Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33].C(N(CC)CC)C>CO>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][CH:17]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)/C(=C/c1ccc(Cl)c(Cl)c1)NC(=O)OCc1ccccc1
Reactant: Nc1ccccc1S
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a deoxygenated solution of methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(3,4-dichlorophenyl)acrylate (10a) (2.17 g, 5.7 mmol) in anhydrous methanol (40 ml) (warmed to dissolve) under nitrogen was added the 2-aminothiophenol (3.1 ml, 28.5 mmol) followed by addition of triethylamine (400 ul, 2.85 mmol). The mixture stirred 3 days at ambient temperature, concentrated to ca. 10 mL, partitioned between cold 1N hydrochloric acid (75 mL) and ethyl acetate (100 mL). The organic phase was separated and consecutively washed with 1N hydrochloric acid (4×), dilute aqueous sodium bicarbonate and brine, dried, filtered and evaporated to give the title compound (10b) as an 4:1 mixture (erythro:threo) (2.8 g, 96%). A 100 mg sample was converted to the HCl salt to provide an analytically pure title compound (32 mg) as a (4:1) mixture. MS APCI, m/z=505 (M+1), 507 (M+3). LC/MS: 2.94 min.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[CH2:3]([NH:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:2]([CH3:12])=[O:1]
Reactant: CCOC(=O)C(=O)NCC(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)NCC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 2-(2-hydroxypropylamino)-2-oxo-acetate (10.7 g, 61.07 mmol) in DCM (100.0 mL), is added Dess Martin periodinane (25.9 g, 61.07 mmol) at 0° C. The reaction mixture is stirred at room temperature for 2 hours, diluted with water (100 mL) at 0° C., and extracted with DCM (2×100 mL). The combined organic layer is washed with water (2×50 mL) and saturated brine (50 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (1:1) to give the title compound as a light yellow oil (9.2 g, 87.03%). ESI/MS m/z 174.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:13]1[CH2:21][CH2:22][C:7]([C:8]#[N:9])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#CCc1ccccn1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1

Procedure:
Prepare by the method of example 30.2 using 2-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH2:21][Br:24])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: O=C(NCCOc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Yield: 90 %

Procedure:
Benzyl-[2-(4-acetyl-phenoxy)-ethyl]-carbamate (10.2 g, 32.5 mmol) was dissolved in methylene chloride (100 ml) and methanol (50 ml), and tetrabutylamonium tribromide (15.7 g, 32.5 mmol) was added in one portion. The reaction mixture was stirred for about sixteen hours, and then quenched with water. The aqueous phase was extracted with ethyl acetate and then washed with saturated aqeous sodium bicarbonate, and saturated Na2S2O3. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo, and the resulting crude material was purified by column chromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) to afford a colorless oil which solidified upon standing. (11.5 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:25]([O:33][C:34]([F:37])([F:36])[F:35])[CH:24]=1>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[O:33][C:34]([F:35])([F:36])[F:37])(=[O:31])=[O:30])[C:3]1=[O:12]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 5.54 g of 3-amino-5-chloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one 5.00 g, 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride, which is the compound described in Preparation 1.18A of the brochure Publication No. WO03/008407, as starting materials, 4.99 g of the title compound (light yellow solid) was obtained by a similar method to Example 2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([Si:38]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[O:39][CH:40]1[CH2:44][CH2:43][C:42]([CH:48]=[CH2:49])([C:45]([OH:47])=[O:46])[CH2:41]1)([CH3:37])[CH3:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.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]>[CH:30]1([C@H:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:49]=[CH:48]/[C:42]5([C:45]([OH:47])=[O:46])[CH2:43][CH2:44][CH:40]([O:39][Si:38]([CH:50]([CH3:52])[CH3:51])([CH:53]([CH3:55])[CH3:54])[CH:35]([CH3:36])[CH3:37])[CH2:41]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1CCC(/C=C/c2ccc3ccc([C@@H](C)NC(=O)[C@@H]4CCCN(C(=O)[C@H](C)NC(=O)[C@@H](O)C5CC5)N4)nc3c2)(C(=O)O)C1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (795.0 mg, 1.493 mmol), 3-triisopropylsilanyloxy-1-vinyl-cyclopentanecarboxylic acid (466.6 mg, 1.493 mmol), tri(o-tolyl)phosphine (91.0 mg, 0.299 mmol) and triethylamine (0.63 mL, 4.479 mmol) in 1,4-dioxane (20 mL) was deoxygenated by bubbling through nitrogen for 5 min. The reaction mixture was then treated with tris(dibenzylideneacetone)dipalladium(0) (136.7 mg, 0.149 mmol). After stirring at 100° C. for 40 min, the reaction was cooled to room temperature and filtered through Celite. The solid was rinsed with ethyl acetate and the volatiles were removed in vacuo to provide the crude title compound (1.493 mmol) as an orange foam. LCMS (m/z) 764.4 [M−H], Tr=3.53 min.
Reaction SMILES: [Cl:1][CH:2]([Cl:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7].S(Cl)([Cl:14])=O>>[Cl:1][CH:2]([Cl:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:14])=[O:7]
Reactant: CC(C)(CC(=O)O)CC(Cl)Cl
Reactant: O=S(Cl)Cl
Product: CC(C)(CC(=O)Cl)CC(Cl)Cl
Temperature: 60 °C

Procedure:
52.25 g of 5,5-dichloro-3,3-dimethyl-pentanoic acid are reacted with 150 ml of thionyl chloride, first at room temperature and thereafter while warming at 60° C. By working up the mixture by distillation, 56.5 g of 5,5-dichloro-3,3-dimethyl-pentanoic acid-chloride of boiling point 114°-115° C./15 are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6](=O)[CH:5]=[C:4]([CH3:12])[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1=CC(=O)C([N+](=O)[O-])C(C)=N1
Product: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1

Procedure:
By the method of Yakugaku Zasshi, 87, 387 (1967), 2,6-dimethyl-3-nitro-4-pyridone (11.23 g, 66.8 mmol) and phosphorus oxychloride (57 ml) were heated together at reflux for 11/2 hours. The excess reagent was removed under reduced pressure, and the residue dissolved in dichloromethane (150 ml). This solution was treated with dilute aqueous sodium bicarbonate until the aqueous layer was at pH 7, and then the organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to give a pale yellow solid, (9.8 g, 79%). Caution: this compound is believed to be a powerful skin irritant.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([CH2:10][NH2:11])[OH:9]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:11][CH2:10][CH2:8][OH:9]
Reactant: NCCO
Reactant: Clc1ncccn1
Solvent: O
Product: OCCNc1ncccn1

Procedure:
2-Chloropyrimidine (5 g) and ethanolamine (15 ml) were stirred for 2 hours at 140° C. After cooling, the mixture was added to water (200 ml) and continuously extracted with ethyl acetate (500 ml) for 16 hours. The organic extract was dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as a solid (m.p. 66° C.), following chromatography on silica-gel in 3% methanol in dichloromethane.
Reaction SMILES: Cl.[Br:2][C:3]1[N:7]([CH2:8]Cl)[N:6]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[N:7]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[N:6]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1nc(Br)n(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(Br)n(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 28.6 %

Procedure:
2.03 g of 5-bromo-3-t-butyl-l-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 1.30 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 24 ml of N,N-dimethylformamide. 2.21 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.76 g of [(5-bromo-3-t-butyl-1H-1,2,4-triazole 1-yl)methyl](3,3, 3-trifluoropropyl)malononitrile (referred as the compound of the present invention (32), hereinafter) shown by below formula.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].C(=O)(O)O.[OH:14][CH2:15][CH:16]([CH2:18][OH:19])[OH:17].C(=O)([O-])[O-].[K+].[K+]>>[C:15]([O:3][C:2]1[C:1]([O:8][CH3:9])=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:14])[CH:16]([CH2:18][OH:19])[OH:17]
Reactant: COc1ccccc1O
Reactant: OCC(O)CO
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1OC(=O)C(O)CO
Temperature: 185 °C

Procedure:
Guaiacol (249 grams), glycerine carbonate (254 grams) and potassium carbonate (1 gram) were combined and heated to 185° C. over a 6 hour period to result in a guaiacol mono-glycerate product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)C1CC=C(c2ccc(F)c(Cl)c2)CC1
Temperature: 100 °C

Procedure:
A flask was charged with (3-chloro-4-fluorophenyl)boronic acid (495 mg, 2.84 mmol), ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (686 mg, 2.27 mmol), Pd(PPh3)4 (262 mg, 0.227 mmol), 1M Na2CO3 (6.81 mL, 6.81 mmol), EtOH (2.8 mL), and DME (8.6 mL). The reaction was degassed with N2, the flask was sealed, and the reaction was heated to 100° C. for 2 hours. The reaction was then cooled to room temperature and diluted with hexanes (100 mL) and EtOAc (20 mL). The mixture was washed with water (2×25 mL) and brine (2×25 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 10% EtOAc/hexanes) afforded ethyl 4-(3-chloro-4-fluorophenyl)cyclohex-3-ene-1-carboxylate. Rf=0.25 (5% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.37 (dd, J=7.1, 2.3 Hz, 1H), 7.20 (m, 1H), 7.05 (t, J=8.8 Hz, 1H), 6.05 (s, 1H), 4.16 (q, J=7.1 Hz, 2H), 2.36-2.62 (m, 4H), 2.17 (m, 1H), 1.84 (m, 1H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CNCC[C@H](O)c1cccs1
Reactant: c1ccc2ccccc2c1
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1

Procedure:
contacting the (S)—N-methyl-3-hydroxy-3-(2-thienyl)-1-propanamine with an activated naphthalene in a reaction mixture under conditions sufficient to produce (3S)—N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-yl-propan-1-amine (Duloxetine) having the structure of formula (VIII); and (e) recovering the (3S)—N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-yl-propan-1-amine from the reaction mixture.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:21].[Na+].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([OH:21])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2O)CC1
Temperature: 25 °C

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.85 g, 6.19 mmol, prepared in Example 5a) in DMSO (6 mL) was added a 2.5M aqueous solution of NaOH (30 mL). The resulting suspension was heated to reflux for 12 h before allowing to cool to room temperature. The suspension was then diluted with water (20 mL), acidified to pH=5 with 6M HCl, and extracted with EtOAc. The organic phase was concentrated in vacuo and the resulting solids were purified by flash chromatography (silica gel, 5.5:1 EtOAc:Hexanes). Product 3′-Hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was obtained as white solids (538 mg, 31.0%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([CH2:17]O)=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:16])[CH2:13][CH2:14][OH:15]>ClCCl>[Cl:5][C:6]1[C:7]([CH2:17][Cl:3])=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:16])[CH2:13][CH2:14][OH:15]
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)c1ccnc(CO)c1Cl
Solvent: ClCCl
Product: CN(CCO)c1ccnc(CCl)c1Cl
Reaction time: 1 h

Procedure:
Thionyl chloride (7.4 ml, 101.5 mmol), dissolved in dichloromethane (50 ml), is added dropwise at 4° C. to a solution of (2-[(3-chloro-2-hydroxymethyl-pyridin-4-yl)-methylamino]-ethanol (10.0 g, 46.1 mmol) in dichloromethane (150 ml). The solution is stirred for 1 h at this temperature, triturated with ice water and neutralized with saturated sodium bicarbonate solution. After separation of the organic layer the aqueous phase is extracted with dichloromethane. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is employed without additional purification for the synthesis described in step b).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CCCC(CCC)n1cc(C#N)c(=O)c2c(Cl)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCC(CCC)n1cc(C#N)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Yield: 48.3 %

Procedure:
5-Choro-4-oxo-1-(1-propylbutyl)-1,4-dihydroquinoline-3-carbonitrile (0.015 g, 0.05 mmol), 2,4-dimethylbenzeneboronic acid (0.012 g, 0.079 mmol), and PdCl2(PPh3)2 (0.010 g, 0.015 mmol) were suspended in toluene (1 mL). K3PO4 (0.074 mL, 0.15 mmol, 2M in water) was added last. The reaction was stirred at 90° C. with stirring overnight. The mixture was cooled, filtered through GF/F paper and concentrated. Flash chromatography (40% Ethyl acetate/hexanes) gave the desired product (0.009 g, 50%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].CC1(C)[O:21][C@H:20]([CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[C:26]([O:34][CH3:35])[CH:25]=2)[CH2:19][O:18]1>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:29]=[C:28]([C:27]3[CH:32]=[CH:33][C:24]([O:23][CH2:22][C@@H:20]([OH:21])[CH2:19][OH:18])=[CH:25][C:26]=3[O:34][CH3:35])[N:30]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: COc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(OC[C@@H](O)CO)cc3OC)no2)cc1C
Yield: 24.8 %

Procedure:
The title compound (13 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-2-methoxy-benzamidine (35 mg, 117 μmol) in analogy to Example 197; LC-MS: tR=0.47 min; [M+1]+=448.09.
Reaction SMILES: [CH:1](O)=O.C=O.C([BH3-])#N.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]=[C:20]([CH:22]3[NH:27][CH2:26][CH2:25][N:24]4[C:28]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)=[N:29][N:30]=[C:23]34)[O:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1>CO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]=[C:20]([CH:22]3[N:27]([CH3:1])[CH2:26][CH2:25][N:24]4[C:28]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)=[N:29][N:30]=[C:23]34)[O:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=CO
Reactant: COc1ccc(-c2nnc3n2CCNC3c2nc(-c3cccc(Cl)c3)no2)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nnc3n2CCN(C)C3c2nc(-c3cccc(Cl)c3)no2)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Formic acid (0.1 mL), formaldehyde (37 wt. % solution in water, 0.1 mL) and sodium cyanoborohydride (1.0 M in THF, 0.1 mL) were added to a solution of 8-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (30 mg, 0.071 mmol) in methanol (0.8 mL) at room temperature. After stirring for 30 minutes, the reaction mixture was diluted with water and then extracted with chloroform (4 times), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel; using 50% ethyl acetate in hexanes, ethyl acetate and 4% 2M ammonia in methanol in dichloromethane afforded the titled compound (23.8 mg, 77%). 1H NMR (CDCl3) δ (ppm): 8.04 (m, 1H), 7.93 (m, 1H), 7.68 (m, 2H), 7.42 (m, 2H), 7.03 (m, 2H), 4.37 (m,1H), 4.07 (m, 2H), 3.89 (m, 3H), 3.82 (m, 2H), 3.11 (m, 1H), 2.88 (m, 1H), 2.56 s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[C:16]([NH2:21])([CH2:19][CH3:20])([CH3:18])[CH3:17]>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:21][C:16]([CH3:18])([CH2:19][CH3:20])[CH3:17]
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: CCC(C)(C)N
Solvent: CCO
Product: CCC(C)(C)NCCOc1cc(F)cc(S(C)(=O)=O)c1
Yield: 76.3 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and tert-amylamine (1.61 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (389 mg, 76.2%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 190.2° C. MS m/z (relative intensity, 70 eV) 303 (M+, 0), 288 (21), 276 (10), 275 (41), 274 (bp), 84 (10).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.O>CO>[C:10]1([CH:8]([OH:9])[CH:7]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: OC(c1ccccc1)C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 145 °C
Yield: 95.2 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 4-amino-1-benzylpiperidine (5.70 g, 0.030 mol) was heated at 145° C. in an oil bath for 15 hours. The cooled mixture was then dissolved in methanol (20 mL) and the solution poured into water (200 mL). The product separated as an oil that solidified on standing. The solid was collected and dried under ambient conditions for 18 hours to obtain 3.68 g (95%) of material. Recrystallization from toluene-isooctane gave 2.31 g of the product as a tan solid; mp 128°-130° C.