Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c([C@H]3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC[C@H](c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-[(3S)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (95 mg, 0.22 mmol), N,N-dimethylglycine (28 mg, 0.27 mmol), EDCl (47 mg, 0.25 mmol), HOBt (33 mg, 0.25 mmol), and N,N-diisopropylethylamine (117 μL, 0.67 mmol) in DMF (2 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MOON and the filtrate was concentrated to provide 35 mg (27%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.27-7.39 (m, 5 H), 7.14 (d, 1 H), 6.61-6.67 (m, 1 H), 5.65 (s, 2 H); 3.95-4.94 (m, 2 H), 2.62-3.32 (m, 5 H), 2.05-2.23 (m, 7 H), 1.70-1.91 (m, 2 H), 1.40-1.64 (m, 1 H); ES-MS m/z 509.18 [M+H]+, HPLC RT (min) 2.23.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH2:15][CH2:16][CH2:17][C:4]=2[N:3]=1.[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21].CCOCC>C(O)CCC>[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[N:7]=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]4[CH2:15][CH2:16][CH2:17][C:4]=4[N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24][CH2:25]1)=[O:21]
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Reactant: Clc1nc2c(c(Oc3ccccc3)n1)CCC2
Solvent: CCCCO
Solvent: CCOCC
Product: COC(=O)C1(c2ccc(Nc3nc4c(c(Oc5ccccc5)n3)CCC4)cc2)CCC1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of 2-chloro-4-phenoxy-6,7-dihydro-5H-cyclopentapyrimidine (0.28 g, 1.1 mmol) and 1-(4-amino-phenyl)cyclobutanecarboxylic acid methyl ester (0.23 g, 1.11 mmol) in 1-butanol (3.0 mL) was stirred at a temperature in the range of 20° C. to 100° C. for 8 to 16 hours. Thereafter, the reaction was cooled to about 20 to 35° C. Anhydrous ether was added and the mixture was stirred for 1 hour at about 20 to 35° C. The separated solid was filtered, washed with ether, and dried in vacuum to afford the title compound as a white solid (0.38 g, 81% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=O)=[CH:31][CH:30]=1.[C:39]([O:47][NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]#[CH:60])=[C:53]([O:61][CH3:62])[CH:52]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[C:39]([O:47][N:48]([CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]#[CH:60])=[C:53]([O:61][CH3:62])[CH:52]=1)[C:36](=[O:38])[CH2:35][C:32]1[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: C#CCOc1ccc(CCNOC(=O)c2ccccc2)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CCN(OC(=O)c2ccccc2)C(=O)Cc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
BOP (2.0 g, 4.5 mmol) is added to a solution of (4-chloro-phenyl)-acetic acid (0.7 g, 4.1 mmol), N-benzoyloxy-2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine (1.4 g, 4.3 mmol) and N-ethyldiisopropylamine (2.8 ml, 16.4 mmol) in 10 ml DMF. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is then poured into water and extracted three times with ethyl acetate. The organic phase is dried over Na2SO4 and concentrated. The crude product is purified by flash chromatography (ethyl acetate:hexane, 1:3) to yield N-benzoyloxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide as an oil.
Reaction SMILES: CCO.C([Cl:7])(=O)C.[CH3:8][C:9]([C:12]1[O:16][C:15]([CH2:17][S:18][C:19]2[S:23][C:22]([NH:24][C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])=[N:21][CH:20]=2)=[N:14][CH:13]=1)([CH3:11])[CH3:10]>O>[ClH:7].[CH3:11][C:9]([C:12]1[O:16][C:15]([CH2:17][S:18][C:19]2[S:23][C:22]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[O:26])=[N:21][CH:20]=2)=[N:14][CH:13]=1)([CH3:8])[CH3:10]
Reactant: CC(=O)Cl
Agent: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCNCC3)s2)o1
Solvent: O
Solvent: CCO
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 40 mL of absolute EtOH cooled in an ice-bath was added acetyl chloride (0.28 mL, 3.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature over 30 min then N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]-thio]-2-thiazolyl]-4-piperidinecarboxamide (1.50 g, 3.94 mmol, 1 eq) was introduced in one portion with stirring to give a thick slurry. Water (˜4 mL) was added until homogeneous then concentrated in vacuo to give a crude pale yellow solid. The crude material was recrystallized (aq EtOH) to afford the title compound (70%) as a white solid, mp 256-258°. Analysis calc'd for C17H24N4O2S2.HCl: C, 48.96; H, 6.04; N, 13.43; S, 15.38; Cl, 8.50. Found: C, 48.69; H, 5.99; N, 13.24; S, 15.27; Cl, 8.31.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:9]1[C:10](=[O:26])[N:11]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:18]([O:20]C)=O)[CH:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>O>[CH:32]1([NH:35][C:18](=[O:20])[C:17]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:15]([N:11]3[CH:12]=[CH:13][N:14]=[C:9]([N:8]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10]3=[O:26])[CH:16]=2)[CH2:34][CH2:33]1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N(CCN(C)C)Cc3ccccc3)c2=O)c1
Reactant: NC1CC1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N(CCN(C)C)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 3-{3-[benzyl-(2-dimethylamino-ethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-4-methylbenzoic acid, methyl ester (Example 121a, 50 mg), cyclopropylamine (1 mL) and water (0.5 mL) was stirred at room temperature for 10 days. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (10 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:31]=[CH:30][C:10]([O:11][CH2:12][C@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.O>O1CCCC1.C(OCC)(=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH2:14][C@@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:12][O:11][C:10]2[CH:30]=[CH:31][C:7]([B:32]([OH:37])[OH:33])=[CH:8][CH:9]=2)[CH:17]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of n-butyllithium (2.5 M in hexanes, 6.9 ml, CAUTION) was added dropwise to a stirring solution of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (1.50 g, Example 21b)) and triisopropyl borate (4.3 ml) in tetrahydrofuran (200 ml) at −70° C. After the addition was complete the reaction mixture was allowed to warm to room temperature. After 1 hour water (200 ml) and ethyl acetate (200 ml) were added. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. This was partly purified by column chromatography over silica eluting with dichloromethane then ethyl acetate then methanol to give the sub-title compound as a glass (2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8]O.S(Cl)([Cl:12])=O>C1COCC1>[ClH:12].[Cl:12][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCc1ccccn1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cl
Product: ClCCc1ccccn1
Yield: 52.9 %

Procedure:
2-(Pyridin-2-yl)ethanol (7.2 g, 58 mmol) and thionyl chloride (10.6 g, 89.1 mmol) were combined in THF (30 mL) and heated at reflux for 16 h. Upon cooling, the solid was filtered off and washed with THF to provide the title compound (4.2 g, 40%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J=5.6 Hz, 1H), 8.51-8.45 (dt, J=7.8, 1.5 Hz, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.91-7.86 (m, 1H), 4.14 (t, J=6.5 Hz, 2H), 3.53 (t, J=6.5 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]([S:5]([CH3:8])(=[O:7])=[O:6])=[CH2:4].[CH2:9]([O:11][CH2:12][C:13]1[N:14]([CH2:26][C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:10].O>O1CCCC1>[CH2:9]([O:11][CH2:12][C:13]1[N:14]([CH2:26][C:27]2([O:33][CH2:4][CH2:3][S:5]([CH3:8])(=[O:7])=[O:6])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:10]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 25 mg, 0.62 mmol) followed by methyl vinyl sulfone (1.30 g, 12.4 mmol) were added to a stirred solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (2.1 g, 6.2 mmol) in tetrahydrofuran (25 mL). The reaction mixture was heated at reflux for 2 hours and additional methyl vinyl sulfone (1 equivalent) and sodium hydride (60% dispersion in oil, spatula tip full) were added. The mixture was allowed to stir overnight at room temperature. Water (50 mL) was added and a precipitate formed that was removed by filtration. The filtrate was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 0.45 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)-1H-imidazo[4,5-c]quinoline as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[CH:9][C:10](=[O:12])[CH3:11].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[C:14]1([C:13](=[O:20])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CC(C)=O
Reactant: O=Cc1ccccc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 8.1 g (0.03 mol) 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride, 180 ml triethylamine, 150 ml ethanol, 21 g of 1-butene-3-one (0.3 mol) and 30.7 g of benzaldehyde (0.29 mol) was gently stirred at 80° C. for 16 hours. Volatile components were removed by evaporation. The 1-phenyl-1,4-pentanedione thus formed was recovered by extraction and subsequent vacuum distillation.
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([SH:10])[C:7]([F:11])=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:2][C:3]1[CH:9]=[C:8]([S:10][C:18]2[CH:17]=[CH:16][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[Cl:12])[C:7]([F:11])=[CH:6][C:4]=1[NH2:5]
Reactant: Nc1cc(F)c(S)cc1F
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 6 h
Yield: 69 %

Procedure:
3.00 Grams of 2,5-difluoro-4-mercaptoaniline hydrochloride, 6.60 g of 3,4-dichlorobenzotrifluoride and 4.90 g of potassium carbonate were dissolved in 30 ml of dimethylformamide, and the resulting solution was stirred for 6 hours at a temperature of from 100° to 110° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with three 100-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 3.60 g of 2,5-difluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]N1C(=O)CCC1=O>CN(C)C=O>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(F)cccc1F
Solvent: CN(C)C=O
Product: Nc1c(F)cc(Br)cc1F
Yield: 61.9 %

Procedure:
Fifty grams (0.39 mole) of 2,6-difluoroaniline was treated with 71.0 g (0.39 mole) of N-bromosuccinimide in 250 ml of dimethylformamide by the procedure of Mitchell, Lai and Williams, J. Org. Chem., 44, 4733 (1979) to give a total yield of 50.2 g (62%) of 4-bromo-2,6-difluoroaniline, m.p.: 64°-66° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[Br-].[O:14]1[CH2:19][CH2:18]C[O:16][CH:15]1[CH:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:21].[Li]CCCC>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:21][CH2:20][CH:15]2[O:14][CH2:19][CH2:18][O:16]2)=[CH:6][CH:5]=1
Reactant: CC(C1OCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=CCC2OCCO2)cc1
Yield: 50.3 %

Procedure:
The olefin was prepared from 4.3 g (26.2 mmol) of the aldehyde 167, 13.94 g of [1-(1,3-dioxan-2-yl)ethyl]triphenylphosphoniumbromide and 12.6 mL (32.0 mmol) of n-BuLi in 75 mL of THF as described for the synthesis of 156 in Example 8. Flash chromatography (elution with 10% ethyl acetate in hexane) gave 3.27 g of the olefin 168. 1H NMR consistent with the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6])[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[Cl:21])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 2L round bottom flask was added 21 g (100 mmol) of (L)-tyrosine ethyl ester (1) (Bachem) and 500 mL of tetrahydrofuran (THF). The mixture was magnetically stirred at room temperature until dissolved, and 500 mL of aqueous NaHCO3 (0.5 M) was added. The mixture was cooled in an ice bath and 19.3 g (110 mmol) of 2-chlorobenzoyl chloride (Aldrich) was added slowly via a glass syringe. The ice bath was removed and the reaction was allowed to warm to room temperature with stirring. After 30 min., the reaction mixture was rotory evaporated under reduced pressure to remove the THF and the remaining aqueous bicarbonate solution was extracted twice with 400 mL ethyl acetate. The combined extracts were washed with 400 mL of satd. aqueous NaHCO3, 400 mL of 0.1 N HCl, 400 mL of water, and 400 mL of satd. aqueous NaCl. The remaining organic layer was dried over Na2SO4 and evaporated to dryness to afford ˜40 g of crude (2) as a pale yellow oil. The crude product (2) was recrystallized from ˜800 mL of boiling ethyl acetate/hexane (˜1:3) and cooled to 4° C. overnight. The resulting crystalline product was filtered and dried under a stream of nitrogen to afford 32 g (92% isolated yield) of purified (2). The N-(2-chlorobenzoyl)-(L)-tyrosine ethyl ester product (2) was confirmed by NMR and electrospray mass spectrometry (see attached) and judged >95% pure by HPLC and TLC (Rf=0.6, 1:1 ethyl acetate/hexane). The remaining 5% impurity (Rf=0.7) was identified as 2-chlorobenzoic acid by HPLC and TLC versus authentic material.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].CN(C)C=O.[Cl:27][CH2:28]/[CH:29]=[CH:30]/[CH2:31]Cl>O1CCCC1>[CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:31]/[CH:30]=[CH:29]/[CH2:28][Cl:27])[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: ClC/C=C/CCl
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OC/C=C/CCl)c1
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
245 mg of (E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine was dissolved in 5 ml of tetrahydrofuran, and under ice cooling, 40 mg of oily sodium hydride was added. After the mixture was stirred for 15 minutes, a dimethylformamide solution (3ml) of 125 mg of (E)-1,4-dichloro-2-butene was added. The mixture was stirred at room temperature for 12 hours, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 216 mg of the captioned compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O>[Fe].CCO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(I)cc1OCc1ccccc1
Temperature: 100 °C

Procedure:
To a mixture of 2-benzyloxy-4-iodo-1-nitrobenzene (2.35 g, 6.62 mmol) and Fe (1.85 g, 33.1 mmol) is added AcOH (24 mL) and EtOH (12 mL) and it is refluxed at 100° C. for 1.5 h. The mixture is then cooled and filtered through Celite. EtOAc (300 mL) is added and it is then washed with sat. NaHCO3 (2×), brine (1×) and dried with NaSO4. It is then concentrated and the residue is purified by column chromatography to give the title compound.
Reaction SMILES: C([N:8]1[CH:13]([C:14]#[N:15])[CH2:12][CH2:11][CH2:10][C:9]1([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]#[N:17])C1C=CC=CC=1.[ClH:26].[H][H]>CO.[Pd]>[ClH:26].[NH2:17][CH2:16][C:9]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:10][CH2:11][CH2:12][CH:13]([CH2:14][NH2:15])[NH:8]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC1(C#N)CCCC(C#N)N1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1CCCC(CN)(CC(=O)O)N1

Procedure:
A solution of 6.00 mmol of tert-butyl (1-benzyl-2,6-dicyanopiperidin-2-yl)acetate in 40 ml of methanol is admixed with 2 ml of 37% strength aqueous hydrochloric acid and 0.600 g of 10% Pd/C. The reaction mixture is hydrogenated with 4 bar of hydrogen at 22° C. for 18 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. From the residue the crude title compound is identified on the basis of the Rf value. The title compound is used without further purification in the next stage.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:11][C:12]1[C:17]([F:18])=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[C:15]([NH2:28])=[C:14]([CH3:29])[CH:13]=1>>[CH2:1]([C:4]1([S:7]([NH:28][C:15]2[C:14]([CH3:29])=[CH:13][C:12]([F:11])=[C:17]([F:18])[C:16]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Product: C=CCC1(S(=O)(=O)Nc2c(C)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Yield: 47.9 %

Procedure:
According to the general procedure B, 1-allyl-cyclopropanesulfonyl chloride (142 mg, 142 mg) was reacted with 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamine (150 mg, 0.4 mmol) to obtain the title product (100 mg, 47%); m/z=521 [M−1]−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=O)=[O:12].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([N:45]1[CH2:44][CH2:43][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:47][CH2:46]1)=[O:20])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1nc2ccccc2s1
Reaction time: 8 h

Procedure:
To a solution of (S)-5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoic acid (˜4.41 mmol) in DMF (8 mL) at RT were added N-Boc-piperazine (820 mg, 1 equiv.), DIEA (1.2 mL, 1.5 equiv.), and HBTU (2.00 g, 1.2 equiv.) The reaction was allowed to stir overnight, and the crude was purified by RP-HPLC (5-100% ACN in H2O) to give (S)-tert-butyl 4-(5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate as a white solid (801 mg, 27% over 2 steps). LRMS (M+Na+)=699.4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16]
Reactant: ClCCCBr
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCCCCl)cccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-Bromo-3-chloropropane (17.3 g) is added to a stirred mixture of 4-hydroxyindanone (14.8 g), potassium carbonate (15.3 g) in DMF/water (150 ml/50/ml) and the reaction mixture stirred at RT for about 4 days. The reaction mixture is partitioned between water and methylene chloride and the organic layer is separated, dried, filtered and evaporated, affording a residue which is chromatographed on a silica gel column to yield the desired product as a white solid.