Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1)[CH:25]=[CH2:24]
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=CCc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (0.82 g) in 1,4-dioxane (40 mL) were added allyltri(n-butyl)tin (0.74 mL) and tetrakis(triphenylphosphine)palladium(0) (0.46 g), and the reaction vessel was equipped with a reflux condenser, and the reaction mixture was stirred at 120° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−3/1) to give 4-allyl-2-chloro-5-(2,3-difluoro-6-methoxybenzyl-oxy)-1-nitrobenzene (0.68 g). This material was dissolved in tetrahydrofuran (20 mL). To the solution were added water (10 mL), 50% aqueous N-methylmorpholine-N-oxide solution (0.96 mL) and osmium(VIII) oxide, microencapsulated (about 10%, 0.23 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/4) to give 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-(2,3-dihydroxy-propyl)-1-nitrobenzene (0.29 g). The title compound was prepared in a similar manner to that described in Reference Example 170 using this material instead of 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-(1,3-dihydroxy-2-propoxy)-1-nitrobenzene.
Reaction SMILES: [OH:1][N:2]([CH:12]([C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20])[CH3:13])[C:3]([N:5]([C:7](OCC)=O)C)=[O:4].[BH4-].[Li+].C1C[O:26][CH2:25]C1>>[OH:1][N:2]([CH:12]([C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20])[CH3:13])[C:3]([NH:5][CH2:7][CH2:25][OH:26])=[O:4]
Reactant: C1CCOC1
Reactant: CCOC(=O)N(C)C(=O)N(O)C(C)c1cc(C)sc1C
Agent: [BH4-]
Agent: [Li+]
Product: Cc1cc(C(C)N(O)C(=O)NCCO)c(C)s1
Reaction time: 8 h

Procedure:
To a stirred solution of ester from Example 59 (1.84 g, 6.13 mmol) in dry THF (15 mL) was added 2M lithium borohydride in THF (5.0 mL, 10.0 mmol) dropwise under nitrogen. The solution was stirred overnight, then quenched by the dropwise addition of methanol (25 mL) and stirred 4 h. The reaction was concentrated, poured into 10% aqueous citric acid (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extract was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography (silica gel, ethyl acetate-hexanes, 50:50, 75:25), followed by crystallization from ethyl acetate-hexanes to provide the desired product. (510 mg). m.p=122°-123.5° C.; NMR (300 MHz, DMSO-d6) 1.29 (3H, d, J=7.0 Hz), 2.28 (3H, s), 2.32 (3H, s), 3.08 (2H, m), 3.35 (2H, m), 4.65 (1H, t, J=5.3 Hz), 5.23 (1H, q, J=7.0 Hz), 6.70 (1H, t, J=5.9 Hz), 6.73 (1H, m), 9.03 (1H, s); MS: (M+H)+ =259
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:18]([OH:20])=O)[NH:13]3)=[CH:5][CH:4]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:18]([C:12]2[NH:13][C:14]3[C:10]([CH:11]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:16][CH:15]=3)=[O:20])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)O)cc23)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(Cc5ccccc5)CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
128 (4.7 g, 17.6 mmol) and 1-benzyl-piperidin-4-ylamine (3.3 g, 17.6 mmol) are dissolved in DMF (70 ml) and after addition of TBTU (6.4 g, 19.4 mmol) and ethyldiisopropylamine (12 ml, 70.4 mmol) the mixture is stirred at room temperature for 2 h. Then the solvent is evaporated at high vacuum. The residue is dissolved in ethyl acetate washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layers are dried over sodium sulfate and evaporated under reduced pressure. The crude mixture is crystallized from methanol.
Reaction SMILES: CI.[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[OH:12])(=[O:5])[CH3:4].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:17])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(NC(C)=O)cc1C(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
Methyl iodide (3.42 ml, 7.81 g, 55 mmol) was added to a stirred mixture of N-(3-acetyl-4-hydroxyphenyl)acetamide (J.Org.Chem. 1995, 60, 4324-4330) (9.65 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol) in dimethylformamide (50 ml). The mixture was stirred at room temperature for 72 hours, then the solvent was evaporated under reduced pressure. Water (100 ml) was added and the mixture was extracted with ethyl acetate (6×100 ml). The combined organic fractions were dried (MgSO4) and evaporated under reduced pressure to give N-(3-acetyl-4-methoxyphenyl)acetamide as a tan solid (10.34 g, 100%), 1H NMR (d6 -DMSO) δ 9.91 (1H, br. s), 7.76 (2H, m), 7.12 (1H, d, J=9.6 Hz), 3.86 (3H, s), 2.52 (3H, s), and 2.01 (3H, s). m/e (CI+) 208 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][N:40]=1)[C:36]#[N:37]>ClCCl.C(OCC)(=O)C>[I:25][CH2:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][N:40]=1)[C:36]#[N:37]
Reactant: N#Cc1ccnc(Oc2cccc(CO)c2)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(Oc2cccc(CI)c2)c1
Reaction time: 0.17 h
Yield: 55.9 %

Procedure:
Mix polymer-supported triphenylphosphine (2.33 mmol/g load capacity, 0.85 g, 1.99 mmol), imidazole (0.14 g, 1.99 mmol) and iodine (0.51 g, 1.99 mmol) in dichloromethane (8 mL) in a vial (0.75 oz). Seal and shake for 10 minutes. Add a solution of 2-(3-hydroxymethyl-phenoxy)-isonicotinonitrile (0.30 g, 1.33 mmol) in dichloromethane (3 mL) and shake for 2 hrs. Filter the resin and wash with dichloromethane (50 mL). Concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in ethyl acetate (25 mL), wash with saturated sodium thiosulfate solution (2×25 mL) and dry over sodium sulfate. Filter and concentrate to give 2-(3-iodomethyl-phenoxy)-isonicotinonitrile as a yellow solid (0.25 g, 53%). Mix the yellow solid (0.25 g, 0.70 mmol), 1-(2,4-dihydroxy-3-methyl-phenyl)-propan-1-one (0.14 g, 0.77 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in acetone (7 mL). Heat to 50° C. for 2.5 hrs. Allow the reaction to cool to ambient temperature and concentrate under reduced pressure to give a solid. Dilute with ethyl acetate (25 mL) and filter. Concentrate the filtrate under reduced pressure to give an oil. Triturate with methanol (50 mL) and filter to give a solid. Purification by flash chromatography using 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes as gradient eluent yields the title compound (0.16 g, 60%): MS (m/z): 387.2 (M−1). 1H NMR (CDCl3) 12.91 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.31-7.24 (m, 2H), 7.21 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.51 (d, J=9.0 Hz, 1H), 5.23 (s, 2H), 3.00 (q, J=7.5 Hz, 2H), 2.19 (s, 3H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[S:8][C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])=[CH:6][CH:5]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:28][CH2:27][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[S:8][C:4]([CH2:2][CH3:3])=[CH:5][CH:6]=6)[C:11]5=[O:32])[CH2:31][CH2:30]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCc1ccc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ccc(CC)s5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[(5-ethylthiophen-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (198 mg, compound B95) 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10) and HBTU (167 mg) in DCM (4.0 ml) is added DIPEA (0.28 ml). The reaction mixture is stirred at RT for 1 h. Saturated aqueous sodium bicarbonate solution (2 ml) is added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified twice by flash column chromatography [amino phase silica gel, eluent: EtOAC] to yield the title compound as a solid.
Reaction SMILES: [OH:1][C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH:14]=1)[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:5][CH2:4][CH2:3][C@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH:14]=1)[OH:1]
Reactant: CN1CCC[C@H]1COc1cccc([C@H](O)CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCC[C@H]1COc1cccc([C@H](O)CCN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ((R)-3-hydroxy-3-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propyl)carbamate (0.32 g, 0.87 mmol) in DCM (10 mL) was added HCl/dioxane (4 mL) at 0° C. and the reaction mixture was stirred at rt for 2 h. After completion of the reaction the solvent was removed in vacuo. The compound was purified by prep HPLC to obtain (R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propan-1-ol (Example 21) as a yellow semi solid. Yield (0.18 g, 68%); 1H NMR (400 MHz, CD3OD) δ 7.29 (t, J=8.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.89-6.87 (m, 1H), 4.82-4.80 (m, 1H), 4.10-4.04 (m, 2H), 3.10-3.02 (m, 3H), 2.68 (s, 3H), 2.65-2.58 (m, 1H), 2.18-2.15 (m, 1H), 2.03-2.01 (m, 2H), 1.99-1.94 (m, 3H), 1.84-1.77 (m, 1H). MS: m/z 265.22 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(I)cc1
Reactant: c1ccc2ocnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 60 °C
Reaction time: 96 h
Yield: 53.7 %

Procedure:
To a three-necked flask equipped with a magnetic stir bar was added 4′-iodo-2-nitrobiphenyl (1.63 g, 5.0 mmol, 1.0 equiv), benzo[d]oxazole (0.72 g, 6.0 mmol, 1.2 equiv), Ag2CO3 (2.76 g, 10.0 mmol, 2.0 eq), Pd(dppf)Cl2.CH2Cl2 (0.20 g, 0.25 mmol, 0.05 eq) and PPh3 (0.13 g, 0.5 mmol, 0.1 eq). The tube was evacuated and back-filled with nitrogen and this evacuation/back-fill procedure was repeated twice. Then solvent CH3CN (25 mL) was added under the protection of nitrogen. The mixture was stirred in an oil bath at a temperature of 55-65° C. for 4 days and then cooled. The solid was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-5:1) as an eluent to afford the desired product 2-(2′-nitrobiphenyl-4-yl)benzo[d]oxazole (0.85 g in 54% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.43-7.49 (m, 2H), 7.61-7.63 (m, 2H), 7.66 (d, J=7.6 Hz, 1H), 7.69-7.73 (m, 1H), 7.83-7.87 (m, 3H), 8.08 (d, J=8.8 Hz, 1H), 8.30 (dd, J=8.0, 1.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16](Cl)[N:15]=[C:14]([CH3:28])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[NH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:32][CH2:31][CH2:30][NH2:29])[N:15]=[C:14]([CH3:28])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C)cn1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 1.00 g 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 2-aminoethanol to give 1.05 g 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=2.93 min, [M+1]+=446.51, [M−1]−=444.53.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.CN(C=O)C.[C:18](=[O:20])=[O:19]>O>[C:18]([C:4]1[C:3]([OH:2])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([OH:20])=[O:19]
Reactant: Oc1cccc2cccnc12
Reactant: O=C=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2cccnc2c1O
Yield: 30.4 %

Procedure:
Potassium salt of 8-hydroxyquinoline (25 mmol, 4.58 g), DMF (50 mL) and an excess of dry ice were heated in a pressure reactor at 120° C. for 12 hours. After cooling, water (150 mL) was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. To the residue, water was added again, and additional insoluble material was collected by filtration. The filtrate was acidified to pH 4 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 7-carboxy-8-hydroxyquinoline in 30.4% yield (1.44 g).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl.C(N)CCCCCCCCCCCCCCCCC>CCOCC.C(O)C>[CH2:1]([NH:19][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[I:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1ccccc1I
Yield: 8 %

Procedure:
A solution of 17.9 g of octadecylamine in a mixture of 300 ml of ether and 10 ml of ethanol was reacted with a solution of 8.0 g of o-iodobenzoyl chloride in 25 ml of ether for 10 minutes. The precipitate which formed contained octadecylamine hydrochloride. This precipitate was recovered and discarded. The volume was thereafter reduced to approximately half at 65° on a water bath. The resulting precipitate was recovered in accordance with the procedure of Example 3. The crude product was recrystallized from benzene to yield 1.2 g of N-octadecyl-o-iodobenzamide as a white microcrystalline solid, m.p. 94°-96°, Rf 0.77.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1>[Pt]>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]([C:13]([F:15])([F:14])[F:16])[CH2:3][CH2:2]2
Reactant: Fc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Agent: [Pt]
Product: Fc1ccc2c(c1)CCC(C(F)(F)F)N2

Procedure:
4-Chloro-6-fluoro-2-trifluoromethylquinoline was reduced with platinum on carbon to give 6-fluoro-2-trifluoromethyltetrahydroquinoline.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=2)=[O:17])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH2:1]([NH:8][C:9](=[O:32])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=2)=[O:17])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1
Yield: 91.2 %

Procedure:
243 mg of ethyl (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-phenoxy)-acetate are stirred in 4.3 ml of ethanol and 0.8 ml of 1N NaOH for 4.5 hrs. at RT. For the working up, the mixture is stirred into ethyl acetate/dilute hydrochloric acid, the organic phase is separated, washed with water and sodium chloride solution, dried over sodium sulphate dried and evaporated in a vacuum. Crystallization from ether gives 208 mg of [4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenoxy]-acetic acid, m.p. 208° C., MS: 427 (M+H)+.
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH2:3]1.NC1CCC(C2C=C3C(=CC=2)NC=C3CCN2CCCC2)(O)CC1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.C1COCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:5]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:6][CH2:7][CH2:2][CH2:3][CH:4]=1
Reactant: NC1CC=C(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CC1
Agent: CS(=O)(=O)Cl
Agent: NC1CCC(O)(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C1=C(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CCCC1

Procedure:
5-(1-Aza-1-methylcyclohex-3-en-4-yl)-3-(2-pyrrolidinylethyl)-1H-indole: (17.6 mg, 13%) from 5-(1-aza-1-methyl-4-hydroxycyclohex-4-yl)-3-(2-pyrrolidinylethyl)-1H-indole (Example 13d, 145 mg, 0.44 mmol), triethylamine (0.95 mL, 6.8 mmol) and MsCl (0.25 mL, 3.2 mmol) in dichloromethane (3.5 mL) and THF (7 mL) with the exception that the reaction was carried out at a gentle reflux overnight and the extraction solvent consisted of a mixture of dichloromethane, chloroform, and ethyl acetate. Starting material (17 mg) was also recovered. The product in this case was converted to the hydrochloride salt which was soluble in methanol; HRMS-FAB+ for C20H27N3 : calculated MH+ :310.22833; found MH+ :310.22650.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:20]2[C:16](=[N:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)[C:15]([C:25]#[N:26])=[C:14]([CH3:27])[CH:13]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[N:20]3[C:16](=[N:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)[C:15]([C:25]#[N:26])=[C:14]([CH3:27])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)n2c(nc3ccccc32)c1C#N
Reactant: Nc1ccc(B(O)O)cc1
Product: Cc1cc(-c2ccc(N)cc2)n2c(nc3ccccc32)c1C#N

Procedure:
General experimental procedure (A) for Suzuki coupling reaction with 4-aminophenyl boronic acid was followed. Reaction was performed on a 241 mg scale of 1-chloro-3-methylpyrido[1,2-a]benzimidazole-4-carbonitrile. Isolated 100 mg (34%) of T672 as a yellow solid. NMR (CD3OD): δ 7.85 (1H, d, J=8.4 Hz), 7.66 (1H, m), 7.43 (2H, m), 7.26-7.30 (2H, m, overlapped), 7.07 (1H, d, J=8.4 Hz), 7.38 (1H, dd, J=9.0, 2.6 Hz), 6.97 (2H, m), 2.80 (3H, s); MS: 299 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)=[N:11][C:7]=1[CH2:6][CH2:5]2.Cl.[CH3:28][O:29][C:30]([NH:32][C@@H:33]([CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:34](O)=[O:35])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][CH3:28])[CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:11][C:7]=1[CH2:6][CH2:5]2
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(Br)cc1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(Br)cc1CC2)C1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
(S)-tert-butyl 2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (314 mg, 0.750 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane, 1 mL) was added. After stirring for 1 h, the reaction mixture was concentrated and the residue was treated with (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (163 mg, 0.750 mmol), HATU (285 mg, 0.750 mmol) and DMF (4 mL). After cooling to 0° C., DIPEA (0.65 mL, 3.75 mmol) was added dropwise and the reaction mixture was allowed to warm to RT. After 4 h, the mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford the title compound (211 mg, 54%).