Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:15])[CH:9]=[N:8]1.Br[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([Cl:42])[CH:36]=1>CN(C=O)C.CCOC(C)=O>[Cl:42][C:37]1[CH:36]=[C:35]([CH:40]=[C:39]([F:41])[CH:38]=1)[O:34][CH2:33][CH2:32][N:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:15])[CH:9]=[N:8]1
Reactant: Fc1cc(Cl)cc(OCCBr)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Cesium carbonate (98 mg, 0.30 mmol) was added to a solution of (E)-tert-butyl (2-(3-(1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (100 mg, 0.30 mmol) in anhydrous DMF (4 mL). A solution of 1-(2-bromoethoxy)-3-chloro-5-fluorobenzene (76 mg, 0.30 mmol) in DMF (1 mL) was then added and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. It was diluted with EtOAc (30 mL) and washed with water (2×40 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The evaporated crude was purified by silica gel column chromatography using a gradient of 0-100% of EtOAc in hexanes to provide 144 mg of (E)-tert-butyl (2-(3-(1-(2-(3-chloro-5-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. MS: ES+(M+Na)+: 523
Reaction SMILES: [CH:1]1([C:6]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na]>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:10][CH2:9][CH:8]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCC(C(=O)C1CCCC1)c1ccccc1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCC2)c2ccccc2)CC1
Yield: 66.9 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde (1.36 mmol) and 1-(2-methoxyphenyl)piperazine (1.49 mmol) with sodium triacetoxyboranehydride (1.77 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazine (370 mg) in 67% yield. The di-hydrochloric acid salt was prepared as described above. m.p.=210-212° C.; MS (m/e): 406 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cccs4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3cccs3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
After a mixture of ethyl 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (653 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2.5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (545 mg, yield: 88%). This was recrystallized from ethanol-hexane. Melting point: 104–105° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5](N)=[C:4]([CH3:12])[CH:3]=1.N([O-])=O.[Na+].C(Cl)Cl.[BrH:20]>O>[Br:20][C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)cc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A suspension of 4-fluoro-2-methyl-6-nitroaniline (5.1 g, 30 mmol) in water (38 mL) and aqueous HBr (15 mL, 40%) was refluxed for 10 minutes and then cooled to 0° C. A solution of NaNO2 (2.07 g, 30 mmol) in H2O (12 mL) was added dropwise at a temperature <10° C. The diazonium solution was stirred for 30 minutes at a temperature of 0° C. to 5° C. and was then added slowly to a stirred mixture of CuBr (4.33 g, 30 mmol) in aqueous HBr (12 mL, 40%) and water (23 mL) at RT. The mixture was stirred at RT for 30 minutes and then on a steam bath for 1 hour. The reaction mixture was cooled to RT, DCM (50 mL) was added, and the mixture was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography, eluting with petroleum ether to give the title compound as an oil (2.0 g, 28%). 1H NMR (400 MHz, CDCl3) δ ppm 7.23 (1H, dd, J1=2.4 Hz, J2=7.2 Hz), 7.14 (1H, dd, J1=2.8 Hz, J2=8.8 Hz), 2.44 (3H, s).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C@H:16]([C:24]([OH:26])=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.[CH3:28][NH:29][O:30][CH3:31].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:31][O:30][N:29]([CH3:28])[C:24](=[O:26])[C@@H:16]([NH:15][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 81.2 %

Procedure:
Triethyl amine (40 g, 0.4 mol) was added to a suspension of Boc-L-phenylalanine (90 g, 0.34 mol) and N,O-dimethylhydroxylamine hydrochloride (36.5 g, 0.37 mol) in DCM (500 mL) at 0° C. with stirring. The suspension was stirred for 10 min and EDCI (HCl salt, 72 g, 0.37 mol) was added. The suspension was stirred for further 3 hours at 0° C. The mixture was quenched with saturated aqueous NaHCO3 (1 L). The layers were separated, and the aqueous phase was re-extracted with DCM (500 mL×3). The combined organic phases were washed with water (1 L×3), 5% KHSO4 aqueous (1 L×3), saturated aqueous NaHCO3 (1 L×3), and brine (1 L×1), was dried (Na2SO4), and was concentrated to dryness. The crude material was further purified by flash chromatography (silica gel, EtOAc/Hexane=1:1) and afforded (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-ylcarbamate (85.1 g, 81% yield) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.1-57.26 (m, 5H), 5.25 (bs, 1H), 4.95 (m, 1H), 3.63 (s, 3H), 3.14 (s, 3H), 2.83-3.07 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:11]3[C:12](=[O:16])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]2[S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])(=[O:27])=[O:26])=[CH:4][CH:3]=1.C1C(=O)N([I:43])C(=O)C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:11]3[C:12](=[O:16])[C:13]([I:43])=[CH:14][CH:15]=[C:10]3[N:9]2[S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])(=[O:27])=[O:26])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(S(=O)(=O)N2c3cccc(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Reactant: O=C1CCC(=O)N1I
Product: N#Cc1cccc(S(=O)(=O)N2c3ccc(I)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1

Procedure:
The titled compound was prepared according to general method B by reaction of rac-3-[cis-2,3-Bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile with NIS.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:7]=2[CH:21]=1>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH2:1])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:7]=2[CH:21]=1
Reactant: Fc1ccccc1C1=NCC(=S)Nc2ccc(Cl)cc21
Reactant: N
Solvent: C1CCOC1
Product: NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Yield: 87 %

Procedure:
800 ml of aqueous ammonia solution (25%) were added to a solution of 27.6 g of 7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester jr., A. D. Rudzik and B. V. Bharat, J.Med. Chem., 1971, 14, 1078-1081) in 900 ml of tetrahydrofuran and the mixture was stirred intensively at room temperature for 72 h. The separated organic phase was concentrated in a vacuum to about 50 ml and the crystals which thereby separated were filtered off. Drying was carried out in a vacuum at 50° C., firstly over calcium chloride, then over phosphorus pentoxide. There were obtained 22.8 g (87%) of 7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamine as a pale yellow crystalline powder of m.p. 248-249° C. (dec.) which was used without further purification for the steps described below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[CH2:10][S:11][CH3:12])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[CH2:10][S:11]([CH3:12])=[O:19])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC(C)Cc1ccc(Cl)nc1
Solvent: ClCCl
Product: CC(Cc1ccc(Cl)nc1)CS(C)=O
Yield: 91.8 %

Procedure:
To a stirred solution of 2-chloro-5-[2-methyl-3-(methylthio)propyl]-pyridine (2.60 g, 12.5 mmol) in CH2Cl2 (35 mL) cooled to −15° C. in an ice-salt bath was added m-chloroperoxybenzoic acid (mCPBA, ˜85%, 2.54 g, ˜12.5 mmol) portion wise at such a rate that the temperature never rose above −10° C. After the addition was over, TLC showed that a single product plus a small amount of starting material was present in the solution. To avoid any sulfone formation, the reaction was quenched at this point by the addition of saturated NaHCO3 (50 mL). The organic layer was separated and the aqueous phase washed with CH2Cl2 (25 mL). The combined organic layers were dried over MgSO4 and the solvent was evaporated to give 2.66 g of crude product as a yellow oil. The oil was triturated with hot hexane (50 mL) and the hexane decanted after cooling. This procedure removed most of the starting material and the resulting product (a mixture of two diastereomers) was directly used for the following step without further purification. [M+H]+=232, 234; δ 1.09 (overlapping d, 3H), 2.57, 2.59 (2 s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Cl[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[O:18][N:17]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[O:18][N:17]=1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1noc(C)c1-c1nc(Cn2c(C)cc3c(Cl)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1 H), 7.81 (d, J=8.5 Hz, 1 H), 7.58 (d, J=8.5 Hz, 1 H), 5.81 (s, 2 H), 3.30 (s, 3 H), 2.66 (s, 3 H), 2.39 (s, 3 H); MS (ES) m/z 368 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.C(OC([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)=O)(C)(C)C>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:31]2[CH:32]=[N:28][NH:29][CH:30]=2)[N:3]=1)[CH3:11]
Reactant: C[C@@H](Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: C[C@@H](Oc1nc(-c2cn[nH]c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 3 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.79 (s, 1H), 7.48 (m, 1H), 7.36 (t, 1H), 6.48 (q, 1H), 6.12 (s, 2H), 1.75 (d, 3H); LCMS: 368 [M+1]; c-Met Ki: 0.065 μM.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][CH:3]1[OH:15].[OH-].[Na+].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.O>[OH:15][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH:2]1[NH:1][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][CH:20]=1)=[O:25]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC1c2cc([N+](=O)[O-])ccc2CCC1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1c2cc([N+](=O)[O-])ccc2CCC1O)c1ccc(-c2ccccc2)cc1

Procedure:
Stir a mixture of 1-amino-7-nitro-1,2,3,4-tetrahydronaphthalen-2-ol (500 mg, 2.40 mmol) and 1N NaOH (4.8 mL, 4.8 mmol) in a mixture of 50 mL of toluene and 50 mL of water for 30 minutes. Added biphenyl-4-carbonyl chloride (570 mg, 2.64 mmol) slowly and stir for four hours at room temperature. Remove the solid by filtration, and wash with toluene. Evaporate solvent under reduced pressure. Biphenyl-4-carboxylic acid (2-hydroxy-7-nitro-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide is obtained in 54% as a white solid: 1H NMR (DMSO-d6) δ 8.87 (1H, d, J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz), 7.99 (2H, d, J=7.6 Hz), 7.79 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz), 7.50 (2H, t, J=7.2 Hz), 7.43(2H, t, J=6.8 Hz), 5.22 (1H, d, J=4.4 Hz), 5.11 (1H, t, J=7.6 Hz), 3.95-4.01 (1H, m), 2.87-3,07(2H, m), 2.08-2.15 (1H, m), 1.81-1.94 (1H, m); MS 389(MH+). The above compound (0.25 g, 0.64 mmol) is reduced in 10 mL of DMF with 48 mg of 10% Pd-C at room temperature under 60 psi (414 kPa) for overnight to form biphenyl-4-carboxylic acid (7-amino-2-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, obtained in 96% as a yellow oil. MS 359 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2.[CH2:17]([S:33](Cl)(=[O:35])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>N1C=CC=CC=1>[CH2:17]([S:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2)(=[O:35])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: Nc1ccc2[nH]c(-c3ccccc3)cc2c1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20.8 g of 5-amino-2-phenylindole are dissolved in 200 ml of pyridine, and 32.45 g of hexadecylsulfonyl chloride are added. After stirring for 2 hours at room temperature, a precipitate is obtained by the addition of water. The precipitate is suction filtered and washed with water. It is then stirred into methanol in the cold, suction filtered and recrystallized from ethanol with the addition of a saturated aqueous sodium dithionite solution. The precipitate is suction filtered, washed with water and a little methanol and dried. 47.4 g of the above mentioned compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12]O)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].S(Cl)([Cl:16])=O>>[Cl:16][CH2:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Product: COc1cc(CCl)ccc1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
A mixture of (3-methoxy-4-nitrophenyl)methanol (0.5 g, 2.73 mmol) and thionyl chloride (0.3 mL, 4.09 mmol) was heated at reflux for 12 h. then the mixture concentrated in vacuo to afford 0.55 g of 4-(chloromethyl)-2-methoxy-1-nitrobenzene, (yield: 100% yield) which was used in further chemistries without purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27](O)=[O:28])=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[NH2:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:39]=[CH:40][CH:41]=1>>[C:43]([NH:42][C:38]1[CH:37]=[C:36]([NH:35][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:41]=[CH:40][CH:39]=1)(=[O:45])[CH3:44]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Reactant: CC(=O)Nc1cccc(N)c1
Product: CC(=O)Nc1cccc(NC(=O)c2cccc(NC(=O)N3CCc4c(cnc5[nH]ncc45)C3)c2)c1

Procedure:
The compound N-(3-{[3-(acetylamino)phenyl]carbamoyl}phenyl)-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid and N-(3-aminophenyl)acetamide as described in general procedure J. The compound was obtained as a solid. LCMS [M+H]: 470.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2COCC[Si](C)(C)C)=[C:7]([O:22][CH2:23][CH:24]2[CH2:28][O:27]C(C)(C)[O:25]2)[CH:6]=1.O.Cl>CO>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[C:7]([O:22][CH2:23][CH:24]([OH:25])[CH2:28][OH:27])[CH:6]=1
Reactant: CC1(C)OCC(COc2cc(Oc3ccc(F)cc3F)cc3c2cnn3COCC[Si](C)(C)C)O1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCC(O)COc1cc(Oc2ccc(F)cc2F)cc2[nH]ncc12
Temperature: 90 °C
Yield: 86.7 %

Procedure:
6-(2,4-Difluoro-phenoxy)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (0.905 g, 1.79 mmol) was dissolved in 20 mL of MeOH. Water (12 mL) and concentrated HCl (12 mL) were added, and the reaction mixture was sealed and heated to 90° C. for 30 minutes. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was taken up in MeOH, made pH neutral by dropwise addition of aqueous NH4OH solution, and concentrated to dryness under reduced pressure. The residue was chromatographed through silica (0%-1 0% EtOAc in hexanes) to give 0.522 g of 3-[6-(2,4-difluoro-phenoxy)-1H-indazol-4-yloxy]-propane-1,2-diol, MS(M+H)=337.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17](Cl)[O:18][CH3:19]>CC(C)=O>[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11]
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(C=O)c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Oven-dried potassium carbonate (1.38 g, 10 mmol) was added to an ice cooled solution of 2,4-dihydroxy-benzaldehyde (1.38 g, 10 mmol) in 10 mL of acetone. MOMCl (1.54 mL, 20 mmol) was added drop-wise and the mixture was stirred at 0° C. for one hour, after which it was gradually allowed to come to RT. The reaction was further stirred for 24 hours at RT and then poured into ice water with vigorous stirring. A Buff colored solid precipitated. The solid was filtered, dried and recrystallized from MeOH:DCM (ca. 30:5 mL) to obtain 1.31 g (72%) of white solid: mp 52-53° C. [Lit.(65) 50-51° C.]; TLC Rf0.43 in hexanes:EtOAc (2:1), 1H NMR (400 MHz, CDCl3) δ 11.38 (s, 1H, OH), 9.74 (s, 1H, CHO), 7.46-7.44 (d, 1H, J=8.4 Hz, Ar—H6), 6.66-6.64 (dd, 1H, 2J=8.4 Hz, 3J=2 Hz, Ar—H5), 6.60 (d, 1H, 3J=2 Hz), 5.24 (s, 2H, O—CH2—O), 3.48 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3) δ 194.8, 164.5, 164.4, 135.6, 116.2, 109.3, 103.6, 94.3, 56.7.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:5])C>[OH-].[Na+].CO>[C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 6 h

Procedure:
1-(2-Ethoxycarbonylpropanoyl)-L-proline (4.1 g.) is dissolved in a mixture of N sodium hydroxide (51 ml.) and methanol (51 ml.). The solution is kept at room temperature for 6 hours and then concentrated to half volume in vacuo. Ion exchange resin (Dowex 50) (50 ml.) is added and the suspension applied to a column of 150 ml. of the same resin. The fractions containing the desired material (carboxyl reaagent positive) are pooled and freeze dried to obtain 1-(2-carboxypropanoyl)-L-proline, yield 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[N:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[NH2:10].N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:26](=[O:27])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[N:11]=1
Reactant: O=C(Cl)Cl
Reactant: NC(=NNc1ccc(I)cc1)c1c(F)cccc1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Yield: 41.7 %

Procedure:
The title a compound was prepared according to the procedure described in step-4 of Intermediate-1 using 2-chloro-6-fluoro-N′-(4-iodophenyl)benzene carbohydrazonamide (0.900 g, 2.31 mmol), pyridine (0.65 mL, 5.79 mmol), phosgene (2.50 mL, 4.63 mmol) and CHCl3 (20 mL). The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.400 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.47 (t, J=9.0 Hz, 2H), 7.54-7.82 (m, 5H), 12.62 (s, 1H). MS (m/z): 414.25 (M−H)−.