Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[OH:2][CH:1]([C:31]1[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=1)[C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:17][O:18][C:19]([CH3:22])([CH3:23])[O:20][CH2:21]3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(C=O)s3)cc2)COC(C)(C)OC1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)NC1(CCc2ccc(-c3ccc(C(O)c4ccc(C)cc4)s3)cc2)COC(C)(C)OC1
Reaction time: 1 h

Procedure:
To a solution of N-(5-{2-[4-(5-formyl-2-thienyl)phenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (0.25 g) in tetrahydrofuran (20 mL) was added dropwise a solution (1 mol/L, 1.36 mL) of p-tolylmagnesium bromide in tetrahydrofuran at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. 0.5M Aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.35 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[O:7])=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: N#Cc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-amino-3-nitrobenzonitrile and was obtained as a light yellow solid as described in Example 1. 1H NMR (CDCl3): 11.58 (s, 1H), 9.18 (d, J=8.7, 1H), 9.04 (d, J=2.4, 1H), 8.65 (d, J=2.1, 1H), 8.26-8.22 (m, 1H), 8.00-7.96 (m, 1H), 7.56 (d, J=9.0, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=O)[NH:8][CH:7]=[N:6]2.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1ccn2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccn2ncnc(Cl)c12
Temperature: 100 °C
Yield: 82 %

Procedure:
A suspension of of 5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (2.57 gm, 17.2 mmole) in POCl3 (28 mL) was heated at 100° C. for 40 min. The excess reagent was removed under vacuum and the residue was dissolved in DCM (300 mL). This was washed with water, dried (Na2SO4), and the solvent removed. Flash chromatography on silica gel using DCM as eluent afforded the product as a yellow solid (2.38 gm, 82%). 1HNMR (CDCl3): δ 2.63 (s, 3H), 6.74 (d, 1H, J=2 Hz), 7.74 (d, 1H, J=2 Hz), 8.05 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1>>[OH:33][CH:30]1[CH2:31][CH2:32][N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(OCCCCl)c1
Reactant: OC1CCNCC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(OCCCN2CCC(O)CC2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 139 using tert-butyl N-[2-(3-chloropropoxy)biphenyl-4-ylmethyl]carbamate instead of 3-(3-chloropropoxy)-4-phenylbenzonitrile and piperidine-4-ol instead of pyrrolidine.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([CH2:13][CH3:14])[NH:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]4[N:23]([C:22]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[N:24]=[N:25][N:26]=4)=[CH:39][CH:38]=3)[C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:15])[CH:5]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.6 %

Procedure:
To a stirred suspension of NaH (17.2 mmol of an 80% dispersion) in dry dimethylformamide (30 mL) at rt was added 5,7-dimethyl-2-ethylimidazo[4,5-b] pyridine (1.51 g, 8.62 mmol) in one portion. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (5.29 g, 9.48 mmol) was added in one portion. The resulting mixture was warmed to rt and stirred for 15 hours. The excess NaH was quenched with water and the bulk of the DMF was removed in vacuo at 40°-50° C. The residue was extracted with EtOAc from brine, dried (K2CO3), and concentrated. Purification by flash chromatography (SiO2, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc) gave 4.25 g of 5,7-dimethyl-2-ethyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4.5-b]pyridine: 1H NMR (300 MHz, CDCl3) δ7.86 (dd, 1H, J=7, 2 Hz), 7.50-7.41 (m, 2H), 7.36-7.21 (m, 10 H), 7.05 (d, 2 H, J=4.5 Hz), 6.95-6.89 (m, 7 H), 6.86 (d, 2 , H, J=4.5 Hz), 5,35 (s, 2H), 2.67 (q, 2, H, J=7.5 Hz), 2.65 (s, 3 H), 2.58 (s, 3 H), 1.25 (t, 3 H, J=7.5 Hz).
Reaction SMILES: C(Cl)(=[O:3])C.[C:5]1([CH:11]2[NH:15][CH2:14][CH:13]([CH2:16][Cl:17])[O:12]2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([NH:15][CH2:14][CH:13]([OH:12])[CH2:16][Cl:17])(=[O:3])[CH3:5]
Reactant: CC(=O)Cl
Reactant: ClCC1CNC(c2ccccc2)O1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NCC(O)CCl
Temperature: 25 °C
Yield: 65 %

Procedure:
15.7 g of acetylchloride are added dropwise to a solution of 39.5 g of 2-phenyl-5-chloromethyloxazolidine in a mixture of 150 ml of chloroform and 16 ml of pyridine at a temperature of -40° C. under agitation. The solution is allowed to warm up to room temperature. After a reaction period of 14 hours, 100 ml of concentrated hydrochloric acid are added. After thoroughly mixing, the aqueous phase is separated and diluted with water to twice its volume and then is saturated with sodium chloride. By extracting the aqueous phase with methylene chloride, drying the methylene-chloride-extract and evaporating the solvent, 19.7 g of N-acetyl-3-chloro-1-aminopropan-2-ol is obtained as an oil which can be used in the following reaction without any purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(N)(=O)=O)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(N)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-methylbenzenesulfonamide (Intermediate 152), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)N)#[CH:20].[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:19]([C:21]1[CH:27]=[C:26]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:23][CH:22]=1)#[CH:20]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: C#Cc1cccc(N)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c1
Yield: 84 %

Procedure:
Prepared from VII and 3-ethynylaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 84%; yellow solid; mp 182° C.; IR (KBr) νmax/cm−1 3295, 3062, 2846, 2225, 1642, 1612, 1581, 1566, 1458, 1404, 1376, 1348, 1306, 1263, 1229, 1165, 1148, 1126, 971, 910, 888, 835; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, 1H, J=8.7 Hz), 8.20 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.40-7.35 (m, 2H), 7.29 (m, 1H), 7.20 (m, 1H), 4.17 (s, 1H); HRMS calcd for C18H10N5S (M+H+): 328.0657, found 328.0659.
Reaction SMILES: Cl.CN.C[CH2:5][N:6](CC)CC.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH:6][CH3:5])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methylamine hydrochloride (5.5 g, 81.46 mmol) was dissolved in DCM (300 ml), and Et3N (40 ml, 285.11 mmol) was added thereto. The reaction solution was then cooled to 0° C.; 3,4-dichlorobenzenesulfonyl chloride (20.00 g, 81.46 mmol) dissolved in DCM (50 ml) was then added dropwise, and stirring was carried out overnight at room temperature (TLC monitoring, silica gel, ethyl acetate). When the reaction was complete, 0.5 N HCl was added, the phases were separated, and the organic phase was washed with water and dried (sodium sulfate). The solvent was removed using a rotary evaporator. Purification was carried out by column chromatography on silica gel (gradient heptane/ethyl acetate 4:1 to 2:1).
Reaction SMILES: [CH:1]1([CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[H][H]>O=[Pt]=O.CO>[CH:1]1([CH:7]([OH:12])[C:8]([Cl:10])([Cl:11])[Cl:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: OC(C1C=CCCC1)C(Cl)(Cl)Cl
Agent: O=[Pt]=O
Solvent: CO
Product: OC(C1CCCCC1)C(Cl)(Cl)Cl

Procedure:
Adam's catalyst (0.2 g) was added to a solution of 1-(2-cyclohexen-1-yl)-2,2,2-trichloroethanol (23 g) in methanol (220 ml) and this mixture was stirred under a slight positive pressure of hydrogen. Uptake of hydrogen was complete after 400 minutes and the solution was then filtered. The filtrate was evaporated to give 1-cyclohexyl-2,2,2-trichloroethanol of 90% purity as judged by G.L.C. An attempt to purify this material by distillation through a spinning band column gave material of only 85% purity due, presumably, to decomposition brought about by prolonged heating. This material was used without further treatment.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:12]([F:11])([F:26])[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 39.4 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 600 mg, 3.4 mmol), 2,5-bis(trifluoromethyl)phenylboronic acid (ChemFocus, LLC, East Brunswick, N.J., USA; 953 mg, 3.7 mmol), copper(II) acetate (746 mg, 4.1 mmol) and triethylamine (575 μL, 4.1 mmol) in 1,2-dichloroethane (18 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,5-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (480 mg, 33%) as a colorless oil that solidified.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>O1CCCC1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
16-Hydroxyhexadecanoic acid (6.81 g, 25.0 mmol) was dissolved in tetrahydrofuran (150 ml) and the solution was cooled to 0° C. before adding pyridine (2.73 g, 34.5 mmol). Methacryloyl chloride (2.61 g, 25.0 mmol) was dissolved in tetrahydrofuran (75 ml) and added dropwise. The mixture was stirred for 1 hour at 0° C., and then at room temperature for 24 hours. The solvent was removed under reduced pressure (room temperature), the residue suspended in either (100 ml) and the mixture washed with distilled water. The ether layer was dried (MgSO4) and the ether evaporated. Chromatographic purification on a silica gel column (1:2 ethyl acetate/hexane) afforded 5.0 g (64%) of the title compound. 1H NMR (60 MHz, CDCl3), δ 1.3 (br s, 26H, (CH2)13), 1.95 (m, 3H, C=CCH3), 2.1-2.6 (m, 2H, CH2COO ), 4.9-4.4 (m, 2H, COOCH2), 5.52 (m, 1H, vinyl), 6.10 (M, 1H, vinyl).
Reaction SMILES: [CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>O>[CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:25][CH:27]2[CH2:28][O:29]2)[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1(c2ccccc2O)Sc2ccccc2N(C)C1=O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(c2ccccc2OCC2CO2)Sc2ccccc2N(C)C1=O

Procedure:
4.7 g (15.0 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-(2-hydroxyphenyl)-2H-1,4-benzothiazin-3-one are stirred for 24 hours at 85° C. with 0.6 g of NaOH, 2 ml of H2O and 50 ml of epichlorohydrin. After dilution with water, the mixture is extracted with methylene chloride, and the extract is dried with sodium sulfate and concentrated. This gives 5.3 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].I[CH3:33]>CN(C)C=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]([CH3:33])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: CI
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C)c(C)cc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
1-[(4,5-dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.2 g, 0.5 mmole) was dissolved in dimethylformamide(15 ml), sodium hydride(12 mg, 0.5 mmole) was added thereto slowly, and then the resulting mixture was stirred at room temperature for 15 min, then followed by addition of iodomethane(71 mg, 0.5 mmole) and subsequently at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dried, filtered and purified by column chromatography to obtain the titled compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[SH:15].Cl[C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1.[OH-].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[S:15][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(Sc2ccc(Cl)cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
Potassium t-butoxide (1.1 g) was added to a solution of 2,4-dichlorothiophenol (1.8 g) in N,N-dimethylformamide (DM F) (5 mL). The mixture was stirred at room temperature for 10 minutes and then 6-chloro 2H-pyridazin-3-one (1.31 g) was added. The reaction mixture was stirred at 100° C. for five hours. The mixture was then cooled to room temperature, poured into water (20 mL) and 20% potassium hydroxide (5 mL) was added. The resulting dark solution was extracted with ethyl acetate (2×10 mL). The aqueous layer was collected and the pH was adjusted to 3 with concentrated hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product, which was purified by silica gel chromatography (1:1 ethyl acetate/hexane as eluent) to afford 6-(2,4-dichloro-phenylsulfanyl)-2H-pyridazin-3-one (418 mg, 15%); NMR 6.88 (d, 1H), 7.10 (d, 1H), 7.24 (dd, 1H), 7.48 (d, 11H), 7.52 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][CH:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH3:15].[Br:22][C:23]1[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=1.C(O)(=O)C>O1CCOCC1>[Br:22][C:23]1[CH:24]=[N:25][C:26]([N:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:3]=2[O:2][CH3:1])[CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH:8]2[CH3:15])=[N:27][CH:28]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(CNC2C3CCN(CC3)C2C)c(OC)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(CN(c2ncc(Br)cn2)C2C3CCN(CC3)C2C)c(OC)c1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
(2,4-Dimethoxy-benzyl)-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine (70 mg, 0.24 mmol) and 5-bromo chloropyrimidine (93 mg, 0.48 mmol) were dissolved in 1,4-dioxane (1 ml). Glacial acetic acid (42 □L, 0.72 mmol) was added and the reaction mixture was stirred under microwave radiation at 150° C. for 30 minutes. The reaction mixture was concentrated in vacuo, redissolved in EtOAc and washed with 1M aqueous sodium carbonate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude reaction mixture was purified by chromatography [eluent gradient: 10-30% MeOH/Et3N (9:1) in EtOAc) to give pure (5-bromo-pyrimidin-2-yl)-(2,4-dimethoxy-benzyl)-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([OH:28])=O)=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Reactant: C1CCNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 70 °C
Reaction time: 60 h
Yield: 52.8 %

Procedure:
A mixture of 5-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (138 mg, 363 μmol), pyrrolidine (240 μl, 2.9 mmol), propylphosphonic anhydride (50% in ethyl acetate, 534 μl, 907 μmol) and diisopropylethylamine (190 μl, 1.09 mmol) in tetrahydrofuran (10 ml) was stirred for 2.5 days at 70° C. The solvent was evaporated; the residue was triturated with saturated aqueous sodium hydrogencarbonate solution and the precipitated solid was filtered off and dried in vacuo. The material was applied on silica and purified by flash chromatography over a 20 g silica column using heptane/EtOAc 10-100% as eluent, affording N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (83 mg, 52.8%) as white solid. Mp. 250-251° C. MS: m/z=434.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:35])[C:10](=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.O.[OH:37]OS([O-])=O.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:35])[C:10](=[O:37])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(OC)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate. (0.510 g, 1.1 mmol) in THF (10 ml) was added water (10 ml) followed by oxone (0.974 g, 1.6 mmol) in portions and the resulting mixture was stirred at room temperature overnight. The solid was removed by filtration and filtrate concentrated in vacuo and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford crude ethyl 3-(4-methoxyphenyl)-2,3-dioxopropanoate as a yellow oil (0.500 g) as a mixture with triphenylphosphine oxide which was used without further purification. LCMS (2) 2.38 min; m/z 237.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][C:19]1[CH:20]=[C:21]([Cl:25])[CH:22]=[N:23][CH:24]=1>CO.[Ni]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][C:19]1[CH:20]=[C:21]([Cl:25])[CH:22]=[N:23][CH:24]=1
Reactant: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2cncc(Cl)c2)c(C(=O)NCc2ccco2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a 0.08 M solution of N-(2-furanylmethyl) 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide (3.7 g, 10 mmol, prepared in Example 35.2) in MeOH was added a 50% aqueous slurry of Raney nickel (˜6 mL). Hydrogen was then bubbled through the resulting solution for one minute. The resulting mixture was stirred at ambient temperature under one atmosphere of hydrogen for 16 hr. The crude reaction mixture was filtered through a pad of Celite® and the filter cake was washed 3× with MeOH. NOTE: Raney nickel is pyrophoric and should always be kept wet with solvent during the filtration. The Raney nickel can be quenched by adding 6M aqueous HCl. The filtrate was concentrated in the presence of benzene to azeotropically remove water. The residue was purified by chromatography (1-3% MeOH in CH2Cl2) to yield 2.6 g (76%) of N-(2-furanylmethyl) 5-amino-2-(3-chloro-5-pyridyloxy)benzamide as a pale brown solid.