Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Br:2][C:3]1[CH:4]=[N:5][C:6](Cl)=[N:7][CH:8]=1.[CH3:10][OH:11]>>[Br:2][C:3]1[CH:4]=[N:5][C:6]([O:11][CH3:10])=[N:7][CH:8]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CO
Agent: [Na]
Product: COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metal (74 mg, 3.10 mmol) was added in portions to CH3OH (25 mL) at 0° C. and the mixture was stirred for 30 min at RT. 5-Bromo-2-chloropyrimidine (500 mg, 2.58 mmol) was added to the above mixture at 0° C., and the resulting reaction mixture was gradually heated to reflux temperature and stirred for 2 h. After complete consumption of the starting material (by TLC), the volatiles were concentrated under reduced pressure; the residue was quenched with ice-cold water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude S (400 mg). The crude material was used directly in the next step without any further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[C:30]([S:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[CH:29][N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>C(O)(C)(C)C>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([S:31][C:30]2[C:23]3[C:22]([NH:1][C@H:2]([C:4]4[N:9]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:8](=[O:16])[C:7]5=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]5[N:5]=4)[CH3:3])=[N:27][CH:26]=[N:25][C:24]=3[N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[CH:29]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 35.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.22 mmol) was treated with 4-chloro-5-((3-methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (109 mg, 0.26 mmol), N,N-diisopropylethylamine (195 μl, 1.12 mmol), cesium fluoride (41 mg, 0.27 mmol) and tert-butanol as a solvent according to the method described in Example 17. The crude was purified using SP1® Purification (0% to 50%, hexane-ethyl acetate) to give 51 mg (35% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]1[N:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:27][C:28]4[N:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][CH:29]=4)[CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Reactant: N#Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2cc(C(=O)c3ccc4c(c3)OCCO4)c(=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
The mixture of 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one (70 mg, 0.228 mmol, 1 eq) in DMF (1 ml) and sodium hydride (11.8 mg, 0.296 mmol, 1.3 eq) was stirred at room temperature for 60 min, followed by the addition of 6-Bromomethyl-pyridine-2-carbonitrile (74.1 mg, 0.296 mmol, 1.3 eq). The mixture was stirred for 60 min, quenched with water, taken up with ethyl acetate, dried over sodium sulfate and purified with flash chromatography to give the desired product (17 mg). LCMS observed for (M+H)+: 424.1.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH2:9][OH:10])([CH3:6])([CH3:5])[CH3:4].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1>C1(C)C=CC=CC=1.O>[C:3]([O:7][CH2:8][CH2:9][O:10][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Br:11])[N:13]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OCCO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCCOc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.8 g, 60% dispersion in mineral oil, 0.169 mol) was added portionwise to an ice-cold solution of 2-(tert-butoxy)ethanol (20.0 g, 0.169 mol) in toluene (500 ml) under nitrogen, and the solution stirred for 30 minutes whilst warming to ambient temperature. 2,6-Dibromopyridine (40.0, 0.169 mol) was added, and the reaction heated under reflux for 3 hours. The mixture was allowed to cool to ambient temperature and was diluted with water (100 ml), and extracted with ethyl acetate (2×400 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow oil (quantitative). 1H nmr (CDCl3, 400 MHz) δ: 1.21 (s, 9H), 3.67 (t, 2H), 4.40 (t, 2H), 6.68 (d, 1H), 7.05 (d, 1H), 7.38 (t, 1H). LRMS: m/z 296/298 (M+23)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]([C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])C(OC(C)(C)C)=O)=[O:7])=[C:4]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6](=[O:7])[CH2:8][C:16]([CH:18]2[CH2:19][CH2:20]2)=[O:17])=[C:4]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)c1ccc(Cl)cc1S(C)(=O)=O)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(Cl)ccc1C(=O)CC(=O)C1CC1
Yield: 99.6 %

Procedure:
A mixture of t-butyl 2-(4-chloro-2-methylsulphonylbenzoyl)-3-cyclopropyl-3-oxopropionate (9.5 g) and 4-toluenesulphonic acid (1.5 g) in toluene was stirred and heated at reflux for 3 hours. After cooling the mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 1-(4-chloro-2-methylsulphonylphenyl)-3-cyclopropylpropan-1,3-dione, (7.1 g) as an orange gum, NMR (CDCl3): 0.8-1.2 (m, 4H), 1.5-1.9 (m, 1H), 3.3 (s, 3H), 5.8 (s, 1H), 7.3-7.6 (m,2H), 7.9 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([O:7][CH3:8])[O:5][CH3:6].[CH3:9][CH:10]([CH3:26])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1)=[O:12]>>[CH3:6][O:5][CH:4]([O:7][CH3:8])[CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH:10]([CH3:9])[CH3:26])[CH:19]=[CH:18][CH:17]=2)[CH2:21][CH2:22]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COC(CCBr)OC
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)OC

Procedure:
Prepared by Procedure G and Scheme B1 using 3-bromo-1,1-dimethoxypropane and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 349.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4]([O-:6])=[O:5].[NH2:10][C@H](C(O)=O)CC.C(N)(C)C.P([O-])([O-])([O-])=O>>[NH2:10][C@H:3]([C:4]([OH:6])=[O:5])[C:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: CC[C@H](N)C(=O)O
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)N
Product: CC(C)(C)[C@H](N)C(=O)O

Procedure:
L-tert-Leucine was produced with a conversion of 97% by conducting reactions using 50 mL of a mixture of 0.3 M trimethylpyruvate, 20 mM L-homoalanine, 0.45 M isopropylamine, 0.5 mM PLP, 50 mM phosphate pH 8, 35 U/mL BCTA and 30 U/mL OATA. 1.365 g of pure L-tert-leucine was obtained through purification based on solubility.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[CH2:17][C:18]([NH2:20])=[O:19]>O.C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:17][C:18]([NH2:20])=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Product: NC(=O)CNc1ccc([N+](=O)[O-])cc1
Yield: 58 %

Procedure:
A mixture of p-nitroaniline (55.2 g, 0.4 mol), calcium carbonate (80 g) and chloroacetamide (149.6 g, 1.6 mol) in 350 ml of water/ethanol (1/1) was refluxed for 42 hours. The resulting mixture was filtered while hot and allowed to cool, and the crystals were filtered off by suction, reslurried in water and then washed with absolute ethanol. After drying, 87.9 g of crude product were obtained. After two recrystallizations from acetonitrile, 45.3 g of pure product were obtained (melting point=178° C.).
Reaction SMILES: N([O-])=[O:2].[Na+].Cl[C:6]1[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]=[C:8]([S:16][CH3:17])[N:7]=1>CN(C)C=O>[F:14][CH:13]([F:15])[O:12][C:10]1[CH:11]=[C:6]([OH:2])[N:7]=[C:8]([S:16][CH3:17])[N:9]=1
Reactant: CSc1nc(Cl)cc(OC(F)F)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(O)cc(OC(F)F)n1
Reaction time: 0.83 h
Yield: 70.8 %

Procedure:
Over 50 minutes, a solution of 8.8 g (0.127 mole) of sodium nitrite in 10 ml of dimethylformamide is added dropwise at 140° C. to a solution of 8.7 g (0.038 mole) of 4-chloro-6-difluoromethoxy-2-methylthiopyrimidine in 10 ml of dimethylformamide. When the addition of the sodium nitrite is complete, the mixture is stirred for 2 hours at 140° to 150° C. The solvent is then evaporated off in vacuo and the residue is crystallised from 1N hydrochloric acid, affording 5.6 g (70% of theory) of 4-difluoromethoxy-6-hydroxy-2-methylthiopyrimidine with a melting point of 236°-237° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Oc2cccc(CO)c2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Oc2cccc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
(3-(5-Methylpyridin-2-yloxy)phenyl)methanol from Step 1 (1.9 g, 8.8 mmol), in dichloromethane (25 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (0.773 mL, 10.6 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was stirred at RT for 5 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated by evaporation to afford the title compound (2.1 g, 99% yield) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[C:13]([CH2:23][N:24]([CH3:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:15]=[C:9]2[N:8]([CH2:33][C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])[CH:7]=1)=[O:5])[CH3:2].O.[CH:43](Cl)(Cl)Cl>CC(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[C:13]([CH2:23][N:24]([CH3:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[N:15]=[C:9]2[N:8]([CH2:33][C:34]2[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=2[F:40])[CH:7]=1)=[O:5])([CH3:43])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)n2c1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)n2c1=O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a solution of the compound obtained in Example 12 (0.10 g, 0.18 mmol) in chloroform (5 ml) is added a solution of titanium(IV) isopropoxide (0.3 ml, 1.0 mmol) in 2-propanol (10 ml). Then the mixture is refluxed at 80° C. for 8 hours, successively is stirred at room temperature for 150 minutes. To this mixture is added a mixture of chloroform (50 ml) and water (50 ml). The aqueous layer is extracted with chloroform (20 ml). The combined organic extract is dried over Na2SO4 and concentrated under reduced pressure to give the residue, which is chromatographed on silica gel to afford white-brown crystalline solid, which is recrystallized from chloroform-n-hexane to afford pale brown crystals (0.58 g, 94%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)C.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[CH:11][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)Cc1ccc(C)nc1
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(CC(=O)NN)cn1
Yield: 72 %

Procedure:
As described for example 112a, (6-methyl-pyridin-3-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was then heated under reflux for 20 h. Evaporation of all volatiles and crystallization from n-butanol and toluene afforded the title compound as a white solid (yield: 72%). 1H-NMR (300 MHz, DMSO): δ=2.42 (s, 3H), 3.32 (s, 2H), 4.21 (s, 2H), 7.17 (d, J=8 Hz, 1H), 7.53 (dd, J=2 Hz, J=8 Hz, 1H), 8.30 (d, J=2 Hz, 1H), 9.23 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(O)c(O)c2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 72 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3,4-dihydroxybenzaldehyde 0.85 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 2.5 hours and cooled to room temperature, and water 357 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 1.25 g.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1>>[C:1]([N:19]1[CH:23]=[N:22][N:21]=[N:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1nnn[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)n1cnnn1

Procedure:
Example 2 is repeated to react palmitoyl chloride with tetrazole in a molar ratio of 1:2.
Reaction SMILES: [H-].[Na+].C(O[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.BrC[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[CH2:29]([O:28][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:11][NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:27])[CH3:30]
Reactant: O=C(Nc1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCNc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Under ice-cooling, 1.87 g of 62% sodium hydride was added to 100 ml of a dimethylformamide (DMF) solution containing 10.00 g of N-benzyloxycarbonylaniline, and the mixture was stirred at room temperature for one hour. Under ice-cooling, to the above mixture was added dropwise 50 ml of a DMF solution containing 10.31 g of ethyl 6-bromohexanoate, and the resulting mixture was stirred at room temperature overnight. DMF was removed under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was dissolved in 160 ml of methanol and 2 g of 10% palladium-carbon (Pd-C) was added to the solution. The mixture was subjected to catalytic reduction at normal temperature under normal pressure for 2 hours. After removing the catalyst by filtration, the filtrate was condensed and the residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 8.13 g of N-ethoxycarbonylpentyl-N-phenylamine (yield; 79%, melting point: 34°-37° C.).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.CCCCCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:30])=[CH:5][CH:6]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: Brc1ccc(Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(F)cc1)c1ccc(Br)s1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85.9 %

Procedure:
A solution of 2,5-dibromothiophene (19.23 g, 75.5 mmol) in anhydrous THF (400 mL) was treated at -78° C. under nitrogen with a 2.5M solution of n-butyllithium in hexane (30.0 mL, 75.5 mmol). The resulting solution was stirred for 45 minutes at -78° C. and then transferred by cannula into a cold (-78° C.) solution of N-methoxy-N-methyl-4-fluorobenzamide (12.57 g, 68.6 mmol), prepared as in step 1, in anhydrous THF (300 mL) with siring. After 30 minutes at -78° C., the reaction was quenched by the addition of a saturated solution of NH4Cl (15 mL) and poured into ethanol (350 mL) containing 10% HCl (140 mL). The mixture was partitioned between brine and 1:1 ether and dichloromethane. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was crystallized from pentane to give 16.8 g (86%) of 2-bromo-5-(4-fluorophenylcarbonyl)thiophene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=4)=[N:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[C:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1>CC(C)=O>[F:55][C:52]1[CH:53]=[CH:54][C:49]([C:48]#[C:47][CH2:46][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]4[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=5)=[N:11][C:10]=4[N:9]=3)=[CH:6][CH:7]=2)=[CH:50][CH:51]=1
Reactant: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Reactant: Fc1ccc(C#CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Yield: 42.9 %

Procedure:
A mixture of 8-(4-Hydroxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.115 g, 0.21 mmol), potassium carbonate (0.067 g, 0.48 mmol), 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.67 g, 0.27 mmol) and acetone (10 ml) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was evaporated and the residue was purified by preparative TLC to obtain pure 8-{4-[3-(4-Fluoro-Phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.061 g, 43%) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](OC)=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.[OH:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:33][CH2:32][CH2:31][OH:30])=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Product: O=C(NCCO)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with 2-hydroxyethylamine gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.18 (d, 1H, J=1.8 Hz), 7.80 (bs, 1H), 7.60 (m, 1H), 7.34-7.16 (m, 3H), 7.10 9t, 1H, 8.4 Hz), 6.85 (bdd, 1H), 6.62 (dd, 1H, J=1.5 and 8.1 Hz), 3.70 (t, 2H, J=4.8 Hz), 3.52 (t, 2H, J=4.0 Hz); LCMS: ret. time: 14.49 min.; purity: 97%; MS (m/e): 424 (MH+).
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[OH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:39]5[CH2:40][CH2:41][C@@H:37]([OH:36])[CH2:38]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: O[C@@H]1CCNC1
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CC[C@@H](O)C1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(((R)-3-hydroxypyrrolidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and (R)-3-hydroxypyrrolidine in a manner analogous to that of 1-(benzo[d][1,3]dioxo-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4].[CH3:19][NH2:20]>CO>[CH3:19][NH:20][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4]
Reactant: CN
Reactant: COC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Solvent: CO
Product: CNC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid methyl ester (50 mg, 0.20 mmol) was suspended in 1 mL of a 33% solution of methylamine in methanol. The suspension was stirred at room temperature for 21 h. Another 2 mL 33% methylamine in methanol was added and the resulting solution stirred another 8 h at room temperature then 15 h at 30° C. The reaction mixture was concentrated in vacuo leaving a yellow solid which was crystallized from DMF/MeOH/CHCl3 to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid methylamide, 36 mg (72%) as a yellow solid: m.p. 321-322° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ2.81 (s, 3H), 3.15 (m, 2H), 3.40 (m, 2H), 7.32 (app t, J=7.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.95 (br q, 1H), 8.09 (br t, 1H), 11.46 (br s, 1H). MS (electrospray, [M+Na]+) 266. Anal. (C13H13N3O2.0.4 H2O) C, H, N.