Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)[CH2:3][O:4]CC1OC1.N1CCCC1.C[CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH3:3][O:4][CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)COCC1CO1
Reactant: CC(C)COCC(O)CN1CCCC1
Solvent: C1CCNC1
Solvent: CCO
Product: COC(C)COCC(O)CN1CCCC1
Reaction time: 1 h

Procedure:
20 g. 1-(2-Methylpropoxy)-2,3-epoxypropane are dissolved in 40 ml. ethanol and the solution is warmed to 55° C. Subsequently, in the course of an hour and while stirring, there is added dropwise a solution of 13 g. pyrrolidine in 25 ml. ethanol. The temperature should thereby not increase above 70° C. After completion of the addition, stirring is continued for 1 hour at 70° C., the reaction mixture is then evaporated and the residue is distilled in a vacuum. There are obtained 35 g. 3-(2-methylpropoxy)-1-pyrrolidinopropan-2-ol; b.p. 134° C./14 mm.Hg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:2]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: O=C(O)C1(c2cccnc2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnc2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
1-(Pyridin-3-yl)cyclopropanecarboxylic acid (30.7 mg, 0.188 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (75 mg, 0.19 mmol), and N-methylmorpholine (83 μL, 0.76 mmol) were combined and dissolved in N,N-dimethylformamide (1.0 mL). Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) (122 mg, 0.207 mmol) was added and the reaction mixture was stirred at 50° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-10% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridin-3-yl)cyclopropanecarboxamide (69 mg, 84%). MS (AP+) (M+H) 435.2; LCMS retention time 1.51 min (Method L).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH2:13].[C:15](O)(=O)C.C(N)=N>>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:13])=[C:6]([Cl:12])[C:7]2[NH:11][CH:15]=[N:10][C:8]=2[CH:9]=1)=[O:14]
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1N
Reactant: CC(=O)O
Agent: N=CN
Product: COC(=O)c1cc2nc[nH]c2c(Cl)c1N
Temperature: 80 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
See step e) of example H7 using 2,4,5-triamino-3-chloro-benzoic acid methyl ester as starting material and 2 equivalents of formamidine acetate. The reaction is stirred 2 days at a temperature of 80° C. Then the mixture is extracted with a solution of NaHCO3 saturated (2 times) and EtOAc. The organic phase is washed once with brine, dried on Na2SO4, filtrated and evaporated. A red-violet solid is obtained within 64% yield. LC/MS: 226/228 (M+1)+
Reaction SMILES: [CH2:1]([C:4]([OH:25])([CH2:22][CH:23]=[CH2:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[CH:2]=[CH2:3].Cl.[CH3:27]COCC>>[CH2:1]([C:4]([OH:25])([CH2:22][CH:23]=[CH2:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:20])([CH3:21])[C:17]([O:19][CH3:27])=[O:18])[CH:2]=[CH2:3]
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)O
Reactant: CCOCC
Agent: Cl
Product: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)OC
Reaction time: 2 h

Procedure:
A cooled ether solution of 2.4 g of the product of Example 8 was added to excess CH2N2 in ether at 0° to 5°; after standing 2 hours, the excess CH2N2 was decomposed with dilute HCl. The ether layer was washed with H2O, with dilute NaHCO3, dried (K2CO3) and evaporated. The residue, 2.5 g, was flash chromatographed on a 10×20 cm column of silica gel in 20% C2H5OCOCH3 --CH2Cl2 ; a single fraction of 0.37 g was used for; a total of 1.35 g of title compound was obtained as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]1=[O:17].[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:3]1=[O:17])(=[O:27])[CH3:26]
Reactant: O=C1N(N2CCOCC2)c2ccccc2C1(O)Cc1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(Cc2ccccn2)C(=O)N(N2CCOCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of alcohol from Example 26 (63 mg, 0.194 mmole) 4-dimethylaminopyridine (78 mg, 0.639 mmole), acetic anhydride (0.06 ml, 0. 639 mmole) in dichloromethane (10 ml) was stirred at 0° C. for 8 hours. The volatiles were removed and the crude mixture applied directly to a silica gel column and eluted with 5% methanol in chloroform (Rf =0.34). The product slowly crystallized from hexane-ethyl acetate at 0° C. to give 41 mg of colorless cubes, m.p. 107°-110° C. after filtration. IR (KBr): 1702 cm-1. High Res. Mass Spec. Calcd. for C20H21N3O4 : 368.1610 (M+H). Found: 368. 1611.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)O[C:4](=[O:18])[CH2:3]1.C(N(CC)CC)C.[NH:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH2:27]>ClCCl>[CH2:31]([O:30][C:28]([NH:26][N:27]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[CH:7][CH:2]([CH3:1])[CH2:3][C:4]1=[O:18])=[O:29])[CH3:32]
Reactant: CC1C=C(c2cccc(C(F)(F)F)c2)OC(=O)C1
Reactant: CCOC(=O)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NN1C(=O)CC(C)C=C1c1cccc(C(F)(F)F)c1

Procedure:
A solution of 4 g (16 mmol) of 3,4-dihydro-4-methyl-6-(3'-trifluoromethylphenyl)-2-(1H)-pyrone in 100 ml dichloromethane is treated with 5.6 ml of triethylamine and 7.31 g (70 mmol) of ethyl hydrazinoformate, and the mixture is refluxed for 8 hours. After cooling, the reaction solution is washed alternately with distilled H2O, dilute HCl and distilled H2O, dried over Na2SO4 and concentrated on a rotary evaporator. The oil which remains is taken up in 150 ml of toluene, the solution is treated with a spatula-tip full of PTSA and the mixture is refluxed on a water separator until the reaction is complete. For working-up, the reaction solution is washed first with dilute K2CO3 solution and then with distilled H2O and subsequently dried over Na2SO4. The oil obtained after the solvent has been evaporated in vacuo is purified by column chromatography on silica gel (eluent: toluene:acetone=95:5).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:12]=[C:13](Cl)[N:14]=[N:15][C:16]=2[O:17][CH3:18])[OH:10])=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C(C2[CH:35]=[C:34]([O:36]C)N=NC=2Cl)O)=CC=1)C>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:12]=[CH:13][N:14]=[N:15][C:16]=2[O:17][CH3:18])=[CH:5][CH:4]=1)[CH3:2].[C:34]([OH:36])(=[O:10])[CH3:35].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:12]=[CH:13][N:14]=[N:15][C:16]=2[O:17][CH3:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2cc(Cl)nnc2OC)cc1
Reactant: CCc1ccc(C(O)c2cc(OC)nnc2Cl)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc(Cc2ccnnc2OC)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The 6:1 mixture of (4-ethylphenyl)-(3-chloro-6-methoxypyridazin-5-yl)-methanol and (4-ethylphenyl)-(3-chloro-6-methoxypyridazin-4-yl)-methanol (10.7 g), 5% palladium/carbon (5.4 g) and acetic acid (80 ml) were suspended and stirred under a hydrogen atmosphere at room temperature for 22 hours. After filtration to remove the insoluble materials, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to chloroform:methanol=10:1) to give 4-(4-ethylbenzyl)-3-methoxy-pyridazine (2.88 g) and 4-(4-ethylbenzyl)-3-methoxy-pyridazine acetate salt (3.32 g).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:32])[NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]=4)=[CH:15][CH:14]=3)[CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH:20]=4)=[CH:17][CH:18]=3)=[O:32])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(NC(=O)Nc3ccc4nccn4c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C2=CCNCC2)cc1)Nc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-(4-(3-imidazo[1,2-a]pyridin-6-ylureido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.57 g, 1.315 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (0.608 ml, 7.88 mmol) and the reaction mixture was stirred at room temperature for 4 hours. Concentration provided the title compound.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[I:21]>O>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([N+:6]([O-:9])=[O:7])[C:12]=1[I:21]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C(F)(F)F)ccc1I
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C(F)(F)F)cc([N+](=O)[O-])c1I
Temperature: 0 °C

Procedure:
A 1:1 mixture of H2SO4/HNO3 (20 ml) was added to 2-methyl-4-trifluoromethylphenyl iodide at 0° C. The mixture was stirred at 0° C. and then warmed to room temperature overnight. LC/MS analysis indicated no remaining starting material. The mixture was diluted with water and extracted with EtOAc (3×50 ml). The combined EtOAc layers were washed with sodium bicarbonate and brine and dried over sodium sulfate. The title compound was obtained after removal of solvent. 1H NMR (CDCl3, 500 MHz): δ 7.71 (s, 1H), 7.69 (s, 1H), 2.68 (s, 3H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:1][CH2:2][C:3]#[C:4][CH2:5][CH3:6])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CCC#CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Yield: 98 %

Procedure:
This compound was synthesized as a colorless oil from hex-3-yn-1-ol (117.0 mg, 1.19 mmol), TsCl (295.5 mg, 1.55 mmol), Et3N (181.3 mg, 1.79 mmol), and DMAP (145.6 mg, 1.19 mmol) in 98% yield by following general procedure 1.1: ESI-MS: 253.1 (M+H+), 275.1 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[OH:14].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:14][C:22]1[CH:23]=[CH:24][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:20][C:21]=1[Cl:26]
Reactant: COC(=O)C(C)c1ccc(Cl)c(O)c1
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CC(C(=O)O)c1ccc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (iii) and 3-chloro-4-fluorophenyl methyl sulfone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[N:10](C)C1C=CC=CC=1>>[CH3:8][C:5]1[C:4]([NH2:10])=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: CN(C)c1ccccc1
Reactant: Cc1cnc(C)cn1
Product: Cc1cnc(C)c(N)n1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of 2,5-dimethylpyrazine (14 g, 0.13 mol) in N,N-dimethylaniline (50 mL) was heated to 170° C. and NaNH2 (22 g, 0.56 mol) was added in portions. The reaction mixture was stirred at 170° C. for 1 h, and the solvent was removed. The product was purified by column chromatography to give 3,6-dimethylpyrazin-2-amine as a brown solid (1.6 g). MS (ESI): m/z 124 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH:3]=1.[C:22]([NH:25][NH2:26])(=[O:24])[CH3:23].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:22]([NH:25][NH:26][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[CH:21][CH:20]=1)(=[O:24])[CH3:23]
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(=O)O)cc2)n1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc(Cl)cc(NCCc2ccc(C(=O)NNC(C)=O)cc2)n1
Reaction time: 15 h
Yield: 55.2 %

Procedure:
To a solution of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid (0.41 g, 1.33 mmol), acetic acid hydrazide (0.1 g, 2 mmol), and triethylamine (0.7 mL, 3.99 mmol) in DMF (3 mL) is added [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoro borate (0.51 g, 1.6 mmol) at room temperature. After 15 h at 20° C., the solid is filtered, and washed with water to afford 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N′-acetyl-hydrazide (267 mg). The filtrate is extracted with EtOAc, and concentrated to afford additional amount of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N′-acetyl-hydrazide (100 mg). LCMS: RT=2 minutes; MS: 364 (M+H).
Reaction SMILES: C([C:3]1[C:4]([NH2:15])=[C:5]([C:12](O)=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8])C.Cl.[CH:17](N)=[NH:18]>C(O)C>[OH:13][C:12]1[C:5]2[C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=[CH:3][C:4]=2[N:15]=[CH:17][N:18]=1
Reactant: CCc1ccc(C(=O)O)c(C(=O)O)c1N
Reactant: N=CN
Agent: Cl
Solvent: CCO
Product: O=C(O)c1cccc2ncnc(O)c12
Yield: 55.4 %

Procedure:
To a solution of ethyl 3-aminophthalic acid (1.00 g) in ethanol (10 ml) was added formamidine hydrochloride (444 mg) and refluxed for 12 hours. After cooling, the formed precipitate was collected by vacuum filtration and the precipitate was washed with ethanol to give 4-hydroxyquinazoline-5-carboxylic acid (504 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:26][OH:27])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl.Cl.COC1C=CC2C3C(N4CCNCC4)=NC4C(C=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:27][N:26]=[C:6]1[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:8]=2[C:23]2[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]1=2
Reactant: CN(C)CCCl
Reactant: COc1ccc2c(c1)C(=NO)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: Cl
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCN(C)C)c1c-2c(N2CCNCC2)nc2ccccc12

Procedure:
9-Methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one O-2-(dimethylamino)ethyl oxime (6r) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6p and 2-dimethylaminoethyl chloride·HCl were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 45%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:17][CH2:18][C:19]([OH:21])=[O:20].Cl>CN(C=O)C.C(O)(C)C>[ClH:17].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][C:19]([OH:21])=[O:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C(O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 20.1 %

Procedure:
1-Benzyl-4-hydroxypiperidine (10 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (5 g, 50% dispersion in mineral oil) in dry DMF (50 ml) at 20° under an atmosphere of nitrogen. The suspension was stirred at 20° for 4 hours, then 2-chloroacetic acid (4.95 g) in DMF (50 ml) was added slowly in two equal portions with a 2 hour interval between each. The resulting thick slurry was stirred at 20° for 24 hours. Isopropanol (75 ml) was added and the slurry was acidified to pH 6 with 2 N hydrochloric acid then concentrated in vacuo. The aqueous residue was adjusted to pH 10 with sodium hydroxide solution and extracted with chloroform (3×100 ml). The aqueous layer was separated, acidified to pH 3 with 2 N hydrochloric acid and extracted with chloroform (3×100 ml). The organic extracts were again discarded and the aqueous phase was concentrated to half volume, filtered and the filtrate evaporated in vacuo to give 2-(1-benzylpiperidin-4-oxy)acetic acid, hydrochloride (3 g), characterised by n.m.r.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7]C(=O)C(C)(C)C.[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(Cl)Cl>C(Cl)Cl.CO>[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19]([C:3]2[C:2]([NH2:7])=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH2:17]1
Reactant: O=C1CCC(C(F)(F)F)CC1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Solvent: CO
Solvent: ClCCl
Product: Nc1ncccc1C1=CCC(C(F)(F)F)CC1
Yield: 26 %

Procedure:
Prepared in analogy to example 262 step a-b), starting from N-(pyridin-2-yl)pivalamide and 4-(trifluoromethyl)cyclohexanone. 3-(4-Trifluoromethyl-cyclohex-1-enyl)-pyridin-2-ylamine was obtained after column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent as a white solid (yield: 26% over 2 steps).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=C(F)C=2)=NOC=1C)=O)C>>[F:19][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCOC(=O)c1c(-c2ccc(F)c(F)c2)noc1C
Agent: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Product: Cc1onc(-c2ccc(F)c(F)c2)c1CO
Yield: 99.6 %

Procedure:
As described for example 88d, 3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (28.5 g, 107 mmol), instead of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, was converted to the title compound (24.0 g, 48%) which was obtained as a light yellow solid. MS: m/e=226.2 [M+H]|.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][CH2:14][CH3:15])[S:5]([C:8]([F:11])([F:10])[F:9])(=[O:7])=[O:6])[CH:2]=[CH2:3].C(OOC(C)(C)C)(C)(C)C.[CH2:26]([O:28][P:29]([O-:33])[O:30][CH2:31][CH3:32])[CH3:27]>>[CH2:12]([N:4]([CH2:1][CH2:2][CH2:3][P:29]([O:30][CH2:31][CH3:32])(=[O:33])[O:28][CH2:26][CH3:27])[S:5]([C:8]([F:11])([F:9])[F:10])(=[O:7])=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: CCOP([O-])OCC
Reactant: C=CCN(CCCC)S(=O)(=O)C(F)(F)F
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCN(CCCP(=O)(OCC)OCC)S(=O)(=O)C(F)(F)F
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Over a 60 minute period, a solution of the above-prepared N-allylsulfonamide (24.60 g, 0.10 mole) and diethylphosphite (15 g) was added dropwise concurrently with a solution of di-t-butyl peroxide (0.90 g) in diethylphosphite (5 g) to diethylphosphite (80 g) being stirred at 150° C. with an argon purge. The resulting mixture was stirred for an additional 1 hour under these conditions. The excess diethylphosphite was distilled at 10-20 torr and the residue fractionally distilled to give 19.64 g (b.p. 150°-153° C. at 0.20 torr) of the desired compound, diethyl 3-(N-butyltrifluoromethanesulfonamido)propanephosphonate. A mixture of the phosphonate prepared above (15.36 g, 0.040 mole) and bromotrimethylsilane (13.46 g. 0.088 mole) was stirred under a reflux condensor and calcium chloride drying tube for 96 hours. Then water (75 ml) was added and the resulting mixture stirred for 15 minutes followed by extraction with three 50 ml portions of diethylether. The ether portions were combined, dried with MgSO4 and evaporated in vacuo to give 12.25 g of the desired compound, 3-(N-butyltrifluoromethanesulfonamido)propanephosphonic acid.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH:13]([CH3:18])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][CH:14]1[CH2:15][CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH3:18]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(N)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (5 g, 64.93 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (1.4 g, 7.56 mmol) in methanol (25 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.5 g, 7.93 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-carbethoxy-3-methylpiperidine. Yield 1.0 g (72%), C9H18N2O2, m/z 187 (M+1), PMR (CDCl3): 0.94 (dd, 3H), 1.22 (m, 1H), 1.26 (t, 3H), 1.6 (m, 1H), 1.82 (m,1H), 2.4 (m,1H), 2.82 (m, 1H), 3.34 (m, 2H), 3.64 (m, 1H) 4.14 (q, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CO.[S:13]([O-])([O-:16])(=[O:15])=[S:14].[Na+].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:13]([OH:16])(=[O:15])=[S:14]
Reactant: O=S([O-])([O-])=S
Reactant: CN(C)c1ccc(N)cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(N)c(S(=O)(O)=S)c1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
N′,N′-dimethyl-p-phenylene diamine (10 g, 0.0735 mols) was added to a round bottom flask. To this was added de-ionised water (160 ml) and methanol (40 ml) and the solution was then cooled to 5° C. Sodium thiosulfate (20 g, 0.0808 mols) in water (20 ml) was added to the solution in one aliquot. Sodium persulfate (17.5 g, 0.0735 mols) in water (40 ml) was added drop-wise over a 15 minute period. The reaction mixture was stirred for 3 hours at 5° C. and then warmed to 22° C. over a period of 1 hour. The dark solid which precipitated was collected via filtration. The black solid was washed with water (50 ml) then dried at 40° C. for 16 hours, 7.88 g (43%).