Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([CH2:7][S:8][C:9]([CH3:40])([CH3:39])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][CH2:35][N:36]=[C:37]=[S:38])[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][S:22][C:20]([CH3:32])([CH3:21])[C:19]([NH:18][CH2:17][CH2:16][N:15]([CH2:34][CH2:35][NH:36][C:37]([NH:58][C:55]2[CH:56]=[CH:57][C:52]([O:51][CH3:50])=[CH:53][CH:54]=2)=[S:38])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]([CH3:40])([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:42][CH:41]=2)[CH3:39])=[O:33])=[CH:29][CH:28]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(CSC(C)(C)C(=O)NCCN(CCN=C=S)CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CSC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)CCNC(=S)Nc2ccc(OC)cc2)cc1
Yield: 87.7 %

Procedure:
A solution of the isothiocyanate 25 (18.9 mg, 0.02986 mmol), triethylamine (7.26 mg, 0.07175 mmol), anisidine (6.9 mg, 0.05602 mmol), and CHCl3 (15 mL) was refluxed for 3 hours and the solvent was removed in vacuo. Flash chromatography of this crude product using 100% EtOAc gave the anisidine derivative 26 as a clear oil (19.8 mg, 87.6% yield). 1H NMR (in CDCl3): δ8.17 (brs,lH,NH--CS--NH--Ar), 7.28 (d,j=8.8 Hz,2H,H2 &H6 --Ar--N), 7.15 (d,j=8.6 Hz,4H,2H3 &H5 --Ar--OCH3), 7.06 (brs,lH,NH--CS--NH--Ar), 7.06 (t,j=5.7 Hz,2H,2NH--CO), 6.90 (d,j=8.9 Hz,2H,H3 &H5 --Ar--N), 6.82 (d,j=8.6 Hz,4H,2H2 &H6 --Ar--OCH3), 3.79 (s,3H,CH3O--Ar--N), 3.77 (s,6H,2CH3O--Ar--CH2), 3.67 (s,4H,2S--CH2 -Ar), 3.61 (q,j=5.3 Hz,2H,N--CH2CH2 --NHCS), 3.14 (q,j=6.2 Hz,4H,2N-CH 2CH2 --NHCO), 2.69 (t,j=5.6 Hz,2H,N--CH2CH2 --NHCS), 2.52 (t,j=6.3Hz,4H 2N--CH2CH2 --NH--CO), 1.51 (br s,12H,4CH3 --C--S) ppm. 13C NMR (in CDCl3): δ181.9 (s,N--CS--N), 175.2 (s,2NH--CO), 158.8 (s,3C1 --Ar--OCH3), 130.0 (s,C1 --Ar--N), 130.0 (d,2C2 &C6 --Ar--OCH3), 129.2 (s,2C4 --Ar--OCH3), 127.0 (d,C2 &C6 --Ar--N), 114.5 (d,C3 &C5 --Ar--N), 114.2 (d,2C3 &C5 --Ar--OCH3), 55.4 (q,3CH3O), 54.4 (t,2N-CH 2CH2 --NHCO), 52.9 (t,N--CH2CH2 --NHCS), 50.1 (s,2S--C--CH3), 42.8 (t,N--CH2CH2 --NHCS), 38.3 (t,2N--CH2CH2 --NHCO), 34.2 (t,2S--CH2 --Ar), 28.3 (q,4CH3 --C--S) ppm. MS (m/z,FAB): 756(4.2, M+). IR (CDCl3): 3320, 2960, 1720, 1655, 1510, 1290, 1245, 1030 cm-1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][CH2:29][NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)NCCn3ccc(-c4ccc(C#N)c(Cl)c4)n3)no2)cn1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (49 mg, 0.20 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off. PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 16 mg of the title compound. 1H-NMR (400 MHz; d6-DMSO): 3.70 δ (m, 2H), 3.91 (s, 3H), 4.38 (m, 2H), 6.89 (m, 1H), 6.97 (d, 1H), 7.85 (m, 1H), 7.94-8.00 (m, 3H), 8.10 (d, 1H), 8.36 (s, 1H), 8.86-9.13 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N+:12]=[N-:13].[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[N:12]3[N:13]=[C:15]([CH2:14][OH:17])[CH:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Solvent: CCOCC
Product: O=c1[nH]c2ccc(F)cc2c2cc(CO)nn12
Reaction time: 0.25 h

Procedure:
2.0 g (0.0113 mole) of 5-fluoro-3-diazooxindole (part B) and 13.1 g. (0.226 mole of 20 equivalents) of 97% propargyl alcohol are refluxed under argon for 4 hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 15 minutes. The beige-colored precipitates are filtered off and dried in vacuo overnight. Yield: 2.3 g, mp 295°-297°, 87.5% crude yield. The crude product is taken up in absolute ethanol (500 ml), treated with activated carbon, filtered through a Celite pad; the pad is washed with 50 ml of hot ethanol. The clear filtrate is concentrated down to a volume of 100 ml and cooled. The white precipitates are filtered off and dried in vacuo at 60° to yield the product (title compound) 1.16 g, mp 303°-304°.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@@H:5]([NH:23][C@H:24]1[C:33]2[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([C@H:5]3[CH2:4][CH2:3][CH2:2][N:23]3[C@H:24]3[C:33]4[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of (1R)-1-[[(1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl) butyl]amino]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (2.6 g) in CH2Cl2 (50 ml) was added SOCl2 (3 ml). After being stirred for 12 hours, the solvent was removed. The residue was dissolved in N,N-dimethylformamide (DMF) (15 ml) and K2CO3 (2 g) was added to the solution. After being stirred for 4 hours at the room temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.22 g). MS (m/z): 675 (M+) IR (Neat): 1560 cm-1NMR (CDCl3, δ): 1.75 (9H, s), 1.5-2.4 (8H, m), 2.7-3.2 (4H, m), 4.0-4.3 (2H, m), 6.15 (1H, d, J=8 Hz), 6.45 (1H, t, J=8 Hz), 6.92 (1H, d, J=8 Hz), 7.2-7.8 (20H, m)
Reaction SMILES: [BrH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:10]([OH:28])[CH2:11][NH:12][C:13]([CH3:27])([CH3:26])[CH2:14][NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].Br>FC(F)(F)C(O)=O>[BrH:1].[C:29]([O:28][CH:10]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:3]([O:2][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:4]=1)[CH2:11][NH:12][C:13]([CH3:26])([CH3:27])[CH2:14][NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(CNC(=O)COc1ccccc1)NCC(O)c1ccc(O)c(O)c1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)COc1ccccc1)NCC(OC(=O)C(C)(C)C)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
A solution of 1-(3,4-dihydroxyphenyl)-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol hydrobromide (0.8 g.) in trifluoroacetic acid (5.4 ml.) was treated with pivaloyl chloride (1.12 ml.) and the mixture was heated under reflux for 40 minutes. The mixture was then evaporated and the residue was dissolved in ether. The solution obtained was treated with ethereal hydrogen bromide until just acid, where upon an oily solid separated. Trituration of this material with ether (20 ml.) gave the triester, 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethyl pivaloate hydrobromide, as a solid (0.6 g.) m.p. 106°-110° C., NMR δ: 8.8 (2H, broad singlet, N+H2); 8.45 (1H, triplet, NHCO); 7.8-6.8 (8H, complex, aromatic protons); 5.43 (1H, broad, =CHO); 3.58 (2H, singlet, CHHD 2OPh); 4.0-3.0 (complex, CH2NH); 1.3-1.2 (33H, broad singlet, C.CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=3)=[CH:10][C:3]=12.Br[C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1>>[CH2:38]([N:36]1[CH:37]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH:12]=4)=[CH:10][C:3]=23)[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35]1)[CH3:39]
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2cccc(N3CCOCC3)c2)cc2c(Br)ccnc21
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(N4CCOCC4)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with 4-bromo-2-[3-(4-morpholinyl)phenyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Using this product crude and following the procedure in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 676.4
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].C(O)(C(F)(F)F)=O.[C:16]1([S:22]([C:25]2[CH:33]=C3[C:28]([CH:29]=CN3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[N+:5]([CH:4]=[CH:3][N:2]1[C:8]2[C:28](=[CH:27][CH:26]=[C:25]([S:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:23])=[O:24])[CH:33]=2)[CH:29]=[CH:1]1)([O-:7])=[O:6]
Reactant: O=S(=O)(c1ccccc1)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C=Cn1ccc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Combine 1-dimethylamino-2-nitroethylene (676.9 mg, 5.83 mmol) and TFA (9.0 ml) and stir until dissolved. Add 6-benzenesulfonyl-1H-indole (1.5 g, 5.83 mmol) and stir at ambient temperature. After 24 hours, pour the reaction mixture into ice/water and adjust to pH 8. After stirring, filter the precipitate, wash with water, and dry to give the title compound as a yellow powder: mp 110° C., dec. MS (ACPI): m/e 329.0 (M+1). Analysis for C16H12N2O4S: Calcd: C, 58.53; H, 3.68; N, 8.53; found: C, 58.54; H, 3.83; N, 7.85.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1)=[O:15]
Reactant: NCc1cc(N)nc(N)c1
Reactant: O=C(Cl)c1ccccc1Br
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Nc1cc(CNC(=O)c2ccccc2Br)cc(N)n1
Yield: 20.2 %

Procedure:
A solution of 172.5 mg (1.25 mmol) 4-aminomethyl-pyridine-2,6-diamine in 5 ml pyridine was treated with 275 mg (1.25 mmol) o-bromobenzoylchloride and a catalytic amount 4-dimethylaminopyridine and stirred for 2.5 h at room temperature. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica eluting with dichloromethane/methanol 9/1 to yield 81 mg (20%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:33])=[C:4]([NH:20][C:21]2[S:25][N:24]=[C:23]([CH3:26])[CH:22]=2)[CH:5]=1)[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3cccs3)C(N)=O)ccc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3cccs3)C(N)=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(thiophen-2-yl)propanamide (13 mg, 0.034 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (10 mg). MS 402.1 (M+H); UV 224.1, 302.6 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:10]1[CH:11]=[CH:12][CH2:13][CH:14]1[C:2]1[CH:9]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH:7]=[O:8]
Reactant: C1=COCC1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cccc(C2CC=CO2)c1
Temperature: 45 °C
Yield: 38.3 %

Procedure:
Ex-119A: 5-Bromobenzaldehyde (0.5 g, 2.7 mmol) and 2,3-dihydrofuran (0.56 g, 8.1 mmol) were dissolved in dioxane (5.0 mL). Nitrogen was bubbled into the solution for 15 min followed by the sequential addition of cesium carbonate (0.96 g, 2.9 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.027 mmol). The solution was immediately heated to 45° C. and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:9) gave 0.18 g (40%) of 3-(2,3-dihydro-furan-2-yl)-benzaldehyde as a clear, colorless oil. 1H-NMR (300 MHz, CDCl3) δ 10.03 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, J=7.2 Hz), 7.62–7.64 (m, 1H), 7.53 (t, 1H, J=7.2 Hz), 6.48 (q, 1H, J=Hz), 5.60 (dd, 1H, J=8.1, 10.8 Hz), 4.98 (q, 1H, J=3.3 Hz), 3.15 (ddt, 1H, J=15.0, 8.1, 2.5 Hz), 2.59 (ddt, 1H, J=15.0, 8.1, 2.5 Hz). MS (EI) m/z=174 ([M]+, 100%). HRMS (EI) Calcd. for C11H10O2: 174.0681. Found: 174.0677.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:20]([Mg]Br)#[CH:21].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[C:10]([CH:11]([OH:12])[C:20]#[CH:21])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: Cc1cccc(-c2nn3c(Cl)cccc3c2C=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2cccc(C)c2)nn2c(Cl)cccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
To a cold (−78° C.) suspension of 7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (10.38 g, 36.2 mmol) in tetrahydrofuran (80 mL) was added ethynylmagnesium bromide (87 mL, 0.5 M in tetrahydrofuran, 43.4 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at 0° C. for 2 hours. The resultant solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate to 7:3 hexanes:ethyl acetate) provided 1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (11.3 g, 77%) as a yellow foam. 1H NMR (CDCl3) δ 8.03 (d, 1H), 7.60 (s, 1H), 7.54 (d, 1H), 7.37 (t, 1H), 7.26 (d, 1H), 7.17 (dd, 1H), 6.98 (d, 1H), 2.67 (s, 1H), 2.43 (s, 3H), 2.38 (s, 1H); MS m/z297 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:34])=[O:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:34])(=[O:36])=[O:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (412 mg, 0.84 mmol) in methanol (46 mL) at 0° C. was added a solution of potassium permanganate (133 mg, 0.84 mmol) in water (23 mL) dropwise. After stirring for 2 h at 0° C., the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silical gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (370 mg, 87%): LC/MS m/e calcd for C26H25N3O4S2 [M+H]+ 508.63, observed 508.2.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6]([C:8]1[C:9]2[C:17]([NH2:18])=[C:16]([C:19](=[O:21])[NH2:20])[S:15][C:10]=2[N:11]=[C:12]([CH3:14])[CH:13]=1)=O)C.C1COCC1>CO>[NH2:18][C:17]1[C:9]2[C:10](=[N:11][C:12]([CH3:14])=[CH:13][C:8]=2[CH2:6][OH:5])[S:15][C:16]=1[C:19]([NH2:20])=[O:21]
Reactant: CCOC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Reaction time: 2 h
Yield: 71 %

Procedure:
LiBH4 (62 mg, 2.04 mmol) was added to a solution of 3-Amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester (205 mg, 0.73 mmol) in 10:1 THF:MeOH (15 mL) at room temperature. After stirring for 2 h, the reaction was quenched by addition of 1M HCl. The mixture was buffered to a pH≈7, diluted with EtOAc, washed sequentially with H2O, brine, dried over Na2SO4, concentrated, and triturated with 50% EtOAc/hexane giving 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (123 mg, 71%) as a yellow solid, m.p. >210° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(cnn2CC2CC2)c1
Temperature: 105 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
To a solution of 5-bromoindazole (15 g, 76.1 mmol) and (bromomethyl)cyclopropane (8.12 mL, 83.7 mmol) in 75 mL of DMF, K2CO3 (16 g, 114.0 mmol) was added. The mixture was heated to 105° C. After 24 hours, starting material was still observed. Additional (bromomethyl)cyclopropane (5.7 mL, 57.0 mmol) was added and reaction was heated to 105° C. for an additional 24 hours. 5-Bromoindazole was again observed so additional (bromomethyl)cyclopropane was added (4 mL, 38 mmol) and the reaction was heated at 95° C. for an additional 48 hours. After disappearance of 5-bromoindazole, the reaction mixture was poured onto DCM/brine. The two layers were separated and the aqueous layer was extracted with DCM (2×) and checked by TLC. No product was observed in aqueous layer. The combined organics were washed with H2O (2×) and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the resulting residue was purified by chromatography with 9.5:0.5 hexane/EtOAc to provide 5-bromo-1-cyclopropylmethyl-1H-indazole (8.74 g, 45% isolated yield). 1H NMR (400 MHz CDCl3) δ 7.93 (s, 1H), 7.86 (d, J=1.57 Hz, 1H), 7.43 (dd, J=8.61, 1.57 Hz, 1H), 7.31 (d, J=8.61 Hz, 1H), 4.24 (d, J=6.26 Hz, 2H), 1.37-1.26 (m, 1H), 0.62-0.55 (m, 2H), 0.43-0.37 (m, 2H); MS (APCI+) m/z 251/253 (M/M+2H, 1:1) was detected.
Reaction SMILES: [C@H:1]1([OH:7])[CH:5]=[CH:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.C1COCC1>[C:10]([O:14][C:15](=[O:18])[CH2:16][O:6][CH:3]1[CH2:2][CH:1]([OH:7])[CH:5]=[CH:4]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O[C@@H]1C=C[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1C=CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 2.0 g (20 mmol) of cis-4-cyclopentene-1,3-diol in 1.5 ml of DMF and 15 ml of THF and, at 0° C., add 799 mg (60% strength, approx. 20 mmol) of sodium hydride in portions. After the end of the addition, warm the mixture to RT and stir at RT for a further 1 h, before adding 2.7 ml (18.2 mmol) of bromoacetic acid tert-butyl ester. Then stir the mixture at RT overnight. Then add water, extract with dichloromethane, wash the organic phase with satd. sodium chloride solution, concentrate under reduced pressure and dry the residue under high vacuum. Isolate the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1→2:1). 1.10 g (25.6% of theory) of the target compound are obtained.
Reaction SMILES: BrC(C1C=CC(C2C=CC=CC=2[Cl:20])=CC=1)C(OCC)=O.C(NC(=O)C(C1C=CC(C2C=CC=CC=2Cl)=CC=1)Br)(C)C.[I:42][CH:43]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2Cl)=[CH:51][CH:50]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45].C(NC(=O)C(C1C=CC(C2C=CC=CC=2Cl)=CC=1)I)(C)C>>[I:42][CH:43]([C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)=[C:51]([Cl:20])[CH:50]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: CCOC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1
Reactant: CCOC(=O)C(I)c1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)NC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)NC(=O)C(I)c1ccc(-c2ccccc2Cl)cc1
Product: CCOC(=O)C(I)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
When ethyl α-bromo-2'-chloro-4-biphenylylacetate in the above procedure is replaced by d ethyl α-bromo-2'-chloro-4-biphenylylacetate, l ethyl α-bromo-2'-chloro-4-biphenylylacetate of N-isopropyl α-bromo-2'-chloro-4-biphenylylacetamide, then the products prepared are d ethyl α-iodo-2'-chloro-4-biphenylylacetate, l ethyl α-iodo-2'-chloro-4-biphenylylacetate or N-isopropyl α-iodo-2'-chloro-4-biphenylylacetamide.