Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[NH:35][N:34]=[C:33]([CH2:36][C:37](O)=[O:38])[N:32]=1)([O-:30])=[O:29]>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:37](=[O:38])[CH2:36][C:33]1[N:32]=[C:31]([N+:28]([O-:30])=[O:29])[NH:35][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C(O)Cc1n[nH]c([N+](=O)[O-])n1
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c([N+](=O)[O-])n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and (5-nitro-1H-[1,2,4]triazol-3-yl)-acetic acid to afford (S)-1-[2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-(5-nitro-1H-[1,2,4]triazol-3-yl)-ethanone as white solid (58 mg). The resulting nitrotriazole was reduced with 10% Pd/C under 1 atm of hydrogen in MeOH to afford the title compound as an off-white solid (15 mg, 39% overall). LC/MS (Method B) 2.20 min, [M+1]+ 491.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: Cc1ccc(CC(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccc(C)nc3)nc12

Procedure:
From (6-methyl-pyridin-3-yl)-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+22.8° (c=1.06, CHCl3), ES-MS m/e (%): 400 (M+H+, 100).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:17]([C:33]3[CH:41]=[C:40]([O:42][CH3:43])[C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])=[O:19])=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1.CN(C)[CH:46]=[O:47]>O1CCCC1>[CH:46]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:17]([C:33]3[CH:41]=[C:40]([O:42][CH3:43])[C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])=[O:19])=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1)=[O:47]
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.8 ml of 2.5 M solution in hexane) was added to a stirred solution of 6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)-sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 92, 400 mg, 0.67 mmol) in anhydrous tetrahydrofuran at −75° C. under a nitrogen atmosphere. After 30 minutes dimethylformamide (0.15 ml) was added to the orange solution, and after a further 30 minutes the mixture was allowed to warm to 0° C. before quenching with excess 1 N hydrochloric acid. Ethyl acetate was added and the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and the product was crystallised from dichloromethane and diethyl ether mixture to give the title compound (187 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].CC([N-]C(C)C)C.[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1.[Cl-].[NH4+]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:30]2([OH:33])[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C2(O)CCOCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a solution of ethyl N-Boc-4-piperidinecarboxylate (2.57 gm; 10.0 mmol) in 100 mL of dry THF was added 6.0 mL (2.0 M) of LDA at −78° C. The mixture was stirred at −78° C. for half hour, and then a solution of tetrahydro-4H-pyran-4-one (2.0 gm; 20.0 mmol) in 5.0 mL dry THF was added thereto. The resultant mixture was stirred at −78° C. for two hours and then warmed up to room temperature and kept for overnight. Saturated ammonium chloride (200 mL) was added and the aqueous layer was extracted with ethyl acetate (3×150 mL). The organic layer was washed with brine and dried over magnesium sulfate, filtered and then concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate 2:1) to give 1.47 gm of the desired product.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH3:13][C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=O.Cl>>[CH3:13][C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1
Reactant: NNC1=NCCc2ccccc21
Reactant: CC(C=O)=Cc1ccccc1
Agent: Cl
Product: CC(C=NNC1=NCCc2ccccc21)=Cc1ccccc1

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (7.3 g.) and α-methylcinnamaldehyde (6.56 g.) and treatment of the reaction mixture with hydrochloric acid gave a solid, which was recrystallized first from ethanol-ether, then twice from N,N-dimethylformamide-ether, affording 1-[2-(2-methyl-3-phenylallylidene)hydrazino]-3,4-dihydroisoquinoline (I: X=C6H5CH=C(CH3), X'=Y=Y'=Z=Z'=H) hydrochloride in two crops (5.6 g. and 4.2 g., m.p. 217°-219° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[C:36](O)([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.O>[C:36]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(4-hydroxyphenyl)propanoic acid (3.32 g, 20 mmol) in dry DMF (20 ml) is carefully added 1,1′-carbonyldiimidazole (3.24 g, 20 mmol) portionwise. The reaction mixture is stirred at 40° C. for 2 hours after which time DBU (6.02 ml, 40 mmol) and tert-butanol (4.78 ml, 50 mmol) are added and the reaction mixture is now stirred at 65° C. for 2 days. The reaction mixture is allowed to cool to room temperature and poured into water (50 ml) and the product is extracted with diethyl ether (3×30 ml). The organics are combined, dried (MgSO4) and the solvent removed in vacuo to give a yellow oil. Purification by flash chromatography (SiO2, EtOAc/iso-hexane) yields 3-(4-Hydroxy-phenyl)-propionic acid tert-butyl ester as a colourless oil. 1H NMR (DMSO-d6) 9.1 (1H, s), 7.0 (2H, d, J=8.45), 6.65 (2H, d, J=8.45), 2.7 (2H, t, J=7.28), 2.4 (2H, t, J=7.28), 1.4 (9H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)cc3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 4-fluoroaniline gave the title compound as a tan solid, mp 177-181° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH2:9][OH:10]
Reactant: BrCc1ccccc1
Reactant: OCc1c(O)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1c(Cl)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-chloro-2-(hydroxymethyl)phenol (for a preparation see Intermediate 6)(1.37 g, 8.62 mmol) in absolute ethanol (30 ml) was added 2 M sodium hydroxide (4.74 ml, 9.49 mmol) and then benzyl bromide (1.03 ml, 8.62 mmol, Aldrich). The solution was stirred at ambient temperature for 3 days under nitrogen. The solvent was removed under reduced pressure to leave an aqueous suspension. The aqueous residue was partitioned between 2 M aqueous sodium hydroxide (40 ml) and ethyl acetate (60 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (40 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound as a very pale brown oil (1.87 g); LCMS: (System 1) (M-H)−=247, tRET=3.20 min.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH:11]2[CH2:14][N:13]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)(=O)C>C(O)C.O.[Fe]>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:13]1[CH2:14][CH:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:12]1
Reactant: O=[N+]([O-])c1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Temperature: 95 °C
Yield: 81.2 %

Procedure:
To a solution of 3-nitro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyridin-2-amine (1.05 g, 3.20 mmol) in ethanol (30 mL) and water (10 mL) was added iron (448 mg, 8.0 mmol) and acetic acid (240 mg, 4.0 mmol) slowly dropwise. The mixture was heated at 95° C. until TLC analysis confirmed the absence of starting materials. The reaction mixture was filtered through a plug of CELITE™ washing with methanol. The black filtrate was concentrated in vacuo, treated with brine (40 mL) and extracted with dichloromethane (3×60 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL) and then dried over sodium sulfate. The filtrate was evaporated in vacuo to give N2-(1-(quinolin-2-yl)azetidin-3-yl)pyridine-2,3-diamine (0.744 g, 2.6 mmol, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25]>>[Cl:1][C:2]1[C:3]2[C:11]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: C#Cc1ccccn1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#Cc3ccccn3)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see, Example 1) with 2-ethynylpyridine according to the General Procedure A. tR: 4.65 min. 1H-NMR (DMSO-d6) δ 8.59 (s, 1H), 8.07 (s, 1H), 7.82 (td, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.36 (td, 1H), 6.84 (br. S, 2H), 5.36 (s, 2H), 3.74 (s, 3H), 2.28 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21]>CN(C=O)C>[CH2:14]([O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH2:19][C:20](=[O:21])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)Nc2ccc(Cl)cn2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 10 g 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester in 200 ml absolute DMF 1.885 g of a 60% suspension of NaH in mineral oil were added in an argon atmosphere. The mixture was stirred for 15 min at RT. 11.76 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture stirred for 2 h at RT. After concentration in vacuo the residue was purified by chromatography on silica gel using CH2Cl2/ethylacetate=8/2. The fractions containing the product were evaporated. Yield: 16.05 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[S:29]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)(=[O:32])(=[O:31])[NH2:30]>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][C:33]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:34][CH:35]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(S(N)(=O)=O)cc2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
4-Oxo-1-phenyl-3-[(4-sulfamoyl-benzoylamino)-methyl]-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 4-sulfamoyl-benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (d, J=8.06 Hz, 1H) 8.77 (t, J=4.63 Hz, 1H) 7.91-8.00 (m, 3H) 7.83-7.89 (m, 2H) 7.52-7.59 (m, 3H) 7.47 (s, 2H) 7.43 (dd, J=6.75, 2.72 Hz, 2H) 4.46 (d, J=4.83 Hz, 2H) 3.40 (s, 3H). MS calcd. for C25H19F3N4O6S [(M+H)+] 561.1, obsd. 561.1.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].[Cl:21][C:22]1[N:31]=[C:30](Cl)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>O>[Cl:21][C:22]1[N:31]=[C:30]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc2ccccc12
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of 2-(isopropylsulfonyl)aniline (450 mg) and N,N-dimethylformamide (10 mL), 55% sodium hydride in oil (200 mg) was added under ice cooling and stirred for 30 minutes, followed by addition of 2,4-dichloroquinazoline (500 mg). The reaction mixture was stirred for 30 minutes under ice cooling and further stirred overnight at room temperature. The reaction mixture was cooled on ice, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1-3:1) to give 2-chloro-N-[2-(isopropylsulfonyl)phenyl]quinazoline-4-amine (0.67 g) as a light-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH:19]([N:22]([CH:37]([CH3:39])[CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])([CH3:21])[CH3:20]>C(O)C.N1CCCCC1>[CH:37]([N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:30][C:29]=1[CH3:36])=[O:27])([CH3:38])[CH3:39]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN(C(C)C)C(C)C)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-methoxy-phenyl) 2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (95 mg, 79%).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][Br:5].[I-].[Na+].BrC1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClC1C=CC=CC=1>[Br:5][C:4]1[C:3]2[O:2][CH:1]=[CH:12][C:13]=2[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: COC(CBr)OC
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: Fc1cc(Br)c2occc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Bromoacetaldehyde dimethyl acetal (1.17 mL, 10.0 mmol) and a catalytic amount of sodium iodide were added to a solution (25 mL) of 2-bromo-4-fluorophenol (0.548 mL, 5.00 mmol) and potassium carbonate (1.38 g, 10.0 mmol) in DMF, and stirred at 80° C. overnight. The solvent was distilled away under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate). The resulting compound (1.12 g, 4.01 mmol) was dissolved in chlorobenzene (5 mL), and added at 120° C. to a solution (5 mL) of a polyphosphoric acid (1.5 g) in chlorobenzene. After the reaction solution was stirred at 120° C. overnight, the solvent was distilled away under reduced pressure. To the residue, ethyl acetate and water were added. Under ice-cooling, this was poured into a 1 N sodium hydroxide aqueous solution, and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane) to thus obtain the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])[OH:6])[CH3:2].[OH-].[Li+].Cl>O1CCCC1>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])[OH:6])[CH3:25]
Reactant: CCN(CC)CC(O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)CC(O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Temperature: 50 °C

Procedure:
Into a 20 mL reaction vessel were combined methyl 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-methylpyridin-2-yl)benzoate (50 mg, 0.15 mmol), tetrahydrofuran (10 mL) and lithium hydroxide (8.7 mg, 0.36 mmol). The mixture was heated at 50° C. for 3 hours. After cooling, the mixture was treated with 7 M aq. HCl (52 μL, 0.36 mmol), and concentrated to afford the crude compound which was used directly in the next step.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[N:14]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)=[N+:15]=[N-:16].N1C=CC=CC=1C1C=CC=CN=1>CN(C=O)C.CCOC(C)=O>[OH:23][C:19]1[CH:18]=[C:17]([N:14]2[CH:3]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=3)[N:16]=[N:15]2)[CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=Nc1cccc(O)c1
Reactant: C[Si](C)(C)C#Cc1cccc(O)c1
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1cccc(-c2cn(-c3cccc(O)c3)nn2)c1
Temperature: 80 °C
Yield: 69.5 %

Procedure:
To 3-TMSE-phenol (4.0 g, 21.02 mmol) in 35 mL of DMF were added 3-azidophenol (3.41 g, 25.2 mmol), CuBr (153 mg, 1.05 mmol), and 2,2′-bipyridyl (328 mg, 2.10 mmol). The mixture was heated at 80° C. for 24 h, cooled to room temperature, then diluted with 250 mL of EtOAc. The combined organic mixture washed with water, and dried over MgSO4. Solvents were removed by rotary evaporation, and the residue was recrystallized in acetic acid/water to give 3.70 g (70% yield) of a brown crystalline solid. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.80 (s, 1H, triazol-H), 7.43-7.26 (m, 6H, Ar—H), 6.95-6.91 (m, 1H, Ar—H), 6.84-6.83 (m, 1H, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 158.6, 157.7, 148.1, 137.9, 131.1, 130.4, 129.7, 118.8, 116.7, 115.6, 115.1, 112.1, 110.7, 107.1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([O-])(O)=[O:10].[Na+].CCOCC.[Li+].CCC[CH2-].C(NC(C)C)(C)C.ClC1C=CN=CC=1.C(OCC)=O>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]=[O:10]
Reactant: Clc1ccncc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOC=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cnccc1Cl
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
4-Chloropyridine hydrochloride (15 g, 99.9 mmol) is free-based by stirring in 1000 mL 1:1 saturated NaHCO3/ether for 1 h. The layers are allowed to separate, the aqueous layer is extracted with ether (2×175 mL), and the combined organic layer is dried over MgSO4, filtered, and concentrated to an oil. THF (300 mL) is chilled to −70° C. in a dry flask. N-butyllithium (105.1 mL, 168.2 mmol) is added drop-wise, and the mixture is placed in an ice bath. Diisopropylamine (23.6 mL. 168.4 mmol) in THF (50 mL) is added drop-wise, the yellow solution is stirred for 30 min, and the reaction is cooled to −70° C. The free-based 4-chloropyridine oil (9.55 g, 84.1 mmol) is dissolved in THF (50 mL) and added drop-wise to the chilled yellow solution, that turned dark red after the addition. The reaction is stirred at −70° C. for 2 h. Ethyl formate (13.6 mL, 168.3 mmol) in THF (25 mL) is then added drop-wise to the dark solution at −70° C. After 2 hours, the reaction is warmed to −10° C. and quenched with water (450 mL). The layers are allowed to separate, and the aqueous layer is extracted with ether (3×200 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated in vacuo to an oil. The crude material is chromatographed over 320 g slurry-packed silica eluting with 30% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to an orange oil which solidified under vacuum, affording 4-chloropyridine-3-carboxaldehyde (C140) as an orange solid (21% yield).