Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(CCN3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 32.3 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.265 g, 0.495 mmol), N-methylpiperazine (0.065 mL, 0.58 mmol), and triethylamine (0.10 mL, 0.74 mmol) in DMF (5 mL) was heated at 70° C. for 20 h. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. Water (25 mL) was added and the resulting precipitate was collected by filtration, washed with water (25 mL) and ether (50 mL), and dried in vacuo to afford a brown solid which was purified by silica gel column chromatography. The appropriate fractions were combined and concentrated to afford N2-(4-{4-amino-1-[2-(4-methylpiperazino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide as a beige solid (0.084 g, 0.16 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.26 (1H, s), 8.11 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=8.4 Hz), 7.29-7.35 (4H, m), 7.15 (1H, t, J=7.4 Hz), 4.46 (2H, t, J=6.8 Hz), 4.04 (3H, s), 3.96 (3H, s), 2.80 (2H, t, J=6.6 Hz), 2.49-2.50 (2H, obscured by DMSO peak), 2.23-2.26 (4H, m), 2.12 (3H, s), and 0.97-0.99 (2H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.24. MS: MH+540.3.
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[N:11][CH:12]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cn1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)nc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of 6-(1-phenoxyethyl)nicotinic acid (100 mg, 0.41 mmol) in dichloromethane (20 mL) were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol), N-hydroxybenzotriazole (81 mg, 0.60 mmol) and triethylamine (122 mg, 1.20 mmol). The resultant reaction mixture was stirred for 30 minutes at room temperature. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.50 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-phenoxyethyl)nicotinamide (50 mg, 32.2%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol), N-isopropyl-methyl-amine (3.67 ml, 35.2 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at 50° C. according to the general procedure C. Obtained as a yellow solid (3.27 g, 74%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([OH:30])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2].[N+](=[CH2:33])=[N-]>CO.C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:33])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)Oc1cc(C(=O)O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2NC21
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Reaction time: 0.33 h

Procedure:
To a solution of 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylic acid (12 mg) in methanol (2 ml) was added a solution of diazomethane (excess) in diethyl ether at room temperature. The mixture was allowed to stand at room temperature for 20 minutes and then evaporated to dryness in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (15:1, v/v) to afford methyl 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5].[OH:23]O.O.[OH-].[Li+]>C1COCC1.O.O>[OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4]([OH:5])=[O:23]
Reactant: OO
Reactant: CCCC[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a 2000 mL roundbottom flask was added (4S)-3-[(2R)-2-(hydroxymethyl)hexanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (4) (82 g, 0.268 mol) in THF/water (4:1, 750 mL). The solution was cooled to 0° C. and H2O2 (130 mL, 1.07 mol) was added dropwise, followed by lithium hydroxide monohydrate (22.58 g, 0.537 mol) in water (130 mL). The reaction mixture was warmed up to rt and stirred overnight. THF was removed under vacuum, and the aqueous solution was washed with ethyl acetate. The aqueous solution was then acidified to pH ˜3.0 and extracted with ethyl acetate. The extracts were dried (Na2SO4), filtered and concentrated to provide the title compound (42 g, 107%). LCMS: (2M+H)+: 313.2.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[O:5].[OH-].[K+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23]>O.CC(C)=O>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4](=[O:5])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(C(=O)c2ccccc2O)cc1
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=S)Oc1ccccc1C(=O)c1ccc(C#N)cc1
Temperature: 50 °C
Yield: 83.4 %

Procedure:
15 g (0.0672 mol) of the 4-(2-hydroxybenzoyl)benzonitrile obtained in Preparation IVb are suspended in a mixture of 150 cm3 of water and 100 cm3 of acetone, 4.15 g (0.0735 mol) of potassium hydroxide are then added and the resulting reaction mixture is stirred and heated for 20 minutes at 50° C. (a red coloration appears, followed by complete dissolution). The solution obtained is cooled to 0° C., a solution of 9.14 g (0.074 mol) of dimethylthiocarbamoyl chloride in 80 ml of acetone is added and the resulting mixture is stirred at room temperature for 3 hours. The reaction medium is hydrolyzed. The precipitate formed is filtered off and then triturated in ether. 17.4 g of the expected product are obtained in the form of a beige solid (yield: 84%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH2:28]1[NH:33][CH2:32][CH2:31][N:30]2[CH2:34][CH2:35][CH2:36][CH:29]12>CS(C)=O>[CH2:28]1[CH:29]2[CH2:36][CH2:35][CH2:34][N:30]2[CH2:31][CH2:32][N:33]1[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1
Reactant: C1CC2CNCCN2C1
Reactant: COc1cc(COc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4CCN5CCCC5C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (585 mg, 1.50 mmol) was added in one portion to 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (379 mg, 3.00 mmol) in anhydrous dimethylsulfoxide (1.50 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford impure product as a yellow solid. The impure material was then repurified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (269 mg, 37%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3].O.[C:34]([O:38][CH2:39][CH:40]=[CH2:41])(=[O:37])[CH:35]=[O:36].O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[N:19]([C:35](=[O:36])[C:34]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C=O
Reactant: C=CCOC(=O)N1CCC[C@H]1/C=C(\C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)/C(C)=C/[C@@H]1CCCN1C(=O)OCC=C

Procedure:
To a solution of (3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (9.96 g) in toluene (150 ml) was added allyl glyoxylate monohydrate (3.68 g). The resulting mixture was heated to reflux with azeotropic removal of water for hours. Evaporation of the solvent gave a residue of allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]glyoxylate, which was dissolved in xylene. After evaporation of the solvent in vacuo, the residue was dissolved in dichloromethane (150 ml). To this solution were added successively 2,6-lutidine (2.75 ml) and thionyl chloride (1.95 ml) at -20° C. After stirring at -20° C. for 15 minutes, the reaction mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml) at 5° C. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in degassed N,N-dimethylformamide (80 ml), and to the solution were added 2,6-lutidine (2.75 ml) and triphenylphosphine (1.29 g). After standing for 6 hours at ambient temperature, the reaction mixture was poured into a mixture of ethyl acetate (400 ml) and water (400 ml). The separated organic layer was washed in turn with water, cold 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-4:6 V/V) to give allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl- 2-oxo-3-20 butenyl]3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (9.78 g).
Reaction SMILES: [OH:1][CH:2]([C:6]#[C:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][I:5].[CH3:11][C:12](=[CH2:14])[CH3:13]>>[C:12]([O:1][CH:2]([C:6]#[C:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][I:5])([CH3:14])([CH3:13])[CH3:11]
Reactant: CCCC#CC(O)CCI
Reactant: C=C(C)C
Product: CCCC#CC(CCI)OC(C)(C)C

Procedure:
The subject compound is prepared from 3-hydroxy-1-iodo-4-octyne (Example 498) and isobutylene by the method of Example 492.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(#N)C>[O:22]=[C:19]1[CH2:20][CH2:21][N:3]2[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]2[NH:1]1
Reactant: CCOC(=O)c1c[nH]c(N)n1
Reactant: C=CC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(n1)NC(=O)CC2
Temperature: 0 °C
Yield: 26.5 %

Procedure:
Ethyl 2-amino-1H-imidazole-4-carboxylate (6.45 mmol, 1 g) and triethylamine (10.04 mmol, 1.016 g) were suspended in dry ACN (30 ml) and cooled to 0° C. Acryloyl chloride (9.67 mmol, 0.875 g) dissolved in dry ACN (4 ml) was added dropwise. The resulting mixture was slowly warmed to RT and subsequently heated to 50° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography. 0.358 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.92 (t, 2H), 4.18 (t, 2H), 4.37 (q, 2H), 7.40 (s, 1H), 8.78 (bs, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[C:14](=[C:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1>O>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([N:10]2[CH2:11][CH2:12][CH2:13][C:14](=[C:15]([CH3:17])[CH3:16])[CH:9]2[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: COc1ccc(CC2NCCCC2=C(C)C)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC2C(=C(C)C)CCCN2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 1.0 g. of 2-(p-methoxybenzyl)-3-isopropylidenepiperidine hydrochloride, 1.1 g. of powdered potassium carbonate, 10 ml. of dimethyl sulfoxide, and 0.4 ml. of p-fluoronitrobenzene was stirred and heated on a steam bath for one hour. The reaction mixture was then poured into water and the water was decanted from the precipitated gum. The gum was washed with several portions of water and then taken up in diethyl ether, and the ether was washed with several portions of water. The ether was dried and filtered, and the filtrate was evaporated to dryness under reduced pressure to yield 1-(p-nitrophenyl)-2-(p-methoxybenzyl)-3-isopropylidenepiperidine as a residue. Neither the residue nor its hydrochloride could be induced to crystallize, although only one component could be observed on thin layer chromatographic analysis using several developing systems on both silica gel and alumina. The nuclear magnetic resonance spectrum (CDCl3) of the crude residue showed: 439 (A2B2), 410, (A2B2), 295 (t,1,J=7 cps), 222 (a,3), 172 (d,2, J=7 cps), 95, (s,3), 76 (d,3,J=1-2 cps). The ultraviolet spectrum (95% ethanol) showed: 272s (ε4100), 286s (ε3500), 400 m (ε16300); lit, p-methylanisole 277 (ε2100), 284 (ε1800); N,N-dimethyl-p-nitroaniline 395 (ε20000).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH2:8][CH2:9][N:10]=[C:11]1[CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH:12]1[CH3:18].C(N(CC)CC)C>CCCCCC>[CH3:18][C:12]1[CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[C:11]=1[N:10]([CH2:9][CH2:8][O:7][CH3:6])[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: COCCN=C1C(C)CCCC1C
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COCCN(C(=O)CCl)C1=C(C)CCCC1C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
Over a period of 3 hours and at 20°-30° C. 37.5 g of chloroacetylchloride are added dropwise while stirring to a solution of 57 g of N-(2-methoxy-ethyl)-2,6-dimethylcyclohexylideneamine in 200 ml of hexane. Afterwards during 2 hours 48 ml of triethylamine are added dropwise in the course of which the temperature of the mixture rises to ca. 50° C. Subsequently the mixture is heated under reflux for 30 minutes and poured onto ice. The organic layer is washed with water and dried over sodium sulfate. The solvent is distilled off and the residue is fractionally distilled: 54.5 g of N-(2,6-dimethyl-1-cyclohexene-1-yl)-N-(2-methoxyethyl)-α-chloro-acetamide are obtained, b.p. 136°-139° C./0.1 Torr.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]#[N:18].[Na].[CH:20]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([S:25][C:2]2[C:10]3[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=2[C:17]#[N:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: SC1CCCC1
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1Cl
Agent: [Na]
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1SC1CCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-difluoromethylbenzimidazole is reacted with the sodium salt of cyclopentanethiol to obtain 4-cyclopentylthio-7-nitro-5-cyano-2-difluoromethylbenzimidazole, m.w., 338.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([CH2:36][C:37]([O:39]C)=[O:38])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:27][CH2:28]3)[CH:17]([CH2:36][C:37]([OH:39])=[O:38])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC1CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(N2CCC(NN3C(=O)CN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(=O)O)CC2)ccn1
Yield: 88.4 %

Procedure:
A mixture of methyl 4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazineacetate (1.17 g) obtained in Example 138 and a 2N aqueous solution of sodium hydroxide (2.0 ml) in methanol (20 ml) and 1,4-dioxane (10 m) was stirred at 40° C. for 2 hours. The reaction mixture was cooled, neutralized with 1N hydrochloric acid, and concentrated under reduced pressure. The residue was combined with saturated brine, extracted with a 10% methanol-containing dichloromethane, dried and concentrated. The residue obtained was crystallized from a mixture of ethanol and ethyl acetate to obtain the title compound (1.01 g) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:11]=1[CH:28]=O>CN(C)C=O>[C:16]1([C:13]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=[CH:15][C:10]3[C:11](=[CH:28][NH:2][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CN
Reactant: O=CC1=C(Cl)C=CC(c2ccccc2)(c2ccccc2)C1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]cc2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 20 °C
Yield: 16 %

Procedure:
0.307 g of ethyl glycinate hydrochloride is added to a suspension of 0.589 g of 2-chloro-5,5-diphenylcyclohexa-1,3-dienecarbaldehyde in 20 cm3 of N,N-dimethylformamide. The reaction mixture is refluxed for about 20 hours. After cooling to a temperature in the region of 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 100 cm3 of ethyl acetate, washed with three times 50 cm3 of water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After purification by flash chromatography on a column of silica [eluent: dichloromethane], 0.11 g of ethyl 5,5-diphenyl-4,5-dihydro-2H-isoindole-1-carboxylate is obtained in the form of a brown solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:23])[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:18]=[C:17]([F:16])[CH:22]=[C:21]([F:23])[CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=330.3 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,5-difluorobenzene boronic acid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([CH3:23])=[C:21]([F:24])[CH:20]=[C:19]([C:25]([NH:27][CH:28]4[CH2:30][CH2:29]4)=[O:26])[CH:18]=3)=[CH:13][CH:12]=2)=[N:8][N:7]=1>CO>[CH:28]1([NH:27][C:25]([C:19]2[CH:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:9]4[O:10][C:6]([CH2:5][O:2][CH3:1])=[N:7][N:8]=4)=[CH:12][CH:13]=3)[C:22]([CH3:23])=[C:21]([F:24])[CH:20]=2)=[O:26])[CH2:30][CH2:29]1
Reactant: C[O-]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [Na+]
Solvent: CO
Product: COCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)cc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Freshly prepared sodium methoxide in methanol (0.2M, 0.8 ml) was added to a solution of (4′-[5-chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 34) (50 mg) in methanol (1 ml) and the reaction stirred at room temperature for 18 hours. Further sodium methoxide in methanol (0.2M, 1.6 ml) was added and the reaction continued for 72 hours. The reaction was reduced to dryness under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was reduced to dryness and loaded onto a bond-elut (silica, 10 g). Eluted with an ethyl acetate/cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-5-fluoro4′-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.