Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@H:12]1[CH2:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:21]([O:20][C:18](=[O:19])[NH:17][C@@H:14]1[CH2:15][CH2:16][C@H:11]([NH2:10])[C@H:12]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:13]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 92.9 %

Procedure:
A mixture of (1S,2R,4R)-(2-benzene-sulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl)carbamic acid benzyl ester (2.96 g, 5.9 mmol) and 20% palladium hydroxide on charcoal (Pearlman's catalyst, 2.0 g) in methanol (100 mL) was stirred under one atmosphere of hydrogen at room temperature for 16.5 h. The mixture was filtered through Celite, and the solids were washed with methanol. The filtrate was concentrated under vacuum and the residue was dissolved in dichloromethane. The solution was dried over sodium sulfate and concentrated under vacuum to provide (1R,3R,4S)-(4-amino-3-benzenesulfonylmethylcyclohexyl)-carbamic acid tert-butyl ester (2.02 g) as a white glassy solid, used without further purification. MS found: (M+H)+=369.62.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[Br:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][CH:45]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][CH:45]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:10])[O:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)o1
Reactant: CC(C)(C)OC(=O)NCC(N)Cc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)NC(=O)c1cc(Br)c(Br)o1
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of 4,5-dibromo-2-furancarboxylic acid (2.81 g, 10.4 mmol), PyBrOP (5.6 g, 12.0 mmol) and diisopropylethyl amine (4.2 mL, 24.0 mmol) in DCM (70 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (2.0 g, 8.0 mmol). After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 2:1) affording the title compound (4.3 g, 82%) as a white solid: LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[C:15]2[S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:14]=2[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][CH:11]=1>O>[N+:23]([C:13]1[C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]=2[C:10]([OH:9])=[CH:11][CH:12]=1)([O-:25])=[O:24]
Reactant: COc1ccc([N+](=O)[O-])c2c1sc1ccccc12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(O)c2sc3ccccc3c12
Temperature: 165 °C

Procedure:
Solid pyridine hydrochloride (1 kg, 8.7 mol) was added to 4-methoxy-1-nitro-dibenzothiophene (iii)(35.44 g, 187 mmol) and the reaction mixed well before heating to 165° C. with continuous stirring. The mixture was maintained like this for 8 hrs, cooled, diluted with water (500 ml) and extracted into dichloromethane (3×200 ml). 3M sodium hydroxide solution was added to the organic extract until a dark solid precipitated from the solution. The filtrate was removed and the liquor acidified to pH1 using concentrated HCl. The resulting bright yellow solid that formed on acidification was then removed by filtration, washed with water and dried to give the title compound that was suitably pure to be used without any further purification. (35.44 g, 77%) m/z (LC-MS, ESP), RT=3.69 min, (M+H)=246.2, (M−H)=244.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH2:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH:29][C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCNC(=O)OCc2ccccc2)CC1
Reaction time: 0.33 h
Yield: 42.4 %

Procedure:
Dissolve 4-[1-(2-amino-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.94 mmol; 396.7 mg) in DCM (20 mL) and add DIPEA (1.41 mmol; 0.25 mL) and benzyl chloroformate (0.94 mmol; 0.14 mL). Stir 20 min and wash with saturated sodium bicarbonate, dry over MgSO4, filter and evaporate. Purify over 40 g silica gel with 0-40% EA/DCM to provide the title compound (222 mg; 42%). MS (ES): m/z=557 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[H-].[Na+].[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
To a slurry of 1.00 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 in 15 mL of DMF was added 0.15 g sodium hydride (60% in mineral oil) portionwise and the mixture stirred for 1 hour. Propanesulfonyl chloride (0.39 mL) is added dropwise, and the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture is filtered to remove a small amount of insoluble material and the filtrate evaporated in vacuo. The product is purified by medium pressure liquid chromatography (MPLC) using silica gel and eluting with a gradient of CHCl3 :EtOAc (2:1) to CHCl3 :EtOAc (1:1) to afford the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][NH:47][CH2:48][CH:41]1[CH2:42][O:43][CH2:44]2)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][N:47]([C:20]([C:19]3[CH:18]=[N:17][C:16]([NH:15][C:12]4[N:13]=[CH:14][C:9]5[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)[C:10]=5[N:11]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:48][CH:41]1[CH2:42][O:43][CH2:44]2)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5COCC(C4)N5C(=O)OCc4ccccc4)cn3)nc2n1C1CCCC1
Yield: 80.3 %

Procedure:
Following general amide formation method 3, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (406 mg, 1.03 mmole) was combined with 3-Oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (266 mg, 0.9 mmole) which gave 7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (0.466 g, 0.723 mmol) in 80% yield. MS m/z 639.3 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=3)[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24]2=[O:45])[CH2:19][CH2:18]1)=O)(C)(C)C>>[C:1]1([NH:7][C:8]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[N:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=4)[C@@H:30]4[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]4)[C:24]3=[O:45])[CH2:19][CH2:18]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: O=C=Nc1ccccc1
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)Nc4ccccc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from starting compound A2 and phenylisocyanate as described for compound 6. Crystallisation from ether. M.p. 109-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}piperazine (1.18 g, 2.76 mmol) in EtOAc (100 mL) and EtOH (25 mL) was added Pd on carbon in one portion. The mixture was stirred at rt under H2 (1 atm.) until complete by TLC. The reaction was filtered through Celite® and concentrated. Purification by flash chromatography provided the title compound of step F (0.690 g, 1.75 mmol, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.42 (m, 2H), 1.75 (d, J=11.4 Hz, 2H), 1.86-1.97 (m, 2H), 2.15 (tt, J=11.3, 3.9 Hz, 1H), 2.54-2.59 (m, 4H), 2.65 (t, J=6.8 Hz, 2H), 2.88-2.94 (m, 6H), 3.00 (s, 3H), 3.25 (t, J=6.8 Hz, 2H), 3.71 (s, 3H), 4.18 (br. s., 2H), 6.25 (dd, J=8.4, 2.6 Hz, 1H), 6.46 (d, J=2.6 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9].C(Cl)(Cl)Cl.O.[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([O:10][CH2:19][CH3:20])=[O:9]
Reactant: CCO
Reactant: O=C(O)COc1cccc(CO)c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)COc1cccc(CO)c1
Reaction time: 72 h

Procedure:
A solution of 3-(hydroxymethyl)phenoxyacetic acid (3.18 g.) in ethanol (30 ml.) was treated with concentrated sulphuric acid (10 drops) and allowed to stand for 3 days. Chloroform (100 ml.) and water (50 ml.) were then added. The organic phase was separated, washed sequentially with saturated aqueous sodium hydrogen carbonate solution (2×50 ml.), water (50 ml.) and saturated brine (50 ml.) and then dried (MgSO4) The dried solution was evaporated and the residue purified by flash column chromatography, eluting with petrol (40°-60° )/ ethyl acetate (60:40 v/v) to give ethyl 3-(hydroxymethyl)phenoxyacetate (2.6 g.) as a colourless oil, NMR: 1.25 (3H,t), 2.8 (1H,br s), 4.25 (2H,q), 4.6 (4H,s) and 6.6-7.4 (4H,m)ppm.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:40][CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[O:23][N:22]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and tert-butylamine (216 mg, 2.96 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CCOCC>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([N:20]=[CH:23][N:24]([CH3:26])[CH3:25])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Solvent: CCOCC
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.1 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine in 10 ml of dimethylformamide dimethyl acetal is warmed on a steam bath. Solution occurs followed by an exothermic reaction and precipitation of a solid. This mixture is stirred at room temperature for 16 hours and then diluted with ether and filtered to obtain the crude product as a yellow solid. Recrystallization of this from acetonitrile gives pure N'-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-yl]-N,N-dimethylmethanimidamide, mp 236°-238° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([Cl:20])[N:14]=1.O>N1C=CC=CC=1>[Cl:12][C:13]1[C:18]([NH:19][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:16]=[C:15]([Cl:20])[N:14]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(Cl)nc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
4-Methoxy-benzoyl chloride (4.15 mL, 30.7 mmol) was added dropwise to a stirred, cooled 0° C. mixture of 2,6-dichloro-pyridin-3-ylamine (5 g, 30.7 mmol) in pyridine (31 mL). Following addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for 30 minutes, at which point the reaction mixture was poured into water causing the formation of a precipitate which was collected by filtration. The collected solids were washed with additional water before drying overnight in vacuo affording N-(2,6-dichloro-pyridin-3-yl)-4-methoxy-benzamide (8.66 g, 29.1 mmol, 95% yield) which was used in subsequent reactions without further purification. ES MS (M+H+)=297.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([CH3:3])[CH3:2].[C:20](O)(=O)[CH:21]([CH3:23])[OH:22]>>[CH:1]([N:4]1[C:5]2[CH:6]=[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][C:18]=2[N:19]=[C:20]1[CH:21]([OH:22])[CH3:23])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cc(C(=O)c2ccccc2)ccc1N
Reactant: CC(O)C(=O)O
Product: CC(O)c1nc2ccc(C(=O)c3ccccc3)cc2n1C(C)C

Procedure:
Reacting 3-isopropylamino-4-aminobenzophenone, prepared by General Preparation 1 (A and B), with lactic acid according to the procedure of General Preparation 2 gave the title product, M+ =308.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes and then a solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, then filtered and concentrated. The resultant crude product was used directly in the next step without further purification (110 mg, 55%). LCMS calculated for C16H15Cl2N2O (M+H)+: m/z=321.0; Found: 321.0
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10]>CO>[C:9]([NH2:10])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: N#Cc1cccnc1
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)c1cccnc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution comprising nitrile hydratase solution 25 (0.697 μmol/min; 0.025 ml) and potassium phosphate buffer (0.1 M; pH 7.0; 0.475 ml) was incubated at different temperatures in the range from 20 to 70° C. for 60 min. The solution was then cooled to 20° C. using an ice bath and 3-cyanopyridine (0.5 M; 0.500 ml) was 30 added. The reaction mixture was incubated at 20° C. for 10 min. The reaction was stopped by adding MeOH. The amount of nicotinamide produced was determined by means of HPLC according to Example 1. After 60 minutes of incubation at temperatures above 40° C., nitrile hydratase activity decreased markedly and, after 60 min of incubation at 50° C., nitrile hydratase activity was only about 25% of the original activity (FIG. 15).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([O:17][Si](C)(C)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([F:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCO
Solvent: CC#N
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred solution of 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (5 g, 16.4 mmol) in acetonitrile at 0° C. was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (6.4 g, 18 mmol). The solution was stirred overnight at room temperature, concentrated, diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 40-60% EtOAc in hexanes to give 3-fluoro-4-oxo-piperidine-1-carboxylic acid benzyl ester (3.1 g) To a stirred solution of 3-fluoro-4-oxo-piperidine-1-carboxylic acid benzyl ester (500 mg, 2 mmol) in ethanol (6 mL) was added sodium borohydride (100 mg, 2.6 mmol). After 0.5 hr, the mixture was concentrated, diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 40-70% EtOAc in hexanes to give (±)-trans-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (120 mg).
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])/[CH2:4][N:5]1[C:9](=[O:10])C2=CC=CC=C2C1=O.[OH2:26].NN>C(O)C>[C:3]([O:26][C:9]([NH:5][CH2:4]/[C:3](/[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[CH:2]/[F:1])=[O:10])([CH3:16])([CH3:4])[CH3:2]
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1C/C(=C/F)COc1ccc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NC/C(=C/F)COc1ccc(Cl)cc1Cl

Procedure:
A solution of (Z)-1-fluoro-2-(2',4'-dichlorophenoxy) methyl-3-phthalimidopropene (0.67 g) and hydrazine hydrate (0.13 g) in ethanol (20 ml) is refluxed for 3 hours. The ethanol is evaporated, the residue extracted with ether and the ether solution washed with dilute aqueous sodium hydroxide, then with water, dried and evaporated. The residue is treated with di-tert-butyl dicarbonate (0.44 g), chloroform (20 ml) and water (6 ml), with added sodium chloride (1 g), for 1.5 hours at reflux to give (Z)-N-t-butyloxycarbonyl-2-(2',4'-dichlorophenoxy)methyl-3-fluoroallylamine. Pure colorless needles (0.43 g) are obtained by silica chromatography using 15% EtOAC in light petroleum as eluant. Cleavage of the butyloxycarbonyl group (HCl/ether) gave (Z)-2-(2',4'-dichlorophenoxy)methyl-3-fluoroallylamine as its hydrochloride salt; colorless needles (0.30 g; 59% yield); mp 135°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:22][C:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:24][CH:23]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Yield: 80.2 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-(4-hydroxybenzyl)-2-methyl-5-phenylvalerate (1.58 g), which is the product of Reference example 7(d), 2-(2-bromoethoxy)tetrahydropyran (0.94 g) and potassium carbonate (1.86 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (1.64 g) as a syrup.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>N1C=CC=CC=1>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:1][C@H:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: Fc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc2ccccc2s1
Yield: 62.1 %

Procedure:
A mixture constituted by (1,1-dimethyl ethyl) L-tyrosinate 4-1 (120 mg, 0.5 mmole) and fluorobenzothiazole (75 mg; 0.5 mmole) in 3 ml of pyridine is heated under reflux for 2 hours. The reaction medium is then evaporated under reduced pressure until a dry extracted is obtained which is purified by chromatography eluting with a heptane/ethyl acetate mixture (100/0→0/100). 115 mg of expected product is obtained.
Reaction SMILES: [F:1][C:2]([F:36])([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[CH:3]([F:25])[O:4][C:5]([F:24])([F:23])[C:6]([F:22])([O:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:7]([F:10])([F:9])[F:8].S(Cl)([Cl:39])=O>>[F:1][C:2]([F:36])([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([Cl:39])=[O:32])=[CH:29][CH:28]=1)[CH:3]([F:25])[O:4][C:5]([F:24])([F:23])[C:6]([F:22])([O:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:7]([F:10])([F:9])[F:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Product: O=C(Cl)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1

Procedure:
4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzoic acid (52.00 g, 0.0912 mol) as prepared in Example 12 and thionyl chloride (365 g, 3.09 mol) were place in an oven dried RB flask equipped with a stirrer, reflux condenser and under nitrogen. The reaction was placed in an oil bath and heated to a gentle reflux overnight. The content was analyzed by proton NMR and shown to be 4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzoyl chloride.