Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[CH3:23][O:24][C:25](=[O:30])[C@@H:26]([NH2:29])[CH2:27][OH:28]>C(Cl)Cl.CN(C=O)C.O>[OH:28][CH2:27][C@H:26]([NH:29][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[C:25]([O:24][CH3:23])=[O:30]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
Compound 2 (2.0 g, 9.00 mmol) was dissolved in CH2Cl2 (10 mL) cooled to −15° C., NMM (1.12 mL, 10.2 mmol) and IBCF (1.26 mL, 1.15 mmol) were added and stirred at 0° C. for 20 minutes. A mixture of (S)-methyl-2-amino-3-hydroxypropanoate (1.59 g, 10.2 mmol) and NMM (1.12 mL) in DMF (3 mL) were added drop wise at −15° C. The resultant reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with DCM (200 mL) and water (25 mL) and was washed with 2N HCl (20 mL) and brine (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography eluting with 20% EtOAc/Hexane to afford compound 3 (2.3 g) as solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:7])=[CH:4][C:3]=1[Cl:16].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[CH3:17][S:7][C:6](=[N:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11])[C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[C:3]([Cl:16])[CH:4]=1
Reactant: C[Si](C)(C)CNC(=S)c1ccc(Br)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.5 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethylthiobenzamide (Example I13) (4.43 g) in butanone (80 ml) was added potassium carbonate (2.73 g) and methyl iodide (1.02 ml). The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:5) to give of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (2.56 g). 1H-NMR (400 MHz, CDCl3): 7.55-7.15 (m, 3H), 3.55 (s, 2H), 1.98 (s, 3H), 0.00 (s, 9H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Mg].II.[P:15](Cl)(=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C1COCC1.[Cl-].[Na+].O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COc1cc(Br)cc(OC)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)c1cc(OC)cc(OC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 1-bromo-3,5-dimethoxybenzene (20 g, 92.1 mmol) in THF (100 ml) was added to a flask (500 ml) with magnesium (2.5 g, 103 mmol), I2 (20 mg) and THF (50 ml) and refluxed for 2 h. The resulting light brown solution was transferred to another flask (500 ml) and was cooled to −78° C. Diethyl phosphorochloridate (17.8 g, 103 mmol) in THF (80 ml) was added at −78° C. within 1 h. The mixture was stirred at −78° C. for 1 h, then slowly warmed up to RT and stirred at RT overnight. Brine (20%, 200 ml) was added to the mixture and it was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 ml×1) and CH2Cl2 (100 ml×1). The combined organic layer was washed with brine (300 ml×2) and dried over MgSO4. It was filtered and the solvent was removed. The residues were purified with silica gel pad (eluent: CH2Cl2 to removed impurities, then CH2Cl2/THF=10/1 to wash out the product). The pure product was obtained as pale a yellow oil after the solvent was removed (20.2 g, 80% yield). 1H NMR (300 Mhz, CD2Cl2) δ: 6.90 (dd, J1=2.1 Hz, J2=14.7 Hz, 2H), 6.63 (d, J=2.1 Hz, 1H), 4.05 (quart, J=6.9 Hz, 4H), 3.83 (s, 6H), 1.31 (t, J=6.9 Hz, 6H). 31P NMR (121.5 MHz, CD2Cl2) δ: 19.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[F:12].C(O)(=O)C>[Fe].CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:11])[C:3]=1[F:12])[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(Cl)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(F)c(F)c(Cl)c1
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
1-Chloro-2,3-difluoro-5-nitrobenzene (3 g, 15.6 mmol) was added to acetic acid (10 mL) and methanol (250 mL). To this mixture was added iron powder (3.0 g) in portions, stirred for 2 h at 60-65° C., cooled to room temperature, and filtered. The filterate was stripped to a brown solid, which was extracted with ethyl acetate (3×200 mL), washed with 1N NaOH (3×100 mL), and brine (2×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and stripped down to yield the product as a pale yellow solid (2.6 g). Yield 100%; 1H NMR (400 MHz, CDCl3): δ 6.41 (m, 2 H), 3.65 (br s, 2 H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([Br:12])[C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1)=[O:23]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:21][C:22](=[O:23])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)[C:8]([CH3:13])=[C:9]([Br:12])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)c(Br)c(C)n1CC(=O)Nc1ccc(Cl)cn1
Reaction time: 2 h
Yield: 26.5 %

Procedure:
To a solution of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (492 mg) in DMF (5 mL) was added Cs2CO3 (912 mg). The mixture was stirred for 30 min at RT after which 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (499 mg) was added. Stirring was continued for 2 h at RT whereupon the mixture was filtered and concentrated. The residue was subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA) to give 4-bromo-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (220 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=CC=2N=N1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C@:32]([N:38]2[C:46]3[C:41](=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39]2)([CH2:36][CH3:37])[C:33]([OH:35])=O)=[CH:28][CH:27]=1.CN1CCOCC1.CN>CN(C=O)C.CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C@:32]([N:38]2[C:46]3[C:41](=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39]2)([CH2:36][CH3:37])[C:33]([NH:8][CH3:12])=[O:35])=[CH:30][CH:31]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@](C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@](C(=O)NC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.34 g, 3.56 mmol) was added to a stirred solution of 4a (967 mg, 2.38 mmol) and 4-methylmorpholine (523 μL, 4.75 mmol) in DMF (12 mL). After 5 min, methylamine (3.56 mL of a 2.0 M solution in methanol, 7.13 mmol) was added, and the resulting mixture was allowed to stir at rt. After 3 h, the reaction mixture was partitioned between ethyl acetate and water. The layers were separated, and the organics were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-85% EtOAc/hexanes as eluent) to afford the title compound 39. m/z (ES) 420 (MH)+; IP=B rating.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)([C:8]1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.CC(OC)(C)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH2:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:15][CH2:8][CH2:1][NH:14][CH2:17]1)[CH3:23]
Reactant: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CO
Product: CCNC1(C(N)=O)CCCNC1

Procedure:
To a suspension of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-1A-3d; 36.1 g, 117 mmol) in methanol (560 ml) at room temperature was added concentrated aqueous HCl (19.5 ml, 234 mmol), resulting in a clear solution. To 20% Pd(OH)2 on carbon (3.75 g) was added methanol (85 ml), followed by the methanolic solution of I-1A-3d. The mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 20 hours. The reaction was then filtered through Celite® and then concentrated to low volume under reduced pressure, at which point a precipitate formed. The suspension was diluted with MTBE (500 ml), stirred for an additional hour, and the precipitate collected by vacuum filtration. The solid was washed with MTBE and then dried, in vacuo, to afford I-1A-3e (24.8 g, 98%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22](OC)=[O:23])=[N:20][CH:21]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)C.O>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(nnn3CC(C)(C)C)c2Br)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)Cn1nnc2c(Br)c(-c3ccc(CO)nc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 5-[4-bromo-1-(2,2-dimethylpropyl)-1H-benzotriazol-5-yl]pyridine-2-carboxylate (132 mg, 0.327 mmol) in THF (3 ml) was cooled to −78° C., followed by the dropwise addition of lithium aluminum hydride (0.360 ml, 1M THF solution, 0.360 mmol). After 1 hour, the mixture was treated with water (15 uL), 2N aqueous sodium hydroxide (15 uL) and water (45 uL). The mixture was warmed to room temperature, diluted with diethyl ether and treated with magnesium sulfate. After stirring for 30 minutes, the mixture was filtered through celite and concentrated in vacuo. The residue was purified via silica gel chromatography (methanol/dichloromethane gradient), providing the titled compound: LRMS m/z (M+H) 375.0 and 377.0 found, 375.1 and 377.1 required.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[C:11]2[C:10]([N:12]3[C:25]4[C:20](=[C:21]([C@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5C(OC(C)(C)C)=O)[CH:22]=[CH:23][CH:24]=4)[C:14]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1>O1CCOCC1.C(Cl)Cl>[CH3:2][C@H:3]1[C:11]2[C:10]([N:12]3[C:25]4[C:20](=[C:21]([C@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:22]=[CH:23][CH:24]=4)[C:14]4([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5)cccc43)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
4M HCl in dioxane (2 mL) was added into a solution of (R)-tert-butyl 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (8 mg, 0.02 mmol) in CH2Cl2 (5 mL). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated, and the crude material was recovered to afford the product 1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((R)-pyrrolidin-2-yl)spiro[indoline-3,4′-piperidine] (3 mg, 47% yield) as a solid. 1H NMR (d6-DMSO, 400 MHz) δ 8.80 (s, 1H), 8.00-8.10 (m, 1H), 7.52 (t, 1H), 7.40 (d, 1H), 5.35-5.45 (m, 1H), 4.60-4.70 (m, 1H), 4.20-4.30 (m, 1H), 3.85-4.00 (m, 1H), 3.70-3.80 (m, 1H), 3.60-3.70 (m, 3H), 3.50-3.60 (m, 2H), 3.20-3.30 (m, 2H), 3.10-3.20 (m, 1H), 2.80-2.90 (m, 1H), 2.50-2.70 (m, 2H), 2.40-2.50 (m, 1H), 2.30-2.40 (m, 1H), 2.10-2.20 (m, 2H), 1.90-2.05 (m, 2H), 1.10 (d, 3H). MS (APCI+) [M+H]+ 390.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[CH2:40])[CH2:10][N:11]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[C:12]([C@H:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15]C=C)=[O:13]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][N:11]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=2[O:38][CH3:39])[C:12](=[O:13])[C@H:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH:40]=1
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)c1cccc(F)c1F)Cc1ccc(OC)cc1OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COc1ccc(CN2CC(c3cccc(F)c3F)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Temperature: 40 °C
Reaction time: 48 h
Yield: 57.5 %

Procedure:
[1,3-bis-(2,4,6-Trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (2.62 g, 3.09 mmol) was added to a solution of benzyl (1R)-1-{[[2-(2,3-difluorophenyl)prop-2-enyl](2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate (6.8 g, 12.35 mmol) in dichloromethane (1800 mL) and the solution was heated to 40° C. After 48 h, additional catalyst was added (0.52 g, 0.61 mmol) and the reaction continued to heat at 40° C. for an additional 48 h. The mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→55% ethyl acetate/hexanes) gave the title compound (3.71 g). MS 523.1 (M+1).
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(C)C)=CC=1.[OH:18]C1C=CC(CC2C=CC(O)=CC=2)=CC=1>>[OH:17][C:14]1[C:15]([OH:18])=[CH:16][C:11]2[C:12]([CH:13]=1)=[CH:7][CH:6]=[CH:5][CH:8]=2
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: Oc1cc2ccccc2cc1O

Procedure:
bis-phenols such as 2,2-bis(p-hydroxyphenyl)propane and bis-(p-hydroxyphenyl)methane
Reaction SMILES: [I-].[K+].[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18]Cl)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:26]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][NH:30][CH:27]4[CH2:29][CH2:28]4)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:26]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-(methylthio)-1-(chloromethyl)-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-(methylthio)-1-[(cyclopropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH2:26][CH2:27][CH3:28])=[CH:20][C:21](OCC)=[O:22])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:21](=[O:22])[CH:20]=[C:19]([CH2:26][CH2:27][CH3:28])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCCC(=CC(=O)OCC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Product: CCCc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-propylvinyl]ureido}-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-propyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 192°-193° C.,
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:33]([N:35](CC)[CH2:36][CH3:37])[CH3:34].N1CCCC1>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:35]3[CH2:36][CH2:37][CH2:34][CH2:33]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Reactant: CCN(CC)CC
Solvent: C1CCNC1
Solvent: CC#N
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
To a solution of 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(3,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (3.334 g, 7.31 mmol) in anhydrous acetonitrile (4 mL) was added triethylamine (3.06 mL, 21.94 mmol) and pyrrolidine (1.831 mL, 21.94 mmol). The solution was stirred at 70° C. for 18 hours. A further equivalent of pyrrolidine (0.61 mL, 7.31 mmol) and triethylamine (1.019 mL, 7.31 mmol) were added to the reaction mixture. The solution was stirred at 70° C. for a further 3 hours. The cooled reaction mixture was evaporated in-vacuo and the residue partitioned between ethyl acetate and water/brine (1:1). The organic phase was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a sticky brown gum (4.226 g). The gum was dissolved in the minimum volume of dichloromethane, loaded onto a 340 g silica pre-conditioned cartridge and purified by chromatography using dichloromethane over 1 column volume followed by 0-30% methanol (+1% triethylamine) in dichloromethane gradient over 14 column volumes followed by 30% methanol (+1% triethylamine) in dichloromethane over 3 column volumes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a sticky brown gum (1.838 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[Sn](Cl)Cl>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1cc(N2CCOCC2)ccc1N
Temperature: 70 °C
Yield: 47.8 %

Procedure:
To a solution of 4-(3-methoxy-4-nitrophenyl)morpholine (Preparation 78, 1.00 g, 4.20 mmol) in EtOH (42 mL) was added tin (II) chloride (2.79 g, 14.69 mmol). The reaction mixture was heated to 70° C. for 18 hours. The reaction mixture was diluted with ice-water (10 mL) and concentrated in vacuo. Aqueous Na2CO3 (2M, 20 mL) was added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by passage through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH to give the title compound (418 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[I:11].C([N:15]([CH:18]([CH3:20])[CH3:19])CC)(C)C.C1(N)CC1>S(Cl)(Cl)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:18]2[CH2:20][CH2:19]2)=[O:8])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodobenzoic acid (9.00 g, 31.9 mmol) was heated to 75° C. in thionyl chloride (15 mL) for 4 h. The reaction mixture became homogeneous and was concentrated and dried azeotropically with toluene. The mixture was dissolved in 1,4-dioxane (10 mL), and diisopropylethylamine (11 mL mL, 64 mmol), and cyclopropylamine (2.45 mL, 35 mmol) and stirred at ambient temperature for about 2 h. The reaction was diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with 3 N HCl (aqueous). The organic layers were combined, washed 2 times with 50 mL of 3 N HCl (aqueous), and 2 times with 50 mL of sodium bicarbonate, dried over sodium sulfate, and concentrated via rotovap to give the title compound. Found MS (ES+): 322(M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][CH:6]1[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7]1=[O:15].CCN(CC)CC.S([Cl:31])(C)(=O)=O.[Li+].[Cl-]>CN(C=O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[CH:6]1[CH2:5][C:4]1[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=1[CH2:2][Cl:31]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CC(=O)N(C)C(Cc2ccccc2CO)C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CC(=O)N(C)C(Cc2ccccc2CCl)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[2-(hydroxymethyl)benzyl]-1,4-dimethylpiperazine-2,5-dione (1.48 g, 5.64 mmol) and Et3N (1.57 ml, 11.28 mmol) in DMF was cooled to 0° C. Mesyl chloride was added via syringe at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting overnight. More Et3N (2 equivalents) and mesyl chloride (1.1 equivalents) was added at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting for 6 hours. LiCl (478 mg, 11.28 mmol) was added and the reaction stirred at ambient temperature for 1.5 hours. The mixture was partitioned between NH4Cl and EtOAc and extracted with EtOAc (3×). The combined organic solutions were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by normal phase chromatography (0-3% MeOH(NH3)/CH2Cl2) to give a yellow oil (1.47 g).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([Si:10]([Cl:12])([Cl:11])[Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 83.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.23 g (0.78 mmol) of tetrabutylphosphonium chloride, 1.00 g (7.90 mmol) of benzyl chloride, and 3.21 g (23.7 mmol) of trichlorosilane were reacted at 130° C. for 4 hrs. The resulting mixture was distilled to give 1.48 g of benzyltrichlorosilane (yield; 83%).
Reaction SMILES: [Na].[CH3:2][C:3]1[O:7][C:6](=[O:8])[NH:5][N:4]=1.[CH2:9]([O:16][CH2:17][C:18](=[O:21])[CH2:19]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.O.[Cl-].[Na+].O>[CH2:9]([O:16][CH2:17][C:18](=[O:21])[CH2:19][N:5]1[N:4]=[C:3]([CH3:2])[O:7][C:6]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCl)COCc1ccccc1
Reactant: Cc1n[nH]c(=O)o1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(CC(=O)COCc2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 5-methyl-1,3,4-oxadiazol-2-one sodium salt (34.6 g, 284 mmol) in DMF (200 mL) at 0° C. was added dropwise a solution of 1-benzyloxy-3-chloro-propan-2-one (56.4 g, 284 mmol) in DMF (80 mL). After completion of the addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. The obtained reaction mixture was diluted with water and brine and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried (Na2SO4). After evaporation of the solvent the desired product was obtained as a brown oil. Purification by flash chromatography (25% EtOAc/heptane) furnished the desired product as a yellowish oil. 1H NMR (400 MHz, CDCl3) 2.27 (s, 3H), 4.27 (s, 2H), 4.62 (s, 2H), 4.75 (s, 2H), 7.30-7.46 (m, 5H).