Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2cccc(C)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c1
Yield: 94 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(3-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 2 & 3, Part C). The mixture was heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 94% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[OH:37][CH2:36][C:35]([NH:34][S:31]([C:27]1[CH:26]=[C:25]([NH:24][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:23])[CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:32])([CH3:39])[CH3:38]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 566.2 [(M−H−]; mp 271° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12]
Reactant: CNCCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 0.08 h

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams), the dimethyl acetal of 3-methylaminopropionaldehyde (4.0 grams) and benzene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux, with stirring, for a period of about 5 minutes. After this time the reaction mixture is stripped of benzene to yield a residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][CH2:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH:59]2[C:64]2[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=2)=[N:54][CH:55]=1.Cl>CN(C=O)C>[Cl:70][C:67]1[CH:68]=[CH:69][C:64]([CH:59]2[CH:58]([CH2:57][O:56][C:53]3[CH:52]=[CH:51][C:50]([Cl:49])=[CH:55][N:54]=3)[CH2:63][CH2:62][N:61]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[N:6]=4)=[CH:15][CH:14]=3)=[O:13])[CH2:60]2)=[CH:65][CH:66]=1
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Reactant: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(C(=O)N3CCC(COc4ccc(Cl)cn4)C(c4ccc(Cl)cc4)C3)cc2)n1

Procedure:
A mixture of 18 mg (0.08 mmol) 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid, 43 mg (0.11 mmol) HATU, 0.1 mL DIPEA and 32 mg (0.09 mmol) 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride in 2 mL DMF was reacted at room temperature over night. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 32 mg (64%) of the title compound as white foam. MS (m/e): 523.3 [(M+H)+].
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[O:12][CH2:13][CH2:14][O:15][S:16](=[O:19])(=[O:18])[NH2:17])C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[O:12][CH2:13][CH2:14][O:15][S:16](=[O:18])(=[O:19])[NH2:17]
Reactant: NS(=O)(=O)OCCOc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: NS(=O)(=O)OCCOc1cccc(O)c1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 17.1 g (0.053 mole) of sulfamic acid 2-[3-(phenylmethoxy)phenoxy]ethyl ester in 250 ml of tetrahydrofuran was added 0.5 teaspoon of 5% palladium on carbon catalyst and the mixture was hydrogenated in a Parr bottle at 40° C. for 2 hr. The catalyst was removed and a fresh 0.5 teaspoon of 5% palladium on carbon catalyst was added and the mixture was hydrogenated at 40° C. for 19 hr, whereby hydrogen uptake ceased. The catalyst was removed by filtration through Celite® and the solvent was evaporated under reduced pressure to yield 12.3 g of a brown, viscous oil that solidified after standing for five weeks at ambient temperature. The solid was triturated with ethyl ether-petroleum ether into a paste. The solvents were decanted and the paste was dried to yield 8.9 g (72%) a white solid, mp 56°-60° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12](=[O:27])[C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:10][O:11][C:12](=[O:27])[C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure U and using cyclopentylacetic acid (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=137-139° C.). The reaction was monitored by tlc (Rf=0.23 in 1:1 EtOAc/hexanes).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:14])[N:8]2[C:12]([N:13]=1)=[N:11][CH:10]=[N:9]2)([OH:3])=O.[CH:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:16]>CN(C)C=O>[OH:14][C:7]1[N:8]2[C:12]([N:13]=[C:5]([CH2:4][C:1](=[O:3])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH2:16])[CH:6]=1)=[N:11][CH:10]=[N:9]2
Reactant: C=CNCc1ccccc1
Reactant: O=C(O)Cc1cc(O)n2ncnc2n1
Solvent: CN(C)C=O
Product: C=CN(Cc1ccccc1)C(=O)Cc1cc(O)n2ncnc2n1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
143 g of 6-carboxymethyl-4-hydroxy-1,3,3a,7-tetraazaindene prepared in Synthesis Example 1 and 98 g of vinylbenzylamine were dissolved in 1 l of dimethylformamide with stirring at room temperature. To the solution, 152 g of N,N-dicyclohexylcarbodiimide was added dropwise. After addition, the mixture was stirred at room temperature for 6 hours to separate white crystals (N,N-dicyclohexylurea). After the reaction, the separated crystals were filtered off and the filtrate was poured into 2 l of water to separate white crystals. The separated crystals were filtered out and recrystallized from acetonitrile to obtain 180 g of the desired 4-hydroxy-6-(N-vinylbenzylcarbamoylmethyl)-1,3,3a,7-tetraazaindene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].Cl.[NH2:13][OH:14].[OH-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:13][OH:14])=[O:11]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NO)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A solution of 14.2 g (75 mmol) of 2,4-dichlorophenylisocyanate in 50 mL of toluene was added to a mixture of 8.26 g (120 mmol) of hydroxylamine hydrochloride and 4.8 g (120 mmol) of sodium hydroxide in a two-phase solvent mixture consisting of 50 mL of water and 50 mL of toluene. The resulting mixture was stirred at 25° C. for 30 minutes and filtered. The solid thus obtained was washed with water and then dissolved in 200 mL of ethyl acetate. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 12.7 g of the title compound of Step A as a white solid melting at 157-158° C. It was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[CH:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:20]([CH3:22])[CH3:21])[CH:28]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cl
Reactant: CC(C)c1cccc(B(O)O)c1
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1cccc(C(C)C)c1

Procedure:
The title compound was prepared in analogy to example 20 step C from 4,6-dichloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (200 mg, 0.67 mmol) and 3-isopropylphenylboronic acid (99 mg, 0.6 mmol). Off-white sticky liquid (90 mg, 35%). LC-MS: 382 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([NH2:17])[N:7]=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=2)[N:4]=1)=[CH2:2].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([NH2:17])[N:7]=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=2)[N:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ccc2c(n1)c(N)nc1ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc2c(n1)c(N)nc1ccccc12
Reaction time: 8 h

Procedure:
To a solution of 3-vinylbenzo[f][1,7]naphthyridin-5-amine (Example 23) in ethyl acetate/ethanol (1:1, 0.07 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred overnight. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo giving 3-ethylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (acetone d-6): δ 8.93 (d, 1H), 8.41 (d, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.51-7.55 (dd, 1H), 7.30-7.34 (dd, 1H), 6.55 (br, 2H), 6.03 (q, 2H), 1.41 (t, 3H). LRMS [M+H]=224.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23](C)[C:24](=O)OCCCC)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:32]B(O)O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+].C(OCC)(=O)C.[ClH:53]>C(O)C.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.O1CCOCC1>[ClH:53].[ClH:53].[CH3:24][NH:23][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH3:32])[CH:3]=2)(=[O:9])=[O:10])[CH:12]=1
Reactant: CCCCOC(=O)N(C)Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(C)c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
Under an argon atmosphere, a mixture of ten-butyl ({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (112 mg), methylboronic acid (18 mg), tetrakis(triphenylphosphine)palladium (23 mg), potassium carbonate (138 mg) and 1,4-dioxane (5 mL) was stirred at 80° C. for one day. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give an oil. The oil was dissolved in ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl acetate to give the title compound as a colorless solid (yield 32.6 mg, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:39]=[C:40]([CH:44]([C:46]2[C:51]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:49]=[CH:48][N:47]=2)[OH:45])[CH:41]=[CH:42][CH:43]=1.C(#N)C.C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:42]3[CH:41]=[C:40]([CH:44]([C:46]4[C:51]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:49]=[CH:48][N:47]=4)[OH:45])[CH:39]=[CH:38][CH:43]=3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:10]=1
Reactant: OC(c1cccc(Br)c1)c1ncccc1C(F)(F)F
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(O)c4ncccc4C(F)(F)F)c3)cc12
Yield: 63 %

Procedure:
504 mg (1.00 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 50 mg (61 μmol) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]-palladium(II) dichloromethane adduct and 337 mg (1.01 mmol) of (3-bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanol were place in a microwave vial. 8 mL of acetonitrile, 3 mL of toluene and 8 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was sealed and irradiated in a Personal Chemistry® Optimizer to 125° C. for 20 min. The resulting mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 397 mg (0.63 mmol, 63%) of {3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-(3-trifluoromethyl-pyridin-2-yl)-methanol as an ivory solid. 1H NMR (500 MHz, DMSO-d6) δ 8.45 (d, 1H), 8.65 (d, 1H), 8.19 (dd, 1H), 8.09 (d, 2H), 8.07 (d, 1H), 8.06 (s, 1H), 7.75 (s, br., 1H), 7.61-7.58 (m, 1H), 7.53 (dd, 1H), 7.45 (d, 2H), 7.43-7.40 (m, 2H), 7.35 (d(m), 1H), 7.21 (d, 1H), 7.09 (dd(d), 1H), 6.24 (d, 1H), 6.09 (d, 1H), 3.83 (s, 3H), 2.36 (s, 3H); MS: m/z 630.1 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[C:30]5[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[NH:24][CH:23]=4)[CH:19]=[C:18]([Cl:33])[N:17]=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[CH:34]1([C:37](O)=[O:38])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.O>[Cl:33][C:18]1[N:17]=[C:16]([NH:15][CH:12]2[CH2:11][CH2:10][CH:9]([CH2:8][CH:5]3[CH2:6][CH2:7][CH:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[CH2:3][CH2:4]3)[CH2:14][CH2:13]2)[CH:21]=[C:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[NH:24][CH:23]=2)[CH:19]=1
Reactant: O=C(O)C1CC1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCC(CC5CCC(N)CC5)CC4)c3)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCC(CC5CCC(NC(=O)C6CC6)CC5)CC4)c3)c2c1
Reaction time: 6 h
Yield: 37.1 %

Procedure:
A mixture of Example 237 (68.5 mg, 0.146 mmol), cyclopropanecarboxylic acid (0.013 mL, 0.161 mmol), HOBT (26.9 mg, 0.176 mmol), EDC (33.7 mg, 0.176 mmol), and triethylamine (0.027 mL, 0.190 mmol) in DMF (2.5 mL) was stirred at room temperature overnight. More EDC (0.6 eq), HOBT (0.6 eq), acid (0.6 eq) and triethylamine (0.7 eq) were added. After 6 hours, water was added to reaction mixture. The precipitate was filtered and purified by reverse-phase HPLC as described in Example 56 to give the title compound (29.0 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 0.67-0.76 (m, 2H), 0.77-0.87 (m, 2H), 0.93-1.45 (m, 12H), 1.47-1.96 (m, 10H), 3.57 (m, 1H), 3.71 (m, 1H), 87 (m, 0.6H), 3.96 (s, 3H), 4.02 (m, 0.4H), 6.88-7.07 (m, 2H), 7.94 (m, 1H), 8.04 (s, 1H), 8.11 (s, 1H). MS (DCI+) m/z 536.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH:5]1[O:7][CH2:6]1)[CH3:2].[Na].[N:11]#[C:12][NH2:13]>CO>[NH2:11][C:12]1[O:7][CH:5]([CH2:4][N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])[CH2:6][N:13]=1
Reactant: N#CN
Reactant: CCN(CC)CC1CO1
Agent: [Na]
Solvent: CO
Product: CCN(CC)CC1CN=C(N)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
0.2 Mole of the 1-diethylamino-2,3-epoxypropane thus prepared is added, drop by drop, to 12.8 g of the cyanamide monosodium derivative dissolved in 200 cc of anhydrous methanol with vigorous stirring. After 15 hours of stirring at ambient temperature, the methanol is evaporated and the residue picked up with 300 cc of ether. The precipitate is eliminated by filtering. The ether phase is washed twice with 2 cc of water then dried on Na2SO4 after decanting. The ether is evaporated under low pressure. The resulting oily phase crystallizes after washing with boiling heptane. 2-Amino-5-diethylaminomethyl-2-oxazoline is thus obtained with a yield of 68%. It is purified by recrystallization in heptane.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:20]([O:22][C:23](=[O:37])[C:24]([NH:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=O)[CH3:21].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:36][O:35][C:31]1[CH:30]=[C:29]2[C:34](=[CH:33][CH:32]=1)[C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:37])=[N:26][CH2:27][CH2:28]2
Reactant: CCOC(=O)C(=O)NCCc1cccc(OC)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCOC(=O)C1=NCCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A mixture of 160 ml of methanesulfonic acid and 45 g of P2O5 was heated with stirring at an oil bath for about ½ hr in order to obtain a homogeneous mixture. The mixture was cooled to RT and a solution of 46 g of N-[2-(3-methoxyphenyl)-ethyl]oxalamic acid ethylester, 5b, in 50 ml of CH2Cl2 was added and the temperature was raised again to 80° C., while distilling off the CH2Cl2. The mixture was kept for 16 hr at 80° C. in order to complete the cyclization reaction. Then the reaction mixture was cooled and poured into ice-water and was made alkaline by careful addition of solid K2CO3. The product was extracted into ethyl acetate. The organic layer was washed with water, dried, concentrated and the residue was chromatographed, using a gradient of heptane/ethyl acetate as eluent, to provide 35 g of 6-methoxy-3,4-dihydroisoquinoline-1-carboxylic acid ethyl ester 5c. MS-ESI: [M+1] 234.14. NMR (CDCl3) δ 1.40 (t, 3, OC2H5), 2.72 (m, 2, CH2), 3.85 (s and m, 5, CH2 and OCH3) 4.40 (q, 2, OC2H5), 6.70, 6.80 and 7.70 (3×m, 3, Ar—H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].S(O)(=O)(C1C=CC([NH2:15])=CC=1)=O.N([O-])=O.[Na+].Cl.[OH-].[Na+].[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[OH:34].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[NH2:15][C:30]1[C:29]([CH3:33])=[CH:28][C:27]([OH:34])=[C:26]([CH3:25])[C:31]=1[CH3:32]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: Cc1cc(O)c(C)c(C)c1N
Temperature: 50 °C
Yield: 84.6 %

Procedure:
Solid Na2CO3 (13.7 g, 129 mmol) was added slowly with stirring at room temperature to a solution of sulfanilic acid (49.4 g, 258 mmol) in water (250 ml). After the reaction mixture became a homogeneous solution (when the mixture could not be dissolved at the temperature, it could be heated a little), the mixture was cooled with ice and a solution of NaNO2 (19.4 g, 280 mmol) in water (50 ml) was added at an inner temperature of below 10° C. Then, this solution was placed in a dropping funnel. The solution was added dropwise to a mixture of concentrated hydrochloric acid (46 ml) and ice (100 g) over about 10 minutes with stirring under ice cooling at an inner temperature of the dropping funnel of below 10° C. After the addition was completed, the reaction mixture was stirred for 30 minutes under ice cooling. Next, water (250 ml), NaOH (56.8 g, 142 mmol) and 2,3,5-trimethylphenol (35.3 g, 259 mmol) were placed in another reaction vessel equipped with a mechanical stirring apparatus and to this mixture was added dropwise the reaction mixture above with stirring under a stream of nitrogen over 15 minutes in the range of -10° C. to 5° C. At that time ice was properly added to the ice bath to cool the reaction system in order to keep a temperature of the contents in the dropping funnel below 10° C. After the addition was completed, the reaction mixture was heated to 50° C. and Na2S2O4 (11.9 g, 68.3 mmol) was added. Then the mixture was heated to 80° C. and further 5 equal parts of Na2S2O4 (214.2 g, 1.23 mol) were added at intervals of 5 minutes. The reaction mixture was stirred for 30 minutes at the same temperature and then cooled. The precipitated crystals were filtered. The crystals obtained were washed with water, dried and then recrystallized from ethyl acetate-isopropyl ether to obtain the desired compound (33.0 g, yield: 84.2%), m.p. 153°-154° C.