Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(OCC)(=O)C.O>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: Fc1cc(Br)cc2c1NC(=S)CC2
Reactant: CC(=O)NN
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Temperature: 25 °C

Procedure:
A suspension of 6-bromo-8-fluoro-3,4-dihydroquinoline-2(1H)-thione (157-4, 1.71 g, 6.57 mmol) and acetohydrazide (0.58 g, 7.89 mmol) in n-butanol (7 mL) was refluxed for 18 h under inert atmosphere. After cooling down to ambient temperature, ethyl acetate (10 mL) and water (10 mL) were added. Then the organic phase was separated, and the water phase was extracted with ethyl acetate (5×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The crude compound was purified by flash chromatography on silica gel to obtain title compound (white solid). 1H NMR (DMSO-D6, 500 MHz) 6=7.79 (dd, J=2.0 Hz, JHF=11.0 Hz, 1H), 7.63 (s, 1H), 2.95 (br s, 4H), 2.46 (d, JHF=8.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[C:23]2[OH:28]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:23]1[C:24]2[C:19](=[C:18]([O:17][CH3:16])[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1cccc2c(O)cccc12
Product: COc1cc2nccc(Oc3cccc4c(OC)cccc34)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 13.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (85 mg) and 5-methoxy-1-naphthol (67 mg) obtained in Example 5 were mixed and stirred at 180° C. for 20 minutes, and the reaction mixture was then purified in the same manner as described in Example 2 to obtain 19 mg of the title compound (yield: 14%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 2.5 °C

Procedure:
In a 1.0 L 4-necked RB flask fitted with a mechanical stirrer and a reflux condenser and under a nitrogen blanket, 1-tert-butyl(2S,4R) 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (100 gm) and dichloromethane (1000 ml) were added at a temperature 25-35° C. while stirring. The reaction mixture was cooled to 0-5° C. and triethyl amine (18.2 g, 0.180M) was added. The reaction temperature was maintained for 15 min and then methane sulfonyl chloride (16.6 g, 0.145M) was added dropwise at 0-5° C. while stirring. The reaction mixture was maintained for 3-4 hr at 0-5° C. The reaction was monitored by TLC. After ascertaining the completion of the reaction, water (168 ml) was added while stirring and the layers were separated. One more dichloromethane (600 ml) extraction was given to aqueous layer. Two water washings were given to the MDC layer. The dichloromethane layer was dried over anhydrous sodium sulphate. The MDC layer (95%) was concentrated under vacuum below 45° C. After distillation n-hexane (600 ml) was added and the mixture stirred for 20 min at 0-5° C. The solid precipitate was filtered and the product was washed with hexane (200 ml). The product was dried at 40-45° C. under vacuum.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[O:15][C:14]([C:16]2[S:20][C:19]([CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:13][N:12]=1>N1C=CC=CC=1>[ClH:9].[N:22]1([CH2:21][C:19]2[S:20][C:16]([C:14]3[O:15][C:11]([NH:10][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:12][N:13]=3)=[CH:17][CH:18]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Solvent: c1ccncc1
Product: Cl
Product: O=C(Nc1nnc(-c2ccc(CN3CCCCCC3)s2)o1)c1ccccc1
Temperature: 80 °C
Reaction time: 240 h
Yield: 57.5 %

Procedure:
1.8 ml (15.0 mmol) of benzoyl chloride was added to 15 ml of pyridine solution containing 278 mg (1.0 mmol) of the compound of Example 43, and the mixture was stirred at 80° C. for 10 days. The reaction solution was concentrated under a reduced pressure, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated, the resulting residue was purified by a silica gel column chromatography. Then, the resulting crude crystals were recrystallized from ethanol-diisopropyl ether to give 241 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].COCCOC.[OH-].[Na+].Cl[CH:20]([F:22])[F:21]>O>[F:21][CH:20]([F:22])[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: FC(F)Cl
Reactant: N#Cc1c(O)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(F)cccc1OC(F)F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
150 g (1.1 mol) of 2-fluoro-6-hydroxybenzonitrile were introduced into 2000 ml of ethylene glycol dimethyl ether. Then, 262.8 g (3.3 mol) of concentrated NaOH were added dropwise. The reaction mixture was heated to 65° C. and 95 g (1.1 mol) of chlorodifluoromethane were passed in. The mixture was stirred at 65° C. for one hour and at room temperature overnight. Then, the reaction mixture was stirred into 3 l of water, followed by extraction repeated three times with a total of 800 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution and dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 211 g (99% of theory) of the desired product with a purity of 97% according to GC. 1H NMR (in CDCl3): δ=6.5-6.9 ppm (t, 1H, OCF2H), 7.15 ppm (m, 2H, arom. H), 7.65 ppm (m, 1H, arom. H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOc1cc(N)c2ncccc2c1
Agent: CN(C)c1ccncc1
Product: CCOc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1
Yield: 32.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-ethoxyquinolin-8-amine (Intermediate 47) (150 mg, 0.8 mmol), benzenesulfonyl chloride (170 mg, 0.96 mmol) and DMAP (cat.) gave the title compound (85 mg, 33%) after purification by column chromatography with n-hexane/DCM (1:0-0:1) as the eluent and recrystallisation from DCM/n-pentane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]2[C:11]=1[C:10](=[N:15][OH:16])[CH2:9][CH2:8]2
Reactant: NO
Reactant: COc1ccc(C)c2c1C(=O)CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C)c2c1C(=NO)CC2
Yield: 87.2 %

Procedure:
7-Methoxy-4-Methyl-1-indanon (1.0 g, 0.006 mol) was dissolved in ethanol (10 mL) and hydroxylamine hydrochloride (0.8 g, 0.012 mol) and sodium acetate (0.96 g, 0.012 mmol) were added. The reaction mixture was heated to reflux for 3 h. Then water (10 mL) was added and a precipitation formed which was filtered. The precipitate was washed with water, isolated and dried under high vacuum to yield 7-methoxy-4-methyl-indan-1-one oxime (1.0 g, 92%) as a white solid; MS: m/e=192.4 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][Li].ClCCCC#C.C([Li])CCC.[CH:19]([B:23](OC(C)C)[O:24][CH:25]([CH3:27])[CH3:26])([CH2:21][CH3:22])[CH3:20].Cl.C(OCC)C>O1CCCC1>[CH:19]([B:23]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][Cl:1])[O:24][CH:25]([CH3:27])[CH3:26])([CH2:21][CH3:22])[CH3:20]
Reactant: [Li]C#CCCCCl
Reactant: CCC(C)B(OC(C)C)OC(C)C
Agent: C#CCCCCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C)B(C#CCCCCl)OC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran (THF) solution of 5-chloro-1-pentynyllithium prepared from 5-chloro-1-pentyne (5.43 g, 53 mmol) and n-butyllithium (20.4 mL, 53 mmol) cooled to -78° C. was added sec-butyldiisopropoxyborane (8.74, 48 mmol) in 48 mL THF. The reaction mixture was stirred at -78° C. for an additional 1 h, then quenched with hydrogen chloride in ethyl ether (15.5 mL, 53 mmol). The cooling bath was removed and the reaction mixture allowed to warm to room temperature. The lithium chloride was allowed to settle and the clear supernatant was decanted via a double-ended needle into a distillation flask. The remaining solid lithium chloride was washed with THF, 2×15 mL, and added to the distillation flask. Volatiles were removed with reduced pressure, followed by high vacuum distillation. Yield: 9.5 g (92%), bp 72°-74° C. (0.1 mm Hg); n20D 1.4496; proton NMR (CDCl3) δ4.43 (septet, J=18 Hz, 1H), 3.60 (triplet, J=18 Hz, 2H), 2.47 (triplet, J=18 Hz, 2H), 1.17 (d, J=18 Hz, 6H), 0.87 (m,6H); boron NMR (EE) δ+41.3 ppm (s); mass spectrum (chemical ionization, isobutane), m/e 213 (M+H, 8%). IR (thin film) 2185, 1325 cm-1. Anal. Calcd. for C12H28BCLO: C, 63.06; H, 9.70; B, 4.73. Found: C, 63.14; H, 9.60; B, 4.48.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:28]([O:30][P:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34])[CH3:29].[H-].[Na+]>O1CCOCC1>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][P:31]([O:32][CH2:33][CH3:34])([O:30][CH2:28][CH3:29])=[O:35])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1

Procedure:
The title compound was prepared by reaction of BocTyrOBzl (371 mg, 1 mmol) and diethylphosphorochloridate (258 mg, 1.5 mmol) with an excess of NaH (60% in mineral oil) in dry dioxane for 3.5 h at 50° C. under argon atmosphere The solvent was concentrated in vacuo and the residue was dissolved in EtOAc and washed several times with a 5% solution of NaHCO3, a 10% solution of citric acid and a solution of satured NaCl. The organic phase was dried (Na2SO4) and concentrated, giving an oil 254 mg (50% yield), that was used without purification for the next step. FAB mass spectroscopy: m/z 508 [MH]+, 530 [MNa]+. H1NMR (200 Mhz, CDCl3) d (ppm)=7.4-6.85 (m, 9H, aromatics), 5.1 (d, 2H, COOCH2—F), 4.6 (m, 1H, N—CH—CO), 4.3-4 (m, 4H, P—O—CH2—CH3), 3 (t, 2H, CH—CH2—F), 1.4 (m, 15H, CH3− CH2+ tBu).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].C(OC(=O)C[N:12]1[CH2:17][CH2:16][C:15](=[C:18]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[CH2:22][CH2:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)[CH2:14][CH2:13]1)C.[CH3:35]O>>[Cl:33][C:30]1[CH:31]=[CH:32][C:19]2[C:18](=[C:15]3[CH2:14][CH2:13][N:12]([CH:1]([OH:4])[CH3:35])[CH2:17][CH2:16]3)[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[CH2:22][CH2:21][C:20]=2[CH:29]=1
Reactant: CO
Reactant: CCOC(=O)CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CC(O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
An aqueous solution of potassium carbonate (299 mg, 2.16 mmol, 5 ml water) was added to a solution of ethyl-(4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-[ 1,2- b]pyridin-11-ylidene)piperidin-1-yl)acetate (214 mg, 0.54 mmol) in methanol (20 ml). The reaction was stirred at room temperature for 24 hours followed by 3 hours at 800° C. Methanol was removed under reduced pressure and the residue partitioned between DCM and brine. The crude product was purified by chromatography on silica gel using a gradient elution of 5% methanol in DCM. Product containing fractions were combined and solvent evaporated to leave 4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}-piperidin-1-yl-ethanol as a white solid (136 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1cccc2ccc[n+]([O-])c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc2ccc(Cl)nc12
Temperature: 80 °C
Yield: 81.5 %

Procedure:
To a solution of 8-methylquinoline 1-oxide (0.440 g, 2.764 mmol) in toluene (10 ml) was added phosphoryl trichloride (1.265 ml, 13.82 mmol), and the reaction was heated to 80° C. for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude material was taken up in EtOAc and washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.4 g, 2.252 mmol, 81.47% yield).
Reaction SMILES: [F:1]C1OC(OC2(CCCCCC(C)C)CCCC(F)O2)(CCCCCC(C)C)CCC1.[C:32]1([CH3:42])[CH:37]=C[C:35](S([O-])(=O)=O)=[CH:34][CH:33]=1.[NH+]1C=CC=CC=1.[CH3:49][CH2:50][OH:51]>>[F:1][C:32]([CH3:42])([CH3:37])[CH2:33][CH2:34][CH2:35][CH2:49][CH2:50][OH:51]
Reactant: CC(C)CCCCCC1(OC2(CCCCCC(C)C)CCCC(F)O2)CCCC(F)O1
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C)(F)CCCCCO
Reaction time: 41 h

Procedure:
A stirred solution of the product from Step I (3.34 g, 0.0144 mol) in absolute EtOH was treated with pyridinium p-toluenesulfonate (0.47 g, 0.00187 mol) and kept under nitrogen at ambient temperature for 41 hours. The mixture was concentrated and the residue, dissolved in EtOAc, was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 5 to 20% EtOAc-hexane to give 1.86 g of 6-fluoro-6-methyl -1-heptanol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:20])[N:4]=1.[C:21](=N)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCCl>[C:21](=[N:1][CH2:2][C:3]1[N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11](=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:20])[N:4]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cccc2nc(CN)n(-c3ccccc3)c(=O)c12
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: Cc1cccc2nc(CN=C(c3ccccc3)c3ccccc3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-aminomethyl-5-methyl-3-phenyl-3H-quinazolin-4-one (2.91 g, 11.0 mmol), benzhydrylideneamine (2.39 g, 13.2 mmol), and 1,2-dichloroethane (15 mL). The reaction mixture was heated at reflux for 4 h under nitrogen atmosphere and then cooled to ambient temperature. Concentration under reduced pressure followed by purification by column chromatography afforded the compound 162 as an orange solid. m.p. 49° C. (dec); 1H NMR (DMSO-d6) δ (ppm) 7.22-7.78 (m, 17H), 6.74 (m, 1H), 4.17 (S, 2H), 2.74 (s, 3H); m/z=430 (M+H). The reaction described above and compound 162 are shown below.
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.B(I)(I)I>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([C:11]23[CH2:12][CH:13]4[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[O:10])=[CH:21][CH:22]=1
Reactant: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Agent: IB(I)I
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(O)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 3.0 g. of N-(4-methoxybenzyl)-1-adamantanecarboxamide in 25 ml. of methylene chloride and cool the solution to about -78° C. Add 2.6 g. of boron triiodide and allow the reaction mixture to warm up to about 0° C. with vigorous stirring. Stir the reaction mixture at about 0° C. overnight, then follow the procedure described in Example 6B and crystallize the residue obtained thereby from ethyl acetate to obtain the product of this Example, m.p. 196°-198° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[S-:13][C:14]#[N:15].[Na+].BrBr.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]#[N:15])=[CH:11][N:12]=1
Reactant: N#C[S-]
Reactant: c1ccc(Nc2nccs2)nc1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CSc1cnc(Nc2ccccn2)s1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(pyridin-2-yl)thiazol-2-amine (4.26 g, 24 mmol) and sodium thiocyanate (3.9 g, 48 mmol, 2 eq) in methanol (100 mL) at 0° C., was slowly added bromine (1.23 mL, 24 mmol, 1 eq) over 2 min, then the temperature was raised to 23° C. and the mixture was stirred for 3 h. The resulting suspension was added to stirring cold water (400 mL) and the resulting precipitate was collected by filtration and vacuum dried (4.5 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00-7.08 (1 H, m), 7.11 (1 H, d, J=8.34 Hz), 7.74-7.84 (1 H, m), 7.89 (1 H, s), 8.39 (1 H, d, J=5.05 Hz), 11.93 (1 H, s). LC/MS (M+H)+: 235.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)ccc2Cl)c1Br
Yield: 53 %

Procedure:
2,5-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-dichlorobenzenesulfonyl chloride according to the procedures described in EExample 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 148-150° C., yield 53%.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:23]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36]Br)[CH2:30][CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:23]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][O:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][N:12]=3)=[CH:21][CH:20]=2)[CH2:30][CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCCCCc1cnc(-c2ccc(OCCC[C@H]3CC[C@H](CCCCC)CC3)cc2)nc1

Procedure:
A mixture of 0.5 g of 4-(5-nonyl-2-pyrimidinyl)phenol, 0.55 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 0.91 g of potassium carbonate and 50 ml of absolute butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave pure 2-(4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenyl-5-nonylpyrimidine with m.p. (C--SC) 83° C., transition SC --N 103° C., cl.p. (N-I) 133° C.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[S:13](=O)(=[O:16])([OH:15])[OH:14].ClS(O)(=O)=O.Cl>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[C:5]=1[NH2:4]
Reactant: CC(=O)Nc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=S(=O)(O)Cl
Product: Nc1c(Cl)cc(Cl)cc1S(=O)(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
204 parts of the crude 2,4-dichloroacetanilide are added to 300 parts of 100% strength sulfuric acid, while stirring. Thereafter, the mixture is heated further to 130° C., and 235 parts of chlorosulfonic acid are added dropwise at this temperature in such a manner that the hydrogen chloride gas liberated can readily be removed. Stirring is then continued at from 135° to 140° C. until the sulfonation is complete, this taking about 1 hour. The mixture is then left to cool to 50°-80° C., and is poured into 1300 parts by volume of water. After steam distillation for a short time, 10 parts of pure 2,4,6-trichloroaniline are obtained, as a by-product, in the distillate. The reaction mixture is then cooled to room temperature, and precipitated 2,4-dichloroaniline-6-sulfonic acid is filtered off and washed with dilute hydrochloric acid. 204 parts of 2,4-dichloroaniline-6-sulfonic acid (calculated as 100% pure) are obtained as a colorless aqueous paste, which can be used in moist form for diazotizations. H-NMR in D2O: 7.3 ppm, 7.6 ppm, J: 3 Hz (as the ammonium salt).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.ClC1N=[C:17]([O:19]C)C([N+]([O-])=O)=CC=1>>[Cl:11][C:4]1[N:3]=[C:2]([O:19][CH3:17])[C:7]([C:8]#[N:10])=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Product: COc1nc(Cl)ccc1C#N

Procedure:
6-chloro-2-methoxypyridine-3-carbonitrile was prepared from 2,6-dichloro-pyridine-3-carboxamide in accordance with the procedure described above for the preparation of 6-chloro-2-methoxy-3-nitro-pyridine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([CH3:7])[CH2:5][OH:6].Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][N:11]=1>C1COCC1>[F:3][C:4]([F:8])([CH3:7])[CH2:5][O:6][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: N#Cc1cncnc1Cl
Reactant: CC(F)(F)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1C#N
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a suspension of sodium hydride (60% dispersed in mineral oil, 315 mg, 7.88 mmol) in THF (20 mL) was added 2,2-difluoropropan-1-ol (757 mg, 7.88 mmol) at 0° C. and the resulting mixture was stirred for 1 h. Then 4-chloropyrimidine-5-carbonitrile (1.00 g, 7.16 mmol) was added in portions and the mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (500 mL×2). The combined organic layers were dried and concentrated and the residue was purified by silica gel chromatography column (12% ethyl acetate in petroleum ether) to afford the title compound (850 mg, 4.27 mmol, 58% yield) as a yellow solid. MS (ESI) m/z 200.0 [M+H]+.