Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CS(C)=O>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution consisting of 0.7 g (1.3 mmol) N,N'-(2-aminoethyl) trans-1,2-diaminocyclohexane-N,N',N",N'",N'" hexaacetic acid in 50 ml dimethylsulfoxide was added 0.9 g (7.8 mmol) N-hydroxysuccinimide and 0.8 g (3.9 mmol) dicyclohexylcarbodiimide. This was stirred at room temperature for 48 hr., during which the white fluffy solid of dicyclohexyl urea formed. This solid was removed by filtration and the filtrate was concentrated to a thick oil under reduced pressure. A solid precipitated from the oil upon the addition of acetonitrile. This solid was collected, washed with cold acetonitrile and dried under vacuum to give 0.54 g of a light brown solid. NMR showed an average of 2 NHS esters so the yield is 56%. No further purification of the solid was attempted; mp 125°-140° C.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH:7]=O)[CH:4]=[C:3]([CH:9]=O)[CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH2:7][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:4]=[C:3]([CH2:9][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:2]=1
Reactant: O=Cc1cc(C=O)cc(-c2ccccc2)c1
Reactant: CCCCNCCCNCCCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCNCCCNCCCNCc1cc(CNCCCNCCCNCCCC)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[1,1′-Biphenyl]-3,5-dicarbaldehyde (0.66 g, 3.15 mmol) and MeOH (50 mL) were added to a round-bottom flask. To the solution was added N1-(3-aminopropyl)-N3-butylpropane-1,3-diamine (1.18 g, 6.31 mmol) and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (0.48 g, 12.62 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aq. NaOH (10%, 100 mL) and EtOAc (100 mL) were added and the reaction mixture stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[O:25])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(Br)cc(C(=O)O)c1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
36 g (0.17 mol) of 5-bromo-2-hydroxy-benzoic acid was dissolved in 500 mL of trifluoroacetic acid. 112 g (0.80 mol) of urotropine was added and the resulting mixture heated to 100° C. for 23 h. The reaction mixture was concentrated to half its volume and the residual liquid poured into 1.8 L of dilute aqueous hydrochloric acid and stirred for 8 h at ambient temperature. The resulting precipitate was filtered off and crystallized from aqueous ethanol to afford 20.3 g (82.9 mmol, 50%) of 5-bromo-3-formyl-2-hydroxy-benzoic acid a pale yellow crystalline solid. 1H-NMR (500 MHz, d6-DMSO): δ 10.29 (s, 1H), 8.13 (d, 1H), 7.95 (d, 1H); MS: m/z 242.9+244.9 (M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([O:25][CH3:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:27])[C:3]=1[OH:28].O[C@@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].BrBr>>[Br:27][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([O:25][CH3:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:28][C@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: COc1c2ccccc2c(-c2cc(Br)c(O)c(Br)c2)c2c1sc1ccccc12
Agent: BrBr
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(OC)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from 2,6-dibromo-4-(6-methoxy-benzo[b]naphtho[2,3-d]thiophen-11-yl )-phenol (Example 63) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96) according to the procedure of Example 107. White solid (0.608 g, 96%): NMR (THF-d8); δ8.29-8.26 (m, 1 H), 7.87 (d., J=8 Hz, 1 H), 7.72 - 7.68 (dd, 2 H, J=4, 2 Hz), 7.60 - 7.56 (m, 2 H), 7.48-7.37 (m, 4 H), 7.32 - 7.28 (m, 2 H), 7.25-7.23 (m, 2 H), 7.20 - 7.15 (m, 2 H), 6.85 - 6.82 (m, 1 H), 5.22(dd, 1 H, J=14, 2, Hz), 4.17 (s, 1 H), 3.71 (s, 1 H), 3.58(s, 6 H), ; MS (FAB+): [M+], 2 bromine isotope pattern, 674 (40%), 676 (66%), 678 (45%); Anal. Calc. for C33H24Br2O4S: C, 58.60, H, 3.58, N, 0.00. Found: C, 58.11, H, 3.53, N, 0.19.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: CS(=O)(=O)c1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2cc(S(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a solution of 3-iodo-5-(methylsulfonyl)-1H-indazole (400 mg, 1.24 mmol) in THF (15 mL) was added t-BuOK (208 mg, 1.86 mmol) slowly at 0° C., mixture stirred for 30 minutes, then iodomethane (262 mg, 1.86 mmol) was added at 0° C., then warmed to room temperature and stirred for 2 hours. Reaction quenched with water (40 mL) and product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a solid which was purified by column chromatography (silica gel, 200-300 mesh, eluting with dichloromethane/methanol=10:1) to give 3-iodo-1-methyl-5-(methylsulfonyl)-1H-indazole (210 mg, 50.6%) as a white solid. LCMS: (M+H)+=337; 1H NMR (300 MHz, DMSO): δ 7.97-7.94 (m, 3H), 4.13 (s, 3H), 3.26 (s, 3H).
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=[O:19])C.[NH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]2[C:30]([NH2:33])=[N:31][O:32][C:28]=2[CH:27]=1>>[NH2:33][C:30]1[C:29]2[CH:34]=[CH:35][C:26]([CH2:25][NH:24][C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:7]3=[O:19])=[CH:27][C:28]=2[O:32][N:31]=1
Reactant: NCc1ccc2c(N)noc2c1
Reactant: CCOC(=O)C(OCC)n1cccc(Nc2ccccc2)c1=O
Product: CCOC(C(=O)NCc1ccc2c(N)noc2c1)n1cccc(Nc2ccccc2)c1=O

Procedure:
Using similar procedures as described in example 25, (RS)-ethoxy-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (example 21.1) was hydrolyzed according to general procedure B. The corresponding acid was reacted according to general procedure C with 6-aminomethyl-benzo[d]isoxazol-3-ylamine (CAS 368426-78-2) to give (RS)-N-(3-amino-benzo[d]isoxazol-6-ylmethyl)-2-ethoxy-2-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetamide. Light green powder. MS 434.2 ([M+H]+)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:5]=1.[NH2:33][CH2:34][CH2:35][CH2:36][NH2:37].[C-]#N.[Na+].O>CO>[NH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:5]=1
Reactant: NCCCN
Reactant: COC(=O)c1ccc(CN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCCCNC(=O)c1ccc(CN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A solution of 15 (473 mg, 1.11 mmol), 1,3-diaminopropane (1.1 ml, 13.1 mmol) and NaCN (7 mg, 0.14 mmol) in methanol (15 ml) was heated under reflux for 24 hours under an Argon atmosphere. After cooling to room temperature the mixture was poured into water (100 ml) and the aqueous layer was washed with ether (2×125 ml), followed by extraction with dichloromethane (3×75 ml). The combined dichloromethane layers were washed with water (50 ml), brine (50 ml) and dried (Na2SO4). Evaporation of the solvent afforded 16 (418 mg, 81%) as a slightly yellow sticky solid. 1H-NMR (CDCl3) δ1.71 (m, 2H), 2.91 (m, 2H), 3.54 (m, 2H), 3.91 (s, 2H), 3.96 (s, 2H), 5.29 (s, 1H), 7.09 (m, 3H), 7.60 (m, 7H), 8.03 (m, 1H), 8.43 (d, 1H, J=4.4 Hz), 8.52 (d, 2H, 4.8 Hz), 8.85 (s, 1H); 1H-NMR (CDCl3) δ30.41 (t), 39.34 (t), 40.51 (t), 56.79 (t), 57.14 (t), 71.86 (d), 121.81(d), 122.07 (d), 122.35 (d), 122.86 (d), 123.82 (d), 128.36 (s), 135.39 (d), 136.23 (d), 136.29 (d), 147.42 (d), 148.95 (d), 149.18 (d), 159.27 (s), 159.58 (s), 162.58 (s), 165.33(s); MS (CI): m/z 468 (M+1).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[N:6]([CH3:11])[CH:7]=[N:8][C:9]=2[N:10]=1.[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:16]([N:3]1[C:4](=[O:12])[C:5]2[N:6]([CH3:11])[CH:7]=[N:8][C:9]=2[N:10]=[C:2]1[Cl:1])[CH2:17][CH2:18][CH3:19]
Reactant: Cn1cnc2nc(Cl)[nH]c(=O)c21
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCn1c(Cl)nc2ncn(C)c2c1=O
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a suspension of 2-chloro-7-methyl-1,7-dihydro-6H-purin-6-one [Ber., 30, 2400 (1897)] (6.68 g, 0.0362 mol) was added 2.03 g (0.0507 mol) of 60% sodium hydride, and the mixture was stirred for 30 minutes. To the mixture was added 8.24 ml (0.0724 mol) of iodobutane. The mixture was stirred at an external temperature of 65° C. for further 30 minutes. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=20:1) to afford 5.38 g (61.8%) of Compound j as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)[N:6]=1.Cl[C:27]([O:29][CH3:30])=[O:28].C(OCC)(=O)C>N1C=CC=CC=1>[NH2:20][C:18]1[C:17]([NH:21][C:27](=[O:28])[O:29][CH3:30])=[CH:16][N:15]=[C:14]([N:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[N:6]2)[N:19]=1
Reactant: Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under argon, 330 mg (0.98 mmol) of the compound from example 12A were initially charged in pyridine (12 ml), the mixture was cooled to 0° C. and 84 μl (108 mmol) of methyl chloroformate were then added dropwise. The reaction mixture was stirred further at RT overnight, and ethyl acetate was then added. The organic phase was washed twice with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was separated by preparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient), giving 241 mg (62% of theory) of the target compound as a colorless solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH:19]=[O:20])[N:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][OH:20])[N:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.620 g, 1.70 mmol) in THF:MeOH (40 mL) at 0° C. was added sodium borohydride (96.3 mg, 2.55 mmol; commercially available from Sigma Aldrich). The reaction was stirred for 30 min at 0° C. at which point TLC analysis indicated the reaction was complete and the solvent was removed under reduced pressure. To the reaction residue was added ethyl acetate (50 mL) and saturated NaHCO3 (15 mL), and the organic layer was separated, dried (Na2SO4) and concentrated. The resulting oil was purified by silica gel chromatography (40% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.540 g, 87%): MS(APCI+): m/z368.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[F:16][C:17]1[N:22]=[CH:21][C:20](N)=[CH:19][CH:18]=1.N1C=CN=C1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([C:20]1[CH:21]=[N:22][C:17]([F:16])=[CH:18][CH:19]=1)[C:5]2=[O:15]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: Nc1ccc(F)nc1
Agent: c1c[nH]cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(c1ccc(F)nc1)C2=O
Temperature: 200 °C
Yield: 12.7 %

Procedure:
5-Amino-6-nitroisoindoline-1,3-dione (2.00 g, 9.66 mmol), 6-fluoropyridin-3-amine (3.25 g, 28.98 mmol) and imidazole (1.32 g, 19.32 mmol) were suspended in diphenyl ether (50 mL). The mixture was stirred and heated to 200° C. for 24 h under argon. Then, the solid was filtered, washed with hexanes and purified by column chromatography (silica-gel, CH2Cl2/Acetone=7/3 v/v) to give a yellow solid product, 0.37 g, 12.7% yield. MS: 300.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.47 (s, 2H), 8.45 (s, 1H), 8.13-8.06 (m, 1H), 8.34 (d, 1H, J=2.1 Hz), 7.56 (s, 1H), 7.41 (dd, 1H, J1=8.7 Hz, J2=3.0 Hz).
Reaction SMILES: [C:1]([C:6]([CH3:22])([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])([O:3][CH2:4][CH3:5])=[O:2].[OH-].[K+]>C(O)C>[C:1]([C:6]([CH3:22])([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:7]([OH:9])=[O:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(C)(Cc1c[nH]c2ccccc12)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Ethyl 2-carboethoxy-3-(3-indolyl)-2-methylpropionate (1.8 g, 5.95 mmol) (S. Masanori, et al., Heterocycles, 1981, 16:941-9), was added to a solution of potassium hydroxide (380 mg, 5.76 mmol) in 4 mL of ethanol. The reaction mixture was stirred at ambient temperature overnight and then heated on a steam bath for 2 hours. The ethanol was evaporated and water (20 mL) was added. The aqueous mixture was extracted with diethyl ether (3×20 mL). The pH of the aqueous layer was adjusted to approximately 1 and it was then extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.5 g (92% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1([N:19]2[CH2:28][C@H:27]([F:29])[CH2:26][C@H:20]2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:46])([F:45])[F:44])[CH:33]=1>>[CH2:1]([C:8]1([N:19]2[CH2:28][C@H:27]([F:29])[CH2:26][C@H:20]2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]([S:38]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][C:34]=2[O:42][C:43]([F:44])([F:45])[F:46])(=[O:40])=[O:39])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C1(Cc2ccccc2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(Cc3ccccc3)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 47.8 %

Procedure:
With 87 mg of the compound obtained in Step 30-2 and of 74 mg 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 67 mg of the title compound (colorless solid) was obtained by a similar method to Example 2.
Reaction SMILES: [C:1](=O)(OC)OC.[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[N:13]([CH3:1])[CH:12]=1)=[O:10]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c2cc(Br)ccc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Alternate procedure: Add dimethyl carbonate (1.3 L, 12.4 mol) to a mixture of 6-bromo-1H-indole-3-carboxylic acid methyl ester (1.3 kg, 5.1 mol) and potassium carbonate (1.41 kg, 10.2 mol) in DMF (6.0 L) at room temperature. Heat the mixture to 130° C. and stir overnight. Cool the reaction mixture to ˜3° C. and add ice-cold water (6 L). Filter the resulting solid, wash with methanol (2 L) and dry in a vacuum oven to afford 1.1 kg (82%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][F:24]>O.[I-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:22][CH2:23][F:24])[C:5]#[N:6]
Reactant: FCCBr
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCF)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a flame dried 50 mL round bottom flask was added 3-bromo-4-hydroxybenzonitrile (1.0 g, 5.05 mmol) followed by 5 mL of dimethyl sulfoxide. Potassium iodide (4.2 mg, 0.025 mmol) and potassium carbonate (1.05 g, 7.58 mmol) were added. The flask was immersed in an oil bath at 85° C. and 1-bromo-2-fluoroethane (0.769 g, 0.45 mL, 6.06 mmol) was added. The reaction was stirred at this temperature for 1 h after which it was cooled to room temperature and diluted with water (10 mL). The resulting solution was extracted with dichloromethane (2×20 mL). The organic layer was then washed with water (3×20 mL) and brine, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to obtain an oil which was purified by silica gel flash chromatography using dichloromethane. Product (1.13 g, 92%) was obtained as a colorless solid. 1H NMR (600 MHz, CDCl3): δ 7.83 (s, 1H), 7.57 (d of d, 1H, J=8.4, 1.8 Hz), 6.94 (d, 1H, J=8.4 Hz), 4.8 (t of d, 2H, J=49, 1.2 Hz), 4.35 (t of d, 2H, J=24, 1.2 Hz). 13C NMR (150 MHz, CDCl3): δ 158.5, 136.9, 132.9, 117.5, 113, 106, 81.5 (d, J=171 Hz), 68.5 (d, J=21 Hz). HRMS: Calc'd for C9H7BrFNO (M+H): 243.9767; Found: 243.9767.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][CH3:9])=[CH:4][F:5].S(=O)(=O)(O)[OH:17]>O>[F:5][CH2:4][C:3]([OH:17])([C:6]([F:12])([F:13])[C:7]([F:11])([F:10])[CH2:8][CH3:9])[C:2]([F:14])([F:15])[F:1]
Reactant: O=S(=O)(O)O
Reactant: CCC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Solvent: O
Product: CCC(F)(F)C(F)(F)C(O)(CF)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol may be prepared by fluorinating commercially available 3,4-hexanedione to form 3,3,4,4-tetrafluorohexane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-hexene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-hexene to form 2-trifluoromethyl-1,3,3,4,4-pentafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.OO>C(O)(=O)C>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1cc(C=O)ccc1O
Agent: OO
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Br)c1O
Temperature: 20 °C
Yield: 152.9 %

Procedure:
Anhydrous acetic acid (20 ml) followed by vanillin (7.5 g; 0.05 mole) were charged into a 100-ml round glass flask equipped with a stirring system, thermometer, a dropping funnel and cooled with a water bath at 20° C. Stirring was begun and then, when the vanillin had dissolved, a solution of bromine (4.8 g; 0.03 mole) in acetic acid (10 ml) was added dropwise. The temperature gradually increased to 30° C. When the bromine addition was complete, acetic acid (20 ml) was added, followed, dropwise, by hydrogen peroxide at a concentration of 30% of H2O2 (2.26 g; 0.02 mole). Stirring was continued for 10 min upon completion of the addition and the heterogeneous reaction mixture was cooled to 20° C. It was next filtered and the cake was washed on the filter with fresh acetic acid (10 ml) followed by ice water (30 ml). After drying under vacuum, a product (10.8 g) melting at 162 ° C. was obtained, in which 5-bromovanillin (10.60 g) was determined by high pressure liquid chromatography. Unconverted vanillin (0.45 g) was determined in the filtrate and the acetic acid wash.
Reaction SMILES: C1CCCCC1.C([Li])(CC)C.Br[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1.CN(C)[C:22](=[O:24])[CH3:23]>C(OCC)C>[C:22]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1)(=[O:24])[CH3:23]
Reactant: Clc1ccc(Br)nc1
Reactant: CC(=O)N(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Cl)cn1
Temperature: -74 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A two liter 4 neck flask was equipped with a stirrer, a thermometer and a 250 mL addition funnel. The reaction setup was flushed with nitrogen overnight. A 1.3 M cyclohexane solution of sec-butyllithium (222 mL, 0.289 mol) was charged to the addition funnel with a cannula. 2-Bromo-5-chloropyridine (57.72 g, MW=192.4, 0.30 mol) and 600 mL of ethyl ether were charged to the flask and then cooled in an acetone/dry ice bath. The temperature of the resultant slurry was -76° C. The sec-butyllithium was added dropwise at a rate to maintain the temperature at -74° C. or lower. The addition took 1.5 hours. When the addition was complete the addition funnel was rinsed with 20 mL of ethyl ether, then charged with 30.7 mL of N,N-dimethylacetamide (MW=87.12, d=0.937, 0.330 mol) and 30 mL of ethyl ether. Ten minutes after the completion of the sec-butyllithium addition, the N,N-dimethylacetamide solution was added dropwise to the reaction mixture, again maintaining the temperature at -74° C. or less. This addition took about 40 minutes. The reaction mixture was held at -76° C. for one hour after the N,N-dimethylacetamide addition was complete, then the bath was removed and the temperature allowed to warm to -30° C. At this temperature the cold bath was replaced and the reaction was quenched with 200 mL of 3 N HCl. The reaction mixture was allowed to warm to room temperature and held overnight. The phases were separated, the ethyl ether phase washed with water and saturated brine and then dried over anhydrous MgSO4. The ethyl ether was stripped, the crude product dissolved in methylene chloride and then treated with one weight equivalent of silica gel. The resulting slurry was filtered through Celite and stripped. The product was recrystallized from hexane to give 29.35 g of 2-acetyl-5-chloropyridine (65% yield based on sec-butyllithium, the limiting reagent).