Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]=[CH:10][N:9]([CH2:15][O:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])[C:8]=2[N:7]=[C:5]1[NH2:6])[CH2:2][CH3:3].C[I:23].[I-].[CH2:25](N1C(=O)C2N(C)CN(COC(O)CCO)C=2N=C1N)CC>CN(C=O)C>[I-:23].[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH3:25])[CH2:10][N:9]([CH2:15][O:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])[C:8]=2[N:7]=[C:5]1[NH2:6])[CH2:2][CH3:3]
Reactant: CCCn1c(N)nc2c(c1=O)N(C)CN2COC(O)CCO
Reactant: CCCn1c(N)nc2c(ncn2COC(CO)CO)c1=O
Reactant: CI
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCn1c(N)nc2c(c1=O)N(C)CN2COC(CO)CO

Procedure:
Following the method of Example 5, using 1-propyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine and methyl iodide in DMF at 60° C. overnight, prepare 1-propyl-7-methyl-9(1,3-dihydroxypropoxymethyl)guanine iodide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])[N:5]=[N:4][C:3]=1[C:22]([OH:24])=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:22]([C:3]2[N:4]=[N:5][C:6]([O:8][CH2:9][C:10]3[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:12][O:13][C:14]=3[CH3:15])=[CH:7][C:2]=2[CH3:1])=[O:24])[CH2:27][CH2:26]1
Reactant: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Reactant: NC1CC1
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)NC1CC1
Yield: 54 %

Procedure:
As described for example 44, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.61 mmol) was converted, using cyclopropylamine instead of 4-amino-tetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate=100:0 to 60:40, 122 mg, 54%) which was obtained as a white solid. MS: m/e=365.3 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:26][N:27]([CH3:31])[C:28](=[O:29])[O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Reactant: CN(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione with N,N-dimethylcarbamoyl chloride and triethylamine in toluene there is obtained 2-[2-chloro-5-[3,6-dihydro-2,6 -dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenoxy]-ethyl N,N-dimethylcarbamate, 1H-NMR (CDCl3, 400 MHz): 7.31 ppm (d,1H), 6.81 ppm (d,1H), 6.36 ppm (s,1H), 4.40°-4.47 ppm (m,2H), 4.16°-4.22 ppm (m,2H), 3.56 ppm (d,3H), 2.92 ppm (s,3H), 2.89 ppm (s,3H);
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1>O1CCCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][CH:1]=[O:2])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(CCN)ccc1O
Reactant: O=CO
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(CCNC=O)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Formic acid (230 g, 5.0 mol) is added dropwise to acetic anhydride (383 g, 3.75 mol) at 0° C. This mixture is stirred for 2 hours at +55° C. and subsequently cooled again to 0° C. Tetrahydrofuran (500 ml) is added at this temperature followed by 4-(2-amino-ethyl)-2-methoxy-phenol hydrochloride (50 g, 0.25 mol). The resulting white suspension is stirred for 18 hours at +75° C., changing into a yellow solution. The reaction mixture is evaporated and the residue is submitted to flash-chromatography to yield N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide. 1H-NMR (300 MHz, CDCl3): 2.85(t, 2H, CH2CH2), 3.57(t, 2H, CH2CH2), 3.82(s, 3H, OCH3), 5.69(bs, 1H, NH), 6.67-7.09(m, 3H, CH arom.), 8.12(s, 1H, CHO).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[CH:14]=[C:13]([C:15](Cl)=[O:16])[O:12][N:11]=1)[CH3:9].O.Cl>ClCCl>[CH2:8]([C:10]1[CH:14]=[C:13]([C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[O:12][N:11]=1)[CH3:9]
Reactant: CCc1cc(C(=O)Cl)on1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C(=O)Nc2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
11.7 g of aniline are added dropwise to 10.0 g of 3-ethylisoxazole-5-carbonyl chloride in 150 ml of dichloromethane, while cooling with ice. The mixture is stirred overnight at room temperature, water and concentrated hydrochloric acid are added and the organic phase is separated off, washed with sodium bicarbonate solution and evaporated down to give 11.8 g of 3-ethylisoxazole-5-carboxanilide as colorless crystals of melting point 122°-124° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[C:12](Cl)(=[O:14])[CH3:13].[C:16](OCC)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1.CCCCCC>[C:12]([O:7][C:6]1[CH:8]=[C:2]([CH3:1])[C:3]([O:11][C:16](=[O:18])[CH3:17])=[C:4]([CH3:10])[C:5]=1[CH3:9])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CCOC(C)=O
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(=O)Oc1cc(C)c(OC(C)=O)c(C)c1C

Procedure:
To a solution of trimethylhydroquinone (30 g) in 200 mL of toluene was added acetyl chloride (28 mL). The reaction mixture was allowed to reflux for 2 hours. More acetyl chloride (28 mL) was added, and the reaction mixture was allowed to reflux for additional 2 hours. After the reaction was complete as indicated by TLC (20% ethyl acetate in hexane), the reaction was allowed to cool down and concentrated in vacuo. Recrystallization of the resulting residue from ethyl acetate and hexane gave 42.3 g of 2,3,5-trimethyl-1,4-phenylene diacetate as a white solid.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.[N:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NCCc1ccccc1
Reactant: NCCCN1CCOCC1
Reactant: COC(=O)c1cccnc1Cl
Product: O=C(NCCc1ccccc1)c1cccnc1NCCCN1CCOCC1

Procedure:
The title compound was prepared in analogy to example 1, but starting from 2-chloro-nicotinic acid methyl ester and subsequently using 3-morpholin-4-yl-propylamine in the first step and phenethylamine in the third step.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:55]1[CH2:60][CH2:59][CH:58]([N:61]2[CH2:64][C:63]([CH2:87][C:88]#[N:89])([N:65]3[CH:69]=[C:68]([C:70]4[C:71]5[CH:78]=[CH:77][N:76](COCC[Si](C)(C)C)[C:72]=5[N:73]=[CH:74][N:75]=4)[CH:67]=[N:66]3)[CH2:62]2)[CH2:57][CH2:56]1>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([N:55]1[CH2:56][CH2:57][CH:58]([N:61]2[CH2:62][C:63]([CH2:87][C:88]#[N:89])([N:65]3[CH:69]=[C:68]([C:70]4[C:71]5[CH:78]=[CH:77][NH:76][C:72]=5[N:73]=[CH:74][N:75]=4)[CH:67]=[N:66]3)[CH2:64]2)[CH2:59][CH2:60]1)=[O:12])[CH3:1]
Reactant: CN(C)Cc1cc(C(=O)O)c(F)c(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)c(F)c(C(F)(F)F)n1
Reaction time: 1 h

Procedure:
A solution of 6-[(dimethylamino)methyl]-3-fluoro-2-(trifluoromethyl)isonicotinic acid (0.0776 g, 0.291 mmol, from Step C) in N,N-dimethylformamide (1 mL) was treated with N,N-diisopropylethylamine (0.3 mL, 2 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.15 g, 0.35 mmol). This mixture was pre-stirred for 1 hour, followed by the addition of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.158 g, 0.320 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). After 3 hours, additional N,N-diisopropylethylamine (0.507 mL, 2.91 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.26 g, 0.58 mmol) were added and the mixture was stirred for 48 hours. The SEM-protected product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Solvent was removed from fractions containing desired product by rotary evaporation. The product was deprotected by stirring with a 1:1 mixture of TFA:DCM for 1 hour, followed by evaporation, and stirring with ethylenediamine (0.2 mL) in methanol for 30 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Fractions containing desired product were frozen and lyophilized. Yield: 0.006 g (3%); LC-MS: 611.2 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.69 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.77 (d, 1H), 7.51 (d, 1H), 6.98 (d, 1H), 4.33-4.21 (m, 1H), 3.87-3.71 (m, 4H), 3.68 (s, 2H), 3.59-3.45 (m, 3H), 3.44-3.10 (m, 2H), 2.71-2.58 (m, 1H), 2.31 (s, 6H), 1.97-1.85 (m, 1H), 1.85-1.72 (m, 1H), 1.56-1.24 (m, 2H). 19F NMR (300 MHz, CD3OD): δ −67.26 (d, 3F), −132.8 (m, 1F).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH:9]=[C:8]([F:23])[C:7]=1[OH:24].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:24][C:7]1[C:6]([F:5])=[CH:11][C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[CH:9][C:8]=1[F:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCC[C@H]1CC[C@H](c2cc(F)c(O)c(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2cc(F)c(OC(C)=O)c(F)c2)CC1

Procedure:
8 g of acetyl chloride is added to a solution of 28.2 g of 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenol and 20 ml of pyridine in 300 ml of toluene, and the mixture is heated at 80° for 1 hour. Cooling and working up in the usual manner gives 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenyl acetate.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[Na]>C(OCC)(=O)C.C(O)C>[C:9]1([CH:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)C(Br)c1ccccc1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)c1ccccc1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
A solution of 25.4 g (0.1 mole) of 1-bromo-1-phenyl-3,3-dimethyl-butan-2-one in 50 ml of ethyl acetate was added dropwise, at the boil, to a solution of 12.85 g (0.1 mole) of 4-chlorophenol and 2.3 g (0.1 mole) of sodium in 100 ml of ethanol. After boiling for 12 hours under reflux, the sodium bromide which had separated out was filtered off hot. The filtrate was distilled in vacuo and the solid residue which remained was recrystallized from ligroin. 20.2 g (67% of theory) of 1-phenyl-1-(4'-chlorophenoxy)-3,3-dimethyl-butan-2-one of melting point 103° C were obtained. pg,48
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]1[CH2:17][CH:16]2[CH2:18][CH:19](O)[CH2:20][CH:15]2[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:19]3[CH2:20][CH:15]4[CH2:14][N:13]([CH3:12])[CH2:17][CH:16]4[CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CC2CC(O)CC2C1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CC2CC(n3cc(I)c4c(Cl)ncnc43)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (0.38 g, 1.36 mmol), 2-methylperhydrocyclopenta[c]pyrrol-5-ol (0.23 g, 1.63 mmol) and triphenylphosphine (0.71 g, 2.72 mmol) in tetrahydrofuran (20 mL) was treated with diethylazodicarboxylate (0.474 g, 2.72 mmol) and stirred for 2 hours at ambient temperature. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (30 ml) and water (10 ml). The organic layer was washed with saturated aqueous sodium chloride (10 ml) then dried over magnesium sulfate then filtered and the filtrate evaporated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica using dichloromethane/methanol (8:2) as mobile phase to yield 4-chloro-5-iodo-7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.25 g): 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (s, 1H), 7.44 (s, 1H), 7.26 (s, 2H), 5.36 (m, 1H), 2.88 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 2.36 (s, 3H), 2.06-2.02 (m, 4H); TLC (dichloromethane/methanol 8:2) Rf =0.29; RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10 min, 1 ml/min) tr=6.50 min; MS: MH+403.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.[CH2:22](O)[CH2:23][OH:24].CN(C=O)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:21][C:10]1[C:11]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:12][C:13]([C:14]([O:16][CH2:22][CH2:23][OH:24])=[O:15])=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[CH:9]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: OCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)OCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.9 %

Procedure:
To a solution of furosemide (OnBio, Canada, 5.2 g, 15.6 mmol) in a mixture of CH2Cl2/DMF (15 mL /20 mL) was added ethylene glycol (Aldrich, Wis., U.S., 4.4 mL, 78.0 mmol) and DMAP (377.5 mg, 3.1 mmol). A solid formed upon the addition of the DMAP and additional DMF (15 mL) was added followed by EDAC (3.9 g, 20.3 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue redissolved in CH2Cl2 (100 mL). The sample was washed with H2O (3×50 mL), brine, and the sample dried (MgSO4). The residue after evaporation was chromatographed on silica gel eluting with 1:1 hexanes/EtOAc to give the title compound (1.4 g, 24% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.45-8.43 (m, 2H), 7.64 (s, 1H), 7.35 (s, 2H), 7.09 (s, 1H), 6.42-6.41 (m, 1H), 6.37-6.36 (m, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 4.28 (br t, 2H), 3.71-3.65 (m, 2H). Mass Spectrum (API-TIS) m/z 375 (MH+).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35](O)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]>ClCCCl.ClCCl>[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]([C:16]1[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(F)cc1Cl
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(F)cc3Cl)C3CC3C#N)c[nH]c12

Procedure:
1.62 g (7.31 mmol) of indium(III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid were added to 1.89 g (6.65 mmol) of the compound from Example 87A with a purity of 80% and 1.50 g (6.65 mmol) of the compound from Example 161A under argon in 75 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative SFC HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.65 g (57% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].O>ClCCCl.C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)=[CH:20][C:19]=1[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CCc1ccc(OC)cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(=O)c2ccc(OC)cc2)c(OC)cc1OC
Temperature: 0 °C
Yield: 69.4 %

Procedure:
36.6 g of aluminum trichloride are suspended in 130 ml of 1,2-dichloroethane, and 42.65 g of 4-methoxybenzoyl chloride are added to the mixture which has been cooled to 0° C. Then, at this temperature, 56 g of methyl 3-(2,4-dimethoxyphenyl)propionate (Example 17) dissolved in 30 ml of 1,2-dichloroethane are added dropwise, and the mixture is then stirred at 50° C. with exclusion of moisture until the reaction is complete (about 36 hours). 200 ml of water are added to the cooled reaction mixture which is then diluted with 400 ml of CH2Cl2, extracted with bicarbonate and water, dried over sodium sulfate and concentrated. The residue is dissolved in diisopropyl ether and precipitated with hexane. Filtration with suction results in 62.1 g of the product, and a further 10.5 g from the mother liquor.
Reaction SMILES: B(O)O.[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].Br[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[N:24][CH:25]=1>>[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:20]2[CH:25]=[N:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH3:18])[CH:13]=1)(=[O:10])=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: Fc1cncc(Br)c1
Agent: OBO
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1-c1cncc(F)c1
Yield: 56.5 %

Procedure:
This compound was prepared analogous to Example 52, starting from N-tert-butyl-3-methyl-benzenesulfonamide boronic acid (0.5 g, 1.84 mmol) and 5-bromo-3-fluoropyridine (357 mg, 2.03 mmol, 1.1 equiv.) After purification on silica-gel with n-heptane/ethyl acetate, 335 mg of the title compound were obtained as a light yellow solid MS (ES): m/e 321.1 (M−H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>O1CCCC1>[Cl:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:9]2)=[CH:6][CH:7]=1)=[O:32]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CCl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (2.93 g, 10 mmol) and triethylamine (3.0 g, 30 mmol) in tetrahydrofuran (50 ml) was added chloroacetyl chloride (2.26 g, 20 mmol). The mixture was stirred at room temperature for 2 hours and partitioned between water and dichloromethane. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the precipitated crystals were collected by filtration, washed with isopropyl ether to give 2-chloro-N-((2S)-4-(((1R)-1-phenylethyl) morpholin-2-yl)phenyl)acetamide (3.5 g, 97%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:11][CH:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:13](=[O:14])[CH:12]([Cl:11])[CH3:16])=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1N
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cscc1NC(=O)C(C)Cl
Temperature: -15 °C
Yield: 82 %

Procedure:
To a suspension of 4-amino-thiophene-3-carboxylic acid methyl ester (2.0g) in dichloromethane (25 mL) was added 2-chloropropionyl chloride (1.13 mL). The reaction mixture was then cooled down to −15° C. and a solution of triethylamine (3.2 mL) in dichloromethane (5 mL) was slowly added over 30 minutes. After such time the reaction mixture was allowed to warm up to room temperature, and the solution was washed twice with water, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a light yellow solid (2.1g, 82%). MS (EI): 247.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:12][OH:13])=[CH:6][C:5]=1[O:14][CH3:15].IC.[C:18](OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:12][O:13][CH3:18])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: CCOC(C)=O
Reactant: COc1cc(CO)cc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1cc(OC)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil; 24.7 g) was added to a solution of (4-bromo-3,5-dimethoxyphenyl)methanol (118.8 g) in N,N-dimethylformamide (960 mL) while cooling with ice, and after stirring for 10 minutes, iodomethane (41.7 mL) was added dropwise, the temperature was increased to room temperature and stirring was continued for 1 hour. The obtained reaction mixture was poured into ice water (2.5 L), extraction was performed with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (121.3 g) was obtained as a colorless oil from the n-hexane:ethyl acetate (4:1) fraction.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][C:24]([OH:27])=[N:23][C:22]=23)=[CH:14][CH:13]=1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31].CCN(CC)CC.CCOC(C)=O>O1CCOCC1>[CH3:37][C:36]1[CH:38]=[CH:39][C:33]([S:30]([O:27][C:24]2[CH:25]=[CH:26][N:21]3[N:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:28])[CH3:1])[CH:11]=[CH:10][N:9]=5)=[CH:17][CH:16]=4)=[C:22]3[N:23]=2)(=[O:32])=[O:31])=[CH:34][CH:35]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccc(-c2cnn3ccc(O)nc23)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccn3ncc(-c4ccc(-c5nccn5COCC[Si](C)(C)C)cc4)c3n2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-ol (15.0 mg, 0.0368 mmol), tosyl chloride (7.0 mg, 0.0368 mmol) and NEt3 (5.13 μL, 0.037 mmol) in dioxane (2 mL) was heated at 80° C. for 18 hours. Additional portions of tosyl chloride (7.0 mg, 0.037 mmol) and NEt3 (5.1 μL, 0.037 mmol) were added and the mixture continued to heat at 80° C. for 12 hours. The cooled reaction mixture was poured into EtOAc and extracted with 10% HCl. The organic extract was dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography, eluting with 1-2% MeOH/dichloromethane, afforded 3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl 4-methylbenzenesulfonate as a brown-yellow film (19.0 mg, 92%). LCMS (APCI+) m/z 562 [M+H]+.