Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][CH2:40][C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40](=[CH:11][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[C:21]([F:24])([F:22])[F:23])[N:3]=[C:2]4[Cl:1])[C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(Cl)nn4Cc3ccc(Cl)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([OH:15])=O)=[CH:11][N:12]=2)[CH:9]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:27][C:28]1([F:45])[CH2:31][CH:30]([C:32]2[O:36][N:35]=[C:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([CH:43]=3)[NH2:42])[N:33]=2)[CH2:29]1>ClCCl.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([NH:42][C:41]3[CH:43]=[C:37]([C:34]4[N:33]=[C:32]([CH:30]5[CH2:29][C:28]([F:45])([F:27])[CH2:31]5)[O:36][N:35]=4)[CH:38]=[CH:39][C:40]=3[CH3:44])=[O:15])=[CH:11][N:12]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1N
Reactant: CC(=O)c1ccc2ncc(C(=O)O)n2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)c1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of 6-acetylimidazo[1,2-a]pyridine-3-carboxylic acid (24r) (71 mg, 0.39 mmol) in dichloromethane (2 mL) was added dropwise oxalyl chloride (173 uL, 1.98 mmol) and a drop of anhydrous N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes and concentrated. The residue was treated with 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (85 mg, 0.29 mmol) in anhydrous pyridine (2 mL) with stirring at room temperature for 30 minutes. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give 6-acetyl-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (115). 1H NMR (400 MHz, d6-DMSO) δ 10.24 (s, 1H), 10.13 (s, 1H), 8.70 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.95 (dd, J=2.0, 9.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.52 (d, J=8.4 Hz, 1H), 3.92-3.84 (m, 1H), 3.24-3.02 (m, 4H), 2.64 (s, 3H), 2.38 (s, 3H). MS m/z 433.16 (M+1)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:17]([C:33]3[CH:41]=[C:40]([O:42][CH3:43])[C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])=[O:19])=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1.CN(C)[CH:46]=[O:47]>O1CCCC1>[CH:46]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:17]([C:33]3[CH:41]=[C:40]([O:42][CH3:43])[C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])=[O:19])=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1)=[O:47]
Reactant: CN(C)C=O
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.8 ml of 2.5M solution in hexane) was added to a stirred solution of 6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 92, 400 mg, 0.67 mmol) in anhydrous tetrahydrofuran at −75° C. under a nitrogen atmosphere. After 30 minutes dimethylformamide (0.15 ml) was added to the orange solution, and after a further 30 minutes the mixture was allowed to warm to 0° C. before quenching with excess 1N hydrochloric acid. Ethyl acetate was added and the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and the product was crystallised from dichloromethane and diethyl ether mixture to give the title compound (187 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[C:14]2=[O:23])[O:4]1.[P:24]([O-])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>N1C=CC=CC=1>[CH2:27]([O:26][P:24]([O:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[C:14]2=[O:23])[O:4]1)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1nccn([C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1=O
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1nccn([C@@H]2O[C@H](COP(=O)(OCc3ccccc3)OCc3ccccc3)[C@H]3OC(C)(C)O[C@H]32)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.9 %

Procedure:
In 4 mL of pyridine was dissolved 0.22 g of methyl 4-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, 0.17 g of dibenzyl phosphate, 0.40 g of triphenylphosphine and 0.30 mL of diisopropyl azodicarboxylate were successively added and stirred at room temperature for 15 hours, and the solvent was removed under reduced pressure. By purifying the residue by column chromatography [eluent: ethyl acetate], 0.37 g of methyl 4-[(3aR,4R,6R,6aR)-6-({[bis(benzyloxy)phosphoryl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained as an orange-colored solid product.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH3:21][N:22](C=O)C>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:21]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[N:22]
Reactant: CN(C)C=O
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To a solution of 2-iodoadenosine (0.500 g, 1.27 mmol) in DMF (70 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.220 g, 0.19 mmol) and n-tributyltin cyanide (0.442 g, 1.39 mmol). The mixture was stirred at 120° C. for 20 h under nitrogen. The solvent was then evaporated and the residue was purified on silica gel to give 2-cyanoadenosine in 86% yield. 2-Cyanoadenosine was converted to I by using in sequence the following procedures: Procedure A (60% yield), Procedure B (89% yield), Procedure C (60% yield), Procedure D (63% yield), Procedure E (70% yield) and Procedure F (70% yield): mp 195°-197° C.; 13C NMR (Me2SO-d6) 625.4, 32.0, 62.6, 82.3, 84.7, 117.0, 120.7, 136.6, 141.5, 147.9, 156.2; 1H NMR (Me2SO-d6) δ2.06 (m, 2H), 2.39 (m, 2H), 3.56 (m, 2H), 4.13 (m, 1H), 4.92 (m, 1H), 6.24 (m, 1H), 7.90 (br.s, 2H), 8.59 (s, 1H); UV (H2O) λmax 297 nm (ε6470), 266 nm (ε9980), 260 nm (ε9270); FAB HRMS obsd (M+ +H) 261.1069, calcd for C11H12N6O2 261.1099.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].N1C=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([CH2:20][Cl:19])[CH:22]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloro-benzoic acid methyl ester (1.5 g) was dissolved in anhydrous methylene chloride (25 ml). Pyridine (1.4 ml) and 3-(chloromethyl)benzoyl chloride (1.4 ml) were added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was then washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to precipitate crystals. The precipitated crystals were collected by filtration through Kiriyama Rohto and were washed with ether to give 5-chloro-2-(3-chloromethyl-benzoylamino)-benzoic acid methyl ester as a useful intermediate (2.4 g, yield 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=O.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:4](=[O:6])[C:3]([O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[CH:18][CH:17]=1)#[N:14]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C)(C(=O)O)c1ccccc1
Product: COC(C)(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(RS)-2-Methoxy-2-phenyl-propionic acid was reacted with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-phenyl-propionamide. Off-white, waxy solid. MS 295.0 ([M+H]+)
Reaction SMILES: [CH3:1][OH:2].[OH-].[Na+].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](S(O)(=O)=O)[C:12]=3[C:11](=[O:25])[C:10]=2[CH:9]=[CH:8][CH:7]=1>O>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[C:13]([O:2][CH3:1])[CH:14]=[CH:15][CH:16]=3)[C:11](=[O:25])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc2c1C(=O)c1cccc(S(=O)(=O)O)c1C2=O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1C(=O)c1cccc(N)c1C2=O
Reaction time: 3 h
Yield: 80 %

Procedure:
40 parts by volume of methanol and 10 parts of sodium hydroxide are dissolved at the boil and 13.3 parts of 1-aminoanthraquinone-5-sulphonic acid are introduced into this solution at 80°C, over the course of 30 minutes, with vigorous stirring. The mixture is now stirred for a further 3 hours at 80°-85°C until only traces of starting material are still present according to chromatography. The mixture is now diluted with 50 parts of hot water and the product is filtered off, washed with boiling hot water until neutral and dried at 100°-120°C. 8.9 parts of 1-amino-5-methoxy-anthraquinone (80% of theory) are obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 70 °C
Yield: 68.3 %

Procedure:
According to the procedure described in Example 50, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (4.405 g, 16 mmol) from Example 1A, 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline from Example 7A (4.837 g, 18 mmol), and Cs2CO3 (8.145 g, 16 mmol) in isopropanol (80 mL) was heated at 70° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as a solid (5.548 g, 68.3%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.25 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.34 (t, 2H), 3.99 (s, 3H), 3.78 (t, 2H), 3.35 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(C1C[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([CH:2]1[CH2:1][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[CH2:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C=O)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
n-Butyl lithium (2.5M solution in hexane, 4.0 mL, 10 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.19 g, 11.7 mmol) in THF (100 mL) at −78° C. After 10 min., the reaction mixture was allowed to warm to rt. After 1 h, the reaction mixture was cooled to −78° C., and a solution of 1-benzyl 4-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (3.07 g, 8.81 mmol) in THF (10 mL) was added dropwise. After 2 h, the reaction mixture was allowed to warm to rt and was quenched with NH4Cl (saturated, aqueous solution). The reaction mixture was diluted with water (100 mL) and was extracted with EtOAc (3×150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chomatography (0 to 20% EtOAc in Hexane gradient) gave 2.33 g (76%) of the desired product as a thick oil. Rf=0.35 in 30% EtOAc/Hexane. LC-MS: RT=10.1 min., [M+H]+=369.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH:26](N(C)C)N(C)C)[CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH:26]=[C:20]1[CH2:21][C:14]2([CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)[CH:17]=[CH:18][C:19]1=[O:22])[CH3:25]
Reactant: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1CC2(C=CC1=O)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Yield: 100 %

Procedure:
9-oxo-3-aza-spiro[5.5]undec-7-ene-3-carboxylic acid benzyl ester, Preparation I-IA-2 (15.2 g, 51 mmol) was dissolved in 180 mL toluene and tris(dimethylamino)methane (22.2 g, 27 mmol) was added. The reaction was heated to reflux for 5 hours and then allowed to cool to room temperature overnight. The reaction solution was concentrated in vacuo to provide the title compound (18.0 g, 100%): +APCI MS (M+H) 354.6; 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (s, 1 H), 7.28-7.40 (m, 5 H), 6.59 (d, J=10.16 Hz, 1 H), 6.01 (d, J=9.97 Hz, 1 H), 5.13 (s, 2 H), 3.52-3.66 (m, 2 H), 3.39-3.52 (m, 2 H), 3.07 (s, 6 H), 2.74 (s, 2 H), 1.58-1.73 (m, 2 H), 1.41-1.58 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8][Si](C(C)C)(C(C)C)C(C)C)=[CH:6][CH:5]=[CH:4][C:3]=1[N:19]1[C:23](=[O:24])[N:22]([CH3:25])[N:21]=[N:20]1.[F-].[Cs+].[CH3:28]N(C)C=O.CI>O>[CH3:1][C:2]1[C:7]([S:8][CH3:28])=[CH:6][CH:5]=[CH:4][C:3]=1[N:19]1[C:23](=[O:24])[N:22]([CH3:25])[N:21]=[N:20]1
Reactant: CN(C)C=O
Reactant: Cc1c(S[Si](C(C)C)(C(C)C)C(C)C)cccc1-n1nnn(C)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CI
Product: CSc1cccc(-n2nnn(C)c2=O)c1C
Temperature: 25 °C

Procedure:
A mixture of 1-(2-methyl-3-triisopropylsilanylsulfanylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 3.63 g, cesium fluoride 2.91 g and N,N-dimethylformamide 10 ml was stirred at room temperature for thirty minutes. To the resulting mixture was added methyl iodide 2.72 g and the resulting mixture was stirred at room temperature for three hours. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-methyl-3-methylthiophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 1.65 g.
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[Cl:7][C:8]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.[OH-].[Na+]>ClCCl>[Cl:7][C:8]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2Cl)nc1
Reactant: CCN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1ccc(Oc2ccc(Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (350 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.4 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour. To this solution, 6-(2,4-Dichloro-phenoxy)-pyridin-3-ylamine (0.5 g) dissolved in 1.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 1 hour. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 3:4 (v:v) gives 0.31 g of the compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9]>Cl>[OH2:9].[ClH:1].[C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:13]=[CH:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:3][C:2]=1[Cl:1])([OH:10])=[O:9].[C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:13]=[CH:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:3][C:2]=1[Cl:1])([OH:10])=[O:9].[ClH:1]
Reactant: CCOC(=O)c1ccc(C=CCn2ccnc2)cc1Cl
Agent: Cl
Product: O
Product: O=C(O)c1ccc(C=CCn2ccnc2)cc1Cl

Procedure:
A mixture of 1-[3-(3-chloro-4-ethoxycarbonylphenyl)prop-2-enyl]imidazole (0.09 g) in hydrochloric acid (3 ml, 6M) was stirred and heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and toluene (10 ml) was added and the reaction mixture re-concentrated. Repetition of the toluene/concentration procedure three times afforded a white solid which was recrystallised from ethyl acetate/ethanol/ether to give 1-[3-(4-carboxy-3-chlorophenyl)prop-2-enyl]imidazole hydrochloride hemihydrate as a white crystalline solid, m.p. 247°-249°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20](OCC)=[O:21])=[C:9]3[N:8]=2)[CH2:3][CH2:2]1.[CH:25]1([C:28](=[N:30]O)[NH2:29])[CH2:27][CH2:26]1.[H-].[Na+].C(O)(=O)C>CN(C=O)C.ClCCl>[CH:25]1([C:28]2[N:30]=[C:20]([C:19]3[N:18]=[CH:17][N:10]4[C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[N:8][C:9]=34)[O:21][N:29]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Reactant: NC(=NO)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c(N1CCOCC1)nc1c(-c3nc(C4CC4)no3)ncn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A mixture of ethyl 5-morpholino-imidazo[1,5-a]quinazoline-3-carboxylate (2.5 g, 7.7 mmol), cyclopropanecarboxamide oxime (3.8 g), crushed 4 Å molecular sieves (7.5 g), and sodium hydride (0.3 g, 60% in mineral oil, 7.7 mmol) in 50 ml of dry DMF was stirred at room temperature for 1 h. Glacial acetic acid (2 ml) and dichloromethane (75 ml) was added, and the mixture was filtered through celite. The filtrate was evaporated and the residue was triturated with water (100 ml). Pale yellow crystals precipitated and was collected by filtration and dried to give 2.3 g of the title compound, m.p. 189°-191° C. A pure product was obtained by recrystallization from CH2Cl2 /ethyl acetate; yield 1.9 g (69%), m.p. 197°-198° C. (Compound 19).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][N:15]=2.[N:20]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[O:13][CH:12]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccnc2o1
Product: C(#Cc1ccccn1)CCc1nc2cccnc2o1
Product: c1cnc2ocnc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (92 mg, 0.58 mmol) and 2(but-3-ynyl)oxazolo[5,4-b]pyridine (100 mg, 0.58 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5 to 98:2) to yield 56 mg (0.22 mmol, 39%) of 2-(4-pyridin-2-yl)but-3-ynyl)oxazolo[5,4-b]pyridine as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[C:4]([C:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=2)=[CH:3]1
Reactant: CN1CCC(=O)CC1
Reactant: Cn1ccc2cc(NS(C)(=O)=O)ccc21
Product: CN1CC=C(c2cn(C)c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 79.7 %

Procedure:
Beginning with 1.23 gm (5.5 mMol) N-methyl-5-methanesulfonylamino-1H-indole and 0.88 mL (7.1 mMol) 1-methyl-4-piperidone, 1.4 gm (80%) of the title compound were recovered as a tan, crystalline powder.