Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[NH2:1][C:2]1[C:3]([Br:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1
Reactant: [Br-]
Reactant: Nc1ccc(Cl)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(O)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.8 %

Procedure:
To a solution of 5-amino-2-chloro-phenol (15.85 g, 110.4 mmol) in dichloromethane (300 ml) and MeOH (150 ml) was added tetrabutylammonium tribromide (58.6 g, 121.4 mmol). The mixture was stirred at room temperature for 20 minutes, and then was partitioned between saturated aqueous Na2SO3 and Et2O. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 5-amino-4-bromo-2-chloro-phenol (4.38 g, 18%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[N:24]1([CH:30]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]CN)=[CH:34][CH:33]=2)[CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([CH:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)[CH3:31])=[CH:37][CH:36]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CC(c1ccc(CCN)cc1)N1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)N1CCCCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.2 g), 2-[4-(1-piperidin-1-ylethyl)phenyl]ethanamine dihydrochloride (0.19 g), N,N-diisopropylethylamine (0.20 g) and ethanol (4 ml) were stirred at 70° C. for 3 hr. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (186 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33](OC)=O)=[CH:26][C:25]=2[O:24]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33]3[NH:22][C:20](=[O:21])[C:3]4[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:2]=4[N:1]=3)=[CH:26][C:25]=2[O:24]1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CC(O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 64.5 %

Procedure:
20 mg (0.066 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 41 mg (0.210 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 1.06 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 19 mg (64%) of a solid, Rf=0.20 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N+:26]#[C-:27])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CO.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:26]=[CH:27][O:35][C:28]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: [C-]#[N+]C(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: c1ccc(COc2ccc(-c3ncoc3-c3ccncc3)cc2)cc1
Yield: 61.2 %

Procedure:
A mixture of 1-((4-(Benzyloxy)phenyl)isocyanomethylsulfonyl)-4-methylbenzene (4.3 g, 11.4 mmol), isonicotinaldehyde (1.34 g, 12.5 mmol) and K2CO3 (3.15 g, 22.8 mmol) in methanol (96 mL) and DME (30 mL) was heated at reflux for 5 h. After removal of solvent, the residue was purified by silica gel chromatography (2:1 hexane/EtOAc) to provide 2.29 g (84%) of a white solid. 1H NMR (400 MHz, CDCl3) δ: 5.12v (s, 2H), 7.03 (d, 2H), 7.46 (m, 6H), 7.56 (d, 2H), 7.61 (d, 2H), 8.02 (s, 1H), 8.58 (d, 2H). MS m/z: 329 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:2]=1.[OH-].[Na+].[CH3:14]I>C(O)C>[CH3:14][N:9]1[N:10]=[N:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8]1
Reactant: CI
Reactant: c1cncc(-c2nnn[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnc(-c2cccnc2)n1

Procedure:
5-(3-pyridyl)-tetrazole (11) (J. M. McManus and R. M. Herbst, J. Am. Chem. Soc., 24 (1959) 1462-64) (10 g, 0.068 mol), sodium hydroxide (2.73 g, 0.068 mol), and methyl iodide (14.5 g, 0.1 mol) in ethanol (100 ml) was stirred at 40° C. overnight. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane (100 ml), and the solution was washed three with water (100 ml). The organic phase wan dried over magnesium sulphate and evaporated yielding 3.21 g (0.020 mol 30%) of 12 with M.P. 108°-110° C. According to the 1H NMR spectrum the product contained less than 10% of the 1-isomer.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)C[OH:15]>>[CH:2]([OH:15])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1]
Reactant: C=CCCCCCCCCCC
Reactant: OCCO
Product: CCCCCCCCCCC(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
A reaction vessel of glass, 3000 ml in inner volume, provided with stirring vanes and a reflux condenser was charged with 810 g (4.82 mols) of 1-dodecene, 900 g (14.52 mols) of monoethylene glycol, and 100 g of the BEA type zeolite (produced by PQ Corp. and marketed under trademark designation of “VALFOR CP 811 BL-25”). The vapor-phase part of the reaction vessel was displaced with nitrogen and then retained in the atmosphere of nitrogen at normal pressure. The reaction mixture was heated to and kept at 150° C. for three hours and meanwhile kept stirred at 600 rpm to induce reaction. The reaction solution was cooled to room temperature. The dodecene phase in the upper layer was separated and distilled to expel the unaltered dodecene. The residue of the distillation was treated under a reduced pressure of 2 mmHg in a boiling point range of 129° to 131° C. to obtain 255 g of a secondary dodecanol ethoxylate composition.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[NH:16][C:15](=[O:21])[C:14]=1[CH3:22].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1>C(#N)C>[Br:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[N:16]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[C:15](=[O:21])[C:14]=1[CH3:22]
Reactant: Cc1c(Br)n(C)c(=O)[nH]c1=O
Reactant: COc1ccc(CCl)cc1OC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cn2c(=O)c(C)c(Br)n(C)c2=O)cc1OC
Temperature: 60 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (98%, 5.57 mL, 36.5 mmol) was added to a suspension of C2 (4.00 g, 18.3 mmol) and 4-(chloromethyl)-1,2-dimethoxybenzene (5.16 g, 27.6 mmol) in acetonitrile (80 mL), and the reaction mixture was heated at 60° C. for 18 hours. After removal of solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) to afford the product as a white solid. Yield: 5.70 g, 15.4 mmol, 84%. 1H NMR (400 MHz, CDCl3) δ 7.08-7.12 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 5.07 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:8]([F:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][O:6]1)=[O:4].[OH-].[Na+:24].O1CCCC1>C(O)C>[Na+:24].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:5]2([C:3]([O-:4])=[O:2])[CH2:7][O:6]2)[F:22])=[CH:16][CH:17]=1
Reactant: COC(=O)C1(C(F)CCCCCOc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C([O-])C1(C(F)CCCCCOc2ccc(Cl)cc2)CO1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a suspension of 1.79 g (5.41 mmol) of 2-[6-(4-chlorophenoxy)-1-fluorohexyl]-2-oxiranecarboxylic acid methyl ester (isomer A) of Example 3 in 5.14 ml of absolute ethanol is added at room temperature 5.14 ml (5.14 mmol) of 1N aqueous sodium hydroxide. After 30 minutes, 4.0 ml of tetrahydrofuran is aded to achieve total dissolution and stirring is maintained for 1.25 hours. Evaporation of the solvents and trituration with pentane and isopropyl ether gives 1.46 g (79.7%) of the title compound: m.p. 112°-125° C.; IR (KBr) 1640, 1608 cm-1 ; NMR (d6 -DMSO) δ 1.47 (4H, m), 1.74 (4H, m), 2.63 (1H, dd, J=8, 3 Hz), 2.73 (1H, d, J=8 Hz), 3.98 (2H, t, J=9 Hz), 5.19 (1H, ddd, J=48, 10, 2 Hz), 6.98 (2H, d, J=8 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]4[C:14]5[NH:13][C:12](=[O:15])[NH:11][C:10]=5[CH:9]=[CH:8][CH:7]=4)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydrobenzoimidazol-2-one and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a grey solid. 1H NMR (DMSO) δ 1.28 (m, 2H), 1.84 (m, 2H), 2.65(m, 1H), 2.81 (m, 4H), 3.62(s, 3h), 3.64(s, 3H). 3.77(m, 2H), 3.89(m, 2H), 4.03(m, 1H), 4.87(bs, 1H), 6.59 (m, 4H), 6.74(d, 1H, J=8.7 Hz), 6.83(d, 1H, J=8.1 Hz), 6.91 (d, 2H, J=9.0 Hz), 7.45(d, 2H, J=9.0 Hz), 10.57 (bs, 1H), 10.69 (bs, 1H); MS (ES) m/z: 598.1 (MH+); HRMS for C29H35N5O7S: 598.2296 (MH+).
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Cl.Br[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>[Pd].C1COCC1>[N:26]1[CH:27]=[CH:28][C:23]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cc(-c2ccncc2)c2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
Palladium catalyst Pd(PPh3)4 (1.00 g, 0.87 mmol) and freshly prepared aqueous sodium hydroxide (4.63 g, 115.9 mmol in 42 mL water) were added to a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (7.03 g, 28.9 mmol) and 4-bromopyridine hydrochloride (5.68 g, 29.2 mmol) in THF (98 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 70° C. in an oil bath for 6 hours. It was then cooled to room temperature and ethyl acetate (400 mL) added. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was triturated with dichloromethane to give 5.1 g (91%) of 4-pyridin-4-yl-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.OC[CH2:15][N:16]1[C:20](=O)C2=CC=CC=C2[C:17]1=O>CN(C)C=O>[CH3:15][N:16]([CH3:20])[CH:17]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Solvent: CN(C)C=O
Product: COc1ccc(C(=CN(C)C)C(C)=O)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(4-methoxy-phenyl)-propan-2-one (1, 8.37 g, 51.0 mmol) in N,N-dimethylformamide (200 mL) was added dimethoxymethyl-dimethyl-amine (2, 27 mL, 203 mmol). The reaction mixture was then stirred for 18 h at 85° C., allowed to cool to ambient temperature and excess solvent and reagents were removed under reduced pressure to give crude 4-dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (3) as yellow oil which was used in the following step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:4]1[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=[C:3]1[CH2:2][N:29]1[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]1
Reactant: CCN1CCNCC1
Reactant: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CBr)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2nc3sc(S(N)(=O)=O)cc3c(=O)n2-c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3 g of 3,4-dihydro-2-bromomethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 40 ml of dimethylformamide, 0.8 ml of 1-ethylpiperazine and 2.7 g of potassium carbonate, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto water, and the mixture was extracted with chloroform. The concentrated residue was purified by silica gel column chromatography, crystallized from ethyl acetate and recrystallized from ethanol to give 320 mg of the title compound, m.p. 203°-204° C. (decomposition).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=3)[N:9]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)=[CH:3][CH:2]=1.[C:38]1([N:44]2[CH2:49][CH2:48][CH2:47][C@@H:46]([NH2:50])[CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]1([N:44]2[CH2:49][CH2:48][CH2:47][C@@H:46]([NH:50][C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:8]=[C:7]4[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:18])[CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H]1CCCN(c2ccccc2)C1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCCN(c2ccccc2)C1)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (97 mg, 0.20 mmol), (3R)-1-phenylpiperidin-3-amine (120 mg, 0.48 mmol), EDC (0.08 g, 0.4 mmol), HOBt (0.07 g, 0.5 mmol) and DIPEA (400 μl, 2.3 mmol) in DMF (2 ml) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to provide crude N-[(3R)-1-phenylpiperidin-3-yl]-3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, which was used as-is without further purification. LCMS calc'd for C43H38N5O [M+H]+=640; found 640.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Li])(C)(C)C.[Cl:15][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCOCC.C1COCC1.O.CCOC(C)=O.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ncccn1
Reactant: Clc1ccc(Br)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Clc1nccc(-c2ccc(Cl)c(Cl)c2)n1
Temperature: -90 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a 1L 3-neck flask fitted with an addition funnel, N2 inlet, magnetic stir bar and thermometer was added 15.26 (0.067 mol) of 3,4-dichlorobromobenzene in 50-75 mL of anhydrous ether. The reaction was cooled to -90° C. and 96 mL of tertbutyllithium (1.7 M solution in pentane) slowly was added over a 0.5 hr while maintaining the temperature below -70° C. The reaction temperature was cooled to -80 to -90° C. and 2-chloropyrimidine (9.10 gm, 0.08 mol) dissolved in anhydrous THF was added. The reaction was stirred for about 2 h and 18 gms of DDQ, (0.077 mol) dissolved in anhydrous THF was added slowly, and the mixture was stirred for a 0.5 h. Three mL of H2O containing 1 mL of HOAc in THF was added and the mixture stirred for 15 minutes. The reaction was diluted with 100 mL of H2O and 100 mL of EtOAc and the mixture transferred to a separatory funnel. The organic layer was separated, dried, filtered and evaporated. The crude product was chromatographed and eluted with 30% EtOAc/heptane and triturated with Et2O to yield 3.22 g of a white solid (20%) m.p. 126-127° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[N+:8]([O-:13])=[C:9]2[CH3:12])=[CH:4][N:3]=1.[CH:22]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.CO>[CH:22]1([C:25]([NH:27][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[CH3:21])[N+:8]([O-:13])=[C:9]3[CH3:12])=[CH:4][N:3]=2)=[O:26])[CH2:24][CH2:23]1
Reactant: NC(=O)C1CC1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(Cl)cc2c(C)[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C)[n+]1[O-]
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 7-chloro-3-(5-fluoro-2-methylphenyl)-1-methyl-2,6-naphthyridine 2-oxide (350 mg, 1.2 mmol), cyclopropanecarboxamide (295 mg, 3.5 mmol), Chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (46 mg, 0.06 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl (120 mg, 0.2 mmol), and cesium carbonate (750 mg, 2.3 mmol) in 1,4-dioxane (5 mL) was heated at 90° C. for 4 hours. The cooled reaction mixture was diluted with dichloromethane (200 mL) and methanol (100 mL), mixed with Celite, filtered, the solids washed with 15% methanol/dichloromethane (2×100 mL), and the filtrate was dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as an off-white solid (400 mg, 100%). 1H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.41-7.31 (m, 1H), 7.22 (m, 2H), 2.66 (s, 3H), 2.10 (m, 1H), 2.08 (s, 3H), 0.94-0.81 (m, 4H). LCMS (Method D): RT=11.358 min, M+H+=352.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[CH2:14]([CH:16](C(C)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:15].[OH-].[K+]>O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]2[CH3:15]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: Nc1ccc(F)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccc(F)cc2c1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-fluoro-phenylamine (9 g, 81 mmol), concentrated hydrochloric acid (20.4 mL), and water (35.1 mL) was added sodium nitrite (6.3 g, 89.1 mmol) dissolved in water (7.8 mL). In a separate flask ethyl 2-ethylacetoacetate (14.4 g, 89.1 mmol) in ethanol (63.6 mL) at 0° C. was treated with potassium hydroxide (5.1 g, 89.1 mmol) in water (7.5 mL) and ice and the above solution added. The pH of the reaction was adjusted to 5-6 and the reaction stirred at 0° C. for 3 hours and then stored in the freezer overnight. The reaction was then extracted with ethyl acetate (100 mL) and the organics washed with saturated brine solution (100 mL), dried with anhydrous magnesium sulfate. Most of the solvent was removed in vacuo before it was added dropwise to a 14.5% ethanolic solution of hydrochloric acid (70 mL) at 78° C. Heating was continued for 2 hours. The solvent was removed in vacuo and the residue treated with dichloromethane (300 mL) and water (100 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried over sodium sulfate and concentrated in vacuo. Purification on a short wash column (silica gel, 25% ethyl acetate/hexane) gave ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate as a white solid. MS (ES) m/z 220.0
Reaction SMILES: C([O:5][C:6](=[O:38])[C@H:7]([CH3:37])[NH:8][C@H:9]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:10][S:11][CH2:12][C@@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>[CH2:35]([O:34][C:32]([C@@H:9]([NH:8][C@H:7]([C:6]([OH:38])=[O:5])[CH3:37])[CH2:10][S:11][CH2:12][C@@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)[C@H](CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)[C@H](CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a mixture of 50 ml of TFA and 10 ml of anisole was dissolved 20.1 g of β-isomer of N-[(R)-1-ethoxycarbonyl-2-[(S)-2-benzyloxycarbonylamino-3-phenylpropylthio]ethyl]-alanine t-butyl ester prepared in Reference Example 53. The solution was stirred at room temperature for 5 hours. The excess of the solvent was evaporated off. The residue was poured into ice water and the mixture was adjusted to a pH of 4 with a saturated aqueous solution of sodium hydrogencarbonate. Then the mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure. To the crystalline residue was added ether to precipitate crystals which were collected by filtration and recrystallized from dichloromethane-ether. Thus the β-isomer of the title compound was obtained. Yield 8.63 g. M.p. 124°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([OH:14])[C:11]([NH2:13])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].Cl[C:16](OCC)=[O:17].O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:11](=[O:12])[NH:13][C:16](=[O:17])[O:14]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: NC(=O)N(O)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2cc(Cl)c(Cl)c(Cl)c2)o1
Reaction time: 1 h

Procedure:
1-(3,4,5-Trichlorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloride-tetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3,4,5-trichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione.