Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O-])([O-])=O.[Cs+].[Cs+].CI.CCOCC>CC(C)=O.[Cl-].[Na+].O>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC=Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: COC(=O)C/C=C/c1ccccc1

Procedure:
4-Phenylbut-3-enoic acid was dissolved in acetone and added to Cs2CO3, then MeI was added. The suspension was refluxed overnight. Et2O and brine were added and the phases separated. Aqueous layer was washed three times with Et2O. Combined organic layers were dried over MgSO4 and the solvent was evaporated in vacuum. (E)-methyl 4-phenylbut-3-enoate (S32) was obtained as a yellow oil (quantitative). Rf (hexane/EtOAc 8:1)=0.28.
Reaction SMILES: [CH2:1]([C:4]([CH2:11][C:12]#[CH:13])(C(O)=O)[C:5]([OH:7])=[O:6])[C:2]#[CH:3].C(=O)=O>>[CH2:1]([CH:4]([CH2:11][C:12]#[CH:13])[C:5]([OH:7])=[O:6])[C:2]#[CH:3]
Reactant: C#CCC(CC#C)(C(=O)O)C(=O)O
Agent: O=C=O
Product: C#CCC(CC#C)C(=O)O
Yield: 79.9 %

Procedure:
The dipropargylmalonic acid (26 gm, 0.443 mol) was heated neat at 135 C until CO2 stopped evolving. It was then allowed to cool to an oil. The oil was distilled at 0.5 psi. The remaining oily residue in the distillation flask and solid were combined (15.7 gm, 79.9% yield) and was used as is in the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([N:21]([CH2:24][CH3:25])CC)C>O1CCOCC1>[C:11]1([C@H:24]([NH:21][C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:25])[CH:18]=[CH:17][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(C#N)cc3)cc12)c1ccccc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
A mixture of 1.27 g (5 mmol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile, 1.4 ml (10 mol) triethylamine and 0.955 ml (7.5 mmol) R(+)-1-phenyl-ethylamine in 25 ml dioxane is heated under reflux for 24 h. A second portion of R(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) is added and heating is continued for 24 h. After addition of a third portion of R(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) and additional 24 h the reaction mixture is cooled to 10° C. and the title compound filtered off and washed with dioxane. From the mother liquor a second crop is obtained after concentration of the solution; m.p. 333-336° C.; MS-ES+: (M+H)+=340.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[ClH:24]>O1CCOCC1>[ClH:24].[ClH:24].[NH:15]1[CH2:16][CH:13]([C:11]2[NH:10][N:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[N:12]=2)[CH2:14]1
Reactant: Cc1cccc(-c2n[nH]c(C3CN(C(=O)OC(C)(C)C)C3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
11.6 g (36.8 mmol) tert-Butyl 3-[3-(6-methylpyridine-2-yl)-1H-1,2,4-triazole-5-yl]azetidine-1-carboxylate are dissolved in 150 mL dioxane. 27.6 mL HCl in dioxane (4M) are added dropwise and the reaction mixture is stirred over night at room temperature. The reaction mixture is evaporated to dryness yielding 13.1 g (76.6%) of the desired salt which is 60% pure and is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[OH-].[Na+].[CH2:19](I)[CH3:20]>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH2:19][CH3:20])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Reaction time: 72 h

Procedure:
A 9.4 g portion of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one was combined with 150 mL of THF, 20 mL of 50% aqueous sodium hydroxide and 12.5 g of ethyl iodide in a flask, and was warmed with stirring to about 37°. Stirring at approximately constant temperature was continued for about 72 hours and the reaction was worked up as described above in Example 2 to obtain 3.88 g of the desired product, m.p. 108°-110°. The product was found to be 98.6% pure by HPLC, eluting with 1:1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:35]
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A163) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C:25]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)([OH:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1cc(Br)cnc1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Br)cnc1C1(O)CCCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 2,5-dibromo-3-methylpyridine (3.88 g) in toluene (70 ml) was added dropwise a 1.6 M solution of n-butyllithium in n-hexane (10.6 ml) at −78° C., and stirred at the same temperature for 1 hour. Then, a solution of N-tert-butoxycarbonyl-hexahydroazepin-4-one (3.0 g) in toluene (16 ml) was added dropwise thereto, and stirred at the same temperature for 5 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (2.14 g) as a colorless clear oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:20][CH:19]([N:21]([CH3:23])[CH3:22])[CH2:18]3)=[C:11]([NH2:24])[CH:10]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.[C:68]([Zn]C#N)#[N:69]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:24][C:11]1[C:12]([N:17]2[CH2:20][CH:19]([N:21]([CH3:22])[CH3:23])[CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[C:2]([C:68]#[N:69])=[CH:7][N:6]=2)[CH:10]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Temperature: 120 °C
Yield: 80.3 %

Procedure:
N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 24, 297 mg, 0.64 mmol), tris(dibenzylidene-acetone)dipalladium(0) (14.62 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (‘XPhos’, 30.5 mg, 0.06 mmol), and dicyanozinc (45.0 mg, 0.38 mmol) were placed in a microwave tube under N2. Poly(methylhydrosiloxane) (12 mg, 0.06 mmol) was then added in degassed DMA (1.92 mL). The resulting mixture was then heated at 120° C. for 2 h in a microwave. The crude mixture was loaded on to a SCX column. The column was flushed with water followed by CH3OH/CH2Cl2. The desired product was eluted from the column using 7M methanolic ammonia in CH2Cl2 and pure fractions were combined and concentrated in vacuo. The residue was dissolved in CH3OH/CH2Cl2 and allowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE (available from Polymer Laboratories) under gravity. The resulting solution was concentrated in vacuo. Purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (139 mg, 48%) as a brown solid after trituration with diethyl ether; 1H NMR: (100° C.) 2.18 (6H, s), 3.17 (1H, t), 3.60 (2H, t), 3.69 (3H, s), 3.87 (2H, br s), 4.00 (2H, t), 6.32 (1H, s), 6.86 (1H, s), 7.11 (1H, t), 7.34-7.46 (1H, m), 8.34 (1H, d), 8.61 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.90 (1H, s); m/z: ES+ MH+ 456.23.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:1]([NH:9][C:10]([NH:26][C:21]1[C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:24]=[CH:23][N:22]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncccc1OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A 1 L round-bottomed flask was charged with benzoyl isothiocyanate (22.4 g, 137 mmol), 3-(benzyloxy)pyridin-2-amine (25 g, 125 mmol), and THF (200 mL). The reaction mixture was stirred at room temperature for 2 hours and the diluted with hexanes to 1 L, and then filtered to afford 1-benzoyl-3-(3-(benzyloxy)pyridin-2-yl)thiourea (44.4 g, 97.9% yield) as a yellow solid. 1H NMR (CDCl3) δ 9.00 (m, 1H), 8.08 (m, 1H), 7.87 (m, 1H), 7.62 (m, 1H), 7.54 (m, 2H), 7.41 (m, 5H), 7.27 (m, 1H), 7.02 (m, 1H), 5.22 (s, 2H). LCMS (25 to 95) Rt=2.64 min, (apci) m/z=201, 364 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([NH2:21])=[O:20])[C:5]2=[O:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[CH:11][CH:10]=3)[C:5](=[O:22])[C:6]([C:19]([NH2:21])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(-c3cccnc3)cc2c1=O
Temperature: 150 °C
Yield: 66.9 %

Procedure:
Compound E (15 mg, 0.042 mmol, 1.0 eq), 3-pyridinylboronic acid (11 mg, 0.087 mmol, 2.1 eq), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.0 mg, 0.0042 mmol, 0.10 eq) and 1N sodium carbonate (0.21 mL, 0.21 mmol, 5.0 eq) were dissolved in dimethoxyethane (0.6 mL) in a microwave vial and heated at 150° C. for 20 minutes in a microwave reactor. The reaction was portioned between ethyl acetate and water and the layers separated. The aqueous phase was extracted with an additional portion of ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography afforded 10.1 mg (68%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=4.3 Hz, 1H), 8.96 (d, J=1.9 Hz, 1H), 8.62 (m, 2H), 8.60 (s, 1H), 8.17 (dt, J=8.0, 1.7 Hz, 1H), 8.09 (dd, J=8.8, 2.3 Hz, 1H), 7.81-7.78 (m, 2H), 7.66 (d, J=4.3 Hz, 1H), 7.57-7.52 (m, 3H), 7.16 (d, J=8.8 Hz, 1H); ES-MS [M+1]+: 360.2.
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@@H:3]1[C@@H:7]([O:8][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
(3S,4R)-Benzyl 3-ethyl-4-hydroxypyrrolidine-1-carboxylate (18.9 g, 76 mmol), 4-methylbenzene-1-sulfonyl chloride (21.68 g, 114 mmol) were dissolved in DCM (100 mL) and cooled in an ice bath. Added N,N-dimethylpyridin-4-amine (1.852 g, 15.16 mmol) and triethylamine (11.51 g, 114 mmol) and let the reaction mixture warm to RT overnight. The suspension was passed over a silica column and eluted with heptanes/EA (9:1 to 4:1 mixtures) to give (3S,4R)-benzyl 3-ethyl-4-(tosyloxy)pyrrolidine-1-carboxylate (28.7 g, 71.1 mmol, 94% yield). LCMS: M+1=404, t=3.07 min.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:26][N:25]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 60.9 %

Procedure:
In a manner similar to Example 4, Step (c), 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid (1.20 g, 0.00372 mol) was allowed to react with hydroxylamine hydrochloride (0.3115 g, 0.00448 mol) in the presence of sodium carbonate (0.4768 g, 0.00450 mol) in absolute ethanol (20 mL) to give 0.764 g of 4-hydroxyimino-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid as a white solid; mp 134-136° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:33][O-:34].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:34][CH3:33])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3cccc(C(F)(F)F)c3)c(Cl)nc12
Reactant: C[O-]
Agent: CO[Na]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of (2,4-dichloro-8-methyl-3-(3-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.87 g, 1.83 mmol, Intermediate 15: step c) and dry sodium methoxide (0.58 g, 10.75 mmol) in toluene was heated in a sealed tube at 110° C. for 12 hours. Starting material was still present, therefore additional NaOCH3 (198 mg, 3.66 mmol) was added and stirring was continued at 110° C. for another 24 hours. The mixture was then cooled to room temperature, diluted with DCM, stirred at room temperature for 30 minutes, and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the white solid product was precipitated from MeOH, filtered and dried to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[N:38])[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[N-:50]=[N+:51]=[N-:52].[Na+].Cl.C([NH+](CC)CC)C.CO.ClCCl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]4[NH:52][N:51]=[N:50][N:38]=4)[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCCCC#N)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCCCc4nnn[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.45 g, 0.67 mmol), sodium azide (0.13 g, 2.04 mmol), and triethylammonium hydrochloride (0.14 g, 1.03 mmol) in N-methylpyrrolidinone (6 mL). Heat to 150° C. After 4 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the aqueous layer three times with ethyl acetate. Adjust the pH of the aqueous layer to about 1 using a 1 M aqueous hydrochloric acid solution. The aqueous layer is again extracted three times with ethyl acetate, and twice with dichloromethane. The aqueous layer is saturated with sodium chloride and again extracted four times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with 20% methanol/dichloromethane to give the title compound: Rf=0.33 (silica gel, 20% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccn1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 36 h
Yield: 24 %

Procedure:
A mixture of tert-butyl 4-(methylamino)piperidine-1-carboxylate (WO 03/089412, p 22), (2 g, 9.33 mmol), 2-bromopyridine (1.35 mL, 13.99 mmol) and N,N-diisopropylethylamine (2.5 mL, 13.99 mmol) was heated at 130° C. for 3 hours. Potassium carbonate (2 g, 14 mmol) was added and the reaction mixture was heated at 130° C. for a further 8 hours. 2-Bromopyridine (1 mL, 10.36 mmol) was then added to the mixture and heating continued at 130° C. for 36 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and extracted with saturated citric acid solution (2×15 mL), and the combined aqueous solution was basified with sodium hydrogen carbonate and extracted with dichloromethane (2×30 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 0:100 to 50:50, to afford the title compound in 24% yield, 646 mg. 1H NMR (CDCl3, 400 MHz) δ: 1.45 (s, 9H), 1.55-1.70 (m, 4H), 2.78-2.90 (m, 5H), 4.10-4.30 (m, 2H), 4.65-4.80 (m, 1H), 6.45-6.55 (m, 2H), 7.40-7.45 (m, 1H), 8.10-8.15 (m, 1H); LRMS APCI m/z 292 [M+H]+
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]3[CH2:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=[C:12]23)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:28][CH:29]([CH3:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=1.O1CCOCC1>CN1CCCC1=O>[OH:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:29]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[N:13]4[CH2:18][CH:19]=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=[C:12]34)[CH:8]=[CH:7][N:6]=2)[CH3:39])=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Reactant: CC(N)Cc1ccc(CO)cc1
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(Cc1ccc(CO)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1

Procedure:
1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (1.1 g, 2.9 mmol) and [4-(2-amino-propyl)-phenyl]-methanol (0.96 g, 5.8 mmol) in 1:1 dioxane: 1-methyl-2-pyrrolidinone (16 mL) was heated to 100° C. for 20 h. The mixture was partitioned between water (30 mL) and ethyl acetate (60 mL). The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-8% 2M NH3 MeOH/CH2Cl2 to afford a white solid. M+1=469. 1NMR (CDCl3) d (3H, 1.21 ppm), s (1H, 1.79 ppm), m (2H, 2.22 ppm), m(1H, 2.79 ppm), m (1H, 2.98 ppm), m (4H, 4.11 ppm), m (1H, 4.13 ppm), b(3H, 4.68 ppm), s (1H, 6.60 ppm), d (2H, 7.21 ppm), d (3H, 7.29 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.17 ppm).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C(O)(=O)C.C(O)(C)C>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:7])[C:6]([C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1ccc(C(O)(c2ccccc2)C(O)(c2ccccc2)c2ccc(C)cc2)cc1
Yield: 98.7 %

Procedure:
0.04 g of acetic acid was added to 35.98 g of isopropyl alcohol, and 4.02 g of 4-methylbenzophenone was dissolved therein. To this solution, ultraviolet rays were irradiated by a high pressure mercury lamp (UVL-100HA, manufactured by Riko Kagaku Sangyo K.K.) to carry out the reaction for 4 hours. After the reaction, the solvent was distilled off to obtain 3.99 g of 1,2-bis(p-methylphenyl)-1,2-diphenyl-1,2-ethanediol (compound (C1)).