Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH:31]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cccc(-c2cccnc2)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(-c3cccnc3)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-pyridin-3-ylphenol (J. Med. Chem. 1981, 24, 1475): 1H-NMR (CDCl3) δ 8.86 (1H, d, J=1.8 Hz), 8.63 (1H, dd, J=4.8, 1.5 Hz), 8.57 (1H, d, J=2.6 Hz), 8.17–8.15 (2H, m), 8.02–7.99 (2H, m), 7.90–7.86 (1H, m), 7.62–7.36 (6H, m), 7.22–7.18 (1H, m), 5.45–5.34 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=6.9 Hz); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.
Reaction SMILES: [K].[NH:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.CN(C)C=O>O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:4]2[C:5](=[O:7])[CH2:6][NH:2][C:3]2=[O:8])=[CH:12][CH:11]=1
Reactant: O=C1CNC(=O)N1
Reactant: Clc1ccc(CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CNC(=O)N1Cc1ccc(Cl)cc1
Temperature: 172.5 °C

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, with magnetic stirring, the potassium salt of imidazolidine-2,4-dione (1.382 g, 10 mmol) and 4-chlorobenzyl bromide (2.055 g, 10 mmol) were combined with 15 mL of anhydrous N,N-dimethylformamide (DMF) and heated to 170-175° C. for 5 hours. The reaction was then cooled to room temperature and poured over 50 mL of water to produce a waxy white precipitate. Recrystallization from ethyl acetate: hexanes produced the title product as a white crystalline solid, 0.775 g (34.5%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:23]2[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-BOC-piperazine (0.102 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature, and diluted with isopropanol (3 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.112 g, 56%). 1H-NMR (500 MHz, DMSO-d6) 1.42 (s, 9H, C(CH3)3), 2.99 (br s, 4H, piperazine N(CH2)2), 3.45 (br s, 4H, piperazine N(CH2)2), 7.02 (s, 2H, NH2), 8.20 (s, 1H, 6-H); LC (Method B)-MS (ESI, m/z): Rt=5.00 min—402, 404 [(M+H)+, Br isotopic pattern].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O-:12])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=2[CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([N:27]3[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]3)=[O:26])[S:24][C:17]=12.C([O-])([O-])=O.[Cs+].[Cs+].O[Li].O>>[OH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([C:25]([C:23]2[S:24][C:17]3[C:18](=[N:19][CH:20]=[CH:21][C:16]=3[O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=4[CH:14]=3)[CH:22]=2)=[O:26])[CH2:28]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)[O-]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li]O
Solvent: O
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)O
Yield: 45 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (283 mg, 1.00 mmole) with 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4a and Cs2CO3 (977 mg, 3.00 mmole) in a manner as previously described for example 1. The crude product was then reacted with LiOH.H2O (227 mg, 5.4 mmole) in a manner similar to that described for example 11c to give a yellow solid (202 mg, 45%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.31 Hz), 8.44 (1H, d, J=8.84Hz), 8.14, 8.07 (1H, s), 8.00 (1H, s), 7.39 (1H, dd, J=2.40, 8.97 Hz), 6.78 (1H, d, J=5.56 Hz), 4.38, 4.33 (1H, br s), 4.01–3.91 (1 H, m), 3.68–3.56 (2H, m), 3.49–3.22 (2H, m), 2.81 (3H, s), 2.07–1.79 (2H, m).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2]1.[C:21]([CH2:24][N:25]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32][N:31]([CH2:37][C:38]([OH:40])=[O:39])[CH2:30][CH2:29][N:28]([CH2:41][C:42]([OH:44])=[O:43])[CH2:27][CH2:26]1)([OH:23])=[O:22].[OH-].[K+]>O1CCOCC1.O>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][N:34]1[CH2:35][CH2:36][N:25]([CH2:24][C:21]([OH:23])=[O:22])[CH2:26][CH2:27][N:28]([CH2:41][C:42]([OH:44])=[O:43])[CH2:29][CH2:30][N:31]([CH2:37][C:38]([OH:40])=[O:39])[CH2:32][CH2:33]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: c1ccc(COCCCCCCCCCC2CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)CCCCCCCCCOCc2ccccc2)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
28.73 g (103.92 mmol) of 1,2-epoxy-11-benzyloxyundecane and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=D03A) are dissolved in a mixture of 50 ml of dioxane/80 ml of water and the pH is brought to pH 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. It is evaporated to dryness, the residue is taken up with 200 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 3 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and filtered off from precipitated potassium chloride. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then added to a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 12.22 g (68% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:18])[CH2:5][CH2:6][S:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH2:17])=[NH:16])[S:12][CH:13]=1)#[N:2].Cl.CC[O:22]CC>C(O)C.C(Cl)(Cl)Cl>[C:1]([NH:3][C:4](=[NH:18])[CH2:5][CH2:6][S:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH2:17])=[NH:16])[S:12][CH:13]=1)(=[O:22])[NH2:2]
Reactant: CCOCC
Reactant: N#CNC(=N)CCSCc1csc(NC(=N)N)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCC(=N)NC(N)=O)cs1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a mixture of 15 ml of ethanol and 10 ml of chloroform was dissolved 0.5 g of N-cyano-3-[(2-guanidinothiazol-4-yl)-methylthio]propionamidine and after passing through the solution a dry hydrogen chloride gas for 1.5 hours under cooling by ice water, the reaction mixture was concentrated under reduced pressure. To the residue was added 10 ml of ethanol, the mixture was concentrated again under reduced pressure. The residue formed was dissolved in a small amount of ethanol and after adding thereto ether and allowing to stand overnight the mixture, the crystals deposited were collected by filtration to provide 0.55 g of N-carbamoyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine.di-hydrochloride. The product shows the following physicochemical properties:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CCN(CC)CC.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])(=[O:26])=[O:24]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of N-(2-hydroxy-5-nitrophenyl)butyramide (Compound 117, 1.75 g, 7.8 mmol) in CH2Cl2 (40 ml) at 0° C. was added Et3N (1.4 ml, 10.1 mmol) and Tf2O (1.7 ml, 10.2 mmol). After 10 min, the reaction was diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[CH:35][C:20]([O:21][S:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=3)(=[O:24])=[O:23])=[C:19]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:42](OC(=O)C)(=[O:44])[CH3:43].[I-].[Mg+2].[I-]>>[C:42]([O:34][C:27]1[CH:26]=[C:25]([S:22]([O:21][C:20]2[CH:35]=[CH:36][C:17]([C:9]3[C:10]4[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=4[C:2]([Br:1])=[C:3]4[C:8]=3[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:18][C:19]=2[CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:24])=[O:23])[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C4CCCC4)c3)c2c1C
Agent: [I-]
Agent: [Mg+2]
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(-c3c4ccccc4c(Br)c4sc(C)c(C)c34)cc2C2CCCC2)ccc1C(=O)O
Yield: 78.5 %

Procedure:
Using 4-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.293 g, 0.450 mmol), acetic anhydride (3.6 mL, 38.2 mmol) and magnesium iodide (0.125 g, 0.450 mmol) the tidle compound was prepared according to the procedure in Example 5. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 10 & 30% EtOAc/pet. ether step gradient gave 0.245 g (79%) of the title compound as a colorless solid, mp 155-167° C.; 1H NMR (DMSO-d6) δ 1.32-1.38 (m, 2 H), 1.49-1.53 (m, 5 H), 1.58-1.63 (m, 3 H), 1.78-1.80 (m, 1 H), 2.30 (s, 3 H), 2.45 (s, 3 H), 3.00-3.28 (m, 1 H), 7.25-7.29 (m, 2 H), 7.36-7.39 (m, 2 H), 7.50 (t, 1 H), 7.67 (t, 1 H), 7.83 (d, b 1 H), 7.93 (dd, 1 H), 8.19-8.22 (m, 2 H), 13.6-13.8 (br. s, 1 H). mass spectrum (-ESI), m/z 691/693 (M-H). Anal. Calcd. for C34H29BrO7S2.0.3H2O: C, 58.42; H, 4.27 N, 0.00. Found: C, 58.38; H, 4.55 N, 0.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:53])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:5](=[O:50])[C:4]([CH3:52])([CH3:51])[NH:3]1.C(O[Cl:59])(C)(C)C>CO>[Cl:59][N:3]1[C:4]([CH3:52])([CH3:51])[C:5](=[O:50])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:2]1([CH3:53])[CH3:1]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a 0° C. solution of 2,2,5,5-tetramethyl-3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41-tetradecaoxatritetracontan-43-yl)imidazolidin-4-one (1.13 g, 1.2 mmol) in methanol (150 ml) was added tert-butylhypochlorite (393 mg, 3.6 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 764 mg (66%) of the title compound. 1H NMR (400 MHz, D2O) δ 3.70 (s, 54H), 3.64 (m, 2H), 3.56 (t, J=7.5 Hz, 2H), 3.39 (s, 3H), 1.54 (s, 6H), 1.37 (s, 6H). 13C NMR (100 MHz, D2O) δ 175.0, 83.6, 71.0, 69.4 (large peak), 67.7, 66.0, 58.0, 40.2, 24.1, 22.6.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH:32]1[O:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[O:34][CH2:33]1>>[O:37]1[C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[O:34][CH2:33][CH:32]1[CH2:31][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:27])=[O:26]
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: BrCC1COc2ccccc2O1
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CC2COc3ccccc3O2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine. MS: ESI (negative): 503 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.IC.[C:24]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]([CH3:24])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccc(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)c2cc(F)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione (742 mg, 2.13 mmol), iodomethane (0.159 mL, 2.55 mmol) and Cs2CO3 (1.039 g, 3.19 mmol) in THF (20 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated. The residue was dissolved in DCM and washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione (742 mg, 96% yield). Mass spectrum m/z 363, 365 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Temperature: 80 °C
Reaction time: 14 h
Yield: 87.9 %

Procedure:
In a 50-ml round-bottom flask, a suspension of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (2.00 g, 4.8 mmol) in absolute ethanol (20 ml) was flushed with nitrogen and sealed with a rubber septum. Hydrazine (0.5 ml, 15.9 mmol) was added, followed by an additional portion of absolute ethanol (20 ml) at room temperature. The reaction mixture was heated to 80° C. for 3.5 hours and then allowed to stir at room temperature for 14 hours. The precipitate was filtered off and washed with absolute ethanol. The filtrate was concentrated in vacuo leaving an oil, which was dissolved in dichloromethane (30 ml) and refiltered. The solvent was evaporated in vacuo affording 1.2 g (86%) of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH:8]=[CH2:9].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:13][CH2:12]1)[CH:8]=[CH2:9]
Reactant: C=CCOC1CCC(=O)CC1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCOC1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution (100 mL) of 1H-1,2,4-triazol-3-amine (2.4 g) and 4-(prop-2-en-1-yloxy)cyclohexanone (5.3 g) in acetic acid was added sodium cyanoborohydride (9.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (3.2 g, 50%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[F:10][C:11]1[C:16]([C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([CH:25]([S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34])[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[C:19]([F:40])[C:18]=2[F:41])=[C:15]([F:42])[C:14]([F:43])=[C:13](F)[C:12]=1[F:45].O.Cl>N1C=CC=CC=1>[CH2:1]([O:7][C:13]1[C:12]([F:45])=[C:11]([F:10])[C:16]([C:17]2[C:18]([F:41])=[C:19]([F:40])[C:20]([CH:25]([S:26]([C:29]([F:30])([F:31])[F:32])(=[O:27])=[O:28])[S:33]([C:36]([F:37])([F:38])[F:39])(=[O:35])=[O:34])=[C:21]([F:24])[C:22]=2[F:23])=[C:15]([F:42])[C:14]=1[F:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: O=S(=O)(C(c1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCOc1c(F)c(F)c(-c2c(F)c(F)c(C(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(F)c2F)c(F)c1F
Temperature: -20 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
Hexanol (1.5 mL, 12 mmol) was added to a pyridine (10 mL) solution dissolved with 60% sodium hydride containing mineral oil (0.56 g, 14 mmol) at 0° C., and the resultant solution was stirred for 1 hour at room temperature. After the solution was cooled to −20° C., {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane (1.2 g, 2 mmol) was added. The reaction solution was stirred at −20° C. for 5 hours. After the reaction, the solution was acidified with 4 M hydrochloric acid water, and was extracted with diethylether. After drying with magnesium sulfate, the solution was filtrated, and the solvent was removed under reduced pressure. The crude product was purified by sublimation (0.2 to 0.3 torr, 80° C.), and {4-(4-hexanoxy-2,3,5,6-tetrafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane was obtained at 94% yield (1.27 g, 1.88 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.83 to 0.94 (m, 3H), 1.26 (br, 2H), 1.33 to 1.38 (m, 2H), 1.45 to 1.52 (m, 2H), 1.84 (5, J=6.8 Hz, 2H), 4.38 (t, J=6.8 Hz, 2H), 4.32 (s, 1H); 19F NMR (CDCl3, 282 MHz) δ−75.0 (s, 6F, 2CF3), −128.4 to −128.3 (m, 1F), −133.6 (dt, J=9.1, 21.3 Hz, 1F), −134.8 (dt, J=9.1, 21.3 Hz, 1F), −139.8 to −139.6 (m, 2F), −140.7 (br, 1F), −156.5 (d, J=19.7 Hz, 2F).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].O>C(O)C>[CH3:24][C:19]1[CH:18]=[C:17]([S:14]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH:22]=[C:21]([CH3:23])[CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(C)cc(C)c1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(S(=O)(=O)N2CCc3ccc(C(=O)O)cc32)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(3,5-Dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (0.40 g, 1.17 mmol) was suspended in ethanol (2.00 mL) and treated with 3N KOH in water (1.17 mL, 3.51 mmol). The mixture was warmed at 50° C. and stirred for 1 hour, then warmed at 70° C. and stirred for 20 min. After cooling to room temperature, the volatiles were evaporated. The residue was dissolved in water (1.00 mL) and the pH set to 1 with 2N HCl. The precipitate was filtered, washing with water, then dried under high vacuum. 1-(3,5-Dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid was obtained as an off-white solid, 0.38 g (98%), MS (ISP): m/e=330.3 (M−H).
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:14])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCc1ccc(CO)cc1
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(CCl)cc1
Yield: 97 %

Procedure:
In 50 ml of chloroform was dissolved 8.63 g (57.5 mmol) of 4-n-propylbenzyl alcohol synthesized in the step (ii), and 8.10 g (68.1 mmol) of thionyl chloride was added to the mixture. The mixture was subjected to reaction at a room temperature for 24 hours. After the completion of the reaction, the chloroform phase was washed successively with an aqueous solution of sodium hydrogencarbonate and water. Chloroform was removed from the chloroform phase to give 9.40 g (55.8 mmol) of 4-n-propylbenzylchloride.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]2)=[O:35])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([C:34]([N:36]5[CH2:37][CH2:38][CH:39]([N:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]5)=[O:35])=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CN(C)C1CCN(C(=O)c2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(C(=O)c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Compound 364 was prepared as a light yellow solid (TFA salt) from compound 4 and compound 365 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.57 (1 H, s), 9.27 (1 H, s), 8.56-8.64 (2 H, m), 8.51 (1 H, d, J=1.7 Hz), 8.44 (1 H, d, J=8.8 Hz), 8.02 (1 H, dd, J=8.7, 2.3 Hz), 5.47 (1 H, quin, J=8.9 Hz), 3.49-3.60 (1 H, m, J=12.0, 12.0, 3.8, 3.7 Hz), 2.91 (6 H, s), 2.48-2.61 (2 H, m), 2.02-2.34 (6 H, m), 1.85-1.98 (2 H, m), 1.70-1.85 (2 H, m, J=12.3, 12.3, 12.2, 4.4 Hz). LCMS-ESI (POS), M/Z, M+1: Found 485.2.