Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[N+:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[C:7]=1[O-:8])#[N:2].N.CO>CO>[C:1]([C:3]1[NH:4][CH:5]=[N+:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([OH:16])[C@H:10]2[OH:11])[C:7]=1[O-:8])#[N:2].[C:1]([C:3]1[NH:4][CH:5]=[N+:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:15]([OH:16])[C@H:10]2[OH:11])[C:7]=1[O-:8])#[N:2]
Reactant: CC(=O)OC[C@H]1O[C@@H]([n+]2c[nH]c(C#N)c2[O-])[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H]([n+]2c[nH]c(C#N)c2[O-])[C@H](O)[C@@H]1O
Product: N#Cc1[nH]c[n+]([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1[O-]
Reaction time: 2 h

Procedure:
To a mixture of 184 mg of 4-cyano-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazolium-5-olate and 1 ml of dry methanol was added 15 ml of 15% (W/W) ammonia/methanol solution under cooling, and the mixture was stirred for two hours at the same temperature. Evaporation of the reaction mixture in vacuo gave a residue, which was purified by column chromatography on reversed phase silica gel [Merck RP-8 eluted with aqueous 10% methanol containing acetic acid (1%)] to give 100 mg of 4-cyano-1-(5-O-acetyl-β-D-ribofuranosyl)imidazolium-5-olate and 32 mg of 4-cyano-1-β-D-ribofuranosylimidazolium-5-olate, which was identified with the authentic sample of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)=[O:4].S(=O)(=O)(O)O.[Br:21]Br.C(O)(=O)C.BrBr.CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[C:7]([Br:21])[N:6]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1ncc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49 g, 43.16 mmol) was dissolved in water (300 mL). Sulfuric acid (4.60 mL, 86 mmol) was added followed by dropwise addition over 30 minutes of a solution of bromine (2.222 mL, 43.1 mmol) in acetic acid (29.6 mL, 517 mmol). The reaction mixture was stirred at RT for 18 hours. A further 100 ml of water was added, followed by a further 0.25 equivalents of the bromine/AcOH mixture (550 μL bromine in 7.4 mL AcOH) and the reaction mixture stirred at RT for an additional 90 minutes. The reaction mixture was diluted with 500 mL water and neutralised by addition of solid NaHCO3 (˜85 g). The suspension was extracted with DCM (3×300 mL) and the combined organic phases washed with sat.NaHCO3(aq) (250 mL), water (250 mL) and brine (100 mL), dried (MgSO4) and concentrated in vacuo. The crude material was recrystallised from boiling MeOH (˜300 mL) to give the title product as a pale orange solid m/z 301.0 [M+H]+ 1H-NMR: [400 MHz, DMSO-d6] δ 7.77 (1H, s, ArH), 7.17 (2H, s, NH2), 3.86 (3H, s, ArCO2CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-bromopyridine-2-sulfonyl chloride (2.7 g, 10 mmol) in DCM (100 mL) was cooled to 0° C. and treated with tert-BuNH2 (5.5 mL, 52 mmol). The resulting mixture was stirred at rt for 48 h. Water (50 mL) was added and the DCM layer were separated, dried and concentrated to obtain compound 32a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.75 (d, J=2.3 Hz, 1H), 8.03 (dd, J=8.2, 2.3 Hz, 1H), 7.90-7.94 (m, 1H), 5.02-5.07 (m, 1H), 1.23 (s, 9H).
Reaction SMILES: [Cl:1][O-].[Na+].[OH:4][C:5]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1>Cl>[Cl:1][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:5]=1[OH:4]
Reactant: [O-]Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2c(Cl)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
The chilled sodium hypochlorite solution is added to the chilled solution of 2-hydroxy-3-naphthoic acid, keeping the temperature below 10° C. When the addition of sodium hypochlorite is completed, the reaction mixture is held at about 10° C. for 2 hours and then heated to the boil. To this solution is then added 250 ml of 14.1% hydrochloric acid. The resulting slurry of deep yellow solid material is heated to the boil and then cooled to ambient temperature. The slurry is filtered, washed with 2 liters of water and dried to constant weight. There is obtained 52.6 grams of 1-chloro-2-hydroxy-3-naphthoic acid (purity 97.2% by HPLC) representing a yield of 91.8% of theoretical.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[Cl:27]>>[Cl:27][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:19]=1[CH2:18][NH:17][C:12](=[O:14])[CH:11]([C:3]1[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[O:15][CH3:16]
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)c(Cl)c1
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2Cl)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid, described in example 66.1 was coupled with 4-aminomethyl-3-chlorobenzonitrile (CAS 202521-97-9) according to general procedure C to give (RS)-N-(2-chloro-4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Light yellow oil. MS 379.2 ([M−H]−)
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@H:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:4]([CH2:5][C:6](OS(C(F)(F)F)(=O)=O)=[CH:7]2)[CH2:3]1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[CH2:9][C@H:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:4]([CH2:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2)[CH2:3]1
Reactant: CN1C[C@H]2CC(OS(=O)(=O)C(F)(F)F)=C[C@@H](C1)N2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C1=C[C@H]2CN(C)C[C@@H](C1)N2C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
To a solution of (1R,5S)-tert-butyl 3-methyl-7-(((trifluoromethyl)sulfonyl)oxy)-3,9-diazabicyclo[3.3.1]non-6-ene-9-carboxylate (14 g, 36 mmol) and diisopropylethylamine (9.47 mL, 54.3 mmol) in methanol (100 mL) and DMF (100 mL) was triphenylphosphine (0.95 g, 3.62 mmol) and palladium (II) acetate (0.407 g, 1.81 mmol). The mixture was stirred under carbon monoxide atmosphere for 24 h. The mixture was concentrated and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, concentrated and the residue was purified on silica gel using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+1)+: 297.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>CN1C(=O)CCC1>[N+:22]([C:21]1[C:16]([N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10]2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Yield: 83.8 %

Procedure:
Anhydrous TEA (0.76 ml, 5.49 mmol) was added to piperidin-4-yl-carbamic acid tert-butyl ester (1 g, 5 mmol) and 2-chloro-3-nitro-pyridine (0.791 g, 5 mmol) in anhydrous NMP (3 ml). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 10 minutes. The brown solution was partitioned between EtOAc and water and the organic phase was washed several times with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as a yellow solid (1.35 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[CH2:36][C:35](=[O:37])[N:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:33]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>C(O)C>[NH2:13][C:12]1[O:37][C:35]2[N:34]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:33]=[C:32]([C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[C:36]=2[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]=1[C:10]#[N:14]
Reactant: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1OC
Reactant: O=Cc1ccc(F)cc1
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2nn(-c3ccccc3)c3c2C(c2ccc(F)cc2)C(C#N)=C(N)O3)cc1OC
Reaction time: 0.02 h
Yield: 51.9 %

Procedure:
A mixture of 4-fluorobenzaldehyde (70.0 μL, 0.675 mmol, 1.0 equ.), malononitrile (45.0 mg, 0.675 mmol, 1.0 equ.) and triethylamine (90.0 μL, 0.675 mmol, 1.0 equ.) in ethanol (3.0 mL) was stirred for 1 min, followed by the addition of the 3-(3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (200 mg, 0.675 mmol, 1 equ.). The reaction mixture was concentrated after 19 h and the crude material was purified by column chromatography (25% ethyl acetate in hexanes to 100% ethyl acetate). The yellow solid was further purified by re-crystallization from ethanol to give 6-amino-3-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (164 mg, 0.350 mmol, 12%) as a white solid. 1H-NMR (400 MHz) CDCl3: 7.80-7.78 (d, 2H), 7.52-7.48 (t, 2H), 7.38-7.35 (t, 1H), 7.25-7.21 (m, 2H), 7.05-6.95 (m, 4H), 6.75-6.73 (d, 1H), 4.91 (s, 1H), 4.84 (s, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 13C-NMR (100 MHz) CDCl3: 163.2, 157.8, 149.2, 148.7, 147.5, 144.9, 138.6, 137.4, 129.3, 129.1, 129.0, 127.1, 125.0, 121.5, 119.8, 119.0, 115.9, 115.7, 110.8, 109.9, 96.6, 64.0, 55.8, 55.7, 37.5; LC/MS-MS: 469.3→403.1 m/z; GS1 and GS2 at 30, DP=6, CE=35, CXP=26, tR=4.16 min.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-:3])=[O:2].[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[C@H:16]1([NH:15][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[N:9]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: N[C@@H]1CCc2ccccc21
Product: O=[N+]([O-])c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
5-Nitro-2-chloroquinoline (CAS 13067-94-2, 2.4 g, 11.5 mmol) and (R)-1-aminoindane (3.13 g, 23.5 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). (R)-Indan-1-yl-(5-nitro-quinolin-2-yl)-amine was obtained as a brown solid (2.67 g, 76%), MS: m/e=306.2 (M+H+).
Reaction SMILES: CO[C:3](=O)[C:4]#[C:5][CH2:6]O.[N:9]1[C:18]2[C:13](=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:51]=[CH:50][C:49]4[C:44](=CC=CC=4)[N:43]=3)=[CH:36][CH:35]=2)(C)[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:23][CH:22]=1.N.[OH2:53]>>[N:43]1[C:44]2[C:49](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:50]=[CH:51][C:42]=1[CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:9]=3)=[CH:22][CH:23]=2)([OH:53])[C:28]#[C:29][C:30]([OH:32])=[O:31])=[CH:35][CH:36]=1
Reactant: O
Reactant: CC(CCC(=O)O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)C#CCO
Agent: N
Product: O=C(O)C#CC(O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
The desired compound was prepared according to the method of Example 1, step 3, except substituting 4,4-bis(2-quinolylmethoxy)phenyl)-4-hydroxy-2-butynoic acid methyl ester, prepared as in step 1, for 4,4-bis(4-(2-quinolylmethoxy)phenyl)-pentanoic acid: mp 169°-172° C.; 1H NMR (300 MHz, DMSO--d6) d 5.35 (s, 4H), 7.04 (d, 4H, J=9 Hz), 7.37 (d, 4H, J=9 Hz), 7.63 (m, 4H), 7.78 (m, 2H), 8.00 (m, 4H), 8.40 (d, 2H, J=8 Hz), 13.75 (bs, 1H); MS (DCI--NH3) m/e: 567 (M+H)+. Anal. Calc'd. for C36H26 N2O4. 0.5 H2O: C, 75.12; H, 4.73;N, 4.89. Found: 75.19; H, 4.80; N, 4.60.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH:28]4[S:33][CH2:32][CH2:31][CH2:30][S:29]4)=[CH:23][C:22]=3[F:34])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:43])C=1>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH:28]4[S:33][CH2:32][CH2:31][CH2:30][S:29]4=[O:43])=[CH:23][C:22]=3[F:34])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C4SCCCS4)cc3F)CC2)CC1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C4SCCCS4=O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
21a (55 mg) was dissolved in 0.5 mL of DCM and cooled to −78° C. mCPBA (24 mg, 1 eq) in 1 mL of DCM was added and the mixture was stirred at room temperature for 2 days. The solution was washed with aqueous Na2CO3 twice then with water and the crude material obtained was purified on preparative HPLC to give 21-1 as a 15:85 mixture of diastereoisomers: LC-MS 530.2 (MH), tR=5.58 (Method 5). EC50: 143 nM.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([CH:18]([F:20])[F:19])=[CH:16][CH:17]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCN(CC)CC.O>C(Cl)Cl>[CH3:21][S:22]([O:11][C@H:10]([C:12]1[CH:13]=[N:14][C:15]([CH:18]([F:20])[F:19])=[CH:16][CH:17]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:24])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(C(F)F)nc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(C(F)F)nc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a stirred solution of (R)-2-(tert-butyldimethylsilyloxy)-1-(6-(difluoromethyl)pyridin-3-yl)ethanol (3.0 g, 9.90 mmol) in dry CH2Cl2 at 0° C. was added MeSO2Cl (1.2 g, 10.9 mmol) and Et3N (1.3 g, 12.9 mmol). The resulting reaction mixture was warmed to room temperature over a period of 2 h. After completion of the reaction, the reaction mixture was treated with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO2, 10% EtOAc/pet. ether) to afford the title compound (2.26 g, 60% yield). MS: 381 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.67 (s, 1H), 7.90 (d, 1H, J=8.3 Hz), 7.68 (d, 1H, J=8.3 Hz), 6.65 (t, 1H, J=55.2 Hz), 5.62-5.66 (m, 1H), 3.98 (dd, 1H, J=11.2, 6.8 Hz), 3.87 (dd, 1H, J=11.2, 4.9 Hz), 3.028 (s, 3H), 0.87 (s, 9H), 0.04-0.05 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.NC(N)=[S:14].II.Cl[CH2:19][C:20]#[N:21]>CO.O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[S:14][CH2:19][C:20]#[N:21]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: N#CCCl
Reactant: NC(N)=S
Agent: II
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COc1ccc2[nH]cc(SCC#N)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of 50 g (0.34 mole) of 5-methoxyindole and 25.8 (0.34 mole) of thiourea in 1700 ml of 50% aqueous methanol was added 340 ml of KI/I2 in water over a 5 minute period and the reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was then evaporated in vacuo to about 1100 ml, 68 ml of 50% aqueous NaOH were added under nitrogen, the temperature brought to 85° and the mixture was stirred at 80°-90° for 40 minutes. The mixture was cooled and filtered through glass wool and under nitrogen, 21.2 ml (25.4 g; 0.34 mole) of chloroacetonitrile were added. The reaction was allowed to proceed under N2 for 18 hours after which the reaction mixture was layered over with about 800 ml of diethyl ether and the ether was separated off having dissolved a large portion of suspended solid material. The aqueous solution was extracted three times with 500 ml portions of ether which were combined with the other washings and dried over anhydrous K2CO3. The ether layer was filtered and evaporated in vacuo to 33 g of 5-methoxy-3-cyanomethylthioindole (42% yield) as a tan solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:11][I:12]>CCOCC>[I-:12].[CH3:1][N+:2]([CH3:11])([CH3:10])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CI
Reactant: CCCCOCCN(C)C
Solvent: CCOCC
Product: CCCCOCC[N+](C)(C)C
Product: [I-]

Procedure:
10 g dimethyl(2-butoxyethyl)amine and 10 g methyl iodide were stirred in 125 ml ether for 24 hours. The precipitate was filtered off and dried. The trimethyl(2-butoxyethyl)ammonium iodide obtained had a melting point of 71°-73° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[C:12](O)([C:14](F)(F)F)=O>N1CCCCC1>[CH3:8][C:6]1[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]2=[C:2]([N:5]2[CH2:14][CH2:12][CH2:2][CH2:3][CH2:4]2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Solvent: C1CCNCC1
Product: Cc1cc(N2CCCCC2)c2[nH]ncc2n1

Procedure:
7-Chloro-5-methyl-1H-pyrazolo(4,3-b)pyridine (1 g) and piperidine (10 ml) were heated under reflux for 24 h. The piperidine was removed in vacuo to yield a pale yellow solid which was washed with water to yield the piperidino-compound (1 g, 78%), Crystallisation from ethanol-water gave pale yellow crystals, m.p. 244°. Found: C, 66.5; H, 7.55.; N, 25.7. C12H16N4 requires C, 66.6; H, 7.5; N, 25.9%), νmax 2660-2200 (broad), 2000-1800 (broad), 1540, 1430, 1355, 1290, 1210, 1020, 980, 810 and 760 cm-1, δ (CF3COOH) 1.97 (6H, s, --CH2 --), 2.70 (3H, s, 5 --CH3), 4.13 (4H, s, --N--CH2 --), 6.59 (1H, s, 6-H), 8.32 (1H, s, 3-H), total proton count 15.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:38]([O:40][C:41]([C:43]1([NH2:52])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])[CH3:39].CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C(Cl)Cl>[CH2:38]([O:40][C:41]([C:43]1([NH:52][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])=[O:9])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])[CH3:39]
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccccc2S(C)(=O)=O)Cc2ccccc2C1
Yield: 139.6 %

Procedure:
To a 40 mL vial containing a stirring bar, 2-(methylsulfonyl)benzoic acid (0.4 g, 2.88 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol). The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added followed by the DIPEA (0.95 mL, 8 mmol). The reaction is allowed to stir for 36 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.32 g of white solid. This material is dissolved in 10 mL of DCM and purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 15% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 5 through 8 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.71 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH2:20]Br)[CH:11]=1.Cl>CN(C=O)C>[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH2:20][O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1COCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (0.5 g of 60% dispersion in oil) in DMF (10 ml) was added trifluoroethanol (0.92 ml) and the mixture stirred for 30 minutes. After this time the mixture was cooled to 0° C. and a solution of methyl 4bromo-2-bromomethylbenzoate (3.52 g) in DMF was added, and the resultant mixture stirred at room temperature for 1 hour. 0.5M HCl was added and the mixture extracted with ether. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to yield methyl 4-bromo-2-trifluoroethoxymethylbenzoate (3.89 g) as a yellow oil, NMR (CDCl3) 3.9(s,3H), 4.0(q,2H), 5.1(s,2H), 7.5(dd,1H), 7.85(d,1H), 7.9(s,1H).
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:15])C=CC=CC=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([CH2:39]C(O)=O)([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][C:35]2([O:38][C:6](=[O:15])[NH:3][CH2:39]2)[CH2:36][CH2:37]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC(=O)O)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (5.59 mL, 39.78 mmol) and diphenylphosphoryl azide (10.86 mL, 5.1 mmol) were added in succession under a nitrogen atmosphere to a solution of A2 (7.9 g) in dry toluene (205 mL). The reaction mixture was heated to 80 to 90° C., evolution of gas being observed which ceased after 90 min. Stirring was continued for a further 2 h at 115° C. After cooling, the reaction mixture was diluted with EtOAc and repeatedly washed with water. The combined aqueous phases were extracted with EtOAc and the combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was washed repeatedly with ether. 5.72 g (60.6% of theoretical over three stages starting from 1-(tert-butyloxycarbonyl)-4-piperidone) of the desired product 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A3) remained as a white solid.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].C[N-]C.C[N-]C.[V+4:13].[CH2:14]([Li])[CH2:15][CH2:16][CH3:17]>CCCCCC>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH2:14]([V+2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:15][CH2:16][CH3:17]
Reactant: [V+4]
Reactant: [Li]CCCC
Agent: C[N-]C
Solvent: CCCCCC
Product: CCCC[V+2]CCCC

Procedure:
To a dark-green solution of 0.048 g (0.21 mmol) of vanadium tetrakis(dimethylamide) in hexane was added from a syringe 0.26 ml of a 1.6 M solution of butyllithium (0.21 mmol) in hexane. Lithium dimethylamide precipitated rapidly. The total volume of liquid in the mixture was about 6 ml. After 15 minutes the mixture was filtered to give a clear green solution of dibutylvanadium bis(dimethylamide) in hexane.