Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.Cl.CO>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:28])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1,1-dimethylethyl {1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}carbamate (1.32 g; 3.39 mmol) was dissolved in a mixture of chloroform (10 ml) and HCl (12 ml) and stirred at rt under argon for 1 h. The salts were then dissolved in MeOH and all solvents removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until a neutral pH was reached. This was then filtered and the solvent removed. The crude residue was subjected to chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient to provide the desired compound (632 mg; 64%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:20]Cl)=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:20][NH:30][C:25]3[N:24]=[C:23]([Cl:22])[CH:28]=[C:27]([CH3:29])[N:26]=3)=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[N:11]=2)[CH:8]=1
Reactant: N#Cc1ccc(-c2nc3ccc(Cl)cn3c2CCl)cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Product: Cc1cc(Cl)nc(NCc2c(-c3ccc(C#N)cc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 4-(6-chloro-3-(chloromethyl)imidazo[1,2-a]pyridin-2-yl)benzonitrile hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. m/e+ 409.0, 411.0 for C20H14Cl2N6; H-NMR (400 MHz, CDCl3) 8.80 (s, 1H), 7.953 (d, J=8.277 Hz, 2H), 7.750 (d, J=8.093 Hz, 2H), 7.593 (d, J=9.533 Hz, 1H), 7.234 (d, J=9.551 Hz, 1H), 6.545 (s, 1H), 5.257 (s, NH), 5.03 (d, J=5.498 Hz, 2H, D, CH2), 2.311 (s, 6H, D, 2CH3) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C1C[O:15][CH2:14]C1>CCOC(C)=O>[N+:8]([C:7]1[C:2]2[NH:1][C:14](=[O:15])[O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c([N+](=O)[O-])cccc2o1
Yield: 65 %

Procedure:
To 2-amino-3-nitrophenol 3b (2 g, 13.00 mmol) dissolved in THF (50 ml) was added in one portion DCI (1.5 equiv., 19.6 mmol, 3.176 g) and the reaction was refluxed for 4 hours. (TLC AcOEt 1/petroleum ether 1). The reaction was evaporated and the crude material was dissolved in HCL 2N and extracted 3 times with chloroform. The combined organic phases were washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The crude solid was crystallized from ether giving 1.5 g of a beige solid. Yield=65% 1HNMR (DMSO, 200 MHz) δ 7.27 (1H, t, J=7.8 Hz), 7.72 (1H, dd, J=8.2 Hz, J′=1 Hz), 7.93 (1H, dd, J=8.4 Hz, J′=0.6 Hz), 12.64 (1H, bs)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=3)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(O)Cc1ccc2ncc(Br)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3ccc(CC(=O)O)cc3c2)cn1
Temperature: 130 °C

Procedure:
To a 20 mL microwave vial was added (3-bromo-quinolin-6-yl)-acetic acid (1 g, 3.77 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester and 1,4-dioxane (10 mL). Nitrogen was bubbled through the mixture for 10 minutes. Potassium carbonate (1.56 g, 11.3 mmol) was and water (5 mL) were then added, and nitrogen was bubbled through the mixture for a further three minutes. After such time dichlorobis(triphenylphosphine)palladium (138 mg, 0.19 mmol) was added, the vial sealed and heated in a microwave for 1250 seconds at 130° C. The mixture was then filtered through celite, which was washed with water and saturated aqueous sodium bicarbonate. The 1,4-dioxane in the solution was removed under vacuum and the remaining aqueous solution washed with dichloromethane three times. The water layer was acidified to pH 6 using 4M hydrochloric acid and the formed precipitate collected via filtration and dried to return the title compound as an off white solid. (500 MHz, DMSO-d6): ES-MS m/z: 268 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(O)(=O)C.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 110 °C
Yield: 53.7 %

Procedure:
A mixture of 1.7 g (10 mmol) 2-chloro-1,3-benzothiazole and 2.6 g (10 mmol) 4-chloroaniline in 20 ml acetic acid was heated to 110° C. for 3 h. The reaction mixtures was diluted with 200 ml water and the resulting mixture was extracted with 3×150 ml ethyl acetate. The combined organic phases were washed with 2×100 ml water, dried with MgSO4, filtered and evaporated to dryness. The residue was recrystallysed from a mixture of hexane/ethyl acetate to yield 1.4 g (54%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([NH:25][C:20]2[C:19]([NH2:26])=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccccc1N
Reactant: Cc1cccc2c1CCC[C@H]2N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cccc2c1CCC[C@H]2N1CCC(Nc2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
(R)-1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-one (1.84 g) was dissolved in dichloroethane (55 ml), and 1,2-phenylenediamine (1.23 g) was added. To the solution were added sodium triacetoxyborohydride (3.61 g) and acetic acid (0.97 ml). The mixture was stirred at room temperature for 24 hr, alkalified with saturated sodium hydrogen carbonate, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (R)-N-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.83 g) as a pale-brown solid.
Reaction SMILES: [C:1]([C:9]1[S:13][CH:12]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]O>>[C:1]([C:9]1[S:13][CH:12]=[C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1csc(C(=O)c2ccccc2)c1
Product: COC(=O)Cc1csc(C(=O)c2ccccc2)c1

Procedure:
9.8 gm of raw 5-benzoyl-thiophene-3-acetic acid were dissolved in 150 cc of methanol. A stream of gaseous hydrochloric acid was bubbled through this solution until the same was saturated. The methanol was evaporated and the residue was taken up in ether. The ethereal phase was washed with an aqueous 10% potassium carbonate solution, then with water until the wash waters were neutral. Thereafter, the ethereal phase was dried over magnesium sulfate, treated with carbon black, filtered and the ether was evaporated. After distillation, 5.45 gm of methyl 5-benzoyl-thiophene-3-acetate were obtained in the form of a colorless liquid, soluble in ether and insoluble in water, boiling at 170° -172° C. under 0.2 mm of Hg.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[CH:33]=[O:34])=[CH:30][C:29]([O:35][CH3:36])=[CH:28][CH:27]=2.C(OCC)(=O)C>C(#N)C>[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[CH:33]=[O:34])=[C:30]([F:21])[C:29]([O:35][CH3:36])=[CH:28][CH:27]=2
Reactant: COc1ccc2ncc(Cl)c(C=O)c2c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(C=O)c2c1F
Temperature: 10 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
Selectfluor (2.4 g, 6.77 mmol, 1.5 eq) is added at 10° C. to a stirred solution of 3-chloro-6-methoxy-quinoline-4-carbaldehyde (1.0 g, 4.5 mmol, 1.0 eq) in acetonitrile (50 mL). After 24 hours stirring at 10° C., the reaction mixture is extracted with ethyl acetate (3×100 mL) and brine (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 5:1, v/v) to afford 3-chloro-5-fluoro-6-methoxy-quinoline-4-carbaldehyde as a yellow solid (620 mg, 57% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]([CH3:14])=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:9]=1)([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[C:5](=[O:15])[NH:6][C:7]([CH3:14])=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:9]=1
Reactant: CCCCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1cc(N)c(=O)[nH]c1C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
A solution of 3-nitro-5-butyl-6-methylpyridin-2(1H)-one (293 mg, 1.40 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) containing 5% palladium/carbon (120 mg) was hydrogenated at atmosphere pressure for 10-20 hours. The catalyst was filtered off and the solvent evaporated. This residue was triturated with diethyl ether to give 224 mg (89%) of grayish product.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][NH:9][CH2:10][C:11]1([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)=O>[CH:5]([N:9]([CH2:10][C:11]1([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:8])=[O:7]
Reactant: CNCC1(N2CCCCC2)CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN(C=O)CC1(N2CCCCC2)CCCCC1
Reaction time: 1 h

Procedure:
Formic acid 98/100% (13.8 g. 0.3 mole) and acetic anhydride (30.6 g. 0.3 mole) were mixed without cooling and kept at room temp. for 1 hr. 1-(1-methylaminomethylcyclohexyl) piperidine (4.2 g. 0.02 mole) was dissolved in formic acid (15 ml) and the formylating agent (25 ml) added slowly. This produced effervescence and a rise in temp. to 60°. The mixture was allowed to stand at room temp. overnight and the solvents then evaporated under reduced pressure to yield a viscous, amber oil (3.79 g. 80%) which crystallised on cooling and gave colourless prisms of 1-(N-formyl-1-methylaminomethylcyclohexyl) piperidine m.p. 94° (from light petroleum b.p. 60°-80°).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([B:10]([OH:12])[OH:11])=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(B(O)O)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(B(O)O)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 3-amino-4-methoxyphenylboronic acid (1 eq, 2.10 mmol, 0.35 g) in CH2Cl2 (5 mL) at −78° C. was added Et3N (6 eq, 13.0 mmol, 1.7 mL). The reaction was stirred for 30 minutes then methanesulfonyl chloride (1.1 eq, 2.30 mmol, 0.26 g) was added. The reaction was then stirred at −78° C. for 1 hour. The reaction was allowed to warm to room temperature and diluted with CH2Cl2. The reaction washed with 1.0N aqueous HCl and the organic phase was extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 4-methoxy-3-(methylsulfonamido)phenylboronic acid (1.92 mmol, 0.49 g, 96%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CN(C)C=O>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:17][CH2:16]1
Reactant: BrCCBr
Reactant: Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)NCCO2
Temperature: 130 °C
Reaction time: 7.5 h

Procedure:
To a solution of 2-aminophenol (8.01 g) in N,N-dimethylformamide (70 ml), potassium carbonate (51.0 g) and 1,2-dibromoethane (9.5 ml) were added and stirred at 130° C. for 7.5 hours and then at room temperature for 3 days. After addition of additional 1,2-dibromoethane (9.5 ml), the reaction mixture was stirred at 130° C. for 6 hours. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 5:1) to give the titled compound, i.e., 3,4-dihydro-2H-1,4-benzoxazine (3.77 g) as a brown oil.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9](N)=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3].N([O-])=O.[Na+]>[Cu]Cl.O.COC(C)(C)C>[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9]([Cl:1])=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3]
Reactant: Cl
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 ml of concentrated hydrochloric acid was added 2.0 g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous solution consisting of 0.42 g of sodium nitrite and 3 ml of water was added under ice cooling. After stirring at the same temperature for 1 hour, 40 ml of t-butyl methyl ether was added and 0.85 g of copper (I) chloride was added. After stirring for 30 minutes, water was added, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was subjected to column chromatography (eluent: hexane/ethyl acetate=2/1) to give 0.52 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[C:15]1([CH:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:15]1([CH:21]([NH:23][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1ccccc1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (1.59 g, 7.57 mmol), 1-phenylethanamine (0.92 g, 7.57 mmol) and N,N-diisopropylethylamine (1.95 g, 15.1 mmol) were stirred at room temperature in dry acetonitrile (50 mL) for 20 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.28 mg, 12% yield). 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 7.80 (t, 1H), 7.31 (m, 5H), 6.33 (t, 1H), 6.22 (d, 1H), 4.58 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[SH:18][CH2:19][CH2:20][OH:21]>CN(C=O)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[S:18][CH2:19][CH2:20][OH:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1SCCO
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a stirred solution of 2-chloro-5-nitroaniline (1.0 g, 5.79 mmol) in DMF (10 mL) was added potassium carbonate (1.60 g, 11.59 mmol) followed by 2-mercaptoethanol (0.813 mL, 11.59 mmol). The resulting mixture was then heated at 60° C. for 2 hours and then at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with water (3×), 1N NaOH, and brine. The organic phase was dried, filtered, and concentrated, giving a red/orange solid (1.19 g, 96%). 1H NMR (DMSO-d6) δ 7.52 (s, 1H), 7.42-7.33 (m, 2H), 5.79 (s, 2H), 4.99 (t, J=5.4 Hz, 1H), 3.55 (q, J=6.2 Hz, 2H), 3.02 (t, J=6.6 Hz, 2H); ESI-MS (m/z, %): 215 (MH+, 23), 169 (100), 111 (63).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[N:10][CH:11]([CH3:15])[CH2:12][O:13][CH3:14])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1C=CC=CC=1>[Cl:23][CH2:24][C:25]([N:10]([CH:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:4]1[CH:5]([CH3:9])[CH2:6][CH2:7][CH2:8][C:3]=1[CH2:1][CH3:2])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: CCC1CCCC(C)C1=NC(C)COC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC1=C(N(C(=O)CCl)C(C)COC)C(C)CCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
174 g (0.83 mole) of 2-ethyl-6-methyl-N-(1-methyl-2-methoxyethyl)-cyclohexylideneamine and 101 g (1 mole) of triethylamine were added dropwise one after the other with stirring and at a temperature of 5° C. to a solution of 94 g (0.83 mole) of chloroacetyl chloride in 3000 ml of benzene. The reaction mixture was then refluxed for 5 hours, cooled to room temperature, washed with water, dried with sodium sulfate, filtered and concentrated under water-jet vacuum. Distillation of the residue under high vacuum gave 150,5 g of a 2-chloro-N-(1-methyl-2-methoxy-ethyl)-N-(2-ethyl-6-methyl-cyclohexenyl)acetamide as a mixture of its isomers b.p. 140°-148°/0.1 Torr.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20]>CN(C)C=O>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 82.8 %

Procedure:
Using 0.21 g of 4-isopropylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.24 g of 2-(4-isopropylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (35)).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:4]([CH3:17])[CH2:3]1.[OH-].[K+].[CH2:20](O)C>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:20])=[CH:14][CH:15]=2)[CH:4]([CH3:17])[CH2:3]1
Reactant: CC1CN(C)CCCC1Oc1ccc(O)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(OC2CCCN(C)CC2C)cc1
Reaction time: 1 h

Procedure:
23.5 g of 1,3-dimethyl-4-p-hydroxyphenoxy-hexahydroazepine are dissolved in 100 ml of absolute ethanol, 200 ml of 0.5 N ethanolic KOH are added, the reaction mixture is stirred for one hour at 20° and evaporated and the residue is taken up in 250 ml of absolute DMF. 12.6 g of dimethyl sulfate are added in portions, while stirring. The mixture is boiled for 2 hours and evaporated and the residue is worked up in the customary manner, giving 1,3-dimethyl-4-p-methoxyphenoxy-hexahydroazepine, 2 oily isomers, Rf 0.36 and 0.55.
Reaction SMILES: [CH3:1][N:2]1CC[O:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[C:21]([Br:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNCCO>CN(C=O)C.CCOC(C)=O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[C:21]([Br:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:29])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)O)cc2)CC1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCCO
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 0.17 h
Yield: 772 %

Procedure:
N-Methylmorpholine (6.7 mL, 60 6 mmol) and 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine-1-carboxylic acid tert-butyl ester (prepared as for compound 5 in WO2001074806) (20.0 g, 50.5 mmol) in DMF (240 mL) were treated with TBTU (17.8 g, 55.6 mmol) under nitrogen. After stirring for 10 min., 2-(methylamino)ethanol (5.3 mL, 65.7 mmol) was added and the solution stirred for 2 h. The reaction was diluted with EtOAc (350 mL), washed with 2% citric acid, 3% NaHCO3, and brine. The aq. washes were extracted with EtOAc (50 mL). The combined organic phases were dried over Na2SO4 then concentrated in vacuo to a solid. After stirring in hexanes for 5 h, the white solid was collected by filtration and dried under high vacuum to afford 21.0 g (92%) of 1A. 1H NMR (500.333 MHz, CDCl3) δ 7.44 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 3.91 (br s, 2H), 3.74 (br s, 2H), 3.54 (t, J=5.8 Hz, 3H), 3.34 (t, J=5.7 Hz, 2H), 3.09 (s, 3H), 3.01 (br s, 1H), 2.64 (t, J=5.9 Hz, 2H), 2.23 (t, J=5.8 Hz, 2H), 1.47 (s, 9H). MS ES+ 453.1.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][NH2:20])=[S:18])[CH:12]=1.Cl.C(OC(=N)CCl)C>CCO.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:18][C:2]([CH2:3][OH:4])=[N:20][N:19]=2)[CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cccc(C(=S)NN)c1
Agent: CCOC(=N)CCl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnc(CO)s2)c1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A mixture of 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.49 g) and 2-chloro-acetimidic acid ethyl ester hydrochloride (0.47 g) in EtOH (6 mL) was heated to 80° C. for 2.5 h. The mixture was diluted with AcOEt and washed with 1N HCl and with brine. The organic layer was dried and evaporated. The residual oil (0.8 g) was dissolved in MeOH (5 mL), MeONa (0.08 g) was added and the solution was heated to 65° C. for 0.5 h. The mixture was diluted with AcOEt and washed with 1N HCl and with brine. The organic layer was dried and evaporated and the residue was crystallized from AcOEt/hexane to give 3-(5-hydroxymethyl-[1,3,4]thiadiazol-2-yl) -benzoic acid methyl ester (0.15 g) as a white solid, MS (ISP) 251.2 [(M+H)+].