Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6](Br)=[CH:5][C:4]2[O:8][C:9]([F:12])([F:11])[O:10][C:3]=2[CH:2]=1.[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C(OCC)C>[F:11][C:9]1([F:12])[O:10][C:3]2[CH:2]=[CH:1][C:6]([B:24]([OH:29])[OH:25])=[CH:5][C:4]=2[O:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-2,2-difluorobenzodioxole (1.18 g, 4.97 mmol) in anhydrous diethyl ether (8 mL) at −78° C. was treated with 2.5M n-BuLi in hexane (2.4 mL, 5.97 mmol), stirred for 1 hour, and treated with triisopropyl borate (1.5 mL, 6.46 mmol). The mixture was slowly warmed to room temperature and stirred for about 18 hours. The reaction was quenched with saturated NH4Cl/10% HCl and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was used directly without further purification. 1H NMR (CD3OD) δ 7.26-7.11 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:35]=[CH:34][C:8]2[N:9]([CH2:23][CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:30]([O:29][C:27]([N:25]([CH3:26])[CH2:24][CH2:23][N:9]1[C:8]2[CH:34]=[CH:35][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CCN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21)C(=O)OC(C)(C)C
Yield: 92 %

Procedure:
1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1.7 g) was prepared by following General Procedure E starting from 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.9 g) and 2 N NaOH (5 mL) in methanol:THF (1:1, 10 mL).
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH2:12][C:13](O)=[O:14])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([CH3:23])=[C:7]([CH3:22])[CH:8]=2)[C:3]1=[O:24].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:13](=[O:14])[CH2:12][C:11]1[N:2]([CH3:1])[C:3](=[O:24])[C:4]2[C:9]([C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:8][C:7]([CH3:22])=[C:6]([CH3:23])[CH:5]=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc2c(-c3ccccc3)c(CC(=O)O)n(C)c(=O)c2cc1C
Reactant: NCc1ccccc1
Product: Cc1cc2c(-c3ccccc3)c(CC(=O)NCc3ccccc3)n(C)c(=O)c2cc1C

Procedure:
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetic acid (Reference Example 56) and benzylamine were reacted (amidation) and treated in substantially the same manner as in Example 101 to yield the title compound as colorless crystals.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[C:14]1[C:32](=[O:33])[N:31]([CH3:34])[C:17]2[N:18]([CH3:30])[C:19]3[C:24]([C:16]=2[CH:15]=1)=[CH:23][C:22]([C:25]1[NH:26][N:27]=[CH:28][CH:29]=1)=[CH:21][CH:20]=3.O>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:14]1[C:32](=[O:33])[N:31]([CH3:34])[C:17]2[N:18]([CH3:30])[C:19]3[C:24]([C:16]=2[CH:15]=1)=[CH:23][C:22]([C:25]1[NH:26][N:27]=[CH:28][CH:29]=1)=[CH:21][CH:20]=3
Reactant: COc1ccc(-c2cc3c4cc(-c5ccn[nH]5)ccc4n(C)c3n(C)c2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)c(-c2ccc(O)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reaction time: 16 h

Procedure:
At −78° C., a 1M solution of BBr3 in CH2Cl2 (2.19 ml, 2.19 mmol) is added to a solution of compound E 3-(2-chloro-4-methoxyphenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one (306 mg, 0.73 mmol) in 3 ml of CH2Cl2. The mixture is stirred at AT for 16 h. H2O is added and the precipitate is filtered off. The solid is taken up in MeOH/CH2Cl2 and the product is adsorbed onto silica. Purification is carried out by column chromatography, elution being carried out with CH2Cl2/5% MeOH. The residue is taken up with MeOH, and the product is washed and filtered with MeOH.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCN1CC(c2ccccc2)NC1=O

Procedure:
Approximately 10.9 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 1 g. of 10% palladium on carbon in 100 ml. of ethanol is hydrogenated in a Parr Shaker apparatus at 30 psig of hydrogen for 45 minutes. The catalyst is filtered, washed with ethanol, and the filtrate is concentrated to give the title compound as a waxy white solid; m.p. 82°-83° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:21]([O:20][C:16]([CH2:17][CH2:18][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)OC(C)(C)C
Temperature: 61 °C
Reaction time: 8.5 h
Yield: 87 %

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (70.0 g, 344 mmol), tert-butyl acrylate (53.0 g, 413 mmol), benzyltrimethylammonium hydroxide (5.76 g, 34.4 mmol) and 1,4-dioxane (1,000 ml) was stirred at 60-62° C. for 8.5 hours. The solvent was distilled off under reduced pressure and water (1,000 ml) and acetic acid. (30 ml) were added to the residue, followed by extraction with ethyl acetate (twice). The extract solution was washed with a 5% aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from isopropanol (230 ml) to obtain ethyl 1-(2-tert-butoxycarbonylethyl)-4-methyl-1H-indole-2-carboxylate (99.2 g). M.p. 78-79° C.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].O>O1CCCC1>[CH3:1][NH:2][S:12]([C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylamine (2 M in tetrahydrofuran) (24 mL, 47.5 mmol) was added to an ambient temperature solution of p-nitrobenzenesulfonyl chloride (3.5 g, 15.8 mmol) in tetrahydrofuran (30 mL). After stirring at ambient temperature for 30 min, the reaction mixture was poured into water and extracted with ethyl aceate. The organic phase was dried (magnesium sulfate) and concentrated to afford N-methyl-4-nitrobenzenesulfonamide which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][O:8][C:9](=[O:25])[C:10](=[N:22][O:23][CH3:24])[C:11]#[C:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[O:14]>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9](=[O:25])[C:10]([C:11]1[CH2:5][C:4]([CH3:6])=[C:2]([CH3:3])[CH2:1][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[N:22][O:23][CH3:24]
Reactant: CON=C(C#CC(=O)c1cccc(Br)c1)C(=O)OC
Reactant: C=C(C)C(=C)C
Solvent: Cc1ccccc1
Product: CON=C(C(=O)OC)C1=C(C(=O)c2cccc(Br)c2)CC(C)=C(C)C1

Procedure:
1.5 ml of 2,3-dimethylbuta-1,3-diene are added to the solution of 300 mg 5-(3-bromo-phenyl)-2-methoxyimino-5-oxo-pent-3-ynoic acid methyl ester in 1 ml toluene. The reaction mixture is heated for 24 hours at 130° in an autoclave. It is subsequently evaporated, stirred with petrol ether and filtered with suction. The filtrate is evaporated to give 300 mg of [2-(3- bromo-benzoyl)-4,5-dimethyl-cyclohexa-1,4-dienyl]-methoxyimino-acetic acid methyl ester as a resinous oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.CO[CH:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]>CN(C)C=O>[NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH:9][CH:20]=[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=3)[C:24](=[O:32])[NH:23][C:22]2=[O:33])=[N:6][CH:7]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1cc(O)c(N)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-amino-2-aminomethyl-pyridin-4-ol (60 mg, 0.19 mmole as the dihydrobromide), 3 mL of N,N-dimethylformamide and triethylamine (101 uL, 0.72 mmole) were stirred for 15 mins, 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (63 mg, 0.19 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in dimethylsulfoxide and purified by HPLC (acetonitrile-water with 0.2% trifluoroacetic acid). The product is isolated by evaporation in-vacuo to give a brown solid, 5.5 mg, (5%); MS (ES+): m/z 437.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[S:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:26]1[C:24]2[CH2:25][N:19]([C:17]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=4[Cl:1])=[CH:35][CH:34]=3)=[O:18])[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a solution of 452 mg of 2,4-dichlorobenzoyl chloride in 6 ml of methylene chloride is added 0.6 g of 10-(4-aminobenzoyl)-10,11-dihydrodibenz[b,f][1,4]thiazepine followed by 0.375 ml of triethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1N HCl, 1N Na2CO3, water and dried over MgSO4. The filtrate is evaporated in vacuo to give 0.72 g of yellowish solid which is purified by silica gel chromatography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.254 g of the desired product as ivory crystals, m.p. 112°-115° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH2:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=S.C(N(C(C)C)CC)(C)C>>[OH:1][CH2:2][CH:3]([NH:11][C:13]1[S:12][CH2:18][C:16](=[O:17])[N:15]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CSC(=S)N1
Reactant: N[C@@H](CO)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NC(CO)Cc2ccccc2)=N1

Procedure:
Similar procedure as described in example 1f was used, starting (R)-1-hydroxymethyl-2-phenyl-ethylamine, rhodanine (2-thioxo-thiazolin-4-one) and DIEA (diisopropylethyl-amine) to give 2-(1-hydroxymethyl-2-phenyl-ethylamino)-thiazol-4-one. LC-MS m/e 251 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O>ClCCl>[C:1]1([N:7]=[C:8]([Cl:20])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(Cl)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-phenylpropionamide(7.46 g, 0.05 mol) and pyridine(13.8 g, 0.18 mol) were dissolved in dichloromethane(300 g) , and the mixture was cooled to 0° C. And then phosphorus oxychloride(8.43 g, 0.05 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred at room temperature (20° C.) for 2 hours to produce N-phenylpropionimidoylchloride.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[O:13][C:12]([C@@:14]([NH:23]C(=O)OC(C)(C)C)([CH3:22])CC3C=CC=CC=3)=[N:11][N:10]=2)[CH:6]=[C:5]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])[N:4]=1.CCO[C:40]([CH3:42])=O>>[NH2:23][CH:14]([C:12]1[O:13][C:9]([C:7]2[CH:8]=[C:3]([N:4]([CH3:5])[CH2:3][CH:8]3[CH2:7][CH:40]3[CH3:42])[N:4]=[C:5]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:33])=[O:34])[CH:6]=2)=[N:10][N:11]=1)[CH3:22]
Reactant: CCOC(C)=O
Reactant: CN(c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(Cl)n1)S(C)(=O)=O
Agent: Cl
Product: CC(N)c1nnc(-c2cc(N(C)CC3CC3C)nc(N(C)S(C)(=O)=O)c2)o1
Temperature: 25 °C

Procedure:
HCl was bubbled through a solution of product from Step B (0.532 g, 1.08 mmol) in 15 mL EtOAc at 0° C. for 5 min. The bright yellow solution was warmed to rt for 1 h, then concentrated to afford N-(4-[5-(1-aminoethyl)-1,3,4-oxadiazol-2-yl]-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide as a yellow foam which was used without further purification. 1H NMR (d4-MeOH, 400 MHz) δ 7.15 (s, 1H), 7.05 (s, 1H), 4.95 (q, J=7.0 Hz, 1H), 3.61 (dd, J=14.5, 8.1 Hz, 1H), 3.43 (dd, J=14.5, 6.9 Hz, 1H), 3.38 (s, 3H), 3.16 (s, 3H), 3.15 (s, 3H), 1.79 (d, J=7.0 Hz, 3H), 1.01 (d, J=5.8 Hz, 3H), 0.82-0.75 (m, 2H), 0.47 (m, 1H), 0.25 (m, 1H); LCMS [M+H]+=395.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([S-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: [S-]c1ccccc1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Product: COc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1

Procedure:
A solution of 1-Chloro-4-methoxy-2-nitro-benzene (3.75 g, 20.0 mmol) was reacted with sodium thiophenolate (3.96 g, 30.0 mmol) at 70° C. for 48 h following the procedure in Example 1e giving the title compound as a yellow oil after silica gel column chromatography eluting with 25% EtOAc/hexane (2.70 g, 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](C)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl.Cl.CN(C)CCO[C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>>[NH2:7][CH:6]1[CH2:8][C:40]2[CH:41]=[C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:44]=[CH:45][C:46]=2[CH2:4][CH2:5]1
Reactant: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 39.8 %

Procedure:
N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-methylphenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol) and 3-{[2-(dimethylamino)ethyl]oxy}-aniline dihydrochloride (112 mg, 0.44 mmol) were coupled according to the procedure of Example 56, Step H to give 25 mg of the title compound (19%). 1H NMR (400 MHz, d6-DMSO) δ 9.63 (s, 1H), 9.53 (s, 1H), 8.81 (d, J=7.2 Hz, 1H), 8.49 (d, J=9.2 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 7.47-7.43 (m, 1H), 7.36 (d, J=4.8 Hz, 1H), 7.30-7.25 (m, 3H), 7.14-7.08 (m, 2H), 6.97-6.95 (m, 2H), 6.52-6.50 (m, 2H), 3.97 (m, 2H), 3.90 (s, 2H), 2.58 (t, J=5.6 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 6H) ppm. ES-LC/MS m/z=604 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:30]1[CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=[CH:34][C:29]=1[F:28])=[CH:13][CH:12]=[C:11]([C:24]([F:25])([F:26])[F:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C(F)(F)F)ccc1F

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 2-fluoro-5-trifluoromethylphenylboronic acid (142 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(2-fluoro-5-trifluoromethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a slight yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[C-:11]#[N:12].[K+]>C(O)C.O>[O:8]=[C:7]([C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CC(=O)c2ccc(C#N)cc2)cc1

Procedure:
To a solution of 25 g of p-cyanobenzaldehyde in 50 ml of ethanol was added 5 g of potassium cyanide in 10 ml of water. The mixture was heated at reflux for 1 hr, cooled, and the crystalline product was filtered and washed with cold ethanol. Recrystallization from acetic acid afforded 4.7 g of the part (a) title compound, mp. 209°-215° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:12][OH:13].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:20]([O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:9]([O:8][CH3:7])[CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: COc1cc(COCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred suspension of finely powdered cesium carbonate (8.0 g, 24.5 mmol) was added 3-methoxy-4-nitrobenzyl alcohol (1.5 g, 8.18 mmol), followed by benzyl bromide, (2 mL, 16.4 mmol). After stirring at room temperature for 18 h, the suspension diluted with 100 mL diethyl ether, and washed with 3×50 mL water, then 50 mL brine. The organic phase was dried over MgSO4, filtered through a plug of silica, and concentrated. The resulting orange oil was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to give 1.87 g, (84%) of the benzyl ether. 1H NMR (400 MHz, CDCl3): δ7.85 (d, J=8.2 Hz, 1H) 7.3-7.4 (m, 5H), 7.26 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 4.59(s, 2H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:21]1[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[N:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:6]
Reactant: NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(6-fluoro-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and m-anisidine (22 μl, 0.193 mmol) similar to Example 13 and isolated as a yellow solid (31 mg, 46%). 1H NMR (CDCl3): 8.77–8.75 (m, 2H), 8.28–8.25 (m, 2H), 7.36 (t, J=8.3 Hz, 1H), 7.13 (s, 1H), 7.03 (s, 1H), 6.98–6.96 (m, 2H), 6.83–6.81 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:20]1([CH2:19][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (300 mg, 1.23 mM), benzyl bromide (210 mg, 1.23 mM), and potassium carbonate (170 mg, 1.23 mM) in 15 mL DMF was stirred at room temperature for 6 hours. The mixture was diluted with 80 mL H2O and chilled in the refrigerator. The resultant white precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 325 mg (79%) of the 9-[(phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSO-d6) δ 7.7 (dd, 1H, J=1 and 8 Hz), 7.45-7.0 (m, 7H), 5.6 (s, 2H), 3.8 (s, 3H), 3.05 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 3421, 1726, 1676, 1636, 1473, 1450, 1435, 1288, 1122, 764, 745, and 706. MS (ES) m/e 334.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1([C:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OCC)(=O)C>C(#N)C>[S:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:28]([N:22]2[CH2:23][CH2:24][N:25]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:26][CH2:27]2)=[N:29]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example 2.7) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.