Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]([CH3:22])[CH3:21])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])[N:40]=[CH:39][N:38]=[C:37]2[O:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:50][C:49]2[CH:51]=[CH:52][CH:53]=[C:47]([O:46][C:37]3[C:36]4[C:41](=[CH:42][C:43]([O:44][CH3:45])=[C:34]([O:33][CH3:32])[CH:35]=4)[N:40]=[CH:39][N:38]=3)[CH:48]=2)=[O:19])[N:7]([CH:20]([CH3:21])[CH3:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C(C)C)c3)c2cc1OC
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.50 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (62 mg, 40%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 7.55-7.59 (m, 2H), 7.37-7.40 (m, 2H), 7.24 (m, 1H), 6.93 (m, 1H), 6.00 (s, 1H), 4.35 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 1.34 (d, J=6.4 Hz, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 505 (M+H)+.
Reaction SMILES: C(S[S:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:26](O)=[O:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[O:27]=[C:26]1[CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24][CH2:23][CH2:22][S:21]1
Reactant: O=C(O)CCC(CCCSSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC1CCCSC1=O
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 2-[3-(tritylthio)mercaptopropyl]pentanedioic acid (150 g, 0.33 mol) in dichloromethane (500 mL) was added dropwise trifluoroacetic acid (110 mL) over 30 minutes. After being stirred for an additional 30 minutes, a solution of triethylsilane (45 mL, 0.33 mol) in dichloromethane (50 mL) was added and the mixture was stirred at 45° C. for 1 hour. The volatiles were removed in vacuo and the residue was triturated with hexanes (500 mL×2). The oily residue was dissolved in toluene (500 mL) containing 10-camphorsulfonic acid (14 g) and refluxed for 6 hours. The liberated water was removed using a Dean-Stork azeotropic adapter. Toluene was then distilled off and the residue was purified by silica gel chromatography (EtOAc/hexanes, 1/4). Subsequent recrystallization from EtOAc/hexanes afforded 23.3 g of 3-(2-oxotetrahydro-2H-thiopyran-3-yl)propanoic acid as a white solid (37% yield): 1H NMR (CD3OD) δ 1.65-1.78 (m, 2H), 2.05-2.18 (m, 4H), 2.35-2.48 (m, 2H), 2.65-2.74 (m, 1H), 3.13-3.29 (m, 2H); 13C NMR (CD3OD) δ 23.3, 27.4, 29.3, 31.2, 32.3, 50.0, 177.0, 206.4. Analysis calculated for C8H12O3S: C, 51.04; H, 6.43; S, 17.03. Found: C, 51.08; H, 6.38; S, 17.16.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.C[O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:18])[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])O)=O.ClC1C=C(C=CC=1F)N.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.O(S(C)(=O)=O)S(C)(=O)=O>CCN(CC)CC>[Br:18][C:16]1[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]2[CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])[N:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH:5]=3)[C:11](=[O:10])[C:13]=2[CH:17]=1
Reactant: Cc1cc(N)n(C)n1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1F
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: Nc1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Product: Cc1cc(N2C(=O)c3cc(Br)n(C(C)C)c3C2c2ccc(Cl)cc2F)n(C)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate D but in the step corresponding to Step D2, 2,5-dimethyl-2H-pyrazol-3-ylamine [3524-32-1] and 5-bromo-2-[(4-chloro-2-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BI1) were used instead of 3-chloro-4-fluoroaniline and 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester respectively. Moreover, in this step, the procedure described for Step L3 using Ms2O and Et3N was used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a solid. ESI-MS: tR=1.14 min, [M+H]+ 465/467/469 (LC-MS 1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][O-:7].[Na+:8].C[OH:10]>>[NH:1]1[CH:5]=[C:4]([C:6]([O-:10])=[O:7])[N:3]=[N:2]1.[Na+:8]
Reactant: c1c[nH]nn1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: O=C([O-])c1c[nH]nn1
Yield: 98 %

Procedure:
17.4 g (0.25 mol) of 1,2,3-triazole was reacted with an equivalent amount of methanolic sodium methoxide solution in 200 ml of methanol by the process described for catalyst 1. The reaction mixture was worked up as described above to give 22.4 g of sodium 1,2,3-triazolate (yield: 98% of theory) in the form of a virtually colourless powder. The product was pure according to its 1H-NMR spectrum and free from starting material.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N+]([O-])(O)=O.S(=O)(=O)(O)[OH:19].[C:23](#[N:25])[CH3:24]>O>[C:23]([NH:25][C:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]([C:11]([OH:13])=[O:12])([CH2:8]3)[CH2:2]1)[CH2:4]2)(=[O:19])[CH3:24]
Reactant: CC#N
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(=O)NC12CC3CC(C1)CC(C(=O)O)(C3)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a 10-L reactor was added 1-adamantanecarboxylic acid (503 g, 2.79 mol; TCI America, Wellesley Hills, Mass., USA) and 70% nitric acid (400 mL, 6.72 mol), and the resulting suspension was cooled at 0° C. with a recirculating chiller. To the mixture was slowly added 98% sulfuric acid (3.00 L, 55.5 mol) at such a rate that the temperature was kept below 10° C. Once the addition completed, acetonitrile (2.00 L, 38.5 mol) was added at such a rate that the temperature was kept below 10° C. After all the acetonitrile was added, the reaction was stirred at 0° C. for 1 hour. The crude reaction was then added to a 20-L reactor filled with about 10-L of ice mixed with a small amount of water and the resulting mixture was stirred and allowed to warm to room temperature. The solids were then filtered and washed with water. More solids precipitated from the acidic aqueous layer and these were filtered as well and washed with water. The combined solid material was then dried under high vacuum at 50° C. for 2 days to afford 432 g (73%) of the title compound, 3-acetylamino-adamantane-1-carboxylic acid, as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:21])=[O:22])[CH3:34])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a solution of [(R)-5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (example 2-2, method D, 2nd step) (400 mg, 0.85 mmol) in acetonitrile (15 mL) was added methyl iodide (182 mg, 1.28 mmol) and potassium carbonate (350 mg, 2.53 mmol). The reaction mixture was stirred at 70° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-5-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (365 mg, 89%) as a yellow oil. MS cald. for C23H27ClFNO5S 483, obsd. 484 (ESI+) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 33 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and [2-(methyloxy)ethyl]amine (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 33% yield) as a yellow solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.22 (br s, 1 H), 8.56 (s, 1 H), 7.46 (s, 1 H), 7.16-7.16 (m, 2 H), 7.03-6.99 (m, 2 H), 4.31 (m, 2 H), 4.12 (s, 2 H), 3.64 (m, 2 H), 3.57 (m, 2 H), 3.49 (m, 2 H), 3.39 (s, 3 H), 1.82 (m, 2 H); HRMS m/z calcd for C22H25N3O5F: 430.1778. Found: 430.1778.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>>[CH2:1]([C:8]1[O:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([O:23][S:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=2)(=[O:31])=[O:30])=[C:19]([CH2:21][CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1O
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Yield: 32.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-hydroxy-phenyl)-methanone (0.5 g, 1.38 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.65 g, 2.74 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 10% EtOAc/hexane gave 0.251 g (32%) of the title compound as an off white solid, mp 143-147° C. 1H NMR (DMSO-d6) δ 1.01 (t, 6 H), 1.84 (s, 3 H), 2.20 (s, 3 H), 2.51 (q, 4 H, with DMSO peak), 3.81 (s, 2 H), 7.01 (d, 2 H), 7.16-7.20 (m, 1 H), 7.23-7.27 (m, 2 H), 7.45 (s, 2 H), 7.49-7.53 (m, 2 H), 8.06 (d, 1 H). mass spectrum (-ESI), m/z 561 (M-H). Anal. Calcd. for C31H30O8S: C, 66.18; H, 5.37; N, 0.00. Found: C, 65.80; H, 5.50; N, 0.22.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=O)=[CH:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1.[CH3:27][N:28]1[CH2:32][CH2:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1.C(Cl)CCl>CN(C=O)C.O>[CH3:27][N:28]1[CH2:32][CH2:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:13](=[O:15])[CH:12]([CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:26])=[CH:35][CH:34]=1
Reactant: Cn1cc(CC(N)C(=O)O)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1CCN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CN1CCN=C1c1ccc(NC(=O)C(Cc2cn(C)c3ccccc23)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of DL-1-methyl-tryptophan (71 mg, 0.33 mmol) in DMF (4 mL), 4-chlorophenyl isocyanate (50 mg, 0.33 mmol) was added. The mixture was then stirred at room temperature overnight. It was filtered. To the filtrate, 4-(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)-phenylamine (150 mg, 0.86 mmol) and H2O (0.5 mL, to solubilize the amine) were added. To the solution, EDC (127 mg, 0.66 mmol) was added. After being stirred at room temperature overnight, the solution was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (108 mg). MS 529.2 and 531.2 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:40]([NH:47][C@H:48]([C:53](O)=[O:54])[C:49]([CH3:52])([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:53](=[O:54])[C@H:48]([C:49]([CH3:52])([CH3:51])[CH3:50])[NH:47][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:46])[CH3:44]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A solution containing the product from Example 2C (0.050 g, 0.094 mmol) in THF (0.5 mL) was treated with Boc-L-tert-leucine (0.022 g, 0.096 mmol), DEPBT (0.042 g, 0.140 mmol), and N,N-diisopropylethylamine (0.08 mL, 0.459 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with 50-100% ethyl acetate/chloroform to give the title compound (0.058 g, 83% yield).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:10][CH2:9][C:8]2=[N:20]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1.Cl>N1C=CC=CC=1>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]1[CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:20][C:8](=[O:29])[CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1C1CCC(=NO)C(c2ccccc2)C1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C1CCC(=O)NC(c2ccccc2)C1
Temperature: 0 °C
Yield: 12.8 %

Procedure:
To a 250 mL round-bottomed flask equipped with nitrogen inlet were added 8.20 grams (29.4 mol) 2-phenyl-4-(2-methylphenyl)cyclohexanone oxime and 80 mL pyridine. Once the solid had dissolved, the solution was cooled to 0° C., and 27.9 grams (147 mmol) p-toluenesulfonyl chloride was added. The reaction was allowed to stir for 16 hours while the ice bath melted and the reaction warmed to room temperature. It was then poured into 300 mL 3N HCl, extracted into ethyl acetate, and the organic layer washed with additional hydrochloric acid and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluent to afford 5.27 grams (64%) of an amorphous solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].FC1C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=C(F)C(F)=C(F)C=1F.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C(CCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(OC(=O)CCCO[N+](=O)[O-])cc1
Yield: 85.5 %

Procedure:
To a solution of 4-acetamidophenol (Paracetamol) (0.96 g, 6.30 mmol) TEA (0.64 g, 6.3 mmol) and DMAP (0.77 g, 6.3 mmol) in CH2Cl2/THF (9:1, 30 ml) kept at 0° C., under stirring and under nitrogen atmosphere, a solution of 4-(nitrooxy)butanoic acid pentafluorophenyl ester (2.0 g, 6.30 mmol) (Preparation 2) in CH2Cl2 (10 ml) was added. The resulting solution was kept under stirring for further 240 minutes at room temperature. The reaction mixture was poured in a pH 3 buffer solution (about 50 ml), acidified with HCl 1 N to pH 3-4 and extracted with CH2Cl2 (2×50 ml). The organic phase washed with brine (100 ml), dried on sodium sulfate and evaporated under vacuum. Purification by Flash chromatography of the residue (n-hexane/AcOEt 1:1) gave the title compound as a white solid (1.52 g, 84%). M.p., NMR and HPLC analysis were consistent with data reported in the literature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]2[S:27][C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[O:13])=[C:2]([Cl:1])[CH:3]=1)(=[O:6])[NH2:32]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid, from Example 227, (0.08 g, 0.20 mmol) in 72 mL of THF was added as a whole HATU (0.082 g, 0.22 mmol) and DIEA (0.12 mL, 0.72 mmol). This reaction mixture was allowed to stir at room temperature for 30 minutes. Next, ammonium chloride (0.12 g, 0.22 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was taken into a large volume of ethyl acetate, washed with water, then saline and dried (Na2SO4). The organic was then concentrated in vacuo to give 322 as a solid residue, purified by RP-HPLC. Yield=25% of theoretical. MS: (ESI+)=442.1
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[N:10]=1>CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[C:11]([Cl:16])[N:10]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: C1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cc(N2CCCC2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of pyrrolidine (0.910 g, 10.7 mmol) in dry DMSO and NaH (0.385 g, 16.0 mmol) was stirred for 30 minutes at 0° C., after which a sample of 2,4,6-trichloropyridine (1.75 g, 9.63 mmol) was added. This reaction mixture was stirred at room temperature for 4 hours, after which time ice cold water was added to quench the reaction. The reaction mixture was then extracted with ethyl acetate, and the extract was washed 3-4 times with water. The organic layer was dried over sodium sulphate and concentrated. The residue was purified by column chromatography over 100-200 mesh silica gel. Elution of the column with 20% acetone in hexanes gave the pure product as a colorless solid (yield: 75%).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:31]=[CH:30][C:20]4[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:33]1C=C(C2C=CC3N=C(NC(NCC)=O)SC=3C=2)C=CC=1.C(N(CC)CC)C.C1(C)C=CC=C(N=C=O)C=1>C1(C)C=CC=CC=1>[C:5]1([CH3:33])[CH:4]=[CH:3][CH:2]=[C:1]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:31]=[CH:30][C:20]4[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4ccccc4)c3)cc2s1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Agent: Cc1cccc(N=C=O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4cccc(C)c4)c3)cc2s1
Yield: 26 %

Procedure:
Similar to the synthesis of 1-(6-(3-phenylaminocarbonylaminophenyl)-2-benzothiazolyl)-3-ethylurea, a mixture of 1-(6-(3-aminophenyl)-2-benzothiazolyl)-3-ethylurea, triethylamine, and 3-tolyl isocyanate in toluene was reacted to give the desired compound 0.023 g (26%). LC/MS 446.2 (M+1); LC retention time 3.76 min.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[F:21][C:22]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:22]=2[F:21])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccn2)c1F
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccn2)c1F

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 435.13 g/mol.