Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[NH:10]/[C:9](=[N:11]/[NH2:12])/[CH2:8][O:7][C:6]=2[N:13]=1.C(O[C:23](OCC)(OCC)[CH2:24][CH3:25])C>>[Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]3[C:23]([CH2:24][CH3:25])=[N:12][N:11]=[C:9]3[CH2:8][O:7][C:6]=2[N:13]=1
Reactant: N/N=C1\COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2n1-c1cc(-c3ccccc3)c(Br)nc1OC2
Temperature: 120 °C
Yield: 40 %

Procedure:
In a 10 ml microwave vial was (E)-6-bromo-2-hydrazono-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (90 mg, 0.282 mmol) in 1,1,1-triethoxypropane to give a yellow suspension. The reaction mixture was heated to 120° C. for 20 minutes. The crude residue was concentrated under reduced pressure and purified by Biotage silica gel chromatography (gradient 100% to 100% n-hexane in ethyl acetate) to give the title compound (41 mg, 40%). 1H NMR (500 MHz, CDCl3): 7.73 (1H, s), 7.54-7.48 (3H, m), 7.45-7.41 (2H, m), 5.56 (2H, s), 3.10-3.00 (2H, q), 1.53-1.48 (3H, t). LCMS (Method D) RT 1.117 min, M+1=358.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[NH:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN1C(=O)c2cc(F)ccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2cc(F)ccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 142.8 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-fluoro-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.27 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.135 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.3 g); mp 180-205° C. (d); MS: m/z=533(M+1); NMR(CD3SOCD3): 1.73 (m,4), 2.17 (broad,2), 2.5 (broad,2), 2.74 (broad,1), 3.49 (m,5),3.69 (m,1), 4.36 (m,1), 4.86 (d,1, J=3.3), 6.75 (d,1, J=8.2) 7.07 (s,1), 7.35 (m,3), 7.92 (m,1). Analysis for C27H31Cl2N4O4F.2.0 HCl: Calculated: C, 53.48; H, 5.49, N, 9.24; Found: C, 53.15; H, 5.53; N, 9.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.CCN(C(C)C)C(C)C.CN(C(O[N:40]1N=[N:47][C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=NC=1CN>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:47][CH2:42][C:41]2[N:40]=[CH:43][CH:44]=[CH:45][N:46]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ncccn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 15.8 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (300 mg, 0.88 mmol), DIEA (0.5 mL, 2.88 mmol) were dissolved in 30 mL of THF, HATU (405 mg, 1.06 mmol) and pyrimidin-2-ylmethylamine (115 mg, 1.06 mmol) were added under ice-water-bath, reacted at room temperature overnight, to the reaction solution was added 100 mL of water, then extracted with dichloromethane, dried with anhydrous sodium sulfate, dried by rotation, then solid was separated with silica gel column (dichloromethane:methanol=40:1) to obtain a white solid 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide 60 mg, yield 16%.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:29][NH:30]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[C:29]([CH:15]([C:4]3[C:3](=[O:7])[C:2]([CH3:1])([C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[C:5]=3[OH:6])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:30]2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Reactant: CC(=O)NCc1c[nH]c2cc(Cl)ccc12
Product: CC(=O)NCc1c(C(C2=C(O)C(C)(c3ccc(C)cc3)C2=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and N-(6-chloro-1H-indol-3-ylmethyl)-acetamide (prepared from C-(6-chloro-1H-indol-3-yl)-methylamine by acylation according to Example 1.2) to give the title compound as an off-white solid. MS: 497.3 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>N1C=CC=CC=1.C(Cl)Cl>[CH2:12]([O:11][C:9]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
4-Aminopyridine (17.34 grams) (184.3) was dissolved in dry pyridine (217 ml.) and cooled to 0° C. over 30 minutes. Ethyl chloroformate (17.2 ml.) (180.7 mmoles) was added and the solution was stirred at 0° C. for 1 hour and then at 25° C. for 40 hours. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and water. The CH2Cl2 was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2%(10% saturated NH4OH in MeOH)--CH2Cl2 to give the title compound (Yield: 10 grams, 33%, M+ 166).
Reaction SMILES: C=O.N[C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[BH3-][C:22]#[N:23].[Na+].[CH3:25]C(O)=O>CC#N.CCOCC.O>[CH3:25][N:23]([CH3:22])[C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: [BH3-]C#N
Reactant: COc1cc(N)cc(CNC(=O)OC(C)(C)C)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: COc1cc(CNC(=O)OC(C)(C)C)cc(N(C)C)c1
Reaction time: 8 h
Yield: 58 %

Procedure:
CH2O (aq, 37%) (0.12 ml, 0.127 g, 1.56 mmol, 4 eq) was added to a stirred solution of tert-butyl 3-amino-5-methoxybenzylcarbamate (0.0975 g, 0.39 mmol, 1 eq) in 5 ml CH3CN. After 10 min NaBH3CN (0.056 g, 0.897 mmol, 2.3 eq) was added. The reaction was adjusted to pH {tilde over ( )} 7 with HOAc. After stirring overnight the reaction was diluted with Et2O/water and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (×2), water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.0638 g (0.228 mmol, 58% yield) of tert-butyl 3-(dimethylamino)-5-methoxybenzylcarbamate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C#N)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Reaction time: 5 h
Yield: 88.5 %

Procedure:
8.56 g (36.7 mmol) of 2-(3-cyano-phenoxy)-2-methyl-propionic acid ethyl ester was dissolved in 65 ml ethanol; then, 6.5 ml acetic acid was added, followed by 0.9 g Pd—C (10%) and the reaction mixture was hydrogenated under 1 atm of H2-pressure during 5 hours. Then, it was filtered (Celite), the filter cake was washed twice with ethanol and the solvents were evaporated. The residue was partitioned between crashed ice/1N NaOH/EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 7.71 g of the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[CH3:29]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: Cc1cc(B(O)O)ccc1F
Product: Cc1cc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)ccc1F

Procedure:
The title compound, white solid (76 mg, 91%), MS (ISP) m/z=334.5 [(M+H)+], mp 223.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:45])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46](Cl)(=[O:56])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([O:8][N:9]([C:16](=[O:45])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:46](=[O:56])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Yield: 80 %

Procedure:
Compound (8) (1.20 g, 1.95 mmol) was reacted with decanoyl chloride (0,565 g, 2.96 mmol) in CH2Cl2 and 1N NaOH following the procedure used for (3). Purification by silica gel column chromatography with 2:1 EtOAc/hexane as the eluant provided 1.20 g (80%) of (10) as an oil: NMR δ 0.90 (t, 3 H, J=6), 1.13-1.40 (m, 14 H), 1.47-1.90 (m, 12 H), 2.23-2.53 (m, 8 H), 3.50-3.77 (m, 6 H), 4.77 (s, 6 H), 7.33 (s, 15 H). Anal. (C46H64N4O6) C, H, N.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>C(Cl)Cl>[OH:22][CH:21]([CH2:23][N:34]1[CH2:33][CH2:32][N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[OH:24])[CH2:36][CH2:35]1)[CH2:20][N:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[N:9]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC2CO2)C1
Reactant: Oc1ccccc1N1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC(O)CN2CCN(c3ccccc3O)CC2)C1
Reaction time: 72 h

Procedure:
1-[3-(4-Iodo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (62 mg, 0.15 mmol) and 4-(2-hydroxyphenyl)-piperazine (34 mg, 0.19 mmol) were combined in CH2Cl2 (0.5 mL) and the solution treated with Yb(OTf)3.H2O (44 mg, 0.071 mmol). The mixture was shaken for 72 h then diluted with CH2Cl2 (1 mL). Purification by preparative TLC (silica, 10% MeOH/CH2Cl2) grave 45 mg (51%) of an off-white powder. TLC (silica, 8% MeOH/CH2Cl2): Rf=0.2. MS (electrospray): m/z calculated for C27H33IN5O3 [M+H]+ 602.15, found 602.2. 1H NMR (CDCl3, 500 MHz, a mixture of amide rotamers): 7.76 (d, J=8.6 Hz,1H), 7.72 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.14 (m, 1H), 7.80 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.86 (t, J=7.7 Hz, 1H), 4.83 and 4.72 (A and B of AB quartet, Jab=15.6 Hz, 1H), 4.61 (s, 1H), 4.22-4.15 (m, 2H), 4.02 (m, 2H), 3.88 (m, 1H), 3.76 (m, 3H), 3.00-2.49 (m, 11H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]#[N:15])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]N1C(=O)CCC1=O>O1CCOCC1>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]#[N:15])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[CH3:25])=[C:19]([Cl:26])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)c1ccc(-c2nc(Cl)c(CC#N)n2Cc2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2nc(Cl)c(CC#N)n2Cc2ccccc2)cc1Cl
Yield: 63.7 %

Procedure:
2 g of 1-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylaminophenyl)imidazole and 1 g of N-chlorosuccinimide were stirred in 30 ml of dioxane at 50° C. for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 100 ml of chloroform, followed by washing twice with water and evaporating to dryness under reduced pressure. The residue was recrystallized twice from 20 ml of methanol, thus yielding 1.4 g of 1-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylamino-3-chlorophenyl)imidazole as slightly yellow, needle-formed crystals, m.p. 142°-143° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OS(=O)(=O)C(F)(F)F)C1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
To 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2.0 g, 6.7 mmol) in CH2Cl2 (34 mL) at 0° C. was added Et3N (0.74 g, 1.0 mL, 7.3 mmol) and Tf2O (2.0 g, 7.0 mmol). After warming to rt, H2O was added and the mixture extracted with CH2Cl2 (2×). The combined organics were dried. Silica gel chromatography (5-25%) gave 1.12 g (39%) of the title compound as a white solid. 1H NMR (CDCl3): 7.20 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 4.95-4.91 (m, 1H), 4.34 (ddd, J=10.0, 6.4, 1.0 Hz, 2H), 4.08-4.04 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:23])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12](=[O:22])[N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])=[CH:7]2.C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:32]([O:31][C:29]([CH:28]1[C:27](=[O:26])[C:3]2[C:2](=[C:11]3[C:6](=[CH:5][C:4]=2[F:23])[CH:7]=[C:8]([C:12](=[O:22])[N:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:14])[CH:9]=[N:10]3)[N:1]=[CH:34]1)=[O:30])[CH3:33]
Reactant: CN(Cc1ccccc1)C(=O)c1cnc2c(N)cc(F)cc2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2c(c(F)cc3cc(C(=O)N(C)Cc4ccccc4)cnc23)C1=O
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 2, in the section relating to the preparation of starting materials, 8-amino-3-[N-benzyl-N-methylcarbamoyl]-6-fluoroquinoline was reacted with diethyl ethoxymethylenemalonate, and then refluxed in diphenyl ether. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 3-ethoxycarbonyl-8-(N-benzyl-N-methylcarbamoyl)-5-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline in 70% yield, mp 201-203° C.
Reaction SMILES: C([C:3](C=C)=[O:4])C.[CH2:7]=O.[C:9]1([CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[OH:10]>O1CCOCC1>[CH2:16]([C:15]([CH3:7])([CH2:13][OH:14])[CH2:3][OH:4])[CH3:9].[CH3:16][CH:9]([OH:10])[CH2:11][CH2:12][CH3:13]
Reactant: C=O
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(=O)CC
Solvent: C1COCCO1
Product: CCC(C)(CO)CO
Product: CCCC(C)O
Reaction time: 2 h
Yield: 55.9 %
Yield: 34 %

Procedure:
126 g of α-ethylacrolein, 300 g of a 30% strength aqueous solution of formaldehyde, 1 g of hydroquinone and 350 g of 1,4-dioxane were combined at 25° C to give a solution. After about 2 hours, 120 g of this solution, which had a pH value of 2-3, were hydrogenated as in Example 1. Analysis of the hydrogenated product gave 55.9% of 2-ethyl-2-methylpropane-1,3-diol and 34% of methylbutanol, relative to the α-ethylacrolein employed.
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[O:14]([CH2:13][C:10]1[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: Brc1ccc(COc2ccccc2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(COc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
To a diethyl ether (250 mL) solution of 5-bromo-2-phenoxymethyl-pyridine (4.40 g, 16.6 mmol) described in Manufacturing Example 54-1-3 was added n-butyl lithium (2.55 M n-hexane solution, 8.46 mL, 21.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 40 minutes at −78° C. N,N-dimethylformamide (1.93 mL, 25.0 mmol) was then added dropwise thereto and stirred for 20 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (1.00 g, 28.3%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[OH:36][CH2:37][CH:38]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:38][CH2:37][OH:36])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CCO)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), and hydroxy-acetaldehyde according to the procedure in Example 21. 1H-NMR (400 MHz, CD3OD): δ 8.18 (d, 1H), 8.02 (s, 1H), 7.22 (dd, 1H), 7.14 (d, 2H), 5.82 (m, 1H), 3.94 (m, 2H), 3.74 (m, 2H), 3.30 (m, 2H), 3.18 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H), 2.20-1.98 (m, 4H), 1.96-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H29N5O2, 420.2 (M+H), found 420.2.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:16])[CH3:15])[OH:4])#[CH:2].I[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:16])[CH3:15])[C:1]#[C:2][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCS2
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Yield: 68.2 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.4 g (6 mmol) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol with 1.6 g (6 mmol) of methyl 4-iodobenzoate, 1.5 g (68%) of the expected ester was obtained in the form of an orange-colored oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,5-difluorophenyl)methanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH:14]1([CH:20]=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH:20]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=3[S:9](=[O:10])(=[O:11])[NH:12]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CC1CCCCC1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Product: N#Cc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
5-Cyano-2-aminobenzenesulfonamide (see compound 37) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 234-237.
Reaction SMILES: [I:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[I-:1].[CH2:2]([P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCC/C=C\CCI
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCC/C=C\CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Temperature: 90 °C
Yield: 100.4 %

Procedure:
A mixture of 0.43 g (1.46 mmoles) of (Z)-1-iodo-3-dodecene and 0.38 g (1.45 mmoles) of triphenylphosphine was heated at 90° C. for 3 hrs. under argon to produce 0.81 g of [(Z)-3-dodecen-1-yl]triphenylphosphonium iodide. This material was used without further purification.