Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[CH:11]=[C:12]([C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])C(=O)C2=CC=CC=C12.Cl>CO.O1CCCC1>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C(C)=O)cc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)=O)cc1CN
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
Hydrazine hydrate (3.06 g) was added to a suspension of 3'-phthalimidomethyl-4'-methoxyacetophenone (15.74 g) in methanol (150 ml) and tetrahydrofuran (150 ml) at room temperature and the mixture was stirred at room temperature for 24 hours. Dilute hydrochloric acid (conc. hydrochloric acid (5 ml) in water (100 ml)) was added slowly to the mixture with cooling and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated. Water (100 ml) was added thereto and the mixture was alkalized to pH 10 with 30% aqueous potassium carbonate solution and extracted with ethyl acetate (300 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 3'-aminomethyl-4'-methoxyacetophenone (4.45 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:21]=[CH:20][C:19]([I:22])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[N:21]=[CH:20][C:19]([I:22])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cc(I)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(I)cnc1Oc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
To a solution of 4-fluorophenol (224 mg, 2.0 mmol) in DMF (5.0 mL) was added sodium hydride (48 mg, 2.0 mmol) at room temperature. After stirring for 10 min, methyl 2-chloro-5-iodonicotinate (J. Org. Chem. 1989, 54, 3618, 594 mg, 2.0 mmol) was added to the reaction mixture. The reaction mixture was stirred under reflux for 16 h. Then the reaction mixture was poured into water (50 mL) and extracted with ether (50 mL×3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by flash column chromatography on silica gel (50 g) eluting with hexane/ethyl acetate (2/1) to afford 644 mg (86%) of the title compound: 1H-NMR (CDCl3) δ 8.51 (1H, d, J=2.3 Hz), 8.41 (1H, s), 7.09 (4H, d, J=6.2 Hz), 3.95 (3H, s); MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](=O)[CH2:19][C:20]#[N:21])=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.NC1C=C[NH:26][N:25]=1.NN>CCO>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:19]=[C:20]([NH2:21])[NH:25][N:26]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc[nH]n1
Reactant: N#CCC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Agent: NN
Solvent: CCO
Product: Nc1cc(Cc2ccc(OCCCN3CCOCC3)cc2)n[nH]1
Temperature: 65 °C

Procedure:
The 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile is then converted to the appropriate aminopyrazole by the following method: Under Ar(g), 0.095gms. of the 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile is dissolved in 2 mL of anhydrous EtOH and then is treated with 0.100 gms. anhydrous hydrazine. The reaction mixture is then heated overnight at 65° C., subsequently, cooled to room temperature and concentrated in vacuo providing 5-[4-(3-morpholin-4-yl-propoxy)-benzyl]-2H-pyrazol-3-ylamine which is use in crude form in the reaction of Example 58.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cccc2c1C(CO)CN2C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1cccc2c1C(COS(C)(=O)=O)CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
A solution of 17 (80 mg, 0.26 mmol) in 5 mL anhydrous CH2Cl2 was cooled to 0° C. and treated with Et3N (79 μL, 0.57 mmol). After 10 min, MsCl (40 μL, 0.52 mmol) was added and the reaction mixture was subsequently warmed to 25° C. and stirred for 3 h. The reaction solution was concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×10 cm, 30% EtOAc/hexane) yielded pure 18 (94 mg, 94%) as a colorless oil: 1H NMR (CDCl3, 250 MHz) δ7.49 (m, 1H), 7.15 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 5.19 (d, J=8.8 Hz, 1H), 5.17 (d, J=8.8 Hz, 1H), 4.58 (dd, J=3.6, 9.7 Hz, 1H), 4.21 (app t, J=8.9 Hz, 1H), 4.00 (m, 2H), 3.79 (m, 1H), 3.46 (s, 3H), 2,71 (s, 3H), 1.54 (s, 9H);13C NMR (CDCl3, 100 MHz) δ153.9, 152.1, 130.5, 110.2, 108.8, 107.7, 103.9, 94.4, 81.0, 69.9, 56.2, 51.1, 37.9, 37.2, 28.2; IR (film) νmax 2976, 1703, 1610, 1479, 1463, 1391, 1355, 1254, 1175, 1154, 1061, 952 cm−1; FABHRMS (NBA/CsI) m/z 520.0388 (C17H25NO7S+Cs+ requires 520.0406).
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[CH3:23][C:24]([NH:27][S:28]([C:31]1[S:39][C:38]2[S:37](=[O:41])(=[O:40])[N:36]([CH2:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH2:35][C:34](=[O:48])[C:33]=2[CH:32]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25].N(CCO)CCO>C1COCC1.C(OCC)(=O)C>[CH3:26][C:24]([NH:27][S:28]([C:31]1[S:39][C:38]2[S:37](=[O:40])(=[O:41])[N:36]([CH2:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH2:35][C@@H:34]([OH:48])[C:33]=2[CH:32]=1)(=[O:30])=[O:29])([CH3:23])[CH3:25]
Reactant: COCCCCN1CC(=O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: OCCNCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCCN1C[C@@H](O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 88.3 %

Procedure:
To a solution of (+)-β-chlorodiisopinocamphenylborane (28.01 g, 0.087 mol) in THF (60 mL) at -20° C. was added a solution of the product from Step B (7.4 g, 0.017 mol) in THF (90 mL); this mixture was stirred for 40 hr while maintaining this temperature. Diethanolamine (9.13 g, 0.087 mol) was added to the reaction mixture which was allowed to warm to room temperature and stirred at this temperature for 2 hr. Evaporation of the THF gave a residue which was dissolved in ethyl acetate (100 mL); this solution was washed with water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The ethyl acetate extracts were combined, washed with brine (2×20 mL), dried (MgSO4), and evaporated to a residue which was purified by column chromatography (silica, 60% ethyl acetate/hexane) to give an oil (6.4 g, 86%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH3:11])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19]CC)=[O:18])C>O>[CH2:1]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([F:10])[C:5]=2[CH3:11])[C:15](=[O:14])[C:16]([C:17]([OH:19])=[O:18])=[CH:22]1)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCNc1cccc(F)c1C
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(F)c(C)c21
Temperature: 110 °C
Yield: 68.3 %

Procedure:
Nine grams of N-ethyl-2-methyl-3-fluoroaniline is allowed to react with 15 g of diethyl ethoxymethylenemalonate under heating at 110° C. for 30 minutes. Then, polyphosphoric acid (obtained from 50 g each of phosphoric acid and phosphorus pentaoxide) is added to be subjected to the reaction at 140° C. for 40 minutes. After the reaction is completed, the mixture is poured into 600 g of water and ice to obtain crystals. The crystals are recovered by filtration, and a 10% sodium hydroxide solution is added to the filtrate and the mixture is refluxed for 1 hour. After refluxing, the reaction mixture is treated with activated carbon and adjusted to pH 2 with concentrated hydrochloric acid, whereby there separate out light yellow crystals. Recrystallization from dimethylformamide yields 10 g of 1-ethyl-7-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as the white, needle-like crystals. mp. 245°-246° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:15])=[C:4]([Cl:11])[N:3]=1
Reactant: CI
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2c(Cl)nc(N)nc21
Reaction time: 0.75 h

Procedure:
The 2-amino-6-chloropurine (1.08 g, 6.4 mmol) was suspended in dry DMF (75 ml) and treated with sodium hydride, 60% dispersion (0.28 g, 7 mmol). The suspension was stirred for 15 min before iodomethane (0.44 ml, 7.06 mmol) was added and the resulting yellow solution stirred for 1 hr 45 min. The solid was filtered and the filtrate evaporated before addition of water for 10 min. The resulting solid was filtered and dried overnight to give the product as a mixture of N-7 and N-9 alkylation products. The residual liquor was left overnight and more crystals were collected the next day and dried.
Reaction SMILES: C(N[C:6]([C:8]1[S:12][C:11]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH2:15][C:10]=2[C:9]=1[CH:18]=[N:19][NH2:20])=[O:7])(C)(C)C>OS(O)(=O)=O>[CH3:17][C:14]1([CH3:16])[CH2:13][C:11]2[S:12][C:8]3[C:6](=[O:7])[NH:20][N:19]=[CH:18][C:9]=3[C:10]=2[CH2:15]1
Reactant: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=NN)c2C1
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2sc3c(=O)[nH]ncc3c2C1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A solution of 282g (3.8 g, 13.0 mmol) in 30% H2SO4 (100 mL) was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and extracted with dichloromethane (3×200 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 282h as yellow solid (1.72 g, 60%). MS-ESI: [M+H]+ 221.0
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Cl)=[CH:15][CH:14]=1.[CH3:21][N:22](C)[C:23]1(C2C=CC=CC=2)CCC2(CCNCC2)CC1>>[F:12][C:13]1[CH:18]=[C:17]([C:8]2([N:22]([CH3:23])[CH3:21])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C1(c2ccccc2)CCC2(CCNCC2)CC1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Cl)cc1
Product: CN(C)C1(c2cccc(F)c2)CCC2(CC1)OCCO2

Procedure:
The reaction was performed starting from 1,4-dioxaspiro[4.5]decan-8-one and 4-fluorophenylmagnesium chloride (1 M in hexane) in an analogous manner to stage 1 amine (A1).
Reaction SMILES: O.C(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)(=O)C.C(OC(=O)C)(=O)C.P(=O)(O)(O)O>C(O)(=O)C>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]=[CH2:6])=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCCc1ccc(OC(C)=O)cc1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
A flask heated by hot oil was fitted with a chilled water overhead condenser, a thermowell with a thermocouple, an overhead stirrer and a vacuum pump. Crude APMC-Ether (20 grams) containing 78.2 weight percent APMC-Ether, 7.2 weight percent APMC and 3.9 weight percent 4-acetoxyphenylmethylcarbinol acetate (sometimes referred to herein as "APMC-Acetate") was mixed in another flask with six (6.0) grams of acetic anhydride. Phosphoric acid (0.022 grams) having a concentration of 85 weight percent that corresponds to 0.32 moles of pure phosphoric acid per 100 moles of APMC-Ether was added to said mixture. The resultant mixture was fed to the hot flask at a rate of 1.2 grams per minute. The hot oil temperature was maintained at about 220° C. to about 230° C. and the reaction mass temperature in the hot flask was maintained at about 180° C. to about 200° C. The vacuum pump maintained a vacuum in the flask at about 80 mm Hg. 4-acetoxystyrene and acetic acid were produced in the hot flask.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc([C@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 94.4 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (154 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (96 mg) according to an analogous synthetic method to Example 404, the title compound (150 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.[ClH:53].[F:54][C:55]([F:63])([F:62])[CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:53][C:34]1[CH:33]=[C:32]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:30])[CH3:29])[CH2:18][CH2:19]4)[C:10]3=[O:31])=[CH:2][CH:3]=2)[CH:37]=[CH:36][C:35]=1[C:38]([N:59]1[CH2:60][CH2:61][CH:56]([C:55]([F:63])([F:62])[F:54])[CH2:57][CH2:58]1)=[O:40]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: FC(F)(F)C1CCNCC1
Reactant: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)c(Cl)c4)cc3)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Treat a solution of 3′-chloro-4′-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.2 g, 0.34 mmol) in CH2Cl2 (15 mL) with 1,1′-carbonyldiimidazole (0.11 g, 0.68 mmol) and stir for 60 minutes at room temperature. Treat the reaction with 4-trifluoromethylpiperidine hydrochloride (0.10 g, 0.51 mmol) and diisopropylethylamine (0.07 g, 0.51 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column, flash with 0% to 50% ethyl acetate in hexanes to afford 0.12 g (49%) of the title compound. MS (m/z): 720 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[N-:25]([C:28]#[N:29])[C:26]#[N:27].[Na+].CO>CN(C=O)C>[NH2:29][C:28](=[N:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)[NH:25][C:26]#[N:27]
Reactant: COc1cc(NC(=O)Nc2cccc(N)c2)ccc1-c1cnco1
Reactant: N#C[N-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(NC(=O)Nc2cccc(N=C(N)NC#N)c2)ccc1-c1cnco1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
To a solution of 50 mg (0.15 mmol) of 49B in 1 ml of DMF was added excess HCl—ether. A precipitate was obtained. Stirring was continued for 0.5 hr and the slurry was then evaporated to dryness. The residue was diluted with 2 ml of DMF and 40 mg (0.45 mmol) of sodium dicyanamide added. The reaction was heated at 50° C. for 3 hr during which time a lightly cloudy, pale yellow solution was obtained. After removal of the solvent, the residue was diluted with 3 ml of water and stirred for 1 hr. The insolubles were removed by filtration to give 76 mg of the crude product. This material was dissolved into methanol and absorbed onto approx. 1 g of silica gel and subjected to flash chromatography on a 30 cc column of silica gel. Elution with 5% MeOH-EtOAc afforded 9 mg (0.023 mmol, 15%) of 49C as a pale yellow solid. (M+H)+ 392+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C:6]1[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[S:9][C:10]=1[CH2:11][C:12]#[N:13].[N-:24]=[N+:25]=[N-:26].[Na+].[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C.O>[NH:24]1[C:12]([CH2:11][C:10]2[S:9][C:8]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:7][C:6]=2[CH2:5][C:4]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=2)=[N:13][N:26]=[N:25]1
Reactant: N#CCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(Cc2nc(N3CCOCC3)sc2Cc2nnn[nH]2)cc1Cl
Yield: 5.2 %

Procedure:
To a solution of 2-(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)acetonitrile (87.0 mg, 0.236 mmol) in DMF (0.74 mL) was added sodium azide (21.6 mg, 0.332 mmol) and NH4Cl (17.8 mg, 9.53 mmol) and the resulting mixture was heated to 140 degrees overnight. More sodium azide (43 mg, 0.66 mmol) and NH4Cl (36 mg, 19 mmol) were added and the reaction was heated to 120 degrees overnight. The reaction was cooled and taken up in ethyl acetate (25 mL) and water (5 ml). The layers were separated and the organic layer was washed with water (3×5 mL).). The organic layer was dried and concentrated in vacuo. The residue was purified by preparative reverse phase chromatography to give 5 mg (5% yield) of the title compound. as a white solid. LC/MS (FA) ES+ 411. 413. 1H NMR (400 MHz, DMSO-d6) δ: 7.50 (d, 1H, J=8.0 Hz), 7.46 (d, 1H, J=2.0 Hz), 7.20 (dd, 1H, J=8.0, 2.0 Hz), 4.41 (s, 2H), 3.88 (s, 2H), 3.65-3.62 (m, 4H), 3.32 (bs, 1H), 3.26-3.24 (m, 4H).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:10])[CH:7](O)[CH3:8].Cl.[CH:12]1[C:22]2[CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[C:17](=[CH:27][CH2:28]OCCN3CCC[C@@H](C(O)=O)C3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.[OH2:41]>>[OH:41][CH2:8][CH2:7][CH2:6][O:10][CH2:28][CH:27]=[C:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:22]=2[CH2:21][CH2:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]1=2
Reactant: O=C(O)[C@@H]1CCCN(CCOCC=C2c3ccccc3CCc3ccccc32)C1
Reactant: O
Reactant: CC(O)CO
Agent: Cl
Agent: [Li]CCCC
Product: OCCCOCC=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexanes (16.8 ml, 2.5 M) was added dropwise to ice-cooled propylene glycol (25 ml) under an atmosphere of nitrogen. When addition was complete the mixture was stirred at room temperature for 15 minutes. A solution of crude 5-(2-bromoethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (10.1 g, prepared as described in Example 3) was added in one portion and the reaction mixture was stirred at room temperature for 42 h. Water (40 ml) was added and the mixture was extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed with water (15 ml), dried over sodium sulphate and the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (200 g) using a mixture of THF and n-heptane (3:7) as eluent. Collecting the proper fractions afforded 4.2 g of 5-(2-(3-hydroxypropyloxy)ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as an oil. TLC: rf=0.18 (SiO2 ; THF/n-heptane=3:7 ).
Reaction SMILES: ClCCC1C=CC=CC=1.Cl[C:11]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:12]=1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]=2)[C:16]([CH3:27])=[N:15]1>>[CH3:27][C:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=2)[N:14]([CH2:13][CH2:12][C:11]2[CH:32]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:15]=1.[CH2:13]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]=2)[CH:16]=[CH:27]1)[C:12]1[CH:11]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Agent: ClCCc1ccccc1
Product: Cc1nn(CCc2ccccc2)c2cc(CC(=O)O)ccc12
Product: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1

Procedure:
The titled compound (1.9 mg) as a white solid was prepared from the compound [102-4] obtained in the process (4) of Example 102 (42.6 mg) and (2-chloroethyl)benzene according to the method of the process (5) of Example 102.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=CC=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29](=O)CCC.Cl.C[C@H]1CC[C@H](N)CC1.C([O:45][C:46](=[O:49])CC)C.Cl.CCN(C(C)C)C(C)C>>[CH2:21]([N:7]([C@H:1]1[CH2:2][CH2:3][C@H:4]([CH3:29])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:46]([OH:49])=[O:45])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:28]
Reactant: CCCC=O
Reactant: CCOC(=O)CC
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C(=O)Nc1ncc(SCCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from butyraldehyde, trans-4-methylcyclohexylamine hydrochloride and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:23])[C:6]([O:8][N:9]=[C:10]([NH2:22])[C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([F:21])[CH:12]=1)=O)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:4][C@H:5]([C:6]1[O:8][N:9]=[C:10]([C:11]2[CH:12]=[C:13]([F:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[N:22]=1)[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)ON=C(N)c1cc(F)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C)c1nc(-c2cc(F)cc(C(F)(F)F)c2)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]-1-azavinyl (2S)-2-acetyloxypropanoate (5.19 g, 15.43 mmol) in anhydrous tetrahydrofuran (20 ml) at 0° C. was added a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (3 ml) dropwise under nitrogen. The reaction mixture was stirred for 3 hours at 0° C., then poured into ethyl acetate (50 ml), washed with water (2×20 ml), brine (30 ml) and dried over sodium sulfate. Solvent was removed under reduced pressure, and the residue purified by flash chromatography, eluting with methylene chloride, to provide (1S)-1-{3-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-yl)}ethyl acetate, LCMS 319.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Br:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3)nccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nccc3c(CBr)cccc23)cc1
Yield: 68.8 %

Procedure:
1-(4-Chlorophenyl)-5-methylisoquinoline (10.2 g) was dissolved in 50 ml of carbon tetrachloride. While the solution was heated under reflux and light was irradiated on it, 7.5 g of N-bromosuccinimide was added. The mixture was heated with stirring. After the reaction, the reaction mixture was cooled. The insoluble matter was removed by filtration. The filtrate was washed in water, dried, and concentrated to remove the solvent. Recrystallization from cold methanol afforded 9.2 g of 1-(4-chlorophenyl)-5-bromomethylisoquinoline as colorless needles having a decomposition point of 116° C.