Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:20][C:21]([F:27])([F:26])[S:22](O)(=[O:24])=[O:23].N([O-])=O.[Na+]>CN(C)C=O>[F:20][C:21]([F:27])([F:26])[S:22]([C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:24])=[O:23]
Reactant: N#Cc1cccc(-c2nc(N)cc3cccnc23)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2nc(S(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-amino-8-(3-cyanophenyl)-1,7-naphthyridine (4.058 g) in dimethylform-amide (DMF) (22 ml) under argon at 0° C. is added trifluoromethanesulfonic acid (11 ml). The mixture is stirred at 0° C. for 10 minutes and then sodium nitrite (2.26 g) is added slowly. The cooling bath is then removed and the mixture stirred at room temperature for 3 hours. The resulting mixture is diluted with ethyl acetate and washed with water, 2 M NaOH and water again. The organic layer is dried over sodium sulfate, then concentrated in vacuo and purified by column chromatography, eluting with 10:0.5 toluene:acetone to yield the title compound. M.p. 102-104° C. MS (m/e)=380.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[NH:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[F:31][C:32]1[CH:66]=[CH:65][C:35]([C:36](/[N:38]=[C:39]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:37])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:36](/[N:38]=[C:39]2\[NH:1][C:2]3[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[CH:4][C:3]=3[N:18]\2[C@H:19]2[CH2:24][CH2:23][C@@H:22]([C:25](=[O:26])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]2)=[O:37])=[CH:65][CH:66]=1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCOCC3)c(F)cc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cc(F)c(OCCN4CCOCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-4-fluoro-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. The product was isolated as an off-white solid (161 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=8 Hz, 6H) 1.53-1.66 (m, 2H) 1.70-1.80 (m, 2H) 2.00-2.08 (m, 2H) 2.52-2.60 (m, 1H) 2.70-2.91 (m, 8H) 3.49-3.70 (m, 4H) 3.89-4.08 (m, 1H) 4.27 (t, J=6.06 Hz, 2H) 4.93 (br. s., 1H) 7.24 (dd, J=8.85, 8.85 Hz, 2H) 7.38 (d, J=10.76 Hz, 1H) 7.77 (d, J=7.73 Hz, 2H) 8.29 (dd, J=8.61, 5.97 Hz, 2H) 12.73 (s, 1H). M/Z calc'd for C30H37F2N5O4: 569.64. found 570 [M+H].
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][CH:10]=O)[CH:7]=1.C1(P(=[CH:33][CH:34]=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][CH:10]=[CH:33][CH:34]=[O:35])[CH:7]=1
Reactant: C[Si](C)(C)c1cc(CCC=O)co1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(CCC=CC=O)co1

Procedure:
3-(2-Trimethylsilyl-4-furyl)propan-1-al is treated with (triphenylphosphoranylidene) acetaldehyde in tetrahydrofuran to give 5-(2-trimethylsilyl-4-furyl)-pent-2-en-1-al which is hydrogenated in the presence of a palladium catalyst to give 5-(2-trimethylsilyl-4-yl)-pentan-1-al. Treating this intermediate with C9H19COCH2PO)OCH3)2 and sodium hydride in trimethylsilylfuran and oxidizing gives 4-(7-oxo-5-hexadecenyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [NH2:1][C@H:2]1[C@@:7]([OH:9])([CH3:8])[C:6]([CH3:11])([CH3:10])[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]3[N:20]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]=[N:18][N:17]=3)=[CH:15][C:3]1=2.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][N:20]1[C:16]([C:14]2[CH:13]=[CH:12][C:4]3[O:5][C:6]([CH3:10])([CH3:11])[C@:7]([OH:9])([CH3:8])[C@H:2]([NH:1][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=4)[C:3]=3[CH:15]=2)=[N:17][N:18]=[N:19]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](N)[C@](C)(O)C(C)(C)O2
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](Nc1ccnc(SC)n1)[C@](C)(O)C(C)(C)O2
Temperature: 120 °C

Procedure:
A mixture containing (3S,4R)-4-amino-3,4-dihydro-6-(1-[3-ethoxycarbonylprop-1-yl]-1H-tetrazol-5-yl)-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (see Preparation 55) (0.6 g), 4-chloro-2-methylthiopyrimidine (0.5 g), anhydrous potassium carbonate (0.7 g) and anhydrous dimethylacetamide (5 ml) was heated at 120° C. for 24 hours. On cooling to room temperature water (10 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The extracts were combined and washed with water (50 ml) then concentrated in vacuo to give an oil which was purified by chromatography on silica eluting with dichloromethane containing ethyl acetate (40%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was further purified by chromatography on silica eluting with dichloromethane containing isopropanol (3.3%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was triturated with hexane to give the title compound as a foam, 0.077 g, m.p. 115°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccco1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccco1
Yield: 79.3 %

Procedure:
20 g of ethyl 3-(4-fluorobenzoylamino)-3-(2-furylcarbonyl)propionate, 100 ml of chloroform and 36.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 15 g of ethyl 2-[2-(4-fluorophenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 78.9%
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27][Cl:28].Cl.O>CN(C)C=O>[Cl:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1)[CH3:24]
Reactant: O=c1c2ccccc2sc2c(O)ccc(O)c12
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCl)CCOc1ccc(O)c2sc3ccccc3c(=O)c12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 0.5 g of 1,4-dihydroxythioxanthone in 20 ml of dimethylformamide is stirred for 0.5 h at room temperature with 6 g of potassium carbonate under anhydrous conditions. Mechlorethamine hydrochloride (0.4 g) is then added and the heterogeneous mixture was stirred for 12 h at 50° C. Water is added and the mixture extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried with sodium sulfate, passed through a plug of alumina and concentrated under vacuum to produce 0.4 g (55%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:37]([C:32]3[C:31]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:40])[F:41])=[CH:26][CH:27]=4)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:38])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(CN2CCN(c3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (0.29 g), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (0.26 g), HOBt (0.16 g), and Et3N (0.12 g) in CH2Cl2 (15 mL) was added at room temperature EDCl (0.23 g) and the mixture was stirred at room temperature for 4 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/AcOEt (90/10) and the solid obtained was recrystallized from EtOH to give the title compound (0.48 g) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=[O:10])[C:3]=1[NH:12][C:13](=[O:18])[CH2:14]C(=O)C.[OH-].[Na+].Cl>C(O)(C)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[N:12]=[C:13]([OH:18])[CH:14]=[N+:9]2[O-:10]
Reactant: CC(=O)CC(=O)Nc1c(Br)cc(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Br)c2nc(O)c[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
The title compound of Step B (11.75 g, 37.29 mmol) was suspended in a mixture of isopropanol (120 mL) and water (120 mL) at room temperature under a nitrogen atmosphere. A solution of sodium hydroxide (14.91 g of a 50% aqueous solution, 186.4 mmol) diluted with water (10 mL) was added dropwise to the mixture over 30 min. The mixture was allowed to stir at room temperature overnight. First, 1N hydrochloric acid and then concentrated hydrochloric acid were added dropwise to the reaction mixture until the pH was approximately 2. Solids were filtered from the reaction mixture. These solids were washed with water and then cold ethyl acetate to afford the title compound of Step C as a reddish-brown solid melting at 241°-243° C. (8.67 g, 91%). 1H NMR ((CD3)2SO): δ2.47 (s,3H), 7.69 (s, 1H), 7.81 (s, 1H), 8.12 (s, 1H), 8.9 (br s, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH:22]=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Na]>ClCCCl>[CH2:32]([NH:39][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Na]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCNCc1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.4 %

Procedure:
To (S)-tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-4-oxobutan-2-yl)carbamate (14.93 g, 33.8 mmol) in DCE (100 mL) at 0° C. was added benzylamine (3.69 mL, 33.8 mmol) and sodium triacetoxyhydroborate (8.60 g, 40.6 mmol) sequentially. After stirring at rt 18 h, it was quenched by addition of saturated NaHCO3 (aq, 300 mL) and stirred for an additional 30 min. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (8 g, 44%). LCMS: Rt=1.08 min, m/z=533.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)[CH3:2].Br[CH2:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=3[O:21][CH2:22][C:16]=2[CH:15]=1>>[CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:33]=[CH:32][C:17]3/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=4[O:21][CH2:22][C:16]=3[CH:15]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: CCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 95.8 %

Procedure:
Using 2-ethyl-1H-benzo[d]imidazole (61 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (170 mg, 96%) was obtained.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:12][C:10]([CH2:9][N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7])=[O:11])[CH3:14]
Reactant: O=c1cccc[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccccc1=O
Yield: 83.9 %

Procedure:
2-Pyridone (4.76 g, 50 mmol) and ethyl bromoacetate (10.02 g, 60 mmol) were dissolved in acetone (100 ml). Potassium carbonate (8.28 g, 60 mmol) was added to the solution and the mixture was refluxed for two hours with stirring. After being cooled, insoluble substances were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, to thereby obtain N-ethoxycarbonylmethyl-2-pyridone (7.60 g, yield 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.CN(C)C=O.[CH3:18][CH:19]([CH3:22])[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:20][CH:19]([CH3:22])[CH3:18])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CC(C)CN
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (7.01 g), anhydrous dimethylformamide (70 ml), and triethylamine (4.72 ml) were combined and cooled to 0° C. 2-Methylpropylamine (3.36 ml) was added dropwise to the resulting mixture. The reaction was stalled at 75% completion, as determined by HPLC and TLC monitoring, after 16 hours. The dimethylfornamide was removed from the resulting reaction mixture under reduced pressure, and the resulting oil was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried with magnesium sulfate, and the solvent was removed under reduced pressure. The resulting yellow oil was put through a column of silica using 90/10 hexane/ethyl acetate. After removing the solvent from the resulting eluted solution, the resulting yellow oil (5.0 g) was dried under high vacuum and used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:14]=2)[N:9](C(OC(C)(C)C)=O)[CH:8]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cn(C(=O)OC(C)(C)C)c2cnc(-n3cncn3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cncn3)cc12
Yield: 82.4 %

Procedure:
A solution of ethyl-3-[1-tert-butyloxycarbonyl-5-(1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-3-yl]prop-2-enoate (1.73 g, 4.5 mmol) and trifluoroacetic acid (5 mL) in dry DCM (20 mL) was stirred at ambient temperature under nitrogen for 5 hours. The solvent was evaporated in vacuo and the residue azeotroped with toluene. The residue was chromatographed on silica eluting with 20% EtOAc in DCM followed by a gradient of 5 to 10% MeOH in DCM to give a colourless solid. This was triturated with ether to give the title compound (1.05 g, 82%) as a colourless solid. mp 235°-238° C. 1H NMR (360 MHz, d6 -DMSO) δ 1.29 (3H, t, J=7.1Hz), 4.20 (2H, q, J=7.1Hz), 6.44 (1H, d, J=16.0Hz), 7.92 (1H, d, J=16.1Hz), 8.22 (1H, s), 8.27 (1H, s), 8.33 (1H, d, J=2.7Hz), 8.76 (1H, s), 9.31 (1H, s) and 12.46 (1H, br s).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[S:7](=[O:9])=[O:8]>CO>[S:1]([S:7]([O-:9])=[O:8])([O-:4])(=[O:3])=[O:2].[Na+:5].[Na+:5]
Reactant: O=S([O-])[O-]
Reactant: O=S=O
Agent: [Na+]
Solvent: CO
Product: O=S([O-])S(=O)(=O)[O-]
Reaction time: 1 h

Procedure:
To 16.6 g. (132 mm.) of sodium sulfite was added 100 ml. of methanol, and then a solution of sulfur dioxide (8.3 g., 130 mm.) in methanol with stirring at room temperature. After stirring for one hour, the reaction mixture was allowed to stand still and after 24 hours, the supernatant portion was removed and thereby, a methanol suspension containing 0.89 moles/l. of sodium pyrosulfite was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:13]([CH2:14][Cl:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][C@H:18]([NH:26][CH3:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO.Cl>C1C=CC=CC=1>[ClH:15].[CH3:27][N:26]([CH2:14][C:13]1[O:16][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH:18]([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN[C@@H](C)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CCl)o2)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: CC(Cc1ccccc1)N(C)Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A solution of 11.9 g (0.05 mole) of 5-(4-nitrophenyl)furfuryl chloride and 14.9 g (0.10 mole) of d-N,a-dimethylphenethylamine in 60 ml of benzene was heated under reflux for 7 hrs. After standing overnight, the solid N,a-dimethylphenethylamine hydrochloride (9 g, 97%) was collected by filtration and washed with benzene. The benzene filtrate was washed with 10% Na2CO3 and water and dried over MgSO4. The solvent was removed on a rotary evaporator, and the residual oil was dissolved in 100 ml of anhydrous ether and 35 ml of nhydrous MeOH. The solution was treated with 20 ml of ethereal HCl and diluted with ether to give an oil. The solvent was removed on a rotary evaporator, and the residual oil was dissolved in ethyl acetate with heating. Cooling gave an oil which was dissolved by the addition of MeOH and 10 ml of etheral HCl. After cooling and dilution with ether, the yellow solid which was deposited was collected by filtration to give 13 g (67%) of N-methyl-5-(4-nitrophenyl)-N-(a-methylphenethyl)furfurylamine hydrochloride; m.p. 168°-175°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]3[O:15][C@H:9]3[C:8]=2[CH:16]=1)(=[O:3])[CH3:2].[OH-].[NH4+:18]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[C@@H:9]([NH2:18])[C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[C@@H]1O[C@H]1C(C)(C)O2
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=O)c1ccc2c(c1)[C@H](N)[C@@H](O)C(C)(C)O2

Procedure:
From (3R,4S)-6-acetyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (Example 1 of GB-A-1511187) by stirring in ethanolic ammonium hydroxide solution.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>CO>[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC
Reaction time: 4 h

Procedure:
Cyclopentylcarbonyl chloride (0.1 mole) is added to 0.1 mole of 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline in 300 ml. of methanol with vigorous stirring at room temperature. Stirring is continued for a period of 2 to 6 hours and the product is isolated according to the procedure of Example 1(a) to provide 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline. If the hydrochloride salt is desired, the base treatment is omitted and evaporation of the solvent provides 4-amino-2-[4-(cyclopentylcarbonyl)-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride, m.p. 279°-280° C. (dec.)(corr.) crystallized from methanol-isopropanol.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@@H:26]([NH2:29])[CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:26]([NH:29][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: CC[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (S)-1-phenylpropylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 330.3 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.49 (br s, 1H); 8.38 (d, J=5.5 Hz, 1H); 7.83 (d, J=7.6 Hz, 1H); 7.27-7.44 (m, 6H); 6.77 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.97 (br s, 1H); 1.97 (m, 2H); 1.03 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:13][C:8]=2[CH:7]=[CH:6]1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([OH:15])[CH2:1][CH3:2])=[CH:13][C:8]=2[CH:7]=[CH:6]1
Reactant: CC[Mg]Cl
Reactant: O=C(c1ccccc1)c1ccc2occc2c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethylmagnesium chloride (2M in tetrahydrofuran, 10.63 mL, 21.26 mmol) under nitrogen at room temperature was added zinc chloride (0.5M in tetrahydrofuran, 5.67 mL, 2.84 mmol) via syringe. The mixture was stirred at room temperature for 1 h. The reaction mixture was brought to 0° C. and benzofuran-5-yl(phenyl)methanone (3.15 g, 14.17 mmol) in tetrahydrofuran (10 mL) was added via syringe. The reaction mixture was stirred at 0° C. for 2.5 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl. EtOAc was added, and the aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give a crude oil. The crude product was purified by silica flash chromatography (0-100% DCM/hexanes) to give 1-(benzofuran-5-yl)-1-phenylpropan-1-ol as an off-white oil. 1H NMR (400 MHz, Chloroform-d) δ ppm 7.69 (1H, d, J=1.6 Hz), 7.60 (1H, d, J=2.2 Hz), 7.39-7.45 (3H, m), 7.28-7.34 (3H, m), 7.22 (1H, tt, J=7.2, 1.4 Hz), 6.73 (1H, dd, J=2.2, 1.0 Hz), 2.38 (2H, q, J=7.3 Hz), 2.09 (1H, s), 0.90 (3H, t, J=7.3 Hz).