Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(=O)O
Reactant: Cc1cccc(Nc2ncnc3cc(N)ccc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2c(Nc3cccc(C)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.3 %

Procedure:
To a stirred solution of 7-amino-4-[(3-methylphenyl)amino]quinazoline (123 mg, 0.49 mmol), acrylic acid (0.04 mL, 0.58 mmol), triethylamine (0.15 mL, 1.1 mmol) in DMF (1.5 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg, 0.64 mmol). The resulting light yellow mixture was stirred at 25° C. for 20 hours and quenched with water. The solid was collected and purified by sonication with a mixture of CH2Cl2/EtOAc/MeOH to give the desired product as a yellow solid (75 mg, 49%), mp 269.7-270° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=O.[C:19]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)([CH3:22])([CH3:21])[CH3:20].C(O)C.[BH4-].[Na+]>O.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[CH2:7][NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:32])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Bromo-2-benzyloxybenzoic acid [International patent application, publication no, WO 96/03380] and tert-butyl-4-aminobenzoate were heated on a steam bath for 2 hours. Ethanol (50 ml) and tetrahydrofuran (50 ml) were added to the hot reaction mixture. The solution was allowed to cool and sodium borohydride (1.4 g) was added. The reaction mixture was then stirred at ambient temperature for 3 hours, poured into water (200 ml) and extracted with dichloromethane (4×100 ml). The combined extracts were dried over magnesium sulphate to give tert-butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate which was used without further purification (18 g).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH:11]([CH2:20][CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([CH:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10]1)[CH3:21]
Reactant: CCC1CCN(C(=O)OC(C)(C)C)c2cc(OC)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1CCNc2cc(OC)ccc21
Yield: 93.8 %

Procedure:
In a oven dried 250 mL r.b. flask equivuipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-1-t-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline (34.0 mg, 117 μmol) in dry CH2Cl2 (1 mL). To the stirred solution was added TFA (1.2 mL) at rt and was allowed to react for 2 h. The dark red solution was quenched with sat NaHCO3 solution (10 mL), extracted with CH2Cl2 (3×25 mL), washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford 21 mg (95%) of the desired amine as a clear light yellow oil. Data for (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline: Rf =0.1 (hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 6.92 (d, J=8.5, 1H), 6.21 (dd, J=2.5, 8.2, 1H), 6.03 (d, J=2.5, 1H), 3.73 (s, 3H), 3.27 (m, 2H), 2.59 (m, 1H), 1.86 (m, 1H), 1.75 (m, 2H), 1.48 (m, 1H), 0.968 (t, J=7.4, 3H).
Reaction SMILES: [F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(C)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC[C@@H]1CNCCN1C(=O)OCc1c(F)ccc(C)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-3-methyl-benzyl) ester (160 mg) was dissolved in methanol (3 mL), 500 μL 4 N HCl in dioxane was added and the mixture was stirred for 18 h at room temperature. The mixture was added to water (10 mL) made alkaline with 1 N NaOH and extracted with ethylacetate. Organic phases were pooled, dried with Na2SO4 and evaporated to give the product as a yellowish oil (120 mg); MS (ISP): 299.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=O)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:21].[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=3)=[O:18])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(CNC(=O)c2cc(C(=O)O)ncn2)ccc1F
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(CNC(=O)c2cc(C(=O)NCc3ccc(F)c(C)c3)ncn2)cc1
Reaction time: 5 h
Yield: 127.3 %

Procedure:
1.3 g (4.5 mmol) of 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid and 1.042 g (5.4 mmol) of ethyl (4-aminomethylphenyl)acetate were dissolved in 30 ml of DMF, after which 1.02 g (4.9 mmol) of dicyclohexylcarbodiimide and 0.607 g (4.5 mmol) of hydroxybenzotriazole were added at 5° C. The mixture was stirred for 5 hours (h) and filtered with suction. The solvent was removed in vacuo and the residue was taken up in ethyl acetate; this solution was washed with a saturated aqueous solution of NaHCO3. The organic phase was dried (MgSO4), filtered and evaporated under reduced pressure. This resulted in 2.66 g of product, which was further purified by means of preparative HPLC. MS (ES+): m/e=464.19.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:19])([F:18])[CH2:16][O-:17]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: [O-]CC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)c([N+](=O)[O-])c1

Procedure:
In a first reaction step, 1-chloro-2,4-dinitrobenzene (II) is reacted with 2,2,2-trifluoroethanolate to form 1,3-dinitro-4-(2',2',2'-trifluoroethoxy)-benzene (III) according to the following reaction: ##STR2## For obtaining this reaction, 4.0 g (0.17 mole) sodium is completely dissolved in 100 ml 2,2,2-trifluoroethanol. Thereafter, 21.5 g (0.11 mole) of finely powdered 1-chloro-2,4-dinitrobenzene is added to the solution. The mixture is then heated under reflux for 3 hours and the excessive trifluoroethanol is distilled off under normal pressure. The remaining oil is dissolved in 210 ml ethanol. Through addition of 170 ml water, the reaction product III is precipitated in a crystalline form. It is sucked off, washed with a water-ethanol mixture (1:1) and then dried over CaCl2. The yield of 1,3-dinitro-4-(2',2',2'-trifluoroethoxy)-benzene is 27.0 g (0.1 mole 95% relative to the use 1-chloro-2,4-dinitrobenzene). The substance has a melting point of 76°-77° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([NH:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=3[N:22]=[CH:21]2)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>CC(N(C)C)=O>[C:10]([NH:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:30])=[CH:28][C:23]=3[N:22]=[CH:21]2)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11]
Reactant: NCc1cccnc1
Reactant: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)O)ccc32)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reaction time: 0.5 h

Procedure:
DIPEA (0.75 mL, 4.31 mmol) was added at rt to a mixture of 1-[3-(acetylamino)phenyl]-1H-benzimidazole-5-carboxylic acid (0.83 g, 2.8 mmol), EDC (0.81 g, 4.22 mmol), HOBt (0.57 g, 4.22 mmol) in anhydrous DMA (10 mL). The reaction mixture was stirred for 30 min prior to the dropwise addition of 3-aminomethylpyridine (0.57 mL, 5.62 mmol). After stirring for a further 25 h, the solvent was removed in vacuo and the crude material purified by column chromatography over silica gel eluting with 5-15% MeOH in DCM. The product was further purified by recrystallisation from acetone to afford 1-[3-(acetylamino)phenyl]-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6): δ 2.09 (3H, s), 4.54 (d, J=6.0 Hz, 2H), 7.35-7.4 (m, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.92 (dd, J=8.4 Hz, 1.2 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 8.46 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.58 (1H, J=1.6 Hz, 1H), 8.68 (s, 1H), 9.21 (t, J=5.6 Hz, 1H), 10.33 (s, 1H); MS (ES+): m/z 386 [MH+]
Reaction SMILES: C[Si]([Cl:5])(C)C.[Br-].C([NH3+])(C)(C)C.[CH:12]1([C:15](=[O:22])[CH2:16][C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])[CH2:14][CH2:13]1.CS(C)=O>C(#N)C.O>[Cl:5][CH:16]([C:17]([CH:19]1[CH2:20][CH2:21]1)=[O:18])[C:15]([CH:12]1[CH2:13][CH2:14]1)=[O:22]
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)(C)[NH3+]
Agent: [Br-]
Solvent: CC#N
Solvent: CS(C)=O
Solvent: O
Product: O=C(C1CC1)C(Cl)C(=O)C1CC1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
Trimethylsilyl chloride (16.6 ml, 130 mmol) was added to a solution of tert-butylammonium bromide (0.70 g, 2.17 mmol) in acetonitrile (50 ml) under nitrogen at 0° C. 1,3-Dicyclopropyl-propane-1,3-dione (ref: WO98155438) (6.62 g, 43.5 mmol) in acetonitrile (15 ml) was then added followed by dimethylsulfoxide (9.25 ml, 130 mmol) dropwise, and the reaction was allowed to warm to room temperature over 4 hours. The mixture was diluted with water (75 ml), extracted with diethylether (3×35 ml) and the combined organic extracts dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with pentane:diethylether (95:5, by volume) to provide the title compound (3.76 g) as an oil, which was an 80:20 mixture of enol:keto forms.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9](=S)[NH:10][C:4]=2[CH:3]=1.[CH2:23]([N:26]([CH2:30][C:31]([NH:33][NH2:34])=O)[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(O)CCC>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9]3[N:10]([C:31]([CH2:30][N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[N:33][N:34]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)NC(=S)CN=C2c1ccc(C(C)C)cc1
Reactant: CCCN(CCC)CC(=O)NN
Solvent: CCCCO
Product: CCCN(CCC)Cc1nnc2n1-c1cc(C)ccc1C(c1ccc(C(C)C)cc1)=NC2

Procedure:
In the manner given in Example 5, a solution of 1,3-dihydro-8-methyl-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to a reflux with (dipropylamino)acetic acid hydrazide to give 9-methyl-1-[(dipropylamino)methyl]-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4)benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20]O>CC1C=CC(S(O)(=O)=O)=CC=1.CC(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: COc1ccc(CO)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)C(F)(F)F)cc1OC
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
4-Chloro-2-trifluoroacetylaniline (4.96 g, 40 mmol) and 3,4-dimethoxybenzyl alcohol (7.39 g, 44 mmol) were added to 2-propanol (40 mL). TsOH (76 mg, 0.4 mmol) was added and the mixture heated to 60° C. and held 3.5 hours. The solution was concentrated in vacuo to 1/2 the original volume, diluted with water (10 mL) and stirred at room temperature. The resulting slurry was filtered and the product dried in vacuo at 30° C. to give 10.16 g (68%) of the title compound as a yellow powder. An analytical sample was obtained by recrystallization from acetonitrile: mp 82-84° C.; 1H NMR (CDCl3) δ 9.05 (brs, 1H), 7.75 (brt, J=2 Hz, 1H), 7.35 (dd, J=2, 8 Hz, 1H), 6.8 (d, J=8 Hz, 3H), 6.75 (d, J=8 Hz, 1H), 4.43 (d, J=5 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl3) δ 179.9, 151.9, 149.4, 148.7, 137.4, 130.8, 130.8, 130.7, 129.4, 119.4, 114.5, 111.5, 111.4, 110.3, 56.1, 56.0, 47.0; 19F NMR (CDCl3) δ 69.61.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]([OH:16])[CH3:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O>O=[Mn]=O.C(Cl)Cl>[NH2:1][C:4]1[C:5]([C:14](=[O:16])[CH3:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CC(O)c1ccc2cccnc2c1[N+](=O)[O-]
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1ccc2cccnc2c1N
Yield: 76 %

Procedure:
In a similar fashion using route 27 general procedure 68, 1-(8-nitro-quinolin-7-yl)-ethanol 409 (200 mg, 1.06 mmol), MnO2 (925 mg, 10.63 mmol) and DCM (5 ml) gave the title compound (150 mg, 78%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.O>ClCCl>[N:26]1([C:32]([N:13]2[CH2:14][CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=3)[CH2:10][CH:11]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:12]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(NC1CNCC(c2cccc(C(F)(F)F)c2)C1)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., 165 mg (0.47 mmol) of N-{5-[3-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 17 ml of dichloromethane, and 71 mg (0.47 mmol) of morpholine-4-carbonyl chloride and 132 μl (0.95 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 202 mg (92% of theory)
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>CCCCCC.C1COCC1.CCOCC>[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[B:28]([OH:33])[OH:29])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1cccc1B(O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
n-Butyllithium (29 ml of a 1.6M solution in hexane, 47.4 mmol) was added dropwise over 10 minutes to a solution of 2,2,6,6-tetramethylpiperidine (6.7 g, 47.4 mmol) in THF (175 ml) cooled to −78° C. A solution of 1-t-butoxycarbonylpyrrole (8.19 g, 49 mmol) in THF (25 ml) was added and the mixture was maintained below −70° C. The reaction mixture was stirred for 1.5 hours at −78° C. and tri-isopropyl borate (17 g, 90 mmol) was added. The reaction mixture was then allowed to warm to ambient temperature over 1 hour. The mixture was diluted with ether (500 ml) and washed with 1M potassium hydrogen sulphate solution (100 ml×3), 1M sodium hydrogen carbonate solution (100 ml×2) and brine (100 ml). The ether phase was dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash column chromatography eluting with isohexanes/ethyl acetate (a gradient from 100/0 to 50/50) to give the 1-t-butoxycarbonylpyrrol-2-ylboronic acid (4.05 g, 43%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][NH:1]2)[C:10]=1[C:11]#[N:12]
Reactant: OC[C@H]1CCCN1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OC[C@H]1CCCN1

Procedure:
Prepared as in Example 24d from (R)-pyrrolidin-2-ylmethanol and 2-amino-6-fluoro-benzonitrile as brown solid (57%). MS 218 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:35][CH2:34][C:9]2[C:10]3[C:15]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=5)=[C:19]([Cl:32])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:33][C:8]=2[CH2:7]1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[C:9]4[CH2:34][CH2:35][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][C:8]=4[S:33][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: CCOC(=O)CC1CCc2c(sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1CCc2c(sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of THF (40 mL) was added 7 g (13.3 mmol, 1 equiv) of {4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-acetic acid ethyl ester. A 1M solution of diisobutylaluminum hydride in hexanes (53 mL, 53 mmol, 4 equiv) was added to the solution and the reaction was stirred at rt for 3 h. The reaction mixture was quenched with Rochelle's salt followed by EtOAc. The solution was separated and the aqueous layer discarded and the organic layer was washed with brine (100 mL) and water (100 mL). The resulting material 5.5 g (85%)was pure white solid of Example 137. 1H-NMR (DMSO-d6) δ 1.5 (m, 3H), 1.95 (m, 2H), 2.93 (dd,1H), 3.16 (2H), 3.53 (m,2H), 4.45 (t, 1H), 5.2 (s, 2H), 7.17 (m, 2H), 7.28 (m,2H), 7.43 (m, 1H), 7.5 (dd, 2H), 7.76 (dd, 1H), 8.05 (s, 1H). LCMS RT=3.46 min; [M+H]+=484.2.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:20]([F:23])([F:21])[F:22])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 16 h
Yield: 83.8 %

Procedure:
Butyryl chloride (1.5 mL, 14.5 mmol) was added dropwise to a mixture of 3-amino-7-(trifluoromethyl)-4-quinolinol hydrochloride (3.5 g, 13.2 mmol), triethylamine (6.1 mL, 43.6 mmol) and anhydrous tetrahydrofuran (30 mL). The reaction mixture was allowed to stir for 16 hours. A small amount of aqueous sodium bicarbonate was added and the reaction mixture was stirred for 0.5 hours. The tetrahydrofuran was removed under vacuum. The resulting solid was stirred with diethyl ether, isolated by filtration, washed with water and diethyl ether, and then dried in a vacuum oven at 80° C. overnight to provide 3.3 g of N-[4-hydroxy-7-(trifluoromethyl)quinolin-3-yl]butanamide as a cream colored solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[CH2:53]=[CH:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:55]1(/[CH:54]=[CH:53]/[C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: C=Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(/C=C/c3ccccc3)cc2s1
Yield: 62 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, Pd(PPh3)2Cl2, dppp, triethylamine, styrene, and two crystals of BHT in anhydrous DMF was reacted according to the procedure of Example 225 to give the desired compound 0.201 g (62%). LC/MS 324.2 (M+1); LC retention time 2.87 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24]Br)=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Mg+].[Br-]>CCOCC.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][CH3:28])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CBr)=CC1(C)C
Reactant: C[Mg+]
Agent: [Cu]I
Agent: [Br-]
Solvent: CCOCC
Product: CCC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of N-tert-butyloxycarbonyl-4-bromomethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (structure 12, where R1 =phenyl) (20 mg, 0.047 mmol) and copper (I) iodide (4 mg, 0.02 mmol) in 1 mL of anhydrous ether at 0° C. was added MeMgBr (0.060 mL, 3M in ether). After 30 min of stirring at 0° C., the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil which was purified by SGC (silica gel, hexane/ethyl acetate, 9:1) giving N-tert-butyloxycarbonyl-4-ethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (16 mg, 91%). 1H NMR (acetone-d6) 7.65 (d, J=8.7, 2H), 7.51 (dd, J=8.0, 1.7, 1H), 7.29 (m, 2H), 7.43 (m, 3H), 5.56 (s, 1H), 2.55 (q, J=8.9, 2H), 1.51 (s, 6H), 1.57 (s, 9H), 1.19 (t, J=8.9, 3H). To a solution of N-tert-butyloxycarbonyl-4-ethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (16 mg, 0.044 mmol) in 1 mL of dichloromethane at 0° C. was added 0.3 mL of trifluoroacetic acid. After 10 min of stirring, the reaction was quenched with saturated NaHCO3, and extracted with dichloromethane. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil that was purified by SGC (silica gel, hexane/ethyl acetate, 7:3) to provide 3 mg (25%) of Compound 112. Data for Compound 112: 1H NMR (acetone-d6) 7.55 (d, J=8.6, 2H), 7.37 (m, 3H), 7.23 (m, 2H), 6.59 (d, J=8.26, 1H), 5.38 (s,1H), 3.76 (s, 1H), 2.48 (q, J=7.4, 2H), 1.29 (s, 6H), 1.17 (t, J=7.4, 3H).