Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)(=O)=O>CN1CCCC1=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:3]=1[CH3:10]
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1cc(OC2CCOCC2)cc(C)c1Br
Temperature: 140 °C

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (3 g) in N-methyl-pyrrolidone (10 mL) is slowly added Cs2CO3 (9.7 g) and tetrahydro-2H-pyran-4-yl methanesulfonate (5.4 g). The mixture is heated for 3 hours at 140° C. After cooling to room temperature the mixture is partitioned between saturated aqueous Na2CO3 solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (MgSO4). The solvents are evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 1.2 g; LC (method 4): tR=1.83 min.
Reaction SMILES: [CH2:1]([N:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:27](=[O:29])=[O:28]>C1COCC1>[CH2:1]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]([C:27]([OH:29])=[O:28])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: c1ccc(CN2c3ccccc3Cc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1c2ccccc2N(Cc2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of Compound 5, N-benzylacridan (10 g, 37 mmol) in 200 mL of dry THF under inert atmosphere was cooled to 78° C. and 25.0 mL of 2.5 M n-butyllithium in hexanes (37.5 mmol) was added dropwise over 15 min. The solution was stirred at −78° C. for 1 h and then warmed to room temperature over 45 min. The reaction mixture was again cooled to −78° C. and ca. 200 g of crushed dry ice was added causing a precipitate to form. The reaction was allowed to slowly warm to room temperature and stirring under argon was continued over night. The mixture was evaporated, the solid was then suspended in 300 mL of water and acidified to pH 3 with 12N HCl. The solid was collected, washed with water, dissolved in CH2Cl2, dried over sodium sulfate and concentrated to afford 11 g of N-benzyl-acridan-9-carboxylic acid. 1H NMR: (CDCl3) ∂ 4.99 (s, 1H), 5.12 (s, 2H), 6.72-6.75 (d, 2H), 6.88-6.94 (t, 2H), 7.10-7.17 (m, 4H), 7.22-7.32 (m, 5H).
Reaction SMILES: [CH2:1](Br)C#C.C[CH:6]([NH2:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:15].[CH3:1][NH:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(N)Cc1ccccc1
Reactant: C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCc1ccccc1

Procedure:
A solution of propargyl bromide (1.1 g, 9.1 mmol) in acetonitrile (8.5 ml) was added dropwise to a stirred mixture of 3-(N-Me, N-Et carbamyloxy)α-methyl phenethylamine.HCl (2.4 g, 8.8 mmol) and potassium carbonate (2.8 g) in acetonitrile (25 ml), and the mixture was stirred at RT for 7 hrs. The reaction mixture was filtered and the filtrate was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc 2:1) to give 1.76 g of the title compound as the free base (73%)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]2[C:14]([I:15])=[C:13]([O:16][CH3:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[C@H:5]([OH:20])[C@@H:4]1[OH:21].CO[C:24](OC)([CH3:26])[CH3:25].CCN(CC)CC>CC(C)=O.CS(O)(=O)=O>[I:15][C:14]1[C:9]([NH:8][C@H:6]2[C@@H:5]3[O:20][C:24]([CH3:26])([CH3:25])[O:21][C@@H:4]3[C@@H:3]([CH2:2][OH:1])[CH2:7]2)=[N:10][C:11]([S:18][CH3:19])=[N:12][C:13]=1[O:16][CH3:17]
Reactant: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c1I
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1I
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 5 (4.00 g, 9.36 mmol) was dissolved in acetone (10 mL) and 2,2-dimethoxypropane (5.75 mL, 46.8 mmol) was added. The solution was cooled to 0° C. and methanesulfonic acid (2 drops) was added. The solution was stirred for 15 min and Et3N (1 mL) was added. The acetone was evaporated and the residue was dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified via column chromatography on silica gel (EtOAc/hexanes) to give the title compound as a white solid. 1H NMR (CDCl3) δ 6.21 (d, J=8 Hz, 1H), 4.65-4.59 (m, 2H), 4.45-4.44 (m, 1H), 3.94 (s, 3H), 3.89-3.85 (m, 1H), 3.76-3.73 (m, 1H), 2.61-2.55 (m, 1H), 2.52 (s, 3H), 2.40-2.34 (m, 1H), 1.85 (br s, 1H), 1.65-1.57 (m, 2H), 1.49 (s, 3H), 1.28 (s, 3H); LCMS 2.54 min, 468 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[CH:9][CH:8]=1)#[N:2].N[NH:29][C:30]([NH2:32])=[S:31].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:32][C:30]1[S:31][C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)=[CH:9][CH:8]=2)=[N:2][N:29]=1
Reactant: NNC(N)=S
Reactant: N#CCCCCc1ccc(NC(=O)Cc2cccc(OC(F)(F)F)c2)nn1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCCCc2ccc(NC(=O)Cc3cccc(OC(F)(F)F)c3)nn2)s1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
1118 (1.0 equiv., 0.154 mol, 58.2 g) was charged into a 500 mL round bottom flask along with thiosemicarbazide (1.2 equiv., 0.184 mol, 16.8 g). TFA (5 vol., 291 mL) slowly added to reaction vessel while stirring. The reaction slurry was heated in a 65° C. bath with an open top reflux condenser. The reaction usually goes to completion after 5 hours (determined by LC/MS). Toluene (10 vol., 582 mL) added to deep red solution, azeotroped by rotary evaporation (bath≦30° C.) to a red oil. Slowly transferred oil to a well stirred 6000 mL Erlenmeyer flask containing 7.5% sodium bicarbonate solution (69 vol., 4.0 L) cooled in a 0° C. bath. The crystals were filtered through a Büchner funnel and rinsed twice with diethyl ether (5 vol., 2×250 mL). Dried under high vacuum to a constant weight to afford N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 657; yield of 55.7 g (80%). 1H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.51-7.26 (m, 4H), 6.99 (s, 2H), 3.88 (s, 2H), 2.87 (m, 4H), 1.71 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]([CH3:28])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[C:7](SC)[N:6]=1>C(O)C.O.O.[Ni]>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]([CH3:28])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[CH:7][N:6]=1
Reactant: CSc1nc(Nc2cc(-c3nnc[nH]3)ccc2C)c(C#N)c(N(C)CC(C)(C)C)n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1ncnc(N(C)CC(C)(C)C)c1C#N
Yield: 10.5 %

Procedure:
To a solution of 4-[(2,2-dimethyl-propyl)-methyl-amino]-2-methylsulfanyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamino]-pyrimidine-5-carbonitrile (60 mg, 0.142 mmol) in 3 mL of 50% ethanol/water (v/v) was added 0.4 mL of 50% Raney-Ni in water solution. The solution was refluxed under argon for 18 hours. The solution was evaporated under vacuum. The resulting residue was purified by flash chromatography to afford 5.6 mg of the final product (Yield: 10%). MS (m/z) calcd for C20H24N8 (MH+), 377.2, found, 377.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][OH:13])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:14](N(CC)CC)C>C(O)=O.CO>[OH:13][CH2:12][CH2:11][N:10]1[C:3]2[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[CH:9][C:2]=2[N:1]=[CH:14]1
Reactant: N#Cc1cccc(N)c1NCCO
Reactant: CCN(CC)CC
Solvent: O=CO
Solvent: CO
Product: N#Cc1cccc2ncn(CCO)c12
Yield: 70 %

Procedure:
3-amino-2-[(2-hydroxyethyl)amino]benzonitrile (38 g, crude), is dissolved in formic acid (150 ml) and stirred under reflux for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure to give a dark solid. This solid is dissolved in 200 ml of methanol with heating and while still hot, 60 ml of triethylamine is added and reflux for 1 hour. The mixture is concentrated under vacuum and the precipitate is filtered and washed with water then dried to give the desired compound (27 g, 70% from intermediate 11).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=2)[NH:3]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>>[CH2:20]([NH:27][S:16]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:11]=[C:10]2[C:12]([F:15])([F:14])[F:13])(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc2[nH]1
Solvent: CCN(CC)CC
Product: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)NCc3ccccc3)ccc2[nH]1
Yield: 92.3 %

Procedure:
Condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 16 mg, 51 μmol) with BnNH2 (7 μL, 54 μmol), employing NEt3 (8 μL, 57 μmol) as base as delineated in Example 1, gave the title compound (18 mg, 90%): δH ((CD3)2SO) =4.00 (d, 2H), 7.05 (s, 1H), 7.10–7.20 (m, 5H), 7.50 (d, 1H), 7.95 (dd, 1H), 8.00 (d, 1H), 8.30 (t, 1H); m/z (ES−)=381.0 [M−H]−.
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][C@H:2]1[O:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:3]1=[O:4]
Reactant: CC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1OC[C@@H](c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide from Step A (1.30 g, 5.71 mmol) in THF (100 mL) at 0° C. was added NaH (493 mg of a 60% dispersion in oil, 12.3 mmol) and the mixture was stirred at ambient temperature for 18 h. Saturated aqueous NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-75:25 to 0:100, to give the title compound. MS: m/z=192 (M+1).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Reaction time: 1 h

Procedure:
4-Hydroxy-3-nitropyridine (10.0 g, 71.38 mmol) was added to 100 ml of phosphorus oxychloride, which was then refluxed under stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was added to 500 ml of ice water, which was then neutralized with 2N sodium hydroxide solution. The reaction mixture was extracted with methylene chloride (300 ml). The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound of a pale yellow solid (9.2 g, 92.0%).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-])=O)[C:3](O)=[O:4]>CCO.[Pt]>[NH2:1][CH:2]1[CH2:6][C:7]2[C:8](=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[NH:14][C:3]1=[O:4]
Reactant: NC(Cc1ccc(Cl)cc1[N+](=O)[O-])C(=O)O
Agent: [Pt]
Solvent: CCO
Product: NC1Cc2ccc(Cl)cc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To a solution of 152A (1.0 g, 4.1 mmol) in 50% aqueous EtOH (40 mL), 10% Pt/C (100 mg) was added under argon and the mixture was hydrogenated at 35 psi for 1 h. The reaction mixture was filtered via a pad of celite and the filtrate was concentrated. The residue was dissolved in cone. HC (10 mL) and stirred at RT for 6 h. The mixture was then concentrated and dissolved in 100 mL of saturated aqueous sodium bicarbonate. The white solid was filtered and dried to afford 0.44 g of 152B.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[OH:17])#[N:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@@H:23]1[O:25][CH2:24]1)(=O)=O>>[CH2:22]([O:17][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[C@@H:23]1[O:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOC(=O)CCCc1ccc(C#N)c(O)c1
Product: CCOC(=O)CCCc1ccc(C#N)c(OC[C@H]2CO2)c1
Yield: 89 %

Procedure:
Using the method of example 30(b), vide supra, ethyl 4-(4-cyano-3-hydroxyphenyl)butanoate (1.4 g, 6 mmol) and (R)-glycidyl nosylate (1.48 g, 5.71 mmol) were used to prepare 1.47 g (88%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH:37][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([CH:7]4[CH2:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: C=CCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: C=CCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 38.3 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-enylpiperidin-4-yl)benzamide was prepared following the procedure as outlined for Example 99, starting from methyl 4-(1-prop-2-enylpiperidin-4-yl)benzoate (0.259 g, 1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) and 2M trimethylaluminium (1.250 mL, 2.50 mmol) in toluene (10 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product was crystallised from DCM/diethyl ether to give on filtration the title compound (0.182 g, 38.3%) as a white solid.
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[Br:11][CH2:12][CH2:13][CH2:14][Cl:15]>C(#N)C>[Br-:11].[Cl:15][CH2:14][CH2:13][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: ClCCCBr
Reactant: CNCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CC#N
Product: CN(CCCCl)CCC[N+](C)(C)C

Procedure:
To a stirred solution of 3.02 g. (14.3 mmoles) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.25 g. (14.3 mmoles) of 3-bromo-1-chloropropane and the mixture is stirred at room temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is extracted with chloroform. The chloroform extract is evaporated and dried to give 2.05 g. (100%) of oily product; NMR δ: 2.2 (3H, S, --NCH3); 3.43 (9H, S, --N+ (CH3)3).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:20][C:21]([OH:23])=[O:22])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
tert-Butyl [[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfinyl]acetate (0.12 g, 0.30 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added to the mixture. The obtained crystals were recrystallized from ethanol to give the titled compound (0.081 g, 79%) as pale yellow crystals.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]([CH3:22])[S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([O:20]C)=[O:19])(=[O:8])=[O:7].Cl>CO.O>[CH3:4][N:5]([CH3:22])[S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([OH:20])=[O:19])(=[O:8])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 50 °C

Procedure:
60.2 g of lithium hydroxide monohydrate are added to a solution of 206.7 g of N,N-dimethyl-2-methoxycarbonyl-5-nitrobenzenesulfonamide in 1500 ml of methanol. The mixture is subsequently stirred at 50° C. until conversion is complete. Following the concentration of the reaction mixture under reduced pressure, the residue is taken up in water and is treated at 0° C. with concentrated hydrochloric acid (pH=1). Filtration with suction followed by drying gives the desired compound. Yield: 162.9 g; m.p.: 160-163° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:24]([O:26]C)=[O:25].[I-].[Li+].N1C=CC=CC=1>O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:24]([OH:26])=[O:25]
Reactant: CCC(CC)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)OC)cnc3c2c1
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
A mixture of methyl 4-oxo-10-(2-ethylbutyramido)-4H-pyrmido[1,2-C]quinazoline-3-carboxylate (3.2 g), anhydrous lithium iodide (8.0 g) and dry pyridine (32 ml) was stirred at 120° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water. Insoluble materials were removed by filtration. The aqueous layer was adjusted to pH 1-2 with conc. hydrochloric acid to give crystals, which were separated by filtration and dried. The crude crystals were washed with methanol three times and recrystallized from acetonitrile to give 4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (0.7 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C(#N)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1

Procedure:
4-Methylimidazole (45.1 g, 0.55 M) and N,N-diisopropylethylamine (161 g, 1.25 M) were dissolved in acetonitrile (800 ml), and 3,4-difluoronitrobenzene (79.5 g, 0.5 M) added. The mixture was stirred and heated to reflux under nitrogen for 24 hours. Solvent was evaporated, the residue dissolved in ethyl acetate (800 ml), washed with water (400 ml), brine (200 ml), and dried (magnesium sulfate). The residue was dissolved in toluene (250 ml), treated with charcoal, filtered, and diluted with hot cyclohexane (75 ml) to crystallise 3-fluoro-4-(4-methylimidazol-1-yl)nitrobenzene (64.7 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]([F:15])([F:14])[F:13])=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:18])=O.O>C1(C)C=CC=CC=1>[Cl:18][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]([F:15])([F:14])[F:13])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1OC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(CCl)ccc1OC(F)(F)F
Temperature: 75 °C
Yield: 73.7 %

Procedure:
5-(Hydroxymethyl)-2-(trifluoromethoxy)benzonitrile (0.150 g, 0.691 mmol) was taken up in toluene (2 mL) and thionyl chloride (0.303 mL, 4.14 mmol) was added. The mixture was heated at 75° C. for 15 min. Water was added and the mixture was extracted with hexanes (2×75 mL). The organics were treated with aqueous NaHCO3. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (120 mg). LCMS m/z=236.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 1.98 (s, 1H), 4.52 (s, 2H), 7.32-7.34 (m, 1H), 7.59-7.62 (m, 1H), 7.68 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[Cl:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: OB(O)c1ccccc1Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccccc4Cl)cc3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2-chlorophenyl boronic acid (0.059 g, 0.38 mmol) to afford 0.074 g (51%). MS (m/z): calcd for C2H25ClN4OS (M+H)+: 466.0; found: 466.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.C([O-])(=O)C.[Na+].[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH2:12][CH3:13])=[C:4]([F:14])[C:3]=1[Br:20]
Reactant: BrBr
Reactant: CCOc1cc(Br)cc(F)c1OCC
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(Br)c(Br)c(F)c1OCC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
To a solution of 5-bromo-1,2-diethoxy-3-fluorobenzene (40.0 g, 0.15 mol) in acetic acid (200 mL), sodium acetate (16.2 g, 0.20 mol) and bromine (31.6 g, 0.20 mol) were added sequentially at room temperature, and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium thiosulfate (400 mL) and water (400 mL) were added sequentially. The mixture was extracted once with heptane (800 mL) and three times with heptane (400 mL). The organic layer was washed sequentially with water (400 mL), once with a 2 N aqueous solution of sodium hydroxide (200 mL), once with a 2 N aqueous solution of sodium hydroxide (100 mL), and water (400 mL), then dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer under reduced pressure and the residue was filtered. The filtrate was then purified by silica gel column chromatography (hexane, ethyl acetate) to give 52.0 g of the title compound (yield:quant.).