Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C([O:13][CH:14](O)[C:15]([F:18])([F:17])[F:16])C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1>[OH:13][CH:14]([NH:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: CCOC(O)C(F)(F)F
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC(O)C(F)(F)F)c1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzamide (22.0 g, 0.141 mol) and trifluoroacetaldehyde ethyl hemiacetal (25.0 g as is, 22.5 g real, 0.156 mol) in dioxane (200 mL) is treated with anhydrous sodium sulfate (10 g, to dry the 10% water in the hemiacetal) and refluxed for 60 hours. The solids are filtered and the filtrate is evaporated to a solid. The solids are dissolved in about 200 mL of 15% ethyl acetate in heptane. Unreacted starting material (5.6 g) crystallizes out and is filtered. The title product is obtained from the mother liquors as a white crystalline solid (22.1 g, 82.9% based on recovery of starting material): mp 139.5-140.5° C.; characterized by 1H and 19F NMR and Mass spectra. 1H NMR (DMSO-d6) δ 9.45 (d, J=8.7 Hz, NH), 7.93, 7.54 (AB with fine splitting, J=8.4 Hz, ArH), 7.54 (broad s, OH), 5.90 (m, J=8.7, 2.9, 5.8 Hz, CH); 19F NMR δ −80.3 (d, J=5 Hz).
Reaction SMILES: CC(=CC)C.OP([O-])(O)=O.[Na+].Cl([O-])(=O)(=O)=[O:13].[Na+].[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][CH:39]=[O:40])[CH:36]=4)[N:31]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=4)[C:30]=3[C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19]1>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][C:39]([OH:13])=[O:40])[CH:36]=4)[N:31]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=4)[C:30]=3[C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19]1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(CC=O)ccc2n1Cc1cccc(OC)c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(CC(=O)O)ccc2n1Cc1cccc(OC)c1
Reaction time: 24 h
Yield: 20 %

Procedure:
2-Methyl-2-butene (2 mL), sodium phosphate monobasic (307 mg, 2.6 mmol) and sodium perchlorate (307 mg, 3.4 mmol) were added to a stirred solution of ethyl 3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-5-(2-oxoethyl)-1H-indole-2-carboxylate (Example 138, 169 mg, 0.34 mmol) in tert-butanol (8 mL) and water (3 mL). The reaction was stirred for 24 h and then diluted with ethyl acetate (100 mL). The solution was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography of the residue over silica gel using 60% ethyl acetate/hexane afforded 35 mg (20%) of the product. The product had: 1H NMR (300 MHz, acetone-D6) δ 6.96-7.57 (m, 8 H), 6.58-6.80 (m, 3 H), 5.83 (s, 2 H), 4.11 (q, 2 H), 3.90 (d, 2 H), 3.70 (s, 3 H), 3.67 (s, 2 H), 1.24-1.40 (m, 1 H), 1.03 (t, 3 H), 0.55-0.65 (m, 2 H), 0.35-0.46 (m, 2 H); mass spectroscopy gave M−H+=512.5 (calc'd exact mass for C31H31NO6=513.22).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[C:10]=2[NH2:16])=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1.C(Cl)Cl.CO>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[C:6]([C:7]2[NH:16][C:10]3[C:11]([NH2:15])=[N:12][CH:13]=[N:14][C:9]=3[CH:8]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1C#Cc1ncnc(N)c1N
Agent: [Cu]I
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccccc2)c1-c1cc2ncnc(N)c2[nH]1
Yield: 6 %

Procedure:
6-[(1-Methyl-4-phenyl-1H-imidazol-5-yl)ethynyl]pyrimidine-4,5-diamine (intermediate 90) (50 mg) and CuI (3 mg) in DMF (2 mL) were heated at 110° C. under an inert atmosphere for 4 hours. The reaction mixture was loaded on to a 1 g SCX column prewashed with DCM:MeOH (3:1). The column was eluted with DCM:MeOH (3:1) and then the product eluted with 7N NH3/MeOH:DCM:MeOH (1:3:1). The product fraction was concentrated and then purified by flash chromatography on silica eluting with DCM:MeOH (9:1) to afford the title compound as a yellow solid (3 mg, 6%);
Reaction SMILES: N[CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[O:37]1[CH2:42][CH2:41][CH:40]([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH2:39][CH2:38]1.C([N:50](CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][CH:43]([CH:40]1[CH2:41][CH2:42][O:37][CH2:38][CH2:39]1)[S:44]([NH2:50])(=[O:46])=[O:45])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)CC1CCOCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC(C4CCOCC4)S(N)(=O)=O)nc32)[C@H](O)[C@@H]1O
Yield: 37.7 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (245 mg, 0.48 mmol), tetrahydro-2H-pyran-4-ylmethanesulfonyl chloride (preparation 21) (95 mg, 0.48 mmol), triethylamine (145 mg, 1.44 mmol) in tetrahydrofuran (23 ml). Purification by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.25) gave the title compound as an oil (118 mg). MS: 654 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[C:15]([CH3:23])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[C:15]([CH3:23])[CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: Oc1ccc2c(c1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc2c(c1)CCCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
4.4 g (29.6 mmol) of 5,6,7,8-tetrahydro-2-naphthol, 5.0 g (26.9 mmol) of 4-chloro-2,5-dimethylnitrobenzene and 5.2 g (37.7 mmol) of potassium carbonate are refluxed in 50 ml of N,N-dimethylformamide for 12 h, poured onto ice, stirred at 0° C. for 15 min, and then filtered. The solid is washed with water and hexane and dried under reduced pressure (6.0 g, 98.0% purity, 70.0% yield, log P (pH 2.3)=5.86).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].IC.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:5]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:6]=[C:7]([S:21][CH3:32])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC1=NC(c2ccc(C#N)cc2)C(C(C)=O)=C(C)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-Acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (example 1; 100 mg, 0.24 mmol), 1-iodomethane (38.0 mg, 0.27 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified via preparative HPLC (RP1 8-column; eluent: aceto-nitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]([N:27]([CH3:35])[CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[O:26])[CH:19]=2)=[C:13]([F:36])[CH:12]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:26])[N:27]([CH3:35])[CH:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[CH:19]=2)=[C:13]([F:36])[CH:12]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)ccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
After dissolving (3-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamic acid benzyl ester (38.7 mg) in tetrahydrofuran (1.5 ml) and methanol (1.5 ml), 10% palladium-carbon (16 mg) was added under a nitrogen atmosphere. The atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 5 hours at room temperature. The catalyst was filtered and then washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of the title compound as a pale yellow oil (28.5 mg).
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si](C(C)(C)C)(C)C)[C:22]=4[Cl:35])[CH3:20])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.O.[N:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][C:40]=1[CH3:48].C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O>[Cl:35][C:22]1[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C@H:19]([O:18][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:36]=[CH:37][C:2]([C:43]4[CH:44]=[N:39][C:40]([CH3:48])=[CH:41][CH:42]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[S:13][C:12]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:20]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1sc(-n2cnc3cc(-c4ccc(C)nc4)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Temperature: 80 °C

Procedure:
To a solution of methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (300 mg, 0.48 mmol) in 4.5 mL of DMA was added 2-picoline-5-boronic acid hydrate (79 mg, 0.58 mmol), 1M Na2CO3 (1.44 ml, 1.44 mmol) and Cl2Pd(dppf) (41 mg, 0.05 mmol), and the reaction was heated to 80° C. The dark reaction was concentrated onto silica gel and purified by flash column chromatography to give the title compound, which was triturated into ether (147 mg, 59%). 1H NMR (400 MHz, d6-DMSO) δ 10.26 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.08 (s, 1H), 8.01 (dd, J=8.0 and 2.4 Hz, 1H), 7.68 (m, 2H), 7.34-7.32 (m, 2H), 7.20-7.11 (m, 2H), 6.91 (d, J=8.0 Hz, 1H), 5.93 (m, 1H), 3.70 (s, 3H), 2.49 (s, 3H), 1.60 (d, J=6.0 Hz, 3H).
Reaction SMILES: C([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:47]2[N:48]=[C:49]([NH:52]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:50][CH:51]=2)\[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:29]([O:31]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:30])=[C:22]([CH:25]=[CH:26][CH2:27]I)[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.[NH2:72][C:73]1[S:74][C:75]2[CH:80]=[CH:79][N:78]=[CH:77][C:76]=2[N:81]=1>CS(C)=O.C(OCC)(=O)C>[NH2:52][C:49]1[S:50][CH:51]=[C:47](/[C:14](=[N:13]/[O:12][C:8]2([C:6]([OH:7])=[O:5])[CH2:11][CH2:10][CH2:9]2)/[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:29]([O-:31])=[O:30])=[C:22](/[CH:25]=[CH:26]/[CH2:27][N+:78]4[CH:79]=[CH:80][C:75]5[S:74][C:73]([NH2:72])=[N:81][C:76]=5[CH:77]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:48]=1
Reactant: Nc1nc2cnccc2s1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=CCI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(/C=C/C[n+]4ccc5sc(N)nc5c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-5', 641 mg, 0.58 mmole) and 2-aminothiazolo[4,5-c]pyridine (97 mg, 0.64 mmole) in dimethylsulfoxide (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2×150 ml), dried over sodium sulfate and concentrated under reduced pressure. The oily residue was triturated with diisopropyl ether and the resulting precipitate (558 mg) was treated with a mixture of 90% trifluoroacetic acid (10 ml) and anisole (2 ml) at room temperature for 1 hour. Concentration of the mixture followed by trituration of the residue with ether gave 313 mg of crude I-5C, which was purified by column chromatography [HP-20, eluted with 30% and 50% CH3OH: the packing in the PrepPAK-500/C18 (Waters), eluted with 10% CH3OH] to give 40 mg (11%) of I-5C. M.p. >150° C. (dec.).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[C:11]3[C:22]4[CH:21]=[CH:20][C:19](OC[C@@H](NC(=O)OC(C)(C)C)CC(C)C)=[CH:18][C:17]=4[O:16][CH:15]([CH3:38])[C:12]3=[CH:13][N:14]=2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:38][CH:15]1[C:12]2=[CH:13][N:14]=[C:9]([NH2:8])[CH:10]=[C:11]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3c(cn2)C(C)Oc2cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc2-3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1Oc2ccccc2-c2cc(N)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((2-(bis(4-methoxybenzyl)amino)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (110 mg, 0.165 mmol) in dichloromethane (10 mL) was added TFA (0.254 mL, 3.29 mmol) and the reaction was stirred at room temperature overnight. The volatiles were evaporated and the crude material was purified by preparative HPLC (0.1% TFA in MeOH) to afford 8-4(S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridin-2-amine (25 mg, 0.069 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 7.74 (m, 2H), 6.84 (s, 1H), 6.75 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 5.18 (m, 1H), 4.32 (m, 1H), 4.15 (m, 1H), 3.65 (m, 1H), 1.83 (m, 1H), 1.65 (m, 5H), 1.04 (m, 6H); LCMS (ESI) m/e 328.2 [(M+H)+, calcd for C19H26N3O2 328.2]; LC/MS retention time (Method D): tR=1.24 min; HPLC retention time (method A): tR=8.42 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(Cl)CCl>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:50]([CH:47]3[CH2:48][CH2:49][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:45][CH2:46]3)=[O:51])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(N3CCN(C(=O)C(F)(F)F)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(1-N-trifluoroacetyl-4-piperazinyl)aniline (3.0 g, 9.9 mmol), Et3N (2.2 mL, 19 mmol), HOBt (1.5 g, 9.9 mmol), 1-t-butyloxycarbonyl-4-carboxypiperidine (2.3 g, 9.9 mmol) and EDC (1.9 g, 9.9 mmol) in DMF (15 mL) was stirred at RT for 18 hr. Solution was concentrated and the residue was dissolved in EtOAc. EtOAc was washed with: H2O, 5% citric acid (2×), water, 5% NaHCO3 (2×), water and brine. EtOAc was concentrated to givethe title compound (4.35 g, 91%). MS (ES) m/e 485 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1C(=O)O[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][C:6]=12)=[O:4].[CH3:16]C(C)=O.C(N[CH2:23][CH3:24])C>O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7]([CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:16][C:23]=1[CH3:24])=[O:4]
Reactant: CC(C)=O
Reactant: COC(=O)c1c2cccccc-2oc1=O
Reactant: CCNCC
Solvent: O
Product: COC(=O)c1c(C)cc2cccccc1-2

Procedure:
2-Methylazulene was synthesized according to a method described in Japanese Patent Laid-Open Publication No. 207232/1987. Specifically, 19.5 g (0.16 mol) of tropolone was reacted with 40 g (0.21 mol) of p-toluenesulfonic acid chloride in pyridine to give 37.1 g of tosylated tropolone. Then, 20 g (0.15 mol) of dimethylmalonate was reacted with 9.7 g (0.18 mol) of NaOMe in methanol at room temperature for 4 hr to give 14.4 g of 3-methoxycarbonyl-2H-cyclohepta(b) furan-2-one (Compound (2)). Then, 12 g of Compound (2), 200 ml of acetone and 70 ml of diethylamine were added, and the mixture was heated under reflux for 30 hr. Thereafter, H2O was added thereto, and the mixture was extracted with toluene to give 39.2 g of methyl-2-methylazulene carboxylate. Further, 25 ml of phosphoric acid was added, and a reaction was allowed to proceed at 85° to 90° C. for one hr. The reaction mixture was decomposed with water, extracted with benzene and dried to give 6.5 g of 2-methylazulene as an intended product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1)=[O:4].[F:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=2)=[CH:17][CH:16]=1>>[F:13][C:2]([F:1])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][C:18]3[CH:28]=[CH:29][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:21][CH:22]=2)[CH2:6]1)=[O:4]
Reactant: O=C(N1CCCC(O)C1)C(F)(F)F
Reactant: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Product: O=C(N1CCCC(OCc2ccc(Oc3ccc(F)cc3)cc2)C1)C(F)(F)F
Yield: 54.6 %

Procedure:
Using 1-trifluoroacetyl-3-hydroxypiperidine (394 mg, 2.00 mmol) and 4-(4-fluorophenoxy)benzylchloride (473 mg, 2.00 mmol), the same procedure was followed as in Step 6a of Example 6 to give 434 mg (55%) of the desired compound as a colorless oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.Br[C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH2:22])=[C:20]([F:26])[CH:19]=1>C(O)(C)C>[ClH:2].[Cl:1][C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:20]([F:26])[CH:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(Br)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Yield: 46.9 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (2.1 g, 8 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2-fluoro-5-hydroxyaniline (1.43 g, 8.9 mmol), (as described in EP 61741 A2), in isopropanol (150 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (1.45 g, 47%).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CO>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:23])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
250 mg of Z-Sta-OH(cf. stage 1.12) are dissolved in 4 ml of 90% strength methanol. 1 ml of a 20% aqueous cesium carbonate solution is added to the solution, and the solvent is then removed in a rotary evaporator. The residue is twice dissolved in 2.5 ml of DMF and each time the DMF is removed again in a rotary evaporator. The residue is dried in a high vacuum, then dissolved in 2.5 ml of DMF and 55 μl of methyl iodide are added to the solution. The whole is stirred for 18 hours at 25° C., the solvent is then removed and the residue is taken up in ethyl acetate. After extraction twice with sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated by evaporation. The residue is flash-chromatographed over 55 g of silica gel (eluant: chloroform/methanol [95:5]). The product-containing fractions are combined and concentrated by evaporation, yielding Z-Sta-OMe in the form of a yellowish oil; Rf (chloroform/methanol [95:5])=0.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([OH:7])=O.Cl.[CH3:17][N:18](C)[CH2:19][CH2:20][CH2:21]N=C=NCC.ON1C2C=CC=CC=2N=N1.CNCCC.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(Br)c1F
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(Br)c(F)c(S(C)(=O)=O)c1

Procedure:
Mix 3-bromo-4-fluoro-5-methanesulfonylbenzoic acid (1.6 g, 5.04 mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (968 mg, 5.04 mmol) and 1-hydroxybenzotriazole (680 mg, 5.04 mmol) in DMF (20 mL) at room temperature for 20 min. Add methyl-propylamine (368 mg, 5.04 mmol) and triethylamine (520 mg, 15.1 mmol) and stir at room temperature for 1 h. Dilute with ethyl acetate, wash with 10% aqueous potassium carbonate, 0.1 N citric acid, 1 N lithium chloride and saturated aqueous sodium chloride, concentrate and purify (silica gel chromatography, eluting with 10:90 to 50:50 ethyl acetate:hexanes) to give the title compound as an oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][CH2:30][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4cccnc42)CN2CCCC2C3)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.328 mmol) in DMF (1 mL) was added a suspension of NaH (40.0 mg, 0.986 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (287 mg, 0.986 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h at RT. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (MeOH-DCM) to yield 11-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;