Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN[C:3]([C:5]1[N:6]([CH2:20][CH3:21])[CH:7]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=1)=[O:4].[CH3:22][CH2:23][Mg+].[Br-]>C1COCC1>[CH2:20]([N:6]1[CH:7]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=[C:5]1[C:3](=[O:4])[CH2:22][CH3:23])[CH3:21]
Reactant: CC[Mg+]
Reactant: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)NC
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1cc(C#Cc2cccc(OC)c2)cn1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere to a cold (0° C.) solution of 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid methyl amide (2.48 g, 7.93 mmol) in THF (40 ml) was added EtMgBr solution (1 molar in THF, 16 mL) over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 18 hours, then poured into ice/1 N HCl solution and extracted with ether. The combined ether extracts were washed with brine, dried over MgSO4 and evaporated to dryness. The resultant residue was purified by flash chromatography (hexane/ethyl acetate 9.5/0.5) to give the title compound as an off white solid (1.8 g, 80% yield), mp 64° C.,
Reaction SMILES: B(F)(F)F.CCOCC.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([OH:16])=[O:15].[N:21](OC(C)(C)C)=O.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl.O1CCCC1>[C:14]([C:13]1[CH:12]=[C:11]2[C:19]([CH:20]=[N:21][NH:10]2)=[CH:18][CH:17]=1)([OH:16])=[O:15]
Reactant: CC(C)(C)ON=O
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
To a solution of boron trifluoride etherate (18 ml) in chloroform (450 ml, Al2O3 treated) at -15° was added a solution of 3-amino-4-methylbenzoic acid (15.1 g) in tetrahydrofuran (150 ml) over 15 minutes and the resulting mixture was then stirred for an additional 5 minutes. To this mixture was added t-butyl nitrite (14 ml), and the reaction was warmed to 5° . After stirring for 1 hour, potassium acetate (49 g) and 18-crown-6 (2.65 g) were added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated, and 3:7 acetone:ethyl acetate (500 ml) and 1N hydrochloric acid (150 ml) were added. After stirring for 2 hours, brine (150 ml) was added to the mixture and the mixture filtered. The aqueous filtrate was extracted with 3:7 acetone:ethyl acetate (2×100 ml). The combined organic extract was dried (MgSO4) and evaporated. The resulting residue was dissolved in hot acetic acid (250 ml) and 250 ml saturated ethereal HCl and 250 ml ether were added sequentially. After cooling to room temperature, the precipitate was filtered and treated with 3:7 acetone:ethyl acetate (500 ml) and brine (100 ml) for 1 hour. After the phases were separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 6-carboxyindazole as a brown solid (9.8 g, 57%), mp >250°.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[OH:20][CH2:21][CH2:22][CH2:23][NH2:24]>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:24][CH2:23][CH2:22][CH2:21][OH:20])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCO
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCO)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.300 g, 1.001 mmol), 3-hydroxypropyamine (0.08 ml, 1.001 mmol) and TEA (0.14 ml, 1.001 mmol) in MeCN (5 ml) was stirred at rt. After 18 h the mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) eluting with 33-80% EtOAc (+0.5% TEA) in petroleum ether 40-60° C. to give the title compound (0.145 g, 43%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.50 (m, 2H), 7.46-7.42 (m, 3H), 5.77 (t, 1H), 3.62 (q, 2H), 3.01 (q, 2H), 1.74 (s, 9H), 1.63 (qt, 2H); Mass Spectrum: M−H+ 337.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:14])[CH:5]([CH2:10][C:11]([CH3:13])=O)C(OC)=O.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]1[C:4](=[O:14])[CH2:5][CH2:10][C:11]=1[CH3:13]
Reactant: COCC(=O)C(CC(C)=O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC1=C(C)CCC1=O
Yield: 79.4 %

Procedure:
201.3 g (0.997 mol) of crude methyl 4-methoxy-2-acetonylacetoacetate are held at reflux temperature for 3 hours with 2.12 liters (0.5 mol) of 2.5% Na2CO3 solution. The reaction mixture is extracted 3 times with 100 ml of CH2Cl2 each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator to give 99.90 g (79.5%) of 2-methoxy-3-methyl-2-cyclopenten-1-one, content 84.2%; b.p. 82°-84° C./27 mbar.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9](=[O:38])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>>[CH3:2][C:3]1[CH:8]=[C:7]([C:9](=[O:38])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:30][CH2:29][N:28]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)ccn1
Temperature: 50 °C
Yield: 25.2 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 2 mL) was added to a solution of (R)-tert-butyl 4-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (example 372, step 1; 100 mg, 201 μmol). The reaction mixture was heated at 50° C. for 17 h, then partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in dichloromethane (5 mL), then cooled to 0° C. and treated with N,N-diisopropylethylamine (78 mg, 604 μmol) and methanesulfonyl chloride (34.6 mg, 302 μmol). The ice bath was removed, then after 3 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (24 mg, 25%). White foam, MS (ESI+): m/z=475.1 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][C:28]5[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=5[O:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.O[Li].O.CO.O>C(O)(=O)C>[O:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:25][C@@H:24]1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=3)[CH2:12][CH2:13]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(CC2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)cc1
Agent: [Li]O
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(CC2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-{1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperidin-4-ylmethyl}-benzoic acid methyl ester (prepared according to General Method C) (80 mg, 0.17 mmol), LiOH.H2O (15 mg, 0.36 mmol), MeOH (3 mL) and water (0.5 mL) is stirred at room temperature for 16 h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is triturated with water to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1([OH:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:19][C:7]1([C:6]2[CH:5]=[CH:4][S:3][C:2]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[OH:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: OB(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2Br)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2-c2ccccc2O)C1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of tert-butyl 3-(2-bromothiophen-3-yl)-3-hydroxypyrrolidine-1-carboxylate (5 g, 13.8 mmol), Pd(OAc)2 (31 mg, 0.14 mmol), Ph3P (147 mg, 0.42 mmol), 2-hydroxyphenylboronic acid (1.74 g, 27.6 mmol) and Na2CO3 (2.9 g, 27.6 mmol) in dioxane (10 mL) and water (10 mL) was refluxed under N2 for 3 h. After the reaction was cooled to room temperature, the reaction mixture was extracted with EtOAc several times. The combined organic layers were washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (4.4 g, 88%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][CH2:21]Cl)[C:14]=3[CH:24]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][CH3:26]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][CH2:21][NH:25][CH3:26])[C:14]=3[CH:24]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCl)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Reactant: CN
Product: CNCCC(=O)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Reaction time: 0.13 h
Yield: 93 %

Procedure:
A solution of 1-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-chloro-propan-1-one (0.100 g., 0.273 mmol) in 4 mL of 2 M methanolic H2NMe was heated in a microwave reactor in a sealed reaction vessel at 80° C. for 2 minutes, then at 130° C. for 8 minutes. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (24:1:0.1 of CH2Cl2:MeOH:NH4OH) to give 0.092 g (93%) of 1-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-methylamino-propan-1-one as a clear oil. MS: 361 (M+H)+, mp: 208.3-214.7° C. (as hydrochloride).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl-:9].[Cl-].[Cl-].[Al+3].ClCl>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:9]
Reactant: Clc1ccc(Cl)nn1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Product: Clc1cc(Cl)c(Cl)nn1
Yield: 145.7 %

Procedure:
44 g 3,6-dichloropyridazine and 22 g aluminium trichloride are heated to 140° C. At this temperature 10.6 l chlorine are piped into the reaction mixture over 4 hours. After cooling the product is extracted with toluene, washed with a 10% sodium chloride solution and distilled (bp=127-129° C.). 44.1 g of product are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1)[CH3:20]
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: CCOc1ccccc1B(O)O
Product: CCOc1ccccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-ethoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 350.0 (M+H)+, retention time 1.40 minutes.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[NH:8][C:7]=1[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[NH2:1][CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[NH:8][C:7]=1[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])C=Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of crude 3-(2'-nitrovinyl)-2,5-dithienylpyrrole (127 mg) in pure dry tetrahydrofuran (1.5 mL) was added with stirring to a suspension of lithium aluminum hydride (47 mg, 1.23 mmol) in boiling tetrahydrofuran (2 mL) at a rate sufficient to maintain reflux. The mixture was refluxed for 35 minutes, then cooled, and the excess of hydride decomposed by successive addition of 50 μL of H2O, 50 μL of 40% aqueous sodium hydroxide solution and 150 μL of water. The reaction mixture was allowed to stir at room temperature for one hour. The resultant suspension was then filtered through a pad of anhydrous magnesium sulfate and the filter cake washed four times with ethyl acetate (50 mL). The combined tiltrate was evaporated under reduced presssure, leaving a straw-colored solid. This solid was then purified on 50 g of silica gel. Elution with methanol: chloroform:ammonium hydroxide. 1:20:0.1, gave 75 mg (82%, 2 steps) of 3-aminoethyl-2,5-dithienyl pyrrole.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:29][C:30]1[CH:31]=[C:32]([NH:36][NH2:37])[CH:33]=[CH:34][CH:35]=1>>[CH2:24]([N:23]([CH2:26][CH3:27])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=4)[N:37]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21])[CH3:25]
Reactant: NNc1cccc(F)c1
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=468.2 (M+H)+
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[CH2:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[N:6]=[C:7]2[C:23]#[N:24])=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Cc3ccccc3)cc12

Procedure:
The title compound was synthesized from 7-benzyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=360.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:14][CH:13]=1.[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:18]([C:17]3[C:12]([Cl:11])=[CH:13][CH:14]=[C:15]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])[C:16]=3[F:20])[OH:19])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(Cl)ccc(OCC(F)(F)F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 5-bromo-7-azaindole (67, 291 mg, 1.48 mmol) in methanol (22 mL) were added 6-Chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (523, 400.0 mg, 1.6 mmol) and potassium hydroxide (1.49 g, 26.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give the compound (524, 300 mg, 42%). MS (ESI) [M+H+]+=453.1, 455.1.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:31]=2)O1>>[CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:27]3[CH:28]=[N:29][N:30]([CH:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]4)[CH:31]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Brc1cnc2ccn(NCc3ccccc3)c2c1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(NCc5ccccc5)c4c3)cn2)CC1

Procedure:
This intermediate was prepared using Suzuki coupling reaction of N-benzyl-6-bromo-1H-pyrrolo[3,2-b]pyridine-1-amine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate as described in example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>COCCOC>[CH2:14]([O:13][P:9]([CH2:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=[C:2]2[CH:7]=1)([O:10][CH2:11][CH3:12])=[O:16])[CH3:15]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOP(=O)(Cc1ccnc(N)c1)OCC
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccc(CP(=O)(OCC)OCC)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
The product from Example 16 (0.87 g, 3.56 mmol) was dissolved in DME (25 mL) and placed in a 100 mL flask. Ethyl bromopyruvate (0.76 g, 3.92 mmol) was added to the flask, and the reaction was allowed to stir under a N2 atmosphere for 16 h. After solvent removal in vacuo, the residue was taken up in abs EtOH (25 mL) and refluxed for 5 h. The reaction was cooled to room temperature and solvent was removed in vacuo. The residue was dissolved in aqueous K2CO3 and the product extracted with EtOAc. Purification via a chromatotron (97/2/1 CH2Cl2 /EtOH/NH4OH) produced 0.38 g (32%) of title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([N:34]([CH3:39])[C:35](=[O:38])[CH2:36][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([N:34]([CH3:39])[C:35](=[O:38])[CH2:36][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(N(C)C(=O)CC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(N(C)C(=O)CC)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-(N-propanoyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[C:15]1([CH3:31])[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:31][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:20]=1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Yield: 35.4 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (197 mg), 4-(4-toluoyl)benzyl bromide (336 mg) and 1N-sodium hydroxide/water (1 ml) in DMF (10 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=5:1:1) and crystallized from methanol to provide the title compound as colorless solid (140 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:15])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].Cl>CS(C)=O>[CH3:15][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]([O:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CN(C)CCC(O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
70 ml of dimethylsulfoxide were added over 10 minutes at 60°-65° C. to a mixture of 20 ml of dimethylsulfoxide and 9.2 g of sodium hydride in a 50% oil disperson and after cooling the mixture to 25° C., 17.28 g of N,N-dimethyl-3-phenyl-3-hydroxy-propanamine were added thereto. The temperature returned to room temperature and 25.2 g of o-chloro-nitrobenzene were added thereto. The mixture was held at 25° C. for one hour and was then extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness to obtain 41 g of raw product which was taken up twice in 100 ml of N hydrochloric acid. The neutral fraction was extracted twice with 400 ml of ether and the aqueous phase was made alkaline by addition of 50 ml of sodium hydroxide solution. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and treated with activated carbon. The mixture was filtered and the filtrate was evaporated to dryness to obtain 22 g of N,N-dimethyl-γ-(2-nitrophenoxy)-benzene-propanamine.
Reaction SMILES: [CH3:1][Li].[C:3]1([C@@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC>[C:3]1([C@@H:9]([CH3:14])[CH2:10][C:11](=[O:13])[CH3:1])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)C[C@H](C)c1ccccc1
Temperature: 25 °C

Procedure:
1.6 M Methyl lithium (17.8 mL, 24.9 mmol) was added over 1 hour to a stirring 0° C. solution of (S)-3-Phenylbutyric acid (2.0147 g, 12.18 mmol) in dry Et2O (61 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature for 1½ additional hours. The reaction was then poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered and concentrated to achieve pure 77 (2.0487 g, (2.0487 g,˜100%): HPLC: 10.081 min. (Note: SM has HPLC retention time of 9.127 min.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)nc4)cc23)CC1
Yield: 39.8 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.2 mg (0.09 mMol) 6-chloropyridine-3-carboxylic acid, 4.4 mg (40%) of the title compound were recovered.