Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[C:16](=S)=[S:17]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:16]([SH:17])=[N:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NNC(=O)c1ccc2occc2c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(-c2ccc3occc3c2)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a solution of 1-benzofuran-5-carbohydrazide (1.50 g, 8.51 mmol) in ethanol (60 mL) were added potassium hydroxide (0.72 g, 12.8 mmol) and carbon disulfide (15.3 mL, 25.5 mmol), and the resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, a mixture of the residue and N,N-dimethylformamide (30 mL) was tightly sealed in a vial, and the microwave was irradiated at 150° C. for 1 min. After cooling, the reaction mixture was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (0.66 g, yield 36%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][N:6]=2.[C:20](N1C=CN=C1)(N1C=CN=C1)=[S:21]>O1CCCC1>[SH:21][C:20]1[NH:1][C:2]2[C:3](=[O:19])[N:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]3[N:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:11]=2[N:12]=1
Reactant: Nc1c(N)c2cccnc2n(-c2ccccc2)c1=O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1c2[nH]c(S)nc2c2cccnc2n1-c1ccccc1
Yield: 47.3 %

Procedure:
Compound 102 (2.0 g, 7.9 mmol) was then suspended in 80 ml of tetrahydrofuran, and 2.3 g (13 mmol) of thiocarbonyldiimidazole was added to the suspension. The mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was triturated with ethanol. The formed crystals were taken by filtration. Recrystallization from DMF gave 1.1 g (yield 47%) of Compound 20 as colorless crystals.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]=2[OH:26])[N:14]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2CCc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(CCc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-chloro-7-cyano-4-hydroxy-1-phenethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 399 (M+H)+.
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:7])[CH:18]=[CH:17][CH:16]=2
Reactant: C#CCCCC(N)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(N)=O)c21

Procedure:
Using Method C above, 5-hexynamide (46 mg, 0.4 mmol) (prepared from 5-hexynoic acid by Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (113 mg, 0.31 mmol) using (Ph3P)2PdCl2 (12 mg) and Cul (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynamide. (Yield 52 mg, 48%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.O1CCCC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Temperature: 25 °C
Yield: 73207.6 %

Procedure:
To an ice-cooled solution of D-valine (50.5 g, 0.43 mol) and triethylamine (145 mL, 1.034 mol) in a 1:1 mixture of tetrahydrofuran and water (350 mL) was added 4-methoxybenzenesulfonyl chloride (88.2 g, 0.43 mmol). The reaction mixture was stirred and allowed to warm to room temperature overnight. The volatile organics were removed and the aqueous phase was extracted with diethyl ether. The aqueous phase was acidified to pH 3 with 10% hydrochloric acid and the product was extracted into ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, and then concentrated to give 2(R)-(4-methoxy-benzenesulfonylamino)-3-methylbutyric acid as a white solid (90.45 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1.[ClH:23].CC[O:26]C(C)=O>>[OH2:26].[ClH:23].[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3nc(-c4ccccn4)cc-3[nH]2)CCN1
Agent: Cl
Product: O

Procedure:
Using the method described in Example 30 by employing 2-(1-pyrrolidinylvinyl)-2-pyridine (freshly prepared before use) (2.20 g, 12.6 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.61 g, 12.6 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (2.2 mL, 12.6 mmol), piperidine (2.0 mL, 20.2 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (Aldrich Chemical Company) (38 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 650 mg (18%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.66 (s, 6), 2.42 (s, 3), 3.74 (s, 4), 7.01 (br s, 1), 7.37 (br s, 1), 7.90 (br s, 1), 8.08 (d, 1, J=7.9), 8.67 (br s, 1), 11.18 (s, 1). MS m/z: 294 (M+1). To a solution of 2-methyl-4-piperidyl-6-(2-pyridyl)pyrrolo[3,2-d]pyrimidine (0.65 g, 2.22 mmol) in-EtOAc (30 mL) was added 1N etheral HCl (Aldrich Chemical Company) (2.20 mL, 2.22 mmol). The precipitate was collected by filtration, washed with EtOAc (2×10 mL), ether (3×15 mL) and dried under vacuum to give 621 mg (85%) of the title compound as a brown colored solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (s, 6), 2.58 (s, 3), 4.06 (br s, 4), 7.16 (s, 1), 7.51 (dd, 1, J=7.4, 7.4), 8.01 (dt, 1, J=1.4, 7.6), 8.24 (d, 1, J=7.9), 8.76 (d, 1, J=4.4), 12.19 (s, 1), 14.36 (s, 1). MS m/z: 294 (M+1). Anal. Calcd. for C17H19N5.1.2HCl.0.4H2O: C, 59.18; H, 6.14; N, 20.30; Cl, 12.53. Found C, 59.23; H, 6.14; N, 20.03; Cl, 12.56.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 14 h
Yield: 87.4 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (1.5 g, 3.88 mmol), phenylboronic acid (0.710 g, 5.82 mmol), Pd(Ph3P)4 (0.449 g, 0.388 mmol) and aqueous Na2CO3 (3.88 mL, 7.77 mmol) in toluene (25 mL) is allowed to stir at 95° C. under nitrogen for 14 hours. The reaction mixture is cooled to room temperature and quenched with brine. The mixture is extracted twice with ethylacetate, and the combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (1.30 g); HPLC retention time=1.61 minutes (condition B); MS (ES+)=328.0 (m-tBu+2); 284.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3 H) 2.48 (A of ABX, Jab=16.1 Hz, Jax=5.9 Hz, 1 H) 2.53 (B of ABX, Jab=16.0 Hz, Jbx=5.3 Hz, 1 H) 2.83-3.00 (m, 2 H) 4.14-4.19 (m, 3 H) 5.06 (br s) 7.26-7.27 (m, 2 H) 7.31-7.35 (m, 2 H) 7.43 (t, J=7.6 Hz, 2 H) 7.52-7.58 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:15])[CH2:13]I)[CH3:10]>CN(C=O)C.O>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1)[CH3:10]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc(N)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
61.1 To a stirred mixture of 2.8 g 3-amino-1,2,4-triazole in 50 ml DMF, 1.57 g NaH were slowly added at 0° C. under an argon atmosphere. After 1 hr stirring at 0° C., 3.31 ml ethyliodoacetate were added. The reaction mixture was stirred at r.t. over night. The mixture was diluted with water and extracted with EtOAc and CH2Cl2/MeOH 9:1. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica, using a gradient from CH2Cl2 to CH2Cl2/MeOH 9:1 and then crystallization from cyclohexane/EtOAc to give 750 mg (3-amino-[1,2,4]triazol-1-yl)-acetic acid ethyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(N(CC)CC)C.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1>CN(C=O)C>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([NH:15][C:13]([NH2:14])=[N:12][C:10]([C:3]3[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=3)=[O:11])[CH2:17]2)[CH:33]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CCCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCC[C@H](NC(N)=NC(=O)c3nc(Cl)c(N)nc3N)C2)c1

Procedure:
A mixture of 1.17 g (4.5 mmol) 4-Aminomethyl-4-phenethyl-piperidine-1-carbocylic acid tert-butyl ester (intermediate 3), 1 mg (4.9 mmol) (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester and 125 μl triethylamin in 50 ml DMF/iso-propanol (1:3) is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure. Then 50 ml 25% TFA in dicholoromethane is added and the mixture is stirred for 2 h at room temperature and evaporated. The residue is treated with excess HCl in methanol and evaporated again to yield 430 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine. Step B: 100 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine, 125 μl triethylamine and 62 mg 3-bromomethyl-benzoic acid methyl ester in 3 ml DMF were stirred at room temperature for 6 h. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:5])C.O.[OH-].[K+].Cl>CO>[C:6]1([C:4]([OH:5])=[O:3])[CH:7]=[CH:8][N:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: CCOC(=O)c1ccn2c1CCCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn2c1CCCC2
Yield: 78.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ethyl ester (2b) (3.0 g, 15.5 mmol) in methanol (46 ml) was added water (23 ml) and potassium hydroxide (6.4 g, 97 mmol) and the mixture was stirred at reflux until complete conversion according to LC/MS (ca. 3 h). 160 ml water was added the mixture was acidified with excess hydrochloric acid. The forming precipitate was filtered off, washed once with water and dried in vacuo to give 2.02 g (79%) of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid as white solid. LC/MS (method 5; MS ionization method ES−): Rt=3.08 min; m/z=164.06 (M−H−).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].Br[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:26]=[C:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:24][C:23]=2[S:31]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])=[O:32])[CH:19]=[CH:20][CH:21]=1>CS(C)=O.C(Cl)Cl>[N:5]1([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:26]=[C:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:24][C:23]=3[S:31]([NH:34][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:32])=[O:33])[CH:19]=[CH:20][CH:21]=2)[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: O=C1CCC(=O)N1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2cccc(CN3C(=O)CCC3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of succinimide (66.6 mg, 0.672 mmol) in DMSO (1 mL) and t-BuOK (52.8 mg, 0.470 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (99.5 mg, 0.224 mmol; see step (e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent to give the sub-title compound in 94% yield as a colourless syrup (97.1 mg, 0.210 mmol).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13]([CH:22]=[O:23])=[CH:12][C:11]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.C1COCC1.[Ag-]=O>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:12][C:13]([C:22]([OH:1])=[O:23])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [OH-]
Reactant: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Agent: O=[Ag-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
At ambient temperature, to a stirred mixture of silver (I) oxide (0.570 g, 2.46 mmol) in H2O (9.8 mL) was added NaOH (0.983 g, 24.6 mmol) and the reaction was heated at 50° C. After 0.5 h, to the reaction was added a solution of 2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carbaldehyde (1.78 g, 4.92 mmol) in THF (9.8 mL) and the reaction was heated at 90° C. for 1h. To the reaction was added silver (I) oxide (0.570 g, 2.46 mmol), NaOH (0.983 g, 24.6 mmol) and H2O (10.0 mL). The reaction was heated at 90° C. for 16 h. The reaction was filtered through a celite pad, rinsing with hot H2O (3×). The filtrate was washed with ether (3×), acidified with 2N HCl (pH 2) and extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated to give 1.73 g (93%) of the title compound. 1H NMR (DMSO-d6) δ2.77-2.80 (m, 2H), 2.88-2.91 (m, 2H), 3.01 (s, 3H), 4.39 (s, 2H), 7.39-7.52 (m, 6H), 7.59-7.62 (m, 4H), 7.89 (s, 2H), 13.07 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (6.27 g, 46.1 mmol) and diisopropyl azodicarboxylate (DIAD, 9.24 g, 45.7 mmol) in dry THF (30 ml) was added drop wise to a solution of 3-Hydroxybenzonitrile (5 g, 37 mmol) and triphenylphosphine (TPP, 11.99 g, 45.7 mmol) in THF (100 ml) at 0° C. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed, diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1.C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1)(=[O:11])=[O:10]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared by adding 2,3-dichloro-benzenesulfonyl chloride (11.2 g) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (10.0 g) to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded 2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 15.11 g (77%).
Reaction SMILES: [O:1]=[C:2]1[CH:6](C(OCC)=O)S[C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]1=2.[OH:16][S:17]([OH:20])(=O)=O>>[O:1]=[C:2]1[CH2:6][S:17](=[O:20])(=[O:16])[C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]1=2
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C1Sc2ccccc2C1=O
Product: O=C1CS(=O)(=O)c2ccccc21
Yield: 90 %

Procedure:
A suspension of Compound X (130.0 g, 0.51 mol) in 350 ml of 10% aqueous H2SO4 was heated at reflux for 6 h (until gas evolution ceased). The reaction mixture was cooled and a white solid precipitated, which was collected by filtration and washed in cold water (30 ml). The product was recrystallized from ethanol to give 83.8 g (90%) of Compound Y as a white crystalline solid:melting point 133°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:41]Br>C(Cl)(Cl)Cl>[Br:41][CH2:15][C:14]([C:9]1[N:10]([CH3:13])[N:11]=[N:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nnn1C
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: Cn1nnc(-c2ccc(F)cc2)c1C(=O)CBr
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A solution of 1-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-ethanone (4.02 g, 18.34 mmol) was dissolved in chloroform (18 mL) and acetic (0.36 mL) was heated to reflux and then a solution of bromine (1.04 mL, 20.17 mmol) in chloroform (9 mL) was added dropwise within 10 min at and after 1 h bromine (0.10 mL, 2.02 mmol) was added and heated under reflux for 1 h. After cooling to room temperature the mixture was poured onto ice-water and the mixture extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (3.48 g, 63%) as a light red solid. MS: m/e=298.1/300.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+].O>CN(C)C=O.S1(CCCC1)(=O)=O>[CH3:1][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C)c[nH]c2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
A mixture of methyl 3-formyl-1H-indole-6-carboxylate (12.0 g), p-toluenesulphonic acid (2.0 g) and p-toluenesulphonylhydrazide (13.0 g) in a mixture of dimethylformamide (100 ml) and sulpholane (50 ml) was heated at 100° C. for 15 minutes and then cooled to room temperature. The mixture was treated with sodium cyanoborohydride (15.0 g, 5 g portions after 10 minute intervals), then heated at 100° C. for 2 hours. After cooling to ambient temperature the reaction mixture was treated with ice water (500 ml) giving a white precipitate. Water (1000 ml) was added and the mixture stirred for 30 minutes then filtered. The off-white solid was washed with warm water then azeotroped with toluene to yield the title compound (10.2 g) as a white solid.
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7](=[O:32])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]#[C:19][Si](C)(C)C)[C:11]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]1)[CH3:5].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:4]([O:6][C:7](=[O:32])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]#[CH:19])[C:11]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]1)[CH3:5]
Reactant: CCOC(=O)CCCc1cn(CC(=O)OCC)c2c(C#C[Si](C)(C)C)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C#Cc1cccc2c(CCCC(=O)OCC)cn(CC(=O)OCC)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ethanol (2 mL) solution of ethyl 4-{1-[2-(ethyloxy)-2-oxoethyl]-7-[(trimethylsilyl)ethynyl]-1H-indol-3-yl}butanoate (98 mg), potassium carbonate (50 mg) was added and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated to obtain the titled compound having the following physical properties (74 mg). Herein, ethyl 4-{1-[2-(ethyloxy)-2-oxoethyl]-7-[(trimethylsilyl)ethynyl]-1H-indol-3-yl}butanoate was prepared by the same operation as in Example 3, except for using ethyl 4-{7-bromo-1-[2-(ethyloxy)-2-oxoethyl]-1H-indol-3-yl}butanoate and ethynyl(trimethyl)silane.