Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH3:32])=[O:30].O>O1CCCC1>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C:11]([N:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:29](=[O:30])[O:31][CH3:32])[C:7]=2[CH:8]=[CH:9]1)=[O:12]
Reactant: Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of (4-amino-1H-pyrrolo[3,2-c]pyridin-1-yl)(2,6-dichlorophenyl)methanone (50 mg, 0.16 mmol) and triethylamine (0.013 mL, 0.18 mmol) in anhydrous tetrahydrofuran was cooled to 0° C. and treated drop wise with methyl chloroformate (0.05 mL, 0.33 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured onto cold water and the precipitated solid was filtered off, washed with hexane and dried to afford methyl [1-(2,6-dichlorobenzoyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]carbamate (35 mg, 60%).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[S:4][N:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][C:5]2[S:4][N:3]=[C:2]([NH:22][CH:19]([CH3:21])[CH3:20])[N:6]=2)=[CH:13][CH:14]=1
Reactant: CC(C)N
Reactant: CC(C)(CNc1nc(Cl)ns1)c1ccc(F)cc1
Product: CC(C)Nc1nsc(NCC(C)(C)c2ccc(F)cc2)n1
Temperature: 110 °C

Procedure:
3-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-thiadiazol-5-amine (50 mg, 0.18 mmol, 1.0 equiv) and i-PrNH2 (0.5 mL, 5.8 mmol) were loaded into a microwave vial, and the resulting mixture was heated to 110° C. for 30 minutes. The reaction mixture was then concentrated in vacuo. Purification by silica gel (20-30% EtOAc/Hexanes) provided the title compound as an off white solid (55 mg, 99%). m/z=309.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[N:14]([CH3:25])[N:13]=1)=[O:11].[F:26]C1C=CC(OC)=C(C2N(C)N=C(C(O)=O)C=2)C=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([F:26])[CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[N:14]([CH3:25])[N:13]=1)=[O:11]
Reactant: COc1ccc(F)cc1-c1cc(C(=O)O)nn1C
Reactant: COc1ccccc1-c1cc(C(=O)Nc2c(F)cccc2F)nn1C
Product: COc1ccc(F)cc1-c1cc(C(=O)Nc2c(F)cccc2F)nn1C
Product: Nc1c(F)cccc1F
Yield: 22 %

Procedure:
The title compound of example 10 was prepared in analogy to the preparation of the title compound of example 1 through the reaction of 5-(5-fluoro-2-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (201 mg) with 2,6-difluoroaniline (105 mg) (22% yield).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([O-:4])=[O:3].N[C:13]1[CH:21]=C2C(C=NN2)=C[CH:14]=1.[CH2:22]([O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25]>CCOCC>[ClH:1].[NH2:9][C:8]1[CH:10]=[C:11]2[C:5](=[CH:6][CH:7]=1)[N:2]=[CH:21][CH:13]=[C:14]2[NH:31][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:33][CH:32]=1.[N+:2]([C:5]1[CH:11]=[C:10]2[C:8](=[CH:7][CH:6]=1)[N:9]=[CH:21][CH:13]=[C:14]2[NH:31][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:33][CH:32]=1)([O-:4])=[O:3]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCOc1ccc(N)cc1
Agent: Cl
Solvent: CCOCC
Product: CCCCOc1ccc(Nc2ccnc3ccc(N)cc23)cc1
Product: CCCCOc1ccc(Nc2ccnc3ccc([N+](=O)[O-])cc23)cc1

Procedure:
The title compound was prepared from the corresponding -nitro compound by catalytic reduction of the nitro group followed by treatment with HCl in ether. The 6-nitro-4-(p-butoxyanilino) quinoline compound was prepared in an analogous fashion to Example 9 with the modification that 4-nitroaniline was used as the starting material instead of 6-aminoindazole and p-butoxyaniline was used in the displacement of the 4-chloro substituent instead of m-anisidine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([Cl:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyloxyacetic acid (4.6 g, 28.0 mmol, 4.0 mL) in DCM (52 mL) was added oxalyl chloride (7.7 g, 61 mmol, 5.3 mL) and a drop of DMF. The reaction mixture was stirred at room temperature for 4 h. Excess of oxalyl chloride was removed in vacuo to give benzyloxy-acetyl chloride. The crude acyl chloride was diluted into DCM (100 mL) and triethylamine (5.3 mL, 41.6 mmol, 4.2 g) was added followed by 4-fluoroaniline (3.5 g, 32 mmol, 3.0 mL). The reaction mixture was stirred at RT overnight. The reaction was then quenched with 1 M aqueous HCl (100 mL), dried and concentrated in vacuo to give 7.1 g (95%) of 2-benzyloxy-N-(4-fluoro-phenyl)-acetamide (33) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 69.2, 73.5, 115.4 (d, JCF=22 Hz), 121.4 (d, JCF=7 Hz), 127.9, 128.2, 128.5, 132.5 (d, JCF=3 Hz), 136.3, 157.6, 160.8, and 167.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[C:25]([C:38]([O:40]C)=[O:39])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:36])([F:37])[F:35])[C:25]([C:38]([OH:40])=[O:39])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
215 mg (0.36 mmol) of the compound from Example 139 were dissolved in 3 ml of THF and 3 ml of methanol, and 0.36 ml of 2 N aqueous sodium hydroxide solution was added. The mixture was stirred at 80° C. for 16 h. For work-up, the mixture was diluted with 10 ml of water and extracted twice with in each case 10 ml of ethyl acetate. The aqueous phase was acidified with 1 N hydrochloric acid and once more extracted with 10 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dried under high vacuum. This gave 222 mg (quant.) of the target compound.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20]N(C)C)[CH:18]=O)=[CH:13][CH:12]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CO.O>[C:4]([C:6]1[C:7](=[O:8])[NH:9][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:20]=1)#[N:5]
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Temperature: 25 °C

Procedure:
To solution of sodium methoxide (7.52 g) in methanol (130 ml) was added cyanoacetamide (5.84 g) followed by 2-(4-chlorophenyl)-3-dimethylaminopropenal and the resulting suspension was refluxed overnight. During this time a yellow solid was formed. The mixture was cooled to room temperature and glacial acetic add (50 ml) was added followed by water (100 ml). The resulting yellow orange solid was filtered off, washed several times with water and dried to yield 8.1 g of 3-cyano-5-(4-chlorophenyl)-2-pyridinone.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][C:25](O)=[O:26])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:28][C@@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O.O>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][C:25]([N:33]5[CH2:32][CH2:31][NH:30][C@H:29]([CH3:28])[CH2:34]5)=[O:26])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)Cc1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Reactant: C[C@@H]1CNCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CN(C(=O)Cc2cn3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccc3n2)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {5-[(adamantan-1-ylmethyl)-carbamoyl]-imidazo[1,2-a]pyridin-2-yl}-acetic acid (40 mg, 0.1 mmol) in DMF (1 mL) is sequentially added (R)-2-methyl-piperazine (43 mg, 0.44 mmol) and 96 mg of BOP (0.2 mmol). After stirring for 2 h at RT, the reaction mixture is diluted with EtOAc and water. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. Purification of the residue by PTLC (10% MeOH, 1% NH4OH in DCM) affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([NH2:20])=O)[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]#[N:20])[N:6]2[CH2:13][C:14]([F:16])([F:17])[F:15]
Reactant: N#Cc1ccc2c(cc(C(N)=O)n2CC(F)(F)F)c1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc2c(cc(C#N)n2CC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
To a suspension of 4-chloro-5-cyano-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (0.05 g, 0.17 mmol) in CH2Cl2 (6 mL) was added pyridine (0.104 g, 1.32 mmol), followed by dropwise addition of TFAA (0.14 g, 0.66 mmol). The mixture was stirred at rt for 4 h and then concentrated in vacuo. The residue was partitioned between EtOAc and 0.5N HCl. The organic phase was washed with 0.5N HCl and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.033 g, 72% yield): MS (ES) m/z 284 (M+1).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(F)c(F)c1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl acetoacetate (8.0 g, 0.069 mol), 3,4-difluorobenzaldehyde (9.8 g, 0.069 mol), acetic acid (0.490 g, 0.008 mole) and piperidine (0.69 g, 0.008 mol) in benzene (1.5 L) were added molecular sieves (37.9 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by trituration from hexane to yield the intermediate methyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-butyrate product as a yellow solid as a mixture of cis and trans isomers. A suspension of the methyl 2-[(3,4-difluorophenyl)methylene]-3- oxo-butyrate thus obtained(12 g, 49.9 mmol), O-methylisourea hemisulfate (11.15 g, 67.76 mmol, 1.5 eq.), and sodium bicarbonate (17 g, 203 mmol, 3 eq.) in DMF (110 mL) was stirred at 60° C. for 8 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by chromatography on silica gel eluting with 25%-30% EtOAc/hexane, to give the product as a pale yellow solid. 1H NMR (CDCl3) d 7.2-7.0 (m, 3H), 6.0 (s, 1H), 5.56 (s, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 2.33 (s, 3H),
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:15]1([CH:14]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)[C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2ccc(Br)cc2)C2CCCCC2)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C2CCCCC2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. The isomers are resolved by methods described herein or known to one skilled in the art. Isomer 1 MS: 524.3 [M−H]−; Isomer 2 MS: 524.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[ClH:1].[ClH:1].[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)[CH:11]=[CH:10]2
Reactant: CN1CCNCC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: CN1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Product: Cl
Yield: 38 %

Procedure:
Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (150 mg) and 1-methyl-piperazine (380 mg). The product was purified by chromatography (SiO2, dichloromethane:methanol 95:5 as eluant), converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane) and recrystallised (methanol/ethyl acetate) to give the title compound as a solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.CN1CCOCC1.N1C(Cl)=NC(Cl)=NC=1Cl.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CC(C)=O>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:44][CH:43]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)O)cc21
Reactant: Nc1ccc(Cl)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (30 mg, 0.082 mmol) in acetone (0.9 ml) was treated with N-methylmorpholine (0.025 ml, 2.4 equiv.) and cyanuric chloride (18 mg, 0.098 mmol, 1.2 equiv.) and stirred at room temperature for 2 hours. 4-Chloro-phenyl-amine (12 mg, 0.098 mol, 1.2 equiv.) was then added, and the mixture was stirred for 12 hours at room temperature. The solvent was evaporated, and the residue dissolved in methanol (2.5 ml) and purified by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). 1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-chloro-phenyl)-amide was obtained as a white solid, 10.6 mg (27%). MS (ISP): m/e=474.9, 477.8 (M−H), δH (300 MHz; d6-DMSO) 10.33 (1H, s), 7.86 (1H, d), 7.79 (2H, d), 7.71 (1H, s), 7.69 (1H, d), 7.60 (1H, d), 7.40 (2H, d), 7.35 (1H, d), 7.21 (1H, d), 4.10 (2H, t), 3.66 (3H, s), 3.12 (2H, t).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2].C1C=CC=CC=1.[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH2:1]([CH:3]1[N:7]([C:22](=[O:23])[CH:21]([Cl:25])[Cl:20])[CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCC1NCC(c2ccccc2)O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC1OC(c2ccccc2)CN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths (21.3) ml. of a solution containing 5.3 g. of 2-ethyl-5-phenyl oxazolidine was diluted with 25 ml. of benzene and 3.1 g. of triethylamine was added. The mixture was cooled in a room temperature water bath and 4.4 g. of dichloroacetyl chloride was added dropwise with stirring. The stirring was continued for about 30 minutes after addition was complete. The solution was washed with water, separated, dried over magnesium sulfate and removed under vacuum. There was obtained a yield of 8.7 g. of the title compound, an oil, ND30 =1.5600.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][C:14]([NH:23][CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH2:1]([N:8]([CH2:10][C:11]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][C:14]([N:23]([CH3:33])[CH3:24])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BC#N
Reactant: CNC1(c2ccccc2)CCC(CN(C)Cc2ccccc2)(c2ccccc2)CC1
Agent: C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(Cc1ccccc1)CC1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from step 10 (diastereomer mixture) (0.350 g, 0.878 mmol) and formalin (1.23 mL, 37% aqueous solution) in acetonitrile (15 mL) was mixed in portions with sodium cyanoboron hydride (0.250 g, 3.86 mmol) and stirred for 45 min at room temperature. Conc. acetic acid was then added until a neutral reaction occurred and the mixture was subsequently stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (3×40 mL). The organic solution was dried over Na2SO4, filtered and concentrated to low volume in a vacuum. The remaining residue was purified by Chromatotron and with cyclohexane/ethyl acetate 1:1. Separation of the diastereomers could not be achieved.
Reaction SMILES: [CH:1](C1C=CC(CN(C)C(=O)OCC2C=CC=CC=2)=CC=1)=O.C(=NC1C=CC=C2C=1COC2=O)C1C=CC=CC=1.C[O-].[Na+].CO.[CH2:45]([O:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[C:73](=[O:74])[C:72]3[C:71]([C:75]([O:77][CH3:78])=[O:76])=[CH:70][CH:69]=[CH:68][C:67]=3[NH:66][CH:65]2[C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)CC>[CH2:45]([O:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[C:73](=[O:74])[C:72]3[C:71]([C:75]([O:77][CH2:78][CH3:1])=[O:76])=[CH:70][CH:69]=[CH:68][C:67]=3[NH:66][CH:65]2[C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CN(Cc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Agent: C[O-]
Agent: O=C1OCc2c(N=Cc3ccccc3)cccc21
Agent: [Na+]
Solvent: CO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A mixture of benzyl 4-formylbenzyl(methyl)carbamate (566 mg, 2 mmol) and 4-(benzylideneamino) isobenzofuran-1-one (474 mg, 2 mmol) in ethyl propionate (15 mL) was cooled to 0° C. A solution of sodium methoxide in methanol [sodium (184 mg, 8 mmol) in methanol (15 mL)] was then added dropwise. After the addition, the mixture was stirred at 25° C. for 18 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 10:1) to give a mixture of methyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (220 mg, yield 20%) as a light yellow solid. LC-MS (ESI) m/z: 535 (M+1)+ and 549(M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(C)C)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(C)C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cccc(O)c2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 40.0 mg (0.076 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.00 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ7.90 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.4 Hz), 7.35 (2H, s), 7.15-7.07 (2H, m), 6.77-6.69 (3H, m), 5.92 (1H, t, J=4.7 Hz), 2.25 (2H, d, J=4.7 Hz), 1.23 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.Cl.[C:14](=O)([O-])[O-].[K+].[K+]>CO>[OH:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([O:10][CH3:14])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)ccc1O

Procedure:
A mixture of 73 g of 5-methoxysalicylic acid, and 95 ml of concentrated hydrochloric acid in 700 ml of methanol was heated under reflux for 48 hours. Potassium carbonate (10 g) was added, and the mixture concentrated to an oily residue which was dissolved in 250 ml of ethyl acetate. This solution was washed with two 100 ml portions of 10% sodium bicarbonate solution, then dried over anhydrous sodium sulfate. Evaporation of solvent afforded the title compound as an amber oil.