Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[C:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=O)(C)(C)C.CS(O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:10]12[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:14](=[O:23])[N:11]1[CH2:12][CH2:13][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N(CC(F)(F)F)C(=O)C2(Cc3ccccn3)CNCCN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5a]pyrazine-7carboxylic acid tert-butyl ester (prepared as described in Step 5, 1.89 g, 4.4 mmol) in CH2Cl2 (20 mL) was added MeSO3H (2.14 g, 22 mmol). The reaction mixture was stirred at room temperature for one hour. Triethylamine (2.45 g, 24.2 mmol) was added to the solution. The organic layer was washed with 100 mL of H2O, brine, dried over MgSO4, and concentrated to give a 1.4 g of the title compound as a yellow oil (97%). The oil solidified upon granulation in hexane or upon cooling.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[NH:31][CH2:30][CH2:28][OH:29]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: NCCO
Product: O=C(Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12)NCCO

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with ethanolamine at 22° C. to give the title compound as a white solid. MS: 421.0 ([M+H]+).
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: O=C1COCC(=O)O1
Reactant: NCCO
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 2-aminoethanol to produce [2-(2-hydroxyethylamino)-2-oxoethoxy]acetic acid, (b) heating to cyclixe the latter to obtain 4-(2-hyroxyethyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 2-(3,5-dioxomorpholino)ethyl methanesulfonate and (d) reacting the mesylate with piperidine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6].[N-:35]=[N+:36]=[N-:37].[Na+]>CS(C)=O>[N:35]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6])=[N+:36]=[N-:37]
Reactant: COc1ccc(CO[C@@H](C(=O)O[C@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CO[C@@H](C(=O)O[C@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])cc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, (1R)-1-phenylethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (34a) (0.42 g, 0.82 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 75 mg (1.15 mmol) of sodium azide (NaN3). After work-up, the crude title compound (34b) was used in the next step without further purification. MS (ESI) m/z 542.02 (M+Na)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:10]=[CH:9]2.[N+](C1C=CC([O:34][C:35](=O)[NH:36][C:37]2[O:41][N:40]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=2)=CC=1)([O-])=O.CO>CN(C=O)C.ClCCl>[C:42]([C:39]1[CH:38]=[C:37]([NH:36][C:35]([NH:1][CH2:2][C:3]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:10]=[CH:9]3)=[O:34])[O:41][N:40]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: CN(C)CCn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CCn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)no3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
A solution of {2-[5-(2-Aminomethyl-4-fluorophenoxy)-indazol-1-yl]-ethyl}-dimethylamine (0.020 g, 0.061 mmol) in DMF (1 mL) was treated with (3-tert-butylisoxazol-5-yl)-carbamic acid 4-nitrophenyl ester (0.020 g, 0.067 mmol) (prepared according to Example 136, Step E). The mixture stirred at room temperature for 18 hours under a N2 atmosphere. The reaction mixture was chromatographed eluting with dichloromethane/ether (10:1) and then 5% MeOH in dichloromethane to afford 5.3 mg of pale yellow oil (18% yield). MS (APCI+) m/z 495 (M+1) detected; 1H NMR (400 mHz, DMSO-D6) δ 10.14 (s, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.22 (d, 1H), 7.16 (m, 2H), 7.08 (m, 1H), 6.88 (m, 2H), 5.93 (s, 1H), 4.48 (t, 2H), 4.35 (d, 2H), 2.70 (t, 2H), 2.17 (s, 6H), 1.23 (s, 9H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][OH:24])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][OH:24])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:30]([CH:38]([CH3:39])[CH3:40])=[CH:31][CH:32]=[CH:33][C:34]=2[CH:35]([CH3:37])[CH3:36])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCO)c2)c2cccnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(CCCO)c2)c2cccnc21
Yield: 100 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-hydroxy-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (10 mg, 0.02 mmol) in methanol (3 ml) were added ammonium formate (5 mg, 0.08 mmol) and 10% palladium-carbon (5 mg), and the mixture was heated under reflux for five hours. After allowed to stand for cooling, the mixture was filtered through a cerite pad, and the filtrate was concentrated. The concentrated residue was diluted with ethyl acetate, and washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and further purified by thin layer chromatography (hexane:ethyl acetate=5:5) to give the title compound (6 mg, 0.02 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[F:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][C:52]=1[CH3:53])[CH2:48]Br.C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:48][C:47]2[CH:50]=[CH:51][C:52]([CH3:53])=[C:45]([F:44])[CH:46]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(CBr)cc1F
Reactant: Cc1cc(/C=C/C(=O)N2CCN(Cc3ccc(CCOc4ccc(Cl)cc4)cc3)CC2)cc(Cl)c1Oc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(Cl)cc6)cc5)CC4)cc3Cl)nc2)cc1F
Reaction time: 4 h

Procedure:
To a solution of (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methyl-phenyl}-1-(4-{4-[2-(4-chlorophenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (400 mg) was added 3-fluoro-4-methylbenzyl bromide (144 mg) and K2CO3 (134 mg) at room temperature, then the reaction mixture was stirred for 4 hours. The reaction mixture was diluted with H2O and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to afford (E)-3-[3-chloro-4-({5-[(3-fluoro-4-methylbenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-chlorophenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one as a colorless amorphous (430 mg).
Reaction SMILES: [S:1]1([CH2:7][CH:6]=[CH:5][CH2:4]1)(=[O:3])=[O:2].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[NH:18][NH2:19].[OH-].[K+]>>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]([CH:5]1[CH2:6][CH2:7][S:1](=[O:3])(=[O:2])[CH2:4]1)[NH2:19]
Reactant: O=S1(=O)CC=CC1
Reactant: NNc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Product: NN(c1ccc2ccccc2c1)C1CCS(=O)(=O)C1
Reaction time: 16 h

Procedure:
To a mixture of 0.5 mole of butadiene sulfone (commercially available from Aldrich, Milwaukee, Wis.) and 0.55 mole of 2-naphthylhydrazine is added 0.005 mole 40% aqueous potassium hydroxide solution. The mixture is kept for 16 hours at 60° C. N-(2-Naphthyl)-N-sulfolan-3-ylhydrazine is isolated and purified.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@@H:14]3[C@@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[N-:19]=[N+]=[N-].[Na+].[NH4+].[Cl-].[OH-].[NH4+].CP(C)C>C(Cl)Cl.C1COCC1.O.[Cu]I.CCO>[NH2:19][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@@H:14]3[C@@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)[C@H]2C[C@H]2O1
Agent: [Cu]I
Agent: CP(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: NC1=N[C@](CF)(c2cc(N)ccc2F)[C@H]2C[C@H]2O1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
To a mixture of (1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (6g-B, 0.61 g, 1.9 mmol), sodium azide (0.388 g, 5.96 mmol), (+)-sodium 1-ascorbate (0.080 g, 0.41 mmol), copper(I) iodide (0.086 g, 0.45 mmol) and (1R,2R)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.075 mL, 0.47 mmol) under argon atmosphere were added EtOH (2.40 mL) and water (1.2 mL). The reaction mixture was heated at 70° C. for 1.5 h. The cooled reaction mixture was poured into a mixture of 10:1 NH4Cl/ammonium hydroxide and diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×) and the combined organic extracts were washed with aqueous saturated NH4Cl solution. The solution was dried over MgSO4 and the filtrate was concentrated in vacuo to give a yellow solid, which was dissolved in THF (8.4 mL) and water (2.8 mL). Trimethylphosphine (1.0 M solution in THF, 1.924 mL, 1.924 mmol) was added and the reaction mixture was stirred at RT for 20 min. The reaction was diluted with CH2Cl2 and water. The phases were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and the filtrate was purified by silica gel flash column chromatography (0% to 5% 2 M NH3 in MeOH/CH2Cl2) to afford the title compound (0.4473 g, 1.766 mmol, 92% yield) as a maize color solid. MS m/z=254.0 [M+H]+. Calculated for C12H13F2N3O 253.1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:18])[CH3:17])([CH3:14])([CH3:13])[CH3:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:18])[CH:10]=2)[CH:6]=[N:7]1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1ccc2cn[nH]c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
6-Bromo-1H-indazole (1.3 g, 6.6 mmol) and t-butylacetate (1.33 mL, 9.9 mmol) in toluene (20 mL) were degassed with argon for 15 mins. Then the mixture was cooled to 0° C. and LiHMDS (16.5 mL, 16.5 mmol, 1M in hexane) was added dropwise. Bis(dibenzylideneacetone)palladium (380 mg, 0.66 mmol) and tri-t-butyl phosphine tetrafluoroborate (383 mg, 1.32 mmol) were added and the mixture was stirred at 10° C. for 2 hours. The mixture was quenched with water (10 mL) then extracted with EtOAc (3×25 mL). The combined organic phases were washed with water (2×10 mL), brine (10 mL) and dried over sodium sulphate (Na2SO4). The filtrate was evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 80:20) to afford the title compound as a white solid (65%, 1.00 g).
Reaction SMILES: [Cl-].[C:2]([O:13][CH2:14][CH3:15])(=[O:12])[C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([O-:8])=O)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:20]([O:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[CH2:33][C:34]#[N:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl>C(Cl)Cl>[C:34]([CH2:33][C:32]1[CH:36]=[C:37]([CH:38]=[CH:39][C:31]=1[O:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[C:2]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])#[N:35]
Reactant: CCOC(=O)c1cccc(C(=O)[O-])c1
Reactant: CCCCCCCCCCOc1ccccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CC#N
Temperature: 0 °C
Yield: 38.6 %

Procedure:
To a solution of 1.45 g of isophthalic acid, monoethyl ester monochloride in 25 ml of methylene chloride cooled to 0° C. by means of an external ice bah were added to 2.73 g aluminum chloride. After stirring for an hour, 1.87 g of 2-decyloxybenzyl cyanide were added. The reaction was stirred at 0° C. for 4 hours and then poured into ice water containing hydrochloric acid. After stirring for 1 hour, the layers were separated. The organic layer was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography over silica gel eluting with a 5-30% ethyl acetate in hexane gradient. The appropriate fractions were pooled and concentrated in vacuo to provide 1.1 g of the title product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:18]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=3[CH:18]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(C(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isopropyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a light yellow solid (9.6%). LCMS: m/z=525.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.41 (s, 1H), 7.34 (d, 1H, J=7.1 Hz), 7.18 (m, 6H), 4.50 (m, 1H), 2.84 (m, 3H), 2.23 (m, 1H), 2.07 (m, 2H), 1.76 (m, 1H), 1.31 (s, 3H), 1.26 (d, 3H, J=6.6 Hz), 1.18 (s, 3H), 0.86 (d, 3H, J=7.1 Hz).
Reaction SMILES: CN(C)C=O.[CH:6]1([N:12]([CH2:30][CH2:31][OH:32])[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:33]=[C:34]1[O:38][C:36](=[O:37])[CH2:35]1>C(N(CC)CC)C>[C:36]([O:32][CH2:31][CH2:30][N:12]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]2)(=[O:37])[CH2:35][C:34]([CH3:33])=[O:38]
Reactant: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)OCCN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To 100 ml of dimethylformamide, there were added 7.45 g of N-cyclohexyl-N-(2-hydroxyethyl)-4-(6-carbostyriloxy)butyramide and 0.5 ml of triethylamine, then the whole mixture was heated at 80° to 90° C. on an oil bath. Next, 1.8 g of diketene were added dropwise to the reaction mixture, then the mixture was stirred for 1 hour at the same temperature. The reaction mixture was concentrated then was purified by a silica gel column chromatography (eluant: chloroform/methanol=50/1), and the solvent was removed by distillation under reduced pressure to yield 6.33 g of N-(2-acetoacetoxyethyl)N-cyclohexyl-4-(6-carbostyriloxy)butyramide in the form of a brownish oily substance.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18](OC)=[O:19])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]([O:31][CH:28]([CH3:30])[CH3:29])=[O:19])[CH2:14][CH2:15]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)O
Reactant: COC(=O)CCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)CCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dispersion of NaH (˜20 mg of a 60% oil dispersion) was added to a solution of 13b (799 mg, 2.37 mmol) in isopropyl alcohol (10 mL). The resulting mixture was immediately stoppered tightly and stirred at RT for 2 h. The reaction mixture was evaporated to dryness and chromatographed over silica gel using 3:1 heptane/EtOAc to give 0.75 g of 13d as a colorless viscous oil. The structure was confirmed by 1H NMR. (Propanoate esters 13e and 13f were similarly prepared using isobutanol and cyclopentanol, respectively (as mentioned above, 13e was also prepared by the previous method using isobutyl acrylate).)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:34]1([C:40](=[S:42])[NH2:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl.CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:41][C:9]=2[C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 2-propen-1-yl [3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate (30 g, 82.9 mmol) in DCM (300 mL), NBS (14.8 g, 82.9 mmol) was added and the solution was allowed to stir at rt for 30 min. The reaction mixture was then concentrated on the rotovap and the resulting oil was diluted with DMSO (240 mL) and 4-morpholinecarbothioamide (14.8 g 101 mmol) was added at once. The reaction was complete after stirring 1 h at rt. The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the product of Step A (40 g, 98.8% yield) which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:21][CH2:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(F)c(F)cc1Cl
Reactant: NCC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(F)c(NCC2CCOCC2)cc1Cl
Reaction time: 36 h

Procedure:
2-Chloro-4,5-difluorobenzenesulfonamide (0.683 g), (tetrahydro-2H-pyran-4-yl)methanamine (0.346 g), N,N-diisopropylethylamine (0.681 ml) and dioxane (10 ml) were heated at 65° C. for 2.5 days. Additional (tetrahydro-2H-pyran-4-yl)methanamine (0.346 g) and N,N-diisopropylethylamine (0.681 ml) were added and heating was continued at 70° C. for 1.5 days. The reaction mixture was concentrated and column chromatographed on silica gel with 0-3% methanol in dichloromethane as eluent. The obtained solid was triturated with dichloromethane to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:22])[CH:4]=[N:3]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[CH:33]=[C:32]([C:35](O)=[O:36])[CH:31]=[C:30]2[C:38]1[NH:42][N:41]=[N:40][N:39]=1>>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[CH:33]=[C:32]([C:35]([N:15]1[CH2:14][CH2:13][C:12]3([CH2:11][C:10](=[O:22])[C:9]4[C:19](=[CH:20][CH:21]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[CH:8]=4)[O:18]3)[CH2:17][CH2:16]1)=[O:36])[CH:31]=[C:30]2[C:38]1[NH:39][N:40]=[N:41][N:42]=1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Reactant: COc1cccc2c(-c3nnn[nH]3)cc(C(=O)O)cc12
Product: COc1cccc2c(-c3nnn[nH]3)cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)cc12

Procedure:
The compound is synthesized according to the procedure described in Example 1, using 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one instead of 4-oxospiro(chroman-2,4′-piperidin)-6-yl acetamide, and 8-methoxy-4-(1H-tetrazol-5-yl)-2-naphthoic acid instead of 4,8-dimethoxyquinoline-2-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.39 (1H, s), 8.21 (1H, d, J=8.0 Hz), 8.12 (1H, s), 8.01 (1H, d, J=2.0 Hz), 7.83-7.77 (3H, m), 7.63 (1H, t, J=8 Hz), 7.15 (1H, d, J=8 Hz), 7.11 (1H, d, J=8.0 Hz), 4.40-4.22 (1H, m), 4.02 (3H, s), 3.83 (3H, s), 3.70-3.30 (3H, m), 2.89 (2H, s), 2.12-1.75 (4H, m). MS [M+H]+=550.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[CH2:19][C@H:18]3[NH:20]C(=O)OC(C)(C)C)=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:28].C(OCC)(=O)C>>[ClH:28].[NH2:20][C@@H:18]1[CH2:19][C@H:17]1[C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [trans-2-(4-{[(3-bromophenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate (407 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (320 mg).