Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[I:23]I>C1COCC1>[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[I:23]
Reactant: II
Reactant: N#Cc1ncc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1ncc(F)c(I)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (5.60 mL, 39.27 mmol) in THF (40 mL) was cooled to 0° C. and n-BuLi (12.56 mL, 31.4 mmol) was added slowly. After 30 minutes, the reaction was cooled to −78° C. and 3,5-difluoropicolinonitrile (4.0 g, 28.6 mmol) in THF (25 mL) was added and the solution was stirred for 30 minutes. A solution of iodine (10.87 g, 42.8 mmol) in THF (35 mL) was cooled to (−78° C.) and added all at once. After about 30 seconds the reaction was quenched with sodium thiosulfate solution (10 mL) and water (20 mL). The mixture was extracted with EtOAc (2×150 mL) and the combined organics were extracted with brine, dried over Na2SO4 and concentrated to give a residue which was purified using silica column chromatography eluted with hexanes/EtOAc to give 3,5-difluoro-4-iodopicolinonitrile.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>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].CO.C(OCC)(=O)C.COCCOC>[Cl:17][C:18]1[C:19]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:7]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: Fc1cccc(CNc2cccc(Br)n2)c1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
To 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (2.0 g, 7.11 mmol) was added 5-chloro-2-fluoropyridin-4-ylboronic acid (1.996 g, 11.38 mmol), PdCl2(dppf).CH2Cl2 adduct (0.465 g, 0.569 mmol), DME (27 ml) and last 2M sodium carbonate (9.25 ml, 18.50 mmol). The crude reaction mixture was stirred at 100° C. for 3 hr, followed by LCMS. The crude mixture was cooled, 25 ml of ethyl acetate and 20 ml of methanol was added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using a 120 g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 1.259 grams of title compound as free base use with out further purification. LCMS (m/z): 332.2 (MH+), retention time=0.92 min.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1>[C:1]([O:4][C@@H:5]1[N:8]([Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
A process according to claim 1, in which (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one is treated with tert-butyldimethyl chlorosilane in the presence of 4-dimethylaminopyridine in an organic solvent and the (3S,4S)-4-acetoxy-3-phenylacetamido-1-tert-butyldi methylsilyl-azetidin-2-one (III) is isolated.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)=[C:9]2[CH2:24][N:25]([C:29](=[O:39])[NH:30][C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:26]([CH3:28])([CH3:27])[C:8]2=[N:7]1)=O)C.[OH-].[Na+].O>CO>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[NH:30][C:29]([N:25]1[CH2:24][C:9]2[C:8](=[N:7][NH:6][C:10]=2[NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[C:26]1([CH3:28])[CH3:27])=[O:39]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(C(=O)OC)cc1)CN(C(=O)Nc1c(Cl)cccc1Cl)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)c2n[nH]c(NC(=O)c3ccc(C(=O)O)cc3)c2CN1C(=O)Nc1c(Cl)cccc1Cl
Temperature: 70 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of 5-(2,6-Dichloro-phenylcarbamoyl)-3-(4-methoxycarbonyl-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.4 g, 0.74 mmol) in methanol (5 mL), 2N NaOH aqueous solution (1.00 mL, 2.00 mmol) was added and warmed to 70° C. After 4 hours stirring, water was added (20 mL) and the aqueous solution extracted with ethyl acetate (1×20 mL). The aqueous phase was acidified with 1N HCl solution and extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over sodium sulphate, the solvent evaporated in vacuo yielding 0.33 g (yield 91%) of the title compound as white solid.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.CN(C=O)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22](F)[CH:23]=1)[C:19]#[N:20]>CCOCC.O>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([S:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=2)[CH:23]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1ccnc1Sc1cc(F)cc(C#N)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 9.2 %

Procedure:
A mixture of NaH (60%, 3.16 g, 79 mmol) in oil was rinsed with dry pentane by syringe (3×10 mL) and excess solvent removed under a steam of N2. Solid 2-mercapto-1-methylimidazole (9.03 g, 79 mmol) was added followed by 200 mL of DMF under ice-bath cooling which resulted in a vigorous evolution of gas. After 15 min, solid 3,5-difluorobenzonitrile (10.00 g, 71.9 mmol) was added and the resulting mixture stirred for 5 days at 60° C. After cooling to rt the mixture was diluted with 500 mL ether and 500 mL water. The resulting white solid was collected by filtration and triturated in 50 mL of boiling ethanol which after cooling to rt was collected by filtration and dried under high vacuum to provide 1.54 g (9%) of 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile: 1H NMR (500 MHz, DMSO-d6): δ 3.54 (s, 3H), 7.40 (d, 1H, J=2 Hz), 7.52 (d, 1H, J=2 Hz), 7.96 (dt, 1H, J=8, 2 Hz), 8.13 (m, 1H), 8.15 (dt, 1H, J=8, 2 Hz); LCMS (m/z): 234.1 [C11H8FN3S+H]+. The ether layer was separated from the filtrate and washed with water, brine, dried (MgSO4) and evaporated. The residue was recrystallized from 30 mL of boiling ethanol to provided after filtration and drying a further 1.57 g (9%) which by HPLC was 75% enriched in 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile. The filtrate was evaporated to provide 5 g of crude product enriched in the title compound. This was adsorbed to 15 g of SiO2 from CH2Cl2 and subjected to MPLC on a 120 g column of SiO2 eluting with % EtOAc in hexanes (time): 35% (10 min), 35-50% (5 min ramp), 50% (20 min) which provided 1.2 g (7%) of 90% HPLC pure title compound as well as 1.96 g (12%) of 98% HPLC pure title compound: 1H NMR (500 MHz, DMSO-d6): δ 3.66 (s, 3H), 7.20 (d, 1H, J=1 Hz), 7.22 (ddd, 1H, J=8, 3, 2 Hz), 7.34 (t, 1H, J=2 Hz), 7.55 (d, 1H, J=1 Hz), 7.72 (ddd, 1H, J=8, 3, 2 Hz); LCMS (m/z): 234.1 [C11H8FN3S+H]+.
Reaction SMILES: FC(F)(F)C1C=C([C:13]2[C:14]3[NH:27][CH:26]=[CH:25][C:15]=3[C:16]3[C:21]([CH:22]=2)=[N:20][C:19]([NH2:23])=[N:18][C:17]=3[NH2:24])C=C(C(F)(F)F)C=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][CH2:45][C:46]([OH:48])=[O:47])O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].COCCOC>[NH2:24][C:17]1[C:16]2[C:15]3[CH:25]=[CH:26][NH:27][C:14]=3[C:13]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[CH:22][C:21]=2[N:20]=[C:19]([NH2:23])[N:18]=1
Reactant: Nc1nc(N)c2c(cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3[nH]ccc32)n1
Reactant: CC1(C)OB(c2ccccc2CCC(=O)O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CO
Product: Nc1nc(N)c2c(cc(-c3ccccc3CCC(=O)O)c3[nH]ccc32)n1
Temperature: 25 °C
Yield: 11.6 %

Procedure:
A mixture of 3-(2-bromo-phenyl)-propionic acid (458 mg, 2.0 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](558 mg, 2.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (132 mg, 0.18 mmol), and potassium acetate (589 mg, 6.0 mmol) was heated to 95° C. for 2 d. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, filtered through a pad of silca gel and sodium sulfate, and concentrated in vacuo to afford 3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid. A solution of 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (prepared as in Example 1, 100 mg, 0.31 mmol), 3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid (102 mg, 0.37 mmol), tetrakis(triphenylphosphine)palladium(o) (71 mg, 0.06 mmol) in a 2.0M aqueous sodium carbonate solution (0.5 mL), ethanol (1.5 mL), and ethylene glycol dimethyl ether (1.5 mL) was heated to 95° C. for 18 h. The resulting mixture was cooled to 25° C., dissolved in methanol and tetrahydrofuran, and filtered through a pad of silica gel and sodium sulfate. The filtrate was concentrated in vacuo. HPLC purification (Shimadzu HPLC, ODSA column from Medchem, 2×10 cm, 10 micro, 10-90% CH3CN/H2O with 0.1% TFA.) afforded 3-[2-(1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-6-yl)-phenyl]-propionic acid (12.5 mg, 12.1%); LRMS for C19H17N5O2 (M+H)+ at m/z=348.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20])[C:8]([CH:23]=[O:24])=[CH:7]2.O1CCCC1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:20])([F:21])[F:22])[C:8]([CH2:23][OH:24])=[CH:7]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of 8-chloro-2-(2-(trifluoromethoxy)phenyl)quinoline-3-carbaldehyde (0.5427 g, 1.543 mmol) in tetrahydrofuran (7.715 mL, 1.543 mmol) at 0° C. was added SODIUM BOROHYDRIDE (0.08757 g, 2.315 mmol) and the mixture was stirred at 0° C. and allowed to warm to room temperature over 1 hour. After 1 h of stirring at 0° C., the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), and the organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (8-chloro-2-(2-(trifluoromethoxy)phenyl)quinolin-3-yl)methanol as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (1 H, s), 8.10 (1 H, dd, J=8.3, 1.3 Hz), 7.95 (1 H, dd, J=7.5, 1.3 Hz), 7.51-7.72 (5 H, m), 5.54 (1 H, s), 4.44 (2 H, s); LC-MS (ESI) m/z 354.0 [M+H]+. The product was carried on crude without purification for the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][N:13]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([OH:12])=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(O)Cc1ccccc1CCl
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8 mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and the solution was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate and extracted with H2O (2×). The aqueous phase was lyophilized and the residue was purified by silica gel chromatography (Biotage/0-10% methanol-CH2Cl2) to give the title compound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid (2.22 g, 87%). 1HNMR (400 MHz, CD3OD) δ 7.37-7.44 (m, 3H), 7.29-7.33 (m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS: Anal. Calcd. for C13H17NO3: 235; found: 236 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CCN(C(=O)c2cnn(C)c2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(F)c2cccnc2c1N1CCN(C(=O)c2cnn(C)c2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-(5-fluoro-8-{4-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperazin-1-yl}quinolin-7-yl)ethanone (0.045 g, 0.12 mmol) and ammonium acetate (0.0909 g, 1.18 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.30 mL, 0.30 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C20H24FN6O (M+H)+: m/z=383.2; Found: 383.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8](Cl)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:15][CH3:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C[O-]
Reactant: COC(=O)c1c(Cl)cc(Cl)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(OC)cc(Cl)nc1Cl
Reaction time: 17 h

Procedure:
To a solution of methyl 2,4,6-trichloronicotinate [(5.04 g, 20.96 mmol), prepared as described in WO2010/31589] in methanol (52 mL) was added the sodium methoxide (25 wt % in methanol, 5.04 mL, 22.0 mmol) at room temperature. The cloudy white mixture was stirred for 17 h, then partitioned between EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-20% EtOAc:heptane) to provide methyl 2,6-dichloro-4-methoxynicotinate. MS (ESI+) m/z 236.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[BrH:14].[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
A mixture of 25 g of 6-aminocarbostyril, 50 g of bis(β-bromoethyl)amine hydrobromide and DMF was stirred at 80°-90° C. for 3 hours. After cooling to room temperature, 8.2 g of Na2CO3 was added to the mixture and stirred at 80°-90° C. for 4 hours. After cooling to room temperature, crystals which precipitated were collected by filtration, washed with ethanol and dried to give 22 g of 6-(1-piperazinyl)carbostyril hydrobromide, m.p. above 300° C., pale yellow rhombic crystals (water-ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:15][CH:14]([OH:16])[CH2:12]2)([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: CC(C)(N)c1ccc(Br)cc1
Solvent: CCO
Product: CC(C)(c1ccc(Br)cc1)N1CC(O)C1
Yield: 38.8 %

Procedure:
1-(4-Bromophenyl)-1-methyl-ethylamine (1 g, 4.67 mmol) and epichlorohydrin (439 μl, 5.6 mmol) in EtOH (15 mL) were heated at 70° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-azetidin-3-ol as a white solid (489 mg, 38%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11]([CH:2]([CH3:1])[CH2:3][CH2:4][NH:5]2)=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC1CCNc2ccccc21
Agent: O=S(=O)(O)O
Product: CC1CCNc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
1,2,3,4-Tetrahydro-4-methylquinoline (55 mg, 0.337 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature was lowered to 0° C. To this solution 90% fuming nitric acid (15 mL, 0.337 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with sat. NaHCO3 (1×3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 36 mg (52%) of 7-nitro-1,2,3,4-tetrahydro-4-methylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.41 (dd, J=8.3, 2.2, 1H), 7.27 (d, J=2.3, 1H), 7.11 (d, J=8.3, 1H), 4.21 (s, 1H), 3.35 (m, 2H), 2.95 (m, 1H), 1.96 (m, 1H), 1.72 (m, 1H), 1.3 (d, J=7.0, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Br)=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH3:16][CH:17]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1OC1C>CC(=O)CC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][N:26]([CH:17]([CH3:16])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: CC(CCc1ccccc1)NCc1ccccc1
Reactant: Nc1ccc(C(=O)CBr)cc1S(N)(=O)=O
Agent: CC1CO1
Solvent: CCC(C)=O
Product: CC(CCc1ccccc1)N(Cc1ccccc1)CC(O)c1ccc(N)c(S(N)(=O)=O)c1

Procedure:
A solution of 2-amino-5-(2-bromoacetyl)benzenesulphonamide (0.5 g), N-(1-methyl-3-phenylpropyl)-N-(phenylmethyl) amine (0.45 g) and propylene oxide (2.5 ml) in 2-butanone (30 ml) was heated under reflux for 3 hours. The solution was then concentrated to a red-brown oil (0.7 g) which was dissolved in absolute ethanol (30 ml) and treated with sodium borohydride (258 mg) at room temperature during 2 hours. Excess borohydride was then destroyed with 2N hydrochloric acid and the ethanol was removed under reduced pressure. The residue was basified with 8% sodium bicarbonate and extracted with ethyl acetate (3 × 50 ml). The extracts were washed with water (100 ml), dried and concentrated to an orange oil (0.63 g). The oil was dissolved in acetone (10 ml) and re-precipitated as an orange solid (340 mg) by addition of petroleum ether (b.p. 60°-80°). Chromatographic purification of this solid on silica plates [Merck St17; elution with chloroform: methanol (5:1 )] and conversion of the product into a hydrochloride salt gave the title compound, 0.2 g, m.p. 133°-136°.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23]C[CH:21]([CH2:24][C:25](OCC)=O)[CH2:20][CH2:19]2)[CH:9]=1.C[Si](C)(C)CCOC[N:46](COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCCC(CC(OCC)=O)C2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:38][Si:2]([CH3:1])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:19][CH2:20][CH:21]([CH2:24][C:25]#[N:46])[CH2:23]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2c(I)cnn12

Procedure:
2-(3-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: O=P(Cl)(Cl)Cl.C([O:8][CH:9](OCC)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]([CH3:33])[CH:31]=O>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:10](=[CH:29][N:30]([CH3:33])[CH3:31])[CH:9]=[O:8]
Reactant: CCOC(COc1ccc(Cl)c(Cl)c1)OCC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Dimethylformamide (29.2 g) was slowly added to 122.7 g of POCl3 in a reaction flask. After the addition was complete, the mixture was heated to 80° C. while 3,4-dichlorophenoxyacetaldehyde diethyl acetal (55.8 g) was added, and the resulting mixture was then heated for an additional two hours at about 80°-85° C. The reaction mixture was cooled to room temperature and poured into about 400 g of potassium carbonate in an ice-water mixture and then extracted with methylene chloride. The methylene chloride extract was then dried and concentrated to a dark oil which solidified upon dilution with ethyl acetate. 22.1 g of the desired, 2-(3,4-dichlorophenoxy)-3-dimethylamino-propenal was obtained and subsequently identified by NMR spectroscopy.
Reaction SMILES: S1C2C=CC=CC=2N=CN1.[Cl:11][C:12]1[C:13]([SH:24])=[CH:14][C:15]2[S:20](=[O:22])(=[O:21])[NH:19]C=[N:17][C:16]=2[CH:23]=1>>[S:20]([C:15]1[CH:14]=[C:13]([SH:24])[C:12]([Cl:11])=[CH:23][C:16]=1[NH2:17])(=[O:21])(=[O:22])[NH2:19]
Reactant: O=S1(=O)NC=Nc2cc(Cl)c(S)cc21
Agent: C1=Nc2ccccc2SN1
Product: Nc1cc(Cl)c(S)cc1S(N)(=O)=O

Procedure:
By replacing the 1,2,4-benzothiadiazine derivative employed in Step A-1 by an equivalent quantity of 6-chloro-7-mercapto-1,2,4-benzothiadiazine-1,1-dioxide and following substantially the same procedure described in Step A-1 there is obtained 2-sulfamoyl-4-mercapto-5-chloroaniline, m.p. 192°-195° C.