Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:3]([CH:23]4[CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][CH2:22]4)[CH:2]([OH:1])[CH3:20])[CH2:9][CH2:8]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:3]([CH:23]4[CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][CH2:22]4)[CH:2]([OH:1])[CH3:20])[CH2:9][CH2:8]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: CC(O)C(C1CNc2ccccc2C1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MEOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].O[CH2:17][CH:18]([CH2:20]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:8]=[C:7]2[C:5]=1[N:6]=[CH:20][CH:18]=[CH:17]2)([O-:3])=[O:2]
Reactant: OCC(O)CO
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: O=[N+]([O-])c1cc(OC(F)(F)F)cc2cccnc12
Yield: 94.7 %

Procedure:
In a similar fashion using route 10 general procedure 20, 2-nitro-4-(trifluoromethoxy)aniline (1.0 g, 4.50 mmol), glycerol (1.3 g, 13.96 mmol) and 3-nitrobenzenesulfonic acid sodium salt (1.32 g, 5.85 mmol), gave the title compound (1.1 g, 95%) which was used in the next step without purification.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(F)F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(difluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.5 g) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:47][C:48](=[O:56])[C@H:49]([CH2:51][CH2:52][C:53](=[O:55])[NH2:54])[NH2:50])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:50][C@H:49]([C:48]([OH:56])=[O:47])[CH2:51][CH2:52][C:53](=[O:55])[NH2:54])=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 233 and L-glutamine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.00-12.89 (br.s, 1 H), 8.94 (s, 1 H), 8.13 (d, 1 H), 7.24 (m, 8 H), 6.98 (m, 7 H), 6.82 (d, 2 H), 6.73 (s, 1 H), 4.16 (m, 1 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 3.95 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.29 (t, 2 H), 2.12 (m, 2 H), 1.94 (m, 3 H), 1.74 (m, 1 H), MS (ESI+) m/z 703 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:24]2[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]2=[O:32])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([F:15])[CH:17]=2)[C:25]1=[O:32])=[O:30]
Reactant: COc1ccc(N2CCC(C(=O)O)C2=O)cc1F
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
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: COc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1F
Yield: 39.5 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.113 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 25% of ethyl acetate in dichloromethane) to give 0.072 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=C(OCCC3CCCCC3)C=C(Br)C=2)=CC=1C)C.C1(C#C)C=CC=CC=1.[CH2:40]([O:42][C:43](=[O:80])[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([S:52][C:53]2[CH:58]=[C:57]([C:59]#[C:60][C:61]3[CH:66]=[CH:65][C:64](CO)=[CH:63][CH:62]=3)[CH:56]=[C:55]([O:69][CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][C:75](Cl)=[CH:74][CH:73]=3)[CH:54]=2)=[CH:48][C:47]=1[CH3:79])[CH3:41]>>[CH2:40]([O:42][C:43](=[O:80])[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([S:52][C:53]2[CH:58]=[C:57]([C:59]#[C:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:56]=[C:55]([O:69][CH2:70][CH2:71][CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH:54]=2)=[CH:48][C:47]=1[CH3:79])[CH3:41]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCC3CCCCC3)c2)cc1C
Solvent: C#Cc1ccccc1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCC3CCCCC3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.58 mmol), phenylacetylen (181.1 mg; 1.8 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 110 mg (33%). HPLC-MS: m/z: 529.6 (M+H)+; Rt: 3.38 min.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:9][C:7]1[CH:8]=[C:3]2[C:4]([C:11]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=3[C:13](=[O:14])[O:15]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of methyl 2-(2,4-dimethoxyphenyl)-5-nitrobenzoate (Reference Compound No. 1-(1), 43.5 g, 137 mmol) in anhydrous methylene dichloride (250 mL) was cooled to −78° C., boron tribromide (96.2 g, 384 mmol) was added thereto, then the mixture was stirred at room temperature for 1 hour. The mixture was cooled to −50° C. and methanol (300 mL) was added thereto. The resulting precipitates were filtered off with methanol to give the titled reference compound (18.0 g) as a yellow solid. (Yield 51%)
Reaction SMILES: O.[N:2]1(O)C2C=CC=CC=2N=[N:3]1.Cl.C(N=C=NCCCN(C)C)C.[I:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=2)[N:27]([S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:26]=1.NN>CN(C=O)C>[I:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([NH:2][NH2:3])=[O:35])[CH:32]=2)[N:27]([S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.471 g, 3.07 mmol) (Aldrich), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.589 g, 3.07 mmol) (Sigma-Aldrich), and 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.13 g, 2.56 mmol) were weighed into a 100 mL round bottomed flask and dissolved in DMF (12 mL). The solution was stirred at RT for 30 min. Hydrazine (1.4 mL, 44.6 mmol) (Aldrich) was added, and the reaction was stirred at RT for 1.5 h. The solution was partially concentrated. The concentrate was diluted with H2O and a precipitate formed. The solid was collected by filtration, washed with H2O, and dried to give 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (0.802 g, 1.762 mmol, 68.8%) as a beige solid. MS (ESI, pos. ion) m/z: 455.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.15 (s, 1H), 7.97-8.02 (m, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.82-7.92 (m, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.52 (br. s., 1H), 2.33 (s, 3H).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[N:16][NH:15][C:14]1=[S:18].[Cl:19][C:20]1[CH:47]=[CH:46][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=[C:29]3[C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH:35]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[Cl:45][C:41]1[CH:40]=[C:39]([C:29]2[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=2)[CH:35]=[C:26]([C:24]([C:23]2[CH:46]=[CH:47][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:17]2[N:13]([CH3:12])[C:14]([SH:18])=[N:15][N:16]=2)[CH:27]=3)[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Reactant: Cn1cn[nH]c1=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(S)nnc1C(O)(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.4 %

Procedure:
nBuLi 1.6M in hexane (0.0086 mol) was added at −78° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0043 mol) in THF (25 ml) under N2 flow. The mixture was stirred at 0° C. for 1 hour, then cooled to −78° C. 8-(4-chlorobenzoyl)-6-(3-chlorophenyl)-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one (0.0024 mol) described in International Publication WO98/40383, was added portionwise. The mixture was stirred at room temperature for 4 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.38 g) was purified by column chromatography over silica gel (15-40 μm) (eluent: CH2Cl2/CH3OH/NH4OH97/3/0.1). The pure fractions were collected and the solvent was evaporated. A part of the residue (0.049 g) was purified by column chromatography over silica gel (10 μm) (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 0.018 g (1%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one, melting point: 193° C. (intermediate 13).
Reaction SMILES: [H-].[Na+].[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=1[CH3:17])([CH3:6])([CH3:5])[CH3:4].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1.Cl>O.C1COCC1>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:21]2[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)[C:11]=1[CH3:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: N#Cc1cnc(Cl)s1
Reactant: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1Nc1ncc(C#N)s1
Temperature: 25 °C

Procedure:
An oven dried flask under N2 was charged with NaH (60% dispersion, 210 mg, 5.25 mmol). 5 mL of anhydrous THF was added followed by 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-methyl-pyridin-2-ylamine (10-2, 0.602 g, 2.39 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.414 g, 2.86 mmol). The resulting solution was heated to reflux. After 19 hours additional NaH (19 mg, 0.48 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.069 g, 0.48 mmol) were added. After an additional 1 hour at reflux the reaction was allowed to cool to room temperature and diluted with water. The pH was adjusted to 7 with 1 M HCl. The resulting precipitate was filtered and washed with water to afford 10-3. 1H NMR (CDCl3) δ 8.41 (bs, 1H), 8.27 (d, 1H, J=5.2 Hz), 7.94 (s, 1H), 7.19 (d, 1H, J=5.2 Hz), 4.74 (s, 2H), 2.21 (s, 3H), 0.96 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:37])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[N:13]=[C:12]2[S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[N+]=[N-].CO>C1COCC1.[Pd]>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[C:15]2[C:11](=[CH:10][C:9]([F:37])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][NH2:1])[C:12]([S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:25])=[O:26])=[N:13]1
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of 7-(2-azido-ethoxy)-1-(3-chloro-benzyl)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.09 g, 0.17 mmoles) and 10% Pd/C in THF (5 mL), and methanol (15 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% CH3OH/CH2Cl2 to afford the title compound as an off-white solid (0.08 g, 0.14 mmoles), MS: (ES+) 511 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=1
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201 mg, 0.91 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (301 mg, 0.87 mmol) [Prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 14.95 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (519 mg, 1.11 mmol) in chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 45%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11](C(OC)=O)[NH:12][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)COCCOCCO>[CH2:1]([C:9]1[CH:10]=[CH:11][NH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)c2ccccc2)c[nH]1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: c1ccc(Cc2cc[nH]c2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
12.0 g (52.4 mmole) of methyl 4-benzoyl-2-pyrrolecarboxylate, 8.79 g (157 mmole) of potassium hydroxide and 10.5 g (210 mmole) of hydrazine hydrate are dissolved in 150 ml of triethylene glycol. Reaction is carried out by stirring the solution at 120° C. for 2 hours and then at 160° C. for 3 hours in the an atmosphere of nitrogen gas. After reaction is finished, the reaction solution is allowed to cool and poured into ice water, followed by extraction with ether. The extract is washed with water saturated with sodium chloride and concentrated. The residue is distilled under reduced pressure to obtain 5.86 g of 3-benzylpyrrole as a colorless liquid. Yield 71.2%. nD29.5 1.5790. Boiling point 95°-98° C. (0.09 mmHg).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[O:7])=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C.[OH-].[Na+].Cl>C(#N)C>[OH:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][CH:3]=1)=[O:24]
Reactant: COC(=O)CCCCCNC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(=O)c1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
To a solution of 2.81 g (10.64 mmol) of methyl 6-(4-aminobenzoylamino)hexanoate dissolved in 50 ml of acetonitrile, very slowly add 1.42 g (9.10 mmol) of 2-hydroxybenzoyl chloride dissolved in 5 ml of acetonitrile. Then add 0.92 g (9.10 mmol) of triethylamine and keep the reaction mixture at room temperature for 24 hours. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the solid has completely disappeared. Immediately acidify with concentrated hydrochloric acid, filter the resulting solid and wash several times with water. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.11 g (33%) of 6-[4-(2-hydroxybenzoylamino)benzoylamino]hexanoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:7]=1[Cl:22]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(N)c(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
Methyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (1.0 g, 3.22 mmol) and N-chlorosuccinimide (474 mg, 3.55 mmol) were dissolved in DMF (20 mL) and allowed to stir under an atmosphere of nitrogen for 24 h. The reaction was quenched with water and diluted with ethyl acetate (100 mL). The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column (5–20% ethyl acetate/hexanes) to afford the product as a clear oil (645 mg, 61%). 1H NMR (400 MHz, CD3OD): δ 7.05 (s, 1H), 6.90–6.87 (m, 1H), 6.76–6.74 (m, 1H), 4.27–4.23 (m, 1H), 3.68 (s, 3H), 2.97–2.92 (m, 1H), 2.78–2.72 (m, 1H), 1.39 (s, 9H); LCMS found for C10H14ClN2O2 (M+H)+: m/z=229.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:32]([CH2:31][N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)#[N:33]
Reactant: N#CCBr
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(CC#N)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (39 mg, 0.10 mmol), 2-bromoacetonitrile (8 uL, 0.12 mmol) and Potassium Carbonate (28 mg, 0.20 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4 and concentrated. The crude product was purified by reverse phase HPLC to give N-(5-(4-(cyanomethyl)piperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 175. MS m/z 427.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.37(d, 1H), 7.94(s, 1H), 7.87(d, 1H), 7.68(d, 2H), 7.55(s, 1H), 7.48-7.44(m, 3H), 7.36(dd, 1H), 3.74(s, 2H), 3.67(s, 2H), 3.17(t, 4H), 2.69(t, 4H), 2.54(s, 3H).