Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[O:33][C:32]1=[O:43].[Cl:44]C1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O=P(Cl)(Cl)Cl>[Cl:44][C:39]1[CH:38]=[C:37]([C@H:34]2[O:33][C:32](=[O:43])[N:31]([CH2:30][C:21]3[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=3[C:4]3[CH:5]=[C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=4[CH3:19])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C@H:35]2[CH3:36])[CH:42]=[CH:41][N:40]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccncc4)[C@@H]3C)c2)c(C)c1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(Cl)c4)[C@@H]3C)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-2-oxo-5-pyridin-4-yl-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (175 mg, 0.296 mmol) in CH2Cl2 (15 mL) at 0° C. under N2, was added 3-chloroperbenzoic acid (146 mg, 0.593 mmol) as a powder. The mixture was stirred at 0° C. for 15 min. Then it was allowed to warm up to room temperature and stirred for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with satd Na2SO3 (1×) followed by satd K2CO3 (2×). The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue obtained was dissolved in POCl3 (10 mL). The resulting solution was heated at 110° C. under N2 for 2 h. Then it was allowed to warm to room temperature and stirred for 2 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and water (10 mL) and washed with satd NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 2″-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=625.2; found=625.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.40 (s, 0.5H); 8.39 (s, 0.5H); 7.97 (s, 1H); 7.90 (t, J=5.8 Hz, 1H); 7.72 (s, 0.5H); 7.69-7.63 (m, 1.5H); 7.48 (d, J=11.8 Hz, 0.5H); 7.44 (s, 0.5H); 7.43-7.37 (m, 1H); 7.32-7.26 (m, 1H); 7.24 (s, 0.5H); 7.20 (s, 0.5H); 7.16 (d, J=2.2 Hz, 0.5H); 7.14 (d, J=2.2 Hz, 0.5H); 7.12-7.06 (m, 1.5H); 7.05 (d, J=5.1 Hz, 0.5H); 5.42 (d, J=8.1 Hz, 0.5H); 5.18 (d, J=8.1 Hz, 0.5H); 4.92 (dd, J=15.9, 18.5 Hz, 1H); 4.19 (d, J=15.8 Hz, 0.5H); 3.99 (d, J=15.8 Hz, 0.5H); 3.95 (s, 3H); 3.88 (s, 3H); 3.81-3.75 (m, 1H); 2.39 (s, 1.5H); 2.35 (s, 1.5H); 0.60 (d, J=6.5 Hz, 1.5H); 0.49 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: C1N=CN([C:6]([N:8]2[CH:12]=[N:11]C=C2)=[O:7])C=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17]2C(N)=N[N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]=2[CH:15]=1.N1C=CN=C1.[F:48][CH:49]([F:52])[CH2:50][OH:51]>O1CCCC1>[F:48][CH:49]([F:52])[CH2:50][O:51][C:6](=[O:7])[NH:8][C:12]1[C:17]2[CH:18]=[N:19][C:14]([Cl:13])=[CH:15][C:16]=2[N:22]([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=1
Reactant: OCC(F)F
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12)OCC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
CDI (395 mg, 2.434 mmol) was added to a stirred, room temperature mixture of 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (500 mg, 1.217 mmol) 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine and imidazole (331 mg, 4.87 mmol) in tetrahydrofuran (12 mL), and the mixture was stirred at room temperature for overnight. 2,2-Difluoroethanol (0.231 mL, 3.65 mmol) was added to the mixture, and the resultant mixture was kept stirring at room temperature for 2 h before the reaction mixture was heated up to 60° C. for overnight. The mixture was cooled and concentrated, and the residue was loaded directly purified with silica gel column chromatography eluting with EtOAc/isohexane=25%, to give 2,2-difluoroethyl(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (570 mg, 1.098 mmol, 90% yield) as a white solid. MS ESI calc'd. for C28H22ClF2N4O2 [M+H]+ 519. found 519.
Reaction SMILES: [CH:1]1([C:6]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27]CC(O)[CH2:24][CH2:23]1.[Na].C1(C)C=CC=CC=1>CCCCCC.CCOCC>[CH:1]1([C:6]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:12])[C:7]([O:9][CH:10]2[CH2:24][CH2:23][N:22]([CH3:27])[CH2:21][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(O)CC1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Agent: [Na]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)C(O)(C#Cc2ccccc2)C2CCCC2)CC1

Procedure:
The reaction of ethyl α-cyclopentyl-α-phenylethynylglycolate (5.4 g., 0.02 mole), 1-methyl-4-piperidinol (3.5 g., 0.03 mole) and sodium (~0.05 g.) in about 85 ml. of toluene was carried out essentially as described in the preceding preparation. However, no solid precipitated upon the addition of 20°-40° petroleum ether at the end of the reflux period. The reaction mixture therefore was poured on ice and HCl and extracted with ether. The ether extracts were washed with dilute HCl. The washings and water layer were combined, made basic with sodium carbonate, and extracted with chloroform. Drying of the basic extract and subsequent distillation of the volatile compound in vacuo yielded a tarry residue which, when treated with ether and hexane gave 1.5 g. (22%) of crude product. The pure compound, m.p. 104°-105°, was obtained by recrystallization from hexane.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([CH:11]=[C:12]1[NH:17][CH2:16][CH2:15][CH2:14][S:13]1)([O-:10])=[O:9].[Cl:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Cl:18][CH2:19][CH2:20][CH2:21][S:22]([N:17]1[CH2:16][CH2:15][CH2:14][S:13][C:12]1=[CH:11][N+:8]([O-:10])=[O:9])(=[O:24])=[O:23]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 ml of triethylamine was added to a solution of 4.8 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine in 100 ml of dichloromethane at -15° C. under nitrogen. Then a solution of 5.9 g of 3-chloropropylsulfonyl chloride in 50 ml of dichloromethane was added drop-by-drop over 25 minutes. The resulting mixture was allowed to warm to room temperature, stirred for one hour and washed with 2% hydrochloric acid solution. The organic phase was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with methanol to give N-(3-chloropropylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (1A), as a solid, m.p.: 99°-99° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][NH2:21])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)cc(-c3ccccc3)c2c1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Example 1, 2,6-dichloro-4-phenylquinoline is reacted at reflux with hydrazine hydrate to give 6-chloro-4-phenyl-2-hydrazinoquinoline.
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH3:15])[CH:9]=[CH:8][N:7]=1)(=O)C.S(Cl)(Cl)=O.[SH:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C[O-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)[C:11]=1[CH3:12])[CH3:15]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCOc1ccnc(COC(C)=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 18.3 %

Procedure:
10.7 g of 2-acetoxymethyl-3-methyl-4-ethoxy-pyridine was dissolved in chloroform, and 28.2 g (4 eq.) of thionyl chloride was added. The mixture was heated to reflux for one hour and then concentrated, and a residue resulting therefrom was dissolved in methanol. The solution was added in advance to 8.4 g (1 eq.) of 2-mercaptobenzimidazole, 71 mL of a 28% sodium methoxide solution, and 150 mL of methanol, and the mixture was heated to reflux for one hour. Methanol was distilled off, and ice and ethyl acetate were added to the residue, to wash the residue by suspending. Produced crystals were collected by filtration and dissolved in methanol, and the solution was dried over anhydrous magnesium sulfate. Subsequently, the methanol solution was concentrated to dryness, and the resultant was dissolved in chloroform. The chloroform layer was dried over magnesium sulfate and then concentrated to dryness, to obtain an amorphous solid. The solid was washed by suspending in ethyl acetate, to obtain 2.8 g of colorless crystals. Total yield 7.9% (purity by HPLC: 98.2%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)C.CO>[C:1]([O:5][C:6](=[O:9])[NH:7][N:8]1[CH:12]=[CH:16][CH:15]=[CH:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)Nn1cccc1
Temperature: 90 °C
Yield: 43.6 %

Procedure:
A flask (fitted with a Dean-Stark trap) containing a stirred solution of tert-butylcarbazate (100, 0.757 mol), 2,5-dimethoxytetrahydrofuran (108 g, 0.832 mol) and 2N HCl (10 mL) in 1,4-dioxane (700 mL) was heated under nitrogen at 90° C. As the reaction progressed over several hours, the solution changed from pale yellow to orange and began to reflux. The reaction was monitored by the amount of distillate collected in the D/S trap (primarily CH3OH, 2 moles/1 mole reagent). As methanol collection approached the theoretical amount (50 mL) a sample was analyzed by TLC (silica gel, 1:3 EtOAc/hexane, ninhydrin stain) to confirm reaction completion. Heating was shut off and the reaction was allowed to cool somewhat before adding saturated sodium bicarbonate solution (˜25 mL) to neutralize the hydrochloric acid. The quenched mixture was filtered through a sintered-glass funnel and concentrated in vacuo to leave an orange, semi-solid residue. The residue was suspended in diethyl ether (minimum volume) and the nearly colorless solids were collected by suction filtration, washed with hexane and air-dried to afford 60.2 g (40%) of product. A second crop (yellow-tan solids) from the mother liquors was isolated: 29.0 g, (19%). Additional material which was present in the mother liquors could be recovered by silica gel chromatography to increase the yield. 1H-NMR (CD3OD): δ 10.23 (br s, 1H), 6.66 (t, 2H, J=2.2 Hz), 5.94 (t, 2H, J=2.2), 1.42 (s, 9H); MS: GC/MS (+esi): m/z=182.9 [MH]+
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5]C(S(O)(=O)=O)=[CH:3][CH:2]=1.[O:12]([CH3:14])[Na].[CH2:15]([OH:19])[CH2:16][CH2:17][CH3:18]>>[C:1]1([CH:6]=[CH:5][C:14]([OH:12])=[CH:3][CH:2]=1)[OH:19].[CH2:15]([O:19][CH2:5][CH2:6][CH2:1][CH3:11])[CH2:16][CH2:17][CH3:18]
Reactant: CO[Na]
Reactant: CCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCOCCCC
Product: Oc1ccc(O)cc1
Yield: 60 %

Procedure:
100 g of cyclohexene-(1)-dione-(3,6)-tetramethyl ketal were dissolved in 1500 g of n-butanol at 20° C. and the batch was acidified while stirring with 0.005 g of p-toluenesulfonic acid. After about 10 minutes the batch was heated for 30 minutes to 90° C., subsequently neutralized with NaOCH3, the formed methanol and the solvent were completely evaporated under slightly reduced pressure and subsequently the reaction product was submitted to a fractionating distillation. 65.3 g of hydroquinone dibutyl ether having a melting point of 46° C. distilled over under a pressure of 5 mm Hg at a temperature of from 125° to 135° C., which corresponded to a yield of 60% of the theory.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:17][CH2:18][CH3:19])=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][C:13]([O:15][CH3:16])=[O:14].CCN(CC)CC>CO.[Pd]>[CH2:18]([O:17][C:5]1[C:4]([F:20])=[CH:3][CH:2]=[C:10]2[C:6]=1[C:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][N:9]2[CH3:11])[CH3:19]
Reactant: CCOc1c(F)cc(Cl)c2c1c(CC(=O)OC)cn2C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOc1c(F)ccc2c1c(CC(=O)OC)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of 30-11 (1.4 g, 4.7 mmol), Pd/C (280 mg, 20%) and Et3N (1.42 g, 14.1 mmol) in MeOH (20 mL) was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered and the filtrate was concentrated to afford 30-12 (1 g, 92%) as a yellow solid. LRMS: calc 265.1 and found: 266.1 [M+1].
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[C:18]([C:19]([F:22])([F:21])[F:20])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:23]1[N:24]=[C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[NH:26][CH:27]=1>>[N:23]1[N:24]=[C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[C:18]([C:19]([F:22])([F:20])[F:21])=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:31])[NH:26][CH:27]=1
Reactant: FC(F)(F)c1nc2ccccc2nc1N1CC2CNCC2C1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Product: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CN(c3nc4ccccc4nc3C(F)(F)F)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 30 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calcd. for C24H20F4N7O, 479.47; m/z found, 480.2 [M+H]+. 1H NMR (CDCl3): 8.12-7.93 (m, 3H), 7.77 (dd, J=8.5, 0.9 Hz, 1H), 7.69 (ddd, J=8.4, 6.8, 1.4 Hz, 1H), 7.52-7.41 (m, 3H), 7.38-7.34 (m, 1H), 4.01-3.79 (m, 3H), 3.78-3.66 (m, 2H), 3.49 (dd, J=23.0, 15.0 Hz, 2H), 3.16-2.88 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:6]([CH3:8])[N:7]=3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: Cc1nc(Cl)c(C#N)nc1-c1ccccc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 75c, the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was treated with 4-(4-fluoro-phenyl)-piperidine and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 3-[4-(4-fluoro-phenyl)-piperidin-1-yl]-5-methyl-6-phenyl-pyrazine-2-carbonitrile as yellow oil; MS: 373 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])C=C.[CH2:7]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH:8]=[CH2:9].[CH3:15][CH2:16]OCC>>[CH2:7]([C:10]12[CH2:14][CH:13]([CH:15]=[CH:16]1)[CH2:12][CH:11]2[C:1]([O:5][CH3:6])=[O:4])[CH:8]=[CH2:9]
Reactant: C=CC(=O)OC
Reactant: C=CCC1=CC=CC1
Reactant: CCOCC
Product: C=CCC12C=CC(CC1C(=O)OC)C2

Procedure:
137 g of methyl acrylate are added dropwise over 30 minutes to a solution of 170 g of allylcyclopentadiene, prepared in accordance with the procedure of Example 1, in 200 ml of ether. The clear solution is boiled under reflux for 2 hours. The ether is distilled off, and the residue is fractionated in vacuo through a column. At a pressure of 20 mm and in the temperature range from 107° to 115° C., 163 g of methyl allylbicyclo[2.2.1]hept-5-ene-2-carboxylate distill in the form of a faintly yellow liquid; nD20 =1.4863.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]>C1(C)C(C)=CC=CC=1>[Cl-:8].[NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]
Reactant: Nc1ncccn1
Reactant: ClCSc1ccccc1Br
Solvent: Cc1ccccc1C
Product: Nc1nccc[n+]1CSc1ccccc1Br
Product: [Cl-]
Yield: 81.2 %

Procedure:
To a solution of 14.1 g of 2-aminopyrimidine in 180 ml of xylene is added a solution of 24.0 g of o-bromophenyl chloromethyl sulfide in 40 ml of xylene. The mixture is heated at 90°-95° for about 15 hours to give about 27.3 g of the named compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9]S(C(F)(F)F)(=O)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1([CH2:8][O:9][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH:21]=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCCCC1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(COc2cccc(C=O)c2)CCCCC1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of compound iii (0.5 mmol), 3-hydroxy-benzaldehyde (iv, 0.6 mmol) and K2CO3 (0.7 mmol) were dissolved in DMF (3 mL). The solution was heated to 80° C. for 4 hr. The solution was poured into water, extracted with ethyl acetate (10 mL) three times, and concentrated. The residue was purified by chromatography and resulted in 0.22 mmol of 3-(1-methyl-cyclohexylmethoxy)-benzaldehyde (v) with a 44% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCCN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a cold (ca -30° ), stirred solution of 26.5 g (0.1 mole) of t-butoxycarbonylphenylalanine (BOC-Phe) and 11.2 g (0.1 mole) of N-methylmorpholine in 150 ml of dimethylformamide (DMF) was added dropwise 13.2 ml (0.1 mole) of isobutylchloroformate. After warming and then holding the temperature at ca. -15° for about ten minutes, the solution was recooled to ca. -39°. To the cold mixture was added additional N-methylmorpholine (12.3 ml, ca. 0.11 mole), followed by 18.5 g (0.11 mole) of methyl 5-aminopentanoate hydrochloride. The mixture was allowed to warm to room temperature and to stand overnight. Solvent and other volatiles were removed by concentration in vacuo. The residue was triturated with ethyl acetate, which was then washed successively with water, 0.5M potassium bisulfate, water, and again with 0.5M potassium bisulfate, and then dried over magnesium sulfate, filtered, and concentrated to a white solid. After collection, the white solid was washed thoroughly with Skellysolve B to give 36.4 g of the title compound, m.p. 98°-100°. Recrystallization from ethyl acetate/Skellysolve B afforded analytically pure crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2Cl)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:22]>O1CCCC1>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:22][C:21]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:19]([Cl:18])[CH:20]=1)=[O:6]
Reactant: COCNC(=O)c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Solvent: C1CCOC1
Product: COCNC(=O)c1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
4-Chloroquinazoline-6-carboxylic acid methoxymethylamide (XIV-1, 5.78 g) was dissolved in tetrahydrofuran (100 ml), and 5.39 g of 3-chloro-4-(pyridin-2-ylmethoxy)aniline was added, followed by stirring at 60° C. for 1 hour. A precipitate was filtered, and washed with tetrahydrofuran to obtain 4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-quinazoline-6-carboxylic acid methoxymethylamide (XI-2, 7.87 g) as a white solid. The filtrate was allowed to stand at room temperature, and the resulting precipitate was collected by filtration, to newly obtain 2.21 g of XI-2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35]>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccc(F)c(F)c4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo-[1,2-α]pyrimidine (250 mg, 0.62 mmol) and 3,4-difluorobenzeneboronic acid (196 mg, 1.24 mmol) were reacted together as described in Example 61. Purification by column chromatography on silica using 2.5% MeOH/CH2Cl2 gave 3-[2-(3,4-difluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 482 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[O:21])[CH:16]=[N:17][C:18]=1[CH3:19].[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC=CC=1>O>[Cl:12][C:13]1[C:18]([CH3:19])=[N:17][CH:16]=[C:15]([CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[CH:14]=1
Reactant: OCCO
Reactant: Cc1ncc(C=O)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc(C2OCCO2)cc1Cl
Yield: 86 %

Procedure:
p-Toluenesulfonic acid (5.53 mg, 0.032 mmol) was added to a mixture of 5-chloro-6-methyl-3-pyridinecarbaldehyde (for a synthesis see WO20006/137485 A1 Example 256) (250 mg, 1.607 mmol), ethylene glycol (179 μl, 3.21 mmol), and toluene (8 ml) and the mixture was heated under reflux as water was azeotropically removed (Dean-Stark). The progression was monitored by TLC (50% hexane:EtOAc) and HPLC. More ethylene glycol (180 μl) and TsOH (3 mg) were added and after 46 hr full conversion was observed by HPLC. 10% Na2CO3 and EtOAc were added. Extraction, drying (MgSO4), and filtration afforded 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine (274.3 mg, 86%) pure enough to be used in the next step.