Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.O1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16]CC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[F:12][C:5]1[CH:4]=[CH:3][C:2]([N:20]2[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH2:19]2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: Fc1ccc(Br)c2ncccc12
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Temperature: 66 °C

Procedure:
To a 2-L reactor with a stirrer, a thermocouple, a condenser and nitrogen inlet were charged 8-bromo-5fluoroquinoline (50 g), tetrahydrofuran (795 g), Pd2(dba)3 (3.78 g), Cymap (1.6 g), and 1,4-Dioxa-8-azaspiro[4.5]decane (47.3 g). the mixture was heated to reflux (66° C.) and the reaction was complete. The reaction mixture was quenched into a 5 L reactor containing 1000 g of water and 640 g of MTBE. The bottom aqueous layer was split off and the organic layer was washed with 5% NaOH (1120 g) and 20% NaCl (2×100 g). The solvent was evaporated, weight 87 g vs 79.4 g by theory.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([Cl:14])[C:3]=1[C:4](OCC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:9]([Cl:14])[CH:10]=[C:11]([CH3:13])[N:12]=1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)c(CO)c(Cl)n1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Ethyl 2,4-dichloro-6-methylnicotinate (10′) (8.04 g, 34.3 mmol) was dissolved in THF (40 mL) and added to a stirred suspension of LAH (6.52 g, 170 mmol) in THF (80 mL) at −78° C. The mixture was stirred for 6 h at this temperature and 1 h at −30° C. and treated cautiously with water (5.5 mL), 15% aqueous NaOH (5.5 mL) and water (16.5 mL) with vigorous stirring. The mixture was warmed to room temperature and filtered. The white precipitate was washed liberally with ethyl acetate. The combined organic portions were dried (MgSO4) and concentrated under vacuum to afford 6.40 g (97%) of(11′) as a colorless oil which solidified on standing: LCMS (MH+, 192).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[C:11](B(O)O)=[CH:10][CH:9]=[N:8]1.FC(F)(F)S(O[C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH3:34])=[N:32][N:33]=[C:29]3[C@H:28]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])[N:27]=[C:26]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[C:25]=2[CH:48]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:26]2[C:25]3[CH:48]=[C:21]([C:11]4[NH:7][N:8]=[CH:9][CH:10]=4)[CH:22]=[CH:23][C:24]=3[N:30]3[C:31]([CH3:34])=[N:32][N:33]=[C:29]3[C@H:28]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])[N:27]=2)=[CH:46][CH:45]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: OB(O)c1ccn[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccn[nH]3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
Sodium carbonate (43.0 mg), 1H-pyrazole-5-boronic acid (24.8 mg) and bis(triphenylphosphine)palladium(II) chloride (13.0 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added. The reaction mixture was heated at 120° C. for 30 min (microwave). Ethyl acetate (2 ml) was added and the water layer was separated. The organic phase was dried and the solvent evaporated. The residue was chromatographed (0-5% methanol:DCM) and the product further purified by MDAP (formate modifier). The resulting gum was loaded on a 1 g SCX-2 column and washed with ammonia in methanol (2M) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-5-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a brown oil (15.6 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([S:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)=[CH:29][CH:28]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Nc1ccc(Sc2ccccn2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)cc3)c(C#N)cnc2cc1F
Yield: 77 %

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 542.1 mg (2.81 mmol) of 4-(pyridin-2-ylsulfanyl)phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to provide 830 mg of 7-fluoro-6-methoxy-4-[4-(pyridin-2-ylsulfanyl)-phenylamino]quinoline-3-carbonitrile as an off-white solid, mp 231-233° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH2:9])[S:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)#[N:11]>>[NH2:9][C:6]1[S:7][C:8]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Nc1nc(C2CC2)cs1
Product: N#Cc1ccc(Oc2sc(N)nc2C2CC2)cc1

Procedure:
The title compound was prepared by analogous procedure to Example 6-1 A using 4-cyclopropyl-thiazol-2-ylamine (WO2005110980) and 4-cyanophenol. m/z 258.1 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5]CC)=O.[CH3:13][P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16]>>[CH3:16][O:15][P:14]([CH2:13][C:3](=[O:5])[C:2]([CH3:1])([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])(=[O:19])[O:17][CH3:18]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)(C)C(=O)OCC
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC

Procedure:
Prepared from ethyl 2,2-dimethyl-caproate and dimethyl methylphosphonate according to the usual method.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH:4]([C:10]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]1[CH3:26].C(Cl)Cl.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:36]([O:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH:4]([C:10]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH:3]1[CH3:26])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC1C(O)[C@@H]2CC(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1C(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@@H]12

Procedure:
Freshly prepared benzhydryl 1-hydroxy-2-methylcarbapenam-3-carboxylate (53 mg., 0.15 mmoles) was dissolved in 5 ml. of methylene chloride and cooled to -10° C. Pyridine (12 mg., 0.15 mmoles), acetic anhydride (15.4 mg., 0.15 mmoles) and 4-dimethylaminopyridine (18.4 mg., 0.15 mmoles) were added and the mixture stirred for 1 hour at -10° C., at which time tlc (4:1 chloroform:ethyl acetate) indicated clean conversion to the acetate ester. The reaction mixture was chromatographed on silicia gel (9:1 methylene chloride:ethyl acetate eluant), yielding purified benzhydryl 1-acetoxy-2-methylcarbapenam-3-carboxylate [Rf 0.65 (4:1 chloroform:ethyl acetate)].
Reaction SMILES: OOS([O-])=O.[K+].[Na+].[Br-:8].CC(C)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[C:17]([CH3:24])[CH:16]=1>C(OCC)(=O)C.O>[Br:8][C:20]1[C:15]([O:14][CH3:13])=[CH:16][C:17]([CH3:24])=[C:18]([C:21](=[O:23])[CH3:22])[CH:19]=1
Reactant: COc1ccc(C(C)=O)c(C)c1
Reactant: [Br-]
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)c(C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Alternatively, 5-bromo-4-methoxy-2-methylbenzoic acid can be synthesized from 4′-hydroxy-2′-methylacetophenone as a starting material. Potassium carbonate (0.720 mg, 5.21 mmol) and methyl iodide (0.542 g, 3.82 mmol) were added to an acetone (10 mL) solution of 4′-hydroxy-2′-methylacetophenone (0.552 g, 3.47 mmol) and stirred at room temperature for 12 hours. Methyl iodide (0.24 g, 1.73 mmol) was further added, and the mixture was heated to reflux for two hours. After cooled to room temperature, the solvent was evaporated under reduced pressure. After chloroform was added to the residue, insolubles were filtered off and the filtrate was concentrated to obtain 4′-methoxy-2′-methylacetophenone (0.57 g). Then, oxone (0.79 g, 1.27 mmol) and NaBr (0.13 g, 1.27 mmol) were added to an acetone (4 mL) water (4 mL) solution of 4′-methoxy-2′-methylacetophenone (0.21 g, 1.27 mmol), and stirred at room temperature for one hour. After water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with water, a saturated sodium carbonate aqueous solution and brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 4:1 mixture (0.28 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone. Then, 4:1 mixture (0.26 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone was added with 5% NaOCl solution (3 mL) and potassium hydroxide (0.92 g) and heated to reflux for 2.5 hours. After cooled to room temperature, the reaction mixture was made acidic with 2M HCl. After the mixture was extracted with ethyl acetate, the organic phase was washed with 1M HCl, brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was washed with methanol to obtain 5-bromo-4-methoxy-2-methylbenzoic acid (112 mg) as a colorless powder.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH2:8]([NH:12][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH2:10][CH3:11]
Reactant: COCC(Cl)C=O
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Butylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-butylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]3[S:24][C:25]([C:35]#[C:36][CH2:37][OH:38])=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)[C:18]=23)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][S:2]([O:38][CH2:37][C:36]#[C:35][C:25]1[S:24][C:19]2=[N:20][C:21]([CH3:23])=[CH:22][C:17]([NH:16][S:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=3)(=[O:15])=[O:14])=[C:18]2[C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(-c2c(C#CCO)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2c(C#CCOS(C)(=O)=O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 0 °C
Yield: 28.9 %

Procedure:
Methane sulfonyl chloride (7.87 μl, 0.101 mmol) was added to a mixture of 3-chloro-N-{2-(3-hydroxy-1-propyn-1-yl)-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 85) (42 mg, 0.084 mmol) and Hunig's base (17.64 μl, 0.101 mmol) in THF (395 μl) and the mixture stirred at 0° C. The mixture was slowly allowed to warm to RT, with stirring, for 2 h. The mixture was then evaporated to dryness and the residue purified on silica, eluting with a gradient of 0-100% ethyl acetate in cyclohexane, to afford the title compound (14 mg). LCMS (A) m/z: 517 [M+1]+ (displacement of OSO2Me by methanol), Rt 1.45 min (acidic).
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([C:28]2[CH2:32][CH:31]([CH2:33][N:34]([C:42]3[CH:46]=[CH:45][O:44][N:43]=3)[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:30][N:29]=2)[CH:24]=[CH:25][C:26]=1I.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][C:57]([Sn](C)(C)C)=[CH:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:21]1[CH:22]=[C:23]([C:28]2[CH2:32][CH:31]([CH2:33][N:34]([C:42]3[CH:46]=[CH:45][O:44][N:43]=3)[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:30][N:29]=2)[CH:24]=[CH:25][C:26]=1[C:57]1[CH2:58][CH2:59][N:54]([C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])[CH2:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)N1CC=C([Sn](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N(CC1CC(c2ccc(I)c(F)c2)=NO1)c1ccon1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3=NOC(CN(C(=O)OC(C)(C)C)c4ccon4)C3)cc2F)CC1
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (141 mg, 0.154 mM) and triphenylarsine (188 mg, 0.616 mM) were dissolved in degassed N-methylpyrrolidone (40 ml) under nitrogen, and stirred for 15 minutes. (5RS)-3-(3-Fluoro-4-iodophenyl)-5-(N-(t-butoxycarbonyl)isoxazol-3-ylaminomethyl)-4,5-dihydro-isoxazole (1.5 g, 3.08 mM) and 1-t-butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridine (1.99 g, 4.62 mM) were added, and the reaction heated at 70–80° for 18 hours. The mixture was filtered through celite and evaporated to dryness, and the residue chromatographed on a 40 g silica Biotage column, eluting with 25% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (817 mg).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([OH:15])[CH:13]=[CH2:14]>>[CH2:12]([O:15][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])[CH:13]=[CH2:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C=CCO
Product: C=CCOC(=O)c1ccccc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A 100-mL three-necked round-bottom flask was fitted with a reflux condenser and, in a nitrogen atmosphere, the flask was charged with phthalic anhydride (4.0 g, 13.5 mmol) and allyl alcohol (4.58 mL), and the contents were stirred at 90° C. for 30 minutes. The unreacted allyl alcohol fraction was distilled off under reduced pressure to give phthalic acid monoallyl ester (yield 5.66 g).
Reaction SMILES: F[C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>C(Cl)Cl>[CH2:12]([NH:15][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:13]=[CH2:14]
Reactant: NS(=O)(=O)c1ncccc1F
Reactant: C=CCN
Solvent: ClCCl
Product: C=CCNc1cccnc1S(N)(=O)=O

Procedure:
5.28 g of 3-fluoropyridin-2-ylsulfonamide and 18.03 ml of allylamine are stirred for 6 hours in a pressurised vessel at a temperature of 125° C. The reaction solution is subsequently concentrated, the crystallisate obtained is dissolved in methylene chloride and a little acetonitrile, the mixture is purified by chromatography using methylene chloride/ethyl acetate (4:1) as the eluent mixture and silica gel as the carrier material. 5.1 g of 3-allylaminopyridin-2-ylsulfonamide (intermediate No. 2.002) of a melting point of 134°-135° C. are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([N:14]2[CH2:15][CH:16]([C:17]3[N:18]=[C:19]([C:22]([F:24])([F:25])[F:23])[S:20][CH:21]=3)[O:26][CH:28]2[C:27]([O:31][CH3:32])=[O:30])[CH3:13])=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: COC(=O)C=O
Product: COC(=O)c1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
Prepared analogously to Example 18 by reaction of N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with methyl glyoxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]3[CH2:21][CH:12]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([I:20])=[CH:15][C:14]=4[C:8]=2[N:7]=[C:6]1[C:22]([O:24]CC)=O)[CH2:11]3.[NH3:31]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]3[CH2:21][CH:12]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([I:20])=[CH:15][C:14]=4[C:8]=2[N:7]=[C:6]1[C:22]([NH2:31])=[O:24])[CH2:11]3
Reactant: CCOC(=O)c1nc2c(n1Cc1ccccc1Cl)C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: N
Product: NC(=O)c1nc2c(n1Cc1ccccc1Cl)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 44 °C
Yield: 100 %

Procedure:
A pressure tube containing a solution of ethyl 3-(2-chlorobenzyl)-8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (89 mg, 0.17 mmol) in methanolic ammonia (5 mL of 7.0M ammonia in methanol) was warmed to 44° C. for 36 hr. Evaporation of the reaction mixture furnished the title compound (86 mg, 0.17 mmol, 100%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.63 (d, J=11.35 Hz, 1H), 2.81 (dd, J=7.72, 3.00 Hz, 2H), 3.14-3.23 (m, 1H), 3.54 (td, J=8.43, 4.26 Hz, 1H), 5.39 (br. s, 1H), 5.92 (s, 1H), 6.42 (d, J=7.57 Hz, 1H), 6.82 (d, J=8.83 Hz, 1H), 7.09-7.15 (m, 1H), 7.17-7.23 (m, 1H), 7.41 (d, J=0.95 Hz, 1H), 7.44-7.66 (m, 1H), 8.83 (d, J=6.94 Hz, 1H); M+1=530/532.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-:34])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1NCc1ccccc1
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A solution of N-benzyl(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (427 mg, 1.29 mmol) in 20 mL of CH2Cl2 was treated with MCPBA (77% max., 325 mg, 1.41 mmol). After stirring for 3 h, the reaction was quenched with saturated NaHCO3 solution and extracted into CH2Cl2. The organic portion was washed with saturated NaHCO3 solution, H2O and brine. The organic was dried over Na2SO4, filtered and concentrated to give N-benzyl(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (393 mg) as a light brown foam.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][O:10][CH:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(N)([NH2:24])(=O)=O>C1S(=O)(=O)CCC1>[C:16]([C:15]1[CH:19]=[CH:20][C:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][O:10]2)=[CH:13][CH:14]=1)#[N:24]
Reactant: CCCCCC1CCC(c2ccc(C(=O)Cl)cc2)OC1
Reactant: NS(N)(=O)=O
Solvent: O=S1(=O)CCCC1
Product: CCCCCC1CCC(c2ccc(C#N)cc2)OC1

Procedure:
A solution of 29.5 g of p-(5-pentyl-2-tetrahydropyranyl)benzoyl chloride and 8 g of sulfamide in 500 ml of tetramethylene sulfone is heated at 120° for 4 hours, evaporated and worked up as usual. 2-p-cyanophenyl-5-pentyltetrahydropyran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34](=O)[CH3:35])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C.[Cl-].C(O[Ti+](OC(C)C)OC(C)C)(C)C>[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH:34]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:35])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(=O)c1ccccc1NC(=O)C1CCN(C(C)=O)CC1
Agent: CC(C)O[Ti+](OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)Nc2ccccc2C(C)Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.8 %

Procedure:
2-(4-Chlorophenoxy)aniline (25 mg, 0.1138 mmol, 1.1 eq) and 1-acetyl-N-(2-acetylphenyl)piperidine-4-carboxamide (30 mg, 0.1040 mmol, 1 eq) were stirred in dry dichloromethane (DCM) at room temperature for 10 min. Tri-isopropoxytitanium chloride (55 μL, 0.2303 mmol, 2.2 eq) was added to the reaction mixture which was stirred at room temperature for an additional 10 min. Sodium triacetoxyborohydride (110 mg, 0.5190 mmol, 5 eq) and acetic acid (3 drops) were added to the reaction mixture which was stirred at room temperature for 16 h. The reaction mixture was then poured onto a solution of saturated aqueous sodium bicarbonate (50 mL) and extracted with DCM (30 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc] gave the title compound (5 mg, 10%) as a clear oil.
Reaction SMILES: C[C:2]([CH3:15])(CC(C)CCN=C=O)CN=C=O.[OH:16][CH2:17][CH2:18][O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22]>>[C:20]([O:19][CH2:18][CH2:17][O:16][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:2][CH3:15])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CC(CCN=C=O)CC(C)(C)CN=C=O
Reactant: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)OCCOCCOCCOCC

Procedure:
Diurethane di(meth)acrylate from 2,2,4-trimethylhexamethylene diisocyanate and 2-hydroxyethyl(methacrylate)