Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11][C:10]=1[C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:28]([O:35][CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:28]([O:35][CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C:25]([C:10]1[NH:11][C:12]([CH2:16][C:17]2[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:23])=[N:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: O=C(O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Reaction time: 0.67 h
Yield: 56.9 %

Procedure:
5-(Benzyloxy)-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (62) (0.2 g, 494 μmol, Eq: 1.00) and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-2-amine (118 mg, 543 μmol, Eq: 1.1) were dissolved in pyridine (3 ml) and cooled in an ice/NaCl bath. POCl3 (227 mg, 138 μl, 1.48 mmol, Eq: 3) was added dropwise. After the addition was complete, stirring of the reaction mixture was continued at 0° C. for approx. 40 minutes. The reaction mixture was quenched with ice and extracted twice with ethyl acetate. The organic layers were washed with NaHCO3, were combined, dried over Na2SO4, filtered and concentrated. The remaining oil was purified by SiO2 flash chromatography (24 g SiO2, hexanes/ethyl acetate 0-50% ethyl acetate). Product containing fractions were combined and concentrated. The remaining oil was treated with hexanes and concentrated again to afford 5-benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (63) (0.17 g, 281 μmol, 57.0% yield) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:33]=[CH:34][CH:35]=3)[O:27][C:28]=2[CH3:29])=[CH:17][CH:16]=1)([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[C:32]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[O:27][C:28]([CH3:29])=[C:24]([CH2:23][CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][C:5]([CH3:13])([CH2:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:4]([OH:42])=[O:3])=[CH:16][CH:17]=3)[N:25]=2)[CH:31]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-3-phenyl-propionic acid ethyl ester (24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-3-phenyl-propionic acid as colorless needles after drying at 50° C. under vacuum for 6 h: 1H NMR (400 MHz, CDCl3) δ8.23-8.21 (m, 1H), 7.94 (d, 1H, J=7.43 Hz), 7.65 (dd, 3H, J=7.04 Hz, J=1.17 Hz), 7.50 (t, 1H, J=7.63 Hz), 7.45 (t, 2H, J=7.04 Hz), 7.38-7.28 (m, 1H), 7.28-7.25 (m, 5H), 6.84 (d, 2H, J=8.99 Hz), 6.75 (d, 2H, J=8.99 Hz), 4.16 (t, 2H, J=6.45 Hz), 3.31 (d, 1H, J=13.69 Hz), 3.14 (d, 1H, J=13.69 Hz). 3.01 (t, 2H, J=6.45 Hz), 2.40 (s, 3H), 1.34 (s, 3H); HRMS (ES+) m/z exact mass calculated for C34H32NO5 534.2280, found 534.2278.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:9][CH2:10][S:11](Br)(=[O:13])=[O:12]>C(Cl)Cl>[Br:9][CH2:10][S:11]([CH:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: C=C1CCCCCC1
Reactant: O=S(=O)(Br)CBr
Solvent: ClCCl
Product: O=S(=O)(C=C1CCCCCC1)CBr
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of methylenecycloheptane (3.3 g) and bromomethanesulfonyl bromide (7.14 g) in methylene chloride (10 mL) was irradiated at -20° C. with an ultraviolet lamp for 1 hour. Evaporation of the solvent gave a solid which was washed with pentane. This solid (9.7 g) was dissolved in methylene chloride (150 mL), chilled in ice and treated dropwise with a solution of triethylamine (3.3 g) in methylene chloride (20 mL). The reaction mixture was stirred for 0.5 hours, washed with dilute HCl and water. The organic layer was separated, dried over anhydrous magnesium sulfate and the methylene chloride removed in vacuo to give oily bromomethanesulfonylmethylene cycloheptane (7.0 g, 96% yield) which was characterized by IR and NMR spectroscopy.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)CCCC>[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCO
Product: NC1CCCCNC1=O
Temperature: 137 °C

Procedure:
30 mmols of L-lysine hydrochloride 1 is neutralized with 30 mmols of NaOH and then 270 mmols of Al2O3 is added, followed by 120 ml of 1-pentanol. This mixture is heated to 137° C. and is refluxed for hours. The yield of α-amino-ε-caprolactam 2 produced by this reaction is about 96%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>ClCCl>[C:16]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@@H](C)C(=O)OC

Procedure:
L-Alanine methyl ester hydrochloride salt (14 g, 0.1 mol) was dissolved in dichloromethane (150 mL) and treated with triethylamine (30.45 g, 0.3 mmol). The solution was stirred and propionyl chloride added dropwise. After stirring overnight the mixture was quenched by addition of 1 M hydrochloric acid (200 mL) and the organic layer separated. The aqueous layer was re-extracted with dichloromethane (3×200 mL) and the combined organic layers were dried with magnesium sulfate, filtered and evaporated to a to a clear oil (16.0 g, quant.).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[OH:20]>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Cc1ccc(O)c(C)c1
Product: Cc1ccc(OCc2ncccc2[N+](=O)[O-])c(C)c1
Yield: 78 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2,4-dimethylphenol, the titled compound was obtained as yellow solid. (Yield: 78%)
Reaction SMILES: C(O)(=O)C.[C:5]([OH:16])(=[O:15])[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.[N+:17]([O-])([OH:19])=[O:18]>O>[OH:12][C:11]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:5]([OH:16])=[O:15])=[CH:14][C:13]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)ccc1O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reaction time: 4 h

Procedure:
A reactor was charged with 525 kg of glacial acetic acid and 50 kg vanillic acid. The mixture was heated with warm water gradually to 50° C. in around 75 minutes. Temperature was set to 16° C. Nitric acid, 31.4 kg was then added gradually over a period of 3 hrs. When the administration was complete the mixture was allowed to stir for additional 3.5-4.5 hours.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:16]([C:18]1[CH:26]=[C:25]([F:27])[C:21]([C:22](Cl)=[O:23])=[C:20]([F:28])[CH:19]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[C:20]([F:28])[C:21]([C:22]([C:3]2[C:4]3[C:5](=[C:6]([NH:10][C:11]([CH:13]4[CH2:14][CH2:15]4)=[O:12])[N:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:23])=[C:25]([F:27])[CH:26]=1)#[N:17]
Reactant: N#Cc1cc(F)c(C(=O)Cl)c(F)c1
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Product: N#Cc1cc(F)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(F)c1

Procedure:
N-[3-(4-Cyano-2,6-difluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropane carboxamide (Compound No. 51) was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide and 4-cyano-2,6-difluorobenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:26])[F:25])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.CCOCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:25])[F:26])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(Br)ccc1OC(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (3.60 g, 0.025 mol) in anhydrous 1,2-dimethoxyethane (8 ml) is added sodium methoxide (1.51 g, 0.028 mol) in one portion. After stirring at this temperature for 5 minutes a solution of 5-bromo-2-difluoromethoxy-benzaldehyde (5.66 g, 0.023 mol) in 1,2-dimethoxyethane (8 ml) is added dropwise over 10 mins, followed by stirring at 0° C. for a further 1 hour. After warming to room temperature the reaction mixture is diluted with ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulfate and evaporated in vacuo to afford 4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (8.89 g) as an orange oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][NH:11][CH3:12].CC1OCCC1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl>O>[CH2:25]([O:24][C:22](=[O:23])[N:11]([CH2:10][CH:9]([O:13][CH3:14])[O:8][CH3:7])[CH3:12])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CNCC(OC)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: COC(CN(C)C(=O)OCc1ccccc1)OC
Temperature: 5 °C

Procedure:
K2CO3 (8.4 kg, 60 mol, 1.8 eq.) and H2O (49.3 kg, 2.6 volumes) were placed in the reaction vessel and stirred. N-methylaminoacetaldehyde dimethylacetal (6.5 kg, 54 mol, 1.6 eq) and MeTHF (20.2 kg, 2.9 volumes) were added. The resulting mixture was cooled to 5° C. Benzyl chloroformate (6.8 kg, 37.6 mol, 1.1 eq.) was added over a period of about 30 minutes, while maintaining the temperature below 10° C. The feed line was rinsed with MeTHF (4.3 kg). The mixture was then maintained at 5° C. and stirred for 1 hour. The layers were separated and the organic layer was washed with 1N HCl (14.3 kg, 11.7 mol, 1.4 volumes) and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:6]=1[Cl:7]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1ncn(Cc2ccc3ccccc3c2)c1Cl
Temperature: 85 °C
Yield: 89.6 %

Procedure:
4,5-dichloroimidazole (40.0 mmol, 5.479 g) and KOH (44.0 mmol, 2.469 g) were placed in a round bottom flask with 100 mL acetonitrile. The mixture was brought to reflux (85° C.) and stirred 1 h until KOH was consumed. 2-Bromomethylnapthalene (40.00 mmol, 8.844 g) was added and the solution was stirred at reflux for 17 hours. KBr was removed by vacuum filtration and the filtrate was collected. The volatiles were removed by rotary evaporation to give 4,5-dichloro-1-(naphthalen-2-ylmethyl)-1H-imidazole as a light brown solid. 4,5-dichloro-1-(naphthalen-2-ylmethyl)-1H-imidazole (18 mmol) was dissolved in acetonitrile (40 mL) in a round bottom flask. The solution was brought to reflux and iodomethane (5 mL) was added. The reaction was stirred at reflux for 20 h after which time it was cooled. The resulting white precipitate was collected by filtration and analyzed. Yield: 89.6% 1H NMR (300 MHz, d6-DMSO): δ 3.86 (s), 5.68 (s), 7.53-7.59 (m), 7.93-8.03 (m), 9.51 (s) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2c(F)cccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1CCc2c(F)cccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step F by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.36 (s,6H), 1.43 (s,9H), 1.91 (m,1H), 2.4-2.8 (m,3H), 3.18 (m,2H), 4.54 (m,1H), 5.18 (br s,1H), 6.66 (d,7 Hz,1H), 6.81 (d,8 Hz,1H), 6.94 (t,8 Hz,1H), 7.18 (m,1H), 7.71 (br s,1H). FAB-MS: calculated for C20H28FN3O4 393; found 394 (M+H,26%).
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1.C(O)(C(F)(F)F)=[O:28].N>C(Cl)Cl.C(Cl)(Cl)Cl>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N+:17]([O-:28])=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5][O:4][CH3:3])[CH3:26])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: COCCN(C)CCCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COCCN(C)CCCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 4.7 %

Procedure:
H2O2 (70%, 3.0 mL, ca. 60.4 mmol) was added dropwise to a stirred solution of TFM (8.4 mL, 60.4 mmol) in DCM (80 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., and added to a solution of 1-oxide 52 (2.0 g, 6.04 mmol) and TFA (1.0 mL, 13.0 mmol) in CHCl3 (80 mL) at 0° C. and the solution stirred at 20° C. for 18 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-18%) of MeOH/DCM, to give 1,4-dioxide 53 (99 mg, 5%) as a red solid: mp 77-79° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.26 (br s, 1H, NH), 3.66 (t, J=6.3 Hz, 2H, CH2), 3.59 (t, J=5.6 Hz, 2H, CH2), 3.36 (s, 3H, OCH3), 3.03-3.12 (m, 4H, H-6, H-8), 2.66-2.71 (m, 4H, 2×CH2), 2.39 (s, 3H, NCH3), 2.19 (p, J=7.4 Hz, 2H, H-7), 1.91 (p, J=6.6 Hz, 2H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.5, 58.9, 56.8, 55.9, 42.5, 40.5, 33.4, 32.4, 25.9, 25.6; HRMS (FAB+) calcd for C17H26N5O3 (MH+) m/z 348.2036, found 348.2032.
Reaction SMILES: O1C=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1>>[C:14]([C:13]1[S:9][CH:10]=[C:11]([C:14]([O:16][C:3]([CH3:2])([CH3:4])[CH3:6])=[O:15])[CH:12]=1)(=[O:15])[CH2:11][CH3:10]
Reactant: O=C(O)c1ccoc1
Reactant: O=C(O)c1ccsc1
Product: CCC(=O)c1cc(C(=O)OC(C)(C)C)cs1

Procedure:
Instead of the starting material compound of Reference Example 104, that is, 3-furan carboxylic acid, 3-thiophencarboxylic acid was used for the similar procedure as in Reference Example 104 to obtain tert-butyl 5-propionyl-3-thiophencarboxylate.
Reaction SMILES: S(=O)(=O)(O)O.C(C1[O:11][C:12]2[C:18]([S:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)(=[O:21])=[O:20])=[C:17]([Cl:29])[CH:16]=[CH:15][C:13]=2[N:14]=1)(C)(C)C>O.O1CCOCC1>[NH2:14][C:13]1[C:12]([OH:11])=[C:18]([S:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])[C:17]([Cl:29])=[CH:16][CH:15]=1
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Yield: 65.4 %

Procedure:
4.27 ml (0.08 mol; 1.20 V) of sulfuric acid diluted in 4.3 ml of water were added dropwise to 3.56 g of 2-tert-butyl-6-chloro-7-(4-methylpiperazine-1-sulfonyl)benzooxazole (0.01 mol; 1.0 eq) in solution in 15 ml of 1,4-dioxane. The reaction medium was refluxed for six and a half hours. The reaction medium was concentrated and 1 N sodium hydroxide was added (to pH 7). The solution was extracted with dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed on silica gel, eluent 95/5 ethyl acetate/dichloromethane. 2.0 g of 6-amino-3-chloro-2-(4-methylpiperazine- 1-sulfonyl)phenol were obtained in the form of a thick brown oil. Yield=68%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].I[CH2:18][CH3:19]>>[CH2:18]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=1[CH3:9])[CH3:19]
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Reactant: CCI
Product: CCOCc1ccc(NC(=O)C(C)(C)C)nc1C

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.445 g, product of example 112 step B]) and iodoethane (0.34 g) as a light yellow oil (0.32 g). MS (ESI): 251.2 (MH+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:25]([Cl:26])=[CH:24][C:23]2[C:18](=[C:19]([CH2:27][N:28]([CH3:30])[CH3:29])[CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=O)C.O>C1COCC1>[Cl:26][C:25]1[C:16]([CH2:14][OH:13])=[CH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:27][N:28]([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cc2c(CN(C)C)cccc2cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc2cc(Cl)c(CO)cc12
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Diisobutylaluminium hydride (1 M in THF, 4.2 ml, 4.1 mmol, 9.0 equiv) was added to a solution of 3-chloro-8-dimethylaminomethyl-naphthalene-2-carboxylic acid ethyl ester (133 mg, 0.46 mmol) in 3.2 ml anhydrous THF at 0° C. After 15 minutes at 0° C., TLC analysis revealed complete conversion of starting material. Water (30 ml) was added, and the mixture was extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of CH2Cl2/MeOH 97:3 to 90:10) afforded the title compound (109 mg, 96%, mixture of 2 regioisomers) as a colorless oil. Data for (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-methanol: 1H NMR (400 MHz, CDCl3): δ=8.36 (s, 1H), 7.85 (s, 1H), 7.74 (dd, J=7.1/1.9 Hz, 1H), 7.44-7.39 (m, 2H), 4.94 (s, 2H), 4.06 (s, 2H), 2.45 (s, 6H). MS (ES+): 250 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]1([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: O=C(O)CC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC1CCCC1)OCc1ccccc1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A mixture of cyclopentylacetic acid (10.02 g, 78.2 mmol), benzyl alcohol (8.45 g, 78.2 mmol) and p-toluenesulfonic acid monohydrate (1.48 g, 7.82 mmol) in benzene (60 mL) was refluxed using a Dean-Stark water separator for 2h. After cooling, benzene was removed and the mixture was diluted with ether (50 mL) and washed successively with saturated NaHCO3 solution, saturated brine solution, dried and evaporated to give the compound (15.40 g) as an oil; 1H NMR (300 MHz, CDCl3)δ: 7.35(m, 5H), 5.10(s, 2H), 2.40(d, j=8 Hz, 2H), 2.26(m, 1H), 1.81 (m, 2H), 1.6 (m, 4H), 1.18(m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:24])=[N:13][N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=1>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:24][C:1](=[O:5])[CH2:2][CH:3]=[CH2:4])=[N:13][N:14]2[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(Cl)cc21
Reactant: C/C=C/C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(=O)Nc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ccc12
Temperature: 19 °C
Reaction time: 16 h

Procedure:
0.45 cm3 of predistilled crotonyl chloride is added to 1 g of 6-chloro-1-[(1,1-dimethylethoxy)carbonyl]-1H-indazole-3-amine described previously, in 40 cm3 of dichloromethane and 1.05 cm3 of triethylamine. The mixture is stirred at about 19° C. for 16 hours. The medium is then concentrated under reduced pressure (20 kPa; 40° C.). The residue is taken up in 100 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is then washed with 50 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under the conditions already described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 45° C.), 120 mg of N-(6-chloro-1-[(1,1-dimethylethoxy)carbonyl]-1H-indazol-3-yl)-3-butenamide are obtained in the form of a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[C:15]([F:29])[C:16]([CH3:28])=[C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=3)[CH:18]=2)=[O:12])[CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[C:15]([F:29])[C:16]([CH3:28])=[C:17]([C:19]3[N:20]=[CH:21][C:22]([C:23]([NH:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4])=[O:25])=[CH:26][CH:27]=3)[CH:18]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
Reactant: CCC(N)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminopentane (147 μl) in DMF (8 ml) was added to a mixture of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid (Intermediate 8, 200 mg), HATU (228 mg) and DIPEA (348 μl) in DMF (8 ml) and the reaction stirred for 18 hours at room temperature. The DMF was evaporated under vacuum and the residue dissolved in ethyl acetate and applied to an SCX SPE (10 g). The SPE was washed with ethyl acetate then methanol/ethylacetate (1:9) and the product elutes with 0.880 ammonia/methanol/ethyl acetate (1:1:8). The product fraction was reduced to dryness under vacuum and purified on a silica SPE (500 mg) eluting with an ethyl acetate/cyclohexane gradient to give after evaporation of the solvents 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide.