Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:25][CH2:26][CH3:27])[C:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:10]2[C:9]2[CH:8]=[CH:7]C=[CH:5][C:4]=2[N:3]=1.C(OC([NH:35]C1C=NC=CC=1B(O)O)=O)(C)(C)C>>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:25][CH2:26][CH3:27])[C:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:10]2[C:9]2[CH:8]=[CH:7][N:35]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1B(O)O
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCNC(=O)OC(C)(C)C
Product: CCCn1nc2c(N)nc3cnccc3c2c1CCNC(=O)OC(C)(C)C
Yield: 20.4 %

Procedure:
A modification of the method described in Example 610 was used to couple tert-butyl 2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethylcarbamate (2.08 g, 5.82 mmol) (Example 51, Parts A through G) with 3-[(tert-butoxycarbonyl)amino]pyridin-4-ylboronic acid (2.77 g, 11.6 mmol). After the first purification by IFC, 0.44 g of tert-butyl 2-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,7]naphthyridin-1-yl)ethylcarbamate was obtained as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:18][OH:19]>CC(O)C.C(OCC)(=O)C>[OH:19]/[N:18]=[C:8](\[NH2:9])/[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:11][CH:10]=1
Reactant: NO
Reactant: N#Cc1ccc(CCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: N/C(=N\O)c1ccc(CCO)cc1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a mixture of 4-(2-hydroxyethyl)benzonitrile (500mg, 3.40 mmol) and sodium bicarbonate (1427 mg, 16.99 mmol) in 2-propanol (50 mL) was added hydroxylamine hydrochloride (472 mg, 6.79 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4, filtered, and concentrated to yield 300 mg of (Z)—N′-hydroxy-4-(2-hydroxyethyl)benzimidamide. MS (m+1)=181. HPLC Peak RT=0.13 minutes. (Analytical Method B).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].C(O)(C)C>O1CCCC1>[CH3:3][CH:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8]
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(CC(=O)O)C(=O)O
Temperature: 85 °C

Procedure:
In a 20 ml-volume Schlenk's tube were charged 65.0 mg (0.5 mmole) of itaconic acid and 14.91 mg (0.01 mmole) of [RuH((-)-BINAP)2 ]PF6, and 2.5 ml of tetrahydrofuran (THF) and 2.5 ml (32.7 mmole) of isopropyl alcohol were added thereto. The mixture was heated at reflux in an oil bath at 85° C. for 24 hours. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of a 1M sodium hydroxide aqueous solution and washed three times with each 10 ml portions of chloroform. The aqueous layer was adjusted to a pH of 1 with concentrated hydrochloric acid and then extracted three times with each 10 ml portions of diethyl ether. The combined ether layer was dried over magnesium sulfate, and the solvent was removed to give 47 to 60 mg of methylsuccinic acid as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH2:1]([C:5]1[N:6]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:16])([F:17])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCC1CC1
Product: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-butyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 2H), 6.57 (s, 1H), 4.05 (d, J=6.3 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.14 (m, 1H), 1.00 (t, J=7.3 Hz, 3H), 0.60 (m, 2H), 0.35 (m, 2H); MS (ES) m/z 321 (M+1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([CH2:28][N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 523.0 [M+H]+; tR=3.11 min (System 1); Rf=0.18 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH:9]=2)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[NH:25][N:24]=[N:23][N:15]=3)[CH:11]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cc(-c3ccc(Cl)cc3)cc(-c3nnn[nH]3)c2)cc1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A mixture of 4,4″-Dichloro-[1,1′;3′,1″]terphenyl-5′-carbonitrile (50 mg, 0.15 mmol), sodium azide (20 mg, 0.31 mmol) and ammonium chloride (16 mg, 0.31 mmol) in DMF (1 mL) was heated at 100° C. for 16 h. The reaction mixture was acidified with 1M HCl solution poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and the solvent was removed in vacuo to give 5-(4,4″-dichloro-[1,1′;3′,1″]terphenyl-5′-yl)-1H-tetrazole yield 36 mg (64%) as an off-white solid. 1H NMR (DMSO) δ 7.49 (d, 2H), 7.23 (t, 1H), 7.17 (s br, 1H), 6.96-6.99 (m, 4H), 6.71-6.74 (m, 4H), LCMS method A R.T. 3.5
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>>[CH3:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:6]=[C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])[N:4]=2
Reactant: CC(C)(C)CN
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC(C)(C)C)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2,2-dimethylpropan-1-amine were reacted to give 258. [M+H]+ 449.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C=C(C=C(OC)C=1)C(O)=O.C(OC(N1CCC(N)CC1)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])[O-].[K+].[K+].[CH3:70][O:71][C:72](=[O:77])[CH2:73][CH2:74][CH2:75]Br>CN(C1C=CN=CC=1)C.ClCCl.O1CCCC1.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:17]=[C:18]([O:24][CH2:75][CH2:74][CH2:73][C:72]([O:71][CH3:70])=[O:77])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCBr
Reactant: COc1cc(O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 95 °C
Reaction time: 22 h
Yield: 92.2 %

Procedure:
1.60 g (4.6 mmol) of 4-(3-hydroxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester [prepared from 3-hydroxy-5-methoxy-benzoic acid by reaction with 4-amino-piperidine-carboxylic acid tert-butyl ester, N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride and N,N-dimethyl-4-aminopyridine in dichloromethane/tetrahydrofuran between 0° C. and rt in analogy to example 60d)] was dissolved in 65 mL of MeCN at rt; 1.29 g (9.4 mmol) of anhydrous potassium carbonate was added at 5° C.; then, 0.61 mL (0.87 g=4.8 mmol) of 4-bromo-butyric acid methyl ester was added drop by drop. The reaction mixture was stirred at 95° C. for 22 hours. It was then cooled down to ambient temperature, poured into crashed ice and extracted twice with EtOAc. The organic phases were washed with water and brine, dried over MgSO4, filtered and evaporated i.V. to yield 1.91 g of the title compound as colorless solid. MS: 451.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([O:18][CH2:19][CH:20]1[CH2:23][N:22](C(OCCCC)=O)[CH2:21]1)=[O:17])([O-:3])=[O:2].C(O)(C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:17])[O:18][CH2:19][CH:20]1[CH2:21][NH:22][CH2:23]1)([O-:3])=[O:2]
Reactant: CCCCOC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of tort-butyl 3-((((2-nitro-5-(thiophen-2-yl)phenyl)carbamoyl)oxy)methyl)azetidine-1-carboxylate (0.50 g, 1.15 mmol, 1 eq.) in dichloromethane (10 mL) was added TFA (3 mL) at 0° C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure. A saturated solution of sodium bicarbonate was added. The obtained solid was filtered and dried under reduced pressure to afford azetidin-3-ylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.35 g, 91% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:19][CH2:18][C@H:17]3[CH2:20][OH:21])[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([O:25]CC)=[O:24])=[CH:7]1.[OH-].[Li+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:19][CH2:18][C@H:17]3[CH2:20][OH:21])[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([OH:25])=[O:24])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CC[C@H]3CO)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccc(N4CC[C@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 4A (1 g) and 0.1M lithium hydroxide (40 mL) in ethanol (50 mL) was stirred for 24 hours, adjusted to pH 4 with 1M hydrochloric acid, treated with water, and filtered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].[CH:10]([OH:12])=O>O>[Br:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:10]=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=CO
Reactant: CNc1cccc(Br)c1
Solvent: O
Product: CN(C=O)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-N-methyl aniline (made as described by Lopez et al. in Tet. Lett., 1999, 40, 11, p 2071-2074 incorporated herein by reference; 7.4 g, 39.5 mmol) in formic acid (20 mL) was refluxed for 3 h. The reaction mixture was then cooled to ambient temperature, diluted with water and extracted with diethyl ether. The organic phase was washed with saturated, aqueous sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a dark brown oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([NH:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[CH3:40][C:41]1([CH3:57])[O:46][CH:45]([C:47]([NH:49][CH2:50][CH2:51][C:52](O)=[O:53])=[O:48])[C:44]([CH3:56])([CH3:55])[CH2:43][O:42]1>C(Cl)Cl>[C:13]([NH:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH:35][C:52](=[O:53])[CH2:51][CH2:50][NH:49][C:47]([CH:45]1[C:44]([CH3:55])([CH3:56])[CH2:43][O:42][C:41]([CH3:57])([CH3:40])[O:46]1)=[O:48])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1N
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1NC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 81.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg) was added to a solution of 372 mg of 2-oleoylaminoaniline and 259 mg of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid in 30 ml of methylene chloride under ice cooling. The mixture was stirred in situ for one night. The reaction mixture was washed with water and dried over anhydrous sodium sulfate, filtered and the filtate evaporation under vacuum to obtain the crude title products. Then, the residue obtained was subjected to silica gel column chromatography to obtain 500 mg of the title compound (yield: 82%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10].[I:18]I>C1COCC1>[F:17][C:16]1[C:11]([C:9]#[N:10])=[N:12][CH:13]=[CH:14][C:15]=1[I:18]
Reactant: N#Cc1ncccc1F
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1nccc(I)c1F

Procedure:
A solution of LDA (40.9 mmol, prepared from 11.4 mL of diisopropyl amine and 16.4 mL of 2.5 M n-butyl lithium in hexanes) in 200 mL THF at −78° C. was treated with 2-cyano-3-fluoropyridine (5.0 g, 40.9 mmol) in 50 mL of THF drop-wise. After 10 minutes a solution of iodine (10.4 g, 40.9 mmol) in 10 mL of TBF was added. After 30 minutes the reaction was quenched with 40 mL of water followed by workup with aqueous sodium thiosulfate. The mixture was diluted with ether, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0–20% ethyl acetate in hexanes to provide 3-fluoro-4-iodopyridine-2-carbonitrile that gave proton NMR spectra consistent with theory.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3ncccc3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-quinolin-6-yl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.[CH2:25]([NH:33][NH2:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:16][C:15]1[CH:14]=[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])[N:33]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:34]=1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: NNCCc1ccccc1
Agent: O=S(=O)(O)O
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(CCc2ccccc2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and phenethyl hydrazine sulfate according to the procedure of Example 28.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:56]([O:57][CH2:58][CH2:59][CH2:60][O:61][C:62]2[C:63]([O:90][CH3:91])=[CH:64][C:65]3[C:71](=[O:72])[N:70]4[CH:73]=[C:74]([C:76]5[CH:81]=[CH:80][C:79]([N:82]6[CH2:87][CH2:86][N:85]([CH3:88])[CH2:84][CH2:83]6)=[CH:78][CH:77]=5)[CH2:75][C@H:69]4[CH:68]=[N:67][C:66]=3[CH:89]=2)=[CH:55][C:12]2[N:13]=[CH:14][C@@H:15]3[CH2:21][C:20](/[CH:22]=[CH:23]/[CH2:24][NH:25][C:26](=[O:54])[C@@H:27]([NH:29][C:30](=[O:53])[C@H:31]([NH:35]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)[CH:32]([CH3:34])[CH3:33])[CH3:28])=[CH:19][N:16]3[C:17](=[O:18])[C:11]=2[CH:10]=1>CN(C=O)C.C(Cl)Cl>[NH2:35][C@@H:31]([CH:32]([CH3:34])[CH3:33])[C:30]([NH:29][C@@H:27]([CH3:28])[C:26]([NH:25][CH2:24]/[CH:23]=[CH:22]/[C:20]1[CH2:21][C@H:15]2[CH:14]=[N:13][C:12]3[CH:55]=[C:56]([O:57][CH2:58][CH2:59][CH2:60][O:61][C:62]4[C:63]([O:90][CH3:91])=[CH:64][C:65]5[C:71](=[O:72])[N:70]6[CH:73]=[C:74]([C:76]7[CH:81]=[CH:80][C:79]([N:82]8[CH2:83][CH2:84][N:85]([CH3:88])[CH2:86][CH2:87]8)=[CH:78][CH:77]=7)[CH2:75][C@H:69]6[CH:68]=[N:67][C:66]=5[CH:89]=4)[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[C:17](=[O:18])[N:16]2[CH:19]=1)=[O:54])=[O:53]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(/C=C/CNC(=O)[C@H](C)NC(=O)[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)=CN1C2=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Piperidine (0.058 mL, 0.590 mmol, 12.0 eq.) was added to a stirring mixture of Fmoc amine 19e (0.050 g, 0.0492 mmol, 1.0 eq.) in anhydrous DMF (0.8 mL) and the mixture was stirred at ambient temperature. After 20 minutes, LCMS showed reaction was completed so the reaction mixture was diluted with DCM (30 mL) and washed with water (3×30 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Co-evaporation with n-hexanes afforded the product as a brown oil, and the material was not subjected to further purification (0.040 g, assumed 100%). LC/MS (1.533 min (ES+)), m/z: 928.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[O:16][C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:17])[CH:14]=2)[NH:11][C:10](=[O:18])[CH:9]=[CH:8]3)[CH2:5]1.[H][H]>O.[Pd]>[NH2:2][CH2:3][CH:4]1[O:16][C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:17])[CH:14]=2)[NH:11][C:10](=[O:18])[CH2:9][CH2:8]3)[CH2:5]1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CN)O2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)CC(CN)O2
Yield: 63.6 %

Procedure:
A hydrochloric acid salt of 2-aminomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline-7-one (1.0 g) was dissolved in water (50 ml). To the solution, 10% palladium-on-carbon (1 g) was added, followed by stirring at 80° C. for 1.5 hours in the atmosphere of hydrogen. After the catalyst was removed by filtration, the mixture was condensed. The resultant residue was recrystallized from methanol--ether to obtain 642 mg of a hydrochloric acid salt of 2-aminomethyl-5-methyl-1,2,8,9-tetrahydrofuro-[3,2-f]quinoline-7-one as colorless prisms (63.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.[OH-].[K+]>C(O)C>[CH3:28][N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]=[C:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])=[CH:26][CH:27]=1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)CCC(=Cc1ccc(OCCCN(C)C)cc1)C2=O
Yield: 81.4 %

Procedure:
Interaction of 16 g of 6-methoxy-1-tetralone and 19 g of 4-(3-dimethylaminopropoxy)benzaldehyde in 95 ml of ethanol in the presence of 0.6 g of potassium hydroxide following the procedure described in Example 1A, yields 27 g of crude product; melting point 68-71° C. Following crystallization from 70 ml of diisopropyl ether, the product weighs 18.6 g, melting point 76°-78° C.
Reaction SMILES: [CH2:1]([F:3])[F:2].[CH:4](/[C:7]([F:10])([F:9])[F:8])=[CH:5]\F>>[CH2:5]=[C:4]([F:2])[C:7]([F:10])([F:9])[F:8].[CH2:1]([F:3])[F:2]
Reactant: F/C=C/C(F)(F)F
Agent: FCF
Product: C=C(F)C(F)(F)F

Procedure:
HFC-32/HFO-1243zf/HFO-1234ze mixture:
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36])(=O)C.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[OH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 0.4 %

Procedure:
2-chlorotrityl chloride resin (3.00 g, 4.5 mmol) was swelled in DCM. 4-Acetoxy-3-nitro-benzoic acid (2.53 g, 11.25 mmol) was dissolved in DMF (7.5 ml) and triethylamine (1.56 ml, 11.25 ml) mixed with the drained resin. The mixture was placed on a shaker for 18 h at rt. Followed by a careful wash with DMF (3×2 min) and methanol (3×2 min). The resin was treated with a solution of 2-phanyl-ethyl amine (2M, 10 ml) in dichloromethane for 1 h at rt. and for 3 h at rt. then washed with dichloromethane (3×2 min) and dried. 36.1 mg resin was added 1% TFA in DCM 10 min filtered, added hexane and evaporated to give 4-hydroxy-3-nitro-benzoic acid (7.8 mg), which correspond to a loading of 1.18 mmol/g.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([C:30]2[NH:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[CH:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([C:30]2[NH:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[CH2:15][C:14]2=[CH:13][CH:12]=[C:11]([CH:36]=[CH:35]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:2]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)c2ccc[nH]2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H]1NC(=O)[C@@H](NC(=O)c2ccc[nH]2)Cc2ccc(cc2)OCCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 51 (45 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.5 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 14 mg, 33%. Rf=0.25 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][NH2:10].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:10][CH2:9][C:2]3[C:1]([CH3:11])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=3[CH3:8])=[O:23])[N:21]=2)[CH:18]=1
Reactant: Cc1cc(C)c(CN)c(C)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: Cc1cc(C)c(CNC(=O)c2cn3cc(Br)ccc3n2)c(C)c1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using mesitylmethanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.