Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.O[C:29]1([C:45]2[C:53]([OH:54])=[CH:52][C:48]3[O:49][CH2:50][O:51][C:47]=3[CH:46]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:30]1=[O:44]>>[OH:54][C:53]1[C:45]([CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:30]2=[O:44])=[CH:46][C:47]2[O:51][CH2:50][O:49][C:48]=2[CH:52]=1
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (84%) as a white powder: 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.19 (m, 1H), 7.01-6.90 (m, 3H), 6.43 (s, 2H), 5.84 (m, 2H), 4.86 (s, 1H), 4.56 (s, 2H), 4.13 (q, 2H), 1.18 (t, 3H); MS (ES+) m/z 378.2 (M+23).
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([CH2:5][O:4][CH:2]([CH3:1])[CH3:3])[CH2:11]3)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CC(C)OCC1CNCCN1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC(C)C)C3)cc21
Temperature: 80 °C
Yield: 107 %

Procedure:
A mixture of 2 g of 2-[(1-methylethoxy)methyl]piperazine, 1.27 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was heated at 80° C. for 3 hours, then evaporated in vacuo. The residue was reevaporated three times from toluene, giving a gum. Ether was added to the gum which solidified. The solid was triturated with ether containing methanol and then dried giving 2.1 g of solid. A 1 g portion was purified by chromatography, giving 650 mg of the desired product, mp 144°-146° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([S:20]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)(=[O:22])=[O:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH:25]1[CH2:26][CH:23]([S:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:11]([CH2:10][CH:7]4[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]4)[C:12]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[N:13][C:14]=3[CH:19]=2)(=[O:22])=[O:21])[CH2:24]1
Reactant: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CN(C(=O)OC(C)(C)C)C4)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CNC4)ccc32)CC1
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl 3-(1-((1-acetylpiperidin-4-yl)methyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)azetidine-1-carboxylate (STEP C, 220 mg, 0.402 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature. After stirring for 40 min, the mixture was concentrated. The residue was diluted with methanol (10 mL) and the solution was filtered through strong cationic exchange column (SCX). The column was washed with 1 mol/L ammonia in methanol (10 mL) to wash out the title compound (176 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:22]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=2[CH:24]=[O:25])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: O=[O+][O-].CO[C:6]([C:8]1[CH:12]=[C:11]([Br:13])[N:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)O)=[O:7].[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[C:29]([CH3:33])=[N:28]1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C=C(Cl)C(=O)N(CC2C=CC(OC)=CC=2)C=1.O(S(C)(=O)=O)S(C)(=O)=O>CCN(CC)CC>[Br:13][C:11]1[N:10]([CH:14]([CH3:16])[CH3:15])[C:9]2[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:32]([C:30]3[C:29]([CH3:33])=[N:28][N:27]([CH3:26])[CH:31]=3)[C:6](=[O:7])[C:8]=2[CH:12]=1
Reactant: Cc1nn(C)cc1N
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: COc1ccc(Cn2cc(N)cc(Cl)c2=O)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate O1 but in the step corresponding to Step O3, 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step D3) and 1,3-dimethyl-1H-pyrazol-4-ylamine (free base generated from the hydrochloride salt [1147222-02-3]) were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 5-amino-3-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one respectively. Moreover, in this step, the procedure described for Step L3 using Ms2O and Et3N was used. The title compound was obtained as a beige solid. tR: 1.18 min (HPLC 3); ESI-MS: tR=1.22 min, [M+H]+ 415/417 (LC-MS 1); TLC: Rf=0.24 (2:1 EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[CH:11]=1)(=[O:9])=[O:8].[Br:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1I.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)(C)C.O1CCOCC1>[Br:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]1[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=1[O:2][CH3:1])[C:29]1[S:33][N:32]=[CH:31][N:30]=1)(=[O:9])=[O:8])=[CH:11]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cccc3c2)c(OC)c1
Reactant: Clc1ccc(I)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4Br)cccc3c2)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A pressure vessel was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate E) (5.00 g, 8.81 mmol), 2-bromo-4-chloro-1-iodobenzene (5.59 g, 17.6 mmol) and Pd(dppf) Cl2 DCM (1.44 g, 1.76 mmol). Dioxane (44.1 mL) and t-butanol (44.1 mL) were added to the reaction vial followed by 1.9 M sodium carbonate in water (13.9 mL, 26.4 mmol). The reaction vial was then swept with nitrogen and sealed with a screw cap. The reaction mixture was stirred and sonicated for 5 min. The resulting light red mixture was then heated to 50° C. After 2 h, LC/MS indicated about 90% conversion of boronic ester to the desired product as [M+Na]+=652. The mixture was cooled to room temperature and filtered through a fritted funnel with EtOAc (150 mL). The filtrate was washed with brine. The organic layers were combined, dried with MgSO4, filtered and concentrated to afford a black oil. The mixture was purified by MPLC (300 g silica gel column eluting with 0 to 50% EtOAc:Heptane) to afford a white solid. MS (ESI): 651.8 [M+Na]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.64 (s, 3H), 3.66 (s, 3H), 5.18 (d, J=16 Hz, 1H), 5.24 (d, J=16 Hz, 1H), 6.31-6.41 (m, 2H), 6.95-7.04 (d, J=9 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.64 (d, J=6.1 Hz, 2H), 7.78-7.80 (m, 2H), 7.98 (d, J=2.25 Hz, 1H), 8.30 (d, J=9.4 Hz, 1H), 8.38 (s, 1H), 8.65 (m, 1H).
Reaction SMILES: [BH4-].[Na+].CO.[Cl:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[N:16]=[C:15]3[S:17][C:18]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:8][C:7]=1[NH:28]C(=O)C(F)(F)F>C(O)C.C(OCC)(=O)C>[NH2:28][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][C:6]=1[Cl:5])[O:10][C:11]1[N:16]=[C:15]2[S:17][C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])=[N:19][C:14]2=[CH:13][CH:12]=1
Reactant: O=C(Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Sodium borohydride (5.63 g, 149 mmol) was suspended in ethanol (100 mL), and methanol (66 mL) was slowly added. To the obtained reaction mixture was added N-(5-{4-chloro-3-[(trifluoroacetyl)amino]phenoxy}[1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (3.4 g, 7.44 mmol) powder in a small portions under cooling in a water bath, and then, the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (150 mL), and partitioned with water (200 mL), and the organic layer was concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with saturated brine (100 mL), the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0), and triturated with diisopropyl ether to give the title compound (2.00 g, 75%) as a white solid.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26]CCC)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].O.[C:32]1(C)C=CC(S(O)(=O)=O)=C[CH:33]=1>C(O)(=O)C>[CH3:26][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH:32]=[CH2:33])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30]
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=CC1CN(c2ncc(C(=O)N(C)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A mixture of 2.84 g (7 mmol) of the same compound II as in Example 70, 1.05 g of p-toluenesulfonic acid monohydrate and 5 ml of glacial acetic acid was stirred at 70° for 2 hours and then worked up as. in Example 5. 2.03 g (=71.5% yield) of pure 4-amino-2-(4-vinyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were obtained, melting point 203°-204°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:17].[Cl:19]OC(C)(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][C:10]1([Cl:19])[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:17]
Reactant: CC(C)(C)OCl
Reactant: COC(=O)CCCC#CCC1C(=O)CCCC1=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCC#CCC1(Cl)C(=O)CCCC1=O
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
7-(2,6-Dioxocyclohexyl)-5-heptynoic acid methyl ester (21.0 g), prepared as described in Example 13, is dissolved in chloroform (300 ml) cooled to 20° C and t-butyl hypochlorite (9.5 g) in chloroform (10 ml) is added to the well stirred solution over a period of 15 minutes. The mixture is stirred for another 30 minutes and allowed to warm up to room temperature. Removal of the solvent affords 7-(1-chloro-2,6-dioxocyclohexyl)-5-heptynoic acid methyl ester, γmaxFilm 1730, 1720.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH3:11])[CH2:5]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]([F:14])([F:13])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2
Reactant: CC1Cc2c(ccc(Br)c2C(F)(F)F)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2c(C(F)(F)F)c(Br)ccc2[nH]1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of 5-bromo-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indole (0.09 g, 0.320 mmol; step C above) in 1,4-dioxane (5 mL) at rt was added DDQ (0.110 g, 0.48 mmol) in one portion. After 1 h, the mixture was poured into water and extracted with Et2O (×3). Combined organics were washed (1 N NaOH, H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.056 g of the title compound as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.07 (bs, 1H), 7.36 (m, 1H), 7.25 (d, J=5.0 Hz, 1H), 6.47 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)[CH:7]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:23][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=2)=[CH:7][C:6]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[CH:12][CH:11]=1
Reactant: CCOCCOc1ccc(C(=O)Nc2cc(N)ccc2C)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCOc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)cc1
Yield: 19.2 %

Procedure:
A solution of N-(5-amino-2-methylphenyl)-4-(2-ethoxyethoxy)benzamide (0.141 g) and triethylamine (0.121 g) in methylene chloride (5 ml) was added to 3-trifluoromethylbenzoyl chloride (0.104 g) and the resultant mixture was stirred at ambient temperature for 18 hours. The mixture was washed in turn with a 1M aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and water. The organic solution was evaporated and the residue was triturated under a mixture of diethyl ether and ethyl acetate. The resultant solid was isolated and dried under vacuum. There was thus obtained the title compound (weight 0.042 g); Mass Spectrum: M+H+ 487.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=1>CN(C=O)C.C(Cl)Cl>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH2:13][CH2:12]2)=[O:16])[CH:19]=[N:20][CH:21]=1
Reactant: Nc1cncc(Br)c1
Reactant: CN1CCC(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)Nc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
Oxalyl chloride (8.67 mmol) followed by DMF (2drops) was added to a solution of 1-methyl piperidine-4-carboxylic acid (XLIII) (5.78 mmol) in DCM and stirred 30 min at room temperature under argon. The volatiles were evaporated under vacuum by avoiding contact with air. Pyridine was added to the residue followed by addition of 3-amino-5-bromopyridine (XL) (5.20 mmol). The solution was further stirred at room temperature for 3 h under argon. The pyridine was evaporated under vacuum. The residue was treated with water, basified by saturated NaHCO3 solution and washed with DCM. The aqueous layer was extracted with n-butanol. The combined organic layer was evaporated. The residue was dissolved in DCM with the addition of few drops of MeOH. The insoluble inorganic solids were filtered off. The filtrate was concentrated under vacuum to get N-(5-bromopyridin-3-yl)-1-methylpiperidine-4-carboxamide (XLIV) as a brown viscous liquid (0.74 g, 43% yield). 1H NMR (DMSO-d6) 1.61-1.69 (m, 2H), 1.77-1.79 (m, 2H), 1.93-1.97 (m, 2H), 2.20 (s, 3H), 2.29-2.35 (m, 1H), 2.84-2.87 (m, 2H), 8.36 (d, J=1.6 Hz, 1H), 8.39 (m, 1H), 8.66 (d, J=1.6 Hz, 1H), 10.33 (s, 1H); ESIMS found C12H16BrN3O m/z 299 (M+H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]([C:16]1[N+:21]([O-])=C(C)[CH:19]=[CH:18][CH:17]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:5]([O:4][CH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:21]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(=O)c2ccccc2)[n+]1[O-]
Product: CC(=O)OCc1cccc(C(=O)c2ccccc2)n1
Reaction time: 1 h

Procedure:
Acetic anhydride (6.6 ml) is heated to 115°, after which 6-benzoyl-2-methylpyridine N-oxide is added in portions over 1 hour. The mixture is then held at 115° for 1 hour after the addition. The reaction is poured onto ice and extracted with ether (3×). The combined ether phases are washed with sat. NaNCO3 (2×) and water until neutral, dried and stripped. The product is preparatory thin layer chromatographed, the least polar band giving 2-(acetoxymethyl)-6-benzoylpyridine.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][OH:34]>C(#N)C>[OH:34][CH2:33][CH2:32][N:5]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:9]2=[O:24])[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCO)S(C)(=O)=O)cc2C1=O
Temperature: 110 °C
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (1 g, 2.82 mmol) (prepared in an analogous manner as previously described in Example 34, Scheme 34, Steps 1, 2, 3) in acetonitrile (15 ml), K2CO3 (0.585 g, 4.23 mmol) and 2-bromoethanol (0.500 ml, 7.05 mmol) were added, and the reaction was heated under MW irradiation at 110° C. for 3 hours. The insoluble inorganic salts were filtered off, and the filtrate was evaporated to dryness. The resulting crude tert-butyl 2-(5-(N-(2-hydroxyethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (1.12 g, 2.81 mmol, 100% yield MS/ESI+ not detectable [MH]+) was used without further purification.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[CH2:10]=[C:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>C1COCC1.II>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:14]2([OH:17])[CH2:15][CH2:16][C:11](=[CH2:10])[CH2:12][CH2:13]2)=[CH:4][CH:5]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C=C1CCC(=O)CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a flask charged with dry, freshly ground magnesium turnings (1.1 g, 45 mmol) and iodine (25 mg, 0.1 mmol) in THF (50 mL) was added a solution of 1,4-dibromobenzene (10.6 g, 45.0 mmol) in THF (30 mL) slowly by dropping funnel over 30 min. The resulting mixture was stirred at rt for 1 hr. The resultant grey Grignard solution was cooled to −78° C. and to it was added a solution of 4-methylenecyclohexanone (3.3 g, 30 mmol) in THF (20 mL) slowly dropwise over 20 min. The reaction was stirred at −78° C. for 30 min before being allowed to stir and warm to rt for 3 h. The resulting reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography (80 g silica gel, 0-50% EtOAc:Hept, monitor for 225 nm) afforded 2.94 g of a colorless oil that was used without further purification. ESI-MS m/z: not ionized [M+H]+, retention time 1.50 min (condition E).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][NH:4][C:5]([CH2:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([N+:15]([O-])=O)[CH:9]=1)=[O:6]>O>[CH3:3][NH:4][C:5]([CH2:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([NH2:15])[CH:9]=1)=[O:6]
Reactant: CNC(=O)Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CNC(=O)Cc1ccc(N)c(N)c1

Procedure:
Reduced iron powder (9.87 g) and then a solution of ammonium chloride (0.373 g) in water (37 ml) were added to a solution of 4-methylcarbamoylmethyl-2-nitroaniline prepared as described in Example 8 (3.34 g) in industrial methylated spirit (186 ml). The mixture was heated under reflux for one hour and was then filtered through diatomaceous earth (sold under the trade name CELITE). The solid material collected was washed with hot industrial methylated spirit. The solvent was removed by evaporation an the residue dried by azeotropic distillation with toluene. The dried residue was recrystallised from industrial methylated spirit to give 4-methylcarbamoylmethyl-o-phenylenediamine (m.p. 140°-142° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25]([OH:27])=O)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[CH:63]([NH:65][NH2:66])=[O:64]>CN(C)C=O>[CH:63]([N:65]([C:25](=[O:27])[C:24]1[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:23]=1[CH:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:7](=[O:21])[N:6]1[CH3:22])[NH2:66])=[O:64]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: NNC=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N(N)C=O
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid (intermediate 6) (75.0 mg, 0.16 mmol)) and triethylamine (57.1 μL, 0.41 mmol) are suspended in N,N-dimethylformamide (2 mL), stirred for 5 min and N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (63.2 mg, 0.20 mmol) is added. The mixture is stirred for 10 min and formic acid hydrazide (10.8 mg, 0.18 mmol) is added. The mixture is stirred overnight at room temperature. Another equivalent of formic acid hydrazide is added to bring the reaction to completion. The crude product is purified by reversed phase HPLC. Yield 30 mg; ESI mass spectrum [M+H]+=500; Retention time HPLC: 0.94 min (HPLC method Z018_S04).
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][S:23]([CH:20]4[CH2:22][CH2:21]4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Product: O=S(=O)(Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2)C1CC1
Yield: 2.5 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and cyclopropylsulfonyl chloride (119 mg, 0.85 mmol) according to the procedure described for example 27. Obtained the title compound as a white solid (7 mg, 2.5%), MS (ISP) m/e=364.3 [(M+H)+].