Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.[OH-:15].[K+]>O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][CH2:11][CH2:12][CH2:13][O:15][C:5]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCCCBr
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Oc1ccc(OCCCCOc2ccc(O)cc2)cc1
Reaction time: 8 h
Yield: 46 %

Procedure:
A five neck five liter round bottom flask equipped with a mechanical stirrer, two condensers, and a dropping funnel is purged with nitrogen then charged under a nitrogen blanket with 1.25 kg (11.36 moles) hydroquinone, 350 grams deionized water, and 231.25 grams (1.07 moles) 1,4-dibromobutane. The reaction mass becomes a stirable slurry as it is slowly heated to reflux under a slow nitrogen purge. A solution of 180 grams (2.7 moles) 85% KOH pellets in 180 grams water is added dropwise under a nitrogen blanket over a two hour period. After about one third of the KOH has been added, the slurry has converted to a tea colored solution; then, after most of the KOH has been added, a white material precipitates in increasing amounts as the refluxing is continued an additional hour. The reaction mixture is quenched before cooling by pouring into 6 liters deionized water. The water slurry is acidified with 30% sulfuric acid and allowed to stand at room temperature overnight before filtering under reduced pressure and washing with several portions of boiling water to remove hydroquinone. The white residue is dried in a vacuum oven at 140° C. to a weight of 240 grams. It is then taken up in 4 liters boiling MEK, treated with decolorizing carbon and filtered through a filter acid, celite, to remove particulates and colored impurities. A total of 154 grams of a white produce is recovered from a series of filtrates. Analysis by gpc shows contamination by higher molecular weight species which are much less soluble in acetone than the desired product; thus, the produce is taken up in boiling acetone, filtered, and cooled to recover 135 grams (46% yield based on the dibromobutane). HPLC analysis showed >90% purity by peak area. Another crystallization from 3 liters boiling acetone yield 116 grams of white "mica-like" crystals (melting point 202° C.-204° C.) with greater than 96% purity by HPLC peak area for use in example 11 and 22. Both 1H and 13C NMR spectra are consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([CH3:21])[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:8][CH:7]=2.[ClH:22]>CCOC(C)=O>[ClH:22].[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([CH3:21])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(C(C)C(=O)OC(C)(C)C)cc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cnc2ccc(C(C)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
Tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate (0.865 g, 3.01 mmol) was dissolved in EtOAc (0.2M, 15 mL), and HCl (g) (0.0915 ml, 3.01 mmol) was bubbled through the solution for approximately 5 minutes. The reaction vessel was sealed and the reaction was stirred at room temperature for 1.5 h until completion. The reaction mixture was concentrated in vacuo to yield 2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride (0.805 g, 99.9% yield) as an orange solid.
Reaction SMILES: [C:1]([CH:3]1[C:7](=[O:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:3]1([CH3:16])[C:7](=[O:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C(C)(C#N)C1
Yield: 55.1 %

Procedure:
To a solution of 1,1-dimethylethyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate (3.9 g, 18.6 mmol) in acetone (185 mL) were added K2CO3 (3.07 g, 22.3 mmol) and MeI (1.39 mL, 22.3 mmol). After 12 h at reflux, the solution was cooled and the solid precipitate filtered. The filtrate was then concentrated and the residue purified by column chromatography (silica, 0.5% MeOH in DCM (1% NH4OH)) affording the title compound (2.3 g, 55%) as a yellow oil: LCMS (ES) m/e 225 (M+H)+.
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].C([C:28]1[S:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][CH:29]=1)=O>CCCCCC>[CH3:3][O:2][CH:1]([O:4][CH3:5])[C:28]1[S:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: COC(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: CCCCCC
Product: COC(OC)c1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethyl orthoformate (7.5 ml) and montmorillonite K-10 (5.0 g) (Aldrich Chem. Co., Milwaukee, Wis.) were mixed and stirred at room temperature for 10 minutes. A solution of 5-formyl-2,2'-bithiophene (5.0 g) (Aldrich Chem. Co., Milwaukee, Wis.) in n-hexane (10 ml) was added and was stirred at room temperature. The reaction was monitored with thin layer chromatography until the reaction was completed. Montmorillonite K-10 was filtered. The filtrate was added to a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (15 ml×3). The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give light yellowish oily product (6.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:28]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:28]=[C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[C:19]2=[O:21]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: COc1cccc(CC(=O)O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (1.74 g, 12 mmol), 3-methoxyphenylacetic acid (2.0 g, 12 mmol), BF3Et2O (5 ml), PCl5 (3.75 g, 18 mmol), DMF (15 ml and 10 ml). 6-Chloro-7-hydroxy-3-(3-methoxy-phenyl)-chromen-4-one precipitated out as a white solid (1.6 g, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[C:27]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C:27]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([CH2:24][O:23][CH2:22][C:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[CH:26]=2)=[CH:40][CH:39]=1)#[N:42]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2Br)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2-c2ccccc2)CC1
Temperature: 120 °C
Yield: 40.3 %

Procedure:
A mixture of tert-butyl 4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate (100 mg, 0.15 mmol), phenyl boronic acid (19 mg, 0.15 mmol), potassium carbonate (43 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.15 mmol) were placed in a sealable vessel and degassed with nitrogen for 5 min. The vessel was then sealed and heated at 120° C. for 3 h. The reaction was poured into brine (20 mL) and extracted with ethyl acetate (4×5 mL). The combined organic layers were dried (MgSO4) and evaporated to dryness. The resulting residue was purified by chromatography on SiO2 with a ethyl acetate/hexanes gradient from 12% to 100%. The product tert-butyl 4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(5-fluorobiphenyl-2-yl)piperidine-1-carboxylate (39 mg, 39%) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.68-7.76 (m, 3H), 7.55 (d, J=8.4 Hz, 2H), 7.44 (m, 3H), 7.18-7.28 (m, 3H), 7.03 (m, 1H), 6.94 m, 2H), 6.67 (m, 1H), 4.52 (s, 2H), 3.52 (m, 2H), 3.47 (s, 2H), 2.90 (m, 2H), 1.91 (m, 2H), 1.45 (m, 2H), 1.38 (s, 9H). Mass spec.: 645.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[CH2:12][C@@:11]3([CH3:16])[C@H:7]([CH2:8][N:9](C(OCC)=O)[CH2:10]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C.Cl>ClCCl.CO>[ClH:1].[Cl:1][C:2]1[C:14]2[C:13](=[O:15])[CH2:12][C@@:11]3([CH3:16])[C@H:7]([CH2:8][NH:9][CH2:10]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1C[C@@H]2c3cccc(Cl)c3C(=O)C[C@]2(C)C1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@]12CNC[C@@H]1c1cccc(Cl)c1C(=O)C2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 10.9 %

Procedure:
cis-Ethyl 6-chloro-3a-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-benzo[e]isoindole-2(9bH)-carboxylate (0.162 mmol, 50 mg) was dissolved in dichloromethane (1 ml). Iodotrimethylsilane (0.487 mmol, 0.070 ml, 98 mg) was added and the reaction mixture was heated to 100° C. for 30 minutes in the microwave. 2 N HCl in MeOH (2 ml) was added to the reaction mixture was stirred at rt for 20 minutes. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 2 N HCl and washed with ether. The acidic extract was basified using 4 N NaOH and extracted with ether. The ether extract was then dried over magnesium sulphate, filtered and concentrated in vacuo to give a crude residue that was purified by basic prep-HPLC. The purified fractions were concentrated in vacuo and then redissolved in 2 N HCl in MeOH and concentrated in vacuo to give cis-6-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H-benzo[e]isoindol-5(9bH)-one hydrochloride (2.4 mg), m/z=236.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[CH3:22][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc(N)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 7.6 %

Procedure:
0.6 g of 4-fluoronitrobenzene, 0.807 g of 4-aminoquinaldine, and 0.705 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 6 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.09 g of 2-methyl-N-(4-nitrophenyl)quinol-4-amine (13) was obtained after purification by chromatography on a column of silica (eluent: 50/50 dichloromethane/heptane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[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]([O:23][C:24]([F:27])([F:26])[F:25])[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:17])(=[O:16])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1OC(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c(OC(F)(F)F)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 14 h
Yield: 44.8 %

Procedure:
3-(3-chloro-4-methoxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (420 mg) was dissolved in N,N-dimethylformamide (5 mL), and lithium chloride (421 mg) was added to the solution, and then the mixture was stirred at 120° C. for 14 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 crystallized from n-hexane-ethyl acetate to obtain the title compound (182 mg) as a colorless crystal.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([F:30])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([F:30])=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: COc1cc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)cc1F
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c12) the title compound is obtained as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([NH:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=O.[OH2:30]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:17](=[O:30])[N:16]([CH3:18])[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: O
Reactant: CNC(c1ccccc1)c1cc(Cl)ncc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1C(=O)Nc2cnc(Cl)cc2C1c1ccccc1

Procedure:
6-Chloro-4-(methylamino-phenyl-methyl)-pyridin-3-ylamine (100 mg, 0.323 mmol) and 1,1′-carbonyl-diimidazole (100 mg, 0.586 mmol) are stirred in THF (5 mL) at room temperature for 1.5 hours. The reaction mixture is added to water and the aqueous phase extracted with dichloromethane. The organic phase is dried over magnesium sulfate. The solvent is removed in vacuo and the residue purified by column chromatography on silica gel using a dichloromethane/methanol gradient. The product fractions are evaporated to dryness to provide the desired compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:23])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH3:28]I>CN(C)C=O>[F:1][C:2]([F:24])([F:25])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:23])[CH:10]=1)([O:8][CH3:28])[C:4]([F:6])([F:5])[F:7]
Reactant: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C)cc(C(OC)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 1 h

Procedure:
To ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate (6.0 g=16 mmol) in 60 ml dry dimethylformamide add sodium hydride dispersion in mineral oil (0.85 g=18 mmol). Stir 1 hour and add methyl iodide (3.0 g=21 mmol). Let stir 2 hours and partition between water and ether. Wash the ether layer with water, dry and concentrate. Recrystallize from ether-hexane to obtain ethyl 2-[4-(hexafluoro-2-methoxy-2-propyl)-2,6-dimethylphenoxy]acetate, m.p. 97°-98° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]=[C:13]([CH2:24][CH3:25])[CH2:14][CH2:15][C:16]1([OH:23])[CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17]1>C(Cl)Cl>[CH2:24]([C:13]1([CH2:12][OH:9])[CH2:14][CH2:15][C:16]2([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22]2)[O:23]1)[CH3:25]
Reactant: C=C(CC)CCC1(O)COCCOC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC1(CO)CCC2(COCCOC2)O1
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a stirred solution of 3.22 g of 3-chloroperbenzoic acid dissolved in 20 ml of methylene chloride under nitrogen, was added dropwise 3.05 g of tetrahydro-6-(3-methylenepentyl)-1,4-dioxepin-6-ol while maintaining the temperature below 30° C. using a water bath. After six hours and 20 minutes, the reaction mixture was washed with a 25% solution of potassium carbonate and a saturated sodium chloride solution, dried and stripped to yield 2.10 g of the desired product as a dark brown liquid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][O:23][CH3:24].CCOC(C)=O>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:22][O:23][CH3:24])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(C)(C)C)nn1COC

Procedure:
Method I was used with ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (1078 mg, 5.49 mmol), caesium carbonate (2.89 g, 8.87 mmol) and chloro(methoxy)methane (426 μl, 5.60 mmol). 16 hours reaction time. Column eluent: 0→10% EtOAc in CH2Cl2. Yield: 485 mg (37%) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[NH:6][C:5]2=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:6][C:5]3=[O:19])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccc(F)cc1
Solvent: c1ccncc1
Product: O=c1[nH]n(Cc2ccc(F)cc2)c2ccc(NS(=O)(=O)c3cccc(Cl)c3)cc12
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.9 %

Procedure:
To a solution of 5-amino-1-(4-fluoro-benzyl)-1,2-dihydro-indazol-3-one (0.100 g) in pyridine (1 mL) was added 3-chlorobenzenesulfonylchoride (0.082 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired 3-chloro-N-[1-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl]-benzenesulfonamide (0.087 g) as a brown solid. MS (ESI+): 432.4 [M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:10][C:9]([CH3:12])=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=Cc1ccc(F)cc1)CO
Solvent: ClCCl
Product: CC(=Cc1ccc(F)cc1)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 53.6 g (0.32 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-ol in 100 ml methylene chloride was added dropwise a solution of 57.1 g (0.48 mole) of thionyl chloride in 100 ml methylene chloride. The reaction mixture was stirred at room temperature for 2 hours, then concentrated by rotary evaporation. The product was checked by NMR, then used crude in the reaction with ammonia.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].CC(C)([O-])C.[K+].[CH3:14][O:15][CH2:16][CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH:29]([CH:43]([CH3:45])[CH3:44])[CH2:30][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38](C)([CH3:40])C)C3CO3)[CH:26]=2)[N:21]([CH3:46])[CH:20]=1>CS(C)=O>[CH3:14][O:15][CH2:16][CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH:29]([CH:43]([CH3:45])[CH3:44])[CH2:30][CH:31]3[CH:38]([CH2:40][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])[O:37][C:36](=[O:42])[NH:35]3)[CH:26]=2)[N:21]([CH3:46])[CH:20]=1
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Reactant: O=C1CCCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCc1cn(C)c2ccc(CC(CC3NC(=O)OC3CN3CCCCC3=O)C(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.115 g of piperidin-2-one, 0.136 g of potassium tert-butoxide in 3 ml of dimethyl sulphoxide is stirred at room temperature over 30 minutes, admixed with 0.26 g of tert-butyl {3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methyl-1-oxiranylpentyl}carbamate (Example 3Ab) and subsequently stirred further at room temperature overnight. The reaction mixture is poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH2:9]([NH2:12])[C:10]#[CH:11]>C(#N)C>[C:1]([NH:3][C:4](=[N:12][CH2:9][C:10]#[CH:11])[S:5][CH3:6])#[N:2]
Reactant: C#CCN
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: C#CCN=C(NC#N)SC
Reaction time: 12 h
Yield: 81.3 %

Procedure:
A solution of dimethyl cyanodithioimidocarbonate (16.0 g; 0.109 mole) and propargylamine (6.03 g; 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, then at ambient temperature for 12 hours. Workup gave 13.58 g (85%) of N-cyano-N'-(2-propyn-1-yl)-S-methylisothiourea; mp 160°-164°.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O.N#N>>[CH2:1]([N:3]1[C:20]([CH3:22])=[CH:19][C:18](=[O:23])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCNC(=CC(=O)OCC)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: N#N
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)n(CC)c(C)cc1=O
Temperature: 170 °C
Yield: 33.3 %

Procedure:
6 g of ethyl beta-ethylamino-4-chlorocinnamate and 12 g of ethyl acetoacetate is mixed in a 50 ml 3-neck flask fitted with a N2 -inlet, magnetic stirring bar, thermometer and a short-path distillation head (with receiver). The reaction mixture is heated (170° C.) for 10 hours. Ethanol and water is collected in the distillation receiver. The reaction mixture are cooled and triturated with ethyl acetate/ether to yield 2.52 g of ethyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:14]Br>C(Cl)(Cl)(Cl)Cl.[W]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC
Yield: 96.1 %

Procedure:
To a refluxing mixture of methyl 2-methoxy-4-methyl-benzoate (21.625 g, 120 mmol) in CCl4 (240 mL) was added dropwise a solution of bromine (6.19 mL, 120 mmol) in CCl4 (75 mL) over 1.5 h. During the bromine addition the reaction was irradiated with a 250 W tungsten lamp. After the addition, the reaction was refluxed for 15 min and concentrated, and vacuum pumped to give methyl 2-methoxy-4-(bromomethyl)benzoate as an oil (29.864 g, 96%).