Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:26]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][N:7]1[C:11](=[O:12])[C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[NH:9][C:8]1=[O:25])=[O:4].ClCCl.CO.FC(F)(F)[C:53]([OH:55])=[O:54]>>[NH2:26][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[N:9]([C:53]([O:55][C:10]([CH3:17])([CH3:13])[CH3:11])=[O:54])[C:8]1=[O:25]
Reactant: COC(=O)[C@H](CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CN1C(=O)N(C(=O)OC(C)(C)C)C2(CCNCC2)C1=O
Yield: 87 %

Procedure:
A solution of 4.6 g (7.5 mmol) of (34.4) in 180 ml of dichloromethane/methanol/trifluoroacetic acid=95.5/3/1.5 is stirred at room temperature for 10 min. The reaction mixture is concentrated and the residue is chromatographed through silica gel. 3.14 g (87%) of (34.5) are obtained after concentrating the product fractions.
Reaction SMILES: [CH3:1][C:2]([N:6]([CH3:11])[CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH2:46][C@@H:47]3[CH2:51][CH2:50][CH2:49][N:48]3[C:52](=[O:56])[CH2:53][C:54]#[N:55])[N:30]=[C:31]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:34][C:33]=3[F:45])[C:24]=12>C(Cl)Cl.CCOC(C)=O>[NH2:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH2:46][C@@H:47]3[CH2:51][CH2:50][CH2:49][N:48]3[C:52]([C:53](=[CH:3][C:2]([CH3:1])([N:6]([CH3:11])[CH:7]3[CH2:10][O:9][CH2:8]3)[CH3:5])[C:54]#[N:55])=[O:56])[N:30]=[C:31]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:34][C:33]=3[F:45])[C:24]=12
Reactant: CN(C1COC1)C(C)(C)C=O
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CN(C1COC1)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a solution of 2-methyl-2-[methyl(oxetan-3-yl)amino]propanal (100.0 mg, 0.6400 mmol) in DCM (5 mL), was added pyrrolidine (0.06 mL, 0.760 mmol). The reaction mixture was cooled to 0° C., followed by addition of TMS-Cl (0.06 mL, 0.51 mmol, the ice bath was removed and reaction mixture was stirred for 10 minutes before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (60 mg, 0.13 mmol). The mixture was stirred for 50 minutes and the reaction was deemed finished by checking progress through TLC and LC-MS. The reaction mixture was washed by 15 ml Sat.Na2HCO3 and the layers separated. The aq. layer was extracted with CH2Cl2 and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed. The residue was loaded on silica gel column and purified by [MeOH:CH2Cl2(1:4)]: EtOAc 20%, 30% to get pure product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile (61.8 mg, 0.1012 mmol, 79.5% yield) as off white solid. LC-MS (ES, m/z): 612 [M+H]
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CC(C)=O>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:21]3[C:22](=[O:24])[CH2:23][O:19][C:20]3=[O:25])=[CH:14][CH:15]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C1COC(=O)N1
Reactant: OCCc1ccc(-n2ccc3cccnc32)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C1COC(=O)N1CCc1ccc(-n2ccc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.6 %

Procedure:
A solution of 1.0 g (4.20 mmol) of 2-[4-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl]ethanol, prepared in step 13.1., 0.51 g (5.04 mmol) of 1,3-oxazolidine-2,4-dione and 1.21 g (4.62 mmol) of triphenylphosphine in 16 ml of tetrahydrofuran, cooled by a bath of acetone and ice, is admixed dropwise with 0.84 g (4.2 mmol) of diisopropyl azodicarboxylate in solution in 2 ml of tetrahydrofuran. The mixture is subsequently heated to ambient temperature again and stirred overnight. 4 g of silica are added and the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 70/30 then 60/40 then 50/50 and 40/60 mixture of cyclohexane and ethyl acetate, to give 1.52 g of product in the form of a sticky solid, which is used as it is in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2cccc(Br)c2)nc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 3-bromophenol (5 g, 27.54 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (4.52 g, 26.16 mmol) in DMF (30 mL) was added K2CO3 and the mixture was refluxed at 110° C. overnight. Distilled water (30 mL) and diethyl ether (30 mL) were added and the mixture was stirred for 30 min. The ether layer was dried over Na2SO4 and concentrated to give pure pure title compound (8.0 g). 1H NMR (500 MHz, CDCl3): δ 7.0 (d, 1H, J=10 Hz), 7.1 (d, 1H, J=1.5 Hz), 7.2-7.3 (m, 2H), 7.4 (d, 1H, J=8 Hz), 7.9 (m, 1H), 8.4 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C:10]2([CH3:17])[CH3:16])=[CH:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])SC)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.[Hg](Cl)Cl>[C:33]([O:32][C:30](=[O:31])[NH:29]/[C:26](/[NH:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C:10]2([CH3:17])[CH3:16])[CH:6]=1)=[N:25]\[C:23](=[O:24])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1ncc(C2CCN(C)CC2(C)C)cc1N
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: ClCCl
Product: Cc1ncc(C2CCN(C)CC2(C)C)cc1N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of 2-methyl-5-(1,3,3-trimethylpiperidin-4-yl)pyridine-3-amine (0.814 g, 3.49 mmol) in DCM (50 mL) were added 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.52 g, 5.23 mmol), mercury (II) chloride (1.42 g, 5.23 mmol) and TEA (2.92 mL, 20.9 mmol). The reaction mixture was allowed to stir overnight at rt then filtered through a Celite® pad and washed with DCM. The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give di-tert-butyl((Z)-{[2-methyl-5-(1,3,3-trimethylpiperidin-4-yl)pyridine-3-yl]amino}methylylidene)biscarbamate (0.79 g, 48%) as a white solid. LCMS (FAL): Rt=5.08 min, m/z=476.6 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][C@@H:6]([OH:7])[C@H:2]([N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
Trans-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.47 mmol) was added to the solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 6.7 mL, 2.25 mmol) and the mixture was heated at 50° C. for 3 hour. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 hours. The residue was then dissolved in dimethyl formamide (5 mL) and potassium carbonate powder (435 mg, 3.15 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (30 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 751 mg (64% yield) of racemic trans-ethyl 1-(1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30]([CH3:37])[C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)#[N:27].CN1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:34]([C:31]3[C:30]([CH3:37])=[CH:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=3)=[O:35])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(NC(=O)OC(C)(C)C)=N2)c1

Procedure:
To a mixture of [(R)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (636 g, 1.77 mol) and 5-cyano-3-methylpyridine-2-carboxylic acid (301 g, 1.86 mol) was added THF (4.2 L) under N2 atmosphere at ambient temperature. To the stirring mixture was added N-methylmorpholine (428 mL, 3.89 mol) and the mixture was stirred to form a homogeneous solution. The reaction solution was cooled to 0-5° C. before addition of isobutyl chloroformate (256 mL, 1.95 mol) via an addition funnel while keeping the reaction temperature under 10° C. After the addition, the mixture was stirred at 0-10° C. for 1 h before filtration. The filtrate was evaporated in vacuo and the resulting residue was dissolved in the mixture of CH2Cl2 (3 L) and methanol (1 L). The mixture was concentrated in vacuo at 400 mbar/35° C. till no more volatile coming out to give a slurry. The slurry was filtered and the filter cake was washed with methanol till the wash getting colorless. The wet cake was dried in a vacuum oven at 45° C. for 24 h to give title compound as a white solid: ESIMS: 504; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 10.00 (s, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.24 (m, 1H), 6.30 (t, 1H), 4.56 (d, 1H), 4.44 (d, 1H), 4.12 (m, 1H), 3.90 (m, 1H), 2.55 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>ClCCl.CO>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: ClCCl
Solvent: CO
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reaction time: 16 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol),1.99 mg of [Ru(η5-2,4-DMP)((R)—(S)—PPF—PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1,000), 12 ml of methanol, 8 ml of dichloromethane and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol). The autoclave was sealed and the hydrogenation was run at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.6% (>99.9% conversion) and an enantiomeric purity of 89%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH2:16]([O:15][C:13]([CH:12]1[CH2:18][CH2:19][N:9]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=2)[CH2:10][CH2:11]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(Br)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2ccc(F)cn2)CC1
Yield: 29.7 %

Procedure:
A mixture of 3.4 g (20 mmol) 2-bromo-5-fluoropyridine, 4.61 g (29 mmol) ethyl isonipecotate and 3.79 g (29 mmol) DIPEA in 5 mL NMP was heated for 15 min to 170° C. and 60 min to 200° C. After cooling to room temperature water was added and the mixture was extracted with ethyl acetate and heptane. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 1.5 g (30%) of the title compound as light yellow oil. MS m/e: 253.3 [M]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][N+:14]#[C-:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH:17]([CH:21]1[CH2:23][CH2:22]1)[CH2:18][CH2:19]Br.O>C(OCC)C.CS(C)=O>[CH:21]1([CH:17]2[CH2:18][CH2:19][C:13]2([N+:14]#[C-:15])[S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:23][CH2:22]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: BrCCC(Br)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: [C-]#[N+]C1(S(=O)(=O)c2ccc(C)cc2)CCC1C1CC1
Reaction time: 1.5 h

Procedure:
In a sulfonation flask 11.1 g (0.28 mol) sodium hydride was suspended in a mixture of 80 ml diethylether and 220 ml DMSO. Then a solution of 19.9 g (0.1 mol) TosMIC and 28.2 g (0.115 mol) (1.3-dibromopropyl)cyclopropane in 30 ml diethylether and 80 ml DMSO was added in 90 minutes. After stirring for 1.5 hours, 70 ml of water was added slowly under ice cooling. The first crop of product was filtered off (16.3 g) and the mother liquor evaporated. The raw material obtained from the mother liquor was then purified by flash chromatography over silicagel (eluent: hexane/ethylacetate 2:1). Overall yield: 19.0 g (68% of theory) of 1-(2-cyclopropyl-1-isocyanocyclobutanesulfonyl)-4-methylbenzene in the form of a solid.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(N)C(=O)OC
Solvent: C1COCCO1
Product: C=C(C)CC(N=C=O)C(=O)OC

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-4-methyl-4-pentenoate, prepared as described by D. Ferroud, J. P. Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-4-methyl-4-pentenoate.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].[C:21]([O:27][CH2:28][C:29]([CH3:41])([CH3:40])[CH2:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32])(=[O:26])[CH2:22][C:23]([CH3:25])=O>CC(O)C>[CH3:25][C:23]1[NH:13][C:14]([CH3:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[Cl:1])[C:22]=1[C:21]([O:27][CH2:28][C:29]([CH3:41])([CH3:40])[CH2:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32])=[O:26]
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1Cl
Yield: 51.9 %

Procedure:
A mixture of 128.7 mg of 2-chloro-3-nitrobenzaldehyde, 88 mg of methyl 3-aminocrotonate and 220 mg of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate in 1 ml of 2-propanol was refluxed for 8 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel to yield 200 mg of desired compound (136).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1.C1COCC1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1cnccn1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a mixture of 6-chloronicotinoyl chloride (160 mg, 0.91 mmol), aminopyrazine (87 mg, 0.91 mmol) and THF (10 ml) was added triethylamine (0.25 ml, 1.82 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 ml), wash with water (50 ml), saturated aqueous NaCl (50 ml), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (3:2) to give 8 mg (4% yield) of the title compound as yellow solid. 1H NMR (CDCl3): 9.68 (d, J=1.2 Hz, 1H), 8.95 (d, J=2.7 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.4 (bs, 1H), 8.33-8.32 (m, 1H), 8.23 (dd, J=2.4, 8.1 Hz, 1H), 7.53 (dd, J=0.6, 8.4 Hz, 1H).
Reaction SMILES: N[CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[C:6]([CH3:25])=[C:7]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:8]([NH:10][CH2:11][C:12]1[C:13](=[O:20])[NH:14][C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])=[O:9].[CH2:27]=O.[C:29]([BH3-])#[N:30].[Na+]>CO>[Cl:24][C:22]1[CH:23]=[C:5]([N:4]([CH2:3][CH2:2][N:30]([CH3:29])[CH3:27])[CH3:26])[C:6]([CH3:25])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[C:13](=[O:20])[NH:14][C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])=[O:9]
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)CCN)c2C)c(=O)[nH]1
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)CCN(C)C)c2C)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
3-((2-Aminoethyl)(methyl)amino)-5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.075 g, 0.199 mmol) was dissolved in methanol (5 mL) and cooled to 0° C., formaldehyde (0.056 g, 1.86 mmol) was added. The resulting reaction mixture was stirred at the same temperature for 30 minutes then sodium cyanoborohydride (0.023 g, 0.366 mmol) was added to above reaction mixture and stirred at room temperature for 4 h. After completion, solvent was removed under reduced pressure and water added before extraction with DCM. The combined organic layers were dried, concentrated and purified by column chromatography to provide 5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylbenzamide (0.040 g, 50%). LCMS: 405.25 (M+1)+; HPLC: 89.93% (@ 254 nm) (Rt; 4.634); 1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.21 (s, 1H), 7.08 (s, 1H), 5.85 (s, 1H), 4.24 (bs, 2H), 2.91 (t, 2H), 2.63 (s, 3H), 2.33-2.35 (m, 2H), 2.11-2.18 (m, 15H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].ClCCl>CN(C)C=O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1)=[N+:14]=[N-:15]
Reactant: CC(C)(O)c1cccc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)c1cccc(CN=[N+]=[N-])n1

Procedure:
2-Bromomethyl-6-(1-hydroxy-1-methylethyl)pyridine (7.61 g, 33 mmol) was dissolved in dimethylformamide (100 mL) and sodium azide (2.6 g, 39.7 mmol) added. After stirring the resultant mixture overnight at ambient temperature, the reaction was poured into dichloromethane and washed well with water. The organic layer was dried (magnesium sulphate), filtered and concentrated to dryness. The resulting yellow oil (5.88 g, 93%) was used without further purification; NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.8 Hz), 7.30 (1H, d, J 8.0 Hz), 7.19 (1H, d, J 7.8 Hz), 4.82 (1H, br s), 4.42 (2H, s), 1.51 (6H, s); LC-MS Retention time 2.06 min, (M+H)+ 193.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:30]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1
Reactant: OCCNCc1ccccn1
Product: Cc1cccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ncccc2C)c1

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol