Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13](Cl)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([NH2:37])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.Cl>C(O)(C)C.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([NH:37][C:25]4[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[C:23]([Cl:22])[CH:24]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a 4-Chloro-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.08 g, 9.40 mmol, 1.05 equiv) in 40 mL of isopropyl alcohol solution was added 3-Chloro-4-(pyridin-2-ylmethoxy)phenylamine (2.10 g, 9.0 mmol, 1 equiv) at rt. 4 N HCl in dioxane (0.1 mL) was added to the reaction mixture to accelerate the reaction. The reaction mixture was heated at 80° C. for 16 h. The mixture was allowed to cool to rt then filtered and washed with IPA (50 mL). DCM (100 mL) and sat. sodium bicarbonate (100 mL) were added to the solid. The mixture was stirred at rt for 1 h before separated the layers. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.50 g of crude material. The crude material was purified by flash chromatography (50% THF/DCM) to yield a light yellow (3.60 g, 6.87 mmol, 76%) as product. 1H-NMR (DMSO-d6) δ 9.32 (broad s, 1H), 8.67 (d, J=4.0 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 8.05 (t, 1H), 7.79 (d, J=2.7 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.53 (t, 1H), 7.24 (d, J=8.9 Hz, 1H), 5.35 (s, 2H), 4.66 (s, 2H), 3.66 (t, 2H), 3.19 (t, 2H), 1.43 (s, 9H); LCMS RT=3.39 min, [M+H]+=524.0.
Reaction SMILES: [OH-].[K+].[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([O:28]C)=[O:27])=[CH:23][C:22]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:21][CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[N:3]1([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([OH:28])=[O:27])=[CH:23][C:22]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:21][CH:20]=4)[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCCCC4)CC3)c(C(=O)O)c2c1
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Potassium hydroxide (0.699 g, 12.46 mmol) in water (10 mL) was added to a solution of methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.47 g, 2.493 mmol) in methanol (30 mL). The mixture was heated to reflux for 5 h before the solvent was removed under reduced pressure. The residue was acidified to pH 5-6 with 2N HCl, and the mixture was allowed to stand overnight at room temperature. The solvent was collected by filtration, washed with water, and dried via azeotrope with benzene to give 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.69 g, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=1.51 Hz, 1H), 8.09-8.15 (m, 3H), 7.91 (d, J=7.53 Hz, 1H), 7.80 (d, J=7.78 Hz, 1H), 7.69 (t, J=7.65 Hz, 1H), 3.51 (s, 2H), 3.28 (s, 3H), 2.48 (br. s., 2H), 2.33 (br. s., 4H), 2.04 (br. s., 1H), 1.84 (t, J=11.29 Hz, 2H), 1.43 (br. s., 6H), 1.29-1.38 (m, 2H), 0.95-1.11 (m, 2H); MS (m/z) 576.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([C@@H:28]([NH2:30])[CH3:29])[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@H:28]([CH:25]4[CH2:27][CH2:26]4)[CH3:29])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C[C@H](N)C1CC1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@@H](C)C3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-cyclopropylethanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.26 (m, 1 H) 0.28-0.36 (m, 1 H) 0.36-0.44 (m, 1 H) 0.44-0.53 (m, 1 H) 0.92-1.08 (m, 1 H) 1.25 (d, J=6.82 Hz, 3 H) 2.43 (s, 3 H) 3.39-3.60 (m, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=6.57 Hz, 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=6.57 Hz, 2 H) 8.59 (d, J=8.08 Hz, 1 H) 8.79-9.05 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 388.2.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18]>C(O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][OH:18])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccc(Br)cc1
Yield: 94 %

Procedure:
A mixture of 4-bromobenzophenone (10.0 g, 0.0383 mol) and hydroxylamine hydrochloride (13.3 g, 0.192 mol) was heated in a mixture of ethanol (250 mL) and pyridine (50 mL) at reflux for 2 hours under an atmosphere of nitrogen. The solvents were removed under the reduced pressure and the residue was partitioned between water (300 mL) and dichloromethane (300 mL). The water phase was further extracted with dichloromethane twice (180 mL each) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under the reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (1:9) as mobile phase to yield (4-bromophenyl)(phenyl)methanone oxime as a white solid (9.93 g, 0.036 mol): 1H NMR (DMSO-d6, 400 MHz) 7.66 (d, 1H), 7.57(d, 1H), 7.33 (m, 7H) TLC (ethyl acetate/heptane 1:5) Rf 0.38.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Br)n2)CC1
Temperature: 20 °C
Yield: 92.8 %

Procedure:
2-bromothiazole-4-carboxylic acid (1.31 g, 6.3 mmol) was combined with tert-butyl piperazine-1-carboxylate (1.2 g, 6.3 mmol) in DCM (15 mL), and then stirred at 20° C. until it formed a clear solution. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.2 g, 6.3 mmol) was then added, and the reaction was stirred at 20° C. for 2 hours. The reaction was concentrated in vacuum, before transferring it to a separation funnel with ethyl acetate. The organic layer was washed with saturated NaHCO3, water, NH4Cl, and then with brine. After drying the organic layer with MgSO4, it was concentrated in vacuum to yield compound 72 (2.2 g, 91%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (1H, s), 3.61 (4H, m), 3.38 (4H, m), 1.42 (9H, s) ppm; LCMS-ESI (POS), M/Z, M+1−C3H9: Found 320.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:14][O:12][CH3:13]
Reactant: CON
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(Cl)c(Cl)c1

Procedure:
Reaction of 3,4-dichlorobenzaldehyde with methoxylamine hydrochloride followed by reduction with sodium cyanoborohydride as described in the preparation of compounds 3-A and 3-B gave the title hydroxylamine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s), 3.99 (2H, s), 5.74 (1H, broad s), 7.20 (1H, dd, J=2.0 Hz and J=8.1 Hz), 7.40 (1H, d, J=8.1 Hz), 7.47 (1H, d, J=2.0 Hz).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[O:18][CH:17]=[CH:16][C:15]=12)=[O:9].CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].CC(=O)OCC.CCCCCCC>CN(C=O)C.CC(=O)OCC>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([N:2]1[CH2:5][CH2:4][C@H:3]1[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[O:18][CH:17]=[CH:16][C:15]=12)=[O:9])=[O:33]
Reactant: COc1ccccc1C(=O)Cl
Reactant: O=C(NC[C@@H]1CCN1)c1cccc2occc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: COc1ccccc1C(=O)N1CC[C@H]1CNC(=O)c1cccc2occc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
To a cold (5° C.) solution of (2S)-benzofuran-4-carboxylic acid-(azetidine-2-ylmethyl)-amide hydrochloride (10 mg), DIEA (0.015 mL) in dry DMF (0.1 mL), was added portionwise 2-methoxy-benzoyl chloride (7.35 mg). The reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EA, washed with water. The organic extract was dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EA/n-heptane: 1/1) gave 7.3 mg (46%) of the title compound as a solid. LC-MS: rt=0.76 min, 365 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:18]=[C:19](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[N:11]1([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:19](=[O:18])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N2CCOCC2)cc1C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(N3CCOCC3)cc2c(=O)o1

Procedure:
To the mixture of 8.9 g of 2-amino-5-(morpholin-4-yl)benzoic acid in 60 mL of dioxane, under stirring and external cold water cooling 10 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 mL of ether. The product is stirred for 5 minutes in the mixture of 50 mL of methanol and 5 mL of triethylamine, it is filtered off and washed with 30 mL of methanol. After drying 7 g of the title product is obtained, m.p.: 235° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[C:25]([CH3:34])=[CH:24][CH:23]=2)[C:4]([S:7][CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[Cl:21])=[O:10])=[N:5][N:6]=1.BrC1N(C2C3C(=CC=C(OC)C=3)C(C)=CC=2)C(S[CH2:42][C:43](NC2C=CC(C(O)=O)=CC=2Cl)=O)=NN=1.O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[C:25]([CH:34]3[CH2:43][CH2:42]3)=[CH:24][CH:23]=2)[C:4]([S:7][CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[Cl:21])=[O:10])=[N:5][N:6]=1
Reactant: COc1ccc2c(C)ccc(-n3c(Br)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Reactant: COc1ccc2c(C)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C3CC3)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 10 (100 mg, 0.32 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (11) (79 mg, 0.32 mmol) were dissolved in DMF (2 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added to the mixture and the precipitate formed collected to give the crude 4-[2-(5-amino-4-[4-cyclopropyl-7-methoxynaphthalen-1-yl]-4H-1,2,4-triazol-3-ylthio)acetamido]-3-chlorobenzoic acid (12) which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=O)[S:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:26]1[S:27][CH:28]=[C:24]([Br:23])[CH:25]=1)/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1cc(Br)cs1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1
Yield: 67.9 %

Procedure:
The title compound was prepared according to the method of Example 94a, employing N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (10.0 g, 30.2 mmol), 4-bromothiophene-2-carbaldehyde (7.52 g, 39.4 mmol), and DBU (5.34 g, 35.1 mmol) in dry dichloromethane (200 mL). Recrystallization from 4:1 (v/v) hexane/ethyl acetate afforded the title compound (8.13 g, 20.5 mmol, 68%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.71 (s, 3H), 5.12 (bs, 2H), 7.10-7.51 (bm, 5H), 7.59 (s, 1H), 7.71 (s, 1H), 7.87 (s, 1H), 8.98 (bs, 1H). MS APCI, m/z=354, 352. LC/MS: 2.53 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[NH:16][CH:17]=[C:18]([C:19]#[N:20])[C:13]3=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].[C:21]([C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[C:31](=[O:36])[N:30]([C:37]1[C:45]3[CH2:44][O:43]B(O)[C:41]=3[CH:40]=[CH:39][CH:38]=1)[N:29]=[CH:28]2)([CH3:24])([CH3:23])[CH3:22].N1C=CC=CC=1.[NH4+].[Cl-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCCl>[C:21]([C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[C:31](=[O:36])[N:30]([C:37]1[C:45]([CH2:44][OH:43])=[C:41]([N:16]3[C:14]4=[N:15][C:10]([C:7]5[CH:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=5)=[CH:11][CH:12]=[C:13]4[C:18]([C:19]#[N:20])=[CH:17]3)[CH:40]=[CH:39][CH:38]=1)[N:29]=[CH:28]2)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Reactant: CCOc1ccc(-c2ccc3c(C#N)c[nH]c3n2)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOc1ccc(-c2ccc3c(C#N)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)cn1
Temperature: 45 °C
Reaction time: 48 h
Yield: 14.7 %

Procedure:
In a 25 mL round-bottomed flask, 6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (110 mg, 416 μmol, Eq: 1.00), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (161 mg, 458 μmol, Eq: 1.10) and copper acetate (102 mg) were combined with 1,2-Dichloroethane (3 ml) to give a blue suspension. Pyridine (65.8 mg, 67.3 μl, 832 μmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. The reaction mixture was poured into 20 mL sat NH4Cl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM) then by SFC to give 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (36 mg, 15%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33]>>[CH3:33][C@H:28]1[N:27]([CH3:26])[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: C[C@@H]1CNCCN1C
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)[C@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.53 (m, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (br. s., 3 H) 2.93-4.70 (m, 7 H) 7.63 (d, J=7.07 Hz, 1 H) 7.71-7.80 (m, 1 H) 7.88-8.77 (m, 4 H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:30]3[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]3=[O:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 4 g of ethyl 2-(3-p-bromophenylureido)thiazol-4-ylglyoxylate, 2 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 50 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH:37]=O)([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:37][CH2:36][NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:39])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
To a solution of 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.378 g, 1.00 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (0.159 g, 1.00 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.223 g, 1.05 mmol). The mixture was stirred at room temperature for 15 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (98:1:1 CH2Cl2—CH3OH—NH4OH) provided 499 mg (96%) of 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a yellow foam. 1H NMR (CDCl3) δ 1.48 (s, 9 H), 1.64 (s, 9 H), 1.69-1.85 (m, 2 H), 1.94-1.99 (m, 1 H), 2.24 (m, 1 H), 2.61-2.87 (m, 3 H), 3.09-3.19 (m, 3 H), 4.07 (dd, J=9.9 Hz, 5.7 Hz, 1 H), 4.26 (d, J=16.2 Hz, 1 H), 4.52 (d, J=16.2 Hz, 1 H), 6.98 (dd, 1H, J=7.7 Hz, 4.7 Hz, 1 H), 7.26-7.32 (m, 3 H), 7.57 (brs, 1 H), 7.74 (m, 1 H), 7.86 (m, 1 H), 8.41 (d, J=3.9 Hz, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7](=[O:25])[C@@H:8]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[Li+].[OH-].C(O)(=O)C>C1COCC1.CO>[C:17]([NH:16][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7](=[O:25])[CH2:6][CH2:5][C:4]([OH:26])=[O:3])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a stirred solution of ethyl-(5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoate (0.300 g, 0.8489 mmol, 1.0 eq) in THF-MeOH (8:2 ratio)(10 mL) was added 0.5N LiOH (10 mL) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then neutralized with glacial acetic acid and then extracted with EtOAc (3×25 mL). The organic extract was dried over anhydrous MgSO4 and evaporation of the solvent afforded a crude yellow residue. Column chromatography on silica gel elution with 100% EtOAc afforded (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoic acid 4 as a white solid (0.232 g, 82%): mp 143-146° C. (lit.12 mp 142-143° C.); Rf 0.25 (EtOAc); IR (KBr) ν 1685 (CO), 1760 (CO), 3150 (COOH) cm−1; 1H NMR (400 MHz, CDCl3) δH 2.48 (2H, t, J=6.8 Hz, —CH2CO), 2.72 (2H, t, J=7.0 Hz, —CH2CO), 2.97 (1H, dd, J=6.4 and 14.4 Hz, —CHαPh), 3.18 (1H, dd, J=6.4 and 14.4 Hz, —CHβPh), 3.81 (2H, br s, —NH and —COOH), 4.87 (1H, t, J=6.8 Hz, —CH—) and 7.05-7.65 (10H, m, Ar—H); 13C NMR (100 MHz, CDCl3) δC 27.5, 34.9, 36.4, 59.5, 126.8, 126.9, 127.9, 128.4 (2C), 128.5 (2C), 129.1 (2C), 131.7, 133.5, 136.3, 167.9, 174.6 and 207.5; HRMS m/z calcd for C19H19NO4 (M+) 325.12854, found 353.13141.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[CH:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.Cl.Cl.[CH:49]([N:52]1[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]1)([CH3:51])[CH3:50]>CN(C=O)C>[CH:49]([N:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[O:23])[CH2:54][CH2:53]1)([CH3:51])[CH3:50]
Reactant: O=C(O)c1cc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2cc3cccnc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.135 g (0.4 mmol) of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, 0.432 g (3.8 mmol) of NEM and 135 mg (0.4 mmol) of TOTU were dissolved in 3 mL of DMF and stirred at RT for 20 min. 89 mg (0.4 mmol) of 1-Isopropyl-piperidin-4-ylamine dihydrochloride salt was added to the reaction solution and stirred at RT for 4 h. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15].ClCCl.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([OH:29])(=[O:1])=[O:28].[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15]
Reactant: CS(=O)(=O)Cl
Agent: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred solutions of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane are added 11.9 parts of N,N-diethylethanamine. Then there are added dropwise (slowly) 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washeed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone, yielding 15 parts (58%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate; mp. 125° C.