Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([CH2:23][CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]3)[C:17]([F:22])=[C:18]2[F:21])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9].O.O.[I:36](O)(=O)(=O)=O.II>C(O)(=O)C.O>[CH2:6]([O:10][C:11]1[C:20]([I:36])=[C:19]2[C:14]([CH:15]=[C:16]([CH2:23][CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]3)[C:17]([F:22])=[C:18]2[F:21])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCCCOc1ccc2cc(CC[C@H]3CC[C@H](CCC)CC3)c(F)c(F)c2c1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1ccc2cc(CC[C@H]3CC[C@H](CCC)CC3)c(F)c(F)c2c1I
Yield: 378.2 %

Procedure:
(The following is performed in a draft chamber.) A mixture of concentrated sulfuric acid (1.5 ml), water (10 ml), and glacial acetic acid (50 ml) was dropped for about 10 minutes into a suspension of 7-butoxy-3-[2-(trans-4-propylcyclohexyl)ethyl]-1,2-difluoronaphthalene(21.4 g, 0.053 mol), periodic acid dihydrate (2.6 g, 0.011 mol), and iodine (5.4 g, 0.021 mol) in glacial acetic acid (100 ml) with vigorously stirring. After stirring at 60° C. for 4 hours, the reaction liquid was cooled, poured into water, and the reaction was terminated. The precipitated solid was dissolved with toluene, the organic layer was separated, and was extracted with toluene from the aqueous layer. After collecting organic layers, it was rinsed, in order, with 10% sodium thiosulfate aqueous solution, with saturated sodium hydrogen carbonate aqueous solution, and with saturated brine, and was dried with anhydrous sodium sulfate. A light yellow solid (21.4 g) was obtained by removing the solvent under reduced pressure and by recrystallizing the obtained orange solid (from acetone). (Yield 73.9%)
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:48][C:49]1[CH:69]=[CH:68][C:52]([CH2:53][N:54]2[CH:59]=[C:58]([C:60]([O:62][CH3:63])=[O:61])[C:57](=[O:64])[C:56]([C:65](O)=[O:66])=[CH:55]2)=[CH:51][CH:50]=1>ClCCl.CN(C=O)C.C(OCC)(=O)C.O>[F:48][C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]2[CH:55]=[C:56]([C:65]([N:6]3[CH2:7][CH:4]([O:3][CH3:2])[CH2:5]3)=[O:66])[C:57](=[O:64])[C:58]([C:60]([O:62][CH3:63])=[O:61])=[CH:59]2)=[CH:68][CH:69]=1
Reactant: COC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)O)c1=O
Reactant: COC1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)N2CC(OC)C2)c1=O
Reaction time: 7 h
Yield: 46.7 %

Procedure:
3-Methoxyazetidine hydrochloride (67 mg), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (206 mg) and triethylamine (100 μl) were added to a solution of the compound obtained in Step 2 of Example 26 (110 mg) in dichloromethane/DMF (2.0/0.5 ml) at room temperature, and the mixture was stirred for seven hours. After adding a small amount of water, the mixture was diluted with ethyl acetate, followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->20:1 (v/v)] to give 63 mg of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]([CH2:31][CH3:32])[C:8](=[O:30])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:31][CH3:32])[C:8](=[O:30])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:13][CH:12]=2)=[CH:33][CH:34]=1
Reactant: CCN(Cc1ccc(Cl)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 88.7 %

Procedure:
Methyl 2-{[2-(4-{2-[(4-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-ethyl]thio}benzoate (0.085 g, 0.170 mmol) was dissolved in a mixture of acetonitrile/water (1/1, 4 ml) and lithium hydroxide (0.008 g, 0.341 mmol) was added. The reaction was performed in an single node microwave oven (5 min. 150 deg). The solvent was removed by evaporation and then HCl (2 ml, 1 M) was added. The water phase was extracted with two portions of EtOAc (20 ml). The combined organic phase was dried (MgSO4) and the solvent was removed by evaporation and gave 0.073 g of 2-{[2-(4-{2-[(4-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoic acid (yield 88.4%) as an oil which solidified on cooling and standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]1[C:33]([CH3:41])=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1>>[F:31][C:32]1[C:33]([CH3:41])=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:36]
Reactant: Cc1c(F)cccc1C(=O)Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: Cc1c(F)cccc1C(=O)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1

Procedure:
In a manner analogous to Example 66, 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 3-fluoro-2-methylbenzoyl chloride are used to prepare the title compound. HRMS calcd for C31H22F2N6O: 532.1823, found: 533.1921 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Reaction time: 2 h

Procedure:
18 g (62.6 mmol) of 6-bromo-4-chloro-3-nitro-quinoline (Example 1c) and 11 g (68.9 mmol) of (2-(4-amino-phenyl)-2-methyl-propionitrile (Example 1e) are dissolved in 350 ml of acetic acid and stirred for 2 h. After this time, water is added and the yellow precipitate is filtered off and washed with H2O. The solid is dissolved in EtOAc-THF (1:1), washed with sat. aqueous NaHCO3 and dried over MgSO4. The organic phase is evaporated to dryness to give the title compound as a yellow solid. ES-MS: 411, 413 (M+H)+, Br pattern; analytical HPLC: tret=3.69 min (Grad 1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[OH:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[OH:26])=[C:11]([C:41]3[CH2:42][CH2:43][O:38][CH2:39][CH:40]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-yl)(4-(trifluoromethyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>ClC(Cl)C>[CH2:17]([O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[NH:9])[CH3:18]
Reactant: NC(=O)c1ccc(Br)s1
Reactant: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Product: CCOC(=N)c1ccc(Br)s1
Temperature: 90 °C

Procedure:
The 5-bromo-thiophene 2-carboxylic acid amide (2BW) (7 g, 34.1 mmols) was dissolved in dichloroethane (170 ml). Triethyloxonium hexafluorophosphate (10.16 g, 40.97 mmols) was added and the resulting mixture was refluxed for 1 hr at 90° C. The reaction mixture was concentrated under reduced pressure, and was taken directly to next step.
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][NH:15]C(=O)C(F)(F)F)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:28]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][NH2:15])[N:10]=[CH:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
To a solution of the product from Step A (48.8 g, 109 mmol) in 1L of methanol was added 1M sodium hydroxide solution (325 mL, 325 mmol). Over the course of four days, additional methanol (3 L) and sodium hydroxide solution (325 mL, 325 mmol) were added. The solution was concentrated in vacuo, and partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][CH3:30])[N:23]=2)=[CH:19]\[CH2:20][NH2:21])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].Cl>N1C=CC=CC=1>[C:8]([C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][CH3:30])[N:23]=2)=[CH:19]\[CH2:20][NH:21][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1nc(/C(=C/CN)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1nc(/C(=C/CNC(C)=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic anhydride (21 μL) was added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-amine in pyridine (1 mL), and the mixture was stirred at room temperature for 1.5 hours. 1 M hydrochloric acid was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to give N-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]acetamide as a pale yellow amorphous (50 mg, 67% (two steps)).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 29.2 %

Procedure:
A mixture of 0.50 g (3.2 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13, Step A), 2.37 g (16.0 mmol) of 2,5-dichloropyridine, 0.85 g (8.0 mmol) of sodium carbonate and 35 mL of isoamyl alcohol was refluxed for 48 h. The hot solution was filtered and the filtrate evaporated. Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.25 g (29%) of the title compound. 13C NMR (CDCl3): δ 31.1, 37.3, 44.7, 49.7, 51.2, 57.2, 62.5, 66.9, 107.9, 119.9, 137.1, 146.1, 157.6. m/z (MH+) 268.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]2[O:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]2[O:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C=Cc2cc3cnccc3o2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCc2cc3cnccc3o2)CC1
Reaction time: 16 h

Procedure:
LiHMDS (5.9 mL of a 1.0 M solution in THF, 5.90 mmol) was added dropwise to a stirred suspension of furo[3,2-c]pyridin-2-ylmethyltriphenylphosphonium bromide hydrochloride (Preparation 6, 1.50 g, 2.94 mmol) in anhydrous THF (25 mL) at 0° C. After 45 min, the mixture was treated with 4-formylpiperidine-1-carboxylic acid tert-butyl ester (0.63 g, 2.94 mmol), before being stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (300 mL), before being washed with H2O (2×100 mL) and dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 1:1) furnished 4-(2-furo[3,2-c]pyridin-2-ylvinyl)piperidine-1-carboxylic acid tert-butyl ester: m/z (ES+)=329.1 [M+H]+. This alkene (830 mg, 2.53 mmol) was dissolved in EtOH (15 mL), then Pd (10% on C, 83 mg, 0.08 mmol) was added. The reaction was stirred under a H2 atmosphere for 16 h, before being filtered through celite. The celite was washed with MeOH, then the combined solutions were concentrated to provide the title compound: RT=2.86 min; m/z (ES+)=331.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][OH:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)C[C@H]2C[C@H]21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To an ice-cooled solution of (1R,3S,5R)-3-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.480 g, 2.15 mmol) in pyridine (5 mL) was added 4-toluenesulfonyl chloride (0.490 g, 2.58 mmol). The reaction mixture was stirred at RT for 6 h and then diluted with Et2O. The organic phase was washed with 1N HCl (3×), aqueous NaHCO3 (3×) and NaCl, then dried (phase separator) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent gradient: c-hexane to c-hexane/EtOAc 4:1) to afford the title compound as a colorless wax. TLC, Rf (c-hexane/EtOAc 4:1)=0.2. MS (LC-MS): 390.0 [M+Na]+, 757.0 [2M+H]+. tR (HPLC conditions k): 4.07 min.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[O:13][C:14]([CH3:17])=[CH:15][N:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:18]>O1CCOCC1>[ClH:18].[NH:8]1[CH2:11][CH:10]([C:12]2[O:13][C:14]([CH3:17])=[CH:15][N:16]=2)[CH2:9]1.[ClH:18]
Reactant: Cc1cnc(C2CN(C(=O)OC(C)(C)C)C2)o1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc(C2CNC2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 57 mg (0.24 mmol) 3-(5-methyl-oxazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL (8 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated to give the desired product as a HCl salt, which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])[CH:34]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:44][O:43][CH2:42][CH2:41][N:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[C:32]([NH:31][C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([NH:23][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]3)[CH:15]=2)[CH:25]=1)=[O:45])[CH3:40]
Reactant: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Product: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(OC4CCN(C(=O)OC(C)(C)C)C4)c3)c2)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-[N-(2-methoxyethyl)-N-methylamino]benzamide to give N-(5-{3-[-(2-methoxyethyl)-N-methylamino]benzamido}-2-methylphenyl)-3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamide in 59% yield; NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 2.08 (m, 2H), 2.18 (s, 3H), 2.96 (s, 3H), 3.22 (s, 3H),3.25 (m, 2H), 3.52 (m, 6H), 5.07 (s, 1H), 6.87 (d, 1H), 7.2 (m, 5H), 7.43 (t, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 9.86 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M-C3H7+ 547.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][CH3:14])[CH:7]=[CH:6]2)#[N:2].[CH2:15]([Sn:19]([N:28]=[N+:29]=[N-:30])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]3[N:28]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[N:29]=[N:30][N:2]=3)[CH:4]=2)[N:9]=1
Reactant: COc1ccc2cc(C#N)ccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: CCCC[Sn](CCCC)(CCCC)n1nnnc1-c1ccc2nc(OC)ccc2c1

Procedure:
6-Cyano-2-methoxyquinoline (0.368 g) and tri-n-butyltin azide (0.73 g) were heated together at 110° for 18 hours to afford 2-methoxy-6-(1-tributylstannyl-(1H)-tetrazol-5-yl)quinoline as a crude oil which was not purified further but was used directly in the preparation of 6-(tetrazol-5-yl)-2-(1H)-quinolone (see Example 43).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[CH2:4][CH2:5][C:6]=1[O:7][CH3:8].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH3:8][O:7][C:6]1[CH2:5][CH2:4][C:3](=[O:9])[C:2]=1[C:12]1[C:13]([CH3:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: COC1=C(Br)C(=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a suspension of 2-bromo-3-methoxy-cyclopent-2-enone (32.3 g 169 mmol), 2,4,6-trimethylphenyl boronic acid (29.5 g, 180 mmol) and freshly ground potassium phosphate (63.7 g) in degassed toluene (800 ml) under N2 is added Pd(OAc)2 (896 mg, 8 mmol) and S-Phos (1.64 g, 4 mmol), and the reaction heated to 90° C. with stirring under N2 overnight. The reaction is partitioned between ethyl acetate (500 ml) and water (500 ml), and the organic layer is removed and the aqueous phase is extracted with ethyl acetate (2×300 ml). The combined organic extracts are evaporated under reduced pressure and the residue is purified to give 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (30.7 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]3[CH2:37][CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]([OH:43])[CH2:40][CH2:41][OH:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:42][CH2:41][CH2:40][CH2:39][OH:43])[N:18]=[C:17]([N:31]3[CH2:37][CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCCN(C)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCCN(C)CC2)nc1OCCCO

Procedure:
The procedure described in Synthesis Example 3 was repeated by use of 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-methylhomopiperazinyl)-4-pyrimidinyl]benzenesulfonamide and 1,3-propanediol, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C1C(=O)N([Br:32])C(=O)C1>>[Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[C:18]=3[Br:32])[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)cc(OC)c1OC
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC

Procedure:
Bromination of 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine) with NBS (1.5 equivalents) was done following the general procedure 3 to give the title compound: HPLC RT was 6.541 min. 1HNMR (CDCl3): δ 6.52 (s, 1H), 5.74(s, 2H), 5.46 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][CH:21]1[C:26]([F:28])(I)[CH:25]=[CH:24][CH:23]=[CH:22]1>>[C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[C:26]([F:28])[CH:25]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ncc(C#C[Si](C)(C)C)cn2n1
Reactant: FC1C=CC=CC1(F)I
Product: CC(C)(C)c1nc2ncc(C#Cc3ccc(F)c(F)c3)cn2n1

Procedure:
The title compound, a light yellow solid, MS: m/e=313.1 (M+H+), can be prepared in accordance with the general method of example 43, step 2 from 2-tert-butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) and 3,4-difluoro-4-iodobenzene.
Reaction SMILES: O[CH:2]=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6]CC)=O.[NH:15]([C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16].[OH-].[Na+].Cl>C(O)C.O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[N:15]1[C:4](=[O:6])[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:2][NH:16]1
Reactant: NNc1ncccn1
Reactant: CCOC(=O)C(=CO)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1c(-c2ccccc2)c[nH]n1-c1ncccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
19.2 g (0.1 mol) of ethyl α-hydroxymethylene-phenylacetate and 11 g (0.1 mol) of 2-hydrazino-pyrimidine in 150 ml of ethanol are boiled under reflux for 3 hours. The mixture is cooled to room temperature, and 9 g (0.1 mol) of concentrated sodium hydroxide solution are then added dropwise, while stirring. Stirring is then continued for 2 hours at room temperature, and the mixture is then boiled under reflux for 2 hours. The mixture is neutralized with concentrated hydrochloric acid, and diluted with 1 l of water. The precipitated crystals are filtered off under suction and dried in the air. 15 g (63% of theory) of 1-pyrimid-2-yl-4-phenyl-pyrazolin-5-one of melting point 159° to 160° C. (from ethanol) are obtained.