Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH3:16])[C:12]=1[C:13]([NH2:15])=[O:14])=O.[OH-].[Na+].CCO>O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]1[NH:15][C:13](=[O:14])[C:12]2[C:11]([CH3:16])=[CH:10][S:9][C:8]=2[N:7]=1
Reactant: COc1ccccc1C(=O)Nc1scc(C)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1nc2scc(C)c2c(=O)[nH]1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
A mixture of 2-(2-methoxybenzamido)-4-methylthiophene-3-carboxamide (0.84 g, 2.9 mmol), 6 N aqueous NaOH (4.8 mL), and EtOH (4.8 mL) was heated at 120° C. for 16 h. The reaction was cooled, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under vacuum to give 2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.48 g, 61% yield). LC/MS: m/z 273.1 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:24])=[O:5])C.[OH-:26].[Na+].O.Cl>C(#N)C>[C:22]([C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:24])([CH3:25])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)(=[O:26])[NH2:23]
Reactant: [OH-]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C#N)c1)N2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
A mixture of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 7.96 mmol), sodium hydroxide (1.8 g, 44.9 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 4 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.58 g, 20%) as a white solid which was used for next step without further purification: MS (ESI) M+1=325.2.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:10]1[O:11][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1>C1COCC1>[C:15]1([C:13]2[N:14]=[C:10]([CH:2]([SH:3])[C:1]([OH:5])=[O:4])[O:11][C:12]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CS
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(S)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 0.25 h

Procedure:
8.15 g. of the cyclohexyl ester of thioglycolic acid is dissolved in 80 ml. of absolute THF, and 2.6 g. of sodium methylate is added thereto. The reaction mixture is agitated for 15 minutes. Then, 12 g. of 2-chloro-4,5 -diphenyl-oxazole (b.p. 170°/0.05 mm.; producible by reacting 4,5-diphenyl-2-oxazolone with POCl3) in 20 ml. of THF is added dropwise. The reaction mixture is refluxed under agitation for 9 hours. The thus-precipitated NaCl is filtered off and the filtrate concentrated by evaporation, thus obtaining the cyclohexyl ester of 4,5-diphenyl-2-oxazolyl mercaptoacetic acid as an oily residue. The latter (16 g.) is refluxed in 150 ml. of ethanol with 8 g. of pulverized K2CO3 for 2 hours. After conducting the usual working-up operation, 4,5-diphenyl-2-oxazolyl-mercaptoacetic acid is obtained, m.p. 137°-138°.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[O:23][C:22]([CH2:24][CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12]([NH:15][C:26](=[O:27])[CH2:25][CH2:24][C:22]3[O:23][C:19]([CH3:18])=[CH:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Cc1cc(-c2ccc(N(C)C)cc2)cnc1N
Reactant: Cc1ccc(CCC(=O)Cl)o1
Solvent: c1ccncc1
Product: Cc1ccc(CCC(=O)Nc2ncc(-c3ccc(N(C)C)cc3)cc2C)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-(4-(dimethylamino)phenyl)-3-methylpyridin-2-amine (120b, 2.27 g, 10.0 mmol) in pyridine (30 ml) was added with 3-(5-methylfuran-2-yl)propanoyl chloride (1.90 g, 11.0 mmol) and then stirred at room temperature for further 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give N-(5-(4-(Dimethylamino)phenyl)-3-methylpyridin-2-yl)-3-(5-methylfuran-2-yl) propanamide (120): 1H NMR (500 MHz, DMSO-d6):δ: 9.99 (s, 1H), 8.46 (s, 1H), 7.84 (s, 1H), 7.55 (m, 2H), 6.81 (m, 2H), 5.98 (s, 1H), 5.94 (s, 1H), 2.94 (s, 6H), 2.87 (t, 2H), 2.65 (t, 2H), 2.21 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=1>CN(C=O)C>[CH2:1]([O:5][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2F)cn(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(C)(=O)=O)cc1-c1cc(C)c(=O)n(C)c1
Reaction time: 1 h
Yield: 23.8 %

Procedure:
To a solution of but-2-yn-1-ol (191 mg, 2.72 mmol) in anhydrous DMF (3 mL) was added NaH (109 mg, 2.72 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at this temperature for 1 hr. The title compound from Step 1 (200 mg, 0.68 mmol) was added and the reaction mixture was stirred at 0° C. for 2 hrs. After this time, it was quenched with sat. NH4Cl solution (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give a crude product that was purified by prep-HPLC to give the title compound (56.01 mg, 23.9%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.88 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.46 (s, 2H), 7.24 (d, J=8.8 Hz, 1H), 4.79 (d, J=2.0 Hz, 2H), 3.62 (s, 3H), 3.08 (s, 3H), 2.22 (s, 3H), 1.87 (s, 3H). LCMS: 346.0 (M+H)+
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>ClCCl>[CH:1]1[C:9]([NH:10][C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 19.8 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.13 g, 0.57 mmol), valeryl chloride (0.068 mL, 0.57 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloromethane (15 mL) provided N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-ylpentanamide (35 mg). MS (ESI) m/z 311; HPLC purity 100% at 210-370 nm, 10.6 min.; 100% at 250 nm, 10.6 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C20H26N2O+H+, 311.21179; found (ESI, [M+H]+), 311.2118.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Cc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 52.9 %

Procedure:
The title compound (70.4 mg) was prepared as in Example 177, Steps C and D, using 204.3 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 204.1 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C19H25N3, 295.42. found, m/z 296.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 4.50 (m, 1H), 3.43-3.40 (m, 2H), 3.32-3.28 (m, 2H), 3.20-3.17 (m, 2H), 2.80-2.77 (m, 2H), 2.43 (s, 3H), 2.04-1.86 (m, 6H), 1.64-1.55 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>ClC1C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:6]2[CH:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: Clc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)nc(N)n2)CC1
Yield: 90.4 %

Procedure:
A mixture of 2,6-diamino-4-chloropyrimidine (2.88 g, 20 mmol) and 1- (tert-butoxycarbonyl)piperazine (5.6 g, 30 mmol) in chlorobenzene (30 ml) was stirred under reflux for 3 hours. After cooling the formed precipitate was collected and stirred with aqueous 1N NaOH (63 ml) at room temperature for 15 minutes. The solids were collected, washed with water and dried, yield: 90.4%, mp. 176°-179° C.
Reaction SMILES: F[B-](F)(F)F.N1(O[C:16](N(C)C)=[N+:17](C)[CH3:18])C2C=CC=CC=2N=N1.C(O)(=O)C1C=CC=CC=1.[N:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:41]([N:43]3[CH2:50][CH2:49][C@:48]4([CH3:53])[C@H:51]([CH3:52])[C@H:44]3[CH2:45][C:46]3[CH:57]=[CH:56][C:55]([C:58]([OH:60])=O)=[CH:54][C:47]=34)=[O:42])=[CH:40][C:35]=2[NH:34][CH:33]=1.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:16][N:17]([CH3:18])[C:58]([C:55]1[CH:56]=[CH:57][C:46]2[CH2:45][C@@H:44]3[C@@H:51]([CH3:52])[C@:48]([CH3:53])([C:47]=2[CH:54]=1)[CH2:49][CH2:50][N:43]3[C:41]([C:39]1[CH:38]=[CH:37][C:36]2[N:32]=[CH:33][NH:34][C:35]=2[CH:40]=1)=[O:42])=[O:60]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)O)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Agent: CNC
Agent: F[B-](F)(F)F
Agent: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H]2Cc3ccc(C(=O)N(C)C)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (90 mg) is added to a solution of (2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylic acid benzoic acid (0.10 g) and ethyldiisopropylamin (53 μL) in dimethylformamide (2 mL). The resulting solution is stirred at ambient temperature for 20 min before dimethylamine (40% in H2O, 60 μL) is added. The solution is stirred overnight. The mixture is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (H2O/MeCN/NH3) to give the product as a solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].O1CCCC1.[NH2:18]/[C:19](=[N:36]\[OH:37])/[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH2:21]1>ClCCl>[O:2]=[C:1]1[O:37][N:36]=[C:19]([C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:25]2)[NH:18]1
Reactant: C[Si](C)(C)CCOC(=O)N[C@H]1CC[C@H](/C(N)=N/O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)N[C@H]1CC[C@H](c2noc(=O)[nH]2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Carbonyldiimidazole (1.24 g, 7.43 mmol) was added to a tetrahydrofuran (20 ml) solution of the compound (1.12 g, 3.71 mmol) obtained in Step 5 above under ice cooling and the resulting mixture was stirred at 50° C. for 24 hours. The reaction mixture was diluted with dichloromethane:methanol [10:1 (v/v)] and washed with 10% aqueous citric acid solution and saturated sodium bicarbonate solution in that order and then the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=9:1→13:7→dichloromethane:methanol=49:1→19:1 (v/v)] to give 757 mg (62%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[Br:10][C:11]1[S:15][C:14]2=[N:16][C:17]([C:19](O)=[O:20])=[CH:18][N:13]2[CH:12]=1>>[Br:10][C:11]1[S:15][C:14]2=[N:16][C:17]([C:19]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=3)=[O:20])=[CH:18][N:13]2[CH:12]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: Nc1ccc(F)c(Cl)c1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using 3-chloro-4-fluoroaniline and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23]Br)[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2].[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:39][C:34]2[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=2[CH2:36][CH2:37][CH3:38])[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCOCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 73.8 %

Procedure:
A mixture of 1.89 g (0.004 mole) of [4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.80 g (0.004 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, and 1.14 g (0.0082 mole) of potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 1.69 g (72% yield) of [4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.[H-].[Na+].Cl[CH:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: CCOC(=O)C(Cl)OCC
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OCC)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon and at 0° C., 10 min apart two portions of in total 350 mg (purity 82%, 1.10 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile were added to a suspension of 53 mg (1.32 mmol, 1.2 eq.) of sodium hydride (60% in mineral oil) in 2.1 ml of dimethylformamide. The reaction mixture was stirred at RT for 60 min and then cooled back to 0° C., 245 mg (purity 90%, 1.32 mmol, 1.2 eq.) of ethyl 2-chloro-2-ethoxyacetate were added and the mixture was stirred at RT for 2 h. This batch together with an analogous test batch was combined with 50 mg (purity 82%, 0.16 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile. After addition of 20 ml of water and phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (IR-50Si, petroleum ether/ethyl acetate 15-50%). Yield: 277 mg (55% of theory based on in total 1.26 mmol of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile employed)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.CN(C)[CH:34]=[O:35]>O1CCCC1>[CH3:9][C:10]1[CH:15]=[C:14]([C:16]2[S:20][C:19]([CH:34]=[O:35])=[N:18][CH:17]=2)[CH:13]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=2)[CH:11]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 85.2 %

Procedure:
Lithium diisopropylamide (1.8M in tetrahydrofuran, 25 ml, 4.46 mmol) was added dropwise to a cooled −78° C. solution of INTERMEDIATE 4 (500 mg, 1.49 mmol) in tetrahydrofuran (7.5 ml). The mixture was stirred at −78° C. for 35 minutes. N,N-dimethylformamide (230 μl, 2.97 mmol) was added, and the resulting mixture was stirred at −78° C. for 1 hour. The mixture then was quenched at −78° C. by the addition of 1 mL of methanol. The mixture was then warmed to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (ethyl acetate/hexanes) afforded 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carbaldehyde (464 mg, 1.27 mmol, 86% yield) as a yellow solid. ESI: [M+H]+ m/z 365.0.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31][N:32]1[C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N:34]=[C:33]1[CH:41]=O>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:41][C:33]2[N:32]([CH3:31])[C:40]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[N:34]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cn1c(C=O)nc2cnccc21
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: C[C@@H]1CN(Cc2nc3cnccc3n2C)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-methyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.83 (brs 1H), 9.01 (s, 1H), 8.41 (d, J=15.8 Hz, 1H), 7.98 (s, 1H), 7.30 (d, J=4.98 Hz, 1H), 4.79-4.75 (m, 1H), 4.13-4.06 (m, 3H), 4.00-3.96 (s, 4H), 3.60-3.52 (m, 2H), 3.30 (t, J=8.7 Hz, 1H), 3.07 (d, J=9.9 Hz, 1H), 2.92-2.89 (m, 1H), 2.82-2.77 (m, 1H), 2.48-2.45 (m, 1H), 2.36-2.27 (m, 2H), 2.19-2.17 (m, 1H), 1.89-1.79 (m, 2H), 1.23 (d, J=6.6 Hz, 3H). MS: (M+H m/z 449.2).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])#[CH:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([NH:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[CH:2])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C#Cc1ccc(C(=O)NC(C)=O)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 22.6 %

Procedure:
4 g (0.021 mol) 4-Ethynyl-3-nitrobenzamide (Compound I-1), 30 ml (0.320 mol) acetic anhydride and 20 ml acetic acid were added into a reaction flask, stirred, and heated to 120° C. for 15 hours. After completion of the reaction monitored by TLC, the mixture was extracted with 300 ml ethyl acetate, and the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, separated by column chromatography to obtain N-acetyl-4-ethynyl-3-nitrobenzamide (Compound I-11), 1.1 g (0.0047 mol), yield 22.6%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[C:18]([OH:19])=[CH:17][N:16]=[C:15]2[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=[CH:22][C:14]=12>CN(C=O)C>[F:12][C:13]1[C:18]([O:19][CH2:2][CH2:3][O:4][CH3:5])=[CH:17][N:16]=[C:15]2[NH:20][CH:21]=[CH:22][C:14]=12
Reactant: COCCBr
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc2[nH]ccc2c1F
Temperature: 65 °C
Yield: 49.7 %

Procedure:
1-Bromo-2-methoxyethane (0.586 g, 4.21 mmol) and potassium carbonate (1.16 g, 8.43 mmol) to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (1.3 g, 4.21 mmol; Example 119, Step A) in DMF (13 mL). The reaction was heated to 65° C. in a sealed tube for 18 hours, cooled down and then filtered. The filtrate was concentrated and purified by reverse chromatography (SP4, 25M, water/ACN 90/10->0/100, 30CV) to yield 4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg, 49.7% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[CH3:22][CH:23]([CH3:25])[O-:24].[Na+].Cl.O>C(O)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:24][CH:23]([CH3:25])[CH3:22])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: CC(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 0.42 h

Procedure:
A solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.25 g, 0.8 mmol) in isopropanol (2.5 ml) containing sodium isopropoxide (0.5M) was stirred at 60° for 25 minutes. After cooling, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 15 minutes at room temperature. The solution was neutralised by addition of aqueous.sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1) and the solution purified by column chromatography on silica gel eluting with chloroform-methanol (7:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-isopropoxypurine which was crystallised from chloroform-carbon tetrachloride (0.18 g, 76%), m.p. 111.5-113.5° C., δH [(CD3)2SO] 1.34 (6H, d, J 6.3 Hz, C(CH3)2), 1.45 (1H, m, 3′-H), 1.74 (2H, q, J 7.2 Hz, 2′-H), 3.3-3.5 (4H, AB part of ABX, 2×4′-H), 4.06 (2H, t, J 7.3 Hz, 1′-H), 4.40 (2H, br, 2×OH), 5.49 (1H, septet, J 6.3 Hz, CH(CH3)2), 6.27 (2H, s, 2-NH2), and 7.83 (1H, s, 8-H).