Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH:19]([CH3:23])[CH2:20][NH:21][CH3:22])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39](=[O:44])[CH2:40][CH2:41][CH2:42]Br>ClCCl>[CH3:37][O:38][C:39](=[O:44])[CH2:40][CH2:41][CH2:42][N:21]([CH2:20][CH:19]([O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1)[CH3:23])[CH3:22]
Reactant: CNCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Reactant: COC(=O)CCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCN(C)CC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Put 25 mg (0.064 mmol) (+/−)-2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-N-methylpropane-1-amine with 13 mg (0.128 mmol) triethylamine in 250 μl dichloromethane. Add 23.2 mg (0.128 mmol) 4-bromobutyric acid methyl ester and stir overnight at RT. Add the same amounts of triethylamine and 4-bromobutyric acid methyl ester again and stir for a further 24 h at RT. Then concentrate by evaporation and purify the residue by thick-layer chromatography on silica gel (solvent: dichloromethane/methanol 95:5). Extract the product-containing zone with dichloromethane/methanol 9:1. 22.4 mg of the target compound is obtained as raw product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[F:10].[C:11]([S:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([S:15][C:16](=[O:21])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[F:10])[C:18](=[O:20])[CH3:19])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: Fc1cc(Cl)ccc1CBr
Product: CC(=O)C(Cc1ccc(Cl)cc1F)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-chloro-2-fluorobenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: CN=C(Cl)Cl.CC1NC=NC=1CSCCN.C1CCN2C(=NCCC2)CC1.[CH3:28][N:29]=[C:30](Cl)[NH:31][CH2:32][CH2:33][S:34][CH2:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[CH3:41].[N:43]#[C:44][NH2:45]>C(Cl)Cl>[C:44]([N:45]=[C:30]([NH:31][CH2:32][CH2:33][S:34][CH2:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[CH3:41])[NH:29][CH3:28])#[N:43]
Reactant: CN=C(Cl)NCCSCc1nc[nH]c1C
Reactant: N#CN
Agent: CN=C(Cl)Cl
Agent: Cc1[nH]cnc1CSCCN
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 19 %

Procedure:
A solution of N-methyl-chloroformimidoyl chloride (1.12 g), 2-(5-methylimidazol-4-ylmethylthio)ethylamine (0.855 g) and DBU (0.988 g) in CH2Cl2 (16 ml was heated under reflux for 6 hrs. To the reaction mixture containing N'-methyl-N-[2-(5-methylimidazol-4-ylmethylthio)ethyl]chloroformamidine was added a solution of cyanamide (0.84 g) and DBU (3.04 g) in CH2Cl2 (16 ml). After refluxing for 15 hrs., the solvent was removed and the residue was chromatographed [SiO2, CH3CN-CH3OH (4:1)]. The crude product was purified by preparative chromatography [SiO2, CH3COOC2H5 --CH3OH-- 28% NH3 (aq) (10:1:1)] and then recrystallization from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (0.24 g). Yield 19.0%, m.p. 139°-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.CS(O)(=O)=O.[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[NH:18][CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C1NCCOc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
A solution of 7-bromochroman-4-one (340 mg, 1.5 mmol) and methanesulfonic acid (3 mL, 23.0 mmol) in DCM was cooled to 0° C. and treated with NaN3 (146 mg, 2.25 mmol) portionwise, while maintaining the internal temperature below 5° C. The reaction was then stirred at 0° C. for 4 h. At completion, the reaction was slowly neutralized with 8 N aq. NaOH, then diluted with DCM (20 mL) and water (20 mL). The layers were separated and the organics were dried over MgSO4, filtered and evaporated to afford 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (370 mg, 100% yield). MS (EI) m/z=242.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[C:12]2([CH2:14][CH2:2][CH2:3][CH3:4])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCI
Product: CCCCC1(CCCC)c2cc(N)ccc2-c2ccc(Br)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16]N1C=NN=C1.CS(C)=O.CC(C)([O-])C.[Li+]>C(O)(=O)C>[NH2:16][C:8]1[C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 4-methyl-3,5-dinitrobenzonitrile (10.5 kg; preparation see U.S. Pat. No. 3,162,675), 4-amino-4H-1,2,4-triazole (17.0 kg) and dimethyl sulfoxide (68.6 kg) was dosed into a mixture of lithium tert-butoxide (12.2 kg) and dimethyl sulfoxide (106.6 kg) over about 50 min, while maintaining the temperature of each solution at 20-25° C. After aging at 20-25° C. for about 2 h, acetic acid (8.9 kg) was dosed into the reaction mixture at about 20° C. over about 10 min. The product was crystallized by dosing water (158 L) into the reaction mixture over about 1.5 h at about 20° C. The product slurry was cooled to 10-15° C. and held at this temperature for about 45 min. The resultant slurry was filtered, and washed with water (106 L). The wet cake obtained was dried in a vacuum tray dryer at about 50° C. and 30 Torr to provide 2-amino-4-methyl-3,5-dinitrobenzonitrile as an orange-brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[C:11](#[N:14])[CH:12]=[CH2:13].N1C=CC=CC=1>O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:13][CH2:12][C:11]#[N:14])[N:7]=1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Reactant: C=CC#N
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(=O)c(Br)nn(CCC#N)c1=O
Yield: 93 %

Procedure:
2.4 g (11.6 mmol) of the triazine 2a and 7 mL (106 mmol) of acrylonitrile are placed in 24 mL of a solution of pyridine and water (1/1) under reflux for 3 h. After concentration, the reaction medium is extracted with AcOEt and then after drying on MgSO4, the organic phases are dry concentrated. After washing the obtained solid with ether, 2.8 g of intermediate 3a are obtained (yield=93%).
Reaction SMILES: O[C:2]1(C2C=CC=CC=2OC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].Br[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1>CCOCC.C1COCC1>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH:2]2[C:6]3[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:4]([C:11]3[CH:12]=[CH:13][C:14]4[O:17][CH2:18][O:19][C:15]=4[CH:16]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:35][CH:36]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Ethyl (1RS) 1-Hydroxy-1-(methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate, A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10: 1 Et2O/ THF (55 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[N:13][N:14]([CH3:18])[C:15]=3[CH:16]=[O:17])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[Cl:24]N1C(=O)CCC1=O>C(#N)C>[Cl:24][C:21]1[S:20][C:19]([C:12]2[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][CH2:4][C:5]=4[CH:10]=3)=[C:15]([CH:16]=[O:17])[N:14]([CH3:18])[N:13]=2)=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nc(-c2cccs2)c(-c2ccc3c(c2)CCCO3)c1C=O
Solvent: CC#N
Product: Cn1nc(-c2ccc(Cl)s2)c(-c2ccc3c(c2)CCCO3)c1C=O
Yield: 102 %

Procedure:
A solution of 4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (3d) (166 mg, 0.51 mmol) and N-chlorosuccinimide (67 mg, 0.50 mmol) in acetonitrile (18 mL) was heated overnight at 60° C. The reaction mixture was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (2×12 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20), to provide 3-(5-chlorothiophen-2-yl)-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazole-5-carbaldehyde (36a) (183 mg, 0.51 mmol, 99%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[O:15][CH3:14])[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCNCc1ccc(OC)cc1OC
Yield: 40 %

Procedure:
0.32 ml of allylbromide (3.66 mM) and 0.7 ml of diisopropyl ethylamine (3.99 mM) were added to the reaction solution containing 500 mg of 2,4-dimethoxybenzylamine (3.33 mM) dissolved in methylene chloride with stirring and the solution was left alone at room temperature. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 276 mg of allyl-(2,4-dimethoxybenzyl)amine (1b) (yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.[Pd]>[NH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][C:9]1=[O:22])[CH2:18]2
Reactant: [H][H]
Reactant: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 2 h

Procedure:
To a solution of (±)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one (40 mg, 0.126 mmol, described in Intermediate 4) in EtOAc (10 mL) was added triethylamine (0.026 mL, 0.189 mmol). The mixture was hydrogenated at 30 psi hydrogen over 10% Pd/C (10 mg). After 2 h, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=287 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[NH:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[Na+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:16][CH2:17][C:18]([N:4]([CH2:5][C:6]([OH:8])=[O:7])[C:3]1[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1])=[O:19]
Reactant: Cc1cccc(C)c1NCC(=O)O
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(C)c1N(CC(=O)O)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
36 g (0.2 mole) of 2,6-dimethylanilinoacetic acid, 400 ml of methylene chloride and 200 ml of 1N NaOH (0.2 mole) are placed into a flask with stirrer, and 17.5 ml (0.22 mole) of chloroacetic acid chloride is slowly added dropwise with stirring, the temperature being maintained at 20°-25° by cooling with ice-water. During the dropwise addition, there is formed a white precipitate. Stirring is continued for 30 minutes and the precipitate is then filtered off with suction; the precipitate is washed with cold water, well pressed out and subsequently dried over P2O5 in a desiccator. For the purpose of obtaining further amounts of final product, the methylene chloride phase is separated in a separating funnel, dried over Na2SO4 and concentrated in vacuo, and the crystalline residue is recrystallised from ethyl acetate. There is obtained a total amount of 44 g (86% of theory) of N-chloroacetyl-2,6-dimethylanilinoacetic acid, m.p. 160° (decomposition).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1([CH2:34][OH:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:26][CH2:27][C:28]3([CH2:34][OH:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC1(CO)CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3(CO)CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and [4-(aminomethyl)tetrahydro-2H-pyran-4-yl]methanol and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccc(CO)cc4)cc23)CC1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), [4-(hydroxymethyl)phenyl]boronic acid (32 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([N:26]4[CH2:25][CH2:24][CH:23]([N:20]5[CH2:21][CH2:22][O:17][CH2:18][CH2:19]5)[CH2:28][CH2:27]4)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(C(F)(F)F)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Yield: 66.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.77 g) and 4-(4-morpholinopiperidin-1-yl)-3-trifluoromethylaniline (1 g), the title compound (1.1 g) was obtained, melting point: 193–194° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH3:30][N:31](C)[CH2:32]CO>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][N:31]([CH3:32])[CH3:30])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: CN(C)CCO
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CN(C)CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 2 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 108, 2-(dimethylamino)ethanol (0.40 mL, 4.0 mmol), 4-dimethylaminopyridine (0.0060 g, 0.049 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0023 g, y. 2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=O.C([BH3-])#N.[Na+]>C(O)C.CO>[CH:7]1([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C1Cc2ccccc2C1
Reactant: COC(=O)CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COC(=O)CNC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glycine methyl ester (0.053 moles, 6.64 g) is dissolved in absolute ethanol (420 ml) and methanol (42 ml), added with 2-indanone (0.053 moles, 7 g), and with sodium cyanoborohydride (0.058 moles, 3.7 g) under stirring, in 40 minutes. The mixture is left under stirring at r.t. overnight, evaporated to dryness under vacuum and the residue is taken up with water (500 ml) and ethyl acetate (500 ml). The phases are separated and the organic phase is extracted with a 0.1N HCl solution (3×200 ml). The acidic solution is adjusted to pH 8.5-9 with a sodium bicarbonate saturated solution and 20 extracted with ethyl acetate (3×250 ml). The organic solution is separated, dried over sodium sulfate and evaporated under vacuum. The resulting product is dried under vacuum at r.t. Yield: 5.8 g (53.4%)
Reaction SMILES: C([O:5][C:6]([C@:8]1([CH3:13])[CH2:12][CH2:11][CH2:10][NH:9]1)=O)CCC.[NH3:14]>CO>[CH3:13][C@@:8]1([C:6]([NH2:14])=[O:5])[CH2:12][CH2:11][CH2:10][NH:9]1
Reactant: CCCCOC(=O)[C@]1(C)CCCN1
Reactant: N
Solvent: CO
Product: C[C@@]1(C(N)=O)CCCN1

Procedure:
A solution of (S)-2-methyl-pyrrolidine-2-carboxylic acid butyl ester (2.3 g) in a 7 M solution of ammonia in methanol (22.2 ml) is heated in a bomb at 70° C. for 10 days. Evaporation of the reaction mixture and trituration with hexanes (20 ml) gives the title compound as an off-white solid. 1H nmr (d6-DMSO, 400 MHz) 7.40 (s, 1H), 6.89 (s, 1H), 2.95-2.84 (m, 1H), 2.72-2.60 (m, 1H), 2.06-1.95 (m, 1H), 1.66-1.44 (m, 2H), 1.42-1.30 (m, 1H), 1.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:5]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)Oc1cc(F)c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 96.6 %

Procedure:
A solution of 5-chloro-2-fluoro-4-[(1-methylethyl)oxy]-1-nitrobenzene (D83, 153 mg, 0.65 mmol) in dimethylformamide (5 ml) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (130 mg, 0.65 mmol) and diisopropylethylamine (0.113 ml, 0.65 mmol) and stirred at approx. 80° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with water and extracted with diethyl ether (×2). The combined extract was dried (MgSO4) and concentrated under vacuum to afford the title compound as a yellow solid (260 mg, 97%).
Reaction SMILES: [C-]#N.[K+].[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[CH2:13]([OH:15])[CH3:14]>O>[OH:15][CH:13]([C:14]1[CH:11]=[CH:12][C:5]([F:4])=[CH:6][CH:7]=1)[C:9]([C:8]1[CH:11]=[CH:12][C:5]([F:4])=[CH:6][CH:7]=1)=[O:10]
Reactant: CCO
Reactant: O=Cc1ccc(F)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(F)cc1)C(O)c1ccc(F)cc1
Reaction time: 72 h

Procedure:
A mixture of potassium cyanide (2.0 g, 31 mmol), 4-fluorobenzaldehyde, 96% ethanol (30 ml) and water (30 ml) was heated at reflux for 0.5 h and then kept at 5° C. for 72 h. The precipitated compound was collected and recrystallised from ethanol/water to give 20 g of 2-hydroxy-1,2-bis(4-fluorophenyl)ethanone.