Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:48])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 300 mg (0.73 mmol) of the compound from Example 289 in analogy to the synthesis of the compound from Example 296. 193 mg (62% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>O1CCOCC1.C(OCC)(=O)C>[Br:2][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCCCCCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: BrCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
Phosphorus tribromide (4.7 ml, 49.8 mmol) was added dropwise to a solution of 5-phenylpentan-1-ol (3 ml, 17.8 mmol) in dioxane (70 ml). The reaction mixture was stirred for 2 hours at room temperature. Another portion of phosphorus tribromide (4.7 m. 49.8 mmol) was added. The reaction mixture was stirred for 16 h at room temprature. It was cooled to 0° C. Water (60 ml) was added dropwise. The reaction mixture was diluted with ethyl acetate (100 ml). The phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50 g), using ethyl acetate/heptane (1:10) as eluent, to give 1.35 g of 1-bromo-5-phenylpentane.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH:17]([CH3:20])[CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH:17]([CH3:20])[CH2:18][OH:19])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)CO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NC(C)CO)=C(C)C1=O
Yield: 92.6 %

Procedure:
Oxidation as described in protocol B, using 102.2 mg (0.329 mmol) of 6-hydroxy-N-(1-hydroxypropan-2-yl)-2,5,7,8-tetramethylchroman-2-carboxamide and 397 mg CAN (2.45 mmol) yielded 98.5 mg of 2-hydroxy-N-(1-hydroxypropan-2-yl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:20]=O>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]([CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH3:20])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(Cl)cc1
Solvent: O=CO
Product: CN(CCCn1ccnc1)C(C)(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 90, N-[1-(4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine was reacted with formaldehyde and formic acid to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)-N-methylpropylamine, b.p. 170° C. (0.03 mmHg).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[O:14][CH:15]([CH3:27])[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[CH3:26])=O)[N:3]=1>ClCCCl.CCOCC.CCCC(C)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][N:10]3[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:15]([CH3:27])[O:14][C:9]=23)[N:3]=1
Reactant: COc1ccc(C(=O)C(C)Oc2[nH]nc(C)c2-n2nc(C)nc2C)c(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCCC(C)C
Solvent: ClCCCl
Product: COc1ccc(-c2c(C)oc3c(-n4nc(C)nc4C)c(C)nn23)c(C)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a dispersion of 2-[4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-yloxy]-1-(4-methoxy-2-methyl-phenyl)-propan-1-one (0.905 g, 2.45 mmol) in 1,2-dichloroethane (20 ml) is added titanium tetrachloride (0.675 ml, 6.12 mmol). The reaction mixture is heated to 85° C. for 2.5 hours and then left at RT overnight. The mixture is quenched carefully with sat. NH4Cl (50 ml) and extracted with EtOAc (2×50 ml). The combined organic extracts are washed with NaHCO3 (50 ml), brine, dried over MgSO4 and concentrated in vacuo to afford a dark brown oil. The crude oil is then taken up in 10% Et2O/iso-hexane (50 ml) and the brown solution is sonicated: no precipitation occurred immediately, but after 2 hours large crystals form. The solid is collected and washed with iso-hexane to give a cream coloured solid. Purification of this solid by recrystallisation from hot Et2O (˜40 ml) yields the title compound as tan crystals; MS: m/z=352.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (1H, d), 7.01 (1H, d), 6.94 (1H, dd), 3.83 (3H, s), 2.30 (6H, s), 2.26 (6H, s), 2.11 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[S:12])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:12][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Product: CCOC(=O)c1nc(SCC(OCC)OCC)[nH]c1C

Procedure:
prepared by reaction of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester with bromoacetaldehyde diethyl acetal. LC-MS: tR=0.70 min; [M+H]+=303.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].Br[C:37]1[CH:42]=[CH:41][N:40]=[N:39][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:37]2[CH:42]=[CH:41][N:40]=[N:39][CH:38]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20]
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: Brc1ccnnc1
Product: CC(c1ccc(-c2ccnnc2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with 4-bromopyridazine [CAS Reg. No. 115514-66-4]. MS (m/e)=464.1 [M+H+].
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:17]2[O:16][C:15]([C:18]([O:20]C)=[O:19])=[C:14]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13]=2[CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH3:7][O:8][C:9]1[C:17]2[O:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCCCCCOc1c(C(=O)OC)oc2c(OC)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCCOc1c(C(=O)O)oc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
A mixture of 1.34 g (0.012 mole) of potassium tert-butoxide in 50 ml of dimethyl sulfoxide (under a nitrogen atmosphere) is treated with 2.3 g (0.0066 mole) of crude 7-methoxy-3-(nonyloxy)-2-benzofurancarboxylic acid, methyl ester. After stirring at room temperature for three hours, the mixture is added to 400 g of ice/water. The new mixture is extracted with dichloromethane (3×250 ml), and the aqueous layer is cooled in ice and acidified with 4.0 N hydrochloric acid. The semisolid precipitate that forms is removed by extracting with dichloromethane (3×150 ml). The combined extracts are backwashed with water (2×200 ml), dried (anhydrous sodium sulfate), and evaporated (vacuum) to yield 7-methoxy-3-(nonyloxy)-2-benzofurancarboxylic acid (0.7 g; 32% yield) as an oil. The crude oil is converted to the corresponding 2-benzofurancarbamoyltetrazole without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1.N1C(C)=C[CH:17]=[CH:16][C:15]=1[CH3:21].BrCCCCBr>CN(C=O)C.C(OCC)(=O)C>[N:1]1([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:21]1
Reactant: CCOC(=O)c1cc(CCN)c[nH]1
Reactant: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: BrCCCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CCN2CCCC2)c[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product obtained in Step G (1.3 g) in DMF (134 ml) there are added 2,6-lutidine (4.15 ml) and 1,4-dibromo-butane (4.68 ml). The reaction mixture is stirred at 80° C. for 12 hours and at ambient temperature overnight. The reaction mixture is diluted with 600 ml of ethyl acetate. The organic phase is washed with saturated aqueous NaHCO3 solution, with water and with saturated aqueous NaCl solution, dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained is purified on silica gel (SiO2: gradient CH2Cl2/MeOH with the addition of 1.4N NH3 in the MeOH) to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[CH:7][C:6]([NH:9]C(OC(C)(C)C)=O)=[C:5]([C:17]([F:20])([F:19])[F:18])[CH:4]=1.C(OCC)C.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5]([C:17]([F:20])([F:18])[F:19])[CH:4]=1
Reactant: CN(C)c1cc(C(F)(F)F)c(NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)c1cc(C(F)(F)F)c(N)cn1

Procedure:
A solution of 0.73 g (2.39 mmol) of 6-dimethylamino-4-trifluoromethyl-3-(tert-butoxycarbonylamino)pyridine, prepared in stage 10.3, in 8.5 ml of 4N hydrochloric acid in dioxane is stirred at reflux for 5 hours. 200 ml of ethyl ether are subsequently added to the cooled reaction mixture. 0.6 g of a precipitate is collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)[C:7]([O:9]C)=[O:8])=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)OC)[C@@H]1CCCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)[C@@H]1CCCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To a solution of (S)-methyl 2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (126 mg, 0.545 mmol) in THF (4 mL) stirring at rt was added a solution of 1M LiOH (1.090 mL, 1.090 mmol) in water. The reaction was stirred at rt for 3 h, neutralized with 1M HCl (1.1 mL) and extracted with EtOAc (3×10 mL). The organics were dried, filtered and concentrated to yield (S)-2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetic acid (Cap-177a) (125 mg) as a clear colorless oil. LC-MS retention time 0.44 min; m/z 218.00 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 5.28 (d, J=8.8 Hz, 1 H), 4.38 (dd, J=8.7, 5.6 Hz, 1 H), 3.96-4.04 (m, 1 H), 3.91 (d, J=11.0 Hz, 1 H), 3.71 (s, 3H), 3.33-3.41 (m, 1 H), 3.24-3.32 (m, 1 H), 2.10-2.24 (m, 1 H), 1.74-1.83 (m, 1 H), 1.63-1.71 (m, 2 H), 1.35-1.49 (m, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1)=[O:5].[CH3:15][O:16][C:17]([NH:19][C:20](=NC(OC)=O)SC)=[O:18]>CO.C(O)(=O)C>[CH3:1][CH:2]([CH3:14])[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:20]([NH:19][C:17](=[O:18])[O:16][CH3:15])=[N:13][C:8]=2[CH:7]=1)=[O:5]
Reactant: CC(C)CS(=O)c1ccc(N)c(N)c1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cc(S(=O)CC(C)C)ccc2[nH]1
Yield: 70 %

Procedure:
To 3.09 g (14.5 mMol) of 4-(2-methylpropyl)sulfinyl-1,2-diaminobenzene in 35 ml methanol and 0.84 ml acetic acid is added 3.11 g (16 mMol) 1,3-bis(methoxycarbonyl)-S-methyl isothiourea, prepared as described in Example 1A(5), and the resulting solution heated to reflux for 3 hours. The solvent is removed in vacuo, the solid digested with water and filtered and washed with ether. The resulting orange solid is recrystallized from 35 ml ethanol to yield 3.0 g of the title compound, m.p. 198°-201°, yield, 70%.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl>[N+:1]1([O-:20])[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCCc2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2c1ccc[n+]2[O-]
Reaction time: 4 h
Yield: 83.7 %

Procedure:
5,6,7,8-Tetrahydroquinolin-5-one (7.12 g) was dissolved in dichloromethane (138 mL), added with 3-chloroperbenzoic acid (14.5 g) under ice cooling, and stirred for 4 hours at the same temperature. After adding a saturated aqueous solution of sodium hydrogen carbonate and diluting with chloroform, insoluble was removed by filtration through Celite. After adding 1 mol/L aqueous solution of sodium hydroxide, it was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residues were suspended in diethyl ether and collected by filtration to obtain the title compound (6.61 g) as a yellow powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]([OH:17])=O)[CH:11]=[N:12][C:6]=2[NH:5][CH2:4][C:3]1=[O:18].[CH3:19][NH:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][C:23]=1[CH3:31]>>[CH3:19][N:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][C:23]=1[CH3:31])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:10]1[CH:11]=[N:12][C:6]2[NH:5][CH2:4][C:3](=[O:18])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: CNCc1c(C)[nH]c2ccccc12
Reactant: CN1Cc2cc(C=CC(=O)O)cnc2NCC1=O
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(C)C(=O)CN2

Procedure:
According to the method of example 35g, 3-(4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid (69 mg, 0.28 mmol) and methyl-(2-methyl-1H-indol-3-ylmethyl)amine (60 mg, 0.34 mmol) were coupled to yield the title compound as a white powder and as a mixture of amide rotomers (40 mg, 35%). 1H NMR (300 MHz, DMSO-d6) 10.86 (s, 1H), 8.12 (bs, 1H), 7.77 (bs, 1H), 7.49-7.41 (m, 2H), 7.34-7.30 (m, 1H), 7.25-7.22 (m, 1H), 7.00-6.85 (m, 3H), 4.84-4.71 (m, 2H), 4.53 (s, 2H), 4.09-4.07 (m, 2H), 2.93-2.91 (m, 6H), 2.40 (bs, 3H); ESI MS m/z 404.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:37][C:38]([NH2:40])=[S:39]>CC(N(C)C)=O>[NH2:40][C:38]1[S:39][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:37]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Product: Nc1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol) in 40 mL of DMA was added NBS (0.88 g, 4.95 mmol). The mixture stirred at room temperature for 30 min. Thiourea (0.36 g, 4.72 mmol) as added and the mixture heated to 80° C. for 1 h. The mixture was poured into 300 mL of ice water and the product was collected by filtration. The crude product was then purified by flash chromatography to give the title compound of Step A (1.61 g, 3.35 mmol, 67.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.94 (s, 2H), 7.64-7.75 (m, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.16-7.29 (m, 5H), 6.52 (d, J=5.6 Hz, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:9]=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:9]=[CH:8][N:7]=1
Reactant: CCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCOc1ccnc(CO)c1C
Yield: 75.3 %

Procedure:
13.4 g of 2-acetoxymethyl-3-methyl-4-butoxy-pyridine was added dropwise to a 25% aqueous solution of sodium hydroxide, and the mixture was allowed to react for one hour at room temperature. The mixture was diluted with toluene, and then the toluene phase was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 8.3 g of 2-hydroxymethyl-3-methyl-4-butoxy-pyridine as an oily matter.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([O-:15])=[O:14].[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33].CC(C)([O-])C.[K+]>O1CCCC1.O1CCOCC1.CO>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[CH:20]=[C:19]2[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(-c3cccnc3)c2c1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)CCn1cc(-c2cccnc2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
Benzyltrimethylammonium hydroxide (0.17 ml of 40% solution in methanol) wasadded to a stirred suspension of 5-nitro-3-(3-pyridyl)-1H-indole (0.95 g) and methyl acrylate (0.41 g) in a mixture of tetrahydrofuran (10 ml) and dioxan (15 ml), and the mixture was stirred at room temperature for 2 hours. Methanol (10 ml) was added to give a clear solution followed by further methyl acrylate (0.41 g) and benzyltrimethylammonium hydroxide solution (0.17 ml) and stirring was continued for an additional 18 hours. Potassium t-butoxide (100 mg) was added and stirring was continued for a further 6 hours and the solution was evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was separated and dried (MgSO,). Evaporation of the solvent gave a solid whichwas crystallised from dichloromethane/hexane to give the title compound (0.48 g), m.p. 123°-125° C. Found: C,62.85H,4.62; N,12.91. C17H15N3O4 requires: C,62.76; H,4.65; N,12.92%.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([CH2:17]O)[CH:13]=[N:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:17][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:16]=2
Reactant: OCc1cnc2cc(-c3ccccc3)ccc2c1
Reactant: O=S(Cl)Cl
Product: ClCc1cnc2cc(-c3ccccc3)ccc2c1
Yield: 96 %

Procedure:
In substantially the same manner as in Reference Example 73, 7-phenyl-3-quinolylmethanol was reacted with thionyl chloride to obtain 3-chloromethyl-7-phenylquinoline. The yield was 96%. Recrystallization from ethyl acetate-hexane gave colorless prisms, 105-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.P(Br)(Br)[Br:11]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Br:11]
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1Br
Product: BrCc1ccccc1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 187.0 g of o-bromobenzyl alcohol at room temperature, with stirring, is added dropwise, 271.0 g of phosphorus tribromide. After the addition is complete, stirring is continued for three hours at room temperature. The mixture is then heated at 90°-100° for 3 hours and poured into 6 kg of crushed ice. The hydrolysis mixture is extracted with three 600 ml portions of ether, the ether extracts are washed, dried, and concentrated to give o-bromobenzyl bromide, bp. about 130°-132° (15mm).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](Cl)=[O:25]>>[Br:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)c1sccc1Br
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4sccc4Br)nc23)CC1
Yield: 49.2 %

Procedure:
Beginning with 0.37 gm (1.6 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.45 gm (2.0 mMol) 3-bromo-2-thiophenecarbonyl chloride, 0.33 gm (49%) of the title compound were prepared essentially by the procedure described in Example 8.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:10](=[S:12])[NH2:11])=[C:7]([NH2:9])[N:8]=1)[CH3:2].S(=O)(=O)(O)O.BrBr>>[NH2:11][C:10]1[S:12][N:9]=[C:7]2[N:8]=[C:4]([S:3][CH2:1][CH3:2])[S:5][C:6]=12
Reactant: CCSc1nc(N)c(C(N)=S)s1
Agent: BrBr
Agent: O=S(=O)(O)O
Product: CCSc1nc2nsc(N)c2s1
Yield: 87 %

Procedure:
27.1 parts of 2-ethylmercapto-4-amino-5-thiocarbamoylthiazole are reacted with 270 parts of sulfuric acid and 0.5 part of bromine as described in Example 1(b). 23.4 parts of 3-amino-5-ethylmercapto-thiazolo-(4,5-c)-isothiazole (87% of theory) of melting point 131°-134° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl.Cl>CN(C=O)C.C(Cl)Cl>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: ClCc1ccccn1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Temperature: 100 °C
Yield: 63 %

Procedure:
2-hydroxy-5-nitrobenzaldehyde (5.0 g, 29.9 mmol), potassium carbonate (4.12 g, 29.9 mmol) and caesium carbonate (9.74 g, 29.9 mmol) were mixed in DMF (30 ml). Picolyl chloride.HCl (5.39 g, 32.9 mmol) was added and the mixture then heated at 100° C. for 5 hours. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, dried and evaporated. Trituration of the residue in ether provided 5-nitro-2-(pyridin-2-ylmethoxy)benzaldehyde as a tan solid (4.87 g, 63%); NMR Spectrum: 5.54 (s, 2H), 7.40 (dd, 1H), 7.56 (d, 1H), 7.69 (d, 1H), 7.89 (t, 1H), 8.47-8.51 (m, 2H), 8.60 (d, 1H), 10.44 (s, 1H); Mass Spectrum: 259 (MH+).