Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[CH:10]([CH2:11][C:12](=[O:16])[NH:13][N:14]=3)[CH2:9][CH2:8][C:7]=2[CH:17]=1.O1[CH:23]=[CH:22][C:21](=[O:24])[CH:20]=[CH:19]1>O>[O:24]=[C:21]1[CH:22]=[CH:23][N:2]([C:3]2[CH:4]=[CH:5][C:6]3[C:15]4[CH:10]([CH2:11][C:12](=[O:16])[NH:13][N:14]=4)[CH2:9][CH2:8][C:7]=3[CH:17]=2)[CH:19]=[CH:20]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Agent: Cl
Solvent: O
Product: O=C1CC2CCc3cc(-n4ccc(=O)cc4)ccc3C2=NN1
Yield: 10.3 %

Procedure:
A stirred mixture of 8-amino-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one hydrochloride (1.5 g) and 4H-pyran-4-one (0.84 g) in water (40 ml) was heated under reflux for 2 hours in a nitrogen atmosphere. The resultant solid was washed with dilute hydrochloric acid to give a crude product, 0.5 g. Purification by column chromatography (silica gel, 9:1 chloroform:methanol) gave the title compound 0.18 g, m.p. >300° C.
Reaction SMILES: [CH3:1][C:2]1([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH2:3]1.CS(O)(=O)=O.[H][H]>[Pt].CCOCC>[CH3:1][C:2]1([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([OH:10])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(C)(OOC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pt]
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CC1(C)CC(O)CC(C)(OOC(C)(C)C)C1
Reaction time: 18 h

Procedure:
The catalytic hydrogenation of 3,5,5-trimethyl-3-(t-butylperoxy)-cyclohexanone, 10.0 g. (0.045 mole), was carried out in a Parr Hydrogenation Apparatus using 1.0 g. 5% Platinum on carbon catalyst and in the presence of 50 ml. of 10% methanesulfonic acid solution. The hydrogenation at 60 p.s.i.g. hydrogen pressure was started at 0° C. and the temperature allowed to rise to 21° C. After 2 1/2 hours, the reaction was stopped, the product taken up in ether, the etheral solution washed to neutrality with water, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure. Examination of the IR spectrum of the product showed that some of the desired product had been obtained as evidenced by the hydroxyl absorption band while some unreduced carbonyl was still present. Further catalytic hydrogenation at 35° C. for 18 hours caused a further increase in hydroxyl absorption band and reduction of the carbonyl absorption band.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([F:9])[C:15]=2[F:16])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OB(O)c1cccc(F)c1F
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc(-c2cnc(Cl)nc2)c1F
Yield: 57.8 %

Procedure:
A reaction of 288 mmol of 5-bromo-2-chloropyrimidine, 288 mmol of 2,3-difluorophenylboronic acid, 576 mmol of sodium carbonate and 5.8 mmol of tetrakis(triphenylphosphine)palladium(0) in 560 ml of toluene, 280 ml of ethanol and 280 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 37.7 g (58%) of a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:4]=1[O:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:18](Br)[CH:17]=1)#[N:2].[CH3:30][N:31](C)C=O>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:4]=1[O:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:18]([C:30]#[N:31])[CH:17]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: CCCCCOc1ccc(C(=O)Oc2ccc(CCCCC)cc2C#N)cc1Br
Product: CCCCCOc1ccc(C(=O)Oc2ccc(CCCCC)cc2C#N)cc1C#N

Procedure:
9.3 g (0.020 mol) of the (2'-cyano-4'-n-pentylphenyl)-3-bromo-4-n-pentyloxybenzoate prepared in Step VI was reacted with cuprous cyanide and N,N-dimethylformamide to yield 3.0 g of purified (2'-cyano-4'-n-pentylphenyl)-3-cyano-4-n-pentyloxybenzoate. The yield was calculated to be 36.7%.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[C:15]2[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16]2.C([C:33]([O:35][CH3:36])=[O:34])#N>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[C:15]2[C:19]=1[C:18](=[O:20])[CH:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:16]2
Reactant: COc1ccc(-c2cccc(C(F)(F)F)c2)c2c1C(=O)CC2
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1Cc2c(-c3cccc(C(F)(F)F)c3)ccc(OC)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.18 mL, 0.36 mmol) was added to a solution of 7-methoxy-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-one (103 mg, 0.34 mmol) in THF (1.1 mL) at −78° C. After 1 h at −78° C., methyl cyanoformate (40 μL, 0.50 mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (3×40 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (12 g column, hexanes→EtOAc, gradient) to afford 26 mg (21%) of methyl 7-methoxy-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate.
Reaction SMILES: [C:1](=O)([O:27]C1C=CC=CC=1)[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:25][CH3:26])=[CH:7][CH:6]=1.[CH:35]1[C:44]2[C:39](=[C:40]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1>>[Cl:24][C:17]1[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]2[N:13]=[C:12]([CH2:25][CH3:26])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][O:2][C:1](=[O:27])[NH:48][S:45]([C:40]4[CH:41]=[CH:42][CH:43]=[C:44]5[C:39]=4[CH:38]=[CH:37][N:36]=[CH:35]5)(=[O:47])=[O:46])=[CH:10][CH:9]=3)[C:15]=2[CH:16]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccc2cnccc12
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccc3cnccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and 5-isoquinolinylsulfonamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][N:26]4C(OC(C)(C)C)=O)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]4)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]c(C3CCCCN3)cc2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H-indol-2-yl)piperidine-1-carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was stirred for 6 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 403.2, found 404.4(M+1)+. Retention time of 0.95 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH:11][CH:10]=1.O.P(Br)(Br)[Br:30]>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:30])=[CH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(-c2ccc(OCCCCCCCCCCCBr)cc2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.5 %

Procedure:
First, 8 g of 2,3-difluoro-4'-(11-hydroxyundecyl)oxybiphenyl and 100 ml of carbon tetrachloride were placed in a 200 ml flask. A solution in which 2.3 g of phosphorus tribromide was dissolved in 50 ml of carbon tetrachloride was added dropwise to the reaction mixture under ice water cooling, and the resultant reaction mixture was stirred at room temperature for 3 hours and under reflux for 2 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/9) and recrystallized from hexane to obtain 4.5 g of 2,3-difluoro-4'-(11-bromoundecyl)oxybiphenyl (Y: 47.8%). The compound thus obtained had a purity of 95.3% by GC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]=[N+:22]=[N-:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[CH:27]>C1(C)C=CC=CC=1>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[CH:27]=[C:26]([C:25]([CH3:29])([CH3:28])[CH3:24])[N:23]=[N:22]2)[CH2:10][CH2:9]1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN=[N+]=[N-])CC1
Reactant: C#CC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2Cn2cc(C(C)(C)C)nn2)CC1
Temperature: 25 °C
Yield: 46.1 %

Procedure:
In a sealed tube, 4-(2-Azidomethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.366 g, 1.15 mmol) was dissolved in toluene (5 mL). 3,3-dimethyl-1-butyne (0.7 mL, 5.64 mmol) was added and the mixture was heated to reflux for about 48 hours and then cooled to r.t. The mixture was concentrated under reduced pressure and purified using silica chromatography (50% ethyl acetate in hexanes) to give the title compound (0.212 g, 60%) as an oil.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[N:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=2)(=[O:11])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: COc1ccc(S(=O)(=O)n2cccc2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)n2cccc2)n[nH]1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
A mixture of 3-methoxy-6-(pyrrole-1-sulfonyl)-pyridazine (0.46 mmol, 11 2mg), conc. HCl (1 mL) and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue and the resulting solid was collected to obtain 6-(pyrrole-1-sulfonyl)-2H-pyridazin-3-one (69%, 73 mg); mp 140° C.-145° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH2:13]C)=[CH:5][C:4]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16]1)[CH3:2]>CCOC(C)=O.CO.[Pt]>[CH2:1]([C:3]1[C:4]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:20]2)=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:8]=1)[NH2:9])[CH3:2]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[2-Ethyl-5-(ethyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.63 g, 1.6 mmol) was taken up in EtOAc (30 mL) and MeOH (5 mL). The catalyst, 5% sulfided platinum on carbon (0.25 g) was added. The reaction was placed under 1 atm of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound without further purification (0.55 g, 1.5 mmol, 91%). MS (ESI) m/z=356 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:27][C:28]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31]>>[F:27][C:28]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:29]=1[C:30]([O:32][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:31]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CN1CCC(=NO)CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CN1CCC(N=O)(OC(=O)c2ccc(F)cc2F)CC1

Procedure:
1-Methyl-4-nitrosopiperidin-4-yl 2,4-difluorobenzoate was prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and 2,4-difluorobenzoic acid using conditions of General Method 3. 1H NMR (400 MHz, chloroform-d) δ 7.59 (2H, dd, 7.5, 2.3 Hz), 7.09 (1H, tt, 8.6, 2.4 Hz), 2.98 (2H, dt, 11.7, 3.6 Hz), 2.32-2.50 (7H, m), 2.04 (2H, dd, 14.2, 2.7 Hz).
Reaction SMILES: [C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31]Cl)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2].[I-].[Na+].C(#N)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>O>[C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCCl
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCN1CCCCC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To 1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)cyclohexyl]-amide (200 mg, 0.44 mmol) was added sodium iodide (66 mg, 0.44 mmol), acetonitrile (2 mL), and piperidine (0.1 mL, 1.3 mmol). The reaction mixture was heated to 50° C. and stirred for 24 hrs. Water (15 mL) was added to the reaction and extracted with three 20 mL portions of ethyl acetate. The combined organics were washed with saturated NaHCO3 (20 mL), dried on sodium sulfate, and concentrated. Purification by column chromatography (5:95 methanol:chloroform) gave 1-(3-piperidin-1-yl-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide as a white solid (150 mg, 68%). MS: 506 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:6](=[O:8])[CH2:5][CH2:4][O:3][CH3:2])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 24.1 %

Procedure:
Proceeding as in Example 1, but substituting 3-methoxypropanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 90, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-methoxypropanoyl)pyrrolidine-2-carboxamide (6.9 mg, 24.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): 9.90 (s, 1H), 7.54 (m, 2H), 7.30-7.25 (m, 3H), 7.21-7.16 (m, 6H), 6.92 (m, 2H), 4.44 (m, 1H), 3.66 (m, 1H), 3.51 (m, 3H), 3.19 (s, 3H), 2.63 (m, 4H), 2.09 (m, 1H), 1.88 (m, 2H). MS (EI) for C28H29FN2O4. found 477.5 (MH+).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[CH:16]1>>[NH2:26][C:19]1[C:18]2[N:17]=[CH:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Product: Cc1nc(N)c2ncn(CCCCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 16-26, 4-morpholinecarbonyl chloride was reacted with 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 347.2214.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11](O)=[O:12].[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+]>S(Cl)(Cl)=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:11][OH:12]
Reactant: O=C(O)c1sc2ncccc2c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: OCc1sc2ncccc2c1Br
Reaction time: 1 h

Procedure:
A solution of 3-bromothieno[2,3-b]pyridine-2-carboxylic acid (14b) (30 mg, 0.12 mmol) in thionyl chloride (2 mL) was refluxed for 1 hour. All volatiles were removed by co-evaporation with toluene. The residue was diluted in dimethoxyethane (2 mL) and sodium tetraborohydride (5 mg, 0.13 mmol) was added to the solution at room temperature. The reaction mixture was stirred for 1 hour, then quenched with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired alcohol (14c) as a white solid without further purification (20 mg, 0.081 mmol, 68%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C.I>O>[CH2:1]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:27]4[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=4)=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(Cl)c3-c3ccc(OC)cc3)cc2)CC1
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(Cl)c3-c3ccc(O)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
4-(trans-4-heptylcyclohexyl)-3′-chloro-4″-methoxyterphenyl of Intermediate 2 was mixed with 100 ml of acetic acid and 5 ml of 59% aqueous hydroiodic acid. The mixture was refluxed about twelve hours, cooled down to room temperature and poured into water. The product was twice extracted with methylene chloride. The combined organic layers were washed by diluted solution of sodium thiosulphate, water and dried over magnesium sulphate. After removing the solvent, the product was recrystallised from toluene-heptane mixture.
Reaction SMILES: Cl[C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[C:9](OC)(=[O:13])C(C)=C>>[CH3:9][O:13][CH2:7][CH:2]([CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)Cl
Reactant: C=C(C)C(=O)OC
Product: COCC(C)C(=O)OC
Yield: 18 %

Procedure:
An analysis of the obtained crude reaction solution by gas chromatography revealed that the conversion of methyl 2-chloro-2-methylpropanoate was 68.8% and the yield of methyl methacrylate was 13.6%. As to another product, methyl 3-methoxy-2-methylpropanoate was obtained in an 18.0% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18](C3C=CC=CN=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](C(N2CCN(C(OC(C)(C)C)=O)CC2)C)[CH:27]=1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[CH3:19])[CH2:16][CH2:17]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CC(c1cccnc1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(c1cccnc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-(1-(pyridin-3-yl)ethyl)piperazine-1-carboxylate (1.1 eq, 0.64 mmol, 186 mg), TFA (2 mL) and CH2Cl2 (2 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (147 mg, 0.58 mmol) in iPrOH (3 mL) and DIPEA (1.5 mL). Filtration and washing as previously described gave the product (106 mg, 41% for two steps) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.33 (d, J=6.7 Hz, 1H, CH3), 3.04 (s, br, 4H, piperazine N(CH2)2), 3.20 (s, br, 4H, piperazine N(CH2)2), 3.59 (q, J=6.8 Hz, 1H, CH), 6.95 (s, br, 2H, NH2), 7.36 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.73 (d, br, J=7.8 Hz, 1H, pyridine H-4), 8.14 (s, 1H, bromopyridine H-6), 8.46 (d, br, J=4.7 Hz, 1H, pyridine H-6), 8.52 (s, br, 1H, pyridine H-2);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[N:21]\[O:22][CH3:23])/[C:17]([NH:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=1.[CH3:24][S-:25].[Na+].O>O1CCCC1>[CH3:24][S:25][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[N:21]\[O:22][CH3:23])/[C:17]([NH:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(SC)n1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
(E)-2-[2-(6-chloropyridin-2-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (1.2 g) was dissolved in tetrahydrofuran (10 ml), and sodium thiomethoxide (1 g) was added. The mixture was heated under reflux with stirring for 5 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (800 mg). mp. 130°-132° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C(OCC)(=O)C>CN(C=O)C.[Cu]=O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(Br)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Reactant: c1cn[nH]c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(-n2cccn2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 100 °C
Yield: 26.9 %

Procedure:
A mixture of 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoic acid (Intermediate 133, 0.1 g), copper (II) oxide (0.004 g), cesium carbonate (0.254 g) and pyrazole (0.018 g) in DMF (2 ml) was sealed in a microwave vial in an atmosphere of nitrogen and heated at 100° C. for 18 hours. After cooling, ethyl acetate was added, and the mixture was filtered through celite. The filtrate was evaporated to dryness and the residue was purified by HPLC, eluting with a mixture of acetonitrile and water containing 0.1% formic acid with a gradient of 40-60% to give 6-(benzenesulphonylmethyl)-2-methoxy-3-(pyrazol-1-yl)benzoic acid (0.026 g) as a white solid.