Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:16]4[CH2:21][N:20]([C:22]([O:24][C:25](C)(C)C)=[O:23])[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:35])[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:38]1N=C(N2CCOC[C@@H]2C)C2CN(C(OC)=O)CC=2N=1.C1(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=C(F)C=2)=O)CC1>>[CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][C@@H:34]4[CH3:38])[C:16]4[CH2:21][N:20]([C:22]([O:24][CH3:25])=[O:23])[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:35])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Agent: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 10 %

Procedure:
Method as described for tert-Butyl 2-(4-(3-(cyclopropylureido)-2-fluorophenyl)-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 143) using (S)-methyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 26) (193 mg, 0.5 mmol) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (182 mg, 0.57 mmol) as starting materials. Reaction mixture was partitioned between EtOAc (50 ml) and water (35 ml), the organic layer passed through a hydrophobic frit and concentrated in vacuo to leave a brown solid. The solid was purified by prep. HPLC at low pH to afford a colourless solid (22 mg, 10%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[C:12]([O-])(=O)[CH3:13].[Na+].[C:17]([C:19]1C(=O)[C:24](Cl)=[C:23](Cl)[C:21](=O)[C:20]=1C#N)#[N:18]>>[NH:18]1[C:21]2=[C:23]3[C:24](=[CH:12][CH:13]=[C:20]2[CH:19]=[CH:17]1)[C:8]1[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=1)[NH:10]3
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(NN)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc2[nH]c3c(ccc4cc[nH]c43)c2c1
Yield: 93.3 %

Procedure:
4-cyanophenylhydrazine hydrochloride (1.36 g; 8.0 mmol), sodium acetate (656 mg; 8.0 mmol); stage B: DDQ (545 mg; 2.40 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (517 mg; 2.24 mmol; yield=56%) in the form of a beige-colored solid.
Reaction SMILES: O.FC1C=CC(C2NN=C(C(N3CCNCC3)=O)C=2C2C=CN=CC=2)=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:39][N:38]=[C:37]([CH2:40][CH:41]3[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]3)[C:36]=2[C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:54]3[CH:55]=[CH:56][N:57]=[CH:58][CH:59]=3)=[C:37]([CH2:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[NH:38][N:39]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Agent: O=C(c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)N1CCNCC1
Solvent: O
Product: Fc1ccc(-c2n[nH]c(CC3CCNCC3)c2-c2ccncc2)cc1

Procedure:
4-[3-(4-Fluorophenyl)-5-(4-piperidinylmethyl)-1H-pyrazol-4-yl]pyridine was prepared using the same method as described for Example A-314, step 1 by replacing 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate with the pyrazole of step 5 of the present Example. Anal. Calc'd for C20H21N4F.2TFA.1.25H2O: C, 49.11; H, 4.38; N, 9.54; Found: C, 48.74; H, 4.02; N, 9.57. MS (MH+): 337 (base peak).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1.C>CO.[Fe](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([CH:6]=1)[NH2:13]
Reactant: CCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CCc1ccc(Cl)cc1N
Yield: 97.1 %

Procedure:
A solution of hydrazine hydrate (6.95 mL, 134.7 mmol) in methanol (50 mL) was added drop wise to a solution of 4-chloro-1-ethyl-2-nitrobenzene (6.25 g, 33.7 mmol) in methanol (120 mL), in the presence of iron (III) chloride (547 mg, 3.4 mmol) and activated charcoal (547 mg) and the reaction mixture was stirred under reflux for 13 h. The solids were filtered over celite, the filtrate concentrated and purified by flash chromatography (hexane/EtOAc 9/1) to obtain the title compound as a light-pink oil (5.09 g, 97%).
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].O.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27](S(O)(=O)=O)=[CH:26][CH:25]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:34]([O:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:22])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: O=C(O)CCCCCCCCCCCCCCCCC(=O)OCc1ccccc1
Temperature: 40 °C

Procedure:
A solution of 1,18-octadecanedioic acid (75 g, 0.24 mol), p-toluene sulfonic acid mono hydrate (2.27 g, 11.9 mmol) and benzyl alcohol (20.7 g, 0.19 mol) in toluene (2.75 L) was heated to reflux for 3 hr. Water was removed by azeotropic distillation during reflux. Celite (25 g) was added and the mixture was cooled to 40° C. and stirred for an additional hour. The mixture was purified by plug filtration through silica using toluene as mobile phase. Fractions containing 1,18-octadecanedioic acid mono benzyl ester was collected and the volume was reduced by vacuum distillation at 75° C. The solution was cooled to 50° C., heptane was added, and the mixture was cooled to 35° C. Upon crystallisation additional heptane was added over a period of 15 min. and finally the mixture was cooled to 10° C. for an additional hour. The product was collected by filtration, washed with heptane and dried in vacuum. Yield of 1,18-octadecanedioic acid mono benzyl ester was 34 g (35%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([NH:16][CH3:17])=[CH:13][C:14]=2[CH3:15])[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[N:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[N:45]=[CH:44][C:43]([C:46]([N:16]([CH3:17])[C:12]3[N:11]=[CH:10][C:9]([CH2:8][N:6]4[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@@H:2]([CH3:1])[CH2:7]4)=[C:14]([CH3:15])[CH:13]=3)=[O:47])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: CNc1cc(C)c(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N(C)C(=O)c2ccc(Oc3ccc(F)cc3)nc2)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (2S)-2-methyl-4-{[4-methyl-6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate (D101) (0.038 g, 0.11 mmol) was dissolved in dry DCM (2 mL). Triethylamine (0.016 g, 0.16 mmol) was added dropwise and after 5 minutes a solution of the acid chloride from step 1 in dry DCM (2 mL) was added dropwise. The reaction mixture was then left stirring under argon at room temperature overnight. Saturated aqueous NaHCO3 (15 mL) was added and the aqueous layer extracted with DCM (3×5 mL). The organic extracts were dried (Na2SO4) and the crude product was purified by column chromatography. Elution with a 0-100% EtOAc/petroleum ether gradient gave the title compound as a colourless oil (0.026 g). MS (ES): MH+ 550.4
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([N:14](S(C)(=O)=O)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1.CC1C=CC(C(OC)=O)=C(NS(C)(=O)=O)C=1>CO>[CH3:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc(C)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: COC(=O)c1ccc(C)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)O)c(NS(C)(=O)=O)c1

Procedure:
An aqueous solution of sodium hydroxide (11.0 g) was added to a solution of a mixture of methyl 4-methyl-2-[N,N-bis(methylsulphonyl)amino]benzoate and methyl 4-methyl-2-(N-methylsulphonylamino)benzoate (23.26 g) in methanol and the resulting suspension was heated at reflux for 1 hour. It was cooled and the methanol was retuoved by evaporation. The aqueous solution was acidified and the resultant solid was filtered off to give 4-methyl-2-(N-methylsulphonylamino)benzoic acid (16.42 g) as a cream solid, m.p. 202°-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1COc2ccc(Br)cc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1[nH]c1c3cc(Br)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 5-bromo-3(2H)-benzofuranone (3.10 g, 14.6 mmol) [Ellingboe, J. et al., J. Med. Chem. 1992,35 (7), 1176-1183] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (5.49 g, 29.1 mmol) in deionized water (200 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 3.65 g (72%) of the title compound as a brown solid: mp 195° C.(dec) which was used without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:24]([O:26]C(C)(C)C)=O)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C[Si]([N:42]=C=O)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:42][C:24]([N:17]1[CH2:18][C@@H:19]([C:20]([O:22][CH3:23])=[O:21])[C@H:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:16]1)=[O:26]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(N)=O)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-1-(1,1-dimethylethoxycarbonyl)-4-(methoxycarbonyl)pyrrolidine (419 mg, 1.0 mmol) in 2 mL of CH2Cl2 at 0° C. was added 2.3 mL of trifluoroacetic acid. The solution was stirred for 12 hr at room temperature, and concentrated to an oil. The oil was dissolved in 2 mL of CH2Cl2 and 4-dimethylaminopyridine 366 mg, 3.0 mmol) was added. To this solution at 0° C. was added trimethylsilylisocyanate (1.15 g, 10.0 mmol). The bath was removed and the resulting mixture was allowed to stir for 60 hr. After dilution with CH2Cl2, the reaction mixture was washed with 1M H3PO4 and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (9:1, CH2Cl2 :methanol) provided a foam. Crystallization with diisopropyl ether afforded trans-1-aminocarbonyl-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine as a white solid (243 mg, 67%), m.p. 127°-129° C. Anal. Calcd for C19H26N2O5 : C, 62.97; H, 7.23; N, 7.73. Found: C, 63.07; H, 7.20; N, 7.76.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]=1.C=[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]1[CH2:18][C:19]([O:21]C)=O.[CH3:23]O>>[C:13]1([CH:18]2[CH2:23][CH:1]=[C:2]3[N:3]([CH2:4][CH2:5][C:6]4[S:10][CH:9]=[CH:8][C:7]=43)[C:19]2=[O:21])[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1=NCCc2sccc21
Reactant: CO
Reactant: C=C1C=CC=CC1CC(=O)OC
Product: O=C1C(c2ccccc2)CC=C2c3ccsc3CCN12

Procedure:
A mixture of 20 g of 6,7-dihydro-4-methyl-thieno[3,2-c]pyridine and 19.8 g of methyl 2-methylenephenylacetate was heated under an argon atomosphere to 80° for 2 hours and subsequently to 110° for 48 hours. Methanol was added to the cooled reaction mixture and the product was left to crystallize out. There was obtained 4,5,8.9-tetrahydro-8-phenyl-7H-thieno[3,2-a]quinolizin-7-one of m.p. 159°-161°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[C:5]=1[NH2:12].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O>[Cl:11][C:6]1[C:5]([NH:12][S:15]([CH3:14])(=[O:17])=[O:16])=[C:4]([CH:9]=[CH:8][C:7]=1[Cl:10])[C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Product: COC(=O)c1ccc(Cl)c(Cl)c1NS(C)(=O)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
A mixture of methyl-2-amino-3,4-dichlorobenzoate (2.2 g) and methanesulphonyl chloride (2.86 g) was stirred at 100° C. for 4 hours. A further quantity of methanesulphonyl chloride (2.86 g) was added and the mixture was stirred at 100° C. overnight. The mixture was poured into water then extracted with ethyl acetate. The combined organic extracts were washed with water, dried (magnesium sulphate) and evaporated to yield a brown oil which was crystallised from cyclohexane/ethyl acetate to yield methyl 3,4-dichloro-2-(methylsulphonylamino)benzoate as light brown crystals (1.4 g), m.p. 100-102° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[C:30]([C:33]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:34])=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:13][CH:12]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[C:30]([C:33]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:34])=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10-{[2′-(azidomethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide (0.49 mmole) of Step B in tetrahydrofuran (3 mL) was added solid triphenylphosphine (0.55 mmole). The mixture was stirred at room temperature for 16 hours. Water (0.3 mL) was then added and the reaction mixture was heated to 45° C. for 3 hours. The solvent was removed by evaporation and the residue was extracted with dichloromethane. The organic solution was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by HPLC (normal phase, 20-70% gradient of [20% methanol in dichloromethane] and hexane, Luna CN bonded packing) and crystallized upon solvent evaporation, m.p. 115-120° C.
Reaction SMILES: COC(=O)C1C=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:6]([C:7]([N:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH3:10])=[O:8])[CH:5]=1.[CH3:32][Mg]Br.[C:35]([CH:38]([CH:40]([C:42]([O-])=O)O)[OH:39])([O-])=O.[K+].[Na+]>C1COCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N:9]([CH3:10])[C:7](=[O:8])[C:6]1[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:42]=[C:40]([C:38]([OH:39])([CH3:35])[CH3:32])[CH:5]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: COC(=O)c1cc(C(=O)N(C)c2cnccc2-c2ccccc2Cl)cc(C(F)(F)F)c1
Reactant: C[Mg]Br
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(C)(C)O)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
To a solution of N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-isophthalamic acid methyl ester (200 mg, 446 μM, example 75) in THF (3.3 mL) were added methyl magnesium bromide (1M solution in butyl ether, 1.6 mL, 1.56 mmol) within 2 min. The reaction was poured on EtOAc (20 mL) and aqueous sodium potassium tartrate solution (20 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (20 mL) and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (115 mg, 57%). MS (ESI): m/z=449.123 [M+H]+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:16][C:17]=1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].O.[C:30]1([CH3:36])[CH:35]=[CH:34]C=CC=1>>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:36][CH:30]1[CH2:35][CH2:34]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cc(N=Nc2ccccc2)ccc1O
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCOc1cc(N=Nc2ccccc2)ccc1OCC1CC1
Reaction time: 2 h

Procedure:
A suspension of 35.4 g of 3-n-decyloxy-4-hydroxyazobenzene and 4 g of pulverised sodium hydroxide in 500 ml of toluene is heated on a water separator until pure toluene distills over. To the mixture there are then added 100 ml of dimethylformamide (anhydrous) and 0.5 g of sodium iodide. The toluene is removed by distillation from the reaction mixture (internal temperature 130°). At 80° there is subsequently added 11 g of cyclopropylmethyl chloride whilst stirring is maintained. After slow heating to 120°-125°, the mixture is allowed to stand for 2 hours at this temperature. The mixture is then cooled; 300 ml of water is added and the whole is repeatedly extracted with toluene. The combined toluene extracts are dried with magnesium sulphate, and the toluene is distilled off. After recrystallisation from ethanol, there is obtained 3-n-decyloxy-4-cyclopropylmethoxyazobenzene, M.P. 58°-60°.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][S:21][CH2:22][CH3:23])C(OCC)=O)=[O:5])C.Cl>[OH-].[Na+]>[C:4]([OH:5])(=[O:3])[CH2:6][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][S:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(CCCCCCOCCSCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCSCCOCCCCCCCC(=O)O
Yield: 97.2 %

Procedure:
A solution of the above ethyl 2-ethoxycarbonyl-9-oxa-12-thiatetradecanoate (2 g, 5.8 mmol) in 20% NaOH (10 mL) was refluxed for 6 h. The solution was acidified with HCl (pH 2), and extracted with ethyl acetate (120 mL). The organic phase was washed with water (2×30 mL), brine (30 mL) and dried (Na2SO4). After evaporation of the solvent, the resulting product was heated on an oil bath at 180° to 200° C. for 15 min. The crude product was purified by Kugelrohr distillation to afford the title compound, 9-oxa-12-thiatetradecanoic acid (1.4 g, 98%); bp 121°-125° C./0.005 torr; IR(neat):3020 (broad) and 1730 cm-1 ; NMR: 1.27 (3H, t, J=7.7 Hz), 1.34 (6H, m), 1.53-1.68 (4H, m), 2.36 (2H, t, J=7.1 Hz), 2.58 (2H, q, J=7.7 Hz), 2.71 (2H, t, J=7 Hz), 3.45 (2H, t, J=6.8 Hz), 3.59 (2H, t, J=7 Hz), and 10.6 ppm (1H, br s); Found: C, 58.11, H, 9.8%. Calcd for C12H24SO3 : C, 58.03, H, 9.74%.
Reaction SMILES: [Se:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][Se:1](=[O:10])[C:5]=2[CH:6]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[Se]1C=Nc2ccccc21
Reactant: O=C(O)c1ccccc1
Solvent: O
Product: O=C(c1ccccc1)c1ccc2c(c1)[Se](=O)C=N2
Temperature: 130 °C

Procedure:
1.98 g (0.01 mol) of benzoselenazolinone, 50 to 60 g of polyphosphoric acid and 1.35 g (0.011 mol) of benzoic acid are introduced into a 100-cm3 round-bottomed flask. The mixture is heated on an oil bath to a temperature of 130° C. for a time T of 3 hours, with stirring. The reaction mixture is then hydrolyzed in 300 cm3 of cold water. The product is drained, washed with water, dried and recrystallized.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]([NH:14][CH3:15])=[C:10]([NH2:13])[C:11]=1[Cl:12])=[O:5])[CH3:2].[CH2:17](OC(OCC)OCC)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]2[N:13]=[CH:15][N:14]([CH3:17])[C:9]2=[N:8][C:7]=1[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1c(C)nc(NC)c(N)c1Cl
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl

Procedure:
2.4 g. of 5-Amino-6-methylamino-4-chloro-2-methylpyridine-3-carboxylic acid ethyl ester (0.01 mol.) and 10 ml. of orthoformic acid triethyl ester are refluxed for 12 hours. After the excess ortho ester has been removed, the residue is recrystallized from ethyl acetate to obtain 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester, m.p. 56°-58° . Yield 2.2 g. (88%).
Reaction SMILES: C(C1C=CN=C(C(O)=[O:13])C=1)CC(C)C.C(C1C=CN=C(C(O)=O)C=1)CCCC.[CH2:29]([CH:31]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH2:32][CH3:33])[CH3:30].OO>C(O)(=O)C.C(Cl)Cl>[CH2:29]([CH:31]([C:34]1[CH:35]=[CH:36][N+:37]([O-:13])=[CH:38][CH:39]=1)[CH2:32][CH3:33])[CH3:30]
Reactant: CCC(CC)c1ccncc1
Reactant: CC(C)CCc1ccnc(C(=O)O)c1
Agent: CCCCCc1ccnc(C(=O)O)c1
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)c1cc[n+]([O-])cc1
Yield: 95 %

Procedure:
4-Isopentylpyridine-2-carboxylic acid, compound 10b (R9=1-ethyl-propyl), was made by employing Method P. To 4-(1-ethyl-propyl)-pyridine (8.5 g, 57 mmol) in acetic acid (30 mL), hydrogen peroxide (17.8 g, 30%, 57 mmol) was added. The resulting reaction mixture was refluxed overnight. The residue obtained on removal of solvent was dissolved in DCM (100 mL), dried over MgSO4. After filtering, the solvent was removed to obtain a brown liquid, 4-(1-ethyl-propyl)-pyridine-N-oxide (9 g, 95%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24]#[N:25])=[CH:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[N:14]=[C:13]([CH3:22])[C:12]=2[CH3:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:10]=2)[C:6]([C:24]#[N:25])=[CH:7]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1nc2ccc(Cl)cc2c(-n2cc(C#N)c3ccc(Br)cc32)c1C
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: CN(C)C=O
Product: Cc1nc2ccc(Cl)cc2c(-n2cc(C#N)c3ccc(-c4cn[nH]c4)cc32)c1C
Temperature: 25 °C

Procedure:
A solution of 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-3-carbonitrile (0.2 g, 0.49 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.188 g, 0.97 mmol), and Pd(PPh3)4 (0.056 g, 0.049 mmol) in a 2M aqueous solution of Na2CO3 (1.5 mL) and DMF (5 mL) was stirred at 100° C. overnight. After this time the reaction mixture was allowed to cool to rt and poured into ice water. The resulting precipitate was filtered and purified via flash column chromatography to give 1-(6-chloro-2,3-dimethylquinolin-4-yl)-6-(1H-pyrazol-4-yl)-1H-indole-3-carbonitrile. 1H NMR (500 MHz, chloroform-d) δ ppm 8.02 (1H, d, J=9.0 Hz), 7.82 (1H, d, J=8.3 Hz), 7.64 (2H, m), 7.58 (2H, m), 7.49 (1H, dt, J=8.3, 0.7 Hz), 6.96 (1H, d, J=2.4 Hz), 6.82 (1H, s), 2.76 (3H, s), 2.01 (3H, s). Mass Spectrum (ESI) m/e=398 (M+1).