Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:13]2[N:12]=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[Cl:14][C:10]1[CH:11]=[N:12][C:13]2[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=2[CH:9]=1
Reactant: CC(=O)OC1CCc2cc(Cl)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC1CCc2cc(Cl)cnc21
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-chloro-6,7-dihydro-5H-cyclopentapyridin-7-yl acetate (1.57 g, 7.42 mmole) in MeOH (36 ml) was added aqueous NaOH solution (1M, 8.9 ml, 8.9 mmole) and the mixture was stirred at 22° C. for 1.5 h. The mixture was diluted with water and extracted with dichloromethane, the organic layer was dried and evaporated to give the title compound as a dark red liquid which crystallized on standing. MS (ESI): m/z=170.1 [M+H]+.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: CCc1cccc(CC)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CCc1cccc(CC)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=315.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-diethylbenzoic acid.
Reaction SMILES: ClC1C(F)=CC(F)=C([N+:8]([O-:10])=[O:9])C=1.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([Cl:22])[CH:15]=1>>[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([Cl:22])[C:15]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: Fc1cc(F)c(Cl)cc1Cl
Product: O=[N+]([O-])c1c(Cl)c(F)cc(F)c1Cl

Procedure:
A synthesis proceeding via four stages can be taken from EP 562 435. 2,4,5-Trichloronitrobenzene is first reacted with an alkali metal fluoride to give 5-chloro-2,4-difluoronitrobenzene. By means of chlorinating denitration the 5-chloro-2,4-difluoronitrobenzene can be converted to 1,3-dichloro-4,6-difluorobenzene. The 1,3-dichloro-4,6-difluorobenzene is nitrated to give 2,6-dichloro-3,5-difluoronitrobenzene. The desired 3,5-difluoroaniline can be prepared from the 2,6-dichloro-3,5-difluoronitrobenzene by reaction with hydrogen with elimination of hydrogen chloride and reduction of the nitro group.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[NH2:47][CH2:48][CH2:49][CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:47][CH2:48][CH2:49][CH2:50][N:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Reactant: NCCCN1CCCC1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCN4CCCC4)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 53.5 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (40 mg, 0.096 mmol), N,N-diisopropylethylamine (0.050 mL, 0.29 mmol), and catalytic DMAP in 2.5 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.069 mL, 0.116 mmol). After 6 min at rt, 1-(3-Aminopropyl)pyrrolidine (16.0 mg, 0.125 mmol) was added and the reaction stirred at rt for 4 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The sample was triturated with EtOAc, and the filtrate chromatographed eluting with CHCl3/MeOH plus triethylamine to give the title compound as a light beige solid (27 mg, 53%). 1H NMR (CDCl3) δ: 8.50 (s, 1H), 8.36-8.44 (m, 2H), 8.10 (s, 1H), 7.58 (s, 1H), 7.46-7.54 (m, 2H), 7.32-7.39 (m, 1H), 7.22-7.31 (m, 2H), 7.10 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 4.46 (s, 2H), 3.53-3.61 (m, 4H), 3.22 (t, J=5.4 Hz, 2H), 2.77-2.97 (m, 7H), 1.82-1.99 (m, 6H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17](O)=[O:18].N>CC(=O)OCC>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17]([NH2:3])=[O:18]
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C(N)=O)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
CDI (42.2 g, 260.4 mmol) was cautiously added to a solution of 3-bromo-5-methylbenzoic acid (16.0 g, 74.4 mmol) in EA (300 mL), and then the mixture was kept at reflux for 3 h. After cooled to room temperature, NH3 (g) was passed though for 1 h. The mixture was filtered and the organic layer was washed with HCl (10%, 100 mL) and water (100 mL). The organic phase was dried over Na2SO4 and concentrated in vacuum to obtain 15.0 g of 3-bromo-5-methylbenzamide as white crystals (yield: 94%). 1H NMR (400 MHz, CDCl3): δ 7.73-7.72 (m, 1 H), 7.56-7.55 (m, 1H), 7.50-7.49 (m 1 H), 2.39 (s, 3 H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>C(COC)OC.CCOCC>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: Sc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 397 mg) in dimethoxyethane (4 ml) was added a solution of 2-pyridinethiol (1.05 g) in dimethoxyethane (6 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added tert-butyl 4-bromo-1-piperidinecarboxylate (2.74 g), and the mixture was refluxed for 2 hours. After cooling, the resulting suspension was diluted with ether and filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; 14% ethyl acetate in n-hexane) to give the title compound (2.2 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[C:1]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[CH:8]=[C:7]([C:16]2[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc([N+](=O)[O-])c(OC)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ncccc1-c1cc(N)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
step 2—To a solution of 98 (0.98 g, 3.1 mmol) in EtOAc/MeOH (2:1, 30 mL) was added 10% Pd/C (0.10 g). A stream of hydrogen gas was bubbled through the solution for 20 min then the solution was stirred at RT for 16 h. The reaction mixture was filtered and concentrated to afford 3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenylamine (100).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:33])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:33][C:21]([CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[CH:22][C:23]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:24][CH2:25]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(F)cc2)CC1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(F)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 27.8 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.38 g), tetrahydrofuran (2 ml) and magnesium (28 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-fluorophenyl)cyclopropane (Example 20) (0.12 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: phenyl; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)-1-(4 -fluorophenyl)cyclopropane (48 mg, 27%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=2)[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:25]=2[C:38]([OH:40])=O)=[CH:19][CH:18]=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH2:55].O>C(Cl)Cl>[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH:55][C:38]([C:25]1[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:27]2[C:32]([C:24]=1[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:18][CH:19]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:40]
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)O)n(CCN(C)C)c3ccccc23)cc1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)NCCN(C)C)n(CCN(C)C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.48 g, 7.71 mmol) was added to a solution of 3-{bis[4-(methoxymethoxy)phenyl]methyl}-1-(2-dimethylaminoethyl)indole-2-carboxylic acid (2.0 g, 3.86 mmol) obtained in Example 48 and N,N-dimethylethylenediamine (0.64 ml, 5.78 mmol) in 30 ml of methylene chloride, followed by stirring at room temperature for 4.5 hours. Water was added to the reaction solution followed by extraction with chloroform. The resulting organic layer was washed successively with 2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.48 g (quantitative) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:14][CH:15]([CH2:17]O)O>>[CH:10]1([CH2:9][C:7]2[CH:6]=[C:5]3[C:3](=[C:2]([Br:1])[CH:8]=2)[N:4]=[CH:17][CH:15]=[CH:14]3)[CH2:11][CH2:12]1
Reactant: Nc1ccc(CC2CC2)cc1Br
Reactant: OCC(O)CO
Product: Brc1cc(CC2CC2)cc2cccnc12

Procedure:
2-bromo-4-(cyclopropylmethyl)aniline and glycerol can be combined to form 6-(cyclopropylmethyl)-8-bromoquinoline,
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:6]1.O.C(=O)([O-])O.[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>COC(C)(C)C>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[CH2:8][CH2:9][O:10][C@@H:5]([CH2:4][NH:3][C:28](=[O:29])[CH2:27][Cl:26])[CH2:6]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2S)-2-Aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (120 g) was dissolved in tert-butyl methyl ether (450 ml), water (450 ml) was added and the mixture was cooled on an ice bath. Sodium hydrogen carbonate (95.56 g) was gradually added and, after the addition, chloroacetyl chloride (29 ml) was added dropwise over about 10 min while maintaining the inside temperature at 15° C. or below. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hr. After 1.5 hr, sodium hydrogen carbonate (3 g) and chloroacetyl chloride (2.7 ml) were successively added to the reaction mixture at room temperature, and the mixture was further stirred for 1.5 hr. The reaction mixture was stood still and partitioned, and the organic layer was obtained as a solution of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}chloroacetamide in tert-butyl methyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (800 mg) obtained in Reference Example 1(2) is dissolved in chloroform (30 ml), and thereto are added morpholine (560 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.24 g) and triethylamine (650 mg) under ice-cooling. The mixture is then stirred at room temperature for 19 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=30/1) to give methyl trans-4-(morpholin-4-ylcarbonyl)cyclohexanecarboxylate (897 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[I-].[K+].Cl[CH:12]1[C:21]2[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>CN(C=O)C>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: ClC1CCCc2cc(Br)ccc21
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCN(C2CCCc3cc(Br)ccc32)CC1

Procedure:
N-Methylhomopiperazine (2.31 g; 20.2 mmol) and potassium iodide (0.35 g; 2.2 mmol) in DMF (13 ml) were reacted with 1-chloro-6-bromo-1,2,3,4-tetrahydronapthalene (2.48 g; 10.1 mmol) in DMF (8 ml) as in Example 15. The yellow oil was kugelrohr distilled to give the title compound, 1.47 g, bp (air bath temperature) 152°-165° C. at 0.10 torr; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H, NCH3), 3.81 (t, 1H, ArCHN), 7.19 (s, 1H), 7.25 (d, 1H), 7.64 (d, 1H). Anal: Calcd. for C16H23BrN2: C, 59.45; H, 7.17; N, 8.67. Found: C, 59.40; H, 7.02; N, 8.30. 1-Chloro-6-bromo-1,2,3,4-tetrahydronaphthalene was prepared as follows:
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[Cl:7][C:8]1[C:13]([C:14](=O)/[CH:15]=[CH:16]/N(C)C)=[CH:12][CH:11]=[CH:10][N:9]=1>CO>[Cl:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][N:3]=[C:4]([NH2:6])[N:5]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CN(C)/C=C/C(=O)c1cccnc1Cl
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1nccc(-c2cccnc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an argon purged 500 mL round bottom flask placed in an isopropanol bath, was added sodium metal (3.40 g, 148 mmol) slowly to methanol (180 mL). The mixture was stirred at RT for about 30 minutes. To this was added guanidine hydrochloride (12.0 mL, 182 mmol) and the mixture was stirred at RT for 30 minutes, followed by addition of (E)-1-(2-chloropyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (12.0 g, 57.0 mmol), attached air condenser, moved reaction to an oil bath, where it was heated to about 50° C. for 24 h. Approximately half of the methanol was evaporated under reduced pressure and the solids were filtered under vacuum, then washed with saturated NaHCO3 and H2O, air dried to yield 4-(2-chloropyridin-3-yl)pyrimidin-2-amine as off white solid. MS m/z=207 [M+1]+. Calc'd for C9H7ClN4: 206.63.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][O:27][CH3:28].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][O:27][CH3:28])[CH2:14][CH2:13]1
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and 1-bromo-2-methoxyethane (0.16 ml, 2.0 mmol). Yield: 0.34 g (61%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 180-181° C. MS m/z (relative intensity, 70 eV) 305 (M+, 2), 261 (14), 260 (bp), 217 (5), 177 (9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[O:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:42]4[CH2:43][CH2:44][N:39]([C:37]([CH:33]5[CH2:34][CH2:35][CH2:36][O:32]5)=[O:38])[CH2:40][CH2:41]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(C(=O)C2CCCO2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(tetrahydrofuran-2-carbonyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=613.98 (M+H+); retention time=0.73 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][F:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:18]>O1CCCC1>[ClH:18].[ClH:18].[F:17][CH2:16][CH2:15][N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CCF)CC1
Agent: Cl
Solvent: C1CCOC1
Product: FCCN1CCCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of 1-tert-butoxycarbonyl-4-(2-fluoroethyl)homopiperazine (550 mg, 2.23 mmol) in 10% aqueous hydrochloric acid (2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature for 2 h, and the reaction mixture was evaporated to dryness under vacuum. Resulting residue was triturated from Et2O/MeOH to afford the titled compound (475 mg, 97%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:11]([NH:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ncc2sccn12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 150 mg (0.98 mmol) of 5-aminomethylimidazo[5,1-b]thiazole in 1 ml of methylene chloride were added 1 ml of acetic anhydride and 0.5 ml of pyridine, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated. The residue was dissolved in methylene chloride, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with ethyl acetate to give 159 mg (yield 83%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][N:6]=[C:5]1SC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][N:6]=[C:5]1[NH:2][CH3:1]
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Reactant: CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CCC(C)c1nnc(NC)n(N)c1=O
Reaction time: 4 h

Procedure:
Monomethylamine was passed for 4 hours into a boiling solution of 42.8 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5 (4H)-one of which 12 ml of glacial acetic acid and 1 g of p-toluenesulfonic acid had been added, and the mixture was then boiled for a further 4 hours under reflux. The solvent was largely evaporated off in vacuo and the oily residue was taken up in methylene chloride and repeatedly shaken with 10% strength sodium carbonate solution. The organic phase was separated off and concentrated by evaporation. 38.6 g (98% of theory) of 4-amino-6-sec.-butyl-3-methylamino-1,2,4-triazin-5 (4H)-one which gradually solidified, remained. The product was purified further by recrystallization from carbon tetrachloride. Melting point = 117° C.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:6]([C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:6]([C:10]1[CH:15]=[C:14]([S:16][CH:3]([CH3:4])[CH2:2][CH:1]=[O:5])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C/C=C/C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(CC=O)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
3.12 Grams of crotonaldehyde (0.042 mole) are added dropwise over a 15 minute period at 17°-22° C. to a solution of 10.8 grams of 2,6-di-tert-butyl-4-mercaptophenol (0.044 moles) and 0.5 gram of triethylamine in 20 ml of toluene and allowed to react in a nitrogen atmosphere at room temperature for 30 minutes and then at 50°-55° C. for two hours. Analysis indicates that the reaction is substantially complete at this point. The product, isolated as a light yellow liquid, is obtained in nearly quantitative yield after stripping off volatiles at 40° to 50° C. at 0.15 mm. Hg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:8]=[N+:9]([O-:20])[C:10]2[CH:19]=[C:18]3[C:14]([CH2:15][CH2:16][CH2:17]3)=[CH:13][C:11]=2[N:12]=1>COCCOC>[O-:20][N+:9]1[C:10]2[CH:19]=[C:18]3[C:14](=[CH:13][C:11]=2[N:12]=[C:7]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[N:8]=1)[CH2:15][CH2:16][CH2:17]3
Reactant: NCCCO
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCO)nc2cc3c(cc21)CCC3
Yield: 97.4 %

Procedure:
3-Aminopropanol (0.99 mL, 12.9 mmol) was added to a stirred solution of chloride 21 (956 mg, 4.3 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 50 (1.09 g, 98%) as a yellow solid: mp (MeOH/DCM) 190-190.5° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.40 (s, 1H, H-5), 5.61 (br s, 1H, NH), 3.78 (br s, 1H, OH), 3.67-3.73 (m, 4H, CH2O, CH2N), 2.97-3.03 (m, 4H, H-6, H-8), 2.15 (p, J=7.5 Hz, 2H, H-7), 1.82-1.88 (m, 2H, CH2); 13C NMR δ 159.2, 155.0, 147.9, 143.6, 130.0, 120.3, 114.8, 59.0, 37.7, 33.1, 33.0, 32.3, 25.7. Anal. calcd for C13H16N4O2: C, 60.0; H, 6.2; N, 21.5. Found: C, 59.8; H, 6.2; N, 21.6%.