Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11](OC)(=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].N1CCCCC1>CO>[CH3:1][N:2]1[C:3]2[C:4](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]1=[O:17]
Reactant: CNc1ncccc1C=O
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1cc2cccnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 83.2 %

Procedure:
8.66 g (64.5 mmol) of 2-(methylamino)nicotinaldehyde was dissolved in methanol (100 mL), and 12.68 g (96.0 mmol) of dimethyl malonate and 2.18 g (25.6 mmol) of piperidine were added to the solution. The resulting mixture was stirred for 7 hours at 80° C. The mixture was cooled, and a solid precipitated therefrom was separated by filtration. The solid was washed with diisopropyl ether, and thus 11.71 g (yield: 84%) of the title compound was obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13](O)(=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>ClCCl>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: COC(=O)c1cc(N)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (0.27 g, 1.6 mmol) in dichloromethane (10 mL) was added arachidonic acid (0.5 g, 1.6 mmol), EDCI (0.32 g, 1.7 mmol) and dimethylaminopyridine (0.020 g, 0.2 mmol). The reaction was stirred (RT, 2 h), and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with 1 N HCl, water, saturated aqueous NaHCO3 and water, and then dried over MgSO4. The crude product was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.6 g of methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate as a brown oil. Mass calculated for C28H39NO4=453.61. found: [M+H]+=454.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:9][C:8]=12.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:10][N:9]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[C:8]=12
Reactant: COc1nccc2c(-c3ccccc3)n[nH]c12
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc2c(-c3ccccc3)nn(Cc3ccc(S(N)(=O)=O)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
To a solution of 7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridine (193 mg) obtained in Step C of Example 10 in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. 4-(Bromomethyl)benzenesulfonamide (220 mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 3 days, and then overnight at 60° C. Sodium hydride (60% dispersion in mineral oil, 70 mg) and 4-(bromomethyl)benzenesulfonamide (220 mg) were added thereto, and the mixture was stirred at 60° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (173 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[C:18](=[O:20])=[O:19].[OH-].[Na+]>C1COCC1.C(OCC)C>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]([OH:20])=[O:19])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc2ccnc(Cl)c2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a suspension of 7-bromo-1-chloroisoquinoline (2.000 g, 8.247 mmoles) in THF (12 mL) and diethyl ether (12 mL) cooled down to −78° C. was added n-BuLi (3.96 mL, 9.9 mmol, 2.5M in hexanes). Stirred for five minutes and then bubbled carbon dioxide while venting with a needle for approximately one minute. The reaction mixture was warmed up to 0° C. and 15 mL of a 1N aqueous sodium hydroxide were added. The mixture was diluted with diethyl ether stirred for 18 h. The organic and aqueous layers were separated and the organics were washed with 1N aqueous sodium hydroxide and water. The aqueous fractions were combined and acidified to pH 4 with 1N aqueous hydrochloric acid. The resulting solids were collected by filtration and dried to give the title compound (1.252 g, 73%). +ESI (M+H) 208.1 1H NMR (400 MHz, DMSO-d6) d ppm 13.58 (br. s., 1H) 8.86 (m, 1H) 8.43 (d, J=5.67 Hz, 1H) 8.33 (dd, J=8.61, 1.57 Hz, 1H) 8.19 (d, J=8.41 Hz, 1H) 8.01 (dd, 1H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[O:12]>CO>[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:1][N:2]([CH2:7][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:11]=1[OH:12])[CH3:3]
Reactant: C=O
Reactant: CNC
Solvent: Oc1ccccc1
Solvent: CO
Product: CN(C)Cc1ccccc1O
Temperature: 60 °C

Procedure:
0.45 kg of dimethylamine was passed, under normal pressure and at a reaction temperature of 20°-25° C., in the course of 5 hours into a mixture of 1.0 kg of phenol, 0.30 kg of paraformaldehyde and 3.1 kg of methanol and the reaction mixture was then warmed to 60° C. for 1 hour. After distilling off methanol and water in vacuo, 1.551 kg of a mixture which contained 0.242 kg of phenol, 0.605 kg of o-dimethylaminomethylphenol, 0.030 kg of p-dimethylaminomethylphenol, 0.302 kg of bis- and tris-dimethylaminomethylphenol and 0.392 kg of condensation and resinification products was obtained and 0.595 kg (49% of theory, relative to converted phenol), of o-dimethylaminomethylphenol could be obtained from this mixture.
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[Li]CCCC.[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21]CC)=O.[C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH3:28]>CC(OC)(C)C>[C:31]([O:30][C:27](=[O:29])[CH2:28][C:19]([C:18]1[CH:24]=[CH:25][CH:26]=[C:16]([Br:15])[CH:17]=1)=[O:21])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(Br)c1

Procedure:
Prepared from hexamethyldisilizane (16.5 mL, 79 mmol) and n-BuLi (48.4 mL, 77 mmol) in TBME (40 mL), then commercially available ethyl 3-bromobenzoate (7.55 g, 33 mmol) and tert-butyl acetate (4.86 mL, 36 mmol) in TBME (80 mL) according to the general procedure III. Obtained as a light yellow oil (9.934 g, 101%; 95% purity).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([CH:21]([F:23])[F:22])[C:18]([C:24]#[N:25])=[C:17](Cl)[N:16]=2)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[SH:28][CH2:29][C:30]([NH2:32])=[O:31]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[C:17]3[S:28][C:29]([C:30](=[O:31])[NH2:32])=[C:24]([NH2:25])[C:18]3=[C:19]([CH:21]([F:23])[F:22])[CH:20]=2)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CS
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2cc(C(F)F)c(C#N)c(Cl)n2)CC1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2cc(C(F)F)c3c(N)c(C(N)=O)sc3n2)CC1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
A suspension of (6′-chloro-5′-cyano-4′-difluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methyl-carbamic acid tert-butyl ester (1.1 g, 2.74 mmol) potassium carbonate (1.9 g, 13.7 mmol) in DMF (15 mL) was treated with 2-mercaptoacetamide (solution of 1 g, 11 mmol in 10 mL of methanol), and the reaction mixture was heated in a sealed tube at 80° C. overnight. The reaction mixture was then cooled to room temperature and filtered. The filtrate was treated with water (50 mL) and the resulting precipitate was collected by filtration to provide 1.03 g (82.4%) of [1-(3-amino-2-carbamoyl-4-difluoromethyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-yl]-methyl-carbamic acid tert-butyl ester as a tan solid.
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][NH2:24])=[O:22]>C(O)C.O.Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][N:24]=[C:14]([C:11]1[NH:12][CH:13]=[C:9]([C@@H:2]([OH:1])[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6])[N:10]=1)[CH3:15])=[O:22]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=NNC(=O)c1cccc(Cl)c1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (194 mg, 0.84 mmol) was suspended in ethanol (4 ml) and water (1 ml). 3-chlorobenzoic acid hydrazide (170 mg, 1.0 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as a ˜3:1 E:Z mixture, as a white solid: 108 mg (33%).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:48]1([CH3:57])[CH:53]=[CH:52][C:51]([C:54](Cl)=[O:55])=[CH:50][CH:49]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:25][C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39])[C:54](=[O:55])[C:51]1[CH:52]=[CH:53][C:48]([CH3:57])=[CH:49][CH:50]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NCC(=O)CCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CC(=O)CCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 42.8 %

Procedure:
A solution of 2-{4-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-3-oxo-butyl}-isoindole-1,3-dione (1.5 g from previous step), triethylamine (245 mg, 2.42 mmol), and p-toluoyl chloride (374 mg, 2,42 mmol) in methylene chloride (10 mL) was stirred at room temperature for 2.0 h. The reaction was washed sequentially with 0.5 N HCl, water, 5% NaHCO3, water, and brine and dried (Na2SO4). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel 3:2 hexanes:EtOAc as eluent) to provide the title compound as a white solid (0.7 g, 35%, 2 steps). MS(ES+) m/e 675 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[F:31][C:32]1[CH:37]=[C:36]([CH:38]=[O:39])[CH:35]=[CH:34][C:33]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:33]2[CH:34]=[CH:35][C:36]([CH:38]=[O:39])=[CH:37][C:32]=2[F:31])[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1ccc(B(O)O)c(F)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: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)cc2F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.62 mmol) and (2-fluoro-4-formylphenyl)boronic acid (158 mg, 0.94 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.26 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 91%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=[O:10])=[O:9].O[CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:54])[NH:31][C:32](=[O:53])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=3)[CH:35]=2)=[N:21]1.Cl>C1COCC1>[CH3:7][S:8]([O:11][CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:54])[NH:31][C:32](=[O:53])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=3)[CH:35]=2)=[N:21]1)(=[O:10])=[O:9]
Reactant: O=C1NC(=O)C(c2nn(CCCO)c3ccccc23)=C1c1cn(-c2ccc3ccccc3c2)c2ccccc12
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCn1nc(C2=C(c3cn(-c4ccc5ccccc5c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Following the procedure of Example 26, pyridine (0.7 g, 8.35 mmol) and methanesulfonic anhydride (1.09 g, 6.26 mmol) were added to Compound 84 (1.07 g, 2.09 mmol) (prepared in Example 24) in THF (20 mL). The mixture was heated at 50° C. for 2 h, then cooled to rt. Another portion of THF (10 mL) was added, followed by addition of 1N HCl (10 mL). The mixture was stirred for 15 min, then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1N HCl (10 mL), water (2×20 mL) and saturated NaCl (20 mL), then dried (Na2SO4) and evaporated in vacuo to obtain a 3-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione analog of Compound 26a (1.1 g, 92%) as a reddish solid. ES-MS m/z 591 (MH+).
Reaction SMILES: [ClH:1].[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[ClH:1].[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:9]2[CH2:10][CH2:11][C@H:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:8]2)=[O:24])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cc2ccccc2)cc1)N1CC[C@H](N2CCCC2)C1
Reaction time: 16 h

Procedure:
A mixture of the HCl salt of 3-(pyrrolidino)pyrrolidine (0.44 g, 2.1 mmol) and 4-benzyl benzoic acid (0.34 g, 1.6 mmol) CH2Cl2 is treated sequentially at room temperature with 0.85 mL of triethylamine and solid benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.2 g, 2.4 mmol), stirred for 16 h under nitrogen, diluted with CH2Cl2, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The concentrate is chromatographically purified. The purified material is treated with ethereal HCl to afford the title compound, identified by H1 NMR and mass spectral analyses.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[S:20][C:21]([C:24]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[O:25])=[CH:22][N:23]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:33][C:32]1[C:27]([NH:26][C:24]([C:21]2[S:20][C:19]([NH:18][C:13]3[CH:12]=[C:11]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[N:16]=[C:15]([CH3:17])[N:14]=3)=[N:23][CH:22]=2)=[O:25])=[C:28]([Cl:34])[CH:29]=[CH:30][CH:31]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
1-(2-hydroxyethyl)piperazine (Compound 3) (65 g, 0.5 mol), 2-(6-bromo-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-formamide (Compound 14) (43.9 g, 0.1 mol), n-butanol (670 mL) and DIPEA (28.3 g, 0.2 mol) were mixed in reaction flask and reacted by refluxing for 7 h. After the reactant was cooled down to room temperature, crystals precipitated overnight. After air pump filtration, the cake was rinsed with n-butanol (500 mL) by stirring for 30 min. Then filtrated and the cake was dried to give white solid target Compound 1 (42.9 g, yield: 87.9%).
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.CCN(CC)CC.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:18]([O:10][CH2:9][C:6]1[S:5][C:4]([Br:3])=[N:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cnc(Br)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cnc(Br)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-bromo-thiazol-5-yl)-methanol (621 mg, 3.20 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.60 mL, 4.23 mmol) followed by DMAP (39 mg, 0.32 mmol) and Ms-Cl (0.33 mL, 4.15 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-bromothiazol-5-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (15 mL) and treated with NaN3 (223 mg, 3.40 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer washed with water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-bromothiazole as a yellow oil. To a solution of the crude azide in THF (12 mL) were added polymer-supported Ph3P (1.2 eq.) and water (4 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 1N NaOH/aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.16 min; [M+CH3CN+H]+=233.91.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9](/[C:12](/[CH3:22])=[CH:13]/[C:14]3[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9](/[C:12](/[CH3:22])=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([CH:18]=[O:19])=[CH:20][CH:21]=3)[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: C/C(=C\c1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C/C(=C\c1ccc(C=O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
0.5 g of p-[(E)-2-(3,4-dihydro-4,4-dimethyl-1-benzopyran-6-yl)propenyl]benzyl alcohol was dissolved in 20 ml of methylene chloride and the solution is treated with 10 g of manganese dioxide. After stirring at room temperature for 6 hours, the solid material is filtered off, rinsed well with methylene chloride and the filtrate was evaporated. After recrystallization of the residue from hexane/ether, there are obtained 350 mg of p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)propenyl]benzaldehyde of melting point 102°-104° C.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.[CH3:14][C:15](N(C)C)=[O:16].Cl>CCOCC>[Br:6][C:7]1[N:8]=[CH:9][C:10]([C:15](=[O:16])[CH3:14])=[CH:11][CH:12]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
BuLi (32.8 ml of a 1.6 M solution in hexanes, 53 mmol) was added dropwise over 10 min to a stirred solution of 2,5-dibromopyridine (12.44 g, 52.5 mmol) in Et2O (600 ml) at −78° C. under nitrogen. The resulting suspension was stirred at −78° C. for 1 h and then heated with dimethylacetamide (5.86 ml, 63 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. 1N HCl (100 ml) was added and the organic layer separated. The aqueous layer was extracted with EtOAc (3×100 ml). The combined organic extracts were dried (MgSO4), concentrated under reduced pressure, then taken up in CH2Cl2 (200 ml) and dry loaded onto silica. Column chromatography on silica using 30-40% EtOAc/iso-hexane as eluent gave the ketone (6.0 g, 57%).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][CH2:10][CH:11]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=1[Cl:25])[CH3:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:14]=1[NH:13][CH:11]([CH3:12])[CH2:10][O:9][CH2:8][C:6]([OH:7])=[O:5])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccc(NC(C)COCC(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(C)COCC(=O)O)c(Cl)c1

Procedure:
Prepared analogously to Example 1g from ethyl 4-[2-(tert.-butoxycarbonylmethoxy)-1-methyl-ethylamino]-3-chloro-benzoate and trifluoroacetic acid in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>CO.C1COCC1.[Pd]>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1Cl
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)O)c(OC)c1Cl
Yield: 99 %

Procedure:
A suspension of 3a (12.57 g, 51.88 mmol) in a mixture of MeOH (50 ml) and THF (200 ml) was hydrogenated at 50 psi in the presence of 10% Pd/C (0.3 g) for 4 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated to afford 12.6 g (51.5 mmol, 99% yield) of analytically pure (HPLC, 1H NMR) 4a as a white solid. 1H NMR (DMSO-d6): δ 7.15 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 2.78 (t, J=7.5 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H).