Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.Cl.[C:22]1([N:28]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=3[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[CH:30]=[N:29][N:28]2[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: Nc1cccc2c1cnn2-c1ccccc1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and 1-phenyl-1H-indazol-4-amine hydrochloride (as the free base, Intermediate 8) except that ca. 5 drops of NMP were added to the reaction mixture.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])=[N:5][N:4]=[N:3]1.[OH:13]O>C(O)=O.O>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:13]
Reactant: OO
Reactant: Cn1nnnc1SCCCCBr
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S(=O)CCCCBr
Temperature: 25 °C

Procedure:
1-Methyl-5-(4-bromobutyl)thio-1,2,3,4-tetrazole prepared in Reference Example 2 is dissolved in formic acid (50 ml). 30% Aqueous hydrogen peroxide (2.3 g) is added to the solution with stirring at room temperature and the mixture is allowed to stand at room temperature for 2 overnights. The mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off to obtain 1-methyl-1,2,3,4-tetrazol-5-yl 4-bromobutyl sulfoxide (5.5 g) as colorless liquid.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reaction time: 18 h

Procedure:
tert-Butyl 3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate [Example 34, step b] (0.70 g) was stirred in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added. The solution was stirred for 18 hours, then the volatiles were removed under reduced pressure to afford the subtitled compound. Yield 1.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[CH3:20])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.Cl>ClCCl>[CH2:25]([O:24][C:22]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])/[C:7]1=[O:11])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(F)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\c2cc(F)ccc2C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one prepared in example 145a (0.20 g, 0.71 mmol) in dichloromethane (3 mL) at 0° C. was added ethyl chloroformate (0.10 mL, 1.1 mmol), followed by the addition of triethylamine (0.14 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The mixture was then poured into aqueous HCl solution (1 N). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, and concentrated to give E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid. The crude product was purified by chromatography to obtain 75 mg yellow solid (Yield 1.7 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:19]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=[N:1][C:2]=12)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CCC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: CCC(=O)Nc1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1

Procedure:
A solution of 1.87 g of 3-amino-4-benzoylpyrazole and 2.46 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]propanamide (Example 169) in 50 ml of glacial acetic acid was refluxed for 15 hours and then evaporated to yield a pale yellow gum. This material was partitioned between an aqueous saturated sodium bicarbonate solution and methylene chloride. The methylene chloride solution was dried with powdered anhydrous sodium sulfate and then passed through a short column of hydrous magnesium silicate adsorbent. The eluate was refluxed in a steam bath and hexane gradually added until turbidity. After cooling, the desired product was recovered by filtration (2.39 g, mp 172°-174° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)[CH3:2].[O:11]1CC[CH2:13][CH2:12]1.C([Li])CCC.[Cl-].[NH4+]>O.CN(C)C(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:12](=[O:11])[CH3:13])[N:5]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCOc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOc1cccc(C(C)=O)n1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
16.8 g of 2-ethoxy-6-bromopyridine were introduced into 220 ml of tetrahydrofuran at -75° C. 54.4 ml of n-butyllithium (1.6-molar solution in n-hexane) were added dropwise at this temperature. Stirring was continued for two hours at -75° C., and 7.6 g of N,N-dimethylacetamide were added dropwise at this temperature. The mixture was stirred for a further hour at -75° C. and then warmed to -10° C., and first approximately 170 ml of 20 percent strength aqueous ammonium chloride solution and then 200 ml of water were added dropwise at this temperature. The mixture was extracted 3 times using methyl tert-butyl ether. The combined organic phases were washed 3 times with water and subsequently dried over sodium sulfate. After the solvent had been stripped off, the residue which remained was chromatographed on silica gel using cyclohexane/methyl tert-butyl ether 8:1. This gave 5.5 g of 2-ethoxy-6-acetylpyridine as a colorless solid (m.p.: 36-37° C).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)Sc1ccc(Br)cc1
Yield: 85.5 %

Procedure:
A solution of 30 g (0.165 mol) of ethyl 2-bromopropionate in 30 ml of anhydrous ethanol is run over the course of 30 minutes into a solution of 29 g (0.150 mol) of p-bromothiophenol, taken as 98% strength, and of 6 g (0.150 mol) of sodium hydroxide pellets in 100 ml of anhydrous ethanol, and the mixture is then stirred for 1 hour at ambient temperature. The inorganic salts formed are removed by filtration and the alcohol is evaporated. The residue is taken up in diethyl ether and the organic phase obtained is washed successively with N sodium hydroxide solution and with water. After drying, and evaporating the solvent, 44.6 g of a limpid pale yellow oil are obtained. The purification of this oil by distillation under reduced pressure gives 37.1 g of a limpid colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[C:6](=[NH:8])[NH2:7])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13](=O)[C:14](=O)[C:15]([F:18])([F:17])[F:16]>>[NH2:8][C:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])=[N:9][C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([C:12]([F:22])([F:21])[F:11])[N:7]=1
Reactant: CCOC(=O)C(N)C(=N)N
Reactant: O=C(C(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N

Procedure:
The title compound was prepared from amino-carbamimidoyl-acetic acid ethyl ester (Intermediate B2) and 1,1,1,4,4,4-hexafluorobutane-2,3-dione analogously to Intermediate B; 10 LCMS Rt=4.72 minutes, [M+H]+ 304.2/326.1 Method 10 minLC_v002.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
(+/−) Tert-butyl 3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (1 g, 3.67 mmol) was taken up in DMF (2 mL) and imidazole (0.500 g, 7.34 mmol) and TBS-Cl (0.609 g, 4.04 mmol) were added. The reaction was stirred at rt over the weekend. An additional 0.2 eq. of TBS-Cl and 0.5 eq. of imidazole was added, and the reaction mixture was heated at 40° C. overnight, then at 45° C. for 24 h. The reaction mixture was diluted with EtOAc and washed with water 4×. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-60% EtOAc/Hex). (+/−) Tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (665 mg) was obtained as a colorless oil.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].O.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[CH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: NCCCCl
Reactant: O=Cc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: ClCCCN=Cc1ccncc1

Procedure:
To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2Cl2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6 Hz, 2H), 2.24 (t, J=6Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH3:10][N:11](C=O)C.[Cu]C#N>N1C=CC=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:10]#[N:11]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: N#C[Cu]
Solvent: c1ccncc1
Product: N#Cc1cc(F)cc(Br)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3-dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (2×30 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (3×40 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35%). 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.54-7.50 (m, 1H), 7.35-7.32 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:21]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1-c1ccccc1)c1ccccc1
Yield: 93.7 %

Procedure:
A 250 mL round bottom flask equipped with efficient magnetic stirring was charged with o-phenylphenol (17.0 g, 0.1 mol), toluene (100 mL) and triethylamine (11.1 g, 0.11mol, 10% excess). Benzoyl chloride (14.7 g, 0.105 mol, 5% excess) was added portionwise over 15 minutes while using an ice bath to help maintain the temperature below 30° C. The initially clear reaction mixture became a white slurry during the acid chloride addition. After stirring at room temperature for an additional 2.5 hours, the slurry was filtered and the clear organic layer was stripped on a rotary evaporator at 60° C./P=3.4 kPa. The light yellow oil crystallized upon cooling. The crude product was recrystallized from a mixture of hexane (100 mL)/toluene (20 mL) yielding 25.7 g (93.8%) white crystals. The structure was confined using 13C and 1H NMR, IR and GC/MS.
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[CH:11](OCC)=[O:12].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH2:24][C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1>O>[CH:11]([CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:27])([F:28])[F:16])[CH:19]=1)[C:25]#[N:26])=[O:12]
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(C=O)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To a slurry of 30.0 g. of sodium methoxide in 1200 ml. of toluene and 43.4 g. of ethyl formate is added dropwise with stirring 98.75 g. of 3-(trifluoromethyl)benzeneacetonitrile in 75 ml. of toluene over a 10 minute period. The temperature of the mixture rises to 35° C. and the mixture thickens. Stirring is continued for 2 hours and then one liter of water is added. The aqueous layer is acidified and a precipitate is formed by scratching to give 85.0 g. of the product of the Example as a white solid, m.p. 103°-106.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=2[CH:25]=O)[C:17]([O:19][CH2:20]C)=[O:18])=O)=[CH:5][CH:4]=1)#[N:2].[NH3:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:27]=[CH:25][C:24]3[C:14](=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:22][CH:23]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C=O)c(NC(=O)CCc2ccc(C#N)cc2)c1
Reactant: N
Product: COC(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1

Procedure:
0.6 g (1.8 mmol) of ethyl 3-[3-(4-cyanophenyl)-propionylamino]-4-formyl-benzoate and 10 ml of methanolic ammonia solution were agitated in a pressure vessel for 36 hours. Then the solvent was distilled off, the residue was chromatographed on silica gel and eluted with methylene chloride containing 0 to 1% methanol. Yield: 0.35 g (62% of theory), Rf value: 0.38 (silica gel, ethyl acetate/cyclohexane=1:1)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[ClH:11].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.CO>C(O)(=O)C>[ClH:11].[ClH:11].[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: O=Cc1cccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Reactant: C1COCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3cccc(CN4CCOCC4)c3)cc2s1
Reaction time: 18 h

Procedure:
290 mg (3.32 mmol) of morpholine and 31 mg (0.50 mmol) of sodium cyanoborohydride are successively added to a solution of 80 mg (0.17 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 33A) in 1.0 ml of a 6:1 mixture of methanol and acetic acid. After 18 h at 80° C., purification is carried out by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated: Drying under high vacuum results in 47 mg (49.8% of theory) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.C(N(CC)CC)C.[C:30]([Cl:38])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[ClH:38].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 mg (176 μmol) of the compound from Example 35 are dissolved in 4 ml DMF, 53.5 mg (529 μmol) triethylamine and 27.3 mg (194 μmol) benzoyl chloride are added, while cooling with ice, and the mixture is stirred overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C(O)(C)C>[Cl:1][C:2]1[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccc1
Reactant: Nc1cc(Cl)ncc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Nc1ccnc(Cl)c1Sc1ccccc1
Reaction time: 24 h
Yield: 97 %

Procedure:
To a 250 mL round flask was added 2-chloro-5-iodo-4-aminopyridine (5.0 g, 19.6 mmol), thiophenol (2.16 g, 19.6 mmol), CuI (0.187 g, 0.98 mmol), ethylene glycol (2.5 g, 39 mmol), potassium carbonate (5.4 g, 39 mmol), and 150 mL of isopropanol. The reaction was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the mixture was purified by a silica gel column. Yield (97%) of 2-chloro-3-phenylthio-4-aminopyridine was 4.5 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH-:11].[Na+].OO>C(O)(C)(C)C>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([OH:11])=[O:6]
Reactant: [OH-]
Reactant: O=Cc1cccc(Cl)c1F
Agent: OO
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 63.6 %

Procedure:
3-Chloro-2-fluorobenzaldehyde (15.9 g, 0.1 mol) was dissolved in tert-butanol (60 ml), stirred and heated under N2 at 50° C. 2M aqueous NaOH (100 ml, 0.2 mol) was warmed to 50° C. and added to the solution of the aldehyde. Aqueous hydrogen peroxide solution (H2O2, 30%, 70 ml, 0.6 mol) was added over 45 min, maintaining the temperature at 55-60° C. The mixture was stirred and heated under N2 for a further 1 h, cooled and concentrated in vacuo. The residual slurry was filtered. The filtrate was washed with toluene (2×xx ml) and acidified to pH 1 with 5N hydrochloric acid whilst stirring vigorously. The resulting solid was collected by filtration, washed with water and dried in vacuo at 50° C. to give 11.1 g of product, mp 179-181° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:33]1([C:39](=[S:41])[NH2:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:41][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:40][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (20 g, 57 mmol) (Intermediate 20) in DMA (300 mL), NBS (10.2 g, 57 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then morpholine-4-carbothioamide (9.2 g, 63 mmol) was added at 0° C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound (20 g, 83.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.20-8.27 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.20-7.26 (m, 1H), 7.08-7.12 (m, 1H), 6.92-6.98 (br, 1H), 6.62 (d, J=5.5 Hz, 1H), 5.90-6.03 (m, 1H), 5.25-5.41 (m, 2H), 5.65-5.70 (m, 2H), 3.57-3.63 (m, 4H), 3.77-3.86 (m, 4H). m/z (ES+): 476 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.C(OC(C)C)(C)C.[C:30]1([CH2:36][O:37][C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:36]([O:37][C:38](=[O:39])[NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:4]([CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:5]=2)[CH:9]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COC(OC)c1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.14 mol), prepared as in Example 65, and diisopropyl ether (0.16 mol) in DCM (1000 mL) was cooled to 10° C., and carbonochloridic acid phenylmethyl ester (also known as benzyl chloroformate) (0.16 mol) was added dropwise, then the reaction mixture was stirred overnight at room temperature and washed with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (eluent: 100% CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.