Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[N:4]3[C:5](=[N:10][CH:11]=[C:3]3[C:2]1=[O:12])[CH:6]=[CH:7][CH:8]=2.[ClH:13]>CO>[ClH:13].[ClH:13].[NH2:1][CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[C:9]2[N:4]3[C:5](=[N:10][CH:11]=[C:3]3[C:2]1=[O:12])[CH:6]=[CH:7][CH:8]=2
Reactant: O=c1[nH]c2cccc3ncc1n32
Agent: Cl
Solvent: CO
Product: NCCCCn1c(=O)c2cnc3cccc1n32
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of 548 mg (1.66 mmol) of 1-[4-tert-butoxycarbonylamino)butan-1-yl)-1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one in 10 ml of methanol was added dropwise 10 ml of conc. HCl. The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue was added acetone. The resulting solid was collected by filtration and washed with acetone to give 400 mg of the desired compound (79.5%, grayish white solid).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:10][CH:9]=2)[N:6]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CS(O)(=O)=O>C(O)CCC>[C:16]1([S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:5]3[N:6]=[C:2]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[S:3][CH:4]=3)=[CH:9][CH:10]=2)=[O:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1CNCCN1
Reactant: O=S(c1ccccc1)c1ccc(Cc2csc(Br)n2)cc1
Agent: CS(=O)(=O)O
Solvent: CCCCO
Product: O=S(c1ccccc1)c1ccc(Cc2csc(N3CCNCC3)n2)cc1
Yield: 94 %

Procedure:
A solution of 6.4 g of 2-bromo-4-(4-phenylsulfinylbenzyl)thiazole (M. P. Kofler: 102° C.) and 6.5 g of anhydrous piperazine in 200 ml of butanol was refluxed for ten hours. Then, the solvent was evaporated and the thus obtained raw oil was taken off with 200 ml of a N solution of CH3SO3H. The insoluble matter was extracted twice with, each time, 20 ml of ether, then alkalized with K2CO3. The thus salted out oil was extracted twice with, each time, 50 ml of chloroform. The chloroform solution was washed with water, dried and evaporated. There was obtained 6.1 g of 1-[4-(4-phenylsulfinylbenzyl)-2-thiazolyl]piperazine, as semicrystallized product.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[N:20]1([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2cc(N3CCCCC3)ccc2C1
Yield: 92.1 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.915 mmol), piperidine (0.297 ml, 3.00 mmol), X-phos (26.1 mg, 0.0546 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.6 mg, 0.00187 mmol) and sodium tert-butoxide (131 mg, 1.37 mmol) in dioxane (6 ml) was stirred under an argon atmosphere for 1 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (280 mg, 92.1%) as an oil.
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[CH:19]=[CH:18][CH:17]=[N:16][C:8]=2[NH:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][C:11]/1=2)C.[Cl-].[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28]([NH2:30])=[NH2+:29].[O-]CC.[Na+].C(OCC)(=O)C>C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28]1[N:30]=[CH:4][C:5]2[C:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]=3[NH:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]=2[N:29]=1
Reactant: CN(C)/C=C1/C(=O)c2cccnc2Nc2cnccc21
Reactant: NC(=[NH2+])NCc1cccc(Cl)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Clc1cccc(CNc2ncc3c(n2)-c2cccnc2Nc2cnccc2-3)c1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A mixture of (E)-6-((dimethylamino)methylene)-6,11-dihydro-5H-dipyrido[2,3-b :4′,3′-f]azepin-5-one (0.303 g), 1-(3-chlorobenzyl)guanidinium chloride (0.500 g) and sodium ethoxide (21% solution in ethanol) (0.5 mL) in absolute ethanol (15 mL) was refluxed in for 3 hours. The reaction mixture was cooled to room temperature and poured into ethyl acetate (150 mL), washed with water (200 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to yield a brown solid. The crude product was purified by flash chromatography (SiO2, gradient 100% ethyl acetate to 5% methanol in dichloromethane) to give the pure desired product, N-(3-chlorobenzyl)-9H-dipyrido[2,3-b:4′,3′-f]pyrimido[4,5-d]azepin-2-amine as a bright yellow solid (0.134 g). M.p.=195-196° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.46-8.07 (m, 7H), 7.42-7.28 (m, 4H), 7.09 (brs, 1H), 4.58 (s, 2H); LCMS (M+H)=387.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[NH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=1[OH:16].C(OC1C=CC=C(N)C=1N)(C)C>>[CH3:5][O:4][CH2:3][CH2:2][O:16][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:13])[C:7]=1[NH2:6]
Reactant: COCCBr
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: CC(C)Oc1cccc(N)c1N
Product: COCCOc1cccc(N)c1N

Procedure:
Prepared from 1-bromo-2-methoxyethan and 2-amino-3-nitrophenol in analogy to 3-isopropoxy-benzene-1,2-diamine.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([OH:38])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:41]([O:48][C:49](=[O:53])[C@H:50]([CH3:52])O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][C@@H:50]([C:49]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:53])[CH3:52])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester and 647 mg benzyl-L-lactate in 25 ml THF were added 1.4 g triphenylphosphine and 938 mg diethylazodicarboxylate. After stirring for 16 h at RT LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.7 g.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[C:26]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:25][N:16]([CH2:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:34][CH2:35][CH3:36])=[O:33])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=1)[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:24]
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OCC

Procedure:
600 mg (1.8 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared as in Example 1(e)), 10 ml of toluene, 300 μl (1.8 mmol) of diethyl malonate and 50 mg (0.35 mmol) of piperidine acetate are introduced into a three-necked flask under a stream of nitrogen. This mixture is refluxed for 6 hours, while separating out the water formed using Dean-Stark apparatus. The reaction medium is cooled, extracted with ethyl acetate and washed with water. The organic phase is separated out after settling has taken place, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (75/25). After evaporation of the solvents, 700 mg (84%) of expected product are collected.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-fluoronitrobenzene (1.0 eq.) in isopropyl alcohol, pyrrolidine (2.2 eq) and triethylamine (11.0 eq) were added and reaction mixture was refluxed overnight. Reaction mixture was cooled to room temperature, product obtained was collected by filtration and dried to get the desired 1-(4-nitrophenyl)pyrrolidine. (Yield=85%)
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[N:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:6]1([C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:3]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1ccccc1N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(N)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccccc2N=C(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
37.8 g (0.11 mol) of 2-bromo-N-(diphenylmethylene)aniline was dissolved in toluene (100 ml), and 14.6 g (0.13 mol) of 2-amino-6-picoline, 5.2 g (5.5 mmol) of tris(dibenzylideneacetone)dipalladium(0), 11.2 g (17.6 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 15.2 g (0.15 mol) of sodium-t-butoxide were added thereto. The mixture was stirred for 2 hours at 100° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with methanol to obtain 42.1 g (yield:>99%) of N1-(diphenylmethylene)-N2-(6-methylpyridine-2-yl)benzene-1,2-diamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])/[C:5](/[O:18][CH:19]([CH3:21])[CH3:20])=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)[CH3:2].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH:19]([O:18]/[C:5](=[CH:6]\[C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([C:12]([NH:30][CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)=[O:14])[CH:15]=1)/[C:4]([O:3][CH2:1][CH3:2])=[O:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)O)c1)OC(C)C
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
65 mg of 5-[(Z)-3-ethoxy-2-isopropoxy-3-oxo-1-propenyl]-2-methoxybenzoic acid and 37 mg of 4-(trifluoromethyl)benzylamine were dissolved in 1 ml N,N-dimethylformamide, and 33 μl diethyl cyanophosphonate and 30 μl triethylamine were added under ice-cooling. After stirring the reaction mixture at room temperature for 16 hours, it was poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 77 mg of ethyl (Z)-2-isopropoxy-3-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl]-2-propenoate was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>[Pd]>[CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH:18][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C3CC3)cs2)n1
Reactant: Brc1cncnc1
Agent: [Pd]
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C3CC3)cs2)n1

Procedure:
The tide compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 4-Cyclopropyl-thiazol-2-ylamine instead of 2-chloro-4-aminopyridine to yield [2-(4-Cyclopropyl-thiazol-2-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester as a yellow solid, MS (ISP): m/e=375.4 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-cyclopropyl-thiazol-2-yl)-amide as a yellow solid, MS (ISP): m/e=275.1 (M+H+). Palladium catalysed arylation in accordance with the general method of example 20, using 5-Bromopyrimidine instead of 3bromopyridine yielded the final compound as a light yellow solid, MS (ISP): m/e=357.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][N:5]([CH2:34][C:35]([O:37]C)=[O:36])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([S:31]([CH3:33])=[O:32])[CH:7]=1.[OH-].[Na+]>CO>[C:35]([CH2:34][N:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([S:31]([CH3:33])=[O:32])[CH:7]=1)[CH2:4][C:3]([OH:39])=[O:2])([OH:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)OC)CC(=O)OC)cc(S(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc(S(C)=O)c1
Yield: 84 %

Procedure:
A solution of 0.53 g (0.93 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-(methylsulfinyl)-5-(octadecyloxy)phenyl]glycine methyl ester and 0.8 ml (4.7 mmol) of 6 N NaOH in 40 ml of methanol was stirred at reflux under argon for 6 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was extracted with 10% THF-ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from THF-ethyl acetate to give 0.42 g (84% yield), mp 147°-149°, of N-(carboxymethyl)-N-[3-(methylsufinyl)-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: N[C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1Cl)=[O:3].I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=[C:15]([C:6]3[CH:5]=[C:4]([CH2:2][OH:3])[CH:9]=[CH:8][CH:7]=3)[C:23]=12
Reactant: NC(=O)c1ccc(B(O)O)cc1Cl
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Product: CC(C)n1nc(-c2cccc(CO)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 48.9 %

Procedure:
A solution of (4-Aminocarbonyl-3-chlorophenyl)boronic acid (16 mg, 0.08 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA32 (9.7 mg, 42% yield). ESI-MS (M+H)+ m/z calcd 331.1, found 331.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: Cc1ccc(-n2cc(Br)cn2)cc1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(-c4ccc(C)cc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-p-tolyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](O)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(C)C(=O)O
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3C(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 89b) and isobutyric acid as brown solid (46%). MS 400 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
Compound 454 (834 mg, 3.00 mmol) was dissolved in DMF (12 mL), and 4-fluorobenzoic acid (3.36 g, 24.0 mmol), EDC hydrochloride (4.12 g, 24.0 mmol) and 1-hydroxybenzotriazole monohydrate (3.68 g, 24.0 mmol) were added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was poured into a mixture of a saturated aqueous solution of sodium hydrogencarbonate (30 mL) and water (30 mL), and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=19:1), followed by recrystallizing from ethanol to afford the entitled Compound 468 (270 mg, 23%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Temperature: 50 °C

Procedure:
To a solution of 30.9 g of 4-acetyl-4'-octylbiphenyl in 50 ml of acetic acid there are added 5.1 ml of bromine for one hour under stirring at the temperature of 50° C. The reaction mass is stirred for 1 hour at room temperature, poured into water, the organic layer is extracted with chloroform, the extract is washed with a 5% aqueous solution of soda, then with water and dried with sodium sulphate. Chloroform is distilled-off in vacuum and the residue is recrystallized from a minimum amount of ethanol to give 38 g of 4-bromoacetyl-4'-octylbiphenyl; from 19.6 g of the product and 16.5 g of benzaldehydeguanylhydrazone there is obtained, following the procedure of Example 1, 0.65 g of 1,1'-bisbenzylideneamino-4,4'-di-[4-(4-octylphenylene)-phenylene]-2,2'-azoimidazole (II /3/). The analysis data are shown in Table 1 hereinbelow.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[NH4+]>C(O)(C(F)(F)F)=O.CO.[Pt](=O)=O>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[N:2]1
Reactant: c1cnc2cn[nH]c2c1
Agent: O=[Pt]=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1n[nH]c2c1NCCC2
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A 250 mL Parr bottle was charged with a solution of 1H-pyrazolo[4,3-b]pyridine (2 g, 16.8 mmol, obtained from J&W PharmLab, LLC) in TFA (20.0 mL) and platinum(IV) oxide (381 mg, 1.68 mmol). The reaction mixture was evacuated twice with hydrogen and shaken under 55 psi pressure of hydrogen for 24 h. The reaction mixture was filtered over celite, and the filter cake washed with 5% methanol in CH2Cl2. The filtrate was concentrated in vacuo to afford a light brown oil that was dissolved in methanol (20 mL). Concentrated ammonium hydroxide solution was added drop wise until the pH remained basic (pH 8). The mixture was concentrated in vacuo then the residue adsorbed on silica gel and purified by chromatography (silica, 150 g column, 50 μm from Analogix, 0 to 5% of a 9:1 methanol:ammonium hydroxide solution in dichloromethane, 15 min) to give a yellow oil. This oil solidified upon drying under high vacuum to yield 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (1.712 g, 13.9 mmol, 83%) as a yellow solid. 1H NMR (CHLOROFORM-d) d: 7.09 (s, 1H), 3.14-3.25 (m, 2H), 2.76 (t, J=6.6 Hz, 2H), 1.88-2.02 (m, 2H). MS (EI/CI) m/z: 124.1 [M+H]+.