Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(Cc4ccc(F)cc4F)C3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol), 2,4-difluorobenzaldehyde (64 μL, 0.59 mmol) and 4 Å molecular sieves in chloroform (7 mL) was heated to reflux for 3.5 hours. After cooling sodium triacetoxyborohydride (0.50 g, 2.36 mmol) was added and the mixture was stirred at RT overnight. Aqueous saturated sodium bicarbonate solution was added and the phases were separated. The aqueous phase was extracted with 10% MeOH/DCM (×4) and the combined organic phase was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 50-100% EtOAc in cyclohexane) to give 372 (122 mg, 50%). LCMS: RT=8.65 min, [M+H]+=494. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=2.33 Hz), 7.90 (1 H, s), 7.33 (1 H, q, J=7.71 Hz), 7.14 (1 H, dd, J=8.27, 2.33 Hz), 7.01 (1 H, d, J=8.26 Hz), 6.86-6.74 (2 H, m), 5.94-5.84 (1 H, m), 4.37 (2 H, t, J=5.06 Hz), 3.83-3.73 (3 H, m), 3.68 (2 H, s), 3.39 (2 H, t, J=5.07 Hz), 3.29-3.23 (2 H, m), 1.61 (6 H, d, J=6.65 Hz)
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12].[H-].[Na+].[CH3:17]I>O1CCCC1>[CH3:17][O:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc2ccccc2n1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccccc2n1OC
Temperature: 25 °C
Yield: 76.5 %

Procedure:
In a nitrogen flow 0.56 g (2.93 mmol) of methyl 1-hydroxy-2-indolecarboxylate was added to a suspension of 0.12 g (2.93 mmol) of 60% sodium hydride in 20 ml of tetrahydrofuran at room temperature. After it was confirmed that the reaction mixture became transparent, 0.83 g (5.86 mmol) of methyl iodide was added to the reaction mixture. The mixture was then refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice water followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.46 g (76.5%) of methyl 1-methoxy-2-indolecarboxylate.
Reaction SMILES: C([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH2:8][C:9]#[N:10])C.[CH:12](O)=[O:13].[OH-].[K+].O>C(O)C>[C:9]([CH2:8][CH2:7][N:6]([CH:12]=[O:13])[CH2:5][C:4]([OH:3])=[O:11])#[N:10]
Reactant: CCOC(=O)CNCCC#N
Reactant: O=CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CCCN(C=O)CC(=O)O
Temperature: 0 °C

Procedure:
A mixture of 21.0 g of N-(2-cyanoethyl)-glycine ethyl ester and 18.3 g of formic acid is refluxed for 2 h. After concentration of this mixture underreduced pressure, the residue is taken up in 50 ml of ethanol, and cooled to 0° C.; there is then added dropwise a solution of 25.5 g of potassium hydroxide and 40 ml of water in 80 ml of ethanol. After the reaction solution has warmed up to room temperature, the solvent is evaporated off, and the residue is acidified to pH 1 with conc. hydrochloric acid. The mixture is saturated with sodium chloride and subsequently extracted with ethyl acetate. The combined organic extracts are concentrated by evaporation to thus obtain N-(2-cyanoethyl)-N-formylglycine, m.p. 112°-114° C. (compound No. 1.1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14].COC(OC)N(C)C.CN(C)C=O.C(OCC)(=O)C>>[Br:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[O:8][CH:9]=[CH:12]2
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])c(Br)ccc12
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A pressure tube (150 mL) was charged with methyl 4-bromo-2-methyl-3-nitrobenzoate (2.1 g, 0.0077 mol), 1,1-dimethoxy-N,N-dimethylmethanamine (3.6 mL, 0.027 mol) and N,N-dimethylformamide (5 mL, 0.06 mol). The mixture was heated at 120° C. for 20 hours the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL, 1 mol). Silica Gel (20 g, 0.3 mol) was then added and the reaction was stirred at room temperature for 12 h. The reaction was filtered and the solvent was removed and the residue was purified by flash chromatography to afford the desired product. MS m/z=271.2 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([NH:12][C@H:13]([C:18]([OH:20])=O)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:35]1([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][N:47]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:48][C@H:49]([OH:59])[C@@H:50]([NH2:58])[CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[N:35]1([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][N:47]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:48][C@H:49]([OH:59])[C@@H:50]([NH:58][C:18](=[O:20])[C@H:13]([C:14]([CH3:15])([CH3:16])[CH3:17])[NH:12][C:10]([O:9][CH3:8])=[O:11])[CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(N2CCCC2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(N2CCCC2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
12.3 ml (88 mmol) of triethylamine are added to a solution of 3.3 g (17.6 mmol) of N-methoxycarbonyl-(L)-tert-leucine, 6.7 g (35.2 mmol) of EDC and 4.8 g (35.2 mmol) of HOBT in 90 ml of DMF (degassed under vacuum) and the whole is stirred at RT for 20 min. After that, 4 g (8.8 mmol) of 1-[p-(pyrrolidin-1-yl)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 8d), dissolved in 20 ml of DMF, are added and the mixture is stirred at RT for 16 h. The reaction mixture is concentrated by evaporation and the residue is taken up in ethyl acetate/water. The organic phase is separated off and subsequently washed consecutively with water, 5% sodium bicarbonate solution (twice), water, dilute brine and brine, with the title compound thereby being obtained. The solvent is removed and the residue is recrystallized from ether in an ice bath, with the title compound thereby being obtained.
Reaction SMILES: [OH:1][CH:2]([C:29]([F:32])([F:31])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[H-].[K+].C1(C)C=CC(S(O[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=O)=O)=CC=1.O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:45]([O:1][CH:2]([C:29]([F:31])([F:32])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:10][CH:11]=1)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(O)C(F)(F)F)cc2)nc1
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(OCCCCCCCC)C(F)(F)F)cc2)nc1
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
1.1 g (2.5 mmol) of (-)-2-(4-(4-hydroxy-5,5,5-trifluoro-1-pentyl)phenyl)-5-decyloxypyrimidine was dissolved in 10 ml of tetrahydrofuran. This solution was added with 0.12 g (3 mmol) of potassium hydride, stirred at 10°-20° C. for 20 minutes, further added with 0.85 g (3 mmol) of octyl p-toluenesulfonate and reacted at 20°-30° C. for 2 hours. The reaction mixture was poured into 100 ml of water and 100 ml of toluene, and the toluene layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 0.80 g of (-)-2-(4-(4-octyloxy-5,5,5-trifluoro-1-pentyl)phenyl)-5-decyloxypyrimidine
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[CH:8][CH:9]=[C:10]([C:16]([O:18]C)=[O:17])[C:11]([C:12]([O:14]C)=[O:13])=[C:6]2[N:5]=[C:4]1[CH3:20])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([N:3]1[C:7]2=[CH:8][CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]([C:12]([OH:14])=[O:13])=[C:6]2[N:5]=[C:4]1[CH3:20])[CH3:2]
Reactant: CCn1c(C)nc2c(C(=O)OC)c(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(C)nc2c(C(=O)O)c(C(=O)O)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A mixture of dimethyl 1-ethyl-2-methyl-4,5-benzimidazoledicarboxylate (5.30 g, 19.2 mmol), methanol and 5N sodium hydroxide (30 mL, I50 mmol) is stirred for 4 hours at 100° C., cooled, acidified with hydrochloric acid and filtered to give the title product as a lemon yellow powder (4.07 g, 85.5%), identified by 1HNMR spectral analysis.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC(O)=O.C([BH3-])#N.[Na+]>O.C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: C1CN(C2CCC3(CC2)OCCO3)CCO1
Reaction time: 2.5 h

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-one (10.0 g, 64.0 mmol), morpholine (20 mL) and AcOH (1.0 mL) was stirred for 2.5 h. Sodium cyanoborohydride (8.05 g, 128.0 mmol) was then added in one portion followed by more morpholine (15 mL). An exothermic reaction occurred and the mixture was cooled for 2 min with an ice-bath. Then the mixture was stirred at room temperature for 16 h. Ethanol (120 mL) and water (28 mL) were added to the resulting thick slurry and the white solid filtered, washed with ethanol (2×) and the filtrate concentrated. Ethyl acetate was then added, the precipitate filtered off, washed with ethyl acetate and the filtrate concentrated. The residual oil was purified by Kugelrohr distillation to give 1 (9.03 g, 62%; b.p.140° C./0.05 mmHg) as a clear oil which solidifies on standing.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C@:34]([OH:49])([C@H:41]([S:43][CH:44]([CH2:47]O)[CH2:45][OH:46])[CH3:42])[CH2:35][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.ClCCl>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C@@:34]([OH:49])([CH2:35][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1)[C@H:41]([S:43][C@@H:44]1[CH2:45][O:46][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])=[CH:12][CH:11]=3)=[O:8])=[CH:24][CH:25]=2)[O:2][CH2:47]1)[CH3:42]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(OCC(F)(F)C(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Molecular sieve 4A (3 g) was added to a mixture of 4-formyl-4′-(2,2,3,3-tetrafluoropropoxy)benzanilide (300 mg, 0.84 mmol) obtained in example 1 (1), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (disclosed in Japanese Patent Application Publication No. Hei-8-333350; 253 mg, 0.70 mmol), p-toluenesulfonic acid monohydrate (160 mg, 0.84 mmol) in anhydrous tetrahydrofuran (10 ml) and anhydrous dichloromethane (5 ml). The resulting mixture was stirred at room temperature for two days. Aqueous sodium hydrogencarbonate solution was added to the reaction mixture at 0° C., and the mixture was filtered to remove the molecular sieve. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting oily residue was chromatographed on a silica gel column using ethyl acetate-hexane (2:1) as the eluant to afford the trans isomer of the title compound (87 mg, yield 18%) as a white solid and then using ethyl acetate-hexane (4:1) as the eluant to give the cis isomer (55 mg, yield 11%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-isopropyl ether to give white powdery crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17].CCO.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.CC(O)=O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:16]([NH2:17])=[CH:15][C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of Et2O (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25 g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(N)c1ccc(Br)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NS(C)(=O)=O)c1ccc(Br)cc1F
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To 1-(4-bromo-2-fluoro-phenyl)-1-methyl-ethylamine (1.2 g, 5.4 mmol) and triethylamine (900 μL, 6.5 mmol) in dichloromethane (10 mL) at room temperature was added methanesulfonyl chloride (500 μL, 6.5 mmol). The solution was stirred 16 h, diluted in 1N HCl(aq) and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to an off-white solid. Flash chromatography (SiO2, 40% ethyl acetate/hexane) gave a white solid (950 mg, 57%). 1H NMR (300 MHz, CDCl3): δ ppm 1.76 (s, 6 H) 2.74 (s, 3 H) 4.88 (s, 1 H) 7.24 (d, J=1.51 Hz, 1 H) 7.27-7.30 (m, 2 H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[C:4]([CH3:13])[CH:3]=1.B1(C=C)OB([CH:20]=[CH2:21])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6]1[CH:5]=[C:4]([CH3:13])[CH:3]=[C:2]([CH:20]=[CH2:21])[N:7]=1)[CH3:10]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CCN(CC)c1cc(C)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CCOCC
Product: C=Cc1cc(C)cc(N(CC)CC)n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 29.5 %

Procedure:
To a solution of (6-chloro-4-methyl-pyridin-2-yl)-diethyl-amine (5.35 g, 26.9 mmol) in DME (75 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (6.48 g, 26.9 mmol, prepared according to F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971) followed by 2 M aq. K2CO3 solution (25 mL) is added. The solution is degassed and put under argon before Pd(PPh3)4 (560 mg, 0.485 mmol) is added. The mixture is stirred for 15 h at 80° C. Another portion of Pd(PPh3)4 (560 mg, 0.485 mmol) is added, and stirring is continued for 6 h. The mixture is cooled to rt, diluted with diethyl ether and washed with sat. aq. NaHCO3. The org. extract is dried over MgSO4, filtered and concentrated. The remaining yellow oil is purified by prep. HPLC to give diethyl-(4-methyl-6-vinyl-pyridin-2-yl)-amine (1.51 g) as a colourless oil; LC-MS: tR=0.68 min, [M+1]+=191.05. 1H NMR (CDCl3): δ 1.20 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 3.56 (q, J=7.0 Hz, 4H), 5.32 (dd, J=10.5, 2.3 Hz, 1H), 6.23 (dd, J=17.1, 2.0 Hz, 1H), 6.23 (s, 1H), 6.36 (s, 1H), 6.65 (dd, J=17.3, 10.5 Hz, 1H).
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C(Cl)CCl>[N:20]1([CH2:1][N:11]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: CCCCCCCCNCCCCCCCC
Reactant: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCCN(CCCCCCCC)Cn1cncn1
Reaction time: 15 h

Procedure:
77 g (0.77 mol) of 30% strength formaldehyde solution were added dropwise to 187 g (0.77 mol) of di-n-octylamine and 54 g (0.77 mol) of 1,2,4-triazole in 400 ml of methylene chloride (or ethylene chloride) at such a rate that the temperature rose to 30° to 35° C. After addition of 200 g of anhydrous sodium sulphate, the mixture was stirred at 35° to 40° C. for 10 to 20 hours, the suspension was filtered off and the filtrate was evaporated. Yield 244 g (98%) of a clear pale yellow oil, nD20 : 1.4709. ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:13]2=[O:35].[CH3:36][NH:37][CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:36][N:37]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:13]3=[O:35])[CH:4]=1)[CH3:38]
Reactant: COc1cccc(-c2nc3ccc(-c4cc(C=O)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cccc(-c2nc3ccc(-c4cc(CN(C)C)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 2-[6-(2-fluoro-5-formylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (19 mg, 0.04 mmol) in dichloroethane (2 mL) and acetic acid (0.05 mL) was added dimethylamine (2M in acetonitrile, 0.50 mL, 1.0 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was then added as a solid with stirring at room temperature for 24 h. The solvent was removed in vacuo, the residue partitioned between ethyl acetate and a 1 N NaOH (aq.), the organic layer was washed with brine, dried (MgSO4) and the solvent evaporated. The resulting residue was subjected to preparative HPLC purification to provide 2-[6-(5-dimethylaminomethyl-2-fluorophenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6a) (10 mg, 0.02 mmol, 50%).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:23][C:22]2=[O:36])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[CH:38]=[O:39].O>C1C=CC=CC=1>[OH:39][CH:38]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:36])[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: CC(C)(C)OC(=O)C=O
Reactant: O=C1NC(SCC#Cc2ccc(F)cc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1

Procedure:
3-(Triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (1.02g) and t-butyl glyoxalate (2.76g) were refluxed in dry benzene (50ml) with provision for the removal of water. After 1 hour the benzene solution was washed 5 times with water, dried and evaporated. The residue was chromatographed on silica to give 1-(1-Hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one as an amorphous solid (.969g).
Reaction SMILES: [CH:1]1([C:4]([CH:6]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:7]([CH:9]2[CH2:11][CH2:10]2)=O)=O)[CH2:3][CH2:2]1.O.[NH2:22][NH2:23]>C(O)(=O)C.C(O)C>[CH:1]1([C:4]2[C:6]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[C:7]([CH:9]3[CH2:11][CH2:10]3)[NH:23][N:22]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: N#Cc1ccc(OC(C(=O)C2CC2)C(=O)C2CC2)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccc(Oc2c(C3CC3)n[nH]c2C2CC2)cc1
Temperature: 90 °C
Yield: 91.9 %

Procedure:
The 4-(1-cyclopropanecarbonyl-2-cyclopropyl-2-oxo-ethoxy)-benzonitrile (44 g, 162 mmol) was dissolved in acetic acid (500 ml). A solution of hydrazine hydrate (8.7 ml, 179 mmol) in ethanol (50 ml) was then added at room temperature and the reaction mixture was heated to 90° C. for approximately 3 hours. The solvents were then evaporated under reduced pressure and the residues were partitioned between diethyl ether (600 ml) and dilute aqueous ammonium hydroxide (25 ml concentrated ammonium hydroxide in 500 ml water), and the layers were separated. The aqueous layer was further extracted with diethyl ether (3×200 ml) and the combined organic layers were washed with water (2×50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The solid was slurried in diisopropyl ether (50 ml), filtered and rinsed with diisopropyl ether (2×30 ml) and pentane (2×100 ml) to provide the title compound (39.5 g, 58%) as a colourless solid. 1H-NMR (400 MHz, CDCl3): δ=0.76-0.81 (m, 8H), 1.59-1.65 (m, 2H), 7.01 (d, 2H), 7.60 (d, 2H); LRMS: APCl+: m/z 266 [MH+]; APCl−: m/z 264 [M−H]−.