Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25]([O:27]C1C=CC=CC=1)=O)[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25]([NH:41][C:38]1[CH:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=1)=[O:27])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Reactant: Nc1ccc(F)cn1
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1ccc(F)cn1

Procedure:
From intermediate 38 and 5-fluoropyridin-2-amine, reacted in an analogous manner to the preparation of intermediate 37. (UPLC-MS 3) tR 1.64 min; ESI-MS 491.3 [M+H]+.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([CH3:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH2:29][C:30]([NH2:32])=[O:31])=[CH:25][NH:26]2)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([CH3:16])=[CH:7][C:6]=2[C:4]2[C:3](=[O:17])[NH:32][C:30](=[O:31])[C:29]=2[C:24]2[C:23]3[C:27](=[CH:28][C:20]([C:19]([F:18])([F:33])[F:34])=[CH:21][CH:22]=3)[NH:26][CH:25]=2)[CH:11]=[CH:12]1
Reactant: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Reactant: NC(=O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C2=C(c3c[nH]c4cc(C(F)(F)F)ccc34)C(=O)NC2=O)c2c(ccn2C)c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a mixture of (1,5-dimethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.40 g, 1.73 mmol) and 2-(6-trifluoromethyl-1H-indol-3-yl-acetamide (0.38 g, 1.57 mmol) in DMF (10 mL) was added absolution of potassium tert-butoxide in THF (1.0 M, 6.3 mL, 6.3 mmol) at room temperature. The reaction mixture was heated at 55° C. for 19 h, cooled to room temperature, and quenched with hydrochloric acid (1.0 N). After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate and the extract washed with water, saturated aqueous sodium bicarbonate and brine dried (sodium sulfate), filtered and evaporated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1,5-dimethyl-1H-indol-7-yl)-4-(6-trifluoromethyl-1H-indol-3-yl)-pyrrole-2,5-dione (400 mg, 60.2%). 1HNMR (d6-DMSO, 400 MHz) 2.26 (s, 3H), 3.58 (s, 3H), 6.36 (d, J=3.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.76 (d, J=1.2 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 7.17 (d, J=3.2 Hz, 1H), 7.40 (s, 1H), 7.68 (s, 1H), 7.96 (d, J=2.8 Hz, 1H), 11.21 (s, 1H), 12.13 (s, 1H); MS (ES, m/z): C23H16F3N3O2: 424.13 (M++1): 422.23 (M+−1).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=2)[C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:28])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]4([C:1]#[N:2])[CH2:4][CH2:5]4)[CH:7]=3)[CH:17]=2)=[N:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
A suspension of 3-(1-cyanocyclopropyl)-N-{2-methyl-5-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (8.5 g, 20.5 mmol), calcium chloride (5.55 g, 50 mmol) and reduced iron (14.5 g, 260 mmol) in ethanol (500 mL)/water (50 mL) was stirred with heating at 80° C. for 4 hr. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethanol. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (6.57 g, 83%) as a green amorphous substance. The amorphous substance was used for the next reaction without further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:16]=1.Cl[CH2:33]/[CH:34]=[CH:35]\[CH2:36]Cl>C1COCC1>[F:29][C:27]([F:30])([F:28])[C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:16]=[C:15]([C:14]3([C:13]([O:12][CH3:11])=[O:31])[CH2:36][CH:35]=[CH:34][CH2:33]3)[CH:20]=[CH:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: ClC/C=C\CCl
Reactant: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccnc(-c3ccc(C(F)(F)F)cc3)c2)CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M in THF, 3.8 ml, 3.8 mmol) was added slowly to a stirred solution of the ester from Example 3, Step 2, (509 mg, 1.7 mmol) in dry THF (8 ml) under N2 such that the internal temperature <−70° C. After 30 minutes cis-1,4-dichloro-2-butene (210 μl, 2.0 mmol) was added. The reaction was maintained at this temperature for 30 minutes, then transferred to an ice bath. After 90 minutes the reaction was removed from the cooling bath and stirred at room temperature for 30 minutes, then quenched with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 8% EtOAc/isohexane to give the title compound (278 mg, 47%) as an oil, which solidified on standing. 1H NMR (400 MHz, CDCl3) δ: 2.81 (2H, d, J 15.2), 3.44 (2H, d, J 15.3), 3.70 (3H, s), 5.79 (2H, s), 7.22 (2H, d, J 4.4), 7.66 (1H, s), 7.73 (2H, d, J 8.1), 8.08 (2H, d, J 8.1), 8.63-8.67 (2H, d, J 5.1); M/Z (ES+) 348 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)CC)C>C(OCC)(=O)C.CS(Cl)(=O)=O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:11][C:16]#[N:18])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: N#CCc1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 3-phenoxybenzylalcohol (25.0 g) and triethylamine (26.3 ml) in ethyl acetate (300 ml), methanesulfonyl chloride (14.6 ml) was added dropwise at 0° C. After stirring for 1 hour, the reaction mixture was washed with saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in acetone (300 ml), admixed with sodium iodide (37.5 g) and then stirred for 1 hour. The reaction mixture was concentrated, and the residue was diluted with water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was dissolved in dimethyl sulfoxide (100 ml) and stirred with sodium cyanide (7.35 g) for 15 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel to obtain 3-phenoxyphenylacetonitrile (8.36 g, yield 32%) as an oil from a fraction eluted with ethyl acetate-hexane (1:7. v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:25]2[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=2[CH3:34])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cc(Cl)cc(Cl)c3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(3,5-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (356 mg, 1 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (167 mg) and piperidine (cat. amount) in ethanol was stirred at rt for 2 days. The reaction was concentrated and triturated with HCl (2M solution) to give the titled compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([C:31]=3[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=4[O:33][CH3:34])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C[O:36][C:37]([C@H:39]1[CH2:44][CH2:43][C@H:42](C(O)=O)[CH2:41][CH2:40]1)=[O:38].O[Li].O>>[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][C:23]([C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([C@H:42]4[CH2:43][CH2:44][C@H:39]([C:37]([OH:38])=[O:36])[CH2:40][CH2:41]4)=[O:7])[CH2:13][CH2:12]3)=[CH:19][CH:18]=1)=[O:22])=[C:31]2[CH3:32]
Reactant: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Li]O
Solvent: O
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)[C@H]5CC[C@H](C(=O)O)CC5)CC4)cc3)[nH]c12

Procedure:
With a procedure similar to the example above, trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester and trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester, followed by a standard LiOH—H2O saponification procedure to remove the methyl ester. LCMS calcd for C29H34N4O5 (m/e) 518, obsd 519 (M+H).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1)(=O)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].N.C>C1(C)C=CC=CC=1>[CH3:2][C:1]1[S:15][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][CH:4]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)CNC(=O)c1cccnc1
Agent: N
Solvent: Cc1ccccc1
Product: Cc1cnc(-c2cccnc2)s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 8.0 g (0.045 mol) of 73 in 125 ml of toluene, 10 g (0.045 mol) of P4S10 was added. The suspension was refluxed for 4 h and left at room temperature overnight. The mixture was poured into ice water followed by basification with ammonia. The two-phase system was stirred with charcoal and filtered. The toluene phase was separated and the aqueous phase extracted with 2×100 ml of toluene. The combined organic phase were dried over MgSO4 and evaporated in vacuo leaving a heavy, yellow oil, 88. Yield: 2.3 g (0.013 mol), 29%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[CH2:20]([Li])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:14]([CH3:15])[CH3:16])[CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22][CH3:23]
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Reactant: [Li]CCCC
Product: CCCCc1cccc(CC)c1/C=N/C(C(C)C)C(C)C

Procedure:
(E)-[1-(2-Butyl-6-ethyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3a) and butyl lithium in analogy to procedure Example 5 a): colourless liquid; NMR (CDCl3, ppm): 0.90 m, 15H (2×(CH3)2C, CH3(CH2)3), 1.20 t, 3H(CH3-CH2), 1.35 m, 2H(CH3CH2(CH2)2), 1.60 m, 2H(CH2CH2CH2), 2.08 m, 2H(NCH(CH(CH3)2)2), 2.48 t, 1H (NCH), 2.84 m, 2H (aryl-CH2CH2), 2.88 q, 2H(CH3-CH2), 7.04-7.08 m, 2H, and 7.20 t, 1H (aryl-H), 8.49 1H (═CHN).
Reaction SMILES: [CH:1]1([N:8]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:9](=[O:24])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=2[OH:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:47](O)=[O:48])[CH3:46])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:47]([O:23][C:12]1[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[NH:10][C:9]([N:8]([CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)=[O:24])=[O:48])[CH3:46])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(O)c(C(C)(C)C)c1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(OC(=O)[C@H](C)NC(=O)OCc2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.7 %

Procedure:
A mixture of 1.5 g of 2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol, 2.16 g of N-benzyloxycarbonyl-L-alanine, 1.95 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), 0.62 g of 4-dimethylaminopyridine (DMPA) and 30 ml of dimethylformamide (DMF) was stirred at room temperature for 5 hours. A saturated saline solution was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 1.3 g of O-(N-benzyloxycarbonyl-L-alanyl)-2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol (yield: 60%, melting point: 126° C.).
Reaction SMILES: [OH:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Si:17]([O:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COC(=O)CCCC[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCC[C@@H](C)O[Si](C)(C)C(C)(C)C
Yield: 71.3 %

Procedure:
A solution of alcohol 25 (2.53 g, 15.89 mmol), imidazole (1.9 g, 27.9 mmol), and tert-butyldimethylsilyl chloride (2.4 g, 15.89 mmol) in DMF (32 mL) was stirred at 23° C. After 16 h the reaction was diluted with Et2O and then washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 hex/EtOAc) afforded 3.11 g (71%) of silyl ether 26 (see scheme 4).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:3])[CH2:29][CH2:28]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: CC(Br)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc2ncccc2c1)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of 6-(1-bromoethyl)-quinoline (0.44 g, 1.86 mmol) and 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.35 g, 1.24 mmol) in DMF (10 mL) was added K2CO3 (0.26 g, 1.86 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, and was then treated with H2O (100 mL) to provide 0.52 g (96%) of a white precipitate after filtration. MS (ESI(+)Q1MS) m/z 435 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 8.82-8.88 (m, 1H), 8.30-8.37 (m, 2H), 7.97-8.02 (m, 1H), 7.76-7.89 (m, 2H), 7.58-7.64 (m, 1H), 7.47-7.55 (m, 1H), 7.22-7.34 (m, 2H), 5.23 (s, 1H), 3.76 (dt, 1H), 3.37-3.52 (m, 1H), 2.96-3.04 (m, 1H), 2.80-2.89 (m, 1H), 2.09-2.21 (m, 2H), 1.82-1.98 (m, 2H), 1.50-1.71 (m, 2H), 1.40 (d, 3H). The pure racemic mixture was separated into enantiomers by prep HPLC chiral chromatography using a CHIRALPAK AD column: 7.5/7.5/85 MeOH/EtOH/Hexane. Enantiomers had retention times of 4.1 and 6.3 minutes. The optical rotations of the enantiomers were [α]D (90:10 CH2Cl2:MeOH, 25° C.)=+19.2 and −14.7, respectively.
Reaction SMILES: O1CCN([CH:7]=[C:8]([C:14](OCC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])CC1.[CH3:19][CH:20]([CH3:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH2:32])=[NH:31].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[CH3:19][CH:20]([CH3:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]1[NH:32][C:14](=[O:15])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:31]=1
Reactant: CCOC(=O)C(=CN1CCOCC1)C(=O)OCC
Reactant: CC(C)COc1ccccc1NC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Diethyl morpholinomethylenemalonate (20.0 g) is added to a solution of N-[2-(2-methylpropoxy)phenyl]guanidine (16.1 g) and potassium carbonate (21.5 g) in ethanol (40 ml) and water (40 ml), and the mixture is heated with stirring at 60° C. for 3 hours. After the reaction is completed, water (100 ml) is added to the reaction mixture with stirring under water-cooling, and the mixture is acidified to pH 3 with 10% aqueous HCl. The resulting precipitate is collected by filtration and dissolved in chloroform (300 ml). The chloroform layer is washed with water twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is recrystallized from DMF to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (16.0 g). M.p. 175°-177° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([O:12]C)=[O:11].[OH-].[Na+]>C1COCC1.O.O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc([N+](=O)[O-])cc1C(=O)O
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Methyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate (5.0 g, 27.17 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 3˜4 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 4.06 g (88%) of the title product. 1H NMR (DMSO) 13.12 (s, 1H), 8.21 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H); 13C NMR 160.97, 134.01, 129.16, 123.81, 111.38, 37.47; MS m/z− 169.1 (M−H).
Reaction SMILES: BrC1C=CSC=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:7]=[N:18][NH2:19])[CH:14]=[CH:13][CH:12]=1
Reactant: NN
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Solvent: O
Solvent: OCCO
Product: COc1cccc(C=NN)c1
Temperature: 130 °C

Procedure:
A mixture of (3-Bromothien-2-yl) (3-methoxyphenyl)methanone (10.0 g), hydrazine hydrate (10 ml, above 99% purity), and 75 ml of ethylene glycol was heated at 130° C. for three hours. The reaction mixture was then quenched with water and extracted with ether. The ether solution was washed three times with water and dried over anhydrous magnesium sulfate. The ether was then evaporated to give 5.5 g of an oil. This was then column chromatographed on a silica gel column packed in hexane using 15% ether/hexane as an eluent. The solid from the column was then recrystallized from ether/hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][C:14](=O)[CH3:15])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:17]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:25])[CH3:9]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccnc2)c1-c1ccccc1

Procedure:
3-Aminopyridine (5 mmol, 0.5 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over silica, but still contained contaminants. This material was triturated in hexane, and the solids were separated by filtration. The solids were washed with benzene two times to yield the named product (m.p. 102° C.-103° C.).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH3:35][C:36]([OH:53])([CH3:52])[CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>O.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>[CH3:35][C:36]([OH:53])([CH3:52])[CH2:37][N:38]1[CH:42]=[C:41]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:21])[F:22])[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:40]=[N:39]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C

Procedure:
8-Bromo-2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (110.0 mg, 0.2557 mmol) dissolved in Acetonitrile (0.534 mL, 10.2 mmol) and with dissolved 2.00 M of Potassium carbonate in Water (0.256 mL). Degas by bubbling nitrogen for 5 min. The reaction was charged with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (102 mg, 0.384 mmol) then Tetrakis(triphenylphosphine)palladium(0) (41.36 mg, 0.03579 mmol). The reaction was heated in microwave at 140 C for 10 min. The reaction was cooled to r.t. then extracted with ethyl acetate. Combined organics concentrated and purified by reverse phase HPLC to give 355. MS: (ESI+)=490.1. 1H NMR (400 MHz, DMSO) δ 8.24 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.41 (dd, J=8.3, 1.8 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 5.74 (q, J=8.9 Hz, 2H), 4.71 (s, 1H), 4.37 (t, J=5.0 Hz, 2H), 4.03 (s, 2H), 3.40 (t, J=5.0 Hz, 2H), 1.09 (s, 6H)