The precipitate was collected by filtration, washed with water, and dried under vacuum to provide 180 mg of 7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74%). LCMS (M+1=298)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[CH3:14][O:15][C:16]1[C:17]([O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:18][C:19]2[CH2:28][CH2:27][C:26](=[O:29])[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:30]=1[O:31][CH3:32].CO>O.C(O)(=O)C>[CH3:14][O:15][C:16]1[C:17]([OH:33])=[CH:18][C:19]2[CH2:28][CH2:27][C:26](=[O:29])[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:30]=1[O:31][CH3:32]
Reactant: COc1c(OS(=O)(=O)c2ccc(C)cc2)cc2c(c1OC)C1=C(CCC1)C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1c(O)cc2c(c1OC)C1=C(CCC1)C(=O)CC2

Procedure:
4.5 g of potash then 10 ml of triethylamine are added to a suspension containing 10 g of 9,10-dimethoxy 8-(((4-methylphenyl)sulphonyl)oxy)2,3,5,6-tetrahydro-benz[e]azulen-4(1H)-one obtained as in Stage B and 100 ml of methanol. The reaction medium is heated under reflux for one hour, acidified by the addition of 20 ml of acetic acid then 20 ml of water is added. Extraction is carried out with dichloromethane, the extracts are washed with water, the solvent is evaporated off at 40° C. under reduced pressure and 5.7 g of expected product is collected.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH:12](OC)(OC)OC>>[CH3:11][C:5]1[C:6]2[S:7](=[O:8])(=[O:9])[N:10]=[CH:12][NH:1][C:2]=2[S:3][CH:4]=1
Reactant: COC(OC)OC
Reactant: Cc1csc(N)c1S(N)(=O)=O
Product: Cc1csc2c1S(=O)(=O)N=CN2
Temperature: 90 °C

Procedure:
200 mg of 2-amino-4-methylthiophene-3-sulphonamide, the preparation of which is described in patent WO 99/03861, are dissolved in 1.5 ml of trimethyl orthoformate. The mixture is heated at 90° C. for 2 hours in an open vessel. After evaporation of the solvent under reduced pressure, the residue is taken up in 3 ml of ethyl acetate. The resulting insoluble material is collected by filtration, washed with diethyl ether and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].N1C=CC=CC=1.[FH:21]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([F:21])[CH:8]=1
Reactant: F
Reactant: Cc1cc(Br)cc(N)c1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(F)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.00 g of 5-bromo-2,3-dimethylaniline (3-11) was dissolved in 50 ml of hydrogen fluoride-pyridine, to which under cooling with ice, 5.00 ml of an aqueous solution of 2.10 g of sodium nitrite was dropped. The resulting mixture was stirred at the same temperature for 30 minutes and further stirred at a room temperature for 1 hour, and thereafter, stirred at 85° C. for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate and the resulting organic layer was washed with sodium bicarbonate solution, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 2.92 g of 5-bromo-1-fluoro-2,3-dimethylbenzene (3-12).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.NC1C=C(C2N=CN(C)C=2C2SC3N=CN=C(N)C=3C=2)C=CC=1.[F:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][C:49]=1[N:58]=[C:59]=[O:60]>>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:59]([NH:58][C:49]4[CH:50]=[C:51]([C:54]([F:55])([F:57])[F:56])[CH:52]=[CH:53][C:48]=4[F:47])=[O:60])=[CH:3][CH:4]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cn1cnc(-c2ccc(N)cc2)c1-c1cc2c(N)ncnc2s1
Agent: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Product: Cn1cnc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 186 but using 6-[4-(4-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 112) in place of 6-[4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 110) and using 2-fluoro-5-trifluoromethylphenyl isocyanate in place of phenyl isocyanate. Colourless solid (48 mg, 73%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (150 mg, 0.37 mmol) was dissolved in methylene chloride (3 ml) at 0° C., and triethyl amine (0.05 ml, 1.11 mmol) and cyclopropyl amine (0.03 ml, 0.56 mmol) were slowly added thereto. The resulting solution was stirred at room temperature for 3 hours, quenched with saturated ammonium chloride solution, extracted with ethyl acetate and filtrated with magnesium sulfate. The crude solution was evaporated and dried under a reduced pressure, to obtain 5-(4-chlorophenyl)-N-cyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, which are not further purified. The resulting product was dissolved in benzene (3 ml), and phosphorus pentachloride (85 mg, 0.41 mmol) was added thereto at room temperature. The solution was stirred for 20 minutes, hydroazoic acid (1.0 ml, 2.0 M solution in benzene) was added thereto and maintained room temperature for overnight. For completion of the reaction, reaction solution was refluxed for 10 minutes and purified by reverse phase preparative HPLC, to obtain the title compound (83 mg, 50%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[C:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)N1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 64.3 %

Procedure:
A solution of 5.23 g (0.0118 mole) of α,α-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol in 100 ml of acetic acid and 20 ml of 2M sulfuric acid was refluxed for 21/2 hours and then poured over ice. The mixture was made basic with 50% sodium hydroxide and the basic mixture was extracted with methylene chloride. The methylene chloride solution was dried (anhydrous sodium sulfate), and the solvent was removed in vacuo. The residue was recrystallized from ether-hexane to give 3.23 g (64.4%) of white crystalline solid, m.p. 90°-92.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[S:12](Cl)([CH3:15])(=[O:14])=[O:13].C(N(CC)C(C)C)C>C(Cl)Cl>[CH3:15][S:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
1.13 g (7.48 mmol) of methyl 4-aminobenzoate was dissolved in 20 mL of anhydrous DCM and 1.97 g (17.19 mmol) of mesyl chloride was added at 4 deg C., followed by the 2.22 g (17.19 mmol) of the diethylisopropylamine. Reaction was carried out overnight at room temperature resulting methyl 4-[(methylsulfonyl)amino]benzoate, which was used in the next step without additional purification.