Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8](Br)[C:7]1=[O:13])[CH3:2].Cl.[N:16]([CH2:19][C@@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:17]=[N-:18].C(OC(N[C@@H](CC1C=CC=CC=1)CO)=O)(C)(C)C.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:28][C@H:20]([CH2:19][N:16]=[N+:17]=[N-:18])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]1=[O:13])[CH3:2]
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Agent: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1ccnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a solution of (3-bromo-2-oxo-2H-pyrazin-1-yl)-acetic acid ethyl ester (8.75 g, 33.5 mmol, preparation described in example 17, step J) in EtOH (60 ml) was added (S)-1-azidomethyl-2-phenyl-ethylamine hydrochloride (7.5 g, 35.3 mmol, prepared from (S)-(−)-2-(tertbutoxycarbonylamino)-3-phenyl-1-propanol following the procedure of Horwell et al (J. Med. Chem. 1991, 34, 404–414) and Boc removal under standard HCl(g) conditions) and triethylamine (10.8 ml, 77.6 mmol). The pressure flask was flushed with argon, sealed and the reaction mixture was stirred at 110° C. for 3 days. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% EtOAc in hexane to 40%) to give (S)-[3-(1-azidomethyl-2-phenylethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester as a brown syrup. 1H NMR (CDCl3, 400 MHz): δ 7.36–7.20 (m, 5H); 6.85 (d, J=4.4 Hz, 1H); 6.41 (d, J=4.4 Hz, 1H); 6.20 (bd, J=8 Hz, 1H); 4.58 (A of AB, d, J=17.5 Hz, 1H));); 4.52 (B of AB, d, J=17.5 Hz, 1H)); 4.43–4.33 (m, 1H); 4.25 (q, J=7.3 Hz, 2H); 3.52 (A of ABX, dd, J=12.5, 5 Hz, 1H); 3.40 (B of ABX, dd, J=12.5, 5 Hz, 1H); 3.00 (A of ABX, dd, J=14, 6.7 Hz, 1H); 2.92 (B of ABX, dd, J=14, 7.9 Hz, 1H); 1.29 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]3[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=3[CH2:9][N:10]([C:11]([NH:13][C:14]([CH3:28])([CH3:27])[CH2:15][NH:16]C(=O)OCC3C=CC=CC=3)=[O:12])[C:4]=2[CH:3]=1>CCO.C1COCC1.[Pd]>[NH2:16][CH2:15][C:14]([NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])([CH3:28])[CH3:27]
Reactant: CC(C)(CNC(=O)OCc1ccccc1)NC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(CN)NC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 32.4 %

Procedure:
The title product of Example 18 (6.5 g, 13.4 mmol) dissolved in a mixture of EtOH and THF was hydrogenated in a standard Parr apparatus using 3% Pd on carbon as catalyst. The reaction was run under a H2 pressure of 5 psi for 5.5 hours at 40° C. to produce the crude product. This material was purified by HPLC on silica gel to yield 1.5 g of the title material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]1[C:14]([CH3:17])=[CH:15][S:16][C:7]1=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH3:22][NH:23][CH:24]1[CH:32]=[CH:31][CH2:30][CH:29]2[CH:25]1[CH2:26][NH:27][CH2:28]2>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:27]1[CH2:26][CH:25]3[CH:29]([CH2:30][CH:31]=[CH:32][CH:24]3[NH:23][CH3:22])[CH2:28]1)[N:8]1[C:14]([CH3:17])=[CH:15][S:16][C:7]1=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: Cc1csc2c(C(=O)O)c(=O)c3cc(F)c(F)c(F)c3n12
Reactant: CNC1C=CCC2CNCC21
Solvent: CS(C)=O
Product: CNC1C=CCC2CN(c3c(F)cc4c(=O)c(C(=O)O)c5scc(C)n5c4c3F)CC21

Procedure:
100 mg (0.318 mmol) of 7,8,9-trifluoro-1-methyl-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid are heated at 80° C. under argon for 2 hours with 97 mg (0.64 mmol) of 2-methylamino-8-azabicyclo[4.3.0]-non-3-ene in 3 ml of DMSO. The mixture is concentrated in a high vacuum, the residue is recrystallized from ethanol and the product is dried.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:7]=1)=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (35.8 grams, 0.305 mole) was added to a benzene solution of 2-chloro-4-nitrobenzoic acid (60.3 grams, 0.3 mole) and the mixture heated to reflux during 5 hours until the evolution of hydrogen chloride had ceased. Aluminum chloride (100 grams, 0.72 mole) was added slowly to the stirred solution during a 3.5 hour period and the temperature rose to 48° C. After the addition, the mixture was warmed to 80° C. for 2 hours, cooled, poured onto ice-water (one liter), concentrated hydrochloric acid (90 ml.) added and the mixture warmed at 40° C. for 3 hours. Benzene extraction followed by successive treatment with 5% aqueous sodium hydroxide, water and calcium chloride yielded, after removal of benzene, a reddish black residue purified by filtration. The pale yellow solid so obtained was further characterized as having a melting point equal to 95.5° - 96.5° C. in 44% yields.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([Br:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[C:10]2[C:5](=[C:6]([Br:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:22])([F:1])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Br)c3n2)nc1
Temperature: 115 °C

Procedure:
To 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-3H-quinazolin-4-one (0.19 g, 0.52 mmol) at rt were added DIEA (0.18 mL, 1.04 mmol) and POCl3 (3.5 mL, 76 mmol) and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and then was concentrated under reduced pressure. The residue was treated with toluene and concentrated to dryness twice. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL), and the separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL), brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline as a brown viscous oil (207 mg, quantitative).
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])C.[OH-].[Na+]>CO>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)/C=C/C=C(c1ccccc1F)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccccc1F)c1ccccc1F
Yield: 93.7 %

Procedure:
As before, (E)-5,5-bis(2-fluorophenyl)-2,4-pentadienoic acid ethyl ester (1.7 g) in methanol (15 mL) was carried out using 4N sodium hydroxide (2.5 mL). After acidification, the product was extracted into dichloromethane (2×50 mL). The combined extracts were dried and evaporated and the residue crystallized from ether-hexane to provide 1.45 g of (E)-5,5-bis(2-fluorophenyl)-2,4-pentadienoic acid, mp 159°-160° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)/[CH:13]=[CH:14]/[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C@@H:22]2[CH2:25][CH2:24][N:23]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=1>C(Cl)Cl>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][C@H:22]1[C:20]1[CH:21]=[C:16]([CH2:15]/[CH:14]=[CH:13]/[CH2:12][OH:11])[CH:17]=[N:18][CH:19]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)/C=C/Cc1cncc([C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1c1cncc(C/C=C/CO)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
DIBAL-H (1.5M in toluene, 4.9 mL, 7.35 mmol, 2.7 equiv.) was added dropwise to a stirred solution of 4-[5-[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]-3-pyridyl]-trans-2-butenoic acid methyl ester (1.00 g, 2.75 mmol) in dry CH2Cl2 at −78° C. The mixture was stirred at −78° C. for 3 hours before the reaction was quenched by adding methanol followed by saturated aqueous sodium potassium tartrate solution. The reaction mixture was then allowed to warm to room temperature where it was vigorously stirred for 1 h. The organic layer was separated, and the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. Filtration and solvent removal afforded the crude product, which was purified by CC (SiO2, 3% methanol in CH2Cl2) to give the title alcohol as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.17 (s, 2H), 7.24 (s, 1H), 6.60 (d, J=18.2 Hz, 1H), 6.38 (m, 1H) 4.49 (m, 1H), 4.33 (m, 1H), 4.10 (dd, J=6.1, 3.2 Hz, 1H), 3.62 (t, J=6.1 Hz, 2H), 3.20 (1H, OH), 2.31 (m, 2H), 1.39 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 156.4, 155.0, 155.0, 140.4, 136.3, 133.3, 125.5, 117.8, 79.5, 71.4, 68.4, 59.9, 46.9, 43.5, 28.3, 18.7; MS (ESI) 335 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([OH:16])[CH2:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cccc(-c3ccccc3)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 0.30 g (0.0014 mole) of 4-phenyl-2-indanone in 10 ml of ethanol was added portion-wise 0.03 g (0.0008 mole) of sodium borohydride. The resulting yellow colored solution was stirred at ambient temperature for 1.5 hours, then concentrated, and 50 ml of water was added. The mixture was extracted with two portions of 50 ml each of diethyl ether. The extracts were combined, dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give, after recrystallization from hexane, 0.13 g of 4-phenyl-2-indanol. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH2:36]=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH3:36])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Product: CN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1-methylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and formaldehyde following General Procedure R.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C(N(CC)CC)C.O>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:23][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(-c2[nH]c(S)nc2-c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2[nH]c(SCc3ccc4ccccc4n3)nc2-c2ccc(F)cc2)cc1
Yield: 95.8 %

Procedure:
A solution of 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl]-1H-imidazole-2-thiol (Example 49) (100 mg, 0.29 mmol), 2-chloromethylquinoline hydrochloride (62 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in 2-propanol (5 ml) was heated at reflux under an argon atmosphere for 4 hours. The reaction was cooled, poured into water (25 ml) and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the residue was purified by chromatography on silica gel using 50% ethyl acetate in toluene as the eluent to give 136 mg (85%) of the desired product. Although initially an oil, this material crystallized on standing: mp 179-182° C. Anal. Calc'd. for C26H20N3O2FS2.5H2O (MW 498.60): C, 62.63; H, 4.25; N, 8.43; S, 12.86. Found: C, 62.98; H, 4.43; N, 8.03; S, 12.60.
Reaction SMILES: C([NH:9][C:10]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)=[N:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([Br:23])=[CH:18][N:17]=1)(=O)C1C=CC=CC=1.C[O-].[Na+].[ClH:36]>>[ClH:36].[ClH:36].[ClH:36].[Br:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]([NH2:9])=[N:24][CH2:25][CH2:26][CH2:27][C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)=[N:17][CH:18]=1
Reactant: Cc1cc(Br)cnc1CCCCN=C(NCCCc1c[nH]cn1)NC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(Br)cnc1CCCCNC(N)=NCCCc1c[nH]cn1
Yield: 60 %

Procedure:
1.00 g (2 mmol) of N1 -Benzoyl-N2 -[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]-N3 -[3-(1H-imidazol-4-yl) propyl]-guanidine is boiled in 20 ml of conc. hydrochloric acid for 18 hours. The aqueous solution diluted to 40 ml after cooling is extracted with 4×20 ml of diethylether, filtered and concentrated by evaporation under vacuum. The residue is taken up twice with 20 ml of absolute ethanol and concentrated by evaporation. The crude product obtained is then converted into the base with sodium methylate and chromatographed on aluminium oxide with ethyl acetate/ methanol (1:1). After concentration by evaporation, the main fraction is taken up with 5 ml of water, 0.5 ml of conc.hydrochloric acid is added, and the mixture is concentrated by evaporation under vacuum. After the mixture has again been concentrated by evaporation with 20 ml of absolute ethanol, 0.62 g (60%) of the title compound is obtained, in the form of a colourless, hygroscopic solid.
Reaction SMILES: [C:1](=[N:32]O)([C:8]1[CH:31]=[CH:30][C:11]([C:12](=[N:28]O)[C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:26]O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:26][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH2:28])[C:11]2[CH:30]=[CH:31][C:8]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH2:32])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: ON=C(c1ccccc1)c1ccc(C(=NO)c2ccc(C(=NO)c3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(C(N)c2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The trioxime from Step 2 (3 g) is dissolved in ethyl alcohol (250 ml) saturated with ammonia gas and Raney nickel W-6 (2 g) added. The mixture is subjected to 500 psi hydrogen pressure and heated to 90° for 2 hours. The catalyst is removed by filtration and 220 ml ethyl alcohol by distillation. A pale yellow crystalline material is filtered and dried. Yield 2.5 g (92% of theory) mp 182°-5°.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.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.O.CN(C)C=O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:9]=[C:10]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: Cc1ccccc1-n1cc(Br)c2[nH]nc(N)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1cc(-c2ccccn2)c2[nH]nc(N)c2c1=O
Temperature: 110 °C
Yield: 11.6 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step F of Example 1 (130 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (114 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (14.9 mg), potassium acetate (80.0 mg) and N,N-dimethylformamide (2.0 mL) was heated with microwave irradiation at 110° C. for 7 hr. The reaction mixture was cooled to room temperature, and 2-bromopyridine (111 mg), aqueous sodium carbonate solution (2 M, 0.350 mL) and tetrakis(triphenylphosphine)palladium(0) (40.4 mg) were added thereto. The reaction mixture was heated with microwave irradiation at 140° C. for 1 hr. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol/dichloromethane) to give the title compound (15.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:1][C:2]1[C:7]([Cl:18])=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Br)cc(N)c1OC
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(Br)c(Cl)c(N)c1OC

Procedure:
To methyl 4-amino-6-bromo-3-methoxypyridine-2-carboxylate (1.45 g, 5.56 mmol) in 10 mL of acetonitrile was added sulfuryl chloride, in excess, via pipette until the solution remained yellow. The solution was heated to reflux for 5 min. The reaction mixture was added to saturated sodium bicarbonate and aqueous phase was extracted with diethyl ether (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid. Solid was washed in 10% diethyl ether/petroleum ether and solid filtered to give 0.580 g of a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][C:4]=1[C:30]1[O:31][CH:32]=[CH:33][CH:34]=1.[C:36](O)(=[O:40])[CH2:37][CH2:38][CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:1][N:2]([CH3:35])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][C:4]=1[C:30]1[O:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)NCC3CCNCC3)c2)cc1-c1ccco1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)N1CCC(CNS(=O)(=O)c2cccc(S(=O)(=O)Nc3ccc(N(C)C)c(-c4ccco4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 373.7 %

Procedure:
To a solution (1.5 ml) of Y516 (60 mg, 0.098 mmol) produced in Example 35 in dimethylformamide were added n-butanoic acid (butyric acid) (20 μl, 0.02 mmol), HBTU (N,N,N′,N′-tetramethyl-O— (benzotriazol-1-yl)uronium Hexafluorophosphate) (40 mg, 0.1 mmol) and DIEA (N,N-diisopropylethylamine) (30 ml, 0.18 mmol), and the mixture was stirred at room temperature for 18 hr. Then, the reaction mixture was cooled, poured into cold water, and extracted with chloroform. The obtained chloroform extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol (40:1)) to give the title compound (Y639) (44 mg, 77%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[N:8][CH:9]=[C:10]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.[OH-].[Na+]>O.S(=O)(=O)(O)O>[N:31]1[C:32]2[CH:23]([CH2:22][CH2:21][CH2:20][N:19]3[C:7]4=[N:8][CH:9]=[C:10]([CH2:12][C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[CH:11]=[C:6]4[N:5]=[N:1]3)[CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cncc(Cc2cnc3c(c2)nnn3CCCC2CCCc3cccnc32)c1
Temperature: 4 °C
Yield: 106.7 %

Procedure:
Sodium nitrite (1.3 g) in water (60 ml) was added over 25 minutes to a solution of 3-amino-2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino]-5-(pyrid-3-ylmethyl)pyridine (5.5 g) in molar sulphuric acid (250 ml) stirred at 4° C. The reaction mixture was stirred at 4° C. for 50 minutes, then allowed to warm to room temperature, basified with 10 molar sodium hydroxide solution to pH 13 and extracted with chloroform (3×150 ml). The chloroform extracts were combined, dried over magnesium sulphate, and the solvent removed to give a brown oil (6.04 g). The oil was chromatographed on silica in 5% MeOH/chloroform to give the title compound as an oil (3.61 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl.N>O>[C:18]([CH2:17][CH2:16][C:15]1[NH:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6](=[O:12])[C:5]([CH3:14])([CH3:13])[C:4]3=[CH:3][C:2]=2[N:1]=1)([OH:20])=[O:19]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(O)CCC(=O)O
Agent: Cl
Agent: N
Solvent: O
Product: CC1(C)C(=O)Nc2cc3[nH]c(CCC(=O)O)nc3cc21

Procedure:
Analogously to Example 1, a solution of 3.82 g. 5,6-diamino-3,3-dimethylindolin-2-one and 2.36 g. succinic acid in 10 ml. 4N hydrochloric acid is heated for 4 hours at 135° C. (bath temperature). The reaction mixture is then evaporated in a vacuum until a thick slurry has formed. 10 ml. water are added thereto and the pH is adjusted to 10 with concentrated aqueous ammonia solution. Insoluble material is filtered off with suction and washed with water and the filtrate is treated with charcoal, filtered and the filtrate evaporated in a vacuum. The evaporation residue is taken up in 10 ml. water and acidified with glacial acetic acid, the title compound thereby precipitating out. After drying for 4 hours in a vacuum at 60° C., there are obtained 2.2 g. of desired compound with a melting point of 130°-135° C. (foaming). This compound contains 1.6 mole of water per mole of compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[BrH:11]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:11])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Cl)cc1
Reactant: Br
Product: Clc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
In a 65 mL glass pressure vessel, 4-chlorophenylethanol (32.725 g, 209 mmol) was warmed to between 90 and 100° C. The vessel was charged with hydrogen bromide gas and the mixture was stirred at +1.38 to +1.93 bar for 4.5 h. The pressure was released and the reaction showed 99.18% conversion by HPLC. The mixture was allowed to cool to room temperature to leave 2-(4-chlorophenyl)ethyl bromide as a brown liquid (53.735 g).