Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33]>C(#N)C.CC(C)=O>[CH2:30]([O:31][CH2:32][CH2:33][N:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[CH3:29]
Reactant: CCOCCBr
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Product: CCOCCn1c(C(OC2CCN(C)CC2)c2cccc(I)c2)nc2ccccc21
Temperature: 60 °C

Procedure:
A solution of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with 60% sodium hydride (47 mg) for 30 min at room temperature. 1-Bromo-2-ethoxyethane (84 μL) is then introduced. After warming at 60° C. for 8 h, dilution with water and extraction with diethylether, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, dioxalate, melting at 88° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10]([NH2:25])=[N:11][C:12](=[O:24])[N:13]([CH:23]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])=[O:4].C([SiH](CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[F:26][C:2]([F:1])([F:27])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]([NH2:25])=[N:11][C:12](=[O:24])[N:13]([CH:23]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])=[O:4]
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C#CCNC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC[SiH](CC)CC
Agent: [OH-]
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1CCCNC(=O)C(F)(F)F
Reaction time: 22 h
Yield: 67.2 %

Procedure:
5-[3-(trifluoroacetamido)propynyl]cytidine (1.25 g, 3.19 mmol, 1.00 equiv.) was dissolved in methanol (30 mL). Palladium hydroxide (0.25 g, 20 wt./wt. % based on propynyl cytidine) and triethylsilane (3.71 g, 31.90 mmol, 10.00 equiv.) were added to the reaction mixture. After 20-24 hours at ambient temperature, the reaction mixture was filtered through glass fiber and the filtrate was concentrated under reduced pressure giving a dark brown residue. The residue was purified by flash chromatography. Removal of solvent from the appropriate fractions afforded 0.85 g (71%) of 5-[3-(trifluoroacetamido)propyl]cytidine as a cream colored solid, which was confirmed by 1H-NM.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18](Cl)=[CH:17][C:16]([CH:20]4[CH2:22][CH2:21]4)=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:25]>CO>[C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18]([NH2:25])=[CH:17][C:16]([CH:20]4[CH2:22][CH2:21]4)=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C3CC3)nc2c1S(=O)(=O)c1ccccc1
Solvent: CO
Product: CSc1nn2c(N)cc(C3CC3)nc2c1S(=O)(=O)c1ccccc1

Procedure:
In an analogous manner to that described in Example 4, from 3-benzenesulphonyl-7-chloro-5-cyclopropyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-benzenesulphonyl-5-cyclopropyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.C(O)C>[CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:17]([NH2:18])=[O:16])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 80 °C
Yield: 80.2 %

Procedure:
30 g iminostilbene are heated to 60° C. in 360 ml acetic acid and 50 ml ethanol, and 20 g 98% sodium cyanate is added within 1.5 hours at this temperature. After a short heating to 80° C., the mixture is further stirred at 60° C., and then cooled to 15° C., sucked off, washed with 20 l acetic acid and dried to yield 29.4 g (80.3% of theoretical) of carbamazepine, having a melting point of 189° C. to 192° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:3]1.N1([CH:35]=[O:36])C2C=CC=CC=2N=N1>C1COCC1>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH:35]=[O:36])[CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[O:3]1
Reactant: O=Cn1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C=O)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 98.2 %

Procedure:
A solution of 1,1-dimethylethyl [[(5S)-2-oxo-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-5-oxazolidinyl]methyl]carbamate (Step 2, 292 mg, 0.841 mmol) in dry THF (16.8 mL) is treated with 1H-benzotriazol-1-carboxaldehyde (148 mg, 1.01 mmol), and the resulting suspension is stirred at ambient temperature for 1.25 hrs and is then concentrated to remove THF. The residue is rediluted with CH2Cl2 (25 mL), washed with 1N aqueous NaOH (2×10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which is then chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with MeOH/CH2Cl2 (2.5/97.5). Those fractions with an Rf=0.60 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 310 mg (98%) of the title compound as an amorphous, glassy solid. MS (ESI+) for C19H25N3O5 m/z 376 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17][CH2:18][C:19](O)=[O:20].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(=O)(O)[O-]>CCOC(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:19](=[O:20])[CH2:18][S:17][CH3:16])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CSCC(=O)O
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CSCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 5 h

Procedure:
2,6-di-t-butylphenol (1.7680 g, 8.66mmol) is placed in a flame dried RBF, and 2-(methylthio)acetic acid (0.80 mL, 9.19 mmol) is then added. This is then blanketed with argon and TFAA (1.30 mL, 9.20 mmol) is added via syringe at a fast rate. A small amount of CH2C12 is added to aid in mixing. The reaction quickly turns violet and darkens. It is followed by TLC using 10% EtOAc in hexanes. After 5 h, the reaction is carefully poured into 70 mL saturated bicarbonate and extracted with 2 portions of Et2O. The combined organics are washed with brine, filtered through cotton, dried over molecular sieves, then concentrated on a rotavap and dried under vacuum. This gives a white solid which can be crystallized from EtOAc/hexanes to give orange crystals, mp=108.5°-109.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9](=[O:17])[C:8]=2[CH:18]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9](=[O:17])[C:8]=2[CH:18]=1
Reactant: O=c1oc2ncccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)oc1ncccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
8-Nitro-4-azabenzo[c]chromen-6-one (Reference Compound No. 1-3-(4), 368 mg, 1.52 mmol) was dissolved in methanol (10 mL), then 5% palladium on charcoal (37 mg) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere at room temperature for 4 days. After the mixture was filtered, the solvent was removed under reduced pressure. Chloroform was added to the obtained residue, and then filtered to give the titled reference compound (298 mg) as a yellow solid. (Yield 92%)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.B1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH:32]=2)OC(C)(C)C(C)(C)O1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:31]3[CH:32]=[C:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][CH:36]=3)=[N:7][C:6]1=2
Reactant: CC1(C)OB(c2cccc(CC(N)=O)c2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Product: NC(=O)Cc1cccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)c1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 3-(2-Acetamidyl)phenylboronic acid pinacol ester using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)(=O)=O.[C-:15]#[N:16].[Na+]>C(#N)C>[CH3:14][O:13][CH:10]1[NH:9][CH:8]=[C:7]([CH2:6][C:15]#[N:16])[CH:12]=[CH:11]1
Reactant: [C-]#N
Reactant: COc1ccc(COS(C)(=O)=O)cn1
Agent: [Na+]
Solvent: CC#N
Product: COC1C=CC(CC#N)=CN1
Yield: 86.8 %

Procedure:
A solution of (6-methoxypyridin-3-yl)methyl methanesulfonate (1.4 g, 6.14 mmol) in acetonitrile (13 mL) was treated with sodium cyanide (0.752 g, 15.3 mmol) dropwise and the reaction mixture was heated at reflux for 48 h. After this time, the reaction was cooled and concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.800 g, 57%) as a white solid. MW=150.18. 1H NMR (CD3OD, 300 MHz) δ 8.12-8.09 (m, 1H), 7.68 (dd, J1=10.9 Hz, h=2.4 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 4.86 (s, 1H), 3.90 (s, 3H), 3.85 (s, 2H); APCI MS m/z 151 [M+H]+.
Reaction SMILES: C([C:3]1[Se:7][C:6]([C@@H:8]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C3C=CC=CC=3)[C@@H:19]([O:20]C(=O)C3C=CC=CC=3)[C@H:9]2[O:10]C(=O)C2C=CC=CC=2)=[N:5]C=1C(N)=O)C.C[O-].[Na+].C1(C)C=CC=CC=1.[C:54]([O:57][CH2:58]C)(=[O:56])[CH3:55]>CO>[C@@H:8]1([C:6]2[Se:7][CH:3]=[C:55]([C:54]([O:57][CH3:58])=[O:56])[N:5]=2)[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]1[OH:10]
Reactant: CCc1[se]c([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)nc1C(N)=O
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C

Procedure:
A gummy suspension of 206.3 g (75.1% pure by HPLC; 0.239 mol) of the blocked ethyl ester, IV, in 700 ml of methanol was heated and stirred on the steam bath until solution occurred. The solution was allowed to cool to room temperature during which time a finely dispersed oily suspension formed. To this suspension was added 17.2 g (318 mmol) of sodium methoxide. The addition was slightly exothermic and resulted in a brown solution. The solution was stirred at room temperature overnight. TLC (SiO2, toluene-ethyl acetate, 10:1) indicated that no starting material remained. To the reaction solution was added 100 g of Dowex 50 W×4 resin (H+) (washed with methanol) and the suspension was stirred for one hour. The resin was filtered off, washed well with methanol, and discarded. The filtrate and washings were evaporated under reduced pressure to give a two phase mixture. The upper, more liquid phase (mainly methyl benzoate) was decanted. The remaining brown viscous gum was triturated two times with ether. (The methyl benzoate was combined with the ether triturates and upon standing yielded some desired product as a solid). The brown viscous gum was treated with approximately 1 l of warm ethanol and triturated. A dark brown material was filtered from the suspension. TLC (SiO2; dichloromethane-methanol, 10:1) indicated that the dark brown material was mostly slower moving impurities in the filtrate and was discarded.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][NH:12][C:13]2[CH:14]=[C:15]3[C:19]4=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]4[C@H:17]4[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]34)[CH:21]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: COc1ccc(C=O)cc1C
Product: COc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cc1C

Procedure:
Using 3-methyl-4-methoxybenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 136. 1H NMR(CDCl3) δ: 7.18-7.10 (m, 2H), 6.78 (d, 1H, J=9.2 Hz), 6.42 (d, 1H, J=1.9 Hz), 6.25 (d, 1H, J=2.2 Hz), 4.59 (ABq, 2H, JAB=14.1 Hz), 4.20-4.10 (m, 1H), 4.13 (s, 2H), 3.83 (s, 3H), 3.74 (app t, 1H), 3.30-3.23 (m, 1H), 3.22-3.10 (m, 2H), 3.09-3.01 (m, 1H), 2.95-2.88 (m, 2H), 2.62 (app t, 1H), 2.48 (app t, 1H), 2.21 (s, 3H), 2.00-1.80 (m, 2H). LRMS (ES)+: 380.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[I:11]Cl>Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:11])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: ClI
Reactant: CC(=O)c1ccccc1N
Agent: Cl
Product: CC(=O)c1cc(I)ccc1N
Temperature: 0 °C

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 1-(2-aminophenyl)ethanone (11 g, 81.48 mmol, 1.00 equiv) in 1N HCl (300 mL). This was followed by the addition of a solution of ICl (14.5 g, 89.51 mmol, 1.10 equiv) in 2N HCl (50 mL) dropwise with stirring at 0° C. The reaction mixture was stirred for 2 h at room temperature in a water/ice bath. The solid were collected by filtration and then washed with 200 mL of ethyl acetate: MeOH (10:1). The title compound was obtained as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]3[CH3:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC1CCCCN1
Reactant: ClCc1coc(-c2ccc(Br)cc2)n1
Product: CC1CCCCN1Cc1coc(-c2ccc(Br)cc2)n1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 16 using 2-(4-Bromo-phenyl)-4-chloromethyl-oxazole (See Intermediate 1) and 2-methylpiperidine. MS (m/e): 336.2 (M+1)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: COCCCBr
Reactant: COC(=O)CC(C)CC(=O)Nc1ccc(C#N)cc1
Product: COCCCN(C(=O)CC(C)CC(=O)OC)c1ccc(C#N)cc1

Procedure:
Using methyl 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoate and 1-bromo-3-methoxypropane, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 8, methyl 5-((4-cyanophenyl)(3-methoxypropyl)amino)-3-methyl-5-oxopentanoate was obtained.
Reaction SMILES: [Na].[CH3:2]/[C:3](/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[N:4]/[OH:5].Br[CH:14]([CH3:18])[C:15]([OH:17])=[O:16]>C(O)C>[CH3:2][C:3](=[N:4][O:5][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: C/C(=N/O)c1ccc(Cl)cc1
Reactant: CC(Br)C(=O)O
Agent: [Na]
Solvent: CCO
Product: CC(=NOC(C)C(=O)O)c1ccc(Cl)cc1

Procedure:
To a solution of 1.85 g of a sodium in 150 ml of absolute ethanol 6.8 g of 4-chloroacetophenone oxime and 8.6 g of α-bromopropionic acid were added in this order with stirring. After the mixture had been stirred for 1 hour the ethanol was removed in a vacuum. The residue was mixed with water and the mixture was washed twice with ether. The aqueous solution then was acidified and extracted twice with ether. The ethereal extracts were washed 6 times with water, dried over anhydrous sodiumsulfate and concentrated by evaporation. After crystallisation of the residue from petroleum ether, the superscribed substance was obtained. After it had been washed once with water and crystallized from a mixture of benzene and petroleum ether te melting point was 88° C.-89° C.
Reaction SMILES: FC1C=CC(C[O:7][C:8](=[O:25])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:11]([F:24])[CH:10]=2)=CC=1.[OH-].[K+].Cl>O.O1CCOCC1>[F:24][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:8]([OH:25])=[O:7]
Reactant: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)c(F)c1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
A mixture of 3-fluoro-4-(4-fluoro-benzyloxy)-benzoic acid 4-fluoro-benzyl ester (8.1 g, 22 mmol) and potassium hydroxide (6.1 g, 109 mmol) in water:dioxane (4:1, 150 mL) was heated at 100° C. for 12 h. After cooling to room temperature the mixture was acidified to pH 3 with HCl and the mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts washed with brine (100 mL) and dried over sodium sulfate. Filtration and half evaporation gave a precipitate which was filtered off and crystallised from ethyl acetate:heptane to afford the title compound (4.9 g, 85%) as a white solid. MS: m/e=263.0 (M−H−).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.FC(F)(F)S(O[CH2:15][C:16]([F:19])([F:18])[F:17])(=O)=O>>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:4](=[O:8])[CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=c1cc(I)cc[nH]1
Product: O=c1cc(I)ccn1CC(F)(F)F

Procedure:
4-iodo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and 2,2,2-trifluoroethyl trifluoromethanesulfonate following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)([O-:8])=[O:7].N1C=CC=CC=1>O1CCCC1>[Br:1][CH2:2][C:3]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:16][CH:15]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C(Cl)CBr
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
Bromoacetyl chloride (113 g) was dropwise added to a stirred solution of 4-nitrobenzyl alcohol (9.2 g) and pyridine (10 ml) in dry tetrahydrofuran (100 ml) at 0° C. over 50 minutes. The mixture was stirred at 0° to 5° C. for 30 minutes, and evaporated in vacuo. The residue was dissolved in a mixture of chloroform (70 ml) and water (20 ml), and then the organic layer was separated. The organic layer was washed with a diluted aqueous hydrochloric acid and water in turn, and then dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was recrystallized from methanol to give crystals (6.74 g) of 4-nitrobenzyl bromoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[CH:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:19][CH2:20][C:21]([NH:24][S:25]([C:28]1[CH:29]=[N:30][CH:31]=[C:32](Br)[CH:33]=1)(=[O:27])=[O:26])([CH3:23])[CH3:22]>>[OH:19][CH2:20][C:21]([NH:24][S:25]([C:28]1[CH:29]=[N:30][CH:31]=[C:32]([C:18]#[C:17][C:16]2[CH:15]=[N:14][N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)[CH:33]=1)(=[O:27])=[O:26])([CH3:23])[CH3:22]
Reactant: C#Cc1cnn2ccc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3ccc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.6) (63 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (77 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (74 mg, 62%). MS (ISP) 482.0 [(M+H)+]; mp 185-186° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 7) (4.4 g, 10.77 mmol) in 1,4-dioxane (30 ml) was added HCl (4M in 1,4-dioxane) (5.39 ml, 21.55 mmol) and the mixture stirred at room temperature for 2 hours. A further portion of HCl (4M in 1,4-dioxane) (16.16 ml, 64.6 mmol) was then added and the mixture stirred for a further 16 hours. The volatiles were then removed in vacuo giving the title compound (3.8 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](Cl)=[O:9])[S:4][N:3]=1.[NH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1C=CC=CC=1>O1CCCC1>[N:12]1([NH:11][C:8]([C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[Cl:7])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NN1CCOCC1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NN1CCOCC1)c1snc(Cl)c1Cl
Temperature: 2.5 °C
Yield: 63.4 %

Procedure:
At 0 to 5° C. and with ice-cooling and stirring, 2.43 g (0.01 mol) of 3,4-dichloro-isothiazole-5-carbonyl chloride are added dropwise over a period of 5 minutes to a mixture of 1.21 g (0.011 mol) of 4-amino-morpholine and 22 ml of absolute pyridine. After the addition, the reaction mixture is admixed with 1.5 ml of absolute tetrahydrofuran, allowed to warm to room temperature and then stirred at room temperature for one hour. The reaction mixture is subsequently concentrated under reduced pressure. The residue that remains is admixed with 60 ml of water and 60 ml of ethyl acetate. The organic phase is separated off and the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are successively washed with 20 ml of saturated aqueous sodium bicarbonate solution and 50 ml of water, then dried over sodium sulphate and concentrated under reduced pressure. The residue is triturated in a mixture of 30 ml methylene chloride and 70 ml of petroleum ether. The resulting solid is filtered off with suction and dried. In this manner, 1.79 g (63% of theory) of N-morpholinyl-3,4-dichloro-isothiazole-5-carboxamide are obtained in the form of a solid of melting point 198 to 199° C.