Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH2:13]([O:15][P:16]([CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>C(O)C>[C:31]([O:30][C:28](=[O:29])[NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][CH2:21][P:16]([O:15][CH2:13][CH3:14])([O:17][CH2:18][CH3:19])=[O:20])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCOP(=O)(CCNCCCNC(=O)OC(C)(C)C)OCC
Solvent: CCO
Product: CCOc1c(N(CCCNC(=O)OC(C)(C)C)CCP(=O)(OCC)OCC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (45 g, 0.265 mole; Aldrich 31,077-8) in absolute ethanol (1.2 L) under nitrogen was added dropwise a solution of N-[3-(t-butyloxycarbonylamino)propyl]-2-aminoethylphosphonic acid diethyl ester (80 g, 0.24 mole) in absolute ethanol (600 mL) and the reaction mixture was stirred at ambient temperature 15 hr. The reaction mixture was concentrated in vacuo and the residue was put on a pad of silica gel (6"×4") and eluted first with a mixture of methylene chloride/hexane 1:1 to remove excessive 3,4-diethoxy-3-cyclobutene-1,2-dione and finally with 10% methanol/methylene chloride to yield the title compound after evaporation as a viscous oil (107 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CI.S(OC)(O[CH3:26])(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]([CH3:26])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cccc([C@H](C)N[C@@H](C)c2ccccc2)c1
Solvent: CI
Product: COc1cccc([C@H](C)N(C)[C@@H](C)c2ccccc2)c1

Procedure:
In another embodiment, the second approach: The methylation reaction is carried out using (S)-1-(3-methoxy phenyl)-N—((S)-1-phenylethyl)ethylamine as a raw material, and methyl iodide or dimethyl sulfate as a methylation agent, so as to obtain (S)-1-(3-methoxyphenyl)-N-methyl-N—[(S)-1-phenylethyl]ethylamine. Methyl iodide or dimethyl sulfate are conventional methylation agents, and the method is common in the art. See OS, CV4, 836 (1963); OS, CV3, 753 (1955), which are incorporated herewith by reference in their entireties.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](=[O:9])[CH3:8].N[C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2SC=1C(=O)C>>[C:7]([C:6]1[S:5][C:4]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:3]=2[C:2]=1[NH2:1])(=[O:9])/[CH:8]=[CH:16]/[C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:18]=1
Reactant: CC(=O)c1sc2cc(F)ccc2c1N
Reactant: CC(=O)c1sc2ccccc2c1N
Product: Nc1c(C(=O)/C=C/c2ccccc2)sc2cc(F)ccc12

Procedure:
The procedure was similar to step S3C, while the starting material was 17B in stead of 3B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])C)=[C:4]([C:12]([OH:22])([C:17]#[C:18][CH:19]2[CH2:21][CH2:20]2)[C:13]([F:16])([F:15])[F:14])[CH:3]=1.C(N(CC)CC)C.ClC(OC(Cl)C)=O.C([O-])([O-])=O.[K+].[K+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:11])[O:22][C:12]([C:17]#[C:18][CH:19]3[CH2:20][CH2:21]3)([C:13]([F:16])([F:15])[F:14])[C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)acetamide (5, R1 is methyl, 1.1 g, 3.3 mmol), toluene (5.5 mL) and triethylamine (0.5 mL, 3.65 mmol) was stirred at 0-5° C. under nitrogen then 1-chloroethyl chloroformate (0.52 g, 3.65 mmol) was added dropwise. The mixture was stirred at 5-10° C. overnight. Water (20 mL) was added and the mixture was separated. The organic layer was evaporated to dryness whereupon N,N-dimethyl formamide (5 mL) and K2CO3 (0.9 g, 6.6 mmol) were added. The reaction mixture was stirred at room temperature for 1 day. Toluene (20 mL) and water (20 mL) were added to the mixture, and the resulting mixture was separated. The organic layer was washed with water (20 mL), and evaporated to dryness to give 6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1H-benzo[d][1,3]oxazin-2(4H)-one as an off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][OH:11].[CH3:12]COCC>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:12][C@H:9]1[CH2:10][OH:11]
Reactant: OC/C=C/c1ccccc1Cl
Reactant: CCOCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: OC[C@@H]1C[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Pd(OAc)2 (13.3 mg, 0.06 mmol) was added to a solution of trans-3-(2-chlorophenyl)-2-propen-1-ol (100 mg, 0.59 mmol) in a solution of CH2N2 in Et2O (ca. 0.6 M, 25 mL). The reaction mixture was stirred at room temperature for 1 h. An additional amount of CH2N2 solution in Et2O (25 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to yield the title compound (85.5 mg, 79% yield).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[O:45][CH2:46][CH2:47][O:48][CH3:49]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[O:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:9][CH:10]=1
Reactant: COCCOc1c(CCl)cccc1OC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cccc1OC

Procedure:
Analogously to Method D, 0.417 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.251 g of 1-chloromethyl-3-methoxy-2-(2-methoxyethoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.20 (1:2 EtOAc-heptane); Rt=6.07.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.CCN(CC)CC.N1C=CC=CC=1.[CH3:53][N:54]1[CH:58]=[C:57]([S:59](Cl)(=[O:61])=[O:60])[N:56]=[CH:55]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:59]([C:57]1[N:56]=[CH:55][N:54]([CH3:53])[CH:58]=1)(=[O:61])=[O:60])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)c1
Yield: 92 %

Procedure:
To methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1) (1.0 equiv) and Et3N (3.0 equiv) or pyridine (3.0 equiv) in CH2Cl2 (0.05 M) was added 1-methylimidazole-4-sulfonyl chloride (1.2 equiv). The reaction was monitored by TLC (10% MeOH—CH2Cl2) and was heated if necessary. After 30 min the mixture was poured into saturated sodium bicarbonate and extracted with CH2Cl2. The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography to afford 92% of the desired product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:48])[C:10]([NH:12][NH:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C:17](=[O:35])[N:16]([CH2:36][C:37]2[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)[N:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]([C:10]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]2=[N:13][N:12]=1)[CH3:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)[C@@H](C)OCc2ccccc2)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)OCc3ccccc3)n21
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a round bottom flask was added (R)-2-(benzyloxy)-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide (70 mg, 0.140 mmol), toluene (3 ml). The reaction was heated to 120° C. POCl3(0.3 ml) was then added and the reaction was stirred at 120° C. for additional 3 hr. The reaction was then cooled to rt and the solution was concentrated. The resulting residue was diluted with EtOAc (30ml). The organic solution was then extracted with saturated NaHCO3 (20 ml), water (20 ml) and saturated NaCl (20 ml). The organic solution was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel, 20%-50% EtOAc/Hex) to give product (R) -4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (40 mg, 44% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:16]([CH:13]([CH3:15])[CH3:14])[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: CC(C)N
Product: CC(C)N1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) and isopropylamine (Aldrich Cat No. 471291). LCMS (M+H)+=254.0/256.0.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([C:33]#[N:34])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(#N)C>[C:33]([C:25]1[CH:24]=[C:23]([C@@H:16]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:30])=[O:31])#[N:34]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a round bottom flask was placed (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (102 mg, 0.19 mmol), ethanol (2 mL), and concentrated hydrochloric acid (3 drops). It was stirred at 25° C. for 1 h. The reaction was then diluted with some acetonitrile and concentrated with silica gel (2 g) in vacuo and purified on a Biotage Flash chromatography system (40S column, silica gel, 100% ethyl acetate to 10% methanol/ethyl acetate) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide (63 mg, 77%) as a light yellow solid: [α]30589=−40.0° (c=0.10, methanol); ES-HRMS m/e calcd for C21H26N4O4S (M+H)+ 431.1748, observed 431.1749; 1H NMR (400 MHz, DMSO-d6) δ 1.12 (m, 2H, CH2), 1.38-1.78 (m, 8H, 4×CH2), 2.12 (m, 1H, CH), 3.36 (s, 3H, SO2CH3), 3.67 (m, 2H, OCH2), 3.86 (m, 3H, ArCHCO and NCH2), 4.83 (t, J=5.3 Hz, 1 H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.95 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.11 (d, Jm=1.6 Hz, 1H, Ar), 8.11 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:37][CH2:13][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:4][CH2:3][C:2]([F:16])([F:15])[F:1])[CH:12]=1
Reactant: N#Cc1ccc(CO)cc1OCC(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)cc1OCC(F)(F)F
Reaction time: 2 h

Procedure:
2-(2,2,2-Trifluoro-ethoxy)-4-hydroxymethyl-benzonitrile (1.4 g, 6.1 mmol) was dissolved in THF (31 ml) and treated with Ph3P (2.4 g, 9.15 mmol) followed by CBr4 (3 g, 9.15 mmol). The reaction mixture was stirred at room temp. for 2 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (20% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: C[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]([OH:16])=O)[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(=O)C(Cl)=O.C[ClH]N.[CH2:32]([N:34](CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:32][NH:34][C:14]([C:4]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:2][N:7]=[N:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: CCN(CC)CC
Reactant: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of methyl 3,5-diphenylpyridazine-4-carboxylic acid (compound 6) (200 mg, 0.72 mmol) in CH2Cl2 (10 mL), oxalyl chloride (230 mg, 1.81 mmol), catalytical DMF were added and stirred at 0° C. for 1 h. After the complete consumption of the acid shown by TLC, the volatiles were removed under reduced pressure and the crude acid chloride obtained was taken up in dry CH2Cl2 (5 mL). A solution of methyl amino hydrochloride (238 mg, 3.62 mmol) in CH2Cl2 (5 mL) cooled to 0° C., triethylamine (219 mg, 2.17 mmol) and acid chloride were added dropwise at 5° C. After the completion of the starting material, the reaction mixture was diluted with CH2Cl2 (20 mL), washed with aq NaHCO3 (5 mL×1), brine (5 mL×1) and dried over anhydrous Na2SO4. The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 30% EtOAc in hexane) to furnish N-methyl-3,5-diphenylpyridazine-4-carboxamide (compound 1) (100 mg, 47%) as a light orange solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14](Cl)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.[NH2:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14]([NH:19][C:20]3[CH:24]=[CH:23][S:22][C:21]=3[C:25]([O:27][CH3:28])=[O:26])(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1sccc1N
Reactant: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)Cl)ccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 50.6 %

Procedure:
Synthesized as described for 3 using 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (500.0 mg; 1.74 mmol), methyl 3-aminothiophene-2-carboxylate (301.4 mg; 1.91 mmol), 4-dimethylaminopyridine (53.1 mg; 0.44 mmol), pyridine (1.40 mL; 17.4 mmol) and anhydrous dichloromethane (200 mL). The crude residue was purified by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 25% v/v over 350 mL gradient elution) to yield the title compound as a white solid (359 mg).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:9][CH2:10][CH2:11][CH2:12][CH:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1>[C:3]1([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:15])[CH:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][CH2:11][CH2:10][OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C(CCCO)c1ccccc1
Reactant: Brc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: OCCCC(c1ccccc1)C(O)(c1ccccc1)c1ccccc1

Procedure:
The compound is prepared from 6.0 g of magnesium turnings in 42 ml of dry tetrahydrofuran, 39.3 g of bromobenzene in 84 ml of dry tetrahydrofuran and 25.4 g of 5-hydroxy-1,2-diphenylpentan-1-one in 75 ml of dry tetrahydrofuran according to the procedure described in Example 1(b). The product is recrystallized from toluene. The yield is 14.9 g (45%) of a product having m.p. 120°-2° C.
Reaction SMILES: ClC1N2C(=O)NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].[Cl-].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][Zn+])=[CH:32][CH:31]=1.ICC.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[C:52](C)[N:51]3[C:55](=[O:69])[N:56]([CH2:58][C:59]4C=CC(C(F)(F)F)=CC=4)[N:57]=[C:50]3[C:49]=2[C:70]2[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=2)=[CH:44][CH:43]=1>>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[C:52]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:51]3[C:55](=[O:69])[N:56]([CH2:58][CH3:59])[N:57]=[C:50]3[C:49]=2[C:70]2[CH:71]=[CH:72][C:73]([Cl:76])=[CH:74][CH:75]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12
Agent: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cc3ccc(OC)cc3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with 4-methoxybenzylzinc chloride, followed by alkylation with iodoethane, in a manner analogous to that in which 7,8-bis(4-chlorophenyl)-5-methyl-2-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one was prepared. HPLC/MS: retention time=4.571 min, [M+H]30 =505.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.[NH2:26][C:27]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[N:30]=[C:29]([N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH3:44])[CH:28]=1>>[C:48]([O:47][C:45]([N:43]([C:29]1[CH:28]=[C:27]([NH:26][C:23](=[O:24])[CH2:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[N:30]=1)[CH3:44])=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: COc1ccc(Cn2nc(N(C)C(=O)OC(C)(C)C)cc2N)cc1OC
Product: COc1ccc(Cn2nc(N(C)C(=O)OC(C)(C)C)cc2NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Yield: 66 %

Procedure:
Using an analogous procedure to that described in Example 22, 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid was reacted with 5-amino-3-(N-tert-butoxycarbonyl-N-methylamino)-1-(3,4-dimethoxybenzyl)pyrazole to give N-[3-(N-tert-butoxycarbonyl-N-methylamino)-1-(3,4-dimethoxybenzyl)pyrazol-5-yl]-2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetamide as a solid in 66% yield; 1H NMR: (DMSOd6) 1.45 (s, 9H), 3.18 (s, 3H), 3.65 (s, 3H), 3.66 (s, 3H), 3.73 (s, 2H), 3.92 (s, 3H), 3.95 (s, 3H), 5.08 (s, 2H), 6.4 (d, 1H), 6.42 (m, 1H), 6.58 (d, 1H), 6.76 (d, 1H), 6.84 (d, 1H), 7.2 (d, 2H), 7.4 (s, 1H), 7.41 (d, 2H), 7.49 (d, 1H), 10.26 (br s, 1H); Mass Spectrum: M+H+ 684.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[C:32]([C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](O)=[O:38])(=[O:34])[CH3:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:32]([C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=2)[C@H:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[CH2:10]1)=[O:38])(=[O:34])[CH3:33]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1C(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R-1-[3,5-Bis(trifluoromethyl)benzoyl)-2-(3,4-dimethylbenzyl)piperazine fumarate (785 mg) was added to a mixture of 2N sodium hydroxide solution (5 ml) and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine. A solution of this piperazine in N,N-dimethylformamide (7 ml) was added to a mixture of 2-acetylbenzoic acid (230 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295 mg) and 1-hydroxybenzotriazole (208 mg) in N,N-dimethylformamide (3 ml) and the whole was stirred at room temperature overnight. The mixture was poured into a saturated sodium hydrogen carbonate solution (78 ml) and the resulting precipitates were filtered off. The filtrate was evaporate din vacuo to give (2R)-4-(2-acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.45 g) as a powder.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available propionyl chloride the title compound is obtained as colorless solid.