Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:42][CH2:43][C:44]2[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=2[CH3:50])=[O:13])=[CH:14][CH:15]=1)[CH3:6]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1F)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3F)cc2)c(O)n1
Temperature: 25 °C
Yield: 19 %

Procedure:
A mixture of 4-(1-(2-fluorophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 2 mmol), N-hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.3 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(2-fluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (75 mg, 38%). LRMS (M+H+) m/z: calcd. 394.17. found 394. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.30 (t, J=4.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.19-6.83 (m, 4H), 5.83 (s, 1H), 5.58 (q, J=6.3 Hz, 1H), 4.27 (d, J=4.8 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.56 (d, J=6.3 Hz, 3H).
Reaction SMILES: Br[CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[CH2:7]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([O:31]C)[N:18]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:14]([NH2:33])[N:13]=1)[CH2:8][CH2:9][CH3:10].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CS(C)=O>[NH2:33][C:14]1[N:13]=[C:12]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])[N:20]=[C:19]2[C:15]=1[NH:16][C:17](=[O:31])[N:18]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4])[CH2:27][CH2:26]1
Reactant: CCC(Br)CC
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(C(CC)CC)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
3-Bromopentane (0.1 mmol) was weighed into a tube and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine (0.452 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and heated at 50° C. for 18 hours. An additional portion of 3-bromopentane (15 μl) and DIPEA (40 μl) was added and heating continued for a further 18 hours. Potassium carbonate (46 mg) was added and heating continued for a further 72 hours. DMSO (200 uL) was added and the resultant mixture filtered, the solution was purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The sample was dissolved in 1:1 DMSO:MeOH and purified by MDAP (Method C) and the solvent was evaporated in vacuo using the Genevac. The material was redissolved in methanol (0.5 ml), and applied to a 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml), the solvent was removed to give the title compound (5.9 mg).
Reaction SMILES: CO[NH:3][CH3:4].[Cl:5][C:6]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[CH:19]=[CH:18][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][N:15]=[CH:14][C:13]=2[CH:17]=1.[CH2:25]([O:27]CC)C>>[Cl:5][C:6]1[CH:21]=[C:20]([N:22]([O:27][CH3:25])[C:23]([NH:3][CH3:4])=[O:24])[CH:19]=[CH:18][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][N:15]=[CH:14][C:13]=2[CH:17]=1
Reactant: CNOC
Reactant: CCOCC
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)c(Cl)c1
Product: CNC(=O)N(OC)c1ccc(Oc2ccc3sncc3c2)c(Cl)c1
Yield: 83 %

Procedure:
A solution of 6.1 parts of N-methoxy-N-methylamine in 100 parts of diethyl ether was added to a solution of 30.3 parts of 5-(2'-chloro-4'-isocyanatophenoxy)-benzisothiazole in 300 parts of diethyl ether at from 20° to 30° C., and after 12 hours at this temperature the reaction mixture was evaporated down and the residue was treated with about 50 parts of diethyl ether. 30.2 parts (83% of theory) of 5-[2'-chloro-4'-(N-methoxy-N-methylaminocarbonylamino)-phenoxy]-benzisothiazole of melting point 128° C. were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Br:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:10]2[C:6]([CH:5]=1)=[N:7][O:8][N:9]=2
Reactant: C1CCNC1
Reactant: Brc1cc(Br)c2nonc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Brc1cc(N2CCCC2)c2nonc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3122 g, 1.12 mmol), pyrrolidine (0.10 mL, 1.12 mmol) and DIPEA (0.20 mL, 1.12 mmol) were dissolved in NMP (2 mL) under argon and stirred in a sealed tube at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl (aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating to give the crude 6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.2247 g, 75% yield). The crude material (0.1964 g, 0.73 mmol) and 3-acetylbenzeneboronic acid (0.1558 g, 0.95 mmol) were added to a tube. The tube was evacuated and purged with argon (3×). 2 M Na2CO3 (1.1 mL, 2.21 mmol) and DME (1.6 mL) were added and the solution was degassed for 15 minutes. Pd(PPh3)4 (0.0422 g, 0.0365 mmol) was quickly added and the tube was heated at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The crude material was dissolved in methanol (12 mL) and cooled to 0° C. NaBH4 (0.0552 g, 1.46 mmol) was added and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with saturated NaHCO3. This thick mixture was diluted with water and extracted with DCM (5×). The extracts were then dried (Na2SO4), filtered and concentrated. The crude material was purified via chromatography (30% EtOAc/Hexane) to afford 0.2029 g (90% yield, over 2 steps) of TRV-1310. 1H NMR (CDCl3) δ=7.65 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.07 (s, 1H), 6.11 (s, 1H), 5.00-4.99 (m, 1H), 3.81 (s, 4H), 2.12-2.09 (m, 4H), 1.92 (d, J=3.0 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])[CH2:9][CH2:10]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 4.94 g piperidin-4-yl-carbamic acid tert-butyl ester, 300 mg DMAP and 5.2 ml triethylamine in 50 ml dichloromethane were added 6.3 ml benzyl chloroformate dropwise at 0° C. After 8 h the suspension was diluted with dichloromethane and washed with half-saturated NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was suspended in heptane, the supernatant solution being decanted yielding the product as colorless solid. Yield: 7.9 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C2)nc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
Ethyl 2-[(3S)-3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}pyrrolidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (237b) (215 mg, 0.52 mmol) was dissolved in methanol (5 mL). A 2 N aqueous lithium hydroxide solution (2.61 mL, 5.22 mmol) was added, and the mixture was stirred at 40° C. for two hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (5 mL) was added to the aqueous layer. The precipitated solid was collected by filtration and washed with water and ethyl acetate to obtain 155 mg of the title compound as a white solid (77%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Br:11].C([Li])CCC.[CH3:17][S:18]SC.Cl>C(OCC)C.CCCCCC>[Br:11][C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[S:6][C:2]=1[S:18][CH3:17]
Reactant: CSSC
Reactant: Brc1sc2ccccc2c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.76 g of 2,3-dibromobenzo[b]thiophene in 75 ml of diethyl ether was cooled to 0° C. and 19 ml of a 1.6M solution of n-butyl lithium in hexane and 10 ml of diethyl ether were added. A pink slurry formed which was stirred for one hour. A solution of 2.7 ml of methyl disulfide in 10 ml of diethyl ether was added and the reaction mixture was stirred for 4 hours at 0° C. Approximately 100 ml of 1N hydrochloric acid were added and the reaction was allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The resulting oil was vacuum distilled at 1.5 torr providing 1 g of the desired subtitled intermediate.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH3:19])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)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>[CH3:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:25]1[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=1)[CH:11]=2
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1CCc1cc2ccc(Br)cc2cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1CCc1cc2ccc(-c3ccc(C#N)cc3)cc2cn1
Temperature: 62.5 °C

Procedure:
The product from Example 52G (0.2 g, 0.6 mmol), 4-cyanophenylboronic acid (0.22 g, 1.5 mmol), bis(triphenylphosphine)palladium dichloride (55 mg, 0.08 mmol), and potassium phosphate (7 mL, 0.2 M in water) were combined in isopropanol (7 mL) and heated at 60-65° C. for 7 hours in a sealed flask. The mixture was filtered through diatomaceous earth, the filtrate was concentrated in vacuo, and then partitioned between MTBE (10 mL) and water (10 mL). The organic layer was separated, washed with aqueous sodium bicarbonate solution (5%, 10 mL), and then extracted with a solution of 2M HCl (15 mL). The pH of the acidic aqueous layer was adjusted with base using potassium carbonate and extracted with isopropyl acetate (15 mL). The organic layer was evaporated in vacuo and the residue was chased with heptane (10 mL) to provide the title compound. 1H NMR (CDCl3) δ 1.12 (d, J=6.0 Hz, 3H); 1.37-1.50 (m, 1H); 1.64-1.85 (m, 2H); 1.85-1.98 (m, 1H); 2.26 (q, J=8.8. Hz, 1H); 2.32-2.43 (m, 1H); 2.50-2.60 (m, 1H), 3.09-3.34 (m, 4H); 7.56 (m, 1H); 7.73-7.81 (m, 4H), 7.84-7.87 (m, 2H), 8.12 (m, 1H); 9.26 (s, 1H); HRMS Calcd. for [C23H23N3+H+]: 342.1970. Found: 342.1974.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:21](=[O:23])[CH3:22])[CH:15]=2)=[C:11]([C:33]#[N:34])[C:10]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=1[Cl:42])C=C.C(O)(=O)C.C(Cl)Cl.C1([SiH3])C=CC=CC=1>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.CCOC(C)=O.C(Cl)Cl>[C:33]([C:11]1[C:10]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[C:9]([C:5]2[NH:6][CH:7]=[CH:8][N:4]=2)[S:13][C:12]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:21](=[O:23])[CH3:22])[CH:15]=1)#[N:34]
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(N(Cc3ccc(OC)cc3)C(C)=O)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CN(C(C)=O)c2cc(-c3sc(-c4ncc[nH]4)c(-c4ccc(Cl)cc4Cl)c3C#N)ccn2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To the solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-3-cyano-4-(2,4-dichlorophenyl)-2-thienyl]pyridin-2-yl}-N-(4-methoxybenzyl)acetamide (1.32 g, 1.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (93.1 mg, 0.0805 mmol) in Acetic acid (15 mL, 260 mmol) and Methylene chloride (30 mL, 500 mmol) under N2 atmosphere was added dropwise PHENYLSILANE (1.10 mL, 8.92 mmol). The mixture was stirred at 40° C. for 2 hours. The solvent was removed in rotavapor then the residue was dried in high vacuum to give a residue. The residue was chromatographed in silica column using 7N NH3-MeOH/DCM (1/99, ˜1 L), then EtOAc/DCM (30/70 to 60/40) to give an impure product. The second chromatograph using EtOAc/DCM (30/70 to 80/20) gave a pure product (0.469 g, yield 50.7%). LCMS: (AA) ES+, 574, 576; ES−, 572, 574. 1H NMR (400 MHz, d1-chloroform) δ: 8.60-8.62 (d, J=5.27 Hz, 1H), 7.71 (d, J=2.00 Hz, 1H), 7.63 (s, br, 1H), 7.55-7.57 (dd, J=5.27, 1.76 Hz, 1H), 7.50-7.52 (dd, J=8.28, 2.01 Hz, 1H), 7.40-7.42 (d, J=8.28 Hz, 1H), 7.18-7.20 (d, J=8.78 Hz, 2H), 7.07 (m, 2H), 6.80-6.82 (d, J=8.78 Hz, 2H), 5.14 (s, 2H), 3.76 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][Al:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:16][N:17]=[Al][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:4]1([Al:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:16][NH:2][CH3:1].[C:4]1([Al:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:1][NH:17][CH3:16]
Reactant: CN=[Al]c1ccccc1
Reactant: CN[Al](c1ccccc1)c1ccccc1
Product: CNC
Product: c1ccc([Al](c2ccccc2)c2ccccc2)cc1

Procedure:
Laubengayer et al., Inorg. Chem., 1, pages 632 to 637 (1962), disclose the reaction of triphenylaluminum and methylamine in toluene solution to form methylamine triphenylaluminum, then methylaminodiphenylaluminum, and then methyliminophenylaluminum. Triphenylaluminum and dimethylamine form dimethylamine triphenylaluminum which is heated to form dimethylaminodiphenylaluminum.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[N:8](COCC[Si](C)(C)C)[C:9]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([Cl:33])[CH:26]=3)[C:18]=2[F:34])=[O:14])=[C:10]([Cl:12])[N:11]=1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:10]1[N:11]=[C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])[NH:8][C:9]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([Cl:33])[CH:26]=2)[C:18]=1[F:34])=[O:14]
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1c(N)nc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Methyl chloroformate (0.020 mL, 0.26 mmol) was added to a solution of 2-amino-4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.050 g, 0.086 mmol) and DIEA (0.075 mL, 0.43 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at RT overnight. TFA (0.5 mL) was added and the reaction mixture was stirred at RT for another 1 h. The reaction mixture was then evaporated and taken up in MeOH (1 mL). NaBH4 (0.030 g, 0.80 mmol) was added and the reaction mixture was stirred overnight. CH2Cl2 and sat'd NaHCO3 were added and the solution was extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered, concentrated and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to afford the title compound (0.008 g, 19%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56 (s, 1H) 7.34-7.44 (m, 2H) 7.25-7.29 (m, 1H) 7.24 (s, 1H) 4.57-4.70 (m, 2H) 3.81 (s, 3H). ES-LCMS: m/z 512.01, 513.97 (M+1).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)[Cl:31]>>[ClH:31].[F:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([F:21])[CH:18]=1)[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(F)cc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Fc1cc(F)cc(OC[C@@H]2CCCN2)c1

Procedure:
A 0.26 g (0.83 mmol) sample of the BOC-protected compound from step 7a was dissolved in 10 mL of 1:1 CH2Cl2 :TFA and stirred at room temperature until tlc showed no starting material. The solvent and reagent were removed by evaporation. The residue was suspended in 10% aqueous HCl, which was then adjusted to pH 12 with K2CO3, and the mixture was extracted with methylene chloride. The solvent was removed, and the residue was dried, then suspended in ether. Addition of ether/HCl precipitated the title product, which was wash with ether and dried to yield 0.62 g of the title compound. MS: 214(M+H)+, 231 (M+NH4)+, 248 (M+NH4NH3)+. NMR (D2O) δ: 1.87-2.33 (m, 4H), 3.41 (t, 2H, J=7), 4.05-4.12 (m, 2H), 4.38 (dd, 1H), 6.62-6.71 (m, 3 H). Anal. Calcd for C11H14ClF2NO.0.45 H2O: C, 51.25; H, 5.82; N 5.43; Found: C, 51.36; H, 5.35; N, 5.45.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(CCl)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In a 250 ml round-bottomed flask at room temperature under nitrogen, (6-methyl-3-pyridinyl)methanol (4.32 g, 35.1 mmol, D8) was dissolved in dry dichloromethane (45 ml) to give a yellow solution, which was cooled down to 0° C. Thionyl chloride (3 ml, 41.1 mmol) was then added. The resulting pale-orange mixture was stirred at 0° C. for 15 minutes and at room temperature for 2 hours. The mixture was concentrated in vacuum and the brown residue was partitioned between DCM (150 ml) and saturated NaHCO3 (100 ml). Phases were separated and the organic was washed with saturated NaHCO3 (2×100 ml), dried over Na2SO4, filtered and concentrated to give the desired compound as brown oil (4.26 g), that was used without further purification in the next step.
Reaction SMILES: CO[C:3](=[O:8])[CH2:4][CH2:5][O:6][CH3:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:19]1([NH:24][C:25]2[C:30]([CH:31]=O)=[CH:29][N:28]=[C:27]([S:33][CH3:34])[N:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1.C(OCC)(=O)C.O>[CH:19]1([N:24]2[C:25]3[N:26]=[C:27]([S:33][CH3:34])[N:28]=[CH:29][C:30]=3[CH:31]=[C:4]([CH2:5][O:6][CH3:7])[C:3]2=[O:8])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COCCC(=O)OC
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Yield: 24.1 %

Procedure:
3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR 6 (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]1[CH2:15][O:14]1)[CH:7]=[CH:6][CH:5]=2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]3[CH2:33][CH:32]4[NH:34][CH2:35][CH:27]3[CH2:28][CH:29]=[CH:30][CH2:31]4)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(Cl)(Cl)Cl>C(O)C>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]3[CH2:33][CH:32]4[N:34]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]5[CH:7]=[CH:6][CH:5]=[C:4]6[C:9]=5[CH:10]=[C:2]([CH3:1])[NH:3]6)[CH2:35][CH:27]3[CH2:28][CH:29]=[CH:30][CH2:31]4)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Cc1cc2c(OCC3CO3)cccc2[nH]1
Reactant: C1=CCC2CNC(C1)CN2c1ccc2c(c1)OCCO2
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1cc2c(OCC(O)CN3CC4CC=CCC3CN4c3ccc4c(c3)OCCO4)cccc2[nH]1

Procedure:
2-Methyl-4-oxiranylmethoxy-1H-indole (25 mg, 0.123 mmol), 7-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene (34 mg, 0.125 mmol), chloroform (1 mL), ethanol (3 mL) were heated for 900 sec. at 130° C. in a μW reaction tube. The solvent was evaporated under reduced pressure to yield a crude solid that was purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.