Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].Br[CH2:32][C:33]#[N:34]>>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:32][C:33]#[N:34])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: N#CCBr
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OCC#N)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared in a similar manner as described for Example 32 starting from N-(2,6-dichlorobenzoyl)-4-(2-hydroxyphenyl)-L-phenylalanine methyl ester and bromoacetonitrile. ESMS: m/z 483 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C:19]3[CH:31]=[CH:30][O:29][C:20]=3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:12].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C:19]3[CH:31]=[CH:30][O:29][C:20]=3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:12])=[O:13]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.304 g) was added to a stirred solution of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 2.93 g) in THF (30 mL). The resultant mixture was stirred at room temperature for 5 minutes until effervescence had ceased. 2-(trimethylsilyl)ethoxymethyl chloride (1.27 g) was added and the solution was stirred at room temperature for one hour. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20% to give methyl 7-[(2-bromo-4-fluorobenzenesulfonyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-4H-furo[2,3-c]chromene-6-carboxylate (3.51 g) as a white foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH2:3]([CH:10]1[CH2:14][CH2:13][N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]1=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (50%, 0.214 g, 4.5 mmol) was added to a solution of 3-benzyl-2-pyrrolidinone (Synthesis, 1996, 8, 941-948; 0.68 g, 3.9 mmol) in THF (15 ml). The solution was stirred at room temperature for 30 minutes. Ethyl bromoacetate (0.48 ml, 4.3 mmol) was added and the mixture stirred for 12 hours. The solvent was removed in vacuo and the residue purified by chromatography eluting with 50% EtOAc in hexane to give the product as a light yellow oil. NMR (90 MHz, CDCl3) 7.2 (m, 5H), 4.2 (m, 3H), 3.25 (m, 1H), 2.75 (m, 2H), 2.3-1.6 (m, 4H), 1.3 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[S:17])SC)[CH2:6][CH2:5]1.[N-:18]=[N+:19]=[N-:20].[Na+]>O.C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:14]([SH:17])=[N:20][N:19]=[N:18]2)[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCN1CCN(CCO)CC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCCN1CCN(CCCn2nnnc2S)CC1
Reaction time: 4 h
Yield: 28.6 %

Procedure:
To a solution of methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]-propyl]-dithiocarbamate (4.8 g) in a mixture of water (15 ml) and ethanol (10 ml) as added sodium azide (1.5 g). The resulting mixture was refluxed with stirring for 4 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was disolved in water and the solution was washed successively with ethyl acetate and diethyl ether and then evaporated. To the residue was added ethanol and the mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was recrystallized from isopropyl alcohol to give 1-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]-1H-tetrazole-5-thiol (1.35 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(N(C)C)=O.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Combine 4-hydroxy benzaldehyde (7.201 g, 59.0 mmol), 6-chloronicotinamide (9.605 g, 57.5 mmol), and potassium carbonate (19.86 g, 143.7 mmol) in dimethylacetamide (190 mL). Stir and heat at 130° C. After 18 h, cool to ambient temperature and dilute with water (600 mL). Extract aqueous layer with ethyl acetate (3×500 mL). Wash combined ethyl acetate extracts with water (1×) and brine (1×), successively, dry over anhydrous magnesium sulfate, filter, and concentrate. Purification by silica gel chromatography (1:1 ethyl acetate:hexanes→ethyl acetate) to provide 6.852 g (49%, 90% pure) of the title compound as a white solid: mass spectrum (electrospray): m/z=243.0 (M+1); 1H NMR (methanol-d4): 9.97 (s, 1H), 8.70 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 8.06-8.02 (m, 2H), 7.42-7.37 (m, 2H), 7.19 (d, 1H, J=9.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)([OH:9])[CH2:10][NH:21][CH2:20][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Yield: 99.9 %

Procedure:
A solution of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (0.60 g, 1.68 mmol), ethanolamine (0.5 mL, 8.3 mmol) and triethylamine (0.5 mL, 3.6 mmol) in iso-propanol (5 mL) was maintained at 50° C. for 72 hours then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with saturated potassium carbonate solution/water (1:9). The aqueous phase was extracted a second time with ethyl acetate, then the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (701 mg, quantitative); LCMS (PS-A2) Rt 2.29 min [M+H]+418, [M−H2O+H]+400.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: C1CCNC1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(CC(=O)N1CCCC1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (6.00 g, 37.1 mmol) in anhydrous DCE (100 mL) was added pyrrolidine (6.19 mL, 2 equiv, 74.2 mmol) in one portion. The reaction was stirred and left at 0° C. for 1 h. Water (100 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with water (3×100 mL) and brine (100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (6.23 g, 85.6%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.47 (s, 6H), 1.82-1.90 (q, J=6.8, 2H), 1.92-2.00 (q, J=6.8, 2H), 2.45 (s, 2H), 3.44-3.50 (t, J=6.8, 4H). 1.43 (s, 6H), 2.11-2.15 (m, 2H), 3.09 (s, 3 H), 3.35 (s, 2H), 3.41 (dt, J=7.2, 4H). LRMS (ESI+) for C9H16N4O (196.1); Found: 197 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](OCC)(OCC)OCC.[C:21]1([C:27]2[CH:28]=[C:29]([NH2:32])[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[CH:11][NH:32][C:29]2[S:30][CH:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:28]=2)[C:4](=[O:5])[O:3]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(-c2ccccc2)cs1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=CNc2cc(-c3ccccc3)cs2)C(=O)O1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Meldrum's acid (1.05 g, 7.3 mmol) was added to triethyl orthoformate (50 ml) and stirred at 30° C. for 1 hr. The reaction mixture was cooled to room temperature and 4-phenyl-thiophene-2-yl-amine (1.07 g, 6.1 mmol) was added in portions. The reaction mixture was heated to 85° C. and stirred at this temperature overnight before cooling to room temperature. The solvent was removed in vacuo to give a residue which was dissolved in DCM and treated with potassium carbonate. After stirring for 30 min the mixture was filtered and the solvent removed in vacuo to give 2,2-dimethyl-5-[(4-phenyl-thiophen-2-ylamino)-methylene]-[1,3]dioxane-4,6-dione. Yield=1.41 g (70%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[N:4]=1.[CH3:21]O.O.O[O:25][S:26]([O-:28])=O.[K+]>C(OCC)(=O)C>[CH3:21][S:26]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[N:4]=1)(=[O:28])=[O:25]
Reactant: CO
Reactant: CSc1nc(CCCO)cc(-c2ccc(C)c(C)c2)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2cc(CCCO)nc(S(C)(=O)=O)n2)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3,4-dimethyl-phenyl)pyrimidine (5.8 g) in a mixed solvent of methanol and water (110 ml, 10:1) was added OXONE (35 g). The mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate (500 ml). The mixture was washed with water (3×500 ml). Organic layer dried over sodium sulphate, solvent removed under reduced pressure to give 2-methanesulphonyl-4-(3-hydroxypropyl)-6-(3,4-dimethylphenyl)-pyrimidine as crude product. To a stirred solution of above 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3,4-dimethylphenyl)pyrimidine in dimethylsulfoxide (50 mL), was added sodium cyanide (2.9 g). The mixture was stirred at room temperature for 4 hours, then poured into ethyl acetate (300 mL) and washed with water (2×200 mL). The organic layer was dried over sodium sulphate, solvent evaporated at reduced pressure, the above residue was flashed on silica gel using Petrol/EtOAc (1:1) as eluent to give 4-(3-Hydroxy-propyl)-6-(3,4-dimethylphenyl)-pyrimidine-2-carbonitrile as product (4.8 g).
Reaction SMILES: CC(O)=O.Cl.[CH3:6][NH:7][CH3:8].[CH:9]([C:11]1[CH:50]=[CH:49][C:14]([CH2:15][CH:16]([NH:24][C:25](=[O:48])[CH2:26][CH:27]([NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:37])=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17](=[O:23])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:6][N:7]([CH2:9][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]([NH:24][C:25](=[O:48])[CH2:26][CH:27]([NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:36])=[O:37])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17](=[O:23])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:49][CH:50]=1)[CH3:8]
Reactant: CNC
Reactant: O=Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
1 ml of AcOH and 0.129 g of dimethylamine hydrochloride are added to a solution of 0.830 g of the compound obtained in step A of Example 17 in 10 ml of DCM, followed by portionwise addition of 0.456 g of sodium triacetoxyborohydride, and the mixture is stirred for 18 hours at RT. The reaction mixture is diluted with DCM, the organic phase is washed with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a chloroform/MeOH mixture (95/5; v/v). 0.52 g of the expected product is obtained.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.C(NC(C)C)(C)C.[Li]CCCC.C1(CC=NC2CCCCC2)CC1.[C:33]([O:37][C:38]1[C:43]([F:44])=[CH:42][N:41]=[CH:40][C:39]=1[CH3:45])([CH3:36])([CH3:35])[CH3:34].C1C[O:49][CH2:48][CH2:47]1>>[C:33]([O:37][C:38]1[C:43]([F:44])=[CH:42][N:41]=[C:40]([CH:47]([CH:6]2[CH2:8][CH2:7]2)[CH:48]=[O:49])[C:39]=1[CH3:45])([CH3:36])([CH3:35])[CH3:34]
Reactant: C1CCOC1
Reactant: Cc1cncc(F)c1OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: C(CC1CC1)=NC1CCCCC1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: Cc1c(C(C=O)C2CC2)ncc(F)c1OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of LDA (1.20 mmol, prepared from diisopropylamine (0.16 mL) and n-BuLi (2.5M in hexanes, 0.48 mL) in THF (2.0 mL) at 0° C. was added N-(2-cyclopropyl-ethylidene)cyclohexylamine (1.24 mmol, from step 3a) dropwise, and the reaction mixture was warmed to room temperature and stirred for 15 minutes. To this solution was added 4-t-butoxy-5-fluoro-3-methylpyridine (0.10 mL, 0.50 mmol) in THF (0.5 mL) dropwise and the mixture was stirred for 3.5 hours. The reaction was then quenched with acetic acid (1M, 3 mL), diluted with hexanes (20 mL) and dilute acetic acid (1M, 20 mL), and stirred vigorously for 1 hour. The organic layer was separated, washed with water, saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel, eluting with 5% to 15% ethyl acetate in hexanes, to afford the title compound (0.098 g, 75% yield) as an oil. MS 266 (M+H)+ ; 1H NMR (CDCl3) δ0.19-0.32 (m, 2H), 0.52-0.75 (m, 2H), 1.42 (d, 9H, J=1.1 Hz), 1.42-1.60 (m, 1H), 2.20 (s, 3H), 3.16 (dd, 1H, J=2.6 Hz, J =8.8 Hz), 8.29 (d, 1H, J=2.2 Hz), 9.86 (d, 1H, J=2.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)cc1N
Solvent: c1ccncc1
Product: CCOC(=O)Cn1nc(-c2ccccc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of ethyl 2-(5-amino-3-phenyl-pyrazol-1-yl)acetate (49 g, 0.17 mol) in pyridine (200 mL) was added acetic anhydride (17.4 g, 0.17 mol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2 and water. The layers were separated and the organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo. CH2Cl2 was added to the residue and the solid was collected by filtration, yielding the title compound as a solid (22 g). The mother liquors were concentrated in vacuo and washed with cold CH2Cl2 to yield a second batch of 15 g.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:18]([C:20]3[O:21][C:22](=[O:36])[C:23]4[C:28]([C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[N:10]=[C:11]([C:12]3[S:16][C:15]([NH2:17])=[N:14][CH:13]=3)[C:4]=12.[CH3:37][C:38](OC(C)=O)=[O:39]>>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:18]([C:20]3[O:21][C:22](=[O:36])[C:23]4[C:28]([C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[N:10]=[C:11]([C:12]3[S:16][C:15]([NH:17][C:38](=[O:39])[CH3:37])=[N:14][CH:13]=3)[C:4]=12
Reactant: CC(=O)OC(C)=O
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(N)s2)c2c(N)ncnc21
Agent: Cl
Product: CC(=O)Nc1ncc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccccc3)c3ncnc(N)c23)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
3-(1-(4-amino-3-(2-aminothiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (Example 59, 23 mg, 0.044 mmol) was dissolved in TEA (124 μL, 0.888 mmol)/Ac2O (419 μL, 4.44 mmol) and stirred at rt for 1 h. The reaction mixture was quenched by the addition of 1M HCl (1 ml) and purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (2.3 mg, 9.9%) as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([OH:12])[CH3:11].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](OS(C)(=O)=O)c1c(Cl)ccc(F)c1Cl
Temperature: 2.5 °C
Reaction time: 0.58 h

Procedure:
To a cooled (ice bath) solution of (S)-1-(2,6-Dichloro-3-fluorophenyl)ethanol (4.00 g, 16.3 mmol) and triethylamine (3.4 mL, 24 mmol) in toluene (20 mL) was added dropwise methanesulfonyl chloride (1.64 mL, 21.1 mmol). A white suspension formed that was stirred at 0-5° C. for 35 min. The reaction mixture was diluted with H2O (20 mL), the layers were separated, and the aqueous layer was extracted with toluene (10 mL). The combined organic layers were washed with water (2×10 mL) and concentrated under vacuum at 40-45° C. to give the title compound as colorless oil containing ≈0.2 eq. of toluene according to 1H NMR. This material was used directly in the next step. 1H NMR (CDCl3, 400 MHz): δ=7.33 (dd, J=9.0, 4.9 Hz, 1H), 7.12 (dd, J=9.0, 8.0 Hz, 1H), 6.45 (q, J=6.8 Hz, 1H), 2.91 (s, 3H), 1.84 (d, J=6.8 Hz).
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[BrH:34].C(O)(=O)C>C(OCC)C>[BrH:34].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CCCCCI
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodopentane as starting materials, and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:12])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c(C)c1

Procedure:
From 4-methoxy-2-methylbenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.7° (c=0.62, CHCl3), ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)(=O)=O.[CH3:26][S-:27].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:14][C:10]1([CH3:13])[O:9][C@H:8]([C@@H:7]([NH:15][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:6][S:27][CH3:26])[CH2:12][O:11]1
Reactant: CC1(C)OC[C@@H]([C@H](COS(C)(=O)=O)NC(=O)OCc2ccccc2)O1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSC[C@H](NC(=O)OCc1ccccc1)[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of the product from Example 27.2 (2.58 g, 6.91 mmol) in dimethylformamide (10 ml) was added sodium thiomethoxide (0.630 g, 8.98 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water (4×), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (ethyl acetate-petrol, 1:4) giving a colourless oil (2.007 g, 89%). 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.12 (ABq, 2H), 5.07 (br. s, 1H), 4.47 (bit, J=7.2 Hz, 1H), 4.05 (t, J=7.2 Hz, 1H), 3.83 (brq, J=7.2 Hz, 1H), 3.70 (dd, J=8.3, 6.8 Hz, 1H), 2.69 (d, J=7.6 Hz, 2H), 2.15 (s, 3H), 1.42 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:18]1([CH2:22][CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)[N:26]=[C:25]2[CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:21]C[CH2:19]1.C(N(CC)CC)C>CC#N>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:43]2[CH2:44][CH2:45][CH:40]([C:25]3[N:24]([CH2:23][CH2:22][N:18]([CH3:21])[CH3:19])[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:30]=4)[N:26]=3)[CH2:41][CH2:42]2)[N:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: Nc1ncnc(Cl)c1C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
The reaction mixture of 4-Amino-6-chloro-pyrimidine-5-carbaldehyde (150.00 mg; 0.95 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (594.52 mg; 0.95 mmol; 1.00 eq.) and Triethyl-amine (0.80 ml; 5.71 mmol; 6.00 eq.) in MeCN 4 ml were stirred at RT for 2 hr, lc-ms showed desired as major. Filtrate, collected white solid as 4-amino-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbaldehyde, 277 mg, yield 56.2%. LC-MS: (M+1=506, obsd.=506).