Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].O[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[O:31]=[C:26]1[CH2:27][CH2:28][C:29](=[O:30])[N:25]1[O:6][C:4](=[O:5])[CH2:3][CH:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of BOC-Asp-OBzl (1.49 g, 4.61 mmol) and N-Hydroxy succinimide (584 mg, 5.07 mmol) in EtOAc (20 ml) was cooled to 0° C. 1,3-Dicyclohexylcarbodiimide (1.05 g, 5.07 mmol) was added portionwise. White precipitate began forming. The resulting mixture was stirred at 0° C. for 10 min. and then allowed to warm to rt. After stirring for 6 h. at rt the mixture was filtered and concentrated in vacuo to give 2-tert-butoxycarbonylamino-succinic acid 1-benzyl ester 4-(2,5-dioxo-pyrrolidin-1-yl) ester as a clear, colorless oil which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[N:7]([CH3:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[CH3:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C(=O)C.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([NH:25][C:26]2[CH:27]=[C:28]([O:29][C:30]3[CH:31]=[CH:32][C:33]4[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]5[CH2:43][CH2:44]5)=[O:41])[N:38]=4)[N:35]=3)[CH:45]=[CH:46][C:47]=2[CH3:48])=[O:12])[N:7]([CH3:13])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C(C)(C)C)nn1C
Yield: 40.3 %

Procedure:
Using 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (61 mg, 0.33 mmol), tetrahydrofuran (1.8 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (44 μL, mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (90 mg, 0.28 mmol) and N,N-dimethylacetamide (1.8 mL), and in the same manner as in Example 119, the title compound (55 mg, 41%) was obtained as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19].Cl>C(Cl)Cl.C(Cl)(Cl)Cl>[C:18]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:11])(=[O:20])[CH3:19]
Reactant: COC(=O)CCCCCN
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
6-Aminohexanoic acid methyl ester hydrochloride (5 g) is dissolved in methylene chloride (20 ml) and thereto are added pyridine (4.5 ml) and acetyl chloride (2 ml), and the mixture is stirred at room temperature for 1 hour and 45 minutes. To the reaction solution are added a 1N-hydrochloric acid and chloroform, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 6-acetylamino-hexanoate (5.19 g) as a crude product. MS (m/z): 188 [M+H]+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:23][CH3:24]>C(O)(=O)C.C(OCC)(=O)C>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:23][CH3:24]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)CCCc2ccccc2)ccc1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C(=O)CCCc2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.79 ml of 65 percent nitric acid in 25 ml of glacial acetic acid is added dropwise to a solution of 2.2 g of 4'-hydroxy-3'-methoxy-4- phenylbutyrophenone in 25 ml of glacial acetic acid and the mixture is stirred at room temperature for an additional 2 hours. The mixture is poured into 150 ml of ice-water and, after treatment with 20 ml of 3N hydrochloric acid, extracted three times with 75 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is taken up in ethyl acetate and filtered over 75 g of silica gel. After recrystallization from acetonitrile, there is obtained 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone in the form of yellow crystals of m.p. 120°-121°.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17]COC)=[C:8](/[CH:21]=[C:22](\[CH2:28][C:29]2[C:37]([O:38][CH3:39])=[CH:36][C:32]3[CH2:33][CH2:34][O:35][C:31]=3[CH:30]=2)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].Cl>CCO>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[OH:17])=[C:8](/[CH:21]=[C:22](\[CH2:28][C:29]2[C:37]([O:38][CH3:39])=[CH:36][C:32]3[CH2:33][CH2:34][O:35][C:31]=3[CH:30]=2)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1OCOC
Agent: Cl
Solvent: CCO
Product: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1O
Yield: 64 %

Procedure:
To a solution of Ethyl (E)-3-[1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate (4.50 g, 8.10 mmol) in EtOH (60 mL) was added 0.6 mL of conc. HCl. After heating at reflux for 3 h, the mixture was concentrated and then diluted with EtOAc. The resulting mixture was washed with 5% NaHCO3, brine and dried (Na2SO4). After removing the solvent, column chromatography of the residue with 25% EtOAc in hexane gave 2.65 g (64%) of the title compound as a solid: m.p. 158-160° C.; MS (ESI) m/z 511 (M+H)+ ; 1H NMR (400 MHz, CDCl3) d 7.58 (s, 1 H), 7.47 (s, 1 H), 7.02 (d, 1 H), 6.78 (s, 1 H), 6.62 (dd, 1 H), 6.59 (d, 1 H), 6.48 (s, 2 H), 5.50 (bs, 1 H), 4.48 (t, 2 H), 4.12 (m, 2 H), 3.85-3.95 (m, 4 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.16 (t, 2 H), 1.67 (m, 2 H), 1.20 (t, 3 H), 1.17 (m, 2 H), 0.80 (t, 3 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[C:23](OCC)=[O:24])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[C:23](=[O:24])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(=O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a solution of ethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (100 mg, 0.25 mmol) obtained in Example 15 in THF (3 ml) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 0.26 mL, 0.5 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was stirred at room temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 29 mg (yield: 28%) of the title compound. Melting point: 142-143° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18]2)=[CH:11][CH:10]=1)[C:6](O)=[O:7].Cl.[CH2:30]([N:32]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN>CN(C)C=O.O.O1CCCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18]2)=[CH:11][CH:10]=1)[C:6]([NH:32][CH3:30])=[O:7]
Reactant: COC(=O)CC(C(=O)O)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C(CC(=O)OC)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.8 %

Procedure:
To a solution of 2-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinic acid 4-methyl ester (310 mg) obtained in Step 6 in N,N-dimethylformamide (4 mL) were added successively 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg), 1-hydroxybenzotriazole hydrate (115 mg) and a tetrahydrofuran solution of methylamine (2M, 0.53 mL), followed by stirring the reaction mixture at room temperature for 13 hours. Then, after addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:1) to give N-methyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succina mic acid methyl ester (278 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21]OS(C)(=O)=O)[N:19]=2)=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]3[CH3:1])[N:19]=2)=[CH:13][CH:14]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: CC1CCCCN1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1C
Yield: 100.6 %

Procedure:
Add 2-methylpiperidine (3.55 g, 36.1 mmol) to a solution of Methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (See Intermediate 13) (1.3 g, 3.61 mmol) in anhydrous THF (15 mL). Reflux the reaction overnight and cool. Wash organic material with 1N HCl (50 mL) and extract aqueous layer with diethyl ether (2×50 mL). Add 5N NaOH to aqueous layer (pH>10) and extract with dichoromethane (2×50 mL). Dry organics over Na2SO4, filter and concentrate to give 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-methylpiperidine (1.32 g, quant).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:36])[C:30]=3[CH:29]=[N:28]2)=[CH:23][CH:22]=1>CS(C)=O.CO>[O:19]1[C:20]2[C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([CH2:6][NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[CH:29]=[N:28][N:27]4[C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)([OH:5])[C:7]([F:10])([F:8])[F:9])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: Nc1cccc2c1cnn2-c1ccncc1
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(CC(O)(CNc1cccc2c1cnn2-c1ccncc1)C(F)(F)F)c1cccc2c1OCC2
Temperature: 150 °C
Yield: 8.5 %

Procedure:
A mixture of racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163, 27 mg, 0.095 mmol) and 1-(4-pyridinyl)-1H-indazol-4-amine (Intermediate 5) (20 mg, 0.095 mmol) was heated by microwave (200 W) at 150° C. for 20 minutes. The crude product was cooled, dissolved in DMSO/MeOH and purified by mass-directed autopreparation. The appropriate fractions were evaporated to give the title compound (4 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[N:26]1([C:31](N)=[NH:32])C=CC=C1.CCN(C(C)C)C(C)C>C1COCC1>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:31]([NH2:32])=[NH:26])[N:4]=2)=[O:10])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: N=C(N)n1cccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=N)N)cs2)c(C(=O)C2CCCC2)c1
Temperature: 60 °C
Yield: 87.9 %

Procedure:
To a solution of 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) in THF (10 mL) was added pyrrole-1-carboxamidine (54 mg, 0.50 mmol) and DIEA (90 μL). The reaction mixture was heated 60° C. for 3 h and concentrated. The crude product was purified by flash chromatography [silica, DCM:ethyl acetate (50:50 to 10:90)] to yield 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(4-guanidinomethyl-thiazol-2-yl)-urea (88 mg, 88%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: N#Cc1cccc(N=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(C#N)c3)c(=O)n(C3CCCC3)c12
Yield: 46.1 %

Procedure:
3-(1-Cyclopentyl-7-methoxy-2,4-dioxo-1,4-dihydro-2H-pyrimido[5,4-c]quinolin-3-yl)-benzonitrile (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 3-isocyanato-benzonitrile (0.5 mmol) following general procedure C. LCMS: m/z 413 [M+1]+.
Reaction SMILES: Cl.N[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[O:12]=[C:13]1[CH2:18][C:17](=O)[CH2:16][CH2:15][NH:14]1>C(O)C>[CH:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][N:3]3[C:11]=2[C:10]=1[C:18]1[C:13](=[O:12])[NH:14][CH2:15][CH2:16][C:17]=13
Reactant: NN1CCc2ccccc21
Reactant: O=C1CCNC(=O)C1
Agent: Cl
Solvent: CCO
Product: O=C1NCCc2c1c1cccc3c1n2CC3
Yield: 201 %

Procedure:
A solution of 1-amino-indoline hydrochloride (1.0 g) and 2,4-dioxopiperidine (663 mg) in absolute ethanol (40 ml) was stirred under nitrogen for 48 h. The solvent was removed in vacuo and the residue was dissolved in diethylene glycol (30 ml) and heated at 200° for 2 h. The solution was allowed to cool, poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 2.5 g) which was purified by short path column chromatography on silica gel (Merck 7729) eluting with System A (400:10:1) to give the title compound (330 mg) as a solid, m.p. 265°-267°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=2)[C:4](=[O:27])[O:3]1>Cl>[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:9]=2)[C:4](=[O:27])[O:3]1
Reactant: C[C@H]1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Agent: Cl
Product: C[C@H]1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1

Procedure:
A solution of tert-butyl 4-{2-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate in 4N HCl indioxane was stirred at room temp for 4 hours and the excess solvent removed. The residue was partitioned between 10% IPA/Chloroform and 1N NaOH. The organic layer was dried over magnesium sulfate, filtered and concentrated. The free amine was used without further purification.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[F:16].S(=O)(=O)(O)O.CCCCCCC>C(O)(=O)C>[Cl:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([I:1])=[C:12]([OH:17])[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: Oc1cc(Cl)c(F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
N-iodosuccinimide (4.61 g, 20.5 mmol), was suspended in glacial acetic acid (20 ml). To this suspension was added 3-chloro-4-fluorophenol (3.0 g, 20.0 mmol) and then concentrated sulphuric acid (0.36 ml, 6.14 mmol) was added dropwise over 5 minutes. The resulting brown/orange suspension was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue was partitioned between water and dichloromethane, the dichloromethane was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give an orange/red oil. The crude product was purified by column chromatography on silica gel using 1:1 ethyl acetate:heptane to give the title compound as a pale orange/brown solid (3.50 g, 60% yield)
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]1[O:27][N:26]=[C:25]([OH:28])[CH:24]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.CC(O)C.Cl>CO>[ClH:21].[NH2:8][CH:9]([CH2:22][C:23]1[O:27][N:26]=[C:25]([OH:28])[CH:24]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)Cc1cc(O)no1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: NC(COc1noc2ccc(Cl)cc12)Cc1cc(O)no1

Procedure:
To a solution of 0.38 g of 3-[2-tert-butoxycarbonylamino-3-(3-hydroxy-5-isoxazolyl)propoxy]-5-chloro-1,2-benzoisoxazole in 2 ml of methanol is added 1.2 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for six hours, after which the solvent is removed by distillation under reduced pressure. Ethyl acetate is added to the residue obtained and the crystals precipitated are collected by filtration, to obtain 0.22 g of pale yellow, crystalline 3-[2-amino-3-(3-hydroxy-5-isoxazolyl)propoxy]-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 188.5°-193.5° C. (decomp.).
Reaction SMILES: ClC1C=CC=CC=1.Cl.[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[NH2:12].[C:18]12([NH:28][C:29]#[N:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>Cl.CO>[C:18]12([NH:28][C:29]([NH:12][C:11]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=3[F:9])=[NH:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: Nc1ccc(F)cc1F
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CO
Product: N=C(Nc1ccc(F)cc1F)NC12CC3CC(CC(C3)C1)C2

Procedure:
A single neck glass 100 ml round bottom flask was charged with chlorobenzene (20 ml), 2,4-difluoroaniline hydrochloride (prepared from the free base, Aldrich, by dissolving in 5% HCl in MeOH and concentrating, 2.0 g, 12 mmol) and 1-adamantylcyanamide (2.13 g, 12 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[CH:26]=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3OCc3ccccc3)ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3O)ccn2)CC1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
tert-Butyl 4-(4-(4-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 115, 1.30 g, 2.20 mmol) was dissolved in ethanol (20 mL) at room temperature and palladium hydroxide on activated charcoal (130 mg) was added. The reaction mixture was heated at 60° C. under a hydrogen atmosphere (50 psi) for 18 hours. The mixture was then filtered through a pad of Celite™, rinsed with ethanol and concentrated in vacuo. The residue was purified on silica gel by Biotage (5% to 60% ethyl acetate in heptane over 20 CV). Further purification by reverse phase using acetonitrile/water (5/95-95/5) with 0.1% formic acid as eluent gave the title compound (650 mg, 59%) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.[CH3:33][S:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:49]=1[NH:48][N:47]=[C:46]2[C:50]1[CH:55]=[CH:54][N:53]=[C:52](S(C)=O)[N:51]=1)(=[O:36])=[O:35]>O>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:52]3[N:51]=[C:50]([C:46]4[C:45]5[C:49](=[C:41]([O:40][CH2:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:35])=[O:36])[CH:42]=[CH:43][CH:44]=5)[NH:48][N:47]=4)[CH:55]=[CH:54][N:53]=3)[CH2:7][CH2:6]2)=[O:9])[CH2:11][CH2:12]1
Reactant: CS(=O)c1nccc(-c2n[nH]c3c(OCCCS(C)(=O)=O)cccc23)n1
Reactant: NC1CCC(C(=O)N2CCC(O)CC2)CC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCCOc1cccc2c(-c3ccnc(NC4CCC(C(=O)N5CCC(O)CC5)CC4)n3)n[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (4-amino-cyclohexyl)-(4-hydroxy-piperidin-1-yl)-methanone (400 mg, 1.5 mmol), DIPEA (0.31 mL, 1.78 mmol) and NMP (1 mL) was stirred at RT for 1 h. Then, 7-(3-methanesulfonyl-propoxy)-3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-indazole (200 mg, 0.5 mmol) was added to the mixture and stirred at 130° C. for 2.5 hours. The reaction mixture was then poured into water, and the precipitate was purified on a silica column using flash chromatography, eluting with hexane:EtOAc:MeOH 5:4.5:0.5 to yield (4-hydroxy-piperidin-1-yl)-(4-{4-[7-(3-methanesulfonyl-propoxy)-1H-indazol-3-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 308).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]([OH:21])[C:7](C=C(C)C)([CH:16]=1)[CH2:8][C:9]1[N+:14]([O-:15])=[CH:13][CH:12]=[N:11][CH:10]=1)#[N:2]>C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:21][C:3]([CH3:4])([CH3:16])[CH2:1][CH:8]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][N+:14]=3[O-:15])[C:7]=2[CH:16]=1)#[N:2]
Reactant: CC(C)=CC1(Cc2cncc[n+]2[O-])C=C(C#N)C=CC1O
Solvent: CCOCC
Product: CC1(C)CC(c2cncc[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 11.5 %

Procedure:
In an analogous manner to that described in the first paragraph of Example 8, from 0.35 g of 6-[5-cyano-2-hydroxy-1-(2-methylpropenyl)benzyl]pyrazine 1-oxide there was obtained 0.02 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyrazine 1-oxide in the form of a white solid of melting point 166°-168° C. (from diethyl ether).
Reaction SMILES: [C:1](=[O:9])([O:7][CH3:8])[O:2][CH2:3][CH:4]([F:6])[F:5].C(Cl)(=O)O[CH2:12][CH2:13]C.C(Cl)(=O)OC>>[C:1](=[O:9])([O:7][CH2:8][CH2:12][CH3:13])[O:2][CH2:3][CH:4]([F:6])[F:5]
Reactant: CCCOC(=O)Cl
Reactant: COC(=O)OCC(F)F
Agent: COC(=O)Cl
Product: CCCOC(=O)OCC(F)F

Procedure:
2,2-Difluoroethyl n-propyl carbonate was prepared as in [Synthesis of 2,2-Difluoroethyl Methyl Carbonate] of Example IV-1, except that propyl chlorocarbonate (7.4 g, 0.073 mol) was substituted for methyl chlorocarbonate (6.9 g, 0.073 mol).