Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH3:22][N:21]1[C:14]2[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:13]=2)[CH2:19][C@H:20]1[CH3:23]
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cccc(CO)c1
Product: C[C@@H]1Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([N:11]([CH:20]([CH3:22])[CH3:21])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])[C:6]2[CH:23]=[CH:24][CH2:25][CH2:26][C:5]=2[C:4](=O)[O:3]1.[NH2:28][C@@H:29](C(O)=O)[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>O>[NH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][C@@H:29]2[C:2](=[O:1])[N:7]([CH2:8][C:9]([N:11]([CH:20]([CH3:22])[CH3:21])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[O:10])[C:6]3[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=3[C:4](=[O:3])[NH:28]2)=[CH:32]1
Reactant: COc1ccc(N(C(=O)Cn2c3c(c(=O)oc2=O)CCC=C3)C(C)C)cc1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)CN2C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)c3ccccc32)C(C)C)cc1
Reaction time: 5 h
Yield: 33.9 %

Procedure:
A mixture of 2-(2,4-Dioxo-6H-benzo[d][1,3]oxazin-1-yl)-N-isopropyl-N-(4-methyoxy-phenyl)-acetamide (1.00 g, 2.71 mmol), D-tryptophan (554 mg, 2.71 mmol) and triethylamine (0.378 mL, 2.71 mmol) are combined in water (20 mL) and stirred for 5 hrs. at 50° C. After concentration in vacuo, the reaction mixture is combined with glacial acetic acid (20 mL) and refluxed for 5 hrs. The reaction mixture is filtered and then concentrated in vacuo to an oil. The oil is dissolved in ethyl acetate and washed consecutively with water (2×), saturated aqueous sodium bicarbonate, and brine. The solution is dried over anyhydrous magnesium sulfate, filtered, treated with activated charcoal, filtered and concentrated in vacuo to a yellow foam. The product is crystallized from methanol (15 mL). The resulting slurry is cooled with an ice/water bath, filtered and washed with cold methanol (3×4 mL), and dried under high vacuum to provide the title compound as white solid (469 mg, 0.918 mmol). 1H NMR (300 MHz, CDCl3): 1.11 (m, 6H); 3.22 (m, 1H); 3.46 (m, 1H); 3.69 (d, 1H, J=16.6 Hz); 3.83 (s, 3H); 4.20 (m, 1H); 4.45 (d, 1H, J=16.6 Hz); 5.06 (m, 1H); 6.06 (d, 1H, J=5.4 Hz); 6.88-7.37 (m, 10H); 7.50 (m, 2H); 7.73 (m, 1H); 8.14 (s, 1H). MS(FAB): [M+H]+ =511.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH:11]3[C:32]([CH3:34])=[CH2:33])[C:5]2=[CH:4][CH:3]=1.[CH3:36]OC([Si](C)(C)C)C.FC(F)(F)C(O)=O>>[CH2:24]([N:12]([CH:11]([CH3:10])[CH3:32])[CH:13]([CH3:14])[CH3:36])[CH3:25].[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH:11]3[C:32]([CH3:34])=[CH2:33])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(C)[Si](C)(C)C
Reactant: C=C(C)C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: CCN(C(C)C)C(C)C
Yield: 166 %

Procedure:
In a manner similar to the method described in example 55d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2.88 g, 4.46 mmol) prepared in example 116b was reacted with trifluoroacetic acid, then ethyl-diisopropyl-amine to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as yellow oil (Yield 1.7 g, 85.8%).
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)=[O:2].[CH3:12]C(C)([O-])C.[K+].CI.O>CN(C=O)C>[CH:1]([C:3]1[N:7]([CH3:12])[CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)=[O:2]
Reactant: COC(=O)c1c[nH]c(C=O)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)n(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a solution of methyl 5-formyl-1H-pyrrole-3-carboxylate (60.0 g, 0.360 mol) in DMF (60 mL) was added potassium tert-butoxide (72.0 g, 0.576 mol). After stirring at rt for 30 min, the mixture was cooled to 0° C. and methyl iodide (132 mL, 1.45 mol) was added. The solution was then stirred at rt overnight. Water was added to quench the reaction and the solution was extracted with DCM (3×200 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), and concentrated to give methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (45.0 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 12.62 (s, 1H), 9.48 (s, 1H), 7.66 (s, 1H), 7.30 (s, 1H), 3.67 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[Br:27][CH2:28][C:29](Br)=[O:30]>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[C:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]([C:29](=[O:30])[CH2:28][Br:27])[CH2:4][CH2:3]1
Reactant: O=C(Br)CBr
Reactant: CN1CCNc2c(C(=O)c3ccccc3F)cccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(C(=O)CBr)c2c(C(=O)c3ccccc3F)cccc21

Procedure:
To a solution of 1-methyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (11.99 g) and pyridine (4.04 g) in methylene chloride (200 ml) was dropwise added a solution of bromoacetyl bromide (5.09 ml) in methylene chloride (10 ml) under stirring at a temperature below 10° C. and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was washed with water twice and dried. Removal of the solvent afforded viscous oil. The viscous oil was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried to give 1-methyl-4-bromoacetyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (17.18 g).
Reaction SMILES: F[C:2]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]3)=[C:19]([CH3:33])[CH:18]=[CH:17][C:3]=1[C:4](=S)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1.O.[NH2:35][NH2:36]>C(O)CCC>[CH:13]([O:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[C:3]3[C:2](=[C:20]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]5)[C:19]([CH3:33])=[CH:18][CH:17]=3)[NH:36][N:35]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: NN
Reactant: CNc1ncc2cc(-c3c(C)ccc(C(=S)Nc4cccc(OC(C)C)c4)c3F)ccc2n1
Solvent: O
Solvent: CCCCO
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(OC(C)C)c5)n[nH]c34)ccc2n1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-N-(3-isopropoxyphenyl)-4-methyl-3-(2-(methylamino)quinazolin-6-yl)benzothioamide (54 mg, 117 μmol) and hydrazine hydrate (11 μL, 234 μmol) in n-butanol (6 mL) was heated in a microwave reactor at 150° C. for 33 min. Solvent was removed and the residue was purified by preparative TLC (50% EtOAc/hexane) to give the title compound. MS (M+H)+ 439.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:6]=1)[C:2]#[CH:3].[N:27]([CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[N+:28]=[N-:29].C1CCN2C(=NCCC2)CC1>CO.[Cu]I>[N:32]1([CH2:31][CH2:30][N:27]2[CH:3]=[C:2]([CH2:1][NH:4][C:5]3[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[CH:6]=3)[N:29]=[N:28]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C#CCNc1cc(Nc2ccc(C3CCOCC3)cc2)ncc1C(N)=O
Reactant: [N-]=[N+]=NCCN1CCCCC1
Agent: [Cu]I
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC(=O)c1cnc(Nc2ccc(C3CCOCC3)cc2)cc1NCc1cn(CCN2CCCCC2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 4-(prop-2-ynylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide (Example 184) (20 mg, 0.057 mmol) was dissolved in 6 mL MeOH. To it were added 1-(2-azidoethyl)piperidine (18 mg, 0.11 mmol), DBU (26 μL, 0.17 mmol) and finally powder CuI (13 mg, 0.068 mmol). The mixture was stirred at RT for 5 h, filtered and subjected to reverse phase prep HPLC to isolate the title compound. MS found for C27H36N8O2 as (M+H)+ 505.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.14 (1H, s), 8.12 (1H, s), 7.39 (2H, dt, J=8.4; 2.0 Hz), 7.24 (2H, dt, J=8.4; 2.0 Hz), 6.20 (1H, s), 4.60 (2H, s), 4.05 (2H, m), 3.73 (2H, m), 3.59 (4H, m), 3.04 (2H, m), 2.87 (1H, m), 1.95 (2H, m), 1.86-1.75 (8H, m) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[CH:10]([CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH3:24][C@H:10]1[C@@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9]1.[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]3=[CH:20][O:21][CH:22]=[CH:18][C:17]3=[CH:16][CH:15]=2)[CH:10]([CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC=C1c1cc(F)cc2ccoc12
Agent: [Pd]
Solvent: CCO
Product: CC1CN(Cc2ccccc2)CCC1c1ccc2ccocc1-2
Product: C[C@@H]1CNCC[C@@H]1c1cc(F)cc2ccoc12
Yield: 40 %
Yield: 33 %

Procedure:
A slurry of 0.80 gm 10% palladium on carbon in 100 mL ethanol was stirred under a hydrogen atmosphere. A solution of 4.23 gm (13.2 mMol) 1-benzyl-3-methyl-4-(5-fluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine in 100 mL ethanol was added and the mixture stirred under the hydrogen atmosphere for about 16 hours. The reaction mixture was filtered through a celite pad and the filter cake was washed with ethanol. The combined filtrates were concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing from 0-6% methanol, and then with 9:1:0.1 dichloromethane:methanol:ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 1.0 gm (33%) cis-3-methyl-4-(5-fluorobenzofur-7-yl)piperidine and 1.75 gm (40%) 1-benzyl-3-methyl-4-(5-benzofur-7-yl)piperidine.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3[C:15]([OH:30])=[C:16]4[C:23](=[O:24])[C:22]5[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[C@@H:12]([C:31]([O:33][CH3:34])=[O:32])[C@@:11]([OH:36])([CH3:35])[CH2:10]2)[CH2:5][C@H:4]([N:37]([CH3:39])[CH3:38])[C@@H:3]1[O:40][C@@H:41]1[O:46][C@@H:45]([CH3:47])[C@@H:44]([O:48][C@@H]2O[C@@H](C)C(=O)CC2)[C@@H:43]([OH:57])[CH2:42]1.[OH-].[Na+]>Cl>[CH3:47][C@@H:45]1[O:46][C@@H:41]([O:40][CH:3]2[C@@H:4]([N:37]([CH3:38])[CH3:39])[CH2:5][C@H:6]([O:8][C@@H:9]3[C:14]4[C:15]([OH:30])=[C:16]5[C:23](=[O:24])[C:22]6[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=6[C:19](=[O:20])[C:17]5=[CH:18][C:13]=4[C@@H:12]([C:31]([O:33][CH3:34])=[O:32])[C@@:11]([OH:36])([CH3:35])[CH2:10]3)[O:7][C@H:2]2[CH3:1])[CH2:42][C@H:43]([OH:57])[C@@H:44]1[OH:48].[CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:30])=[C:16]4[C:23](=[O:24])[C:22]5[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:31]([O:33][CH3:34])=[O:32])[C:11]([OH:36])([CH3:35])[CH2:10]2)[CH2:5][CH:4]([N:37]([CH3:39])[CH3:38])[CH:3]1[OH:40]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@H](O)[C@H](O[C@H]5CCC(=O)[C@H](C)O5)[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2CC(N(C)C)C(O)C(C)O2)CC1(C)O)C(=O)c1c(O)cccc1C3=O
Product: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)C(O[C@H]4C[C@H](O)[C@H](O)[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O

Procedure:
A solution of 100 mg of auramycin A in 50 ml of 0.5% hydrochloric acid was hydrolyzed at room temperature for 40 minutes. The reaction mixture was neutralised by dilute sodium hydroxide solution and extracted with 100 ml of chloroform twice. The chloroform extracts were combined and concentrated in vacuo to a small volume. The concentrate was chromatographed with thin layer chromatography plates (chloroform:methanol, 5:1). The bands containing auramycin C and D were scraped off, extracted with a solvent mixture of chloroform and methanol (4:1) and concentrated in vacuo to dryness to give 12 mg of pure auramycin C and 35 mg of auramycin D.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15]>C1COCC1>[C:10]([CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:12]([O:13][CH2:14][CH3:15])=[O:16])#[N:11]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium hydride (24.5 g, 1.02 mol) in THF was added benzyl cyanide (50.0 g, 0.426 mol) at −10° C. The reaction mixture was stirred for 15 min at the same temperature. Diethyl carbonate (60.5 g, 0.512 mol) was added to the reaction mixture and the reaction mixture was allowed to come to room temperature and heated to 40° C. (Caution: Reaction will start suddenly and exothermic). The heating path was removed immediately once the reaction was started and the reaction mixture was cooled under ice/acetone. The solution was allowed to come to room temperature and stirred for 1 h. The reaction mass was cooled to 0° C. and quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (250 mL×3). The combined organic layer was washed with water (200 mL), brine solution (200 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-cyano-2-phenylacetate as crude compound as crude compound (71.0 g). The crude compound was taken to the next step without further purification. LC-MS (M+H)+=190.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (5H, m), 5.65 (1H, s), 4.18 (2H, m), 1.18 (3H, t, J=7.2 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:22])=[C:7]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N+:15]=2[O-:21])[CH:10]=[C:11]([CH3:13])[CH3:12])[CH:8]=1)#[N:2].S(=O)(=O)(O)O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:22][C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N+:15]=3[O-:21])[C:7]=2[CH:8]=1)#[N:2]
Reactant: CC(C)=CC(c1cc(C#N)ccc1O)c1cccc(C)[n+]1[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cccc(C2CC(C)(C)Oc3ccc(C#N)cc32)[n+]1[O-]
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
350 mg of 2-[1-(5-cyano-2-hydroxyphenyl)-3-methyl-2butenyl]-6-methylpyridine N-oxide in 15 ml of dichloromethane were stirred with 100 μl of concentrated sulphuric acid for 1 hour. A further 100 μl of concentrated sulphuric acid were added and stirring was continued for 30 minutes. The mixture was washed with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:9) for the elution to give an oil which crystallized from diethyl ether. There was obtained 0.26 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-6-methylpyridine N-oxide of melting point 165-167° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[N:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[C:13]=[S:14]>C1C=CC=CC=1.C(N(CC)CC)C>[F:27][C:25]([F:26])([F:28])[C:17]1[CH:16]=[C:15]([NH:12][C:13]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=2)=[S:14])[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[N:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc(NC(=S)Nc2cc(C(F)(F)F)nc(C(F)(F)F)c2)cc1
Yield: 72.9 %

Procedure:
A mixture of 4-aminobenzotrifluoride (1.48 g) and 4-isothiocyanato-2,6-bis(trifluoromethyl)pyridine (2.5 g, 0.01 mole) in dry benzene (25 ml) containing several drops of triethylamine was heated under reflux for 7 hours. Removal of the solvent and triethylamine gave the title compound as a colorless solid 2.9 g, m.p. 125°-132° C. Crystallization from benzene furnished a sample, m.p. 132° C.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:3].[CH3:17][O:18][N:19]=[CH:20][CH3:21].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:17][O:18][N:19]1[CH:20]([CH3:21])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16]
Reactant: C=C(C)C1CCCCCCCCCCC1=O
Reactant: CC=NOC
Agent: CON1C(=O)CCCCCCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCCCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclododecanone (2.00 g, 9.02 mmol), acetaldehyde O-methyl oxime (0.99 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (2.33 g, 88% yield). Mixture of E/Z isomers in a ratio of 3:1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH2:21](Br)[C:22]#[CH:23]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:23][C:22]#[CH:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCO
Reactant: C#CCBr
Product: C#CCOCCn1c(COCC)nc2cnc3ccccc3c21
Yield: 101 %

Procedure:
Using the general method of Example 1 Part A 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.39 g, 5.123 mmol) was reacted with propargyl bromide (80% in toluene, 1.7 mL, 15.37 mmol) to provide 1.6 g of 2-(ethoxymethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of trans-3,4-difluorocinnamic acid (10 g, 54 mmol) in 300 mL methanol was added concentrated sulfuric acid (2 mL). The solution was stirred 48 h at ambient temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2×100 mL), brine (1×100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25](N)[CH3:26])=[N:23][CH:24]=1.CC[N:30](C(C)C)C(C)C>CCCCO>[F:17][C:5]1[C:4]([NH2:30])=[N:3][C@H:2]([NH:7][CH:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])[N:8]([C:9]2[CH:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[NH:12][N:13]=2)[CH:6]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)n[nH]1
Solvent: CCCCO
Product: CC(N[C@H]1N=C(N)C(F)=CN1c1cc(C2CC2)[nH]n1)c1ccc(F)cn1
Temperature: 175 °C
Yield: 61.8 %

Procedure:
A mixture of 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-amine (Method 9; 0.200 g, 0.788 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.116 g, 0.828 mmol), and DIEA (0.17 ml, 0.946 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 40 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.175 g, 62%). 1H NMR (400 MHz) 12.47 and 11.98 (s, 1H), 10.15 and 9.27 (s, 1H), 8.48 (s, 1H), 7.89 and 7.81 (s, 1H), 7.65 (m, 1H), 7.42 (b, 1H), 7.20 (b, 1H), 5.76 and 5.64 (s, 1H), 5.00 (m, 1H), 1.85 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 0.95 (m, 1H), 0.85 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 357. Found: [M+H]+358.
Reaction SMILES: [CH3:1][N:2]1[C:13]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[CH:11]=[N:10][NH:9]3)[CH:4]=[C:3]1[C:14]([OH:16])=O.C[N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[NH4+].O>C(#N)C.C(N(CC)CC)C>[CH3:1][N:2]1[C:13]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[CH:11]=[N:10][NH:9]3)[CH:4]=[C:3]1[C:14]([NH2:18])=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(C(=O)O)cc2ccc3[nH]ncc3c21
Agent: F[B-](F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(C(N)=O)cc2ccc3[nH]ncc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of 1-methyl-1,6-dihydro-1,6,7-triaza-as-indacene-2-carboxylic acid D2 (0.46 mmol) in dry acetonitrile (6 mL) and triethylamine (0.13 mL), first TBTU (2 eq) and, after 10 min, 30% aq ammonium hydroxide solution (2 eq) were added under stirring at rt. After 2 h at rt, the mixture was poured into water and the slurry was extracted with AcOEt. The organic layer was washed with brine, dried (Na2SO4) and concentrated to yield a crude product that was purified by chromatography on silica gel (eluant: MeOH/DCM 1:9). Obtained the title compound (10%). ESI (+) MS: m/z 215 (MH+). 1H NMR: 4.36 (s, 3H), 6.95 (bs, 2H), 7.29 (s, 1H), 7.31 (d, J=8.73, 1H), 7.58 (d, J=8.73, 1H), 8.73 (s, 1H), 13.32 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27]F)[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.Cl[C:31]1[O:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1.NC1C=CC(F)=C([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)C3C=CC=CC=3)=N2)C=1.CN1C(=O)CCC1>O.CCOC(C)=O>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]4([CH3:27])[CH2:13][C@@H:12]([C:14]([F:16])([F:15])[F:17])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:9]4)[CH:7]=3)[O:32][C:33]=2[CH:39]=1
Reactant: Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Reactant: Clc1ccc2nc(Cl)oc2c1
Agent: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@]1(c2cc(Nc3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 72.3 %

Procedure:
A mixture of N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.200 g, 0.506 mmol, prepared as described in Example 1 Step 9 but using N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide 4g), 2,6-dichlorobenzoxazole (0.133 g, 0.708 mmol), potassium carbonate (4l, 0.126 g, 0.911 mmol) and NMP (2 mL) was stirred at 120° C. for 4.5 h, the mixture was diluted with water and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 40 g, 0-30% DCM-hexane in 15 min. The product was obtained as a white solid (0.200 g). MS m/z=547 [M+H]+. Calculated for C26H19ClF4N4O3: 546.9.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9][Br:10])=O)=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.[C:12]([NH2:15])(=[S:14])[CH3:13]>C(Cl)Cl>[BrH:10].[CH3:13][C:12]1[S:14][CH:9]=[C:7]([C:6]2[CH:5]=[CH:4][C:3]([OH:11])=[CH:2][CH:1]=2)[N:15]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: ClCCl
Product: Br
Product: Cc1nc(-c2ccc(O)cc2)cs1

Procedure:
4-(2-Methylthiazol-4-yl)-phenol hydrobromide was prepared from α-bromo-4-hydroxyacetophenone and thioacetamide as described in Preparation 48; m.p. 250-251° C. (CH2Cl2).