Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(C)cc1
Yield: 100.7 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.3 g, 99%) as an oily product.
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([NH:17][C:18]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)/C=C/C(C)O
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/C(C)OC(=O)NC1CCCCC1

Procedure:
Reaction of 21 (rac-Ethyl (2E)-4-hydroxypent-2-enoate) (1.44 g, 10 mmol) with cyclohexyl isocyanate (2.53 ml, 20 mmol) in toluene (8 ml) according to Example 1. Purification by flash chromatography (AcOiPr:heptane fraction 15:85 to 25:75) yields 5 (rac-Ethyl (2E)-4-(cyclohexylaminocarbonyloxy)pent-2-enoate) (2.29 g, 85%) as a yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH:17][C:18]([C:20]1[S:21][C:22]2[CH2:23][N:24]([C:29](SC)=[N:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][CH2:26][C:27]=2[N:28]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]#[C:40][NH2:41]>C1COCC1>[C:40]([NH:41]/[C:29](=[N:30]\[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[N:24]1[CH2:25][CH2:26][C:27]2[N:28]=[C:20]([C:18]([NH:17][C:10]3[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[S:21][C:22]=2[CH2:23]1)#[N:39]
Reactant: N#CN
Reactant: COc1ccc(NC(=O)c2nc3c(s2)CN(C(=Nc2ccccc2)SC)CC3)c(NC(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2nc3c(s2)CN(/C(=N/c2ccccc2)NC#N)CC3)c(NC(=O)OC(C)(C)C)c1

Procedure:
A solution of methyl 2-({2-[(tert-butoxycarbonyl)amino]-4-methoxyphenyl}carbamoyl)-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbimidothioate (1 eq) obtained in step I, cyanamide (10 eq) in very small quantity of THF was heated at reflux temperature for 15 h.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:43]4[CH:44]=[N:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=4)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ccc(C(F)(F)F)nc2)cc1

Procedure:
The title compound was prepared using analogous conditions described in Step A of Example 97 using racemic cis-2-(5-(benzo[d]thiazol-2-ylmethoxy)-1-(4-bromobenzyl)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid. MS (ESI): mass calcd. for C35H29F3N4O3S, 642.71; m/z found, 643.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.00-8.88 (d, J=2.2, 1H), 8.29-8.22 (dd, J=8.2, 2.2, 1H), 8.05-7.94 (m, 2H), 7.92-7.84 (d, J=8.2, 1H), 7.79-7.71 (m, 2H), 7.62-7.51 (m, 2H), 7.51-7.41 (m, 2H), 7.38-7.26 (m, 3H), 6.01-5.75 (q, J=17.2, 2H), 5.75-5.62 (d, J=1.3, 2H), 3.83-3.57 (m, 1H), 3.03-2.90 (d, J=4.5, 1H), 2.42-2.27 (td, J=13.8, 13.3, 9.5, 1H), 2.27-2.16 (m, 1H), 2.13-2.05 (d, J=12.7, 1H), 2.01-1.93 (m, 1H), 1.88-1.74 (dd, J=15.2, 10.3, 1H), 1.74-1.64 (s, 1H), 1.64-1.45 (q, J=11.0, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(C2C=NC3C(C=2Cl)=CC(OC)=C(F)C=3)=O)[CH2:8][CH2:7]1>C(N(CC)CC)C>[ClH:3].[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(Cl)c(C(=O)N[C@H]3CC[C@H](C)CC3)cnc2cc1F
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](N)CC1
Product: Cl

Procedure:
The crude acid (1 g,), thionyl chloride, trans-4-methylcyclohexylamine hydrochloride (150 mg, 1 mmol), and triethylamine (0.3 mLs) afforded crude N-(trans-4-methylcyclohexyl)-4-chloro-6-methoxy-7-fluoroquinoline-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9]
Reactant: O=C([O-])[O-]
Reactant: CC1(CC(=O)O)CCCCCC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CC1(C)CCCCCC1=O
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-2-oxocycloheptaneacetic acid (3.0 g, 0.0163 mole, obtained as described above), anhydrous potassium carbonate (2.76 g, 0.020 mole) and methyl iodide (8 ml) in acetone (50 ml) is stirred and heated to reflux for 2 hrs. Methyl iodide (3ml) is added and heating to reflux is continued for another 3 hrs. The solvent is evaporated, the residue taken up in water (50 ml), saturated with sodium chloride, and extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to yield 1-methyl-2-oxocycloheptaneacetic acid methyl ester as an oil, νmaxCHCl3 1730, 1700 cm-1, nmr (CDCl3) δ1.2 (s), 3.67 (s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:12]3[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([CH:18]=3)[NH2:17])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.S(=O)(=O)(O)[OH:23].OOS([O-])=O.[K+].[OH-:33].[Na+]>O>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([CH:18]=3)[NH2:17])(=[O:23])=[O:33])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1cc(Sc2cccc3cnccc23)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Nc1cc(S(=O)(=O)c2cccc3cnccc23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
According to the method in (b) method of Example 2, a mixture of 5-(5-isoquinolylsulfanyl)-2-nitroaniline 5.00 g (16.8 mmol), concentrated sulfuric acid 50 ml and OXONE (trademark) 20.70 g (33.7 mmol) was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the solution was neutralized with an aqueous 4N sodium hydroxide solution, the precipitates were collected and washed with water then with ether to give 5-(5-isoquinolylsulfonyl)-2-nitroaniline 5.54 g (quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[CH3:13][C:14](C)(C)C([O-])([O-])[O-]>S(=O)(=O)(O)O.CO>[CH3:13][C:14]1[O:12][C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2nc(C)oc2c1
Temperature: 160 °C
Yield: 61.9 %

Procedure:
In a 50 ml round-bottomed three-necked flask equipped with a 12-inch Vigraux column and a Dean Stark trap assembly were placed methyl 4-amino-3-hydroxybenzoate (10.0 g, 60 mmole), trimethylorthoacetate (10.8 g, 90 mmole), and concentrated sulfuric acid (0.25 g, 2.6 mmole). The resulting well-stirred mixture was heated at 115° C. until approximately 8 ml of methanol were collected in the Dean Stark trap. The reaction mixture was heated at 160° C. for another 60 minutes. The reaction mixture was cooled to room temperature and dissolved in ethyl acetate. The resulting organic solution was extracted sequentially with saturated aqueous sodium bicarbonate (1×100 ml), water (2×50 ml), brine, and dried over anhydrous magnesium sulfate. The solvent was removed in the rotary evaporator yielding 7.1 g of the expected methyl 2-methylbenzoxazole-6 carboxylate used as such in the next step.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH3:22])[CH2:11]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[OH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH3:22])[CH2:11]1
Reactant: C[C@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of the ester of step B (1.0 g, 3.48 mmol) in MeOH (30 mL) was added K2CO3 (1.2 g, 8.7 mmol). After being stirred at room temperature for 4 hours, the solution was concentrated. The residue was taken up in ether. The resulting solution was washed with brine, dried over MgSO4 and concentrated. Flash chromatography eluting with a gradient of 0% to 20% to 40% EtOAc/hexanes provided 0.56 g of the title compound. MS calculated (M+H)+ 202, found 202.1.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:46][CH2:47]I>O1CCOCC1>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O:25][CH2:47][Cl:46])=[O:24])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)OCCl
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
To a solution of 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid (5.88 g, 15.5 mmol) in dioxane (100 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (10.1 g). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (100 mL) and then chloroiodomethane (11.3 mL, 155 mmol) was added and the solution was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane/ethyl acetate (1:1 v/v, 200 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1-4% MeOH in CH2Cl2), to give 3.95 g of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([O:28][CH2:29][CH3:30])[N:23]=[C:22]([NH2:31])[CH:21]=1>C(Cl)Cl.N1C=CC=CC=1.O>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([O:28][CH2:29][CH3:30])[N:23]=[C:22]([NH:31][C:10](=[O:12])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:21]=1
Reactant: CCOc1nc(N)cc(N)c1C#N
Reactant: COc1cccc(CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1nc(NC(=O)Cc2cccc(OC)c2)cc(N)c1C#N
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
To a solution of 28 mg (0.17 mmol) of (3-methoxyphenyl)acetic acid in 0.5 mL of CH2Cl2 (or the minimum amount necessary for dissolution) was added 20 μL (0.22 mmol) of oxalyl chloride. The solution was swirled, allowed to stand for 5 minutes at ambient temperature, then added to a solution of 30 mg (0.14 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 0.5 mL of pyridine. The mixture was shaken for 15 minutes, diluted with 1 mL of water and concentrated under reduced pressure. The residue was taken up in 3 mL of ethyl acetate, and extracted with water (2×1 mL), 1M HCl(aq.) (1×1 mL), saturated NaHCO3(aq.) (2×1 mL), and brine (1×1 mL), dried over MgSO4, filtered, and concentrated to a solid. This was recrystallized from 1 mL of methanol to provide 9 mg (16%) of a colorless solid. 1H NMR (300 MHz, d6-DMSO) 610.28 (s, 1H), 7.22 (m, 1H), 7.16 (m, 1H), 6.89 (m, 4H), 6.81 (m, 1H), 4.34 (q, 2H, J=7.1 Hz), 3.74 (s, 3H), 3.67 (s, 2H), 1.31 (t, 3H, J=7.1 Hz); MS (ESI) m/e=299 (M−Et+H)+, 327 (M+H)+, 349 (M+Na)+.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][C:16](Cl)=[O:17].[CH3:19][C:20]1(C)[O:27]C(=O)C[C:22](=O)[O:21]1.Cl>ClCCl>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][C:16](=[O:17])[CH2:19][C:20]([O:21][CH3:22])=[O:27]
Reactant: O=C(Cl)Cc1cccc(Cl)c1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Cc1cccc(Cl)c1Cl
Temperature: 20 °C
Reaction time: 12 h

Procedure:
At 0° C., 36.3 g (0.46 mol) of pyridine and then within 2 hours a solution of 42.5 g (0.19 mol) of 2,3-dichlorophenylacetyl chloride in 100 ml of dichloromethane were added dropwise to a solution of 28.8 g (0.20 mol) of Meldrum's acid in 200 ml of dichloromethane. The mixture was then stirred for 12 hours at about 20° C. and subsequently stirred into 100 ml of 10% strength hydrochloric acid. The organic phase was then separated off and the aqueous phase was extracted two more times with dichloromethane. Finally, the combined extracts were dried over magnesium sulfate and concentrated. The residue was dissolved in 300 ml of methanol and heated under reflux until the formation of gas had ceased. The mixture was then concentrated. Yield: quantitative.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].[OH-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[N:7]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.3307 g, 7.2 mmol) dissolved in acetone (15 mL) stirring at 0-5° C., was added a solution of 3-nitroaniline (1.0023 g, 7.2 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (2.9 mL, 7.2 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was poured over crushed ice. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. The product was used with no further purification, (158a, 2.01 g, 98%), mp 173° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 21.5 min, 97.1% purity; MS (TOF MS ES+): m/z 370 (80.33), 291 (43.4), 286 (M+H, 100).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2cccn2[Si](C(C)C)(C(C)C)C(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc[nH]2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
5-Methyl-2-[1-(triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole (215 mg, 0.67 mmol) synthesized in Example (3b) was dissolved in tetrahydrofuran (8 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.87 mL, 0.87 mmol) was added, followed by stirring at room temperature for 30 minutes under nitrogen atmosphere. Water (10 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-30%) to afford the desired compound (100 mg, yield 91%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19](F)=[CH:20][C:21]=3[O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:16]=2)[CH:12]=[C:11]([CH3:35])[N:10]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:20][C:21]=3[O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:16]=2)[CH:12]=[C:11]([CH3:35])[N:10]=1
Reactant: COCCO
Reactant: Cc1cc(-c2nc3cc(F)cc(OCCN4CCCC4)c3c(=O)[nH]2)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc(OCCN2CCCC2)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-ethanol (1.35 g, 17.8 mmol) in DMF (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.36 g, 8.89 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one (0.34 g, 0.89 mmol) and the reaction mixture was stirred at 70-80° C. for 16 h, then cooled to room temperature. Water (10 mL) was added, and the mixture was neutralized to pH approximately 6 with acetic acid. Solvent was evaporated; the residue was purified by the Simpliflash system (2-5% 7.0M ammonia in methanol and CH2Cl2 as eluent). The compound was further purified by preparative HPLC to give the title compound as a yellow solid. Yield: 72 mg (18%). MP 60.4-62.3° C. 1H NMR (400 MHz, CDCl3): δ 10.23 (br s, 1H), 8.50 (br s, 1H), 7.60 (s, 2H), 6.76 (br s, 1H), 6.43 (br s, 1H), 4.35 (m., 2H), 4.21 (m, 2H), 3.79 (s, 3H), 3.47-3.38 (m, 6H), 2.64 (s, 6H), 1.99 (m, 4H). MS (ES) m/z: 437.09 (M−1) (100%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[O:22]1C2CCCC(N)C=2C=C1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[CH:15]=[CH:14][O:22][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCCc2occc21
Product: CCc1cnc(CC)c(NC2CCCc3occc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 4,5,6,7-tetrahydro-1-benzofuran-4-amine and making non-critical variations provided the title compound as a oil:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>C(O)(C)C.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=S1(=O)CCCO1
Solvent: CCOCC
Solvent: CC(C)O
Product: CN1CCN(CCCS(=O)(=O)O)CC1
Reaction time: 8 h

Procedure:
N-methyl piperizine (4.68 g) was dissolved in isopropanol (25 ml) and treated with 1,3-propanesultone (5.7 g) with cooling to maintain the temperature of the reaction below 50° C. The reaction mixture was allowed to stand at room temperature overnight, then diluted with ether and the white solid filtered. On standing, the white solid became a sticky semi-solid (7.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[CH:5][CH:4]=1.ClN1C(=[O:24])CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:24])[CH2:11][C:6]2=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2ccn(-c3ccccc3)c2n1
Solvent: ClCCl
Product: COc1ccc2c(n1)N(c1ccccc1)C(=O)C2
Temperature: 125 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
To a stirred solution of 9.64 g (43 mmol) of the compound of step 1 in DCM (250 ml) was added N-chlorosuccinimide (6.02 g, 45 mmol) in one portion at room temperature. The reaction mixture was stirred for 12 h and the solvent was evaporated. The remaining residue was dissolved in a mixture of acetic acid (180 ml) and phosphoric acid (31 ml) and heated to 125° C. for 1 h. The solution was cooled to room temperature and concentrated in vacuo. The remaining residue was poured onto ice and the aqueous phase was extracted with EA. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The remaining oil was purified by column chromatography on silica gel (EA/HEP) to give 4.80 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@H:17](O)[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[C:29]1(=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[NH:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([N:30]2[C:31](=[O:38])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]2=[O:39])[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@@H](O)CC[C@H]1c1cccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](N2C(=O)c3ccccc3C2=O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
In an oven-dried 100 mL round-bottomed flask was dissolved tert-butyl (5S,6S,9S)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (35.3 mg, 0.090 mmol) (9, azeotroped with dry benzene) in methylene chloride (3 mL) to give a colorless solution. isoindoline-1,3-dione (26.5 mg, 0.180 mmol) and triphenylphosphine (47.3 mg, 0.180 mmol) were added, followed by diisopropylazodicarboxylate (0.026 mL, 0.135 mmol). The mixture was stirred at rt under nitrogen. After 22 h, the mixture was directly subject to flash column chromatography up to 50% ethyl acetate/hexane afforded one major peak. Concentration afforded the desired product as a colorless oil. 1H NMR indicated that some elimination product might also be present. This was carried onto next reaction without further purification and characterization.