Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH2:6]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([Li])CCC.[C:28]1([C:34]2[CH:43]=[CH:42][CH:41]=[C:36]([C:37](OC)=[O:38])[C:35]=2[OH:44])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:6]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:37]([C:36]2[C:35]([OH:44])=[C:34]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:43]=[CH:42][CH:41]=2)=[O:38])=[CH:21][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1cccc(-c2ccccc2)c1O
Reactant: CCCCCCCCCCc1ccc(N)cc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(NC(=O)c2cccc(-c3ccccc3)c2O)cc1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a tetrahydrofuran (20 ml) solution of 4-decylaniline (3.07 g, 13.14 mmol), cooled to 0°-5° C. (inert atmosphere), is added n-butyllithium (2.3 M, 13.14 mmol). The deeply colored solution is stirred for ten minutes, after which a tetrahydrofuran (20 ml) solution of methyl 3-phenylsalicylate (1.00 g, 4.38 mmol) is added. The temperature is allowed to rise to 25° C. over a 30 minute period. The reaction is quenched by pouring the contents into 10% hydrochloric acid (100 ml). The organics are extracted into ethyl acetate, washed with 10% hydrochloric acid, dried (sodium sulfate), and concentrated to give 2.77 g of crude solid. Chromatography (Kieselgel 60, dichloromethane) affords N-(4-decylphenyl)-2-hydroxy-[1,1'-biphenyl]-3-carboxamide (1.69 g, 90%), mp 74°-75° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=1)=[O:5].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](Br)[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[CH3:27][O:28][C:29]([C:30]1[CH:31]=[C:32]([C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:12][CH:11]=2)[C:33]([CH3:36])=[CH:34][CH:35]=1)=[O:38]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: CC1(C)OB(c2ccc(NC(=O)c3c(F)cccc3F)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
A suspension of 2,6-difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (359 mg, 1 mmol), 3-bromo-4-methyl-benzoic acid methyl ester (228 mg, 1 mmol), benzyl(chloro)bis(triphenylphosphine)palladium (38 mg, 0.05 mmol) and K2CO3 (690 mg, 5 mmol) in 1-methylpyrrolidinone (NMP) (5 ml) was degassed with vacuum and heated at 120° C. for 10 hr. After cooling down to room temperature, ethyl acetate (EtOAc) (200 ml) was added and the mixture was washed with water (60 ml×3). The EtOAc was evaporated and the residue was purified by column chromatography on silica gel (Hexanes:EtOAc) to give Compound 1 (286 mg, yield 75%).
Reaction SMILES: CS[C:3]1[N:8]=[N:7][C:6](SC)=[C:5]2[CH:11]=[N:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:4]=12.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[O:24]1[CH2:25][CH2:26][N:21]([C:3]2[N:8]=[N:7][C:6]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:5]3[CH:11]=[N:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:14][C:4]=23)[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: CSc1nnc(SC)c2cc(-c3ccccc3)ncc12
Product: c1ccc(-c2cc3c(N4CCOCC4)nnc(N4CCOCC4)c3cn2)cc1
Temperature: 180 °C

Procedure:
1 part by weight of 1,4-dimethylmercapto-7-phenylpyrido(3,4-d)pyridazine and 10 parts by volume of morpholine are placed in a glass tube, and the glass tube is sealed. The reaction system is heated at 180° C for 8 hours. The excess amount of morpholine is removed by evaporating under reduced pressure, and water is added to the residue. Thus precipitated crude crystals are collected by filtration. The crude crystals are adsorbed on a column packed with silica-gel, followed by eluting with a mixture of acetone and benzene (1:4). The eluate is concentrated under reduced pressure and recrystallized from methanol to obtain 1,4-dimorpholino-7-phenylpyrido(3,4-d)pyridazine as pale yellow needles melting at 186° to 188° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O.[C:29]([O:32][CH2:33]C)(=[O:31])C>CO>[CH3:33][O:32][C:29]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1)=[O:31]
Reactant: Brc1cnc(N2CCCC2)c(OCC2CCCC2)n1
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1

Procedure:
To a solution of 0.563 g (0.0017 mol) 5-bromo-3-cyclopentylmethoxy-2-pyrrolidin-1-yl-pyrazine in 4 mL methanol and 2 mL ethyl acetate was added 0.050 g PdCl2dppfCH2Cl2 and 0.48 mL (0.0035 mol) triethylamine and the mixture was stirred under an atmosphere of 70 bar carbon monoxide at 110° C. for 18 h in an autoclave. The solids were removed by filtration and the mother liquor was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with water (2×) dried over sodium sulfate, evaporated and the residue was purified by chromatography on silica gel with dichloromethane:ethyl acetate=19:1 to yield 0.423 g of the title compound as slightly yellow orange crystals melting at 69-70° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C:6]([CH3:15])([S:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:7])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH2:2]([O:4][C:5](=[O:16])[C:6]([S:8][CH:9]1[CH2:10][CH2:11][N:12]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:13][CH2:14]1)([CH3:15])[CH3:7])[CH3:3]
Reactant: CCOC(=O)C(C)(C)SC1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)SC1CCN(S(C)(=O)=O)CC1
Yield: 41.9 %

Procedure:
To a solution of 4.47 g (16.74 mmol) of 2-methyl-2-(piperidin-4-ylsulfanyl)-propionic acid ethyl ester hydrochloride salt in anhydrous THF (30 mL) are added 13.45 mL (77.36 mmol) of N,N-diisoproylethylamine, followed by 2.98 mL (38.58 mmol) of methanesulfonyl chloride. The reaction mixture is heated for 2 d to 60° C. The mixture is concentrated under reduced pressure and the residue is partitioned between saturated aqueous NaHCO3 solution (75 mL) and ethyl acetate (75 mL). The basic aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layer is separated and washed with brine (50 mL), dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography (silica, eluent: heptanes, 30% ethyl acetate) to give 2.17 g of 2-(1-methanesulfonyl-piperidin-4-ylsulfanyl)-2-methyl-propionic acid ethyl ester as a brown solid. Yield: 42%, ES-MS: m/z 310 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.22 (3H, t, J=7.11 Hz), 1.47 (6H, s), 1.59-1.69 (2H, m), 1.92-2.00 (2H, m), 2.70 (3H, s), 2.90-2.99 (3H, m), 3.39-3.47 (2H, m), 4.10 (2H, q, J=7.12 Hz)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#N)[CH3:12].C(O)(=[O:23])C.O>C1(C)C=CC=CC=1>[CH2:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:23])[CH3:12]
Reactant: CC(=O)O
Reactant: CCc1cccc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Add a 1 M solution of diisobutylaluminum hydride in toluene (76 mmol) dropwise to a solution of m-ethylbenzonitrile (38 mmol) in toluene (50 mL) under nitrogen in a dry ice-acetone bath. Stir for 30 minutes then add acetic acid (20 mL) dropwise followed by water (100 mL). Stir the reaction for 2 hours. Separate the layers and extract the aqueous with toluene. Dry the combined organic layers over sodium sulfate, and evaporate to give the title compound (4.5 g, 88% yield). 1HNMR (400.43 MHz, CDCl3): δ 9.97 (s, 1H), 7.69-7.66 (m, 2H), 7.46-7.40 (m, 2H), 2.71 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.CS[C:15](=[N:20][CH3:21])[S:16]([O-:19])(=[O:18])=[O:17]>C(#N)C.CO>[CH3:21][NH:20][C:15]([S:16]([OH:19])(=[O:18])=[O:17])=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: NCCSCc1ncccc1Cl
Reactant: CN=C(SC)S(=O)(=O)[O-]
Solvent: CC#N
Solvent: CO
Product: CNC(=NCCSCc1ncccc1Cl)S(=O)(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-chloropyrid-2-ylmethylthio)ethylamine (2.03 g) in dry acetonitrile (150 ml) was added dropwise, with stirring, to a solution of 1-methylthio-1-methyliminomethanesulphonate (1.69 g) in dry acetonitrile (150 ml) at 50°. The mixture was stirred at 60° for 30 minutes and then allowed to cool. The mixture was stripped to dryness, dissolved in methanol and absorbed onto silica gel. Chromatography on a column of silica gel produced a viscous oil which was collected by eluting the column with a chloroform/methanol mixture and evaporating off the solvent. The viscous oil analysed by micro-analysis and nuclear magnetic resonance spectroscopy to the title compound.
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[SH:11].[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[C:19]([OH:21])=[O:20].N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH:17]1[CH:12]2[CH2:18][CH:15]([CH2:14][CH:13]2[C:19]([OH:21])=[O:20])[CH2:16]1
Reactant: Sc1ccc2ccccc2c1
Reactant: O=C(O)C1CC2C=CC1C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: O=C(O)C1CC2CC(Sc3ccc4ccccc4c3)C1C2
Temperature: 65 °C
Reaction time: 24 h

Procedure:
In a 50-mL one neck round bottom flask, 2-naphthalenethiol, Catalog No. 270849 from Aldrich Co. (1.50 g) was dissolved in tetrahydrofuran (3.36 g). In the same flask, 5-norbornene-2-carboxylic acid, Catalog No. 147230 from Aldrich Co. (1.32 g), and 2,2′-azobis(2-methylpropionitrile), Catalog No. 441090 from Aldrich Co. (0.014 g), were added. The flask was heated while stirring in a 65° C. oil bath for 24 hours. The product, 6-(2-naphthylthio)bicyclo[2.2.1]heptane-2-carboxylic acid (2.82 g) was isolated by removing tetrahydrofuran by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32]C)[CH2:30]C.Cl.ClCl>ClCCl.CO>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:32]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1Cl

Procedure:
Prepared analogously to Example 3.7.c. from (4′-chlorobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-diethylaminoethoxy)phenylamine. Yield: 0.28 g (58% of theory); melting point: 226° C.-233° C.; C27H26Cl2N2O2 (M=481.41)*HCl; calc.: molecular ion peak (M+H)+: 481/3/5 (Cl2); found: molecular ion peak (M+H)+: 481/3/5 (Cl2); Rf value: 0.45 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[O:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])=[N:32][N:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[O:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])=[N:32][N:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: ClCc1nnc(-c2ccccc2Cl)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2nnc(-c3ccccc3Cl)o2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
85 mg (0.28 mmol) of the compound from Example 5A were dissolved in 5 ml of acetonitrile, and 180 mg (0.55 mmol) of cesium carbonate and 66 mg (0.29 mmol) of 2-(chloromethyl)-5-(2-chloro-phenyl)-1,3,4-oxadiazole were added. The mixture was stirred at 80° C. for 1 h. For work-up, the mixture was cooled to RT, and 10 ml of water were added. The mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 66 mg (48% of theory) of the target compound.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16]C.[O:19]1CCC[CH2:21][CH:20]1OC1CCCCO1.C(Cl)(=O)C>C(O)(=O)C>[C:20]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:19])[CH3:21]
Reactant: CCCCC/C=C\CCCCCCCCCCO
Reactant: C1CCC(OC2CCCCO2)OC1
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CCCC/C=C\CCCCCCCCCCOC(C)=O
Reaction time: 3 h
Yield: 55.7 %

Procedure:
9 g. of (Z)-11-hexadecenol-tetrahydropyranyl ether (Formula III, R=H, Y=tetrahydropyranyl) are dissolved in 25 ml. of acetic acid. 6 ml. of acetyl chloride are added, and the solution is boiled on an oil bath of about 80° C. for 3 hours. The mixture is cooled, poured onto 50 g. of ice, and extracted thrice with a total amount of 200 ml. of hexane. The extracts are combined, washed with 30 ml. of water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled off in fine vacuo. 5.3 g. (55.7%) of (Z)-11-hexadecenyl acetate are obtained; b.p.: 142°-144° C./0.25 mmHG.; 120°-122° C./0.05 mmHg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: CCc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 200 mg of 4-ethylbenzaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 15 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.32 g of 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH2:9])=[NH:8].[CH:10]1(C2N=C(C#N)SC=2)[CH2:12][CH2:11]1>>[CH:10]1([C:5]2[N:4]=[C:3]([C:7]([NH2:9])=[NH:8])[S:2][CH:6]=2)[CH2:12][CH2:11]1
Reactant: N=C(N)c1nccs1
Reactant: N#Cc1nc(C2CC2)cs1
Agent: Cl
Product: N=C(N)c1nc(C2CC2)cs1

Procedure:
Compound M was prepared in analogy to thiazole-2-carboxamidine (Compound A1) with the procedure shown in Scheme 5 by using 4-cyclopropyl-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile. 1H NMR (CDCl3-d, 400 MHz): δ 9.68 (br, 1H), 9.56 (br, 1H), 2.23-2.19 (m, 1H), 1.01-0.92 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][OH:21])=[N:4][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)=[CH:6][N:7]=1.NC1C(N[C@@H](C2C=CC=CC=2)[CH2:38][OH:39])=NC(Br)=CN=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:21][CH2:20][C@@H:19]([N:18]1[C:3]2=[N:4][C:5]([C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][CH:12]=[N:13]4)=[CH:6][N:7]=[C:2]2[NH:1][C:38]1=[O:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ncc(-c2cccc3ncccc23)nc1N[C@H](CO)c1ccccc1
Reactant: Nc1ncc(Br)nc1N[C@H](CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccc2ncccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1[C@H](CO)c1ccccc1
Yield: 51 %

Procedure:
(S)-2-(3-Amino-6-(quinolin-5-yl)pyrazin-2-ylamino)-2-phenylethanol. (S)-2-(3-Amino-6-bromopyrazin-2-ylamino)-2-phenylethanol (0.882 g, 2.26 mmol), quinoline-5-boronic acid (0.544 g, 2.48 mmol) tetrakis(triphenylphosphine)-palladium (0.331 g, 0.287 mmol), potassium carbonate (1.25 g, 9.08 mmol), water (8 mL) and dimethylformamide (30 mL) were reacted according to General Procedure B. The crude material was purified via Biotage silica gel chromatography (0-10% methanol/dichloromethane, 40S column) to afford the title compound (0.524 g, 51% yield). MS (ESI) m/z 358.3 [M+1]+.
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([NH:6][C:7](=O)[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])O.[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Li+].S(Cl)(Cl)=O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[F:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([F:15])[C:8]=1[C:7]1[O:17][CH2:3][CH:4]([C:22]2[CH:23]=[CH:24][C:19]([I:18])=[CH:20][CH:21]=2)[N:6]=1
Reactant: COC(=O)C(O)NC(=O)c1c(F)cccc1F
Reactant: Ic1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Temperature: 23 °C
Reaction time: 72 h
Yield: 46.1 %

Procedure:
The compound of Step A of Example 1 (31.0 g, 0.13 mol) and iodobenzene (40.2 g, 0.19 mol) were suspended in sulfuric acid (100 mL) and stirred for 3 days at 23° C. The mixture was poured onto ice and extracted with dichloromethane (200 mL). The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. Methanol (200 mL) and thionyl chloride (6 mL) were added and the mixture and heated at reflux for 30 min. The methanol was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (200 mL). Lithium borohydride (55 mL, 2N in tetrahydrofuran, 0.11 mol) was added slowly and after completion of the addition, the mixture was heated at reflux for 1 h. The mixture was cooled, and quenched by slow addition of aqueous hydrochloric acid (200 mL, 1N). The mixture was extracted with dichloromethane (200 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was then treated with toluene (100 mL) and thionyl chloride (23 mL, 0.3 mol). The mixture was heated to reflux for 45 min and then evaporated under reduced pressure. The residue was dissolved in methanol (200 mL) and treated with aqueous sodium hydroxide (30 mL, 50% solution). The mixture was heated to reflux for 30 min and then evaporated under reduced pressure. The residue was partitioned between water (100 mL) and dichloromethane (200 mL). The dichloromethane solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexanes/ethyl acetate (10:1) as eluent to give the title compound (23.1 g) as a white solid: m.p.: 105°-106° C. 1H NMR (CDCl3, 200 MHz) δ 7.7 (m,2H), 7.5 (m, 1H), 7.1 (m, 1H), 7.0 (m,2H), 5.4 (m, 1H), 4.8 (m, 1H), 4.3 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Product: Cc1cc(C)cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethyl-benzoic acid. LC-MS (basic): tR=0.96 min; [M+H]+=460.0.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([SH:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[Na].Br[CH2:23][CH2:24][Cl:25]>C(O)C.C1(C)C=CC=CC=1>[Cl:25][CH2:24][CH2:23][S:16][CH:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: SC1c2ccccc2CCc2ccccc21
Reactant: ClCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: ClCCSC1c2ccccc2CCc2ccccc21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of the above crude thiol (4.53 g, 0.020 mol) in absolute ethanol (7 ml) was added dropwise to a stirred solution of sodium ethoxide, freshly prepared from absolute ethanol (25 ml) and sodium (0.46 g, 0.020 mol). Stirring was continued for 0.5 h at ambient temperature. 1-Bromo-2-chloroethane (8.60 g, 0.060 mol) was added dropwise and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with toluene (20 ml) and filtered. The filtrate was evaporated in vacuo and stripped with toluene, affording 5.72 g (99%) of crude 5-(2-chloroethylsulfanyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8](Br)[C:9]([OH:11])=[O:10].[CH2:13]([N:15]1[C:19]([C:20]([C:22]2[CH:27]=[C:26]([OH:28])[C:25]([OH:29])=[C:24]([Cl:30])[C:23]=2[Cl:31])=[O:21])=[CH:18][CH:17]=[N:16]1)[CH3:14].Cl>CN(C)C=O.O>[Cl:30][C:24]1[C:25]2[O:29][CH:8]([C:9]([OH:11])=[O:10])[O:28][C:26]=2[CH:27]=[C:22]([C:20]([C:19]2[N:15]([CH2:13][CH3:14])[N:16]=[CH:17][CH:18]=2)=[O:21])[C:23]=1[Cl:31]
Reactant: CCn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Reactant: O=C(O)C(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nccc1C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Reaction time: 5 h
Yield: 38.1 %

Procedure:
6.9 g of potassium carbonate and 2.83 g of dibromoacetic acid are added to a solution of 3.01 g of (1-ethylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)-methanone in 30 ml of dimethylformamide and the mixture is at 80° C. for 5 hours. After cooling the reaction mixture, water is added thereto and the mixture is adjusted to pH 1 by addition of 6N hydrochloric acid. The resultant crystals are collected by filtration, washed with water and recrystallized from dimethylformamide-water to give 1.36 g of 4,5-dichloro-6-(1-ethyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid.