Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[Cl:12]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[Cl:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)O)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
A mixture of 4-methoxybenzoic acid (0.46 g; 3 mmol) and N-chlorosuccinimide (NCS) (0.36 g; 2.7 mmol) in trifluoroacetic acid (5 ml) was stirred for 3 h at ˜70° C. After removing solvent under reduced pressure the residue was treated with H2O (10 ml). The solid was filtered off and purified by FCC (SiO2; EtOAc) to give the title compound (0.38 g; 68%) as a colourless solid. 1H-NMR (CDCl3) 3.97 (s, 3H); 6.96 (d, 1H, J=8.7 Hz); 8.0 (dd, 1H, J=2; 8.7 Hz); 8.11 (d, 1H, J=2 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2[CH:16]=[N:17][C:18]([Cl:20])=[N:19][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]N(C)C(=O)C.IC.[H-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:21])[C:10]2[CH:16]=[N:17][C:18]([Cl:20])=[N:19][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)c2nc(Cl)ncc2N1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)CCN(Cc2ccccc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.144 g (0.0005 mole) of 9-benzyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-22), 1 mL of N,N-dimethylacetamide and 0.047 mL (0.00075 mole) of iodomethane at 0 degrees was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.134 g of 9-benzyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-22) as an yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]#[N:14]>>[C:1]([NH:14][CH2:13][CH2:12][C:11]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCN
Reactant: O=C(Cl)c1ccccc1
Product: N#CCCNC(=O)c1ccccc1

Procedure:
Benzoyl chloride and aminoethylcyanide are reacted to give N-benzoyl-aminoethylcyanide, which is reacted with hydrogen sulfide in ammonia to yield the thioamide, which is reacted with an appropriate a-halo ketone to yield the desired thiazole. Treatment with 5N hydrochloric acid removes the protecting benzoyl group to give the desired amine product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:11][S:12](O)(=[O:14])=[O:13]>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of butylbenzene (4.13 g, 30.8 mmol) in CHCl3 (50 mL) was added chlorosulfonic acid (17 mL, 29.8 g, 256 mmol) and the mixture was stirred at rt for 20 h. The mixture was poured on ice (200 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The yellow oily residue (ca 88% yield) was used without further purification in the next reaction; 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7 Hz), 1.34-1.41 (m, 2H), 1.62-1.67 (m, 2H), 2.73 (t, 2H, J=8 Hz), 7.41 (d, 2H, J=8 Hz), 7.94 (d, 2H, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.[NH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=1.CC(C)N=C=NC(C)C.C(#N)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:24]([F:26])([F:27])[F:25])[CH2:22][CH2:23]3)[C:17]([NH:31][C:32]3[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[CH:34][CH:33]=3)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
188 mg (426 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (racemate), 82.4 mg (426 μmol) of tert-butyl 4-aminobenzoate, 6.1 mg (43 μmol) of Oxima and 66 μl (0.43 mmol) of DIC in 4 ml of dimethylformamide were reacted according to General Method 5B. Following preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)], the title compound was obtained. Yield: 157 mg (59% of theory)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][C:13]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[NH2:21].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[NH2:21][C:11]1[C:10]([O:9][CH3:8])=[C:15]([NH:16][S:23]([CH3:22])(=[O:25])=[O:24])[CH:14]=[C:13]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[CH:12]=1
Reactant: COc1c(N)cc(C2(C)CC2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(N)cc(C2(C)CC2)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 50.4 %

Procedure:
Triethylamine (521 mL, 3.74 mmol) was added to a solution of 2-methoxy-5-(1-methyl-cyclopropyl)-benzene-1,3-diamine (718 mg, 3.74 mmol) in methylene chloride at −10° C. Methanesulfonyl chloride (290 μL, 3.74 mmol) was then added dropwise over a 10 min period and the resultant solution was allowed to slowly warm to rt over 2 h. The mixture was quenched with saturated aqueous NaHCO3 and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ammonium hydroxide/35% ethyl acetate in hexanes to 1% ammonium hydroxide/50% ethyl acetate in hexanes) provided a red solid which was triturated with a diethyl ether/hexanes (1:1) to yield Compound 1 (510 mg, 51%) as a pale brown solid: mp 144–146° C. ESI MS (m/z 271, M+H).
Reaction SMILES: [CH3:1][C:2]1([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[C:20]1(=O)N(C2CCCNC2=O)C(=O)C2=CC=CC=C12>>[CH3:20][O:8][C:3]1[C:2]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]=1
Reactant: CC1(N2C(=O)c3ccccc3C2=O)CCCNC1=O
Reactant: O=C1NCCCC1N1C(=O)c2ccccc2C1=O
Product: COC1=NCCCC1(C)N1C(=O)c2ccccc2C1=O

Procedure:
By analogy with the method described in example 1 (step 1.1), using 2-(3-methyl-2-oxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione (prepared by analogy to the method described in Liebigs Annalen der Chemie (1987), (7), 647-8. Archiv der Pharmazie (Weinheim, Germany) (1989), 322(8), 499-505, (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH2:8][C:9](=O)[CH3:10])(=O)[CH3:6].[ClH:12]>C(O)C>[ClH:12].[SH:3][C:2]1[N:4]=[C:9]([CH3:10])[CH:8]=[C:5]([CH3:6])[N:1]=1
Reactant: NC(N)=S
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)nc(S)n1
Yield: 80 %

Procedure:
76 Grams (1.0 mole) of thiourea was suspended in a solution of 120 g. (1.2 moles) of acetylacetone in 2,500 ml. of ethanol. The resulting suspension was mixed with 250 ml. of concentrated hydrochloric acid, and then reacted under reflux for 2 hours. After completion of the reaction, the reaction liquid was cooled, whereby beautiful yellow needle-like crystals of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride were formed. The reaction liquid was allowed to stand overnight to sufficiently deposit the crystals, which were then recovered by filtration and dried to obtain 140 g. of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride in yield of 80 %.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5](OC)=[O:6].[Li+].[BH4-].C1COCC1>CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:5][OH:6]
Reactant: COC(=O)c1cc(I)c(Oc2ccc(OC)cc2)c(I)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(I)cc(CO)cc2I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a dry 15 ml 2-necked flask fitted with a serum stopper and a reflux condenser under argon was added methyl 3,5-diiodo-4-(4′-methoxyphenoxy)benzoate (1.02 g; 2.0 mmol) followed by 2M LiBH4 in THF (2.0 ml; 4.0 mmol). The mixture was stirred at RT overnight. EtOAc (10 ml) was added to consume excess LiBH4, and the resulting mixture stirred at RT under argon. After approximately 20 min, a moderate exotherm was observed and the reaction became cloudy. The reaction was digested with saturated NH4Cl (20 ml), EtOAc added (20 ml) and the resulting layers partitioned and separated. The organic layer was washed with saturated NaCl (25 ml), then dried over Na2SO4, filtered and evaporated to give a pale amber oil. The crude product was applied to a filter pad of silica gel (10 g, 230-400 mesh) and eluted with EtOAc/hexanes (3:7). Fractions containing product were combined and evaporated to give 592 mg (61%) of the product as a white solid. Crystallization from EtOAc/hexanes afforded 347 mg of 3,5-diiodo-4-(4′-methoxyphenoxy)benzyl alcohol (9) as a crystalline white solid. NMR (CDCl3) d 3.78 (s, 3H), 4.52 (s, 2H), 6.72 (m, 2H), 6.83 (m, 2H), 7.82 (s, 2H). TLC: Rf0.47 (EtOAc/hexanes, 3:7)
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([N:7]1[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]1[CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CNCCN1Cc1ccccc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
tert-Butyl (3S)-3-methylpiperazine-1-carboxylate (380.0 g, 1.897 mol) and benzyl bromide (248 mL, 2.09 mol) were mixed in acetonitrile (440 mL). Triethylamine (300.0 mL, 2.152 mol) was carefully added and the mixture was refluxed overnight. After the mixture was cooled down to room temperature, the solid was filtered out. The filtrate was concentrated. The residue was combined with the solid and dissolved in methylene chloride. The methylene chloride solution was washed with 1N NaOH and dried over magnesium sulfate. After the solvent was removed, the residue was directly treated with 6 N HCl at 0° C., and 3 hours later, the solution was basified by slowly adding solid sodium hydroxide. The resulting mixture was extracted with methylene chloride and the extracts were dried over magnesium sulfate. After removal of the solvent, 330 g (91.4%) of product was obtained. The product was used directly for next step. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.30 (m, 5H), 4.05 (d, 1H), 3.15 (d, 1H), 2.92 (m, 1H), 2.83 (m, 2H), 2.67 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.36 (bs, 2H), 2.06 (m, 1H), 1.14 (d, 3H). MS (EI) 191.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH3:18])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:10]1[C:11]2[C:16](=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(F)ccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)cc21
Yield: 60.9 %

Procedure:
12.68 g (50.7 mmol) 6-Fluoro-3-methyl-indazole-1-carboxylic acid tert-butyl ester, prepared as in Part C, is combined with 9.92 g (55.7 mmol, 1.1 equiv) N-Bromosuccinimide and 1.23 g (5.1 mmol, 0.1 equiv) Benzoyl peroxide in 600 mL CCl4 and refluxed 10 h. The reaction mixture is filtered and the filtrate concentrated in vacuo and purified by flash chromatography on 300 g silica gel eluted successively with DCM/Hexanes (1:2, 3 L), (1:1, 3 L). Appropriate fractions were combined and concentrated in vacuo to give 10.18 g (30.9 mmol) of 3-Bromomethyl-6-fluoro-1-tert-butoxycarbonyl-1H-indazole as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.82 (m, 2H), 7.13 (m, 1H), 4.76 (s, 2H), 1.72 (s, 9H); TLC Rf =0.17 (EtOAc/Hexanes, 1:19).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([O-:9])=[O:8].F[C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[C:20]#[N:21].Cl>CN(C=O)C>[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][C:19]=1[C:20]#[N:21])([O-:9])=[O:8]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
Add cesium carbonate (1.3 g, 4 mmol) to a solution of 2-nitro-aniline (276 mg, 2 mmol) and 2-fluoro-5-trifluoromethyl-benzonitrile (378 mg, 2 mmol) in DMF (10 mL) at room temperature then stir the resulting dark red solution at room temperature for 16 hours and 2 hours at 50° C. Cool down and pour into a mixture of ice and concentrated hydrochloric acid (50 mL, v/v). Extract the aqueous phase with dichloromethane (3×300 mL), wash with water and brine and dry over MgSO4 to yield the title compound as a yellow solid (480 mg, 80%): mp 160-161° C.; 1H NMR (CDCl3) δ 7.14 (ddd, 1H), 7.48 (dd, 1H), 7.58 (dd, 1H), 7.60 (d, 1H), 7.76 (dd, 1H), 7.92 (d, 1H), 8.27 (dd, 1H), 9.63 (bs, 1H). MS (ESI/neg) m/z (rel intensity) 306.1 (100).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>CN(C=O)C.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:2]=[C:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Yield: 78.6 %

Procedure:
1-((1,1'-Biphenyl)-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (1030 mg, 3.3 mmol) is alkylated by treating with 0.31 mL (3.3 mmol) of methyl bromoacetate and 132 mg (3.3 mmol) and 132 mg (3.3 mmol) of 60% NaH/mineral oil in DMF and stirring maintained for about 17 hours. The mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried (MgSO4), and concentrated at reduced pressure. The product is purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1000 mg (79% yield) of ((1-((1,1'-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid methyl ester; mp 99°-102° C.
Reaction SMILES: [CH3:1][S:2](Br)(=[O:4])=[O:3].[CH2:6]([O:9][CH3:10])[CH:7]=[CH2:8].OO.C(N(CC)CC)C>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][S:2]([CH:8]=[CH:7][CH2:6][O:9][CH3:10])(=[O:4])=[O:3]
Reactant: C=CCOC
Reactant: CS(=O)(=O)Br
Agent: OO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COCC=CS(C)(=O)=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
159 g (1 mole) of methanesulfonyl bromide are slowly added dropwise, at 45° C., to a mixture of 78 g (1.07 moles) of methyl allyl ether, 7.5 g of zinc chloride and 3.3 ml of 50% strength hydrogen peroxide. After the exothermic reaction has subsided, the mixture is stirred for a further 30 minutes and is diluted with 450 ml of benzene, and 135 g (1.33 moles) of triethylamine are added at room temperature, whilst cooling. After 2 hours, the precipitate is filtered off and the solvent is distilled off. Distillation of the residue gives 125 g of 1-methylsulfonyl-3-methoxy-prop-1-ene, boiling point 114°-115° C./0.3 mm Hg. According to the NMR spectrum, the product is a mixture of cis and trans isomers in the ratio of 15:85.
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O>N1CCCCC1.C(O)C>[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=Cc1ccc(O)cc1O
Reactant: O=C1C=c2ccccc2=N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1ccc(O)cc1O
Temperature: 25 °C

Procedure:
A mixture of 1.33 g of indole-2-one (10 mmol), 1.38 g of 2,4-dihydroxybenzaldehyde (10 mmol) and 3 drops of piperidine are refluxed in 40 ml of ethanol for 5 hours. The desired product precipitates as a yellow solid during the reaction. After cooling to room temperature, the product is filtered off, washed with ethanol and dried in vacuo. Yield 1.28 g (51%).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.[ClH:24]>[OH-].[Pd+2].[OH-].C(O)C>[ClH:24].[ClH:24].[O:15]1[CH2:16][CH2:17][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13][CH2:14]1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCOCC3)C2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: C1CN(C2CNC2)CCO1
Reaction time: 72 h

Procedure:
A mixture of 1-diphenylmethyl-3-morpholinoazetidine (prepared in an analogous manner to the compound of preparation 22 above) (18.6 g), palladium hydroxide (2 g), ethanol (200 ml) and 1N aqueous hydrochloric acid solution (52 ml) was stirred under an atmosphere of hydrogen at 345 kPa (50 p.s.i.) for 3 days. The catalyst was then removed by filtration and the filtrate evaporated to dryness. Addition of dichloromethane (100 ml) to the residue and trituration gave a solid which was recrystallised from methanol to give the title compound (10.2 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12]CC[CH2:9][O:8]1)=[N+:2]=[N-:3].[CH3:13]C1(C)OC(COS(C2C=CC(C)=CC=2)(=O)=O)CO1>>[N:1]([CH2:4][CH:5]1[CH2:9][O:8][C:7]([CH3:12])([CH3:13])[O:6]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: [N-]=[N+]=NCCOC1CCCCO1
Product: CC1(C)OCC(CN=[N+]=[N-])O1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 408, using toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (37.8 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 20:80 as the eluent to afford the title compound as colourless foam.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:27]=[CH:26][N:13]([C@@H:14]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:15]2[O:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:28])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:32]([O:51][CH3:52])=[C:33]([CH:48]=[CH:49][CH:50]=1)[C:34](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([NH:9][C:10]1[CH:27]=[CH:26][N:13]([C@@H:14]2[O:25][C@H:22]([CH2:23][O:24][C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:33]3[CH:48]=[CH:49][CH:50]=[C:31]([O:30][CH3:29])[C:32]=3[O:51][CH3:52])[C@@H:20]([OH:21])[C@H:15]2[O:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:28])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Product: CCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 49 %

Procedure:
N4-Benzoyl-2'-O-propylcytidine (3.0 g, 0.007 mol) was treated with dimethoxytrityl chloride (1.5 g) as per the procedure of Example 72 to give 1.5 g of pure product. Anal. Calcd. for C40H42N3O8. 1/2H2O: C, 68.45; H, 6.18; N, 5.99. Found: C, 68.39; H, 5.99; N, 5.95.
Reaction SMILES: C1(NN[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=C(NNc1ccccc1)c1ccc(F)cc1F
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a stirred mixture, under nitrogen, of 49.6 g of 2,4-difluorobenzoic acid, 2-phenylhydrazide, 64.3 g of triphenylphosphine, and 500 ml of anhydrous acetonitrile was added 19.3 ml of carbon tetrachloride. The reaction mixture was stirred at ambient temperature for about 16 hours, concentrated, and extracted with diethyl ether (3×). The diethyl ether extract was filtered and concentrated to a residue, which was flash chromatographed on silica gel, eluting first with ethyl acetate-hexane and, in a subsequent run, with ethyl acetate alone. Concentration of the appropriate fractions yielded 47.5 g (89%) of α-chloro-2,4-difluorobenzaldehyde, phenylhydrazone.
Reaction SMILES: [C:1]1(=[O:14])C2C(C3C(C=2)=CC=CC=3)=CN=N1.[CH:15]1[C:28]2[C:19](=[CH:20][CH:21]=[C:22]3[C:27]=2[CH:26]=[CH:25][CH:24]=[N:23]3)[N:18]=[CH:17][CH:16]=1>>[CH3:1][O:14][C:20]1[CH:21]=[C:22]2[C:27]([CH:26]=[CH:25][CH:24]=[N:23]2)=[C:28]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: c1cnc2ccc3ncccc3c2c1
Reactant: O=C1N=NC=C2C1=Cc1ccccc12
Product: COc1cc2ncccc2c2cccnc12

Procedure:
Some phenanthrolines are very reluctant to undergo the usual basic oxidative rearrangement to the corresponding diazafluorenone. This is true of 4,7-phenanthroline, for instance. In this case, one uses 2-methoxyparaphenylenediamine in a double Skraup synthesis to produce the enolether, 5-methoxy-4,7-phenanthroline (150). Reaction of it with concentrated sulfuric acid and fuming nitric acid yields 4,7-phenanthrolin-5,6-quinone (151). The quinone undergoes oxidative rearrangement to produce 1,8-diazafluoren-9-one (152). Hydrazine reduction produces 1,8-diazafluorene (153) which is alkylated to the target compound, 9,9-bis(4-pyridinylmethyl)-1,8-diazafluorene (154). Other diazafluorenes produced by this method include 1,5-diazafluorene, (Scheme 67, 157), 1,6-diazafluorene, 2,5-diazafluorene, 3,5-diazafluorene, and 4,5-diazafluorene. See references for Scheme 64 and: French patent 1,382,542; French patent 1,369,626, U.S. Pat. No. 2,640,830, Swiss patent 275,433. ##STR87##
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[C:20]([CH:34]2[CH2:36][CH2:35]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:41]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:41])[C:20]([CH:34]2[CH2:36][CH2:35]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 241, 2.28 g, 4.35 mmol) following the procedure described for Intermediate 20. The desired product was obtained as an orange foam (1.07 g, 47%).