Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[C:61](B(O)O)[CH:60]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:61]2[CH:60]=[N:59][C:68]3[C:63]([CH:62]=2)=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Yield: 62 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-quinolinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (62%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH2:15][C:16](=O)[CH3:17])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:14][C:10]1[C:9]([CH3:15])=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1.[Cl:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]2[C:9]=1[CH:15]=[C:16]([CH3:17])[NH:7]2
Reactant: CC(=O)Cc1c(Cl)cccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N)cccc1Cl
Product: Cc1cc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 69 %

Procedure:
To a solution of the crude [3-Chloro-2-(2-oxo-propyl)-phenyl]-carbamic acid tert-butyl ester (5.21 g) in dichloromethane (180 ml) was added trifluoroacetic acid (20 ml). The reaction mixture was stirred at room temperature for 5 days and then partitioned between dichloromethane and 5% sodium bicarbonate solution. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give 4-Chloro-2-methyl-1H-indole and 3-Chloro-2-methyl-phenylamine as a mixture (2.6 g mixture, 69% yield of 4-Chloro-2-methyl-1H-indole). 1H NMR (CDCl3) d: 2.45 (s, 3H), 6.32-6.33 (m, 1H), 6.98-7.18 (m, 3H), 7.96 (bs, 1H), M−H: 164.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH:23][S:24]([C:27]1[C:32]2=[N:33][S:34][N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.COC(=O)[C@@H](NC(=O)C1C=CC(I)=CC=1N)CC1C=CC(Cl)=C(Cl)C=1.ClS(C1C2C(=NSN=2)C=CC=1)(=O)=O.N1C=CC=CC=1.NCCN(CCN)CCN>C(Cl)Cl>[N:35]1[S:34][N:33]=[C:32]2[C:27]([S:24]([NH:23][C:17]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=3[C:15]([NH:14][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=3)[C:3]([OH:37])=[O:2])=[O:36])(=[O:25])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1N
Agent: NCCN(CCN)CCN
Agent: O=S(=O)(Cl)c1cccc2nsnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester. To a solution of (S)-2-(2-amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (39 mg, 0.079 mmol) in DCM (1 mL) was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (37 mg, 0.158 mmol) and pyridine (30 μL, 0.371 mmol). The mixture was-shaken overnight at rt, then polymer bound tris(2-aminoethyl)amine resin was added. The resulting mixture was shaken for 2 h, and the resin was removed by filtration and rinsed with DCM. TBD methyl polystyrene resin was then added and the mixture was shaken for 2 h. The liquid was drained and the resin was washed with DCM (3×). A solution of 10% TFA in DCM (3 mL) was added to the resin and the mixture was shaken for 1.5 h. The resin was removed by filtration, washed with 10% TFA in DCM and the filtrate was concentrated to provide the desired product as a white solid (55 mg, 99%). 1H NMR (400 MHz, CDCl3): 11.10 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 8.02 (d, J=1.5, 1H), 7.75 (dd, J=8.8, 7.1, 1H), 7.37-7.32 (m, 2H), 7.16 (d, J=2.0, 1H), 6.96 (d, J=8.3, 1H), 6.92 (dd, J=8.2, 2.0, 1H), 6.67 (d, J=7.3, 1H), 4.96 (q, J=5.7, 1H), 3.83 (s, 3H), 3.20-3.12 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C(S)CC.C(O)(=O)C>CN(C=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Agent: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Temperature: 130 °C
Yield: 61.8 %

Procedure:
To a solution of 1-cyclopentyl-3-ethyl-6-(3-methoxyphenyl methyl)pyrazolo[3,4-d]pyrimidin-4-one (4.49 g, 13 mmol) in DMF (123 mL) was added 97% NaH (1.26 g), followed 20 minutes later by propanethiol (2.96 g, 39 mmol). The reaction mixture was heated at 130° C. overnight, cooled to room temperature and then ice water, followed by acetic acid were added. A precipitate formed which was collected by filtration, recrystallized from ether and dried at 110° C. and 2 mm Hg to afford 2.72 g of 1-cyclopentyl-3-ethyl-6-(3-hydroxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 195-197° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:16]3[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: c1cc(CN2CCNCC2)ccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.052 g, 0.25 mmol) and isopropanol (4.5 ml) was added 1-[(4-pyridyl)-methyl]-piperazine (0.049 g, 0.28 mmol) followed by diisopropylethylamine (0.05 ml, 0.28 mmol). The reaction mixture was heated at 45° C. for 24 h, then allowed to cool to room temperature, and diluted with isopropanol (3 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as yellow solid (0.035 g). The filtrate was concentrated in vacuo, and purification of the residue on a isolute silica column using 0 to 5% methanol in ethyl acetate/dichloromethane (v/v; 1:1) as eluant gave an additional 0.036 g of the product (total yield: 81%); 1H-NMR (500 MHz, DMSO-d6) 3.09 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.34 (d, J=5.81 Hz, 2H), and 8.51 (d, J=5.88 Hz, 2H) (pyrid-4-yl protons), 8.06 (s, 1H, 6-H);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1cccc2ccc(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc2ccc(Cl)nc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 8-methyl-1H-quinolin-2-one (107) (580 mg, 3.6 mmol) and phosphorus oxychloride (5 mL) was stirred at 60° C. overnight. The mixture was then poured onto ice water and extracted with DCM (3×50 mL). The combined extracts were washed with water (2×100 mL) and dried with Na2SO4, and the solvent was removed. The residue was chromatographed on silica gel using 5% to 20% EtOAc in petroleum ether to give product (108) as small colorless crystals (400 mg, 2.3 mmol, 63% yield).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C@H:6]([NH:20][C:21](=[O:29])[CH2:22][CH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.[OH-].[Na+].Cl>CCO>[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]([CH2:7][C@@H:6]([NH:20][C:21](=[O:29])[CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH2:5][C:4]([OH:30])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-butyric acid ethyl ester (137 mg, 0.297 mmol) in DCM (8 mL) at room temperature is added DBU (1.507 mL, 10.00 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction is extracted with DCM. The combined organic layer is washed with saturated NH4Cl, brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced. The obtained residue is purified by flash chromatography (silica gel, 2% to 10% EtOH/DCM) to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid ethyl ester (37 mg). To the obtained ester in EtOH (2 mL) at room temperature is added aqueous 1M NaOH (1 mL, 1.0 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction is added 1 mL of aqueous 1M HCl to pH=4, and the mixture is purified by reverse phase HPLC [30% to 60% acetonitrile-H2O (0.1% TFA)] to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid. HPLC retention time=1.24 minutes (condition C); MS (m+1)=380; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (dd, J=6.7, 2.1 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 2.69-2.82 (m, 2H), 3.02 (t, J=7.7 Hz, 2H), 4.17-4.29 (m, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.34 (tt, J=7.3, 1.3 Hz, 1H), 7.42-7.48 (m, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.64 (dd, J=8.2, 1.1 Hz, 2H), 8.00 (d, J=8.1 Hz, 1H), 12.21 (br. s., 1H), 15.92 (br. s., 1H). Chiral HPLC retention time=5.64 min. Column: Daicel CHIRALCEL OJ-H (4.6×100 mm); flow rate=1 ml/min.; eluent: EtOH (containing 0.1% TFA)/heptane=2/8.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13](C(OC(C)(C)C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2[nH]nc(NS(=O)(=O)c3ccc(Cl)s3)c12
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl 3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazole-1-carboxylate (for a preparation see Intermediate 6) (155 mg, 0.35 mmol) was dissolved in DCM (0.2 mL) and TFA (0.4 mL) was added. The solution was stood at room temperature for 30 min, and then blown down to dryness under a stream of nitrogen in a Radley's blow down unit to give the title compound (200 mg). LCMS (System D) RT=1.02 min, ES+ve m/z 344 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[O:12])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCNc1cccc(Br)c1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC(CCNc1cccc(Br)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-one (50 mg, 0.148 mmol) in 4:1 THF/methanol (5 mL) was cooled to 0° C. NaBH4 (11 mg, 2 equiv) was added. After 10 min, the mixture was warmed up to rt slowly and stirred for 2 h. The mixture was concentrated, diluted with EtOAc (7 mL), washed with 1% aq HCl (1 mL), and dried over Na2SO4. Filtration and concentration afforded crude 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-ol which was used without further purification. LC-MS (3 min) tR=1.93 min, m/z=342,343(M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17](Br)[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17]([C:27]#[N:28])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c3ccccc3n(-c3ccccc3)c2c1O
Product: CCOC(=O)c1nc(C#N)c2c3ccccc3n(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 105(a) from 1-bromo-4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 358 (M+H)+.
Reaction SMILES: [CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:2].[CH3:20]C(C)([O-])C.[K+].COS(OC)(=O)=O>O1CCCC1>[CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:20])=[O:2]
Reactant: Cc1ccsc1C(Cc1ccccc1O)N(C)C=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1ccccc1CC(c1sccc1C)N(C)C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To an ice-water chilled solution of 5.10 g of N-formyl-2-hydroxy-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 100 ml of tetrahydrofuran, was added 2.24 g of potassium t-butoxide and then a solution of 2.52 g of dimethylsulfate and 25 ml of tetrahydrofuran dropwise, with stirring. The mixture was stirred at ice-bath temperature for 30 min, at room temperature for one hr, and at reflux for 30 mins. Additional dimethylsulfate and potassium t-butoxide were added and the mixture was refluxed for 20 min. The reaction mixture was decanted into 40 ml of water and basified with 10% sodium hydroxide solution. The mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was combined with a previous sample. The combined residue was purified by preparative HPLC (Water Associates Prep LC/System 500, silica gel, material applied as a solution in dichloromethane, eluted with ethyl acetate-hexane (1:1, 200 ml/min flow rate). The appropriate fractions were combined and concentrated. The residue crystallized during refrigerated storage. Recrystallization from cyclohexane afforded 3.5 g of the product, mp 80°-83° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.C([CH2:13][C:14](=O)[C:15]([O-:17])=[O:16])C.[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[CH2:19]([O:17][C:15]([C:14]1[NH:9][C:4]2[C:5]([CH:13]=1)=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])=[O:16])[CH3:20]
Reactant: NNc1ccccc1Cl
Reactant: CCCC(=O)C(=O)[O-]
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2cccc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with ethylpyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give 7-Chloro-1H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water (3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7-Chloro-1H-indole-2-carboxylic acid (0.089 9). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N,N-diisopropylethylamine (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0.6 mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.56 9). 1H NMR (400 MHz, CDCl3): δ 9.17 (br s, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.21 (dd, J=7.6, 0.8 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 3.88 (br m, 4H), 2.45 (t, J=5.1 Hz, 4H), 2.29 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#N)=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:2]=1.CC(O)=[O:22].CN(C=O)C.[PH2]([O-])=O.[Na+]>N1C=CC=CC=1.O.[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:22])=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:2]=1
Reactant: N#Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Reactant: CC(=O)O
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a suspension of (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbonitrile (984 mg, 3 mmol) in pyridine (30 mL) was added HOAc (8 mL), followed by DMF (30 mL). The resulting mixture was heated and sonicated to make a clear solution. After cooling to 0° C., a solution of sodium hypophosphite (1.408 g, 16 mmol) in H2O (8 mL) was added, followed by Raney-Nickel 2400 (slurry in H2O, 0.8 mL). The resulting mixture was heated at 60° C. (oil temp.) for 1 h before cooling to rt. H2O (50 mL) was added and the mixture was extracted with EtOAc (100 mL+50 mL×2). The combined extracts were dried (Na2SO4). Removal of low boiling point solvents gave a yellow solution in DMF (30 mL); H2O (500 mL) was added with swirling and a yellow precipitate formed. After standing 10 min, the resulting precipitate was collected by suction filtration, rinsed with H2O and dried under high vacuum to give the title compound (500 mg, 50%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.90 (s, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H, partially overlapping with the singlet at 8.18 ppm), 8.18 (s, 1H, partially overlapping with the doublet at 8.19 ppm), 7.75 (d, J=16.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.59 (d, J=16.8 Hz, 1H), 7.43 (dd, J=8.0 Hz, 5.2 Hz, 1H); MS ESI 250.0 [M+H]+, calcd for [C15H11N3O+H]+ 250.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[CH3:24])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:31][CH:30]=[CH:29]2.O.[C:52]([OH:56])(=[O:55])[CH:53]=O>>[C:47]([O:46][C:44]([N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][CH:53]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:10](=[O:11])[NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)=[C:16]([CH3:24])[CH:17]=3)[C:52]([OH:56])=[O:55])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Reactant: O=CC(=O)O
Solvent: O
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1

Procedure:
Using a procedure analogous to that used to prepare 2D, 30D (420 mg, 1.30 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 30E (308 mg) as a tan solid. MS (ESI) m/z 696.15 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH:10]([N:8]1[CH2:9][CH:6]([N:26]2[CH2:25][CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]2)[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-yl methanesulfonate (26.53 g, 83.68 mmol), tert-butyl piperazine-1-carboxylate (18.68 g, 100.41 mmol) and K2CO3 (23.09 g, 163.36 mmol) in CH3CN (200 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to RT and diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (25.5 g, 80% yield).