Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]1=[O:15])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]1=[O:15])[O:16][CH2:17][CH3:18])[CH3:2]
Reactant: CCOC(=O)C(OCC)n1cccc([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(OCC)n1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of (RS)-ethoxy-(3-nitro-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (3.91 g) at r.t. in ethanol (25 ml) under an argon atmosphere was added 10% Pd/C (215 mg). The reaction mixture was then stirred at r.t. under a hydrogen atmosphere for 16 h. The catalyst was filtered off on a celite pad and washed with ethanol. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, cyclohexane=>cyclohexane/EtOAc 2:3) to give (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester as yellow oil. MS 241.2 ([M+H]+)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:21]=[CH:22][N:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.CCCCC.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[C:48](Cl)=[O:49]>C1COCC1>[C:27]1([S:24]([N:20]2[CH:21]=[C:22]([C:48]([C:47]3[CH:51]=[C:52]([O:56][CH3:57])[C:53]([O:54][CH3:55])=[C:45]([O:44][CH3:43])[CH:46]=3)=[O:49])[N:23]=[C:19]2[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=S(=O)(c1ccccc1)n1ccnc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole (10ya) (5.0 mmol) in anhydrous THF (100 mL) at −78° C. was added 1.7 M tert-butyllithium in pentane (1.2 equiv, 6.0 mmol) and stirred for 10 min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.2 equiv, 6.0 mmol) in THF was added at −78° C. and stirred overnight.2 The reaction mixture was quenched with 100 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (300 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 3:1) to give a white solid. Yield: 30%. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=10 Hz, 1H), 8.04 (d, J=10 Hz, 2H), 7.91 (s, 1H), 7.76 (d, J=5 Hz, 2H), 7.65 (t, J=10 Hz, 1H), 7.55-7.58 (m, 5H), 7.40 (s, 2H), 7.33-7.36 (m, 3H), 7.25 (t, J=10 Hz, 1H), 4.05 (s, 3H), 4.03 (s, 6H). MS (ESI) calcd for C33H27N3O8 657.0. Found 680.1 [M+Na]+.
Reaction SMILES: [Na:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13]>C(O)C>[Na:1].[C:2]([C:4](=[C:12]([OH:13])[C:11]([F:18])([F:17])[F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(O)C(F)(F)F
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution obtained by dissolving 24.0 g (1.04 mol) of sodium metal in 400 ml of ethanol, 113.1 g (1.00 mol) of ethyl cyanoacetate was dropwise added with stirring at the room temperature. After stirring for one hour, 150.0 g (1.05 mol) of ethyl trifluoroacetate was dropwise added to the reaction mixture and stirred for 3 hours at the same temperature. After finishing the reaction, the reaction mass was concentrated as intact under reduced pressure. Precipitated solid was the desired product. Ethyl 2-cyano-3-hydroxy-4,4,4-trifluoro-2-butenoate sodium salt thus obtained was 221.86 g. The yield was 96 %. Following results were obtained by NMR analysis. 1H-NMR (acetone-d6, bppm): 1.21(3H, t, J=6.9 Hz), 4.09(2H, q, J=6.9 Hz)
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:24]([NH2:26])=[O:25]>>[C:24]([C@@H:23]([NH:22][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])[CH2:27][CH:28]1[CH2:30][CH2:29]1)(=[O:25])[NH2:26]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: Cl
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and (S)-2-amino-3-cyclopropylpropanamide hydrochloride (Example 97 a) as starting materials. MS (EI): m/e=382.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CCCCO>[CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc[nH]c12
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: c1ccc(CSc2nc(Nc3ccccc3)c3[nH]cnc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzylthio-6-chloropurine (3.9 g) and aniline (3.42 g) in n-BuOH (100 ml) in the presence of triethylamine (7.5 ml) were refluxed for 2 h. Reaction mixture was cooled to room temperature, dried at a rotary vacuum evaporator, cooled with ice and 400 ml water was added with vigorous shaking. At standing overnight at −16° C. crude dark-brown solid was formed, which was dried into constant weight and chromatographically purified over 100 g silica packed in chloroform. The column was eluted with 500 ml 100% chloroform followed by 500 ml 1.25% MeOH/chloroform and then 1.5 L 2.5% MeOH/chloroform; 100 ml fractions collected and fractions 12 to 15 were dried to yield light-brown solid which were recrystallized from MeOH in the presence of active carbon. Yield 1.18 g of white, amorphous solid. TLC (2.5% MeOH/chloroform) shows only a single spot with no contaminants. HPLC purity: 98+%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([CH3:20])=[CH:13][N:12]=1.O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>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>[Cl:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:15][C:14]([CH3:20])=[CH:13][N:12]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: Cc1cnc(Cl)c(B(O)O)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Temperature: 90 °C
Yield: 44.6 %

Procedure:
A glass microwave reaction vessel was charged with 4-chloro-6-methyl-1,3,5-triazin-2-amine (0.350 g, 2 mmol), 2-chloro-5-methylpyridin-3-ylboronic acid (combi-blocks catalog number BB-3511) (0.6 g, 3 mmol), sodium carbonate, monohydrate, crystal (J.T. Baker catalog number 3600-01) (0.450 g, 7 mmol), tetrakis(triphenylphosphine)palladium (0) (Strem chemicals catalog number 46-Z150) (0.3 g, 0.2 mmol). Degassed 1,2-dimethoxyethane (Aldrich catalog #255527) (11 mL, 109 mmol) and water (1 mL, 2 mmol) were added to the mixture. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 90° C. for 30 min. The mixture was filtered through Celite® (diatomaceous earth) and washed with ethyl acetate. The crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3/MeOH in dichloromethane, to provide 4-(2-chloro-5-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.210 g, 36% yield).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>>[F:28][C:29]([F:38])([F:39])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])=[CH:32][CH:31]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 4-trifluoromethyl-benzylamine (94%, white crystals). HPLC-MS: m/z=429.2 (M+1); Rt: 4.35 min.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[Cl-:11].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:11][C:1]1[CH:6]=[CH:5][C:4]([C:7]([C:3]2[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: [Cl-]
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 122.6 %

Procedure:
A stirred solution of m-toluoyl chloride (10.0 g, 64.7 mmol) in chlorobenzene (13.2 ml) at 80° C. was treated with aluminum chloride (8.63 g, 64.7 mmol) in portions over 30 minutes. The mixture was stirred 15 hours at 80° C., cooled to ambient temperature, stirred 16 hours, and quenched by addition of ice and concentrated hydrochloric acid (5.0 ml). The mixture was extracted three times with dichloromethane, and the combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was dissolved in boiling n-hexane, treated with activated charcoal, filtered, and cooled. The product was filtered and dried to provide 9.15 g of 3-(4-chlorobenzoyl) toluene. The filtrate was concentrated under vacuum and filtered to provide an additional 0.28 g of product. Total yield was 9.42 g (63%), m.p. 103°-105° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:20])([CH3:19])[C@H:3]1[OH:21].C(N(CC)CC)C.Br[CH2:30][C:31]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[CH:38][C:32]=1[C:33](OCC)=[O:34].Cl>CN(C)C=O>[CH3:20][C:4]1([CH3:19])[C@@H:3]([OH:21])[C@H:2]([N:1]2[CH2:30][C:31]3[C:32](=[CH:38][CH:39]=[CH:40][C:41]=3[N+:42]([O-:44])=[O:43])[C:33]2=[O:34])[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:17])([F:18])[F:16])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3c(cccc3[N+](=O)[O-])C2=O)[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
0.362 g of trans-4 amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran-3-ol (prepared from its hydrochloride, in turn prepared as described in Preparation 9) and 0.30 ml of triethylamine were added to a solution of 0.367 g of ethyl 2-bromomethyl-3-nitrobenzoate in 7.4 ml of dimethylformamide, and the resulting mixture was stirred at 100° C. for 1 hour in an atmosphere of nitrogen. The reaction mixture was then stirred under reflux of the solvent (at 152° C.) for a further 1 hour, after which the mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract was then washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and a with saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:1:1 by volume mixture of ethyl acetate, cyclohexane and tetrahydrofuran as the eluent. The product obtained from the eluate was recrystallized from a mixture of tetrahydrofuran and hexane to give 0.295 g of the title compound, melting at 292°-295° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[C:12](O)(=O)[CH2:13][CH2:14][C:15]#[CH:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[CH2:15]([C:16]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])[N:11]=1)[CH2:14][C:13]#[CH:12]
Reactant: C#CCCC(=O)O
Reactant: Cc1ccccc1C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C#CCCc1nc(-c2ccccc2C)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
In a reactor tube, a mixture of N′-hydroxy-2-methylbenzamidine (555 mg, 3.7 mmol), 4-pentynoic acid (363 mg, 3.7 mmol), HOBT (0.56 g, 3.7 mmol) and EDCI.HCl (1.06 g, 5.55 mmol) in dioxane (7.4 mL) was stirred at R.T for 3 h. After this time the mixture was heated at 80° C. overnight in a reaction block. The mixture was concentrated. The organic layer was washed with water, NaOH 1N and water. The solvent was evaporated in a Genevac for 75 min at 40° C. using the low boiling point program. The crude product was purified by flash chromatography (Prepacked 10 g silicagel column) with DCM as eluent to afford 250 mg of 5-(but-3-ynyl)-3-o-tolyl-1,2,4-oxadiazole (Yield: 32%) as yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)[S:7][CH:8]=1)#[N:2].C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][C:30](=[O:34])[C:31]([NH2:33])=[O:32])[O:26][CH2:25]2)=[CH:20][C:19]=1[F:35]>>[C:1]([CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][C:30](=[O:34])[C:31]([NH2:33])=[O:32])[O:26][CH2:25]4)=[CH:20][C:19]=3[F:35])=[CH:11][CH:10]=2)[S:7][CH:8]=1)#[N:2]
Reactant: N#CCc1csc(-c2ccc(Br)cc2)n1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Product: N#CCc1csc(-c2ccc(-c3ccc(N4CO[C@@H](CC(=O)C(N)=O)C4)cc3F)cc2)n1

Procedure:
The same procedure as in Example 1 was conducted, except for adding 4-(4-cyanomethyl thiazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:16].[C@H:17]12C[C@H](NC1)CN2C(=O)C>>[ClH:16].[CH2:9]1[CH:10]2[CH2:11][NH:12][CH2:13][CH:14]2[CH2:15][N:8]1[C:6](=[O:5])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Product: CC(=O)N1CC2CNCC2C1

Procedure:
The title product KK is prepared from hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester according to the procedure described for the synthesis of Intermediate O.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:44]4[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]4)[S:7][C:8]=3[N:9]=2)[CH3:36])[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCS(=O)(=O)CC3)sc2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (140 mg, 269 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (112 μL, 807 μmol) and thiomorpholine 1,1-dioxide (109 mg, 807 μmol), and the mixture was stirred at 60° C. for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (94 mg, 56%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](F)[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C@H:14]1[CH2:18][CH2:17][NH:16][C@H:15]1[CH3:19].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([N:16]2[CH2:17][CH2:18][C@H:14]([OH:13])[C@@H:15]2[CH3:19])[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C#N)c(Cl)c(Cl)c1F
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(Cl)c(Cl)c1N1CC[C@H](O)[C@@H]1C

Procedure:
Using 2,3-dichloro-4-fluoro-5-methylbenzonitrile (1.02 g), 0.9 M-dimethyl sulfoxide solution (5.56 ml) of (2S,3S)-3-hydroxy-2-methylpyrrolidine and lithium carbonate (370 mg), the title compound was obtained as a colorless solid (yield: 53 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13](CC4C=CC(OC)=CC=4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:40])[F:41])[CH:33]=2)=[CH:43][CH:44]=1
Reactant: COc1ccc(Cn2c(=O)c3c(nc(CCCOc4cccc(OC(F)(F)F)c4)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c(=O)c2c1nc(CCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione (105 mg, 0.167 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise followed by trifluoromethanesulfonic acid (0.25 mL) at 0° C. The reaction was stirred at 0° C. for 10 min, then at room temperature for 16 h. The reaction was quenched with saturated sodium bicarbonate and extracted with DCM. The organic phase was washed with water, dried over sodium sulfate, and concentrated to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione (66 mg, 77.6% yield) as a yellow oil. LCMS retention time 2.868 min; LCMS MH+ 509.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.N1C(C)=CC=CC=1C>ClCCl>[O:27]=[C:23]1[CH2:22][CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:25][C:24]1=2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C
Yield: 91.8 %

Procedure:
Trifluoromethanesulfonic anhydride (1.7 mL, 10 mmol) was added slowly over 1 hour to a solution of 6-hydroxy-1-tetralone (1.62 g, 10 mmol) and 2,6-lutidine (1.28 mL, 10 mmol) in dry dichloromethane (10 mL) cooled to 0° C. After 1 hour the solution was diluted with dichloromethane (10 mL) and washed with 1 M hydrochloric acid (20 mL). The organic layer was re-extracted with dichloromethane (50 mL) and the combined organics washed with 1 M hydrochloric acid (10 mL). The organics were dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, CH2Cl2) to provide 2.7 g of compound 2 (93%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccc(Br)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccc(Br)cc2)CC1)c1ccccc1
Yield: 83.5 %

Procedure:
0.108 g (0.0004 mol) of 1-(4-bromo-benzyl)-piperidin-4-ol and 0.12 ml (0.00085 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.125 g (83.5%) of 1-(4-bromo-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[CH:19])=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Pocedure E; benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine (Intermediate 126, 85.0 mg, 0.27 mmol) in methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight at ambient temperature. The crude alkyne (65 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(N(CC)CC)C>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 97 %

Procedure:
10 g (100 mmole) of succinic anhydride, 10 mL (97 mmole) of benzyl alcohol and 10 mL of triethylamine were combined, the mixture was heated to reflux, allowed to reflux for about 5 minutes, and then was allowed to stir unheated for 1 hour. After this time, the mixture was poured into 250 mL of 1M hydrochloric acid and was extracted with 2-75 mL portions of ethyl acetate. The organic phases were combined, washed with deionized water, washed with brine, and then were dried over anhydrous magnesium sulfate. The organic phase was concentrated to oil which upon sitting yielded crystalline 19.6 g (94% yield) of the title compound.