Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([OH:9])[CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>ClCCl>[C:17]([O:9][CH:3]1[CH:4]2[CH:5]([O:6][CH2:7][CH2:8]2)[O:1][CH2:2]1)(=[O:19])[CH3:18]
Reactant: OC1COC2OCCC12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC1COC2OCCC12
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Hexahydrofuro[2,3-b]furan-3-ol (IV, 60 g) was dissolved in dichloromethane (300 mL) and cooled to 0-5° C. To the cooled solution triethylamine (58.2 g), N,N-dimethylaminopyridine (1.12 g) was added, acetic anhydride (56.5 g) was added for 30-60 minutes at the same temperature, the mass temperature was raised to 25-35° C. and stirred for 2-4 hours. After completion of reaction the mass was cooled to 10-20° C., water (120 mL) was added, stirred for 30 minutes, separated the organic layer, washed with 10% sodium chloride solution (120 mL) and distilled out dichloromethane to get title compound (yield 72 g). Further, the product was purified by fractional distillation to get pure Hexahydrofuro[2,3-b]furan-3-yl acetate III (yield 54 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([NH:30][C:31]([C:33]4[C:34](=[O:46])[N:35]([C:39]5[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:32])=[C:25]([F:47])[CH:24]=3)[CH:19]=[CH:18][N:17]=2)[CH:13]=[N:12]1)(C(C)(C)C)(C)C.CO.[ClH:50]>>[ClH:50].[F:47][C:25]1[CH:24]=[C:23]([O:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([C:14]3[CH:13]=[N:12][N:11]([CH2:10][CH2:9][OH:8])[CH:15]=3)[CH:21]=2)[C:28]([F:29])=[CH:27][C:26]=1[NH:30][C:31]([C:33]1[C:34](=[O:46])[N:35]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1)=[O:32]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Agent: Cl
Solvent: CO
Product: O=C(Nc1cc(F)c(Oc2ccnc(-c3cnn(CCO)c3)c2)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Yield: 89 %

Procedure:
A solution of N-(4-((2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.121 g, 0.183 mmol) in 1.0M HCl in MeOH (2.75 mL, 2.75 mmol) was stirred at RT for 1 h. The solids were collected via filtration, rinsed with a small amount of MeOH and dried under high vacuum at 80° C. to afford N-(2,5-difluoro-4-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (95 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H); 8.54-8.58 (m, 4H); 8.30 (s, 1H); 8.12 (dd, J=6.6, 2.2 Hz, 1H); 7.63-7.72 (m, 2H); 7.54-7.56 (m, 2H); 7.37 (m, 2H); 7.13 (s, 1H); 6.71 (m, 1H); 4.15 (t, J=5.3 Hz, 2H); 3.70 (t, J=5.4 Hz, 2H); MS (ESI) m/z: 548.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O.C(O)(=O)C>[Fe].C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[Cl:1])[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Yield: 99.7 %

Procedure:
A mixture comprising 1.00 g (2.86 mmol) of 4-(4-chloro-3-nitrobenzyl)amino-6-chloroquinazoline, 0.85 g of powdered iron, 10 ml of acetic acid and 50 ml of ethanol was heated under reflux for several hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.91 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH:39]([OH:42])[CH2:40][CH3:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][CH3:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: CCC(O)CN
Product: CCC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-butanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.48 Hz, 3 H), 1.33-1.48 (m, 2 H), 1.49-1.59 (m, 4 H), 1.60-1.75 (m, 4 H), 2.37-2.44 (m, 2 H), 3.17-3.27 (m, 1 H), 3.33-3.42 (m, 4 H), 3.45-3.59 (m, 2 H), 4.16-4.24 (m, 4 H), 4.96 (d, J=5.26 Hz, 1 H), 7.14 (ddd, J=8.95, 6.63, 2.11 Hz, 2 H), 7.38-7.44 (m, 2 H), 8.00 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.44 (t, J=5.16 Hz, 1 H), 17.22 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C>[ClH:1].[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCc3ccccc3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Temperature: 0 °C

Procedure:
At 0° C., a 2-molar solution of hydrogen chloride in diethyl ether is added dropwise to a solution of tert-butyl 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-carboxylate (IV-1, 640 mg). The reaction mixture is stirred at 0° C. and then slowly warmed to room temperature. The mixture is stirred overnight, and the solvent and excess hydrogen chloride are then removed. This gives 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (590 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)(=[O:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:22]([F:23])([F:25])[F:24])([C:26]([F:27])([F:28])[F:29])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1ccc(C2CC(C(O)(C(F)(F)F)C(F)(F)F)=NN2c2ccccc2Cl)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 23.1 %

Procedure:
5-(6-Bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 4 of Preparation 20, 2-acetylphenylboronic acid (8.0 mg, 0.05 mmol), Pd(dppf)Cl2 (3.0 mg, cat.), and a 2N sodium carbonate solution (0.4 mL) were added to N,N-dimethylformamide (0.4 mL). The reaction mixture was stirred at 100° C. for 16 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.O([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])S(C(F)(F)F)(=O)=O>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2[nH]ccc2-c2ccncc2)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccncc2)c1-c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
31 ml (47.4 mmol) of a 1.57 N solution of butyllithium in hexane were added to a solution of 11.30 g (47.4 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 7(i) above] in 300 ml of tetrahydrofuran at −78° C. and the mixture was stirred for 10 minutes. At the end of this time, 13.4 ml (49.8 mmol) of triisopropylsilyl triflate were added to the reaction mixture at the same temperature. After removal of the cooling bath, the mixture was stirred at room temperature for 30 minutes. 200 ml of water and 300 ml of a saturated aqueous solution of sodium hydrogencarbonate were then added to the reaction mixture before extracting with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to give 18.70 g (quantitative yield) of the title compound as a reddish purple oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[N:11]O)[CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: ON=Cc1ccc2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc2cc[nH]c2c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
2-Chloro-1-methylpyridium iodide (1.316 g) was added to a solution of 1H-indole-6-carbaldehyde oxime (D11) (750 mg) in dry THF (80 mL) at RT. After stirring for 10 min, triethylamine (2.284 mL) was added to the reaction mixture. The reaction mixture was heated to 50° C. and stirred at 50° C. for 3.5 hours, then left overnight with stirring at RT. The mixture was heated to refluxed for 5 hours. The solvent was evaporated. The residue was dissolved in EtOAc (100 mL) and water (100 mL) was added. The organic fraction was separated. The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1H-indole-6-carbonitrile (D12) as a brown solid (680 mg). δH (DMSO-d6, 400 MHz): 6.60 (1H, m), 7.32 (1H, dd), 7.68 (1H, m), 7.72 (1H, d), 7.88 (1H, m), 11.68 (1H, br s). MS (ES): C9H6N2 requires 142; found 141.0 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:12].[I:13]N1C(=O)CCC1=O>CC#N>[Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][C:9]([I:13])=[C:4]2[C:3]=1[CH3:12]
Reactant: Cc1c(Cl)oc2c(N)nccc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1c(Cl)oc2c(N)ncc(I)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
2-chloro-3-methylfuro[2,3-c]pyridin-7-amine (1.0 g, 5.5 mmol) in MeCN (30 mL) was treated with N-iodosuccinimide (1.70 g, 7.52 mmol), added portionwise over a 5 min period. The mixture was stirred at RT for overnight. The reaction was quenched with 20% aqueous Na2S2O3 and stirred for 10 min. EtOAc (100 mL) was added and the phases separated. The organic phase was washed with 20% aqueous Na2S2O3, then water and finally with brine. After drying over Na2SO4, the organic extracts were filtered and concentrated in vacuo. The material was purified using flash chromatography (30% EtOAc:DCM) to afford 1.15 g (68%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.73 (br s, 2H), 2.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([O:8][CH2:17][CH3:18])=[CH:6][N:7]=1
Reactant: Oc1cnc(Cl)cc1I
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cnc(Cl)cc1I
Temperature: 25 °C

Procedure:
6-Chloro-4-iodo-pyridin-3-ol (0.41 g, 1.62 mmol) was dissolved in anhydrous DMF (4 mL) and stirred at room temperature. Potassium carbonate (0.67 g, 4.9 mmol) and iodoethane (0.40 mL, 4.9 mmol) were added sequentially. The mixture was heated to 60° C. and maintained for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with diethyl ether (25 mL) and washed with 20% aqueous citric acid (25 mL). The aqueous was extracted with diethyl ether (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane resulting in a tan solid (0.42 g, 91%). 1H NMR (400 MHz, CDCl3): δ7.80 (s, 1H), 7.74 (s, 1H) 4.18 (q, J=7.1 Hz, 2H), 1.51 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:24]([O:26]C)=[O:25])[C:6]2[O:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:23]=1)#[N:2].O[Li].O.CC(O)=O>CO.C(Cl)Cl.O>[C:1]([C:3]1[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[C:6]2[O:10][C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:8][C:7]=2[CH:23]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1cc2c(c(C(=O)O)c1)OC(c1ccccc1)(c1ccccc1)O2
Reaction time: 16 h

Procedure:
To a solution of methyl 6-cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (60 mg, 0.168 mmol, 1 eq.) in a mixture of 3 mL MeOH and 0.5 mL CH2Cl2, a solution of LiOH.H2O (21 mg, 0.5 mmol, 3 eq.) in 3 mL H2O was added. The reaction mixture was vigorously stirred 16 h at r.t., then acidified with 10% AcOH in H2O and extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, and the solvents evaporated under reduced pressure to yield the desired compound as a colorless solid.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][C:6]#[C:7][OH:8])([CH3:4])[CH3:3].CCN(CC)CC.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>CCOCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH2:7][O:8][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C[Si](C)(C)CC#CO
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)OCC#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilyl propyn-1-ol (1 g, 7.8 mmol) and Et3N (1.4 mL, 10 mmol) in Et2O (10 mL) is cooled to −20° C. and a solution of methacryloyl chloride (0.9 mL, 9.3 mmol) in Et2O (5 mL) is added dropwise over 1 h. The mixture is stirred at this temperature for 30 min, and then allowed to warm to ambient temperature overnight. Any precipitated ammonium salts can be removed by filtration, and volatile components can be removed under reduced pressure. The crude product is then purified by flash chromatography.
Reaction SMILES: [C:1](O[K])(C)(C)C.[C:7]([O:11][C:12](=[O:22])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]=O)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8].OS([O-])(=O)=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(=O)OCC>[C:7]([O:11][C:12](=[O:22])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]=[CH2:1])[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CC(C)(C)O[K]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tBuOK (13.78 g, 122.7 mmol) was added in one portion to a white suspension of methyl triphenylphosphonium bromide (43.85 g, 122.7 mmol) in THF (145 mL) at rt under nitrogen. The resulting suspension was stirred for 1 h at rt and a solution of trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (13.95 g, 61.37 mmol) in THF (40 mL) was added. The mixture was stirred 30 min at rt. A 10% NaHSO4 solution (240 mL) was added and the mixture was diluted with EA (500 mL). The two layers were decanted and the aq. layer was extracted once with EA (250 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was quickly filtered (EA-Hept 1-2) to afford the title compound as a white solid (13.58 g).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[N:16]=[CH:15][N:14]=[C:10]3[N:11]=[CH:12][NH:13][C:9]=23)[O:4][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25]Br>CN(C)C=O>[CH2:6]([NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:10]2[C:9]=1[N:13]=[CH:12][N:11]2[CH2:25][CH2:24][Br:23])[C:3]1[O:4][CH:5]=[CH:1][CH:2]=1
Reactant: c1coc(CNc2ncnc3nc[nH]c23)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCn1cnc2c(NCc3ccco3)ncnc21
Yield: 60 %

Procedure:
Kinetin (2 g, 9.3 mmol) and K2CO3 (2.4 g, 23 mmol) were mixed in 100 ml dimethylformamide (DMF). 1,2-Dibromoethane (5.2 g, 27.6 mmol) was added to the reaction mixture and then it was mixed at room temperature for 12 h, humidity was regulated by CaCl2 tube. Solvent was evaporated to dryness in vacuo to yellow solid and then 100 g ice was added. The mixture was shaken at least 1 h to until a white precipitate was formed. The solid was filtered off, washed with water and dried at 50° C. The product was recrystallised from methanol. Yield: 60%. 1H NMR (DMSO-d6): 3.95 (2H, t, J=5.91), 4.58 (2H, t, J=5.91), 4.69 (2H, s (br)), 6.23 (1H, d, J=2.94), 6.36 (1H, t, J=2.94), 7.54 (1H, d, J=2.94), 8.15 (2H, m), 8.24 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([F:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19])(=[O:15])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([F:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:19])[C:17]([O:16][C:13](=[O:15])[CH3:14])([CH3:22])[CH3:21]
Reactant: Nc1ccc(S(=O)(=O)F)cc1Cl
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)C(=O)Nc1ccc(S(=O)(=O)F)cc1Cl
Yield: 49.2 %

Procedure:
A solution of 2-chloro-4-fluorosulphonylaniline (2.5 g, 12 mmol), 2-acetoxyisobutyryl chloride (2.35 g, 14 mmol) and pyridine (1.2 ml, 14.5 mmol), in DCM (50 ml) was stirred at ambient temperature for 18 h. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography using 25% EtOAc/isohexane and the oily product, the title compound (2.0 g, 5.9 mmol), solidified on standing. MS: 336.
Reaction SMILES: [CH:1](N)(C)[CH3:2].C([Li])CCC.[CH3:10][C:11]1([CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18](C(=O)C)[CH:19]=2)[S:14][CH2:13][CH2:12]1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C>O1CCCC1.CCCCCC>[CH3:24][C:11]1([CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:14][CH:13]([C:1]#[CH:2])[CH2:12]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Reactant: CC(C)N
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: C#CC1CC(C)(C)c2ccccc2S1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.441 g (14.2405 mmol) of isopropylamine in 30 ml dry tetrahydrofuran under argon at -78 degrees C. was added dropwise 9ml of 1.6M (14.4 mmol) n-butyl lithium in hexane. After stirring this solution at -78 degrees C. for 1 hour, it was treated dropwise with a solution 2.95 g (13.389 mmol) of 4,4-dimethyl-6-acetyl-thiochroman (Compound 62) in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78 degrees C., the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide [prepared using 2.882 g (28.481 mmol) of diisopropylamine and 18 ml of 1.6M (28.8 mmol) n-butyllithium in hexane] in 60 ml dry tetrahydrofuran at -78 degrees C. The cooling bath was removed and the solution stirred at room temperature for 15 hours, then quenched with water and acidified to pH 1 with 3N hydrogen chloride. The mixture was extracted with 5×50 ml pentane and the combined organic fractions washed with 3N hydrogen chloride, water, saturated NaHCO3 and saturated NaCl, then dried (MgSO4). Solvent was then removed in vacuo, and the residue purified by kugelrohr distillation (100 degrees C., 0.7mm) to give the title compound as a pale yellow solid. PMR (CDCl3): & 1.34 (6H, s), 1.94-1.99 (2H, m), 3.04-3.08 (3H, m), 7.06 (1H, d, J~8.4 Hz), 7.17 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.51 (1H, d, J~2.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:23])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:23])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:16])(=[O:17])[CH2:8]1)=[O:6]
Reactant: COc1c(F)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(F)c(O)c(Cl)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
3-(3-chloro-5-fluoro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (307 mg) was dissolved in N,N-dimethylformamide (6 mL), and lithium chloride (163 mg) was added to the solution, and then the mixture was stirred at 100° C. for 16 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (296 mg) as a pale yellow amorphous product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:20]=[CH:19]2)=[O:15]>ClC(Cl)C>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH:20]=[C:19]2[C:5](=[O:7])[CH3:6])=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)c(C(C)=O)cn2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a suspension of 10.7 g (80 mmol) of aluminum chloride in dichloroethane (80 ml) was added dropwise 4.83 g (40 mmol) of acetic anhydride. After stirring for 15 min, to the mixture was added dropwise 6.31 g (20 mmol) of the above-mentioned 1-benzenesulfonylindole-5-carboxylic acid methyl ester in dichloroethane (60 ml). After stirring for 2 hours at room temperature, to the mixture were added 5.33 g (40 mmol) of aluminum chloride and 2.04 g (20 mmol) of acetic anhydride. After stirring for 30 min, the mixture was poured into ice-water, extracted with ethyl acetate. The extract was washed twice with water, aqueous sodium bicarbonate and dried, and then concentrated. The obtained crystal was washed with isopropyl ether to give 6.82 g of 3-acetyl-1-benzenesulfonylindole-5-carboxylic acid methyl ester. Yield: 96%.