Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].O.Cl.[NH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26].C([O-])(=O)C.[Na+]>O>[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15]3([S:26][CH2:25][C@@H:24]([C:27]([OH:29])=[O:28])[NH:23]3)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)c1ccc(OC2CCC(=O)CC2)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
In a solvent mixture consisting of 21 ml of ethanol and 9 ml of water were dissolved 3.10 g of 4-(4-isopropylphenoxy)-1-cyclohexanone, 2.35 g of L-cysteine hydrochloride monohydrate and 1.10 g of sodium acetate. The mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl ether were added to the concentrate. The deposited crystal was collected by filtration, and there was obtained 2.45 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][NH:10][CH3:11])=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[CH2:20][CH2:21]2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: CNCc1ccc(F)c(Br)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNCc1ccc(F)c(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Temperature: 150 °C
Yield: 65.8 %

Procedure:
To the solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.52 g, 2.39 mmol) in p-dioxane/H2O (15/5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.15 g, 3.60 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol), and K2CO3 (1.33 g, 9.6 mmol). The result mixture was heated in a microwave machine at 150° C. for 15 mins. The organic layer was separated and concentrated. The residue was redissolved in EtOAc (˜70 mL), washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by CombiFlash chomatograph to afford 0.65 g (66%) of the title compound. LC-MS m/z 414 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1CCCCC1>[CH2:20]([N:19]([CH2:8][CH2:9][CH2:10][Cl:11])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Product: ClCCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a stirred suspension of K2CO3 (200 g, 1.5 mole) in cyclohexane 200 mL and 1-bromo-3-chloropropane (540 gms, 3.4 mole) is added dropwise over a period of 1 h at 20° C. dibenzyl amine (442 g, 2.24 mole). After complete addition the reaction is allowed to stir for an additional 20 h. The crude reaction mixture is filtered and then washed with saturated NaCl (3×100 mL). The organic phase is extracted with 3N HCl (3×100 mL). The resulting aqueous phase, containing the desired product as the hydrochloric salt, is washed with hexanes (3×100 mL) to remove any residual BCP. The aqueous phase is subsequently basified with 50 wt % NaOH and extracted with cyclohexane (3×100 mL). After solvent removal 324 g (53% yield) of the title compound was isolated as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH:7]1([CH:13]2[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:7]1([CH:13]2[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]2[C:2]([O:4][CH3:5])=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(C2CCCCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(C2CCCCC2)C1
Reaction time: 3 h
Yield: 129.5 %

Procedure:
Methyl chloroformate (1.344 mL, 17.36 mmol) in DCM (50 mL) was added to a solution of methyl 2-cyclohexylpiperidine-4-carboxylate hydrochloride (3.50 g, 13.35 mmol) and DIPEA (1.88 mL, 10.76 mmol) in DCM (100 mL). The reaction solution was stirred for 3 h. 1.88 mL DIPEA and 1.345 mL methyl chloroformate was added and the reaction continued overnight (16 h). The organic phase was washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to give crude dimethyl 2-cyclohexylpiperidine-1,4-dicarboxylate (4.90 g). MS m/z 284 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@@H:43]([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[K+].[CH3:48][N:49]([CH3:53])[C:50](Cl)=[O:51]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@@H:43]([O:45][C:50](=[O:51])[N:49]([CH3:53])[CH3:48])[CH3:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@H](C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@H](C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 100 mg of (S)-1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propan-2-ol (diastereomer 2) (from example 34b) in 10 ml tetrahydrofuran are added 34 mg of potassium hydride and 0.14 ml of N,N-dimethylcarbamoyl chloride at room temperature. The reaction mixture is stirred for one additional hour, diluted with water and extracted with tert-butyl methyl ether. The combined organic phases are dried and concentrated under reduced pressure to afford the crude title compound. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.41 (EtOAc-heptane 2:1); Rt=5.47.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:8][C:9]=1[CH2:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:38])C=1.[Na]>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[S:8][C:9]=1[CH2:10][S:11]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc(C#N)cc1
Agent: [Na]
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CS(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 200 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzonitrile (prepared according to the method described in example 14) in 4 ml of dichloromethane at 0° C. was added 80 mg of meta-chloroperbenzoic acid. The resulting mixture was stirred at 0° C. for 5 hours, at room temperature for 2 hours than kept in the fridge overnight. A saturated aqueous solution of sodium hydrogenocarbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of 1 to 4% acetone/dichloromethane) to give 185 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfinyl]-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethanesulfinyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:67])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:24]([O:61][CH3:62])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:59][CH3:60])[C@@H:34]([CH3:58])[C:35](=[O:57])[NH:36][C@H:37](/[CH:45]=[CH:46]/[C:47]1[CH:52]=[CH:51][C:50]([S:53]([OH:56])(=[O:55])=[O:54])=[CH:49][CH:48]=1)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2].O[N:69]1[C:73](=[O:74])[CH2:72][CH2:71][C:70]1=[O:75].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:75]=[C:70]1[CH2:71][CH2:72][C:73](=[O:74])[N:69]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:67])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:24]([O:61][CH3:62])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:59][CH3:60])[C@@H:34]([CH3:58])[C:35](=[O:57])[NH:36][C@H:37](/[CH:45]=[CH:46]/[C:47]1[CH:48]=[CH:49][C:50]([S:53]([OH:56])(=[O:55])=[O:54])=[CH:51][CH:52]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(S(=O)(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(S(=O)(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 8 mg (7.5 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(2S,3E)-1-phenyl-4-(4-sulphophenyl)but-3-en-2-yl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide in 2 ml of DMF were added 8.6 mg (74.8 μmol) of N-hydroxysuccinimide, 8.5 mg (22.4 μmol) of EDCI and 0.1 mg (0.75 μmol) of DMAP. The reaction mixture was stirred at RT for 20 h. Subsequently, 1.3 μl (7.5 μmol) of Hünig's base were added and the mixture was stirred for 1 h. The reaction mixture was then purified by prep. HPLC. 2.6 mg (72% purity, 21% of theory) of the title compound were obtained.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:12]([O-:17])(=[O:16])[CH:13]([CH3:15])[OH:14].C[N+](C)(C)C>CN(C)C=O>[C:12]([O:17][CH2:2][C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])[CH:13]([CH3:15])[OH:14]
Reactant: CC(O)C(=O)[O-]
Reactant: O=C(CBr)Oc1ccccc1
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Product: CC(O)C(=O)OCC(=O)Oc1ccccc1
Yield: 31 %

Procedure:
Phenyl bromoacetate (45.0 g, 0.209 mol) was added to a stirring solution of tetramethylammonium lactate (40.7 g of an 88% aq soln, 1.05 eq) in 50 mL of dimethylformamide at room temperature. The resulting tetramethylammonium bromide which separated from the reaction mixture as a solid was removed by filtration and washed with ethyl acetate. The dimethylformamide and ethyl acetate solutions were combined and washed with a NaHCO3 /brine solution, the separated aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was chromatographed on silica gel (ethyl acetate/hexane) to give the title compound (14.7 g, 31%): 1H NMR δ 1.50 (d, 3H, J=7.0), δ 3.12 (d, 1H, J=5.3), δ 4.40-4.49 (m, 1H), δ 4.87 (d, 1H, J=16.1), δ 4.99 (d, 1H, J=16.2), d 7.09-7.40 (5H, phenyl); HRMS calcd for C10H8O5TMS (M--CH3) 281.0845, obsd 281.0856.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:19]=[C:3]([OH:2])[CH:4]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(-c2nc3cc(OC)cc(CO)c3o2)cc1
Product: Oc1ccc(-c2nc3cc(O)cc(CBr)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 20, step e (Route b), from 5-methoxy-7-(hydroxymethyl)-2-(4-methoxyphenyl)-1,3-benzoxazole with prolonged stirring in the presence of boron tribromide, and was obtained as a light brown solid, m.p. 250-260° C. (dec); MS m/e 321 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([O:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][O:14][C:12]([NH:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:13]
Reactant: COC(=O)C1(NC(=O)OCc2ccco2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCCCC1)OCc1ccco1
Reaction time: 18 h
Yield: 74.4 %

Procedure:
28.13 g (0.1 mol) of 1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid methyl ester was added to a mixture solution of 150 ml of 2N aqueous sodium hydroxide solution and 200 ml of tetrahydrofuran, and the mixture was heated under reflux for 18 hours. After the solvent was distilled off, water was added to the residue and the mixture was washed with diethyl ether. After potassium hydrogensulfate was added to the aqueous layer to acidify it, the mixture was extracted with ethyl acetate twice. After the organic layer was washed with saturated brine, it was dried with anhydrous magnesium sulfate, and thereafter the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the mixture was stirred for 18 hours. The obtained crystal was collected by filtration to obtain 19.89 g (74%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+].Cl>O>[C:1]1([C:7]2[N:11]=[CH:10][N:9]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc[nH]n2)cc1
Reactant: O=C(O)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCn1cnc(-c2ccccc2)n1
Temperature: 115 °C
Reaction time: 66 h

Procedure:
A mixture of 3-phenyl-1H-1,2,4-triazole (1.46 g, 9.05 mmol), 3-chloropropionic acid (1.08 g, 9.96 mmol) and sodium hydroxide (2M, 9.05 mL, 18.1 mmol) in water (3 mL) was heated to 115° C. and stirred for 66 h. Another 0.5 equivalents of each 3-chloropropanoic acid and sodium hydroxide were added (pH increase to 11) and stirring was continued for another 24 h. Hydrochloric acid (2M, 10 mL) was added, the suspension was filtered and extracted with dichloromethane. The product was obtained after purification by supercritical fluid chromatography as light brown solid (236 mg, 1.09 mmol, 12.0%). MS: M=218.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[C:3]=1[C:17]#[N:18].[C:19](OCC)(=[O:25])[C:20](OCC)=[O:21]>>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:20](=[O:21])[C:19](=[O:25])[NH:1][C:2]=2[C:3]=1[C:17]#[N:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccccc1-c1ccc(N)c(N)c1C#N
Product: COc1ccccc1-c1ccc2[nH]c(=O)c(=O)[nH]c2c1C#N

Procedure:
This crude 3,4-diamino-2′methoxy-biphenyl-2-carbonitrile was stirred in diethyl oxalate (5 mL) at reflux for 5 h. The solution was concentrated in vacuo to give 320 mg (quantitative yield) of the title compound as an insoluble solid. MS (ES) [m+H] calc'd for C16H11N3O3, 294; found 294.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:38][NH:39]2)C1C=CC=CC=1)C>>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:39][CH3:38])=[O:3])=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]ncc2c1
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
3-(1H-Indazol-5-yl)-N-methyl 3-phenyl-acrylamide CCIV was prepared from 3-(1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [C:1]1([C:14]([O:16][CH3:17])=[O:15])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1([S:24]([N:27]2[C:39]3[C:38](Br)=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[C:18]1([S:24]([N:27]2[C:39]3[C:38]([N:12]4[C:13]5[C:1]([C:14]([O:16][CH3:17])=[O:15])=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2cccc(Br)c21
Reactant: COC(=O)c1cccc2c1[nH]c1ccccc12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c3ccccc3n(-c3cccc4c5ccccc5n(S(=O)(=O)c5ccccc5)c34)c12

Procedure:
8.0 g (42.2 mmol) of copper(I) iodide, 11.7 ml (97.5 mmol) of trans-cyclohexanediamine are added to a well-stirred suspension of 26.3 g (117 mmol) of methyl 9H-carbazole-1-carboxylate, 45.2 g (117 mmol) of 9-benzenesulfonyl-1-bromo-9H-carbazole and 416.4 g (1961 mmol) of potassium phosphate in 1170 ml of dioxane, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol. Yield: 43 g (81 mmol), 70% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C1(C)C=CC(S(O[CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1Br

Procedure:
The above 3'-bromo-4'-hydroxy-4-acetylbiphenyl (200 g) was treated with 1.2 times equivalents of R 1-methylheptyl p-toluenesulfonate and potassium hydroxide in 97% ethanol (1 l) for 6 hours under reflux. The reaction mixture was worked up in a usual way to obtain crude oily 3'-bromo-4'-(1-methylheptyloxy)-4-acetylbiphenyl (163 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][CH:19]1[C:25](=[O:26])[NH:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:24]1[C:25](=[O:26])[C@@H:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH2:20][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]1=2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a −78° C. solution of 3-tert-butoxycarbonylamino-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one (0.94 g, 3.38 mmol) in 20 ml of anhydrous tetrahydrofuran and stirred for 30 minutes. Methyl bromoacetate (o0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to room temperature. The reaction was diluted with 100 ml of ethyl acetate and washed with 0.3N potassium hydrogen sulfate (50 ml), water (2×50 ml), and brine. The combined organics were dried over anhydrous sodium sulfate, filtered, and evaporated to afford a gum that was purified by flash chromatography eluting with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:21]([O:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH3:30])[C:31]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11])=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
There are introduced into a reactor, with stirring, 2.13 kg of methyl(2S)-2,3-dihydroindole-2-carboxylate, 1 kg of triethylamine, 30 litres of tetrahydrofuran and then, after 10 minutes' stirring at room temperature, 1.9 kg of N-[tert-butyloxycarbonyl]-(S)-alanine and 2 kg of dicyclohexylcarbodiimide. The heterogeneous mixture is then stirred at room temperature for 6 hours, and is subsequently cooled to 0° C. and filtered.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)=[N:5][N:6]=1.Br[CH2:13][CH2:14][C:15]([F:19])=[C:16]([F:18])[F:17]>O1CCOCC1.CN(C)C=O>[F:19][C:15](=[C:16]([F:18])[F:17])[CH2:14][CH2:13][S:1][C:2]1[O:3][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)=[N:5][N:6]=1
Reactant: Sc1nnc(C2CCCO2)o1
Reactant: FC(F)=C(F)CCBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: FC(F)=C(F)CCSc1nnc(C2CCCO2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1594.3 %

Procedure:
2.1 g (0.019 mol) of potassium t-butylate are introduced into a solution of 3.2 g (0.018 mol) of 2-mercapto-5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazole in a mixture of 80 ml of 1,4-dioxane and 10 ml of dimethylformamide. 4.9 g (0.026 mol) of 1-bromo-3,4,4-trifluoro-3-butene are then added dropwise at 25° C. and the reaction mixture is stirred at room temperature for 16 hours. The solvent mixture is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. This solution is extracted with water, ice-cold 1 N sodium hydroxide solution and water in succession, dried with sodium sulfate and filtered and the solvent is distilled off under reduced pressure. 80.43 g of the desired product are obtained as a yellow oil (nD27 =1.4904).