Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10]OCCOC.C([Li])CCC>CCCCCC.CCOCC>[CH3:10][O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1]
Reactant: C#CCC(O)CCCC
Reactant: COCCOC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C#CCC(CCCC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.26 parts of 1-octyn-4(RS)-ol in 10 parts by volume of ethylene glycol dimethyl ether, cooled to about -40° is added dropwise 4 parts by volume of 2.5 M n-butyl lithium in hexane. The cooling bath is removed and 4 parts of trimethyloxonium hexafluorophosphate is added. The resulting reaction mixture is stirred at room temperature for about 1 hour, then is diluted with ether, washed successively with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford 1-octyn-4(RS)-ol methyl ether.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][CH:37]([CH3:45])[CH2:38][CH2:39][CH:40]=[CH:41]B(O)O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:41]=[CH:40][CH2:39][CH2:38][CH:37]([CH3:45])[CH3:36])=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CC(C)CCC=CB(O)O
Product: CC(C)CCC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 5-methyl-1-hexenylboronic acid (43 mg, 0.3 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(5-methyl-hex-1-enyl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7](=[O:18])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[N:12][O:11][C:9]=2[N:10]=1)[CH2:3][CH3:4].[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH:35]=O)([CH3:29])([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>CO>[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH:1][CH:2]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:7](=[O:18])[C:8]2[C:13]([C:14]([F:16])([F:15])[F:17])=[N:12][O:11][C:9]=2[N:10]=1)[CH2:3][CH3:4])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CCC(N)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
To a solution of 10 (0.358 mmol) in MeOH (5.0 mL) was added (3-oxo-propyl)-carbamic acid tert-butyl ester (116 mg, 0.671 mmol), followed by NaBH(OAc)3 (142 mg, 0.671 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added to quench the reaction, the aqueous phase was extracted with EtOAc three times. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by SiO2 chromatography (EtOAc:heaxanes/1:2) to give 11 (120 mg, 53%). 1H NMR (CDCl3): δ 7.35–7.18 (m, 5H), 5.67 (d, J=15.9 Hz, 1H), 5.18 (d, J=15.9 Hz, 1H), 7.47–7.34 (m, 5H), 5.73–5.66 (m, 2H), 5.48–5.46 (m, 1H), 4.92–4.91 (m, 1H), 2.02–1.80 (m, 2H), 1.46 (s, 9H), 0.92 (t, J=7.14 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=[O:6]>C1COCC1>[CH3:1][N:2]([CH3:3])[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.2 30 ml of a 40% dimethylamine solution in 200 ml of THF are initially introduced. 20 g of methyl 4-chlorocarbonylbenzoate are dissolved in 300 ml of THF and added dropwise, and the mixture is stirred at room temperature for a further 2 hours. The solvent is removed, and the mixture is subjected to conventional work-up, giving 19.2 g of methyl 4-(N,N-dimethylaminocarbonyl)benzoate (“BB”), m.p. 107°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[S:29][C:28]2=[N:30][CH:31]=[C:32]([C:33](O)=[O:34])[N:27]2[CH:26]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:32]3[N:27]4[C:28]([S:29][C:25]([CH3:24])=[CH:26]4)=[N:30][CH:31]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1cn2c(C(=O)O)cnc2s1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1cn2c(C(=O)NC[C@@H]3C[C@@H]4C[C@@H]4N3C(=O)c3nc(N)sc3-c3cccc(F)c3)cnc2s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=497.1.
Reaction SMILES: C([O:9][CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)(=O)C1C=CC=CC=1.[N:26]#[C:27][NH2:28].[OH-].[K+]>CCO>[NH2:26][C:27]1[O:9][C:10]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[N:28]=1
Reactant: N#CN
Reactant: O=C(OC(C(=O)c1ccc(F)cc1)c1ccncc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(-c2ccc(F)cc2)c(-c2ccncc2)o1
Yield: 9.9 %

Procedure:
A mixture of 1-(t-butyldimethylsilyloxy)-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone [See Ex. 79 (a) of Adams et al., WO93/14081] (5.16 g, 15.0 mmol), cyanamide (0.95 g, 22.5 mmol) and KOH (0.55 g, 9.8 mmol) in EtOH (20 mL) was heated at reflux for 1 h. After cooling, the precipitate was filtered and washed with EtOH. Recrystallization from CH2Cl2/MeOH afforded the title compound as a yellow solid (0.38 g): ESMS (m/z): 256 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25]C)=[O:24])(=[O:16])=[O:15])[CH:9]=1.[OH-].[Na+].CO>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([OH:25])=[O:24])(=[O:15])=[O:16])[CH:9]=1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1cccc(-c2ccccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1cccc(S(=O)(=O)Nc2ccsc2C(=O)O)c1
Temperature: 60 °C
Yield: 48.2 %

Procedure:
To a solution of 82 (78 mg; 0.20 mmol) in tetrahydrofuran (2 mL) were added aqueous sodium hydroxide (1 mL; 2N) and methanol (0.5 mL), sequentially. The reaction mixture was heated at 60° C. for 17 hours, allowed to cool to room temperature, and then extracted with aqueous sodium hydroxide (20 mL; 2N). The aqueous layer was washed with dichloromethane (20 mL), acidified with aqueous hydrochloric acid (20 mL; 6N), and extracted with dichloromethane (30 mL). The organic layer was washed with aqueous saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting white solid was purified by a silica gel plug eluting with a 25% to 100% ethyl acetate gradient to yield the title compound as a white solid (36 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[NH2-].[Na+].O>C1(C)C=CC=CC=1>[CH:14]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9])([CH3:16])[CH3:15]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Temperature: 80 °C

Procedure:
To a solution of 58 parts of α-phenylacetonitrile in 300 parts by volume of toluene is added 83 parts of 2-chloro-N,N-diisopropylethylamine dissolved in 300 parts by volume of toluene. The mixture is heated with stirring to about 80° C. and then 22 parts of sodium amide is added slowly over a period of 30 minutes. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer is separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether and the ether extract dried over calcium sulfate, concentrated and distilled to afford α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile, as an oil. This compound is represented by the following structural formula ##STR15##
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:29]1[CH2:30][CH2:31][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1ccc(C2CCNCC2)cc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCC(c2ccccc2)CC1

Procedure:
Using general procedure 1 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and 4-phenyl-piperidine (0.122 g, 0.76 mmol) gives the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]1[NH:28][C:27](=[O:29])[N:26]2[C:30]([CH3:36])=[N:31][C:32]([CH2:33][CH2:34][CH3:35])=[C:25]2[N:24]=1)[CH3:11]>ClCCl>[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]1[NH:28][C:27](=[O:29])[N:26]2[C:30]([CH3:36])=[N:31][C:32]([CH2:33][CH2:34][CH3:35])=[C:25]2[N:24]=1)[CH3:11]
Reactant: OCCN1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CCO)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
86 mg (0.66 mmol) of hydroxylethylpiperazine are added to a solution of 90 mg (0.22 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 16 hours. After chromatographic purification (dichloromethane/methanol=95:5), 63 mg (57%) of 2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-phenyl}-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[Cl:8][C:9]1[CH:17]=[C:16]2[C:12](/[C:13](=[CH:19]/[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])/[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.C(O)(=O)C>CO>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]([CH:19]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)CC(C[N+](=O)[O-])C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To a solution of nitromethane (Aldrich) (1.7 g, 27 mmol) in methanol (20 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (5.9 g, 27 mmol). After the mixture was stirred at room temperature for 10 min, a solution of E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (3.4 g, 14 mmol) in methanol (20 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then acetic acid (2.5 g, 41 mmol) was added. The mixture was concentrated to a small volume, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:5, 1:3) to give the racemic 6-chloro-3-(3,3-dimethyl-1-nitromethyl-butyl)-1,3-dihydro-indol-2-one as a white foam (3.8 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][S:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([S:22][CH3:21])=[CH:24][CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CSc1ccc(CN)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CSc1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (200 mg, 0.54 mmol) from above and 4-methylthiobenzylamine (99.0 mg, 0.65 mmol). The title compound was obtained as a solid (100 mg, 19% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.35 (1H, m), 8.98 (2H, s), 8.46 (1H, s), 7.22 (4H, m), 4.35 (2H, m), 2.34 (3H, s). MS m/z: 484.11, 486.14 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1>>[Cl:18][C:15]1[CH:14]=[N:13][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:17][CH:16]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Clc1cnc(Cl)nc1
Product: Oc1ccc(-c2ncc(Cl)cn2)cc1
Yield: 29 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-hydroxybenzene boronic acid and 2,5-dichloro-pyrimidine to afford the title compound as a pale yellow solid (1.91 g, 29%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:24]=[C:23]([CH3:25])[C:16]([O:17][CH2:18][CH:19]([OH:22])[CH2:20]O)=[C:15]([CH3:26])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.CC[N:30](C(C)C)C(C)C.CS(Cl)(=O)=O.N>C1COCC1.CO>[NH2:30][CH2:20][CH:19]([OH:22])[CH2:18][O:17][C:16]1[C:15]([CH3:26])=[CH:14][C:13]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([Cl:1])[CH:7]=3)[O:12][N:11]=2)=[CH:24][C:23]=1[CH3:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)cc(Cl)n1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)cc(Cl)n1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of (RS)-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (134 mg, 0.345 mmol) in THF (5 mL), DIPEA (89 mg, 0.69 mmol) followed by methanesulfonylchloride (43 mg, 0.379 mmol) is added at 0° C. The mixture is stirred at it for 2 h before 7 M NH3 in MeOH (1.2 mL) is added. The mixture is stirred at 65° C. for 16 h before the solvent is removed in vacuo to give crude (RS)-1-amino-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol as beige resin; LC-MS: tR=0.80 min, [M+1]+=388.96.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8].C(OCC)(=O)[CH2:20][C:21]([O:23]CC)=[O:22].[H-].[Na+].Cl>O1CCCC1>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:3]=1[CH2:2][CH2:20][C:21]([OH:23])=[O:22]
Reactant: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4-chloromethyl-5-methyl-3-(4-trifluoromethylphenyl)isoxazole (1.37 g) in tetrahydrofuran (50 ml) was added to a mixture of diethyl malonate (1.20 g), sodium hydride (60%, oil, 0.21 g) and tetrahydrofuran (20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[5-methyl-3-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (1.25 g, yield 84%). The crystals were recrystallized from ethanol-hexane. melting point: 138–139° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([Cl:16])=[C:13](Br)[CH:14]=1>C1(C)C=CC=CC=1.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>[Cl:16][C:12]1[N:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:14][C:13]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cnc(Cl)c(-c2cccnc2)c1
Temperature: 25 °C
Yield: 220.1 %

Procedure:
To a solution of 3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (500 mg, 1.28 mmol) in toluene (10 mL) was added 3-pyridinyltributyltin (564 mg, 1.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol). After being heated under reflux for 16 h, the resulting mixture was cooled to room temperature. Solvent was removed, and the residue was chromatographed (silica gel; EtOAc/hexane, 2:19 to 1:1) to afford an oil (428 mg, 86%): 1H NMR (CDCl3, 300 MHz) δ1.45 (s, 9H), 1.94 (m, 1H), 1.98-2.10 (m, 2H), 3.31-3.45 (m, 2H), 3.88-4.30 (m, 4H), 7.22 (m, 1H), 7.40 (m, 1H), 7.83 (td, 1H, J=1.5, 9.0 Hz), 8.16 (d, 1H, J =3.0 Hz), 8.64-8.73 (m, 2H); MS (CI/NH3) m/z 390 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[CH3:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[NH2:26]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:26][C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH3:8])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:4]
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CSCCCCCNc1c(NC(=O)C(F)(F)F)cnc2ccccc12
Yield: 153.8 %

Procedure:
A cool solution of trifluoroacetyl chloride (3.5 g, 26.5 mmol) in toluene was slowly added to a solution of N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (6 g, 23.1 mmol) in a mixture of toluene and pyridine. A heavy yellow precipitate formed. The reaction mixture was stirred over the weekend and then concentrated under reduced pressure to provide 13.2 g of crude 2,2,2-trifluoro-N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([CH3:21])[CH:23]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-methylbenzylamine (47.0 mg, 0.39 mmol). The title compound was obtained as a solid (35 mg, 24% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.36 (1H, m), 8.99 (2H, s), 8.48 (1H, s), 7.20 (1H, m), 7.09 (3H, m), 4.35 (2H, m), 2.27 (3H, s). MS m/z: 452.12, 454.14 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17]([C:18]#[N:19])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:24][C:23]#[CH:22])=[CH:6][C:5]([N:9]2[C:17]([C:18]#[N:19])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: C#CCBr
Reactant: N#Cc1c2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(C#N)c3n(c2=O)CCCC3)c(F)cc1Cl

Procedure:
The product of Example 57, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,3,5,6,7,8-hexahydro-3- oxoimidazo[1,5-a]pyridine-1-carbonitrile (2.6 g, 0.0085 mol) was treated with 1.5 g (0.010 mol) of an 80% solution of propargyl bromide in toluene and 1.4 g (0.01 mol) of potassium carbonate in refluxing acetone, as described in Example 34, to furnish, after recrystallization from ethanol, 2.2 g of 2-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2,3,5,6,7,8-hexahydro-3-oxoimidazo[1,5-a]pyridine-1-carbonitrile (XXI) (m.p. 166°-8° C.).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:25]=[C:26]2[CH2:32][C:31](=[O:33])[N:30]([CH3:34])[C:27]2=[N:28][CH:29]=1)=[O:23]>O1CCOCC1>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:21][C:22]([C:24]3[CH:25]=[C:26]4[CH2:32][C:31](=[O:33])[N:30]([CH3:34])[C:27]4=[N:28][CH:29]=3)=[O:23])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C(=O)Cc2cc(C(=O)CBr)cnc21
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1C(=O)Cc2cc(C(=O)CN3CCN(c4ccccc4)CC3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Add 63 mg (3.9×10-4 mol) of N-phenylpiperazine and then, very slowly, 0.08 ml (5.57×10-4 mol) of triethylamine to a previously prepared solution of 100 mg (3.72×10-4 mol) of 1,3-dihydro-5-bromoacetyl-1-methyl-2H-pyrrolo[2,3-b]pyridin-2-one (Preparation 19) in 3 ml of dioxane. After 30 minutes' stirring at room temperature, the resulting precipitate is removed by filtration and the flitrate is concentrated under reduced pressure to obtain the title product in a yield of 78%. ##STR75##
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH2:12][CH:13](C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([Mg]Cl)(C)C>>[CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH:12]([CH3:13])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(O)CCN(C)Cc1ccccc1
Reactant: CC(C)[Mg]Cl
Product: CC(C)C(O)CCN(C)Cc1ccccc1

Procedure:
Using a method similar to that for 1-(Benzyl-methyl-amino)-5-methyl-hexan-3-ol, isopropylmagnesium chloride affords the title compound: mass spectrum (ion spray) m/z=222.1(M+1); 1H NMR (CDCl3) δ 7.34-7.23 (m, 5H), 6.21 (br s, 1H), 3.63 (d, 1H), 3.51-3.47 (m, 1H), 3.42 (d, 1H), 2.81-2.74 (m, 1H), 2.59-2.54 (m, 1H), 2.19 (s, 3H), 1.72-1.47 (m, 3H), 0.95 (d, 3H), 0.89 (d, 3H).