Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Mg].C(Br)C.[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC>[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([CH2:1][CH3:2])([OH:15])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: -10 °C

Procedure:
To a solution of ethyl magnesium bromide prepared from 3.9 g. of magnesium turnings and 17.4 g. of ethyl bromide in 50 ml. of dry ether a solution of 9.3 g. of 4-chloro-4'-hydroxy-benzophenone in 40 ml. of dry ether is added dropwise, with stirring at -10° C., in nitrogen atmosphere. The reaction mixture is allowed to warm up to room temperature, stirred at this temperature for an additional half an hour, and is then poured onto a solution of ammonium chloride in ice water under cooling. The aqueous phase is extracted with ether, the ethereal phases are combined, washed to neutral with water, and dried over anhydrous magnesium sulfate. After filtering the solvent is distilled off in vacuo, the residue is decolored with charcoal in methanol, the solution is filtered, and the solvent is evaporated under reduced pressure. The crude mixture is crystallized from a mixture of benzene and ethyl acetate to yield 5.5 g. of the named compound, melting at 148° to 149° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:39][CH2:40][C:41]([NH:43][C@H:44]([B:49]1[O:53][C@@H:52]2[CH2:54][C@@H:55]3[CH2:58][C@H:57]([C@:51]2([CH3:61])[O:50]1)[C:56]3([CH3:60])[CH3:59])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([B:49]1[O:53][C@@H:52]2[CH2:54][C@@H:55]3[CH2:58][C@H:57]([C@:51]2([CH3:61])[O:50]1)[C:56]3([CH3:59])[CH3:60])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:6]
Reactant: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1ccccc1Br)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 2-bromobenzoic acid (0.124 g, 0.62 mmol) in DCM (2.25 mL) were added EDCI (0.119 g, 0.62 mmol), HOBt (0.084 g, 0.62 mmol), N-methyl morpholine (0.185 mL, 1.68 mmol) and 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide (0.2 g, 0.56 mmol). The reaction mixture was allowed to stir for 2 h and was concentrated. The residue was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-bromo-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.22 g, 78%).
Reaction SMILES: [SH:1][CH:2]([CH2:10][CH2:11][SH:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+]>O>[S:12]1[CH2:11][CH2:10][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[S:1]1
Reactant: O=C(O)CCCCC(S)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCC1CCSS1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.3 %

Procedure:
8.0 grams (0.038 mole) of 6,8-dimercapto octanoic acid were added to 1.54 grams (0.038 mole) of sodium hydroxide in 90 ml of water and the solution formed adjusted to pH 9 with dilute aqueous sodium hydroxide. The solution was extracted twice, each time with 30 ml of methyl tertiary butyl ether, the aqueous solution separated off and the residual ether removed in a vacuum. The solution was diluted with 200 ml of water, 7 mg of iron (III) sulfate added and oxygen led in with stirring at room temperature. After 2.5 hours the reaction solution had reached a pH of 12.4, the supply of oxygen was ended and the precipitated iron salt filtered off. The clear yellow solution was acidified with 10% hydrochloric acid at 5° C. to 10° C., further stirred for 1 hour at pH 1 and the precipitated crude product filtered off. The precipitate was washed with water, dried in a vacuum and recrystallized from ethyl acetate/hexane. After drying there were obtained 5.9 grams (75% of theory) of 1,2-dithiolane-3-pentanoic acid as yellow crystals having a melting point of 61° C. to 62° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][C:10]1[CH:11]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(C)cc1Br
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)cc1-c1ccccc1C(F)(F)F
Temperature: 110 °C
Reaction time: 20 h

Procedure:
Under argon, 500 mg (2.18 mmol) of methyl 2-bromo-4-methylbenzoate together with 655 mg (3.27 mmol) of 2-(trifluoromethyl)phenylboronic acid were dissolved in 10 ml of toluene, and 86 mg (0.22 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 100 mg (0.11 mmol) of tris(dibenzylideneacetone)dipalladium and 927 mg (4.37 mmol) of potassium phosphate were added successively. The mixture was heated to 110° C. and stirred at this temperature for 20 h. For work-up, the reaction mixture was allowed to cool to RT and diluted with 20 ml of ethyl acetate and 20 ml of water. After phase separation, the aqueous phase was extracted two more times with in each case 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: first cyclohexane/ethyl acetate 30:1, then 20:1). This gave 597 mg (86% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([CH3:19])[CH:21]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1ccc(-c2ocnc2C(=O)O)cc1C
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(C)c(C)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3,4-dimethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.11 min; [M+H]+=405.09.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH:19]=[O:20])[CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].[CH3:27]O>>[CH3:27][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[CH:19]=[O:20])[CH:8]=1
Reactant: CO
Reactant: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid (1 g, 2.98 mmol) in MeOH (10 mL) was added thionyl chloride (0.43 mL, 5.97 mmol), and the reaction was heated to 65° C. for 2 hours, and then stirred overnight at room temperature. The mixture was neutralized with 1N aqueous NaOH and extracted three times with EtOAc. The combined organic layer was washed with H2O, dried, and concentrated, and the residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the title compound, as well as the corresponding acetal.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([CH3:27])[CH:18]=3)[N:8]=2)[CH:6]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[C:19]([CH3:27])[CH:18]=4)[N:8]=3)[CH:6]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F

Procedure:
N-tert-Butyl-3-{1-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example E.73) (0.50 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as an off white solid (0.118 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][CH:2]1[CH:11]([Cl:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:18])(=[O:17])[CH2:3]1.[CH2:19]([N:21]1[C:25](O)=[CH:24][CH:23]=[N:22]1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(O)(CC)(C)C>[Cl:1][CH:2]1[CH:11]([Cl:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([O:16][C:25]3[N:21]([CH2:19][CH3:20])[N:22]=[CH:23][CH:24]=3)=[O:15])[C:9]=2[CH3:13])[S:4](=[O:17])(=[O:18])[CH2:3]1
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)O)ccc2c1C(Cl)C(Cl)CS2(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCC(C)(C)O
Product: CCn1nccc1OC(=O)c1ccc2c(c1C)C(Cl)C(Cl)CS2(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
1.5 Grams (4.9 mmol) of 3,4-dichloro-5-methyl-6-carboxythiochroman-1,1-dioxide was dissolved in 5 ml of t-amyl alcohol, and 1.1 g (5.3mmol, 1.2 eq.) of 1-ethyl-5-hydroxypyrazole and 1.1 g (5.3 mmol, 1.2 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 2.5 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate and hexane, and liberated N,N'-dicyclohexylurea was filtered off. An organic layer was concentrated under reduced pressure and purified by column chromatography (silica gel/ethyl acetate) to give 1.9 g (yield 95%) of 3,4-dichloro-5-methyl-6-(1-ethylpyrazol-5-yl)oxycarbonylthiochroman-1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[C:9](OC)=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][N:5]=1)([O-])=[O:2].[NH2:16][NH2:17]>>[OH:2][N:1]1[C:4]2[N:5]=[CH:6][CH:7]=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=2[N:17]=[N:16]1
Reactant: NN
Reactant: COc1c(C(C)(C)C)ccnc1[N+](=O)[O-]
Product: CC(C)(C)c1ccnc2c1nnn2O

Procedure:
The above-identified compound is prepared by reacting 2-nitro-3-methoxy-4-t-butylpyridine with hydrazine in accordance with the procedure described in Example 1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.C(N(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[C:21][C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: C=Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C#Cc1ccc(F)cc1

Procedure:
A mixture of methyl 2-bromo-5-nitrobenzoate (5 g), 4-fluorostyrene (3.5 g), tributylamine (0.39 g), bis-(triphenylphosphine)-palladium(II)chloride (0.3 g), sodium bicarbonate (2.65 g) and water (30 ml) was stirred and heated at reflux under an argon atmosphere for 1.5 hours. The reaction was then cooled, suspended in dichloromethane (200 ml) and passed through a pad of silica (chromatography grade) eluting with more dichloromethane The dichloromethane was then evaporated away and the residue treated with iso-hexane (200 ml) to give methyl 2-[2-(4-fluorophenyl)ethynyl]-5-nitrobenzoate (compound 74) as a yellow precipitate which was filtered and dried, (5.05 g).
Reaction SMILES: ClCl.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[CH3:4]
Reactant: CCc1ccc(O)cc1
Reactant: Sc1ccccc1
Agent: ClCl
Solvent: ClCCl
Product: CCc1ccc(O)c(Sc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorine gas was passed into a stirred, cooled (0° C.) solution of 4-ethylphenol (30.5g) and thiophenol (22g) in dichloromethane (100ml) for 3 hours. The solution was stirred overnight at room temperature the solvent was distilled off on a rotary evaporator and the residual oil was distilled, the product being in the higher boiling fraction (160°-180° C. at about 0.5 cm Hg). This fraction was chromatographed on a silica column, being eluted with hexane progressively enriched with chloroform to give the title compound (12.5g), as a clear liquid, nD23 =1.6130.
Reaction SMILES: N[C@@H](C)C(N[C@@H](C)C(N(CC)C[C@H](C)CO[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[CH2:22][C@@:21]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:24]([O:26]C)=[O:25])[CH2:20][CH2:19]2)=O)=O.[OH-].[Li+]>O1CCCC1.CO.O>[C:32]([O:31][C:29]([NH:28][C:21]1([C:24]([OH:26])=[O:25])[CH2:20][CH2:19][C:18]2[C:23](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCN(C[C@H](C)COc1cccc2c1C[C@@](NC(=O)OC(C)(C)C)(C(=O)OC)CC2)C(=O)[C@H](C)NC(=O)[C@H](C)N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCc2ccccc2C1

Procedure:
In analogy to Example 4.3.8.a, 18.0 mg (32.0 mmol) of methyl (R)-8-[(S)-3-[[(S)-2-[(S)-2-amino-propionylamino]-propionyl]-ethyl-amino]-2-methyl-propoxy]-2-tert.butoxycarbonylamino-1,2,3,4-tetrahydronaphthalene-2-carboxylate in 1 ml of tetrahydrofuran/methanol/water (3:1:1) were reacted with 320 μl of 1N lithium hydroxide solution. After working up and purification according to Example 4.3.8.a 17.0 mg (96.8%) of (R)-8-[(S)-3-[(S)-2-[(S)-2-amino-propionylamino]-propionyl]-ethyl-amino]-2-methyl-propoxy!-2-tert.butoxycarbonylamino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid were obtained as a white powder. MS: 549 (M+H+), 216.9 (100), 91.1 (75), 149.0 (36), 513 (35), 471 (31), 109 (29).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[CH2:18]([Li])CCC.CI>>[CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: COc1cccc(C(=O)Nc2ccccc2)c1
Reactant: [Li]CCCC
Solvent: CI
Product: COc1cccc(C(=O)Nc2ccccc2)c1C

Procedure:
WO 95/09843 describes a multistage process for the preparation of 3-acetoxy-2-methylbenzoic acid. This process starts from 3-methoxybenzoyl chloride. The 3-methoxybenzoyl chloride is reacted with aniline to give 3-methoxy-N-phenylbenzamide. In a second step, the 3-methoxy-N-phenylbenzamide is reacted with 2 equivalents of n-butyllithium and then alkylated using methyl iodide. 3-Methoxy-2-methyl-N-phenylbenzamide is formed here, which is then reacted with aqueous hydrochloric acid and aqueous hydrogen bromide in boiling acetic acid with hydrolysis of the amide group and cleavage of the methoxy group to give 3-hydroxy-2-methylbenzoic acid. The 3-hydroxy-2-methylbenzoic acid must be acylated with acetic anhydride in order to obtain the 3-acetoxy-2-methyl-benzoic acid. The individual reaction steps are described in greater detail in WO 95/09843 under Preparation 9 A, B and C and Example 81.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][C:27]=3[O:29][CH3:30])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Product: COc1ccc(-c2c(F)ccc3c(N)c(C(=O)NC4CCC4)nnc23)c(OC)c1
Yield: 65 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 2,4-dimethoxy-phenyl boronic acid (205 mg) were reacted to afford the title compound (133 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, 1H), 8.47 (m, 1H), 7.70 (m, 1H), 7.18 (m, 1H), 6.70 (m, 1H), 6.64 (m, 1H), 4.49 (m, 1H), 3.85 (s, 3H), 3.65 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=397 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[S:6]1(=[O:23])=[O:22].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)C>[F:21][C:16]1[CH:15]=[C:14]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]3)[S:6]2(=[O:23])=[O:22])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(CCCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Reaction time: 48 h
Yield: 66.9 %

Procedure:
A solution of 1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2, 0.5 mmol) in anhydrous dimethylformamide (3 mL) was treated with tert-butyl piperazine-1-carboxylate (0.19 g, 1 mmol) and N,N-diisopropylethylamine (0.17 mL, 1 mmol). The reaction mixture stirred at ambient for 48 h. The reaction mixture was diluted with ethyl ether (10 mL) and washed with H2O (2×10 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/hexane) to provided tert-butyl 4-{3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperazine-1-carboxylate (0.17 g, 67%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[C:10]([CH3:15])=[N:11][O:12][C:13]=2[CH3:14])[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:4]([C:23](=O)[CH3:24])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[C:10]([CH3:15])=[N:11][O:12][C:13]=2[CH3:14])[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:4]([CH:23]([NH2:32])[CH3:24])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2c(C)noc2C)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: Cc1noc(C)c1-c1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of 1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethanone (40 mg, 0.11 mmol), ammonium acetate (86 mg, 1.1 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.28 mL, 0.28 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product (35 mg, 87%). LCMS calculated for C20H21ClFN2O (M+H)+: m/z=359.1. found: 359.1.
Reaction SMILES: [Cl:1][C:2](Cl)=[CH:3][C:4](=[O:14])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7].Cl(O)(=O)(=O)=O.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[O:7][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][C:4](=[O:14])[CH:3]=1
Reactant: O=C(C=C(Cl)Cl)CC(=O)N1CCOCC1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1cc(Cl)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 75.4 %

Procedure:
To a suspension of 2 (11.3 g, 44.9 mmol) in dioxane was added perchloric acid (11.4 ml, 0.14 mol) and the reaction was heated at 90° C. under N2 for 1 hour. The reaction was cooled, neutralised with 2M NaOH (75 ml) and filtered. The aqueous layer was extracted with DCM (4×30 ml) and the organic layers were combined and dried over MgSO4. The organic layer was further treated with charcoal and filtered through celite. The dark yellow filtrate was evaporated in vacuo, and the resulting solid was triturated with hexane (50 ml) and dried to give 3 (7.3 g, 75%) as a light yellow powder. m/z (LC-MS, ESP): 216 (M++1). 1H-NMR (300 MHz, DMSO-d6): 3.3 (t, 4H), 3.65 (t, 4H), 5.4 (d, 1H), 6.25 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=1)[NH2:22].[Cs].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=1
Reactant: COc1cc(N)ccc1-c1cnnc(C)c1
Reactant: CNc1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs]
Solvent: C1COCCO1
Product: CNc1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Temperature: 120 °C

Procedure:
A mixture of 2-chloro-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (50 mg, 0.20 mmol), 3-methoxy-4-(6-methylpyridazin-4-yl)aniline (42 mg, 0.20 mmol), cesium rbonate (127 mg, 0.39 mmol), palladium (II) acetate (7 mg, 0.03 mmol) and 2-(dicyclohexylphosphino)-biphenyl (10 mg, 0.03 mmol) in dioxane (2 mL) was heated under argon at 120° C. for 90 minutes in a microwave reactor. 2-Chloro-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (72 mg, 0.28 mmol, 1.4 eq), palladium(II) acetate (7 mg) and 2-(dicyclohexylphosphino)biphenyl (10 mg) was added and the mixture was heated at 120° C. for 90 minutes in a microwave reactor. The mixture was filtered through a short silica gel plug which was washed with 10% solution of methanol in ethyl acetate (75 mL). The eluate was concentrated in vacuum and the residue was purified by preparative to give the title compound as a solid, 22 mg (26%).