Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([C:27]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:50][CH2:49]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:14][CH:15]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 744.4 [(M+H)+]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]2[CH2:14][C:15]3[C:20]([CH:9]12)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:21][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[O:13]=[C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]2[C:20]3[C:15]([C:14](=[O:21])[C@@H:10]2[CH2:11]1)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3ccccc3C21
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C[C@H]2C(=O)c3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester F1 (5.00 g, 18.2 mmol) in acetone (90 mL) and water (20 mL) was added KMnO4 (14.7 g, 93 mmol). The solution was stirred for 48 h at room temperature and filtered. The solution was concentrated to half the volume and sodium thiosulfate solution was added (2%, 50 mL). The solution was extracted with ethylacetate, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (7/3) to give the desired product F26 (1.6 g, 30%). LCMS (method E): 0.81 min; ES+: 597 (2M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:27][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]([O:25][CH3:26])=[CH:23][C:12]=1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)OCc2ccccc2)c(N)cc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (90 g) was charged to acetonitrile (660 g). 85% Sodium dithionite (75 g) was added to the solution and the temperature adjusted to 20° C. Water (516 g) was then added, maintaining the temperature at 20° C. The slurry was then heated to 65° C. and stirred for 30 minutes. Sodium dithionite (75 g) was added and the mixture stirred for another 30 minutes. The lower aqueous phase was removed. Concentrated hydrochloric acid (33% w/w, 12.48 g) was then added to adjust to a pH of <1. The suspension is held for 1 hour. The slurry was cooled to 20° C. over 30 minutes. Sodium hydroxide solution (20% w/w, 59.29 g) was added to give a pH of 10. The slurry was cooled to 0° C. and stirred for one hour. The product (benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate) was isolated by filtration, washed twice with water (2×222 ml) and then dried at 60° C. under vacuum. Yield: 78.81 g, 95%; NMR Spectrum (CDCl3) 3.8 (s, 3H), 5.1 (s, 2H), 5.3 (s, 2H), 6.2 (s, 1H), 7.3-7.4 (m, 10H); Mass Spectrum (M+H)+=364.1.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:37]=[C:38]([C:43](=O)[C:44]([F:47])([F:46])[F:45])[CH:39]=[C:40]([Cl:42])[CH:41]=1.O>C1(C)C=CC=CC=1>[C:11]1([S:10][CH:9]=[C:43]([C:38]2[CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]([Cl:35])[CH:37]=2)[C:44]([F:47])([F:46])[F:45])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: c1ccc(SC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C(=CSc1ccccc1)c1cc(Cl)cc(Cl)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
Triphenyl[(phenylsulfanyl)methyl]phosphonium chloride (50.0 g, 116 mmol) and potassium carbonate (32.2 g, purity 98%, 233 mmol) were suspended in toluene (1 L) under an inert gas atmosphere (argon) and cooled to 5° C. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanone (29.5 g, purity 96%, 116 mmol) and polyethyleneglycole (MW 1500, 8.76 g, 5.82 mmol) were added and the reaction mixture was stirred for five and a half hours at 5° C. and after warming to room temperature stirred for additional two hours. Water (500 mL) was added and the phases were separated. The water phase was extracted with toluene and the combined organic phases were washed with water (2x) and brine. After drying over sodium sulfate, filtration and evaporation the crude mixture was treated with n-heptane (250 mL) and left in the freezer overnight. The solid was filtered off and the solvents of the filtrate were evaporated. This material was again taken up in n-heptane (100 mL) and kept in the freezer for three days. Filtration and evaporation of the solvent gave 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfide (41.6 g, 96% purity, 99% yield; E/Z=94/6—determined by GC).
Reaction SMILES: [ClH:1].Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:16][C:17]([C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[CH:31]=O)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19].Cl.Cl.FC1C=CC(C(F)(F)F)=CC=1CNC1CCCNC1C1C=CC=CC=1>>[ClH:1].[ClH:1].[C:3]1([C@H:9]2[C@@H:14]([NH:15][CH2:31][C:30]3[CH:33]=[C:26]([C:17]([F:16])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])[CH:27]=[CH:28][C:29]=3[O:34][CH3:35])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C=O
Agent: Cl
Agent: Fc1ccc(C(F)(F)F)cc1CNC1CCCNC1c1ccccc1
Product: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 1 and Compound 17 in the same manner of Compound 2.
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([C:11]([OH:13])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:44][CH:45]1[CH:52]2[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:54][CH:46]1[CH2:47]3)[CH2:51]2>ClCCl.CN(C=O)C.O>[CH:46]12[CH2:54][CH:50]3[CH2:49][CH:48]([CH2:53][CH:52]([CH2:51]3)[CH:45]1[NH:44][C:11]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:9]=1[Cl:10])=[O:13])[CH2:47]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)n1ncc(C(=O)O)c1Cl
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reaction time: 1 h
Yield: 82.7 %

Procedure:
tert-Butyl-5-chloro-1H-pyrazole-4-carboxylic acid (Intermediate 9, 0.5 g, 2.47 mmol) was dissolved in a mixture of dry dichloromethane (12 mL) and dry DMF (3 mL). DIPEA (2.6 mL, 14.9 mmol) and TSTU (0.9 g, 2.7 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (0.44 g, 2.34 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried under vacuum and purified by C-18 reverse phase preparative-HPLC with a gradient of 10-100% acetonitrile/water to give 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (650 mg, 83%). Mass spectrum: m/z: 336.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(4-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (preparation analogous to US 2005/59668) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:18]1.[CH:48](OC1C=CC([N+]([O-])=O)=CC=1)=[O:49].[OH-].[Li+]>C1COCC1.O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:19]2[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:21](=[O:22])[N:17]([CH2:16][C:15]([NH:14][CH2:13][CH:12]([NH:11][CH:48]=[O:49])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)=[O:37])[N:18]=2)=[CH:35][CH:34]=1
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=CNC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 μl (112 μmol) of N,N-diisopropylethylamine were added to a solution of 60 mg (102 μmol) of the compound of Example 58A in 1 ml of THF. The mixture was cooled to 0° C., 18 mg (107 μmol) of 4-nitrophenyl formate were then added a little at a time and stirring was continued at 0° C. for 1 h. Since LC/MS analysis of the reaction mixture indicated the additional formation of an O-formylated byproduct, 408 μl of a 1 N solution of lithium hydroxide in water were added to the reaction mixture. Stirring of the mixture was then continued at RT overnight. The volatile components were then removed on a rotary evaporator. The residue was dissolved in a little DMSO and separated by preparative HPLC [Method 8]. The product-containing fraction was freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 35 mg (59% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([N:40]2[C:39](=[O:41])[C:38]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]3[C:36]2=[O:46])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OC(Cc1ccccn1)c1cccc(Cl)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(Cc1ccccn1)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.9 %

Procedure:
38.6 g of the 1-(6-chloropyridin-2-yl)-2-(pyridin-2-yl)ethyl alcohol prepared in the Preparative Example 20, 47.8 g of triphenylphosphine and 26.8 g of phthalimide were dissolved in 500 ml of tetrahydrofuran, followed by the addition thereto of 31.7 g of diethyl azodicarboxylate. The obtained mixture was stirred at room temperature overnight and concentrated, followed by the addition thereto of diethyl ether. The obtained mixture was filtered to remove insolubles and the filtrate was purified by silica gel chromatography (with a hexane/ethyl acetate (2:1) mixture) to give 77.1 g of the title compound as a roughly purified product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)([O-:19])=[O:18]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-acetylpiperazine (5.0 g; 39.0 mmol) in THF (50 ml) was added triethylamine (5.6 ml; 39.0 mmol) and 3-nitrobenzylbromide (8.4 g; 39.0 mmol). The mixture was stirred at ambient temperature for 1 hour and the solvent was removed by evaporation. The residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and evaporated under reduced pressure to leave 6m2, quantitatively.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:17]([Cl:18])=[C:16]2[C:11]([C:12]([O:19][CH3:20])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)=S>C(O)C>[Cl:18][C:17]1[C:8]([NH:7][C:5]2[NH:4][CH2:3][CH2:2][N:1]=2)=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[O:19][CH3:20]
Reactant: COc1ncnc2c(Cl)c(NC(=S)NCCN)ccc12
Solvent: CCO
Product: COc1ncnc2c(Cl)c(NC3=NCCN3)ccc12

Procedure:
A suspension of the thiourea prepared above (0.4 g) in ethanol (50 ml.) was stirred under reflux conditions (78°) with mercuric oxide (0.5 g) for 4 hours and filtered while hot. Evaporation of the filtrate yielded a white solid which was recrystallised from ethanol to give 0.1 g of 8-chloro-7-(2-imidazolin-2-ylamino)-4-methoxyquinazoline as a free base, m.p. 238°-239°.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][N:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[C:10]2=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:31]1([C:2]2[C:7]([CH2:8][N:9]3[N:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=5)=[CH:14][CH:15]=4)[C:10]3=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1Cc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1Cc1cccnc1C1CC1
Temperature: 100 °C

Procedure:
A mixture of 2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (25 mg, 0.053 mmol), cyclopropyl boronic acid (14 mg, 0.16 mmol), dppf(Pd)Cl2 (6 mg, 0.0079 mmol), potassium carbonate (29 mg, 0.021 mmol) in degassed dioxane (1 mL) was heated at 100° C. for 3 hours. The layers were separated, the organic layer was concentrated and the residue was purified by reverse phase HPLC to provide 2-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C24H18F3N3O2. 438.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:17](Cl)Cl.CO.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(OCC)C>[CH2:1]([C:3]1([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: ClCCl
Reactant: CCC1(CC(=O)O)CCc2ccc(O)cc21
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCC1(CC(=O)OC)CCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A 25 mL conical flask was charged with 42.3 (0.11 g, 0.50 mmol) and 10:1 DCM/MeOH (5 mL). To the orange solution was added (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, commercially available from Aldrich) (0.30 mL, 0.60 mmol) dropwise (vigorous gas evolution). The resulting solution was stirred for 15 minutes at room temperature, quenched with acetic acid (0.029 mL, 0.50 mmol), and concentrated. The residue was purified by silica gel flash chromatography (0-30% EtOAc/hexanes) to afford 42.4 (0.104 g, 89% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].[CH:18]1([CH2:21]O)[CH2:20][CH2:19]1>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([O:6][CH2:21][CH:18]1[CH2:20][CH2:19]1)=[O:5]
Reactant: CC(C=CCC(C)CCCC(C)C)=CC(=O)O
Reactant: OCC1CC1
Solvent: c1ccccc1
Product: CC(C=CCC(C)CCCC(C)C)=CC(=O)OCC1CC1

Procedure:
The acid chloride of 3,7,11-trimethyldodeca-2,4-dienoic acid (0.1 mole) is reacted with 0.2 mole of cyclopropylmethyl alcohol in benzene to yield cyclopropylmethyl 3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 1-methylimidazole
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[N:16]=[C:12]3[NH:11][C:10]([CH3:25])=[C:9]2[C:26]#[N:27])=[CH:4][C:3]=1[F:28].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[N:16]=[C:12]3[N:11]=[C:10]([CH3:25])[C:9]=2[C:26]#[N:27])=[CH:4][C:3]=1[F:28]
Reactant: COc1ccccc1-c1cn2c(n1)NC(C)=C(C#N)C2c1ccc(Cl)c(F)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: COc1ccccc1-c1cn2c(-c3ccc(Cl)c(F)c3)c(C#N)c(C)nc2n1
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a stirred suspension of 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carbonitrile (180 mg, 0.46 mmol) in CH2Cl2 (5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (103 mg, 0.46 mmol) in one portion. The reaction was kept at ambient temperature for 2.5 h, diluted with CH2Cl2 and washed with satd aq NaHCO3 (5×). The organic layer was washed again with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine-6-carbonitrile (168 mg, 94%) as a light orange solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([OH:28])[C@H:19]([NH:22][C:23](=[O:27])[CH:24]([F:26])[F:25])[CH2:20][F:21])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3]1>C(O)C.[Pd]>[O:29]=[S:2]1(=[O:1])[CH2:3][CH:4]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([OH:28])[C@H:19]([NH:22][C:23](=[O:27])[CH:24]([F:26])[F:25])[CH2:20][F:21])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:5]1
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3=CS(=O)(=O)C3)nc2)cc1)C(F)F
Agent: [Pd]
Solvent: CCO
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3CS(=O)(=O)C3)nc2)cc1)C(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
To a stirred solution of the product of step 6, Example 18 (0.042 g, 0.099 mmol, 1 eq) in ethanol (10 mL) is added palladium on carbon (0.010 g, 10% w/w). Resulting reaction mixture is stirred at room temperature for 16 hours. After completion of the reaction, reaction mixture is filtered through celite bed and filtrate is concentrated in vacuo. The crude compound is purified by preparative TLC using 50% ethyl acetate in hexane to afford desired compound (0.010 g) which is washed with n-pentane (3×5 mL) and dried to afford title compound (0.006 g): 1H-NMR (400 MHz, DMSO) δ: 4.03-4.07 (m, 1H), 4.29-4.31 (m, 2H), 4.45-4.57 (m, 5H), 4.64-4.68 (m, 1H), 4.88-4.90 (m, 1H), 5.92 (d, 1H, J=4.16 Hz), 6.20 (t, 1H, J=53.72 Hz), 7.46 (d, 2H, J=8.28 Hz), 7.53 (d, 1H, J=8.08 Hz), 7.71 (d, 2H, J=8.4 Hz), 8.08-8.11 (dd, 1H, J1=8.2 Hz, J2=2.4 Hz), 8.86 (d, 1H, J=8.64 Hz). 8.93 (d, 1H, J=2.36 Hz). LCMS (m/z): [M+H] 428.9.
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]([O:15]C)=O.N1C2C(=O)CCCC=2C=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][NH2:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:13](=[O:15])[CH2:12][CH:3]3[C:2]([C:11]4[N:10]=[CH:9][CH:8]=[CH:7][C:6]=4[CH2:5][CH2:4]3)=[N:36]2)=[CH:31][CH:30]=1
Reactant: COC(=O)CC1CCc2cccnc2C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: O=C1CCCc2cccnc21
Product: O=C1CC2CCc3cccnc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-8-oxoquinoline-7-acetate (prepared from 6,7-dihydroquinoline-8(5H)-one according to the method of Wu et al supra) and 4-chlorophenylhydrazine.