Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CCCP(=O)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: NCc1ccccc1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)NCc3ccccc3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 4.5 mL CH2Cl2 at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.131 mL, 0.22 mmol). After 5 min at rt, benzyl amine (0.023 mL, 0.21 mmol) was added and the reaction stirred at rt for 23 hours. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with aqueous NaHCO3 solution, H2O, brine, dried with anhydrous Na2SO4 and evaporated to a solid. The solid was chromatographed eluting with CHCl3/EtOAc plus 5% MeOH and then triturated with acetone/hexane to give the title compound as a light beige solid (20 mg, 28%). 1H NMR (Acetone-d6) δ: 8.39 (br. s., 1H), 8.12 (s, 1H), 7.58 (br. s., 1H), 7.27-7.38 (m, 5H), 7.16-7.26 (m, 2H), 4.59 (d, J=5.6 Hz, 2H), 4.30 (s, 2H), 3.66 (t, J=5.3 Hz, 2H), 2.82 (t, J=5.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:4][O:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:20](OC(=O)C)(=O)C>C(OCC)(OCC)OCC>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:3]2[C:2]3[N:1]=[CH:20][N:9]=[C:7]([OH:8])[C:6]=3[O:5][N:4]=2)=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(-c2noc(C(N)=O)c2N)cc1
Solvent: CCOC(OCC)OCC
Product: CS(=O)(=O)c1ccc(-c2noc3c(O)ncnc23)cc1
Temperature: 25 °C

Procedure:
To a suspension of 4-amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid amide (2.5 g, 8.9 mmol) in CH(OEt)3 (30 mL), was added acetic anhydride (10 mL) at ambient temperature. The reaction was heated to reflux for 5 h and cooled to room temperature. The reaction was concentrated under vacuum and poured into H2O (50 mL). The organic material was extracted with ethyl acetate (50 mL), dried over MgSO4 and concentrated under vacuum. The crude product was used for the next step without further purification. LCMS 292.0 [M+H].
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2F)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[CH:9]=[CH:8][C:7]([C:6]([NH:5][CH:3]5[CH2:4][N:1]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:2]5)=[O:37])=[CH:12][C:11]=4[O:13][CH3:14])=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(S(C)(=O)=O)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in DCM (2.5 mL, 1:2:2) was added DIEA (50 μL, 0.285 mmol), followed by methanesulfonyl chloride (23 μL, 0.21 mmol). After stirring overnight the solvent was removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (9.3 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.79 (m, 6H) 1.96 (br. s., 2H) 3.05 (s, 3H) 3.92 (s, 3H) 3.94 (d, J=1.77 Hz, 2H) 4.03-4.15 (m, 4H) 4.61-4.72 (m, 1H) 4.76-4.87 (m, 1H) 7.24 (d, J=6.57 Hz, 1H) 8.08 (s, 1H) 8.27 (d, 1H) 8.31 (s, 1H) 8.73 (d, J=3.79 Hz, 1H). [M+H] calc'd for C25H30F3N7O5S, 598. found 598.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[C:3]1=[C:10]=[CH:11][CH:12]([OH:16])[CH2:13][CH2:14][CH3:15].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:17][C:2]1([CH3:1])[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[CH:3]1[CH2:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCCC(O)C=C=C1C(C)CCC(C)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(O)CCC1C(C)CCC(C)C1(C)C
Yield: 95 %

Procedure:
2 G (8.5 mM) of 1-(2,2,3,6-tetramethyl-1-cyclohexylidene)-1-hexen-3-ol in 20 ml of ethyl acetate were hydrogenated in the presence of 0.2 g of palladium at 5% on charcoal, in an autoclave containing a hydrogen atmosphere maintained at a pressure of 100 atm. After filtration, the mixture was concentrated and distilled by means of a bulb apparatus (bath temp.: about 130°) under reduced pressure. There were thus obtained 1.9 g (yield 95%) of a mixture containing about 80% by weight of 1-(2,2,c-3,t-6-tetramethyl-r-1-cyclohexyl)-3-hexanol and 10% of 1-(2,2,t-3,c-6-tetramethyl-r-1-cyclohexyl)-3-hexanol accompanied by minor amounts of 1-(2,2,c-3,c-6-tetramethyl-r-1-cyclohexyl)-3-hexanol and 1-(2,2,t-3,t-6-tetramethyl-r-1-cyclohexyl)-3-hexanol.
Reaction SMILES: ClC1C=CC([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:9])=CC=1.[Cl:18]C1C=CC(CC(O)=O)=CC=1>S(Cl)(Cl)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:8]([Cl:18])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
4,4'-Dichlorodeoxybenzoin can be prepared by heating 4-chlorophenylacetic acid (85g) in thionyl chloride (59.5g) under reflux for 2.5 hours to yield 4-chlorophenylacetyl chloride (45.5g) which is subsequently dissolved in chlorobenzene (30g) and added dropwise with cooling to a stirred aluminium chloride (73g). The resultant mixture is cooled and stirred for a further 0.5 hours and then heated at 100° for one hour. The mixture was again cooled and poured into a mixture of conc. hyrochloric acid (200ml) and ice (1 liter) precipitate on standing crude 4,4'-dichlorodeoxybenzoin which on recrystallisation from methanol has a melting point of 115°-116°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]2[O:21][C@:22]3([CH2:30][N:31]=2)[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]3)=[N:17][CH:18]=1>C1COCC1>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]2[O:21][C@:22]3([CH2:30][N:31]=2)[CH:27]2[CH2:28][CH2:29][N+:24]([O-:6])([CH2:25][CH2:26]2)[CH2:23]3)=[N:17][CH:18]=1
Reactant: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cnc(Cl)cn3)O1)C2
Reaction time: 2 h
Yield: 94 %

Procedure:
3-Chlorobenzoperoxoic acid (104 mg, 0.466 mmol) was added to a solution of (R)—N-(5-chloropyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (114 mg, 0.388 mmol) in THF (3 mL) at room temperature and stirred for 2 h. The mixture was concentrated and the crude product was purified by flash chromatography on a 40 g silica gel cartridge with 10 to 30% [9:1 MeOH/NH4OH] in EtOAc, 30 min. Pure fractions were pooled, concentrated and dried. The residue was dissolved in EtOAC/MeOH 95:5, passed thru a 0.22 micron filter, concentrated and dried under high vacuum to yield (S)-2-(5-chloropyrazin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (113 mg, 94% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:17][CH2:16][C:15]3[CH:21]=[CH:22][C:12]([O:11][C:8]4[N:7]=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=4)=[CH:13][C:14]=3[CH2:20][CH2:19]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)nc1
Reaction time: 0.5 h

Procedure:
N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (150 mg, 0.5 mmol) was dissolved in 2.5% acetic acid in methanol (5 ml) and treated dropwise with cyclopentanone (0.09 ml, 1 mmol). The mixture was stirred for 30 minutes and then (polystyrylmethyl)trimethylammonium cyanoborohydride (2.04 mmol/g, 490 mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, applied to a SCX cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.25:2.25:97.5) to afford the title compound (E223). MS (ES+) m/e 366 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:29]([C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)(=[O:31])=[O:30])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (150 mg) in anhydrous DCM (4 ml) and triethylamine (90 ul) was added 2-thiophenesulfonyl chloride (101 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(thiophene-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (208 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 412. NMR (DMSO): 2.53-2.58 (4H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.30-7.32 (1H, m), 7.52 (1H, s), 7.65-7.67 (1H, m), 8.08-8.10 (1H, m), 9.08 (2H, s) MS (ESI+): MH+559.15 (15%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:16][NH2:17])=[O:13])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)CCCc1ccc(O)cc1
Solvent: O
Solvent: CO
Product: NNC(=O)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of methyl 4-(4-hydroxyphenyl)butyrate (4.93 g, 0.025 mol) and hydrazine hydrate (25.4 g, 0.254 mol) in methanol (64 mL) was heated under reflux for an hour. It was then cooled down to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to give the titled compound as a white crystal (3.30 g, 67%). 400 MHz 1H NMR (DMSO-d6) δ 9.10 (s, 1H), 8.89 (s, 1H), 6.93 (d, J=8.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.32 (s, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.97 (t, J=7.2 Hz, 2H), 1.71−1.67 (m, 2H); Mass (M−H−)=193.27.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH:8]=[CH:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.[Li].Cl[Si:15]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1>[CH3:20][C:19]([NH:18][Si:15]([CH3:17])([CH3:16])[CH:7]1[C:6]2[C:10](=[CH:11][C:12]3[CH2:1][CH2:2][CH2:3][C:4]=3[CH:5]=2)[CH:9]=[CH:8]1)([CH3:22])[CH3:21]
Reactant: C1=Cc2cc3c(cc2C1)CCC3
Reactant: CC(C)(C)N[Si](C)(C)Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C=Cc2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
1,2,3,5-Tetrahydro-s-indacene, lithium salt (1.790 g, 11.04 mmol) in THF (25 mL) was added drop wise to a solution of ClSi(CH3)2-NH-tBu (2.157 g, 16.56 mol) in THF (50 mL). This mixture was then allowed to stir at room temperature overnight. After the reaction period the volatile materials were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a yellow oil (2.799 g, 88.8% yield).
Reaction SMILES: [CH3:1][N:2]1[C:9]([CH3:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[C:9]([CH:10]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:8]([N+:11]([O-:13])=[O:12])[C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Step 1 intermediate, 1,3,6-Trimethyl-5-nitrouracil (0.60 g, 3.012 mmol) in dry N,N-dimethylformamide (5.0 mL) was added N,N-dimethylformamide dimethyl acetal (0.53 g, 4.447 mmol) and the reaction mixture was stirred at room temperature for 2 h. After this time, diethyl ether was added to the reaction mixture and the precipitate was collected by filtration and washed with diethyl ether to give 0.45 g of the product as brownish solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.98 (s, 6H), 3.16 (s, 3H), 3.40 (s, 3H), 4.78 (d, J=12.6 Hz, 1H), 7.05 (d, J=12.6 Hz, 1H); APCI-MS (m/z) 255.11 (M+H)+.
Reaction SMILES: FC(F)(O[C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)C(F)F.[S-:15][C:16]#[N:17].[K+].BrBr>C(O)(=O)C>[S:15]1[C:9]2[CH:8]=[CH:7][CH:13]=[CH:12][C:10]=2[N:11]=[C:16]1[NH2:17]
Reactant: Nc1ccc(OC(F)(F)C(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccccc2s1
Yield: 27.8 %

Procedure:
The procedure is as in Example 1, starting with 4-(1,1,2,2-tetrafluoroethoxy)aniline (10 g), potassium thiocyanate 18.5 g), bromine (2.4 cc) and acetic acid (80 cc). After purification on a column of silica (1 kg; particle size: 0.063-0.200 mm), eluting with a mixture of cyclohexane and ethyl acetate (50:50 by volume), and recrystallization in toluene (22 cc), 6- 1,1,2,2-tetrafluoroethoxy)-2-benzothiazolamine (2 g), m.p. 161° C., is obtained.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[SH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CN(C)C=O>[C:22]([CH2:21][CH2:20][S:19][C:15](=[S:16])[NH:14][C:12]1[C:11]([O:17][CH3:18])=[CH:10][C:8]2[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=2[CH:13]=1)([OH:24])=[O:23]
Reactant: O=C(O)CCS
Reactant: COc1cc2nc(C(C)(C)C)sc2cc1N=C=S
Solvent: CN(C)C=O
Product: COc1cc2nc(C(C)(C)C)sc2cc1NC(=S)SCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.8 g (0.10 mole) of 2-tert.-butyl-6-isothiocyano-5-methoxy-benzthiazole are dissolved in 150 ml of dimethylformamide and 14 g (0.13 mole) of 3-mercaptopropionic acid are added. The solution is stirred at room temperature under nitrogen for 2 hours, then poured onto 2 kg of ice and stirred until the product has become solid. It is filtered off, washed with water and heated in 700 ml of toluene, decanted from water, dried over sodium sulphate, clarified with active carbon and filtered. The filtrate is diluted at 30°-40° with approximately 700 ml of petroleum ether and cooled slowly to 5°, filtered off and subsequently washed with petroleum ether. N-[2-tert.-butyl-5-methoxy-benzthiazol-6-yl]-dithiocarbamic acid S-(2-carboxyethyl)-ester having a melting point of 154°-156° is obtained: ##STR14##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:23][OH:24])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Yield: 50.7 %

Procedure:
To a solution of 3.5 g (11.7 mmol) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 65 ml of anhydrous EtOH was added 3.25 g of hydroxylamine hydrochloride, followed by a solution of 2.92 g (11.7 mmol) NaOH in 8 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was evaporated and poured into a solution of 6 ml 6N HCl and 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. After evaporation of the solvent under vacuum, 5.11 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant furnished 1.86 g (50.7%) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1025.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccccc2)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of 3-bromo-4-fluorobenzaldehyde (2.03 g, 10.0 mmol) and phenol (0.941 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.66 g, 12.0 mmol), and the mixture was stirred at 90° C. for 16 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-15:85) to give the title compound (2.27 g, yield 82%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].CO.[Cl:15][O-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][Cl:15]
Reactant: [O-]Cl
Reactant: Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc(Cl)c(CCl)c(Cl)c1
Reaction time: 3.75 h

Procedure:
A solution of 2,6-dichloro-4-nitrotoluene (2.0 g 9.7 mmol) in tetrahydrofuran: methanol mixture (20:11 cm3) was added slowly to a vigorously stirred solution of 10-14% aqueous sodium hypochlorite (15 cm3) at 0° C. After 3.75 h at this temperature, the mixture was poured into dilute hydrochloric acid and then extracted with chloroform (30 cm3). The organic extract was dried and evaporated to yield an organge oil which was purified by flash chromatography over silica gel eluting with an ethyl acetate-petroleum ether gradient. The title compound was obtained as a pale orange solid, m.p. 37°-9° C. (1.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:28]
Reactant: CCN(CC)CCCl
Reactant: Cc1ccc(-c2oc3ccccc3c2S(=O)(=O)c2ccc(O)cc2)cc1
Product: CCN(CC)CCOc1ccc(S(=O)(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxyphenylsulfonyl)-2-(4-tolyl)benzofuran with 2-diethylaminoethyl chloride according to the procedure of Example 1 gives the title compound.
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][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].C(N(CC)CC)C>C(Cl)Cl>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A solution of benzoyl chloride (16.9 ml, 0.146 moles) in 200 ml of methylene chloride was added under nitrogen dropwise over approximately 1 hour to a solution of 2-amino-1-phenylethanol (20.0 g, 0.146 moles) and triethylamine (20.0 ml, 0.146 moles) in 300 ml of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 2 hours and then at room temperature for approximately 2 hours. The solid formed was collected by filtration and dried to give N-(2-hydroxy-2-phenyl-ethyl)-benzamide (20.33 g, 58%) as a white solid, mp 140-143° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([Cl:13])=[C:10]([Cl:12])[N:11]=1.[CH2:22]=[O:23]>C1COCC1>[Cl:12][C:10]1[N:11]=[C:7]([CH2:22][OH:23])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[Cl:13]
Reactant: C=O
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(CO)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
nBuLi (2.0 mL, 3.2 mmol, 1.6 M in hexane) was added dropwise to a solution of 2-bromo-4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (1.1 g, 3.2 mmol) in THF (50 mL) at −78° C. under N2. The mixture was stirred for 30 min and paraformaldehyde (960 mg, 32 mmol) was then added. The mixture was allowed warm up to room temperature and stirred for 6 h and then quenched by aqueous NH4Cl. Extracted with EtOAc and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-30% EtOAc in hexane) to give the title compound (614 mg, 65%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.37 (2H, s) 4.70 (2H, d, J=1.2 Hz) 3.58 (2H, dd, J=8.9, 7.7 Hz) 0.89-0.96 (2H, m) 0.00 (9H, s). LCMS: m/z 297 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=[O:2].S(Cl)(Cl)=O>ClCCl>[CH2:5]([O:2][C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 170.3 %

Procedure:
Compound 9 (0.291 g) obtained in Example 9 was dissolved in dichloromethane (2.9 ml) and thionyl chloride (1.5 ml) was added thereto, followed by stirring at room temperature for one hour. The solvent was distilled off under reduced pressure, the residue was again dissolved in toluene, and the solvent was distilled off under reduced pressure. Benzyl alcohol (2 ml) was added to the residue followed by heating under reflux for 30 minutes. The reaction solution was concentrated and the residue was recrystallized from ethanol to give Compound 13 (0.304 g, 85.2%) as a white solid.