Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([NH2:13])=[CH:5][CH:4]=1.[C:14](Cl)(Cl)=[S:15].O>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:6]1[C:7]([C:9]([F:10])([F:11])[F:12])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N=C=S)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 6-methoxy-2-(trifluoromethyl)pyridin-3-amine (6.99 g, 36.4 mmol) in tetrahydrofuran (60 mL) and saturated aqueous sodium hydrogen carbonate (60 mL) was added dropwise thiophosgene (2.8 mL, 36.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (8.49 g, 36.3 mmol, quant.) as a pale orange oil.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[I:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[NH2:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[I:8][C:9]1[CH:10]=[C:11]([NH:12][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cc(I)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cc(I)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
1.38 g (13.8 mmol) Acetylacetone, 3.95 g (13.8 mmol) 3-iodo-5-trifluoromethyl-aniline, and 0.1 g (1.6 mmol) 4-toluenesulfonic acid are dissolved in 150 ml toluene. The reaction mixture is refluxed for 7 h with a Dean-Stark trap to remove water. After cooling down to room temperature, the suspension is filtered. The solid is purified by recrystallisation from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH:51]2[CH2:53][CH2:52]2)[C:34]([NH:40][C@H:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][C@@H:42]2[OH:50])=[N:35][C:36]=1[CH:37]1[CH2:39][CH2:38]1>>[CH:51]1([C:33]2[C:34]([NH:40][C@@H:41]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:43][C@@H:42]3[OH:50])=[N:35][C:36]([CH:37]3[CH2:39][CH2:38]3)=[C:31]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[Cl:8])[N:32]=2)[CH2:53][CH2:52]1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O[C@H]1Cc2ccccc2[C@@H]1Nc1nc(C2CC2)c(Br)nc1C1CC1
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (1S,2S)-1-[(5-bromo-3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.85–0.99, 1.67, 1.82, 2.48, 3.10–3.13, 3.27–3.28, 4.79, 5.40, 5.42, 7.30–7.51; MS (ESI+) for C25H23Cl2N3O m/z 452 (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]>C(OCC)(=O)C.CCOCC>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(N)=O)[C@@H](C)CC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC[C@H](N)C(=O)N[C@H](C(N)=O)[C@@H](C)CC
Reaction time: 1 h
Yield: 96 %

Procedure:
4.5 g (13.7 mmoles) of BOC-Nva-Ile-NH2 are suspended in 20 ml of ethyl acetate, and 12 ml of a 6 n hydrochloric acid solution in ethyl acetate are added to the suspension. After one hour of standing the reaction mixture is diluted with ether, and the separated precipitate is filtered off. The resulting 3.6 g of crude product are recrystallized from a mixture of methanol and ether to obtain 3.5 g (96%) of H-Nva-Ile-NH2.HCl; m.p.: 254°-255° C., Rf5 =0.45, [α]D25 =+3.8° (c=1%, in methanol).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22]([NH:25]S(C(C)(C)C)=O)([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CO.Cl.O1CCOCC1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(NS(=O)C(C)(C)C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reaction time: 8 h

Procedure:
2-Methyl-propane-2-sulfinic acid {1-[6-(4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-1-methyl-ethyl}-amide (76.3 mg, 0.172 mmol) in Methanol (1.9 mL, 48 mmol) was added 4.0 M of Hydrogen chloride in 1,4-Dioxane (0.97 mL, 3.9 mmol) and was stirred overnight. After removal of solvent, the residue was dissolved in DMSO, then HPLC give product as a gel (53 mg, 91%). LCMS Rf=1.58 min m/z 341.20 ([M+1], 100%). 1H NMR (400 MHz, CHLOROFORM-d) Shift=8.22 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.45 (dd, J=2.6, 9.2 Hz, 1H), 7.15 (s, 1H), 4.38-4.24 (m, 1H), 2.28 (d, J=10.4 Hz, 2H), 1.93 (d, J=12.9 Hz, 2H), 1.88 (s, 6H), 1.58-1.40 (m, 2H), 1.31-1.01 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>>[S:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:10]1[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: Nc1ccccc1S
Product: OCc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 160 °C
Yield: 13.7 %

Procedure:
To (4-hydroxymethyl-phenyl)-acetic acid (2 g, 12 mmol) was added 2-amino-benzenethiol (13.2 g, 12 mmol) and the mixture was heated at 160° C. for 48 h. The crude residue was then partitioned between EtOAc (200 mL) and 1 N NaOH (200 mL). The organic layer was separated, washed with satd. aq. NaCl (200 mL), dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 80% EtOAc in hexanes) afforded the title compound as a colorless oil (0.42 g, 14%). MS (ESI): mass calcd. for C15H13NOS, 255.34; m/z found, 456.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.00 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.48-7.45 (m, 1H), 7.39-7.28 (m, 5H), 4.71 (s, 2H), 4.44 (s, 2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[O-]CC.[Na+].Cl[C:14]1[C:15](=[O:26])[C:16]2[C:21]([C:22](=[O:25])[C:23]=1Cl)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl>C(O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:23]3[C:22](=[O:25])[C:21]4[C:16]([C:15](=[O:26])[C:14]=3[O:5][C:4]=2[CH:3]=1)=[CH:17][CH:18]=[CH:19][CH:20]=4
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: Oc1cccc(O)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c1oc1cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Resorcinol (6.6 g, 60 mmol) in ethanol (80 mL) was added dropwise to a stirred ethanolic sodium ethoxide solution (prepared by dissolving 3.8 g of sodium metal in 120 mL of absolute ethanol) containing 2,3-dichloro-1,4-naphthoquinone (6.9 g, 30 mmol) at 0° C. After stirring at room temperature overnight, the black reaction mixture was acidified with 5N HCl at 0° C. The yellow solid that precipitated was collected by filtration, washed successively with water, methanol, diethyl ether and air-dried to give crude 12 as a deep yellow solid (7.1 g, 88%); mp>310° C. (lit.>300° C.);Cheng 1993 JMC TLC (chloroform/acetone, 8:1): Rf 0.47; νmax (KBr) 3400 (OH), 1670 and 1620 (C═O) cm−1; δH (400 MHz, DMSO-d6) 7.05 (1H, d, JC-5-H, C-4-H=8.54 Hz, C-4-H), 7.16 (1H, s, C-2-H), 7.2-7.7 (2H, m, C-8-H and C-9-H), 7.95 (1H, d, JC-4-H, C-5-H=8.5 Hz, C-5-H), 8.2-8.7 (2H, m, C-7-H and C-10-H) and 10.53 (1H, br s, exchanged with D2O, C-3-OH); MS m/z (FAB+) 265.1 [70, (M+H)+], 255.3 (75), 243.2 (30), 173.2 (100); MS m/z (FAB−) 263.1 [100, (M−H)−], 242.1 (20), 210.1 (25), 198.1 (45), 181.1 (35); Acc. MS (FAB+) 265.0502 C16H9O4 requires 265.0501.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:45]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[C:44](=[O:53])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)=[CH:32][C:31]=1[CH3:54])(C(C)(C)C)(C)C>C1COCC1>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([N:45]2[C:44](=[O:53])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[C:36]2[C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][OH:26])=[C:31]([CH3:54])[CH:32]=2)=[CH:47][CH:48]=1
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1OCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1OCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A 1M THF solution of TBAF (1.90 mL, 1.90 mmol) was added to a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylphenyl)-3-(4-chlorophenyl)quinazolin-4(3H)-one (0.340 g, 0.65 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 100% EtOAc in heptane, afforded the title compound as a white solid (0.190 g, 72%). 1H-NMR (300 MHz, DMSO-d6): δ 8.17 (dd, J=6.8, 1.0 Hz, 1H), 7.89 (d, J=6.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.55-7.59 (m, 1H), 7.28-7.48 (m, 4H), 7.21 (d, J=1.5 Hz, 1H), 7.04-7.16 (m, 1H), 6.77 (d, J=8.7 Hz, 1H), 4.81 (t, J=5.7 Hz, 1H), 3.86-4.01 (m, 2H), 3.60-3.77 (m, 2H), 2.06 (s, 3H). MS (APCI) m/z: 407 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[CH:21][CH:20]=[N:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nccnc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4nccnc4c3O2)C1
Temperature: 80 °C

Procedure:
To a solution of (2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.856 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.639 g, 3.222 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.248 g (77%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.36 (silica, methanol:ethyl acetate 1:9); mp >220° C. dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH3:20])=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[CH2:19]([NH:18][CH2:17][CH2:16][N:15]1[CH2:14][CH2:13][CH2:12][C:7]2[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:4]1=[O:3])[CH3:20]
Reactant: CCNCCNCCCc1[nH]cc(C)c1C(=O)OCC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCNCCN1CCCc2[nH]cc(C)c2C1=O
Temperature: 140 °C
Yield: 153.6 %

Procedure:
2-[3-(2-Ethylamino-ethylamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 62c (350 mg, 1.245 mmol) and trimethyl aluminum (1.25 ml, 2.49 mmol) were dissolved in 75 ml of toluene under stirring, the resulting mixture was heated to reflux at 140° C. in an oil bath for 24 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, adjusted to about pH 3 with hydrochloric acid (6 mol/L) and stirred for 30 minutes. The mixture was adjusted to pH 14 with aqueous sodium hydroxide solution (12 mol/L) and extracted with dichloromethane (100 ml×4). The combined organic extracts were washed with saturated brine (150 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(2-ethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 62d (450 mg) as a yellow oil to be used directly in the next step.
Reaction SMILES: [Cl-].[NH2:2][C:3]([NH2:5])=[NH2+:4].CC(C)([O-])C.[K+].[CH3:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]1[CH2:23][C:24](OCC)=[O:25].Cl>CN(C)C=O.O>[CH3:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]1[CH2:23][C:24]([NH:4][C:3]([NH2:5])=[NH:2])=[O:25]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
4.3 g of guanidinium chloride are added to a suspension of 5.2 g of potassium tertbutoxide in 100 cm3 of dimethylformamide. The reaction mixture is stirred under an inert atmosphere at a temperature in the region of 20° C. for 1 hour, followed by addition of a solution of 2 g of ethyl (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 20 cm3 of dimethylformamide. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours, followed by addition of 100 cm3 of water. The pH is adjusted to 8 by adding 50 cm3 of 1 N hydrochloric acid, and the mixture is concentrated under reduced pressure (0.6 kPa) at a temperature in the region of 30° C. The evaporation residue is taken up in water and then filtered. 0.35 g of N-[(2-methyl3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of an off-white solid melting at 214° C. Mass spectrum EI: m/e 246 (M+), m/e 159 (base peak), m/e 146.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:19])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][C:20](=[O:22])[CH3:21])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(N)(Cn1cncn1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCC(Cn1cncn1)(NC(C)=O)c1ccc(Cl)cc1
Yield: 32 %

Procedure:
To a stirred, cooled (0° C.) solution of 0.54 g (1.94 mmols) of [2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-hexylamine and 0.02 g (0.15 mmols) of N,N-dimethylaminopyridine in 10 mL of methylene chloride under nitrogen was added dropwise 0.50 mL (5.28 mmols) of acetic anhydride. After 5 days the reaction was quenched with the addition of methanol and the solvents were removed to give a white solid. The solid was dissolved in toluene which was removed under reduced pressure to remove any acetic acid. The resultant solid was recrystallized from chloroform to give 0.2 g (32%) of white crystals, melting point 178.5°-179° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCCC2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
An oven dried test tube was charged with Pd2(dba)3 (4.5 mg, 0.005 mmol), 27 (7.4 mg, 0.015 mmol), 4-chloroanisole (140 mg, 0.98 mmol), pyrrolidine (85 mg, 1.2 mmol), NaOt-Bu (135 mg, 1.4 mmol), toluene (2 mL), and purged with argon. The mixture was heated to 80° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with ether (5 mL), filtered through a plug of celite, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 165 mg (95%) of the title product as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]2=[N:8][S:9][N:10]=[C:4]2[CH:3]=1.[C:11]1(/[CH:17]=[CH:18]/B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[C:11]1(/[CH:17]=[CH:18]/[C:2]2[CH:7]=[N:6][C:5]3=[N:8][S:9][N:10]=[C:4]3[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Brc1cnc2nsnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C(=C/c1cnc2nsnc2c1)\c1ccccc1

Procedure:
To 6-bromo[1,2,5]thiadiazolo[3,4-b]pyridine (for a preparation see Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1979), 17B(1), 13-16) (1.9 g, 8.79 mmol), [(E)-2-phenylethenyl]boronic acid (1.561 g, 10.55 mmol) and tetrakistriphenylphosphine palladium(0) (0.508 g, 0.440 mmol) was added 1,4-dioxane (38 ml) and then potassium carbonate (1.276 g, 9.23 mmol) in water (19 ml). The reaction was then stirred at reflux for 1.5 hours. The cooled reaction was partitioned between chloroform and water. The phases were separated with a hydrophobic frit and the organic extracts concentrated to give a black solid/gum (˜2.4 g). This crude material was purified by chromatography on silica eluting with 20-50% EtOAc in cyclohexane to give the product as a yellow/brown solid (0.88 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:19]=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:21][Mg]I>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:19]([OH:20])[CH3:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2cc(C=O)cnc2c1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc2cc(C(C)O)cnc2c1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of 7-(heptyloxy)quinoline-3-carbaldehyde (1.6 g, 5.9 mmol) in THF (30 mL) at 0° C. was added CH3MgI (2 g, 12 mmol, 2 eq.) dropwise over 10 min. The mixture was warmed to rt over 8 h. Then, the reaction mixture was quenched (water), extracted (EA), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (PE-EA, 1:5) to give desired compound as yellow oil (1.35 g, yield 80%). ESI-MS: 288 (M+H)+. 1H NMR (300 MHz, CDCl3) δ: 0.90 (t, 3H), 1.32-1.41 (m, 6H), 1.43-1.49 (m, 2H), 1.56-1.58 (d, 2H), 1.78-1.85 (m, 2H), 4.02 (t, 2H), 5.02-5.07 (q, 1H), 7.14-7.17 (m, 1H), 7.36 (s, 1H), 7.60-7.63 (d, 1H), 8.01 (s, 1H), 8.72 (s, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:42]=[CH:41][C:12]3[C:13]4[CH:19]=[CH:18][C:17]([C:20]5[CH:21]=[CH:22][C:23]6[N:27]=[C:26]([C@@H:28]7[CH2:32][CH2:31][CH2:30][N:29]7[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:24]=6[CH:40]=5)=[CH:16][C:14]=4[S:15][C:11]=3[CH:10]=2)O1.Br[C:45]1[NH:49][C:48]([C@@H:50]2[CH2:54][CH2:53][CH2:52][N:51]2[C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=[N:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.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].CN(C)C=O>[C:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:26]1[NH:25][C:24]2[CH:40]=[C:20]([C:17]3[CH:18]=[CH:19][C:13]4[C:12]5[CH:41]=[CH:42][C:9]([C:45]6[NH:49][C:48]([C@@H:50]7[CH2:54][CH2:53][CH2:52][N:51]7[C:55]([O:57][CH2:58][C:59]7[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=7)=[O:56])=[N:47][CH:46]=6)=[CH:10][C:11]=5[S:15][C:14]=4[CH:16]=3)[CH:21]=[CH:22][C:23]=2[N:27]=1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)sc3cc(B5OC(C)(C)C(C)(C)O5)ccc34)cc2[nH]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc(Br)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)sc3cc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc34)cc2[nH]1
Temperature: 85 °C
Yield: 67.7 %

Procedure:
A mixture of (S)-tert-butyl 2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (870 mg, 1.5 mmol), (S)-benzyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (620 mg, 1.8 mmol), tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.15 mmol), PdCl2(dppf) (110 mg, 0.15 mmol), 2M aqueous potassium carbonate (2.2 mL, 4.4 mmol), dimethoxyethane (12.2 mL) and dimethylformamide (2.4 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85° C. for 2 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (750 mg, 70%). LCMS-ESI+: calculated for C43H42N6O4S: 738.30; observed [M+1]+: 739.19.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30].C(N(CC)CC)C>ClCCl>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1
Reactant: NCC(F)(F)F
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2nc(NCC(F)(F)F)ncc2c(=O)[nH]1
Reaction time: 96 h

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.72 g), 2,2,2-trifluoroethylamine hydrochloride (0.97 g) and triethylamine (0.73 g) in dichloromethane (15 ml) was stirred at ambient temperature for 48 hours and allowed to stand for 4 days. A yellow solid had formed which was collected by filtration and washed with dichloromethane. The filtrate was washed with dilute hydrochloric acid (15 ml) then water (10 ml) and the aqueous layers extracted with dichloromethane (2×7.5 ml). The combined organic layers were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product. This was eluted from a silica column with diethyl ether:chloroform (4:1) and the combined fractions containing product were evaporated under reduced pressure to yield a residue which was recrystallized from isopropanol to yield the title compound, 0.13 g, m.p. 214-215.5° C.