Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6]2[C:19]([O:20]C(=O)C)=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.C[O-].[Na+]>CO.C(O)(=O)C>[OH:4][C:5]1[C:6]2[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)Oc1cccc2sc(-c3ccccc3)c(OC(C)=O)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1cccc2sc(-c3ccccc3)c(O)c12

Procedure:
A solution of 3,4-diacetoxy-2-phenylbenzo[b]thiophene (28 mg) in methanol (5 ml) was treated with a catalytic amount of sodium methoxide for 18 hours at room temperature. One drop of acetic acid was added, and the solution was evaporated. The residue was dissolved in dichloromeethane, filtered and the filtrate evaporated to give 3,4-dihydroxy-2-phenylbenzo[b]thiophene as a light yellow solid; yield 20 mg; m/z 242 (M+.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][CH2:32][OH:33].C(N(CC)CC)C.[ClH:41]>CC#N>[ClH:41].[ClH:41].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:31][CH2:32][OH:33])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCI
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CCO)CC2
Yield: 27 %

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol), 2-iodoethanol (17 μL, 36 mg, 0.21 mmol) and triethylamine (105 μL, 0.82 mmol) were dissolved in MeCN (2 mL) and heated to reflux for 3 h. The mixture was then concentrated and purified by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) providing the free base. This was converted to the HCl salt (2 N HCl/Et2O) providing the title compound (22 mg, 27%) as a yellow solid: mp 162-168° C.; 1H NMR (500 MHz, CD3OD) δ 7.63 (dd, J=7.6, 2.0 Hz, 2H), 7.51-7.50 (m, 3H) 7.46-7.43 (m, 2H), 7.41-7.38 (m, 1H), 7.09 (dd, J=8.3, 1.7 Hz, 1H), 6.36 (dd, J=7.6, 2.7 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.82 (d, 1H, partially masked by solvent), 4.520 (d, J=14.3 Hz, 1H), 4.06-4.02 (m, 3H), 3.77 (s, 3H), 3.70-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.33-3.31 (m, 2H, partially masked by solvent); ESI MS m/z 430 [M+H]+; HPLC (Method B) 95.1% (AUC), tR=12.4 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[O:16]>ClCCl>[C:5]([C:13]1[CH:12]=[C:11]([CH:15]=[O:16])[N:10]([CH3:9])[CH:14]=1)(=[O:7])[CH3:6]
Reactant: Cn1cccc1C=O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C=O)n(C)c1
Yield: 97.8 %

Procedure:
To a suspension of aluminium chloride (22.9 g, 172 mmol) in anhydrous dichloromethane (100 ml) and acetylchloride (4.5 g, 57.3 mmol)was added a solution of 1-methyl pyrrole-2-carboxaldehyde (5 g, 46 mmol) in anhydrous. dichloromethane (20 ml). The mixture was refluxed for 90 min, poured into ice and stirred until melted. The layers were separated and aqueous layer was extracted with dichloromethane (2×100 ml). The organic phase and extracts were combined, dried over sodium sulfate. The solvent was removed in vacuo to give the title compound (6.8 g, 94%), 1H NMR (d6-DMSO) d 9.6 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 3.9 (s, 3H),2.4 (s,3H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16](=O)[C:15]2[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][CH:8]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.O.[NH2:34][NH2:35]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16]2=[N:34][NH:35][C:18](=[O:20])[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=32)[NH:9][CH:8]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(F)(F)F)cc1)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.34 mmol) in 85% hydrazine monohydrate (4 ml) and methanol (6 mL) was stirred at room temperature for 2 h. The mixture was filtered and washed with water to give the title compound (25 mg, yield: 18%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.46 (s, 3H), 4.81 (d, J=10.8 Hz, 1H), 5.07 (d, J=10.8 Hz, 1H), 6.82 (s, 1H), 6.97 (d, 1H), 7.16 (d, J=8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.58-7.69 (m, 5H), 12.22 (d, 1H); LC-MS (ESI) m/z: 412 (M+1)+.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:67]1([CH2:73][SH:74])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O1CCOCC1.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]>[CH2:73]([S:74][C:2]1[C:3]([F:15])=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: O=C1CCCN1c1ccc(F)c(Br)c1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CCCN1c1ccc(F)c(SCc2ccccc2)c1F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Intermediate 93 (1 g, 3.62 mmol) in dioxane (30 ml) was stirred under argon. DIPEA (1.26 ml, 7.24 mmol), xantphos (0.126 g, 0.22 mmol) and Pd2(dba)3 (0.099 g, 0.11 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.41 ml, 3.44 mmol) was slowly added and the reaction stirred for 3 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction with ethyl acetate (three times), the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:6]1)=[O:4].[OH-].[K+]>C(O)C.O>[C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:6]1)([OH:4])=[O:2]
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)OC)C3)nc2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)O)C3)nc2n(CCC)c1=O
Temperature: 10 °C

Procedure:
1.41 g (3.9 mmol) of 8-(3-methyloxycarbonylcyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione are suspended in 10 ml of ethanol and 1 ml of water, 0.77 g of potassium hydroxide are added and the mixture is refluxed for 30 minutes. After cooling to 10° C. the mixture is acidified, the crystals precipitated are suction filtered and the filtrate is extracted with dichloromethane. The combined organic extracts are dried and evaporated down; the residue is combined with the filtered crystals. In this way 1.27 g (93.4% of theory) of the title compound are obtained are beige crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([NH:20][CH2:21][CH:22](O)[CH2:23][CH3:24])[CH:16]=[CH:17][C:18]=1[Cl:19].O>C1(C)C=CC=CC=1.CS(O)(=O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]2[N:20]([C:15]3[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([C:12]([F:27])([F:11])[F:26])[CH:14]=3)[CH2:21][CH:22]([CH2:23][CH3:24])[O:7]2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: CCC(O)CNc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cccc(C=O)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1CN(c2ccc(Cl)c(C(F)(F)F)c2)C(c2cccc(C#N)c2)O1

Procedure:
Meta-cyanobenzaldehyde (2.1 g, 0.016 mole) was added to 4.3 g of 1-(3-trifluoromethyl-4-chlorophenylamino)-2-butanol in 50 ml of toluene and 2-3 drops of methane sulfonic acid was added. The mixture was refluxed under a modified Dean-Stark apparatus until no more water came off and the mixture was stripped on a rotary evaporator. Yield was 6 g of product, nD30 1.5774. It was characterized by IR and NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2ccccc2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(O)c2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 2-methyl-l-naphthol (7.9 g, 0.05 mmol) in dichloromethane, anhydrous aluminum chloride (7.2 g) was slowly added with stirring, followed by slow addition of acetyl chloride (4.7 g) to start reaction. The reaction mixture was stirred at 10° C. or below for 1 h, then at room temperature for 3 h. Thereafter, the mixture was poured into ice water. Then, the reaction product was extracted with dichloromethane and the extracted layer was washed with water. Further, the extracted layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized with benzene, giving the desired compound, 2-methyl-4-acetyl-l-naphthol, in an amount of 3.9 g.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:15]([F:14])([F:25])[F:26])=[O:19])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.27-1.37 (m, 2 H) 1.56-1.63 (m, 2 H) 2.19 (s, 3 H) 2.21 (s, 3 H) 3.90-3.96 (m, 2 H) 5.99 (s, 1 H) 7.52-7.61 (m, 2 H) 7.66-7.71 (m, 1 H) 7.72-7.77 (m, 1 H); MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.C1C(=O)N([I:17])C(=O)C1>C(O)(=O)C>[CH2:8]([C:6]1[N:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[I:17])[CH3:9]
Reactant: CCc1cc(O)ncn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCc1nc[nH]c(=O)c1I
Reaction time: 30 h

Procedure:
To a stiffed solution of 70 g (0.56 mol) 4-hydroxy-6-ethyl pyrimidine in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min The reaction is stiffed for 30 h at RT until all starting material is consumed. The reaction mixture is diluted with water and the solid product is filtered off and washed with sodium thiosulfate solution to remove excess iodine. After drying, the desired product is obtained as a solid (90 g; 64%) which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][NH:33][C:16]1[N:15]=[C:14]2[NH:13][C:12](=[O:24])[N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH2:20][C:19]2=[CH:18][N:17]=1)[CH3:26]
Reactant: CCN(CC)CCCN
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Product: CCN(CC)CCCNc1ncc2c(n1)NC(=O)N(c1cc(OC)cc(OC)c1)C2
Yield: 40 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1121 g (0.861 mmol) of diethylaminopropylamine were reacted. The residue was chromatographed eluting with acetonitrile/ethanol/triethylamine (8:1:0.5 v/v/v) to give 0.0476 g (40%) of the title compound: HPLC=89% pure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C:11](OCC)=[O:12].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)Cc1cc2ccccc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ester 4-1 (0.54 g, 2.6 mmol) was dissolved in 13 mL CH2Cl2 at -78°, and DIBAL (1M in CH2Cl2, 5.8 ml, 5.8 mmol) was added dropwise. The mixture was stirred at -78° for 15 min then warmed to RT for 30 min and quenched in sat. aqueous Na/K tartrate. This solution was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated. Flash chromatography (silica 50% EtOAc/hexane) provided 4-2 as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cc(F)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2cc(F)cc(Cl)c2)cc1
Yield: 88.9 %

Procedure:
To a solution of 3-chloro-5-fluorophenol (1.46 g, 10 mmol) and 1-fluoro-4-nitrobenzene (1.41 g, 10 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.76 g, 20 mmol) and the reaction mixture was heated to reflux for 4 hours. After filtration, the solvent was removed. The residue obtained was washed with n-hexane (2 times 15 mL) and dried to afford the title compound (2.38 g) which was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([NH2:49])[CH3:48])=[CH:43][CH:42]=1>C1COCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:49][C@H:47]([C:44]2[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=2)[CH3:48])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: O=C(O)[C@H]1COCCN1c1nc(Cl)ncc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccc(Cl)cc1
Yield: 72.2 %

Procedure:
To a 50 mL round-bottom flask were added (R)-4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (460 mg, 1.426 mmol), 1-hydroxybenzotriazole (193 mg, 1.426 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg, 1.711 mmol) in THF (10 mL) to give a beige solution. After 5 minutes (S)-1-(4-chlorophenyl)ethylamine (0.220 mL, 1.569 mmol) was added to the solution, which was allowed to react at room temperature for 1.5 hours. The reaction mixture was subsequently partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by normal phase column chromatography (20-50% EtOAc gradient in hexanes over 20 minutes) to give a diastereomeric mixture of the title compound as a white foam (474 mg, 72.2%). 1H NMR (400 MHz, DMSO-d6) δ 1.35-1.42 (m, 3H), 3.50-3.63 (m, 2H), 3.69-3.79 (m, 1H), 3.83-3.93 (m, 1H), 4.23-4.39 (m, 2H), 4.85-4.89 (m, 1H), 4.90-5.03 (m, 1H), 7.33-7.41 (m, 4H), 8.44-8.48 (m, 1H), 8.48-8.57 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H17BrCl2N4O2, 458.99; found 459.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[CH3:35].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([O:27][C:18]3[C:17]4[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=4)[N:21]=[CH:20][CH:19]=3)=[C:29]([CH3:35])[CH:30]=2)=[S:12])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 64%).
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=N/S(C2SC=CC=2)(=O)=O)/[CH:3]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:35][S:32]([C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)(=[O:34])=[O:33])[CH:3]=1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Reactant: NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc21

Procedure:
5.2.35 N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)naphthalene-2-sulfonamide (12f) was prepared according to the procedure for (12a) except using naphthalene-2-sulfonamide, TiCl4.2THF and THF as solvent which afforded the title compound 594.8 mg (77.9%) as a yellow solid, m.p.: 200-202° C.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH3:41])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH3:41])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](c3cccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3cccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: C1CCNCC1
Product: Cc1cc(Br)ccc1C(=O)N1CCCCC1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-methyl benzoic acid and piperidine.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:24][C:25]1[CH:29]=[C:28]([C:30]2[S:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[O:27][N:26]=1>CN(C=O)C>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:24][C:25]1[CH:29]=[C:28]([C:30]3[S:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:27][N:26]=1)[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2)=[O:6])([CH3:3])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1cc2cc(C(=O)OC(C)C)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)OC(C)C)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.24 g 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester 5-isopropyl ester in 80 ml DMF, 456 mg sodium hydride (60% in mineral oil) were added at RT. After stirring for 30 min 5.3 g 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. Then additional 91 mg sodium hydride (60% in mineral oil) and 1.06 g 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and stirred for 2 h at RT. After removal of the solvent under reduced pressure the residue was taken-up in DCM (300 ml) and washed twice with water. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with heptane/ethyl acetate 6:1. The fractions containing the product were collected and the solvent evaporated under reduced pressure. Yield: 6.3 g.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cccc(-c2cc(OC)cc(OC)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cc(O)cc(O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To 395 mg (1.62 mmol) of 3,5,3′-trimethoxybiphenyl was added 9 mL of 1.0 M BBr3 in CH2Cl2. The mixture was stirred at ambient temperature for 1.5 h, then poured over 60 mL of ice, and extracted with ethyl acetate (2×25 mL). The combined organic layers were back extracted with water (1×25 mL), then brine (1×25 mL), dried over MgSO4, filtered, and concentrated to an oil. This was heated under vacuum at 110° C. to provide the titled compound (308 mg, 94%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink solid (389 mg).