Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[NH2:30][C:31]1([CH3:35])[CH2:34][S:33][CH2:32]1.O>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7](=[O:27])[NH:30][C:31]2([CH3:35])[CH2:34][S:33][CH2:32]2)[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC1(N)CSC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC2(C)CSC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 50 °C
Yield: 40 %

Procedure:
To a solution of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (1.13 g, 2.56 mmol) (prepared according to WO 02/48115, example 2D) in tetrahydrofuran (15 ml) is added 3-amino-3-methyl-thietane (the product of step 3) (0.66 g, 6.40 mmol), and the mixture is heated for 48 hours at 50° C., then to reflux for 12 hours. The cooled reaction mixture is poured into water, extracted with ethyl acetate, the combined organic layers washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product is purified by flash chromatography (ethyl acetate/hexane 1:2) to afford 560 mg (40%) of the title compound as a white solid, m.p. 238-241° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:4].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([NH:23][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:25][CH2:26]3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(CCl)c1ccc2c(c1)CCCC2
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-chloroacetyl-1,2,3,4-tetrahydro naphthalene (20.87 g.), 4-benzamidopiperidine (20.4 g.) and triethylamine (11.1 g.) in dimethylformamide (200 ml.). was stirred for 3 days at room temperature. The crystals which had formed during this time were then filtered off, washed and dried. A portion of this crystalline solid (4.0 g.) was dissolved in ethanol (50 ml.) and acidified with ethanolic hydrogen chloride to give 4.0 g. of the hydrochloride of the title compound, m.p. 270° C (decomp.). (Found: C, 69.5; H, 7.2; N, 6.8; C24H28N2O2.HCl requires C, 69.8; H, 7.1; N, 6.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.C(OC([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:34]3[CH:35]=[N:31][NH:32][CH:33]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3cn[nH]c3)cc21
Yield: 44 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (109 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylic acid-tert-butyl ester as in General Procedure 4B, then added 6 mL CH2Cl2 and TFA (0.6 mL), and purified on normal phase silica gel chromatography to give the title compound as an off-white solid (44% yield). m.p.=271° C., LCMS: m/z=394.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.50 (2H, m), 3.66 (2H, m), 4.05 (3H, s), 4.61 (2H, s), 6.50 (1H, d, J=1.5 Hz), 7.40 (1H, s), 7.50 (1H, s), 7.56 (3H, m), 7.68 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH2:1]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([C:19]2[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[C:25]([C:31](=O)[C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:34][CH:33]=3)=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=O)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].O1CCCC1>[CH2:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:25]2[CH:24]=[C:20]([C:21]([OH:23])=[O:22])[C:19]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:52][CH:51]=3)=[CH:27][C:26]=2[C:28]([OH:30])=[O:29])=[CH:33][CH:34]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCCCCCCCC)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCCCCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A solution of 133 grams of 2,5-bis(4-dodecylbenzoyl)terephthalic acid and 1 L of tetrahydrofuran was treated with 8 grams of 10% palladium on carbon (as a catalyst) and heated to 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give a white solid. The solid was triturated with ethyl acetate, and the residue was dried to give 2,5-bis(4-dodecylbenzyl)terephthalic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7]O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:25].[Li+]>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][Br:25])[CH3:2]
Reactant: [Br-]
Reactant: CCOc1ccccc1CCO
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1CCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1.35 g (8.12 mmol) of 2-ethoxyphenethyl alcohol and 2.05 g (20.03 mmol) of triethylamine in 15 ml of dichloromethane was slowly added 1.86 g (16.24 mmol) of methanesulfonyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 2 h and was poured into 200 ml of mixed solution of hexanelether(1:1). It was washed with 30 ml of water, dried over MgSO4, filtered through a plug of silica gel and concentrated. The residue was dissolved in 30 ml of acetone and 2.82 g (32.48 mmol) of lithium bromide was added slowly at 0° C. The reaction mixture was refluxed for 5 h and volatiles were removed. The residue was added 150 ml of ether, washed with water (30 ml ×2), dried over MgSO4, filtered through a plug of silica gel and concentrated to give 2-ethoxyphenethyl bromide as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH:25]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:25]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26]2)=[O:21])=[CH:22][CH:23]=1
Reactant: O=C1CCNN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)n2ccc(=O)[nH]2)cn1
Yield: 5 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-pyrazolidinone hydrochloride instead of 2-aminoethyl isopropylether, to the title compound (12 mg, 5%) which was obtained as a white solid. MS: m/e=375.0 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]#[N:11])=[N:3]1.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CCO>[OH:14][N:13]=[C:10]([C:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[N:2]([CH3:1])[N:3]=1)[NH2:11]
Reactant: NO
Reactant: Cn1nc(C#N)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cn1nc(C(N)=NO)cc1[N+](=O)[O-]
Yield: 28.4 %

Procedure:
To a solution of 1-methyl-5-nitro-1H-pyrazole-3-carbonitrile (2.4 g, 15.8 mmol, Princeton) and hydroxylamine hydrochloride (3.29 g, 47.3 mmol) in EtOH (0.50 mL) was added potassium carbonate (10.9 g, 79 mmol) and the mixture was refluxed for about 2 h. The reaction mixture was filtered hot and the collected solid was rinsed with EtOH (50 mL) and then MeOH (100 mL). The filtrate was concentrated under reduced pressure. The crude material was partitioned between DCM (40 mL) and water (20 mL). The aqueous layer was acidified to about pH 2 using 1 N HCl and back extracted with DCM (20 mL). The aqueous layer was basified using saturated NaHCO3 and the precipitate was collected by vacuum filtration and dried to afford N′-hydroxy-1-methyl-5-nitro-1H-pyrazole-3-carboximidamide (1.24 g, 4.49 mmol, 67%). LC-MS (Table 1, Method g) Rt=1.07 min, m/z 186 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 9.78 (s, 1H), 7.22 (s, 1H), 5.71 (s, 2H), 4.16 (s, 3H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:58])[CH2:46][N:47]3[C:51]4[CH:52]=[CH:53][C:54]([OH:56])=[CH:55][C:50]=4[O:49][C:48]3=[O:57])[CH2:41][CH2:40]2)=[CH:35][C:34]=1[O:59][CH3:60].[O:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH:62]1[O:67][CH2:68][CH2:69]O>C1COCC1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:40][CH2:41][N:42]([C:45](=[O:58])[CH2:46][N:47]3[C:51]4[CH:52]=[CH:53][C:54]([O:56][CH2:69][CH2:68][O:67][CH:62]5[CH2:63][CH2:64][CH2:65][CH2:66][O:61]5)=[CH:55][C:50]=4[O:49][C:48]3=[O:57])[CH2:43][CH2:44]2)=[CH:35][C:34]=1[O:59][CH3:60]
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(O)ccc43)CC2)ccc1Cl
Reactant: OCCOC1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCOC5CCCCO5)ccc43)CC2)ccc1Cl
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a mixture of PPh3 (70 mg, 0.27 mmol, 1.1 eq), and DEAD (40 mg, 0.23 mmol, 1 eq) in THF (0.5 ml), was added 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (54) (100 mg, 0.24 mmol, 1 eq) in THF (1 ml). The reaction mixture immediately turned clear and was heated to 85° C. 2-(Tetrahydro-pyran-2-yloxy)-ethanol (38.5 mg, 0.27 mmol, 1.1 eq), was then added to the reaction solution, and stirred for 3 hours at rt. The isolated crude product was purified with HPLC to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-3H-benzooxazol-2-one (55).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([N:19]2[CH2:20][CH2:22][CH2:25][CH2:23]2)=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 3-methylpyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (348 mg, 1.52 mmol) in DMF (10 mL) were added DIPEA (0.53 mL, 3.04 mmol), pyrrolidine (0.25 mL, 3.04 mmol) and HATU (693 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with a 0.1N aqueous HCl solution and brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (334 mg, 78%). 1H NMR (400 MHz, CHCl3-d): δ 3.61-3.38 (m, 8 H); 2.00-1.79 (m, 6 H); 1.47-1.44 (m, 9 H); 1.33 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:24]=[C:23]2[C:17]([N:18]([CH3:29])[C:19](=[O:28])[CH2:20][CH2:21][N:22]2[CH:25]([CH3:27])[CH3:26])=[CH:16][N:15]=1)[C:7](O)=[O:8])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:24]=[C:23]2[C:17]([N:18]([CH3:29])[C:19](=[O:28])[CH2:20][CH2:21][N:22]2[CH:25]([CH3:26])[CH3:27])=[CH:16][N:15]=1)[C:7]([NH:54][CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1)=[O:8])[CH3:2]
Reactant: CN1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirred solution of 3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]benzoic acid (Intermediate 163; 80 mg, 0.20 mmol), HATU (115 mg, 0.30 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 35 mg, 0.30 mmol) in DMF (5 mL) was added diisopropylethylamine (105 μl, 0.60 mmol). The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a white foam (87 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(OC(C)(C)C)=O)=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c2c(N)ncnn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.5 %

Procedure:
To a suspension of butyl 4-amino-5-{4-[(tert-butoxycarbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (174.5 mg, 0.41 mmol) in dichloromethane (4 mL) was added TFA (2 mL). The solution was stirred at rt for 6.5 h and then the volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and then this solution was washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate, and concentrated to dryness under reduced pressure to afford 132.7 mg (99%) of the title compound. 1H-NMR (DMSO-d6) δ 8.10 (bs, 1H), 8.02 (s, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.08 (s, 1H), 6.64 (d, J=8.4 Hz, 2H), 5.55 (bs, 1H), 5.34 (s, 2H), 4.24 (t, J=6.5 Hz, 2H), 1.70-1.63 (m, 2H), 1.46-1.37 (m, 2H), 0.93 (t, J=7.4, 3H); MS [M+H]+=326.3; LCMS RT=2.07 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][CH:40]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(CCc3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2c(CCc3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 60b (55.0 mg, 0.102 mmol) in DCM (2 mL) at RT was added TFA (500 μL, 6.53 mmol). After stirring at rt for 0.5 h, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:9 MeOH-DCM) to afford the title compound 79 (with 1.1 eq TFA) as a white solid. 1H-NMR (CDCl3; 400 MHz) δ: 8.03 (d, J=8.6 Hz, 2H), 8.00 (d, J=5.6 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.56-7.62 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.11 (d, J=5.6 Hz, 1H), 3.87-4.05 (m, 8H), 3.57 (t, J=7.1 Hz, 2H), 3.34-3.43 (m, 2H), 3.07-3.18 (m, 2H), 2.71-2.83 (m, 2H), 1.77-1.95 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C28H29N5O3, 484.2 (M+H). found 484.5.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[C:6]([F:29])=[CH:7][C:8]([F:28])=[C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=3[CH3:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH:10]=1>C(O)(=O)C.CO>[NH2:4][C:5]1[C:6]([F:29])=[CH:7][C:8]([F:28])=[C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18]([O:2][CH3:1])[C:19]=3[CH3:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH:10]=1
Reactant: C[O-]
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
Methanol (500 mg) and sodium methoxide (28% methanol solution; 200 mg) were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (350 mg), and the mixture was heated and stirred at 40° C. for 2 days. Acetic acid (2 drops) was added to the reaction mixture to collect solids by filtration. The solids were washed with ethanol and dried to obtain the title compound (290 mg) as a pale yellow powder.
Reaction SMILES: C(OC([N:8]=[C:9]([NH:39]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:38]=[CH:37][C:14]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.CCOCC>C(OCC)(=O)C>[ClH:36].[NH:10]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:24])=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:37][CH:38]=1)[C:9]([NH2:39])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N=C(N)Nc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Reaction time: 3 h
Yield: 171.2 %

Procedure:
To 1-[4-(2,3-di-tert-butoxycarbonylguanidino)benzoyl]-4-(6-chloronaphthalene-2-sulfonyl)piperazine (295 mg) was added 4 N hydrochloric acid in ethyl acetate solution (20 ml) and the solution was allowed to stand at room temperature for 3 hours, to which was added ether. The precipitate was filtered, washed with ether and dried to give a colorless solid of the title compound (191 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:28][CH2:29][CH2:30]I>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:30][CH2:29][F:28])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC(NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)OC(C)(C)C)c1cccc(OCCF)c1
Reaction time: 9 h
Yield: 73.2 %

Procedure:
To methyl 3-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (4.46 g, 20 mmol) in THF was added cesium carbonate (9.84 g, 30 mmol) and 1-fluoro-2-iodoethane (5 g, 30 mmol) and the mixture was stirred for 9 hours. After filtration the filtrate was concentrated in vacuum to yield 5.0 g of methyl 3-[(tert-butoxycarbonyl)amino]-3-[3-(2-fluoroethoxy)phenyl)propanoate.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (120 mg, 0.27 mmol) in dichloromethane (2 mL). After 1 h, the mixture was concentrated and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 346.1 (M+1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[CH:26]=CC=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:39]1C=CC=C[N:40]=1)CCC>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[N:22]([CH3:23])[CH:39]=[N:40][CH:26]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc2cc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: Cc1cc2cc(-c3cncn3C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-5-yl)naphthalen-2-yl)acetic acid (65) was prepared in a similar fashion to compound 63 with the substitution of 1-methyl-5-(tributylstannyl)-1H-imidazole for 2-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) was isolated as an amorphous white powder. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H28ClN2O3: 463.98; found: 463.81. 1H-NMR: 400 MHz, (CD3CN) δ: 8.54 (s, 1H); 7.99 (s, 1H); 7.84 (s, 1H): 7.62-7.50 (m, 3H); 7.45-7.32 (m, 3H), 5.24 (s, 1H); 3.80 (s, 3H); 2.60 (s, 3H); 0.99 (s, 9H).