Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].B1([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C2CCCC1CCC2.[OH-].[Na+]>[Pd].O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(Cc4ccccc4)cc3)cnc12
Reaction time: 24 h
Yield: 68.3 %

Procedure:
According to a modification of a literature procedure (Suzuki, A. et al Tetrahedron Lett. 1986, 27, 6369–6372) a mixture of 57 mg (0.12 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester and 5 mg (0.006 mmol, 5 mol %) of Pd catalyst was placed into a carousel tube. After a vacuum and argon cycle, tetrahydrofuran (THF) (2 mL) was added, followed by 0.29 mL (0.144 mmol, 1.2 equiv) of B-Benzyl-9-BBN 0.5 M solution in THF, and 0.12 mL (0.36 mmol, 3 equiv) of 3 N NaOH solution, and the resulting mixture was heated reflux under argon overnight. Since analysis by LC-MS revealed unreacted starting material still present, 0.12 mL (0.06 mmol) of B-Benzyl-9-BBN, 5 mg (0.006 mmol, 5 mol %) of Pd catalyst, and 0.12 mL (0.36 mmol) of 3 N NaOH solution was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over sodium sulfate, passed through a small pad of Celite, and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; 2% ethyl acetate in dichloromethane) to afford 36 mg (68% yield) of desired 6-(4-benzyl-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR (containing traces of impurities); LC-MS—calcd for C28H29N3O2 [M++H]+: 440.23, found: 440.2.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH3:16][S:17]([NH:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1)(=[O:19])=[O:18]>CO>[OH:1][CH:3]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:2][N:30]1[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:24]2[CH:33]=[CH:34][C:21]([NH:20][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:22][CH:23]=2)[CH2:28][CH2:29]1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCNCC2)cc1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CC(O)COc3cccc4ccccc34)CC2)cc1
Temperature: 25 °C

Procedure:
Add 7.89 g (42.4 mmol) of 1,2-epoxy-3-(1-naphthalenyloxy)propane to a solution of 12.0 9 (42.4 mmol) of 1-[4-[(methylsulfonyl)amino]benzoyl]piperazine in methanol. Heat the resultant solution at reflux for about 46 h. Cool the solution to room temperature and evaporate the solvent. Triturate the residue with ether toobtain crystals of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].[CH3:39][N:40](C)C=O.CN.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH3:39][NH:40][C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18]
Reactant: CN(C)C=O
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.026 g, 0.000049 mol;) was dissolved in N,N-Dimethylformamide (2 mL, 0.03 mol;) and 2.0 M of Methylamine in Tetrahydrofuran (0.2432 mL) and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.024 g, 0.000063 mol;) were added. The reaction was checked after 2 hours and it showed that both product and starting material were present. The reaction was pushed by further addition of methylamine and HATU, but the reaction could not be pushed past 60-70 percent completion. The reaction was therefore worked up by concentration then dissolving in methylene chloride and washing 1× with saturated bicarbonate, and 1× with brine before drying with magnesium sulfate and concentration. The crude showed very little starting material left after workup, the acid was most likely removed by the bicarb wash. The crude was dissolved in DMSO and injected onto the Gilson for HPLC purification to give the pure product at 1.20 548.54. ES (+) MS m/e=548.54; NMR (400 MHz, DMSO-d6) δ ppm 2.55 (s, 3H), 2.78 (d, 2H, J=7 Hz), 5.22 (m, 2H), 6.66 (t, 1H, J=8 Hz), 6.97 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.25 (d, 1H), 11.97 (s, 1H)
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.CN(CCN(C)C)C.[O:34]=[CH:35][C@@H:36]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:37]>C1COCC1>[C:41]([O:40][C:39]([NH:38][CH:36]([CH3:37])[CH:35]([C:12]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1)[OH:34])=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(O)C(C)NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of LDA (prepared by adding n-BuLi (27.7 mL, 55.5 mmol) to diisopropylamine (8.04 mL, 57.3 mmol) in THF (40 mL) at 0° C., stir for 30 min) was added 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4500 mg, 18.5 mmol) in TMEDA (16.6 mL, 111 mmol) dropwise via syringe pump at −78° C. for 20 min. The mixture was stirred at the same temperature for 30 min, and (S)-tert-butyl (1-oxopropan-2-yl)carbamate (9931 mg, 57.3 mmol) in THF (20 mL) was added slowly by syringe pump for 20 min. The mixture was stirred at −78° C. for 30 min, and quenched with saturated NH4Cl at −78° C., warmed up to rt and diluted with EtOAc (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by column chromatography (MeOH/DCM, gradient 0-10%) to afford the title compound. LC/MS: [(M+1)]+=417
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[C:4]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[CH:14][CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl.CCOC(C)=O>[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]3[C:10](=[O:20])[N:11]([CH3:19])[C:12]4[C:17]([CH:18]=3)=[CH:16][N:15]=[CH:14][CH:13]=4)[C:3]=2[Cl:21])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc(N)c2Cl)cc2cnccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(=O)c(-c2c(Cl)ccc(NC(=O)c3ccc(CCl)cc3)c2Cl)cc2cnccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
To a solution of 3-(3-amino-2,6-dichloro-phenyl)-1-methyl-1H-[1,6]-naphthyridin-2-one (30 mg, 0.0937 mmol) in the dichloromethane (7 mL) is added 4-(chloromethyl)benzoyl chloride (53.2 mg, 0.28 mmol). After the mixture is stirred 24 hours at room temperature, it is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column elute with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (NH3, 2N)(95/5%) to give the titled intermediate as a solid (32.4 mg, 73.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH2:21][C:22](OCC)=O)=O)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]2[CH2:21][CH2:22][C:3]3[C:2](=[CH:7][CH:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=3)[NH:1]2)=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Product: COC(=O)Cc1ccc2c(c1)CCC(c1ccc(OC)cc1)N2

Procedure:
Using methyl p-aminophenylacetate and ethyl p-methoxybenzoylacetate as starting raw materials, treatment was made similarly to Example 1 to obtain aimed product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][OH:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH:30]=[O:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(C=O)nccc4o3)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 25 mg, 58 μmol) in CH2Cl2 was added Dess-Martin periodinane (32 mg, 75 μmol). After 3 h at 20° C., the mixture was diluted with MeOH, adsorbed onto SiO2 and purified by column chromatography to furnish the title compound: RT=3.27 min; m/z (ES+)=429.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[O:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17]C(O)=O>O1CCCC1>[O:12]=[C:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:9]([NH2:8])=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)CCCCC(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)CCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Oxalyl chloride (0.508 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of 6-oxo-6-phenylhexanoic acid (1.00 g) in tetrahydrofuran (15 ml) at room temperature, which was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate (25 ml) and added dropwise to a stirred mixture of 25% aqueous ammonia (20 ml) and ethyl acetate (25 ml) at 0° C. After stirring at room temperature for 2 hours, water (200 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 6-oxo-6-phenylhexanamide (885 mg, yield 89%) as colorless crystals. m.p. 113-114° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)=[C:19]([CH:22]=1)[C:20]#[N:21]>>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[CH:16]=[CH:17][C:18]=1[N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)#[N:21]
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Reactant: O=C(O)c1ccc2ccccc2c1
Product: N#Cc1cc(NC(=O)c2ccc3ccccc3c2)ccc1N1CCC(O)CC1
Yield: 67.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using naphthalene-2-carboxylic acid (0.44 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (0.5 g), the title compound (0.58 g) was obtained. melting point: 183-185° C.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C@H:3]1[N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:5](=[O:11])[O:4]1.[Li+].CC([N-]C(C)C)C.CCCCCC.C1C[O:31][CH2:30]C1>>[O:11]=[C:5]1[O:4][C@@H:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[N:7]2[CH2:8][CH2:9][CH2:10][C@:6]12[CH:30]=[O:31]
Reactant: O=C1O[C@@H](C(Cl)(Cl)Cl)N2CCC[C@H]12
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: O=C[C@]12CCCN1[C@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37 %

Procedure:
To reactant 155a (4.8 g, 19.8 mmol) suspended in anhydrous THF (100 mL) at −78° C., was added 2.0 M LDA in Hexane (14.9 mL, 29.7 mmol) over 20 min period. The mixture was stirred at −78° C. for 45 min, then let it warm up to 0° C. over 3 hour. Reaction was monitored by TLC. After completion, the reaction was quenched by adding aq. 10% citric acid slowly. It was extracted with EtOAc twice, washed with brine. The organic layer was dried through (Na2SO4), and concentrated; the residue was purified by CombiFlash using EtOAC/Hexane as eluents to give (3S,7aS)-1-oxo-3-(trichloromethyl)hexahydropyrrolo-[1,2-c]oxazole-7a-carbaldehyde 155b 1.99 g, 37%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:26])[C:24]#[CH:25]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:26][CH2:23][C:24]#[CH:25])=[O:12])[CH2:8]1
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A mixture of 4.85 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of anhydrous potassium carbonate in 20 ml of tetrahydrofuran was stirred while 1.1 g (0.02 mole) of 2-propynylamine was added dropwise from a needle and syringe. After stirring for 30 min, a small piece of ice was added and stirring continued for 17 hr. The reaction mixture was diluted with 200 ml of water then extracted with 3×50 ml of methylene chloride. The combined extracts were dried by passing through Whatman phase separating paper then concentrated in vacuo to an oily residue (3.73 g). This residue was dissolved in 30 ml of methylene chloride and chromatographed in three portions (3 runs) on a spinning TLC plate (chromatotron) with an ethyl acetate-methylene chloride gradient from 10%-100% ethyl acetate. A white solid (1.8 g) was obtained on concentration of the product fractions. Recrystallization from isopropyl ether yielded 0.93 g (17.9%) of white crystalline product, m.p. 121°-123° C.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][C:17]1([CH2:21][CH2:22][CH3:23])[CH2:20][O:19][CH2:18]1)(=O)=O.O>CN(C)C=O>[CH2:1]([S:8][CH2:20][C:17]([CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:21][CH2:22][CH3:23])[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC1(COS(C)(=O)=O)COC1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CO)(CSCc1ccccc1)CSCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzyl mercaptan (25.0 ml) in dry dimethylformamide (100 ml) was stirred at 0° C., under a current of nitrogen. Sodium hydride (6.0 g., 80% dispersion in oil) was added carefully and the mixture was stirred at 0° for 1 hour. 3-n-Propyloxetan-3-ylmethyl methanesulphonate (10.0 g.) was added and the mixture was stirred at 0° C. for 1 hour. The mixture was refluxed with stirring for 6 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica, eluting with 1:4; diethyl ether:hexane. 2,2-Di-(benzylthiomethyl)pentan-1-ol was obtained as a pale yellow oil (15.6 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH:15]([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH:15]([CH3:17])[CH3:16])[C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC(C)I
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (400 mg, 2.00 mmol) and 2-iodopropane (375 mg, 2.20 mmol) in acetonitrile (7 mL) was added Cs2CO3 (1.31 g, 4.01 mmol). The reaction mixture was stirred at 90° C. for 2 h, filtered and concentrated. Purification via MDAP afforded the title product (40 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Temperature: 150 °C
Yield: 81.2 %

Procedure:
The following reaction was split into two batches with half the amounts: methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (D19) (1.5 g, 4.85 mmol), phenylboronic acid (1.183 g, 9.70 mmol), potassium carbonate (2.011 g, 14.55 mmol) and palladium tetrakistriphenylphosphine(0) (0.561 g, 0.485 mmol) were dissolved in DMF (24 ml) and the mixture heated in the microwave for 30 min at 150° C. The two reactions were combined and diluted with ethyl acetate (50 mL) and the mixture filtered through kieselguhr to remove palladium residues. The filtrate was concentrated in vacuo to reduce the amount of DMF and then the residue partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic phase was washed with further sodium bicarbonate (50 mL) and then water (50 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The brown solid was purified by silica chromatography, eluting with 0-25% EtOAc in iso-hexane over 35 minutes to give the title compound as a white solid (935 mg, 3.94 mmol). δH (d6-DMSO, 400 MHz): 8.42 (1H, d), 8.29 (1H, dd), 7.81 (1H, d), 7.65 (2H, m), 7.60-7.50 (3H, m), 3.92 (3H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH2:11][CH2:10]2)(=[O:6])=[O:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.[Cl-].[Na+].O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[C:34]([N:12]3[C:13]4[C:9](=[CH:8][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=4)[CH2:10][CH2:11]3)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a suspension of sodium hydride (0.25 g, 2 eq) in 10 mL of DMF, was added 5-methanesulfonyl-2,3-dihydro-1H-indole (0.63 g, 1 eq). The mixture was stirred at room temperature for 10 minutes then 3a (1 g, 3.19 mmol) was added. The resulting mixture was heated up to 80° C. for 18 h. The reaction mixture was then allowed to cool down to room temperature and brine (200 mL) was added. The solution was extracted with DCM twice (200 mL then 50 mL). The combined extracts were washed with brine (2×50 mL), dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil which was purified by column chromatography (elution with 10-100% ethyl acetate and 0.1% TEA in hexanes) to give 0.61 g of 4a (40% yield), LCMS 475.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:27]=[CH:28][C:22]=1[F:21]
Reactant: CC1(C)OB(c2ccc(F)c(N)c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)c(N)c3)ccn2c1=O
Yield: 102.8 %

Procedure:
Methyl 8-(3-amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (122 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (128 mg, 98%). ESI-MS m/z: 367 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][C:8]=2[S:7][C:6]1=[NH:13])[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](O)=[O:21].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][C:8]=2[S:7]/[C:6]/1=[N:13]\[C:20](=[O:21])[C:19]1[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2c(sc1=N)COC2
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)COC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of Example 17A (220 mg, 0.56 mmol) in tetrahydrofuran (10 mL) were added 5-chloro-2-methoxybenzoic acid (114 mg, 0.61 mmol, Aldrich), 1-hydroxybenzotriazole (93 mg, 0.61 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (117 mg, 0.61 mmol) and triethylamine (0.23 mL, 1.7 mmol, Aldrich). The reaction mixture was stirred at 80° C. for 2 h, then cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-100% EtOAc in hexanes) to afford 60 mg (30%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3H), 1.33 (t, 2H), 1.74 (t, 2H), 3.80 (s, 3H), 4.10 (t, J=7.3 Hz, 2H), 4.87-5.08 (m, J=1.7 Hz, 4H), 7.13 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.8, 3.1 Hz, 1H), 7.75 (d, J=3.1 Hz, 1H); MS (ESI+) m/z 367 (M+H)+; Anal. Calculated C17H19ClN2O3S: C, 55.66; H, 5.22; N, 7.64. Found: C, 55.46; H, 5.03; N, 7.74.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[CH2:12]([O:15]CC=C(C)CCC=C(C)C)[CH:13]=C>>[C:12]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:15])[CH3:13]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: C=CCOCC=C(C)CCC=C(C)C
Product: CC(=O)OC/C=C(\C)CCC=C(C)C

Procedure:
A reaction was performed by the procedure of Example 1, except for using geraniol instead of 1-octanol. The reaction mixture was analyzed by gas chromatography to find that 1-allyloxy-3,7-dimethyl-octa-2,6-diene and geranyl acetate were formed in yields of 85% and 1%, respectively.