Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)OC(=O)C=1.[Na+].[Cl-:9].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[OH-:15].[Na+]>O>[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[Cl:9][C:10]([Cl:11])([OH:15])[CH2:12][CH3:13]
Reactant: [Cl-]
Reactant: [OH-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: O
Solvent: ClCC1CO1
Product: CCC(O)(Cl)Cl

Procedure:
A sulfonation flask is charged with 87.5 pans of hydrolysed polymaleic anhydride (0.5 COOH equivalents, molecular weight 500-2,000, e.g. Belclene® 200), 80 parts of water and 3 parts of NaCl. After 31 parts of epichlorohydrin have been added, the reaction mixture is heated to 80°-85° C. for about 1 hour, cooled down to room temperature and neutralised with sodium hydroxide solution (pH about 6.8). Excess epichlorohydrin and dichloropropanol formed in the course of the reaction are then distilled off azeotropically. After adjustment to a solids concentration of 50%, the product is a mixture of 35% of polymer, 15% of 3-chloro-1,2-propanediol and 50% of water.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(F)ccc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.38 g, 1.11 mmol) in tetrahydrofuran (8.4 mL) and water (2.8 mL) was treated with lithium hydroxide monohydrate (56 mg, 1.34 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with water (100 mL), acidified with a 2N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 99%) as a light yellow foam: HR-ES-MS m/z calculated for C16H17NO4F2 [M+Na]+ 348.1018, observed 348.1018; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H), 1.38-1.52 (m, 1H), 1.62 (ddd, J=14.0, 9.7, 4.4 Hz, 1H), 1.77-1.84 (m, 1H), 4.17 (d, J=18.2 Hz, 1H), 4.28 (d, J=18.2 Hz, 1H), 4.63 (dd, J=11.6, 4.4 Hz, 1H), 5.05 (s, 1H), 7.21-7.33 (m, 1H), 7.46-7.62 (m, 2H), 12.83 (br. s., 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([CH:14]=[CH2:15])=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)([O-])O.[Na+]>ClCCl>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([CH:14]=[CH2:15])=[CH:7][N+:8]([O-:24])=[CH:9]2)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cncc2cccc([N+](=O)[O-])c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=Cc1c[n+]([O-])cc2cccc([N+](=O)[O-])c12
Reaction time: 3.5 h
Yield: 108.7 %

Procedure:
The 5-nitro-4-vinylisoquinoline (23 g) obtained in Step A mentioned above was dissolved in dichloromethane (400 ml), then slowly added with m-chloroperbenzoic acid (43 g, Tokyo Kasei Kogyo), and stirred for 3.5 hours. The reaction mixture was cooled on ice, and then neutralized by addition of saturated aqueous sodium hydrogencarbonate. Then, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (27 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.Br[CH2:27][C:28](Br)=[O:29].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:27][C:28]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: NCc1ccccn1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [NH2:1][C:2]1[C:23]([NH2:24])=[CH:22][C:5]2[CH2:6][C@@H:7]3[C:12]([CH3:14])([CH3:13])[C@:11]([CH3:15])([C:4]=2[CH:3]=1)[CH2:10][CH2:9][N:8]3[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:25](O)(=O)[CH3:26]>>[F:19][C:17]([F:20])([F:18])[C:16]([N:8]1[CH2:9][CH2:10][C@:11]2([CH3:15])[C:12]([CH3:13])([CH3:14])[C@H:7]1[CH2:6][C:5]1[CH:22]=[C:23]3[N:24]=[C:25]([CH3:26])[NH:1][C:2]3=[CH:3][C:4]=12)=[O:21]
Reactant: CC(=O)O
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Product: Cc1nc2cc3c(cc2[nH]1)[C@]1(C)CCN(C(=O)C(F)(F)F)[C@H](C3)C1(C)C
Temperature: 130 °C
Reaction time: 3 h

Procedure:
1-[(2R,6S)-8,9-Diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (600 mg) dissolved in glacial acetic acid is stirred at 130° C. for 3 h. After cooling to ambient temperature, the solution is concentrated under reduced pressure and the residue is taken up in ethyl acetate. The organic solution is washed with aqueous K2CO3 solution and brine and dried (MgSO4). The solvent is removed under reduced pressure to give the crude title compound as a foam-like solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].I[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]>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.C1(C)C=CC=CC=1.CCO>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[C:15]([C:22]([F:23])([F:24])[F:25])[CH:16]=1)#[N:19]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: N#Cc1ccc(I)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1ccc(-c2cccc(C(N)=O)c2)c(C(F)(F)F)c1

Procedure:
The title compound was synthesized from 3-(aminocarbonyl)phenyl boronic acid and 4-iodo-3-(trifluoromethyl)benzonitrile (I-IX-6) according to the procedure described for Ex IX-10, using Pd(PPh3)4 catalyst and PhMe/EtOH (4:1) as organic cosolvents. LC/MS (method A) 2.18 min, m/z 291 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[Cl-].[Cl-].[Cl-].[Al+3].O.Cl[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH2:3][CH2:2][OH:1])[C:16]3[C:11]([C:10]=2[CH:9]=1)=[CH:12][C:13]([C:10]([CH3:11])([CH3:5])[CH3:9])=[CH:14][CH:15]=3)([CH3:26])([CH3:25])[CH3:24]
Reactant: OCCn1c2ccccc2c2ccccc21
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)c1cc(C(C)(C)C)ccc1n2CCO
Reaction time: 0.02 h
Yield: 84 %

Procedure:
To a solution of 9-(2-hydroxy ethyl)carbazole (1.65 g, 7.81 mmol) in 2-chloro-2-methylpropane (25.0 ml) was added aluminum trichloride (0.54 g, 4.05 mmol) at room temperature under nitrogen atmosphere and stirring. After 1 minute, the addition of AlCl3, insoluble 9-(2-hydroxyethyl)carbazole disappeared. The reaction was carried out at room temperature for 25 minutes, and water (20.0 ml) was added. The product was extracted with ethyl acetate (3×20.0 ml). The organic layer was washed with water (3×60.0 ml), and then ethyl acetate was evaporated under vacuum. The product was applied to a silica gel column [ethyl acetate/hexanes (3.5:6.5)] to yield 2.1 g (84.0%) of a white solid after recrystallization from dichloromethane/hexanes.
Reaction SMILES: [CH2:1]([N:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:18][CH2:19][S:20][C:21]#[N:22]>O1CCCC1>[Cl-:18].[CH3:16][N+:15]([CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:19][S:20][C:21]#[N:22]
Reactant: N#CSCCl
Reactant: CCCCCCCCCCCCCCN(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC[N+](C)(C)CSC#N
Product: [Cl-]

Procedure:
The reaction was carried out similar to the other examples, using tetrahydrofuran, tetradecyldimethylamine and chloromethylthiocyanate. The product was a brown solid with 80% purity.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]=[C:4]1[C:13](=O)[C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17]C)=[O:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1.Cl.[NH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=1)[NH2:22]>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([N:21]2[CH:3]([CH:2]([CH3:19])[CH3:1])[CH:4]3[CH2:5][O:6][C:7]4[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=4[C:13]3=[N:22]2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC(C)C)C2=O
Reactant: Cc1cc(NN)ccc1C#N
Agent: Cl
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C(C)C)ccc1C#N
Yield: 52 %

Procedure:
The title compound was prepared from methyl 3-(2-methylpropylidene)-4-oxochroman-7-carboxylate (Preparation 32; 260 mg, 1.0 mmol) and 4-hydrazinyl-2-methylbenzonitrile hydrochloride (Preparation 2; 275 mg, 1.5 mmol) according to Method B and Method C (yellow solid, 196 mg, 0.523 mmol, 52% yield, approximately 7:1 mixture of cis:trans diastereomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s., 1H), 7.93 (d, J=8.2 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.09 (dd, J=8.6, 2.3 Hz, 1H), 4.76-4.86 (m, 2H), 4.42 (dd, J=13.1, 10.4 Hz, 1H), 4.02 (ddd, J=13.2, 10.6, 5.9 Hz, 1H), 2.42 (s, 3H), 2.06-2.17 (m, 1H), 0.83 (d, J=7.4 Hz, 3H), 0.81 (d, J=7.4 Hz, 3H). ES-MS m/z 376 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][S:11](=[O:13])(=[O:12])[NH2:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(Cl)c1Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(Cl)c1Cl
Yield: 71.9 %

Procedure:
This compound was prepared according to the procedure of Example 75. Thus, a mixture of 16.3 g (0.10 mole) of 2,3-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene gave 17.4 g (72%) of the title compound as an off-white solid, mp 116°-117° C. (benzene).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=O)=O.[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40](Cl)=[O:41])[CH:36]=1>N1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:30]([C:29]([CH3:33])([CH3:32])[C:21]1[CH:22]=[C:23]2[C:28](=[C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2][CH3:1])=[CH:6][CH:7]=3)[C:40]([C:37]3[CH:36]=[C:35]([CH3:34])[O:39][N:38]=3)=[O:41])[CH:20]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)#[N:31]
Reactant: CC(C)(C#N)c1cc(-c2cccc(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Reactant: Cc1cc(C(=O)Cl)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CSc1ccc(N(Cc2cccc(-c3cc(C(C)(C)C#N)cc4cccnc34)c2)C(=O)c2cc(C)on2)cc1
Reaction time: 12 h

Procedure:
A mixture of the amine from Step 1 (1.0 eq) and 5-methyl-isoxazole-3-carbonyl chloride (1.8 eq) in pyridine (0.35M) was stirred for 12 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 3:2) afforded the desired compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].C([O-])([O-])=[O:18].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(CO)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CO)COc1ccc(Cl)cc1C=O
Yield: 33 %

Procedure:
5-Chloro-benzaldehyde (3.1 g, 20 mmol), 3-bromo-2,2-dimethyl-propan-1-ol (3 mL, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.5 g) were mixed in DMF (20 mL). Then mixture was irradiated under microwave at 200° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give title compound as yellow solid (Yield: 1.6 g).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[C:37]([S:38](Cl)(=[O:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1>>[Cl:31][C:32]1[C:37]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2Cl)c1

Procedure:
By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg), sodium hydride (60% in oil, 180 mg), 15-crown-5 (0.90 mL) and 2-chloro-3-pyridinesulfonyl chloride (716 mg), the title compound was obtained as an amorphous form (yield 716 mg, 69%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[C:3]([CH3:10])[CH:4]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)c(C)c1

Procedure:
The title compound was prepared by reacting 4-bromo-3-methylanisole (10 g, 0.050 mol) with n-butyl lithium (24 mL of 2.5 M solution in hexane, 0.055 mol) followed by triisopropyl borate (57.7 mL, 47.02 g, 0.25 mol) according to method F to yield 5.7 g (69%) of a white solid: MS (ESI) m/z 313 (2M-H2O—H)−.
Reaction SMILES: C(=O)([O-])O.[Na+].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>C(#N)C>[CH2:16]([NH:15][CH2:20][CH3:19])[CH3:17].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:25]1)=[O:22]
Reactant: Brc1ccccn1
Reactant: O=C(N[C@H]1CCNC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCNCC
Product: O=C(N[C@H]1CCN(c2ccccn2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 75 °C
Yield: 16.8 %

Procedure:
Sodium hydrogen carbonate (28.6 mg) was added to a solution of (2S)-1-(1,3-benzoxazol-2-y1)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide (104.9 mg) [see Example 4] and 2-bromopyridine (52.7 mg) in acetonitrile (5 ml). The reaction mixture was heated to 75° C. for 48 hours, after which time additional sodium hydrogen carbonate (28.6 mg) was added and the mixture was heated under reflux for a further 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 93:7:1, by volume, dichloromethane:methanol: 0.88 aqueous ammonia solution, and was then further purified by a second column eluting with 95:5, by volume, ethyl acetate:diethylamine to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-(2-pyridinyl)pyrrolidin-3-yl]-2-piperidinecarboxamide (11 mg) as a brown oil.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[Cl:13][CH2:14][C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:13].[CH3:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][O:1][NH2:2])[N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1nc(CCl)cs1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(CON)cs1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
N-Hydroxyphthalimide (15.2 g) was dissolved in DMF (120 ml) and 4-chloromethyl-2-methyl-thiazole (18.4 g) was added. The mixture was cooled in an ice bath and a solution of triethylamine (28.6 ml) in DMF (30 ml) was added drop-wise. The cooling bath was removed and the reaction mixture was stirred at room temperature for 3 days. The mixture was poured into water (600 ml) and the precipitated material was isolated by filtration washed with water and dried in vacuo. This phthalimide intermediate (21.4 g) was refluxed in ethanol (150 ml) containing n-butylamine (7.7 ml) for 2.5 hours. The mixture was cooled to room temperature and 4M hydrochloric acid in diethyl ether (25 ml) was added. The mixture was placed at 0-5° C. over night at the resulting precipitated material was isolated by filtration and washed with cold ethanol and diethyl ether, affording the title compound (11.2 g) as a white crystalline material. 13C-NMR (DMSO-d6) δ 166.85, 147.15, 121.35, 70.03, 18.37.
Reaction SMILES: C1C(=O)N(OC(CCSSCCC(NCCN[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]2[S:33][CH2:32][C@@H:31]3[NH:34][C:35]([NH:37][C@H:30]23)=[O:36])=[O:24])=O)=O)C(=O)C1.C(=O)([O-])[O-:39]>P([O-])([O-])([O-])=O>[OH:39][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:30]2[C@@H:31]([NH:34][C:35]([NH:37]2)=[O:36])[CH2:32][S:33]1)=[O:24]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCNC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
BSA (manufactured by Oriental Yeast K.K., F-V; 30 mg) was dissolved in 0.1M phosphate buffer (pH 7.0; 1 ml), and thereto was added an NHS-SS-biotin solution (manufactured by Pierce Chemical Co., 16.8 mg/ml in 0.1M phosphate buffer, pH 7.0; 1 ml) and the mixture was reacted at 30° C. for 1 hour. The reaction solution was centrifuged and the supernatant was subjected to Sephadex G-25 column (φ1.5 cm×30 cm, eluent: 50 mM carbonate buffer, pH 9.6) to give a biotin-BSA fraction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[CH:4][N:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cnc(Cl)nc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ncc(NC2CCOCC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 22.2 %

Procedure:
In a 100 mL round bottomed flask containing 2,4-dichloropyrimidin-5-amine (1.0 g, 6.10 mmol) in 16.5 mL of dichloromethane was added dihydro-2H-pyran-4 (3H)-one (0.794 g, 7.93 mmol), cooled to 0° C. then added the solution of titanium tetrachloride (0.740 ml, 6.71 mmol) in 10 mL of dichloromethane. The reaction was removed from the ice bath and with continued stirring, slowly warmed to room temperature. After 3.5 h, sodium cyanoborohydride (1.15 g, 18.29 mmol) was added in 4 equal portions over 10 minutes and the reaction was stirred at room temperature for 16 h. The suspension was diluted with water (150 mL) and transferred to an appropriate separatory funnel. The layers were separated and then extracted the aqueous layer with MTBE (1×150 mL). The organic layers were combined, washed with sat. NaCl, dried over Na2SO4, filtered and concentrated in vacuo affording a clear orange oil. The crude oil was purified by silica chromatography (30% EtOAc/Hexanes); the appropriate fractions were combined and concentrated in vacuo to afford 2,4-dichloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-amine (0.336 g, 60% pure, 22% yield). MS [M+H] found 249.1.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[C:13](=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)[CH3:4].[H][H]>[Pd]>[ClH:1].[CH2:3]([C:5]1([C:16]2[NH:17][CH:18]=[N:19][CH:20]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)[CH3:4]
Reactant: [H][H]
Reactant: CCC1(c2c[nH]cn2)C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: Cl
Product: CCC1(c2cnc[nH]2)Cc2ccccc2C1
Temperature: 82.5 °C
Reaction time: 6 h

Procedure:
Palladium catalyst (1.4 g of 10% Pd/C) was suspended in the hydrochloric acid solution of 2-ethyl-2-(1H-imidazol-4-yl)indan-1,3-dione hydrochloride. The obtained suspension was poured into a hydrogenation autoclave. Hydrogen was supplied to autoclave to 3.0 bar. The reaction mixture was stirred and heated to 80-85° C. The typical hydrogenation time was 6 hours. After hydrogenation the reaction mixture was filtered to remove the catalyst. The filtrate was cooled to (−5)° C., the precipitates were separated by filtration. The obtained crude 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride was dried at 50° C. under reduced pressure. The yield was 3.7 g of a white powder.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]=1.[CH2:17]([C:23](=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:17]([C:23](=[CH:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:24]([OH:25])[CH2:9][C:10]1[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1nccnc1C
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC(=Cc1ccccc1)C(O)Cc1nccnc1C
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly to a solution of 2,3-dimethylpyrazine (10.8 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of α-hexylcinnamaldehyde (23.7 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[N+:12]([C:15]1([CH2:21][CH2:22][C:23](=[S:25])[NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-:14])=[O:13]>>[N+:12]([C:15]1([CH2:21][CH2:22][C:23]2[S:25][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)CCC1([N+](=O)[O-])CCCCC1
Product: O=[N+]([O-])C1(CCc2nc3c(s2)Cc2ccccc2-3)CCCCC1

Procedure:
2-Bromo-1-indanone, 3-(1-nitrocyclohexyl)propanethioamide