Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.N1C=CC=CC=1.C(Cl)Cl.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][C:30](=[O:32])[CH3:31])([CH3:18])[CH2:13]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.5 g, 1.80 mmol), pyridine (0.29 ml) and DCM (40 ml) at 0° C. was added acetic anhydride (0.34 ml). The reaction mixture was stirred at RT for 6 h. Water was slowly added and the reaction mixture extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH2:28][OH:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCl.C(Cl)Cl>[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH:28]=[O:29])([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)OC[C@@H]1C
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C=O)OC[C@@H]1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
To a solution of oxalyl chloride (0.036 ml, 0.42 mmole) in dry CH2 Cl2 (0.5 ml) there was added dropwise a solution of dry DMSO (0.049 ml, 0.69 mmole) in dry CH2Cl2 (0.1 ml) at -78° C. over 5 min. After stirring for 10 min at -78° C., a solution of (2S,3R,4S,5S)-[3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol (0.1 g, 0.345 mmole) in dry CH2Cl2 (0.1 ml) was added dropwise to the resulting milky suspension over 5 min at -78° C. After stirring for 15 min at -78° C., triethylamine (0.24 ml, 1.73 mmole) was added dropwise to the reaction mixture over 3 min, and stirring was continued for 30 min at -78° C. The reaction mixture was then warmed up to room temperature gradually and partitioned between CH2Cl2 (10 ml) and water (10 ml). The methylene chloride layer was washed with brine (5 ml×2), dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (1:9) as an eluent to give (2R,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-carbaldehyde (0.085 g, 86% yield) as a colorless oil; EI-MS: m/z 288 (M+); 1H-NMR (CDCl3)d: 0.85 (3H,d,J=7 Hz), 0.87 (9H,s), 2.28 (1H,m), 3.12 (1H,dd,J=4 & 5 Hz), 3.28 (3H,s), 3.59 (1H,dd,J=5 & 11.5 Hz), 3.81 (1H,d,J=4. Hz), 3.81 (1H,dd,J=9 & 11.5 Hz), 4.08 (1H,dd,J=4 & 5 Hz), 9.80 (1H,s).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([C:13]3[S:14][C:15]([C:18]4[CH:23]=[C:22]([NH:24][C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH:21]=[C:20]([CH3:35])[CH:19]=4)=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([C:13]3[S:14][C:15]([C:18]4[CH:23]=[C:22]([NH:24][C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH:21]=[C:20]([CH3:35])[CH:19]=4)=[CH:16][N:17]=3)[OH:12])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(=O)C3CCC4(CC3)OCCO4)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)C3CCC4(CC3)OCCO4)s2)c1
Reaction time: 1 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]dec-8-yl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanone (Ex 1-20) (100 mg, 0.20 mmol) in methanol (5 mL) was added sodium borohydride (22.5 mg, 0.60 mmol). After one hour, water was carefully added and then diluted with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (0-100% ethyl acetate gradient with hexanes) afforded 1,4-dioxaspiro[4.5]dec-8-yl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol. MS ESI calc'd. for C24H26F3N4O3S [M+H]+ 507. found 507. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.97-7.94 (m, 2H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.15 (s, 1H), 6.18 (d, J=5.1, 1H), 4.61 (t, J=5.1, 1H), 3.80 (s, 4H), 2.30 (s, 3H), 1.84-1.72 (m, 1H), 1.71-1.61 (m, 2H), 1.61-1.51 (m, 2H), 1.52-1.28 (m, 4H). rhSyk=++.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21]C)=[O:20])[C@@H:8]([O:10]C(C3C=CC=CC=3)=O)[CH2:9][C@@H:3]1[CH2:4][CH2:5]2>Cl>[CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([OH:21])=[O:20])[C@@H:8]([OH:10])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)O)[C@@H](O)C2
Temperature: 112.5 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Commercially available (−)-cocaine (Sigma Chemical Co.) was dissolved in 1.25 M HCl (1 g cocaine/12 ml). The mixture was allowed to stir for 16 hours at 110-115° C. (gentle reflux). After cooling to room temperature, the mixture was thoroughly extracted with ether to remove the benzoic acid by-product. The acidic aqueous layer was evaporated on a rotary evaporator under high vacuum and then the residue was redissolved in water and lyophilized to afford a white solid that required no further purification (92% yield).
Reaction SMILES: O[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH3:21])[C:19]([SH:22])=[N:18][CH:17]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]([CH3:21])[C:19]([S:22][CH2:2][C:3]3([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]3)=[N:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: OCC1(CO)CCC1
Reactant: Cn1c(-c2ccc(Cl)cc2)cnc1S
Product: Cn1c(-c2ccc(Cl)cc2)cnc1SCC1(CO)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 19a from [1-(hydroxymethyl)cyclobutyl]methanol and 5-(4-chlorophenyl)-1-methyl-1H-imidazole-2-thiol. 1H NMR (300 MHz, CDCl3) δ 7.41-7.25 (m, 5H), 3.62 (s, 2H), 3.49 (s, 3H), 3.46 (s, 2H), 2.04-1.63 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:15])([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][S:23]([CH2:26][C:27](O)=[O:28])(=[O:25])=[O:24])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][S:23]([C:26]2[C:27](=[O:28])[O:15][C:5]3[C:6]([CH:7]=2)=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:24])=[O:25])=[CH:30][CH:31]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Reactant: O=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3oc2=O)cc1

Procedure:
A solution of 3,5-dinitrosalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][C:4]=2[N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=O)[N:7]=1.[CH:19]([C:22]1[N:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:19]([C:22]1[N:27]=[C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]3[N:7]=[C:2]([CH3:1])[C:3]4[CH:17]=[CH:16][C:15](=[O:18])[NH:14][C:4]=4[N:5]=3)[CH2:30][CH2:29]2)[CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cccc(N2CCNCC2)n1
Reactant: Cc1nc(OCCCC=O)nc2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(OCCCCN2CCN(c3cccc(C(C)C)n3)CC2)nc2[nH]c(=O)ccc12
Reaction time: 0.17 h

Procedure:
4-(4-Methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde (74.2 mg, 0.3 mmol) and 1-(6-isopropyl-pyridin-2-yl)-piperazine (62.8 mg, 0.306 mmol) were combined in methylene chloride and stirred in a vial over sieves for 10 min. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and the reaction was stirred overnight. The reaction was quenched by slowly adding water and then the mixture was filtered. The residue was partitioned between CH2Cl2 and water and the organic layer was concentrated. Purification by liquid chromatography (MPLC, gradient of 100% CH2Cl2 to 100% of a 10% MeOH in CH2Cl2 solution) gave the title compound as a low melting solid (55 mg, 0.126 mmol, 42%). MS: APCI: M+1: 437.3 (Exact Mass: 436.26).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:24])[C@@H:13]([NH2:23])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:24])[C@@H:13]([NH2:23])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester (0.8 g, prepared as described in WO2006114774) in CH2Cl2 (15 mL) was added TFA (15 mL) and the reaction mixture stirred for 2 h at RT. The solution was evaporated to dryness to give 0.9 g of the desired product as clear oil.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCOCC1.[CH2:25]([O:27][CH:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:29])[CH3:26].O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:33]3[CH:32]=[N:31][N:30]([CH:28]([O:27][CH2:25][CH3:26])[CH3:29])[CH:34]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
To a 250 mL round bottom flask equipped with a stir bar, condenser and 3-way valve was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 30 g, 0.112 mol), 1,4-dioxane (300 mL, 4.0 mol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14, 35.8 g, 0.134 mol, 1.2 equiv), water (150 mL, 8.3 mol) and potassium carbonate (K2CO3, 61.9 g, 0.448 mol, 4.0 equiv) at room temperature. The resulting mixture was degassed four times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (5.0 g, 0.00433 mol, 0.039 equiv). The reaction mixture was then degassed four times back filling with nitrogen each time before being warmed to 85° C. The reaction mixture was stirred at 85° C. for 2-5 h. When the reaction was deemed complete, the reaction mixture was allowed to cool to room temperature before being diluted with 20% aqueous brine (250 mL) and ethyl acetate (250 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions was washed with water and brine, dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 25% to 40% ethyl acetate/hexane gradient elution) to afford {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (18) as a orange oil, which was directly used in the subsequent reaction assuming the theoretical yield. For 18: C19H25N5O3 (MW, 371.43), LCMS (EI) m/e 372 (M++H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:2]([O:9][C:10]([CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1CCCN1
Reaction time: 18 h
Yield: 55.2 %

Procedure:
L-Proline benzyl ester hydrochloride (96 mg, 2.0 eq) in DMF was put into a flask and K2CO3 (132 mg, 2.0 eq) was added, stirred for a while, and 3-(2-chloro-6-trifluoromethyl-4-yl-pyridin-3-yl)-acrylic acid (50 mg) was added at room temperature. The reaction mixture was stirred for 18 hrs. After the reaction was completed through the TLC checking, the mixture was diluted with EtOAc, washed with 1N HCl solution. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a crude 6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl carboxylic acid benzyl ester (45 mg). N-(4-Aminomethyl-5-ethynyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (30 mg, 0.11 mmol) was reacted with 6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl-carboxylic acid benzyl ester (45 mg) to give 1-{3-[2-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylcarbamoyl)-vinyl]-6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl-carboxylic acid benzyl ester (3.2 mg, 4.5%) after purification by column chromatography (EtOAc/MeOH=10/1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([NH2:21])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]#[N:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#CCCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.44 g of 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanamide (example 24) and 0.52 ml pyridine in 5.8 ml dioxane is cooled to 0° and 0.51 ml trifluoroacetic anhydride is added over a period of 1 h. The mixture is then stirred at room temperature for 3 h. The reaction is quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (2×20 ml). The combined organic extracts are dried, filtered and evaporated to give 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanenitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:17][CH2:18][O:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:10]#[N:11].[N:25]1[N:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]2=[C:27]([C:34](Cl)=[O:35])[CH:26]=1>O1CCCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([C:6]2[N:5]([CH2:17][CH2:18][O:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[N:4]=[CH:3][C:2]=2[NH:1][C:34]([C:27]2[CH:26]=[N:25][N:29]3[CH:30]=[CH:31][CH:32]=[N:33][C:28]=23)=[O:35])[CH:8]=1)#[N:11]
Reactant: COc1ccc(C#N)cc1-c1c(N)cnn1CCOC[Si](C)(C)C
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCOC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 140.9 %

Procedure:
3-(4-amino-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)-4-methoxybenzonitrile (717 mg, 2.08 mmol) in tetrahydrofuran (20 mL) was added to pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (262 mg, 1.45 mmol) in tetrahydrofuran (5 mL) at 0° C. After addition, the mixture was warmed to room temperature, and then stirred overnight at this temperature. The mixture was concentrated to give 1.0 g (98%) of N-(5-(5-cyano-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=490.1.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[SH:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[O:5]=[C:3]([CH3:4])[CH2:2][S:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([OH:15])=[O:14]
Reactant: CC(=O)CCl
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 63.2 %

Procedure:
To a solution of chloroacetone (5.18 g, 55.99 mmol) in DMF (25 ml) were added thiosalicylic acid (8.63 g, 55.99 mmol) and potassium carbonate (7.74 g, 55.99 mmol), and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added water and ethyl acetate and the mixture was separated by a separating funnel. The aqueous layer was acidified with 1N diluted hydrochloric acid (about pH 4) and extracted with ethyl acetate. Further the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration the solvent was removed in vacuo to give the subject compound (7.44 g, 63%).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[H-].[Na+].[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.[NH4+].[Cl-]>C1COCC1>[CH3:15][O:16][C:17](=[O:20])[CH2:18][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[N:8]=[CH:9][CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)CBr
Reactant: c1cnc(-c2ncc[nH]2)nc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)Cn1ccnc1-c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a suspension of 2-(1H-imidazol-2-yl)-pyrimidine hydrochloride (1.4 g, 7.7 mmol) in THF (50 mL) is added 40% NaH in mineral oil (675 mg, 15.4 mmol), the mixture is stirred at room temperature for one hour, and bromoacetic acid methyl ester (1.3 g, 8.4 mmol) is added. The reaction mixture is stirred at ambient temperature overnight. After aqueous NH4Cl solution (50 mL) is added, the mixture is extracted with ethyl acetate (20 mL×6) and CH2Cl2 (10 mL×6). The organic extracts are combined, dried over Na2SO4, and concentrated. The resulting residue is purified on a silica gel column with 100:10:1 CH2Cl2/MeOH/NH4OH as eluent to yield the titled compound (650 mg).
Reaction SMILES: Br[C:2]1[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]=[C:7]([NH:11][CH2:12][CH3:13])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C(N(CC)CC)C.COCCOC>O>[CH2:12]([NH:11][C:7]1[N:8]=[C:9]([CH3:10])[C:4]2[CH:3]=[C:2]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]=2[N:6]=1)[CH3:13]
Reactant: OB(O)c1cccs1
Reactant: CCNc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: O
Product: CCNc1nc(C)c2cc(-c3cccs3)c(=O)n(C(C)C)c2n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 18 %

Procedure:
Pd(dppf) dichloromethane adduct (0.077 g, 0.095 mmol) was added to a suspension of 6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.154 g, 0.474 mmol), 2-thiophene boronic acid (0.079 g, 0.616 mmol), and triethylamine (165 μL, 1.19 mmol) in 10:1 DME:water (1.5 mL). The reaction was heated to 100° C. After 5 h, the reaction was cooled to room temperature, filtered though a Celite plug and concentrated in vacuo. The residue was purified on SiO2 (3:2 hexanes:ethyl acetate) to give 2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one (28 mg, 18% yield) as a light yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.60 (dd, J=4.0, 1.2 Hz, 1H), 7.38 (dd, J=5.2, 0.8 Hz, 1H), 7.10 (dd, J=4.8, 3.2 Hz, 1H), 5.93 (bsept, 1H), 5.13 (bs, 1H), 3.54 (pent, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.28 (t, J=7.6 Hz, 3H); MS (EI) for C17H20N4OS: 329.0
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([SH:16])[CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14].[F:17][C:18]([F:31])([F:30])[CH2:19]OS(C1C=CC=CC=1)(=O)=O.Cl>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([S:16][CH2:19][C:18]([F:31])([F:30])[F:17])[CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14]
Reactant: Oc1c(Cl)cc(S)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1c(Cl)cc(SCC(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 71.1 %

Procedure:
64 g of potassium carbonate were added to a solution of 41.9 g of 3,5-dichloro-4hydroxy-benzenethiol in 200 ml of N,N-dimethylformamide under nitrogen atmosphere. To the stirred mixture were dropped at 30° to 40° C. 55 g of 2,2,2-trifluoroethyl-benzenesulfonate. The whole was stirred at 60° to 70° C. for 6 hours, cooled, mixed with 1.5 l of water, and acidified to pH 2 by dropwise addition of hydrochloric acid. A resulted oil was extracted with toluene and the toluene extract was washed with water. The washed toluene extracted was stirred with 160 ml of a 25% aqueous potassium hydroxide solution, and a water layer was separated. Then the separated water layer was acidified to pH 2 by adding hydrochloric acid. A resulted oil was extracted with toluene. The toluene extract was washed with water, dried over anhydrous sodium sulphate, and evaporated to give a residue. The residue was distilled under reduced pressure to give 42.3 g of 2,6 -dichloro-4-(2,2,2-trifluoroethylthio)-phenol which boiled at 85° to 88° C./1 mmHg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=1.[OH:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:18][NH2:19].O>C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:19][CH2:18][CH:17]([OH:16])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cc1ccc(OCCCO)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCCCO)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 27.4 %

Procedure:
A mixture of 1-[4-(3-hydroxypropoxy)phenyl]-propan-2-one (1.8 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (1.8 g) were mixed in dry benzene (80 ml) and boiled under reflux in a Dean and Stark apparatus until water evolution was complete. The solvent was evaporated, the residue dissolved in methanol, platinum oxide (50 mg) added and the imine reduced in the presence of hydrogen at atmospheric pressure. When hydrogen uptake ceased the catalyst was removed by filtration and the solvent evaporated. The residue was chromatographed on silica-gel in 4% methanol-dichloromethane to give the title compound (0.94 g) as a colourless oil. Crystallisation from etherhexane gave a white solid, mp 97°-103°, as a 74:26 mixture of diastereoisomers.