Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[C:16]([CH3:21])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:29]2[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[C:16]([CH3:21])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1Br
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 53.9 %

Procedure:
(4-Bromo-3-methyl-benzyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-2c: 250 mg, 0.675 mmol) was added to a 5 mL microwave vial and dissolved in 2 mL of 1,2-dimethoxyethane. To this solution was added 4-nitro-phenyl boronic acid (146 mg, 0.878 mmol) and 1 mL of a 2M aqueous sodium carbonate solution and tetrakis(triphenylphosphine) palladium (0.040 g, 0.0338 mmol). The reaction mixture was purged with nitrogen and sealed before heating to 80° C. by microwave irradiation for 15 minutes. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography eluting with 15% ethyl acetate in heptane. Collection and extraction of the product-containing band followed by concentration under reduced pressure afforded the title compound (I-8a: 0.150 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29]CCS(C)(=O)=O)[CH2:25][CH2:24]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:55][O:56][C:57]([C@@H]1CNCCN1C)=[O:58]>>[CH3:55][O:56][C:57]([C@@H:25]1[CH2:24][N:23]([C:21]([N:11]2[C@@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C@@:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:54])[N:9]=[C:10]2[C:36]2[CH:41]=[C:40]([S:42](=[O:44])(=[O:43])[NH:45][C:46]([CH3:48])([CH3:49])[CH3:47])[C:39]([Cl:50])=[CH:38][C:37]=2[O:51][CH2:52][CH3:53])=[O:22])[CH2:28][CH2:27][N:26]1[CH3:29])=[O:58]
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reactant: COC(=O)[C@@H]1CNCCN1C
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)[C@H](C(=O)OC)C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with (S)-1-methyl-piperazine-2-carboxylic acid methyl ester to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H45N5O6SCl3 [(M+H)+] 792.2151, observed 792.2148.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[N:23]=[N:24][C:25]([N:28]([CH3:30])[NH2:29])=[CH:26][CH:27]=1>>[Cl:21][C:22]1[N:23]=[N:24][C:25]([N:28]([CH3:30])[NH:29][C:18]([C:8]2[CH:9]=[N:10][C:11]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:20])=[CH:26][CH:27]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: CN(N)c1ccc(Cl)nn1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and 3-chloro-6-(1-methylhydrazinyl)-pyridazine (CAN 76953-33-8) as starting materials; MS (EI) 430.4 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:27])=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:7]=2[CH:26]=1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[F:2][C:3]1[C:4]([F:27])=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH:25][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:7]=2[CH:26]=1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(F)c(F)cc34)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(F)c(F)cc34)CC2)CC1)C1CCOCC1

Procedure:
The title compound, MS: m/e=476.3 (M+H+), was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine hydrochloride (example 62, step 1) and tetrahydro-pyran-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[Na+]>C1COCC1.C(O)C>[OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cc3)c(O)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 400 mg (0.92 mmol) of ethyl 4-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)benzoate with 336 mg (8.4 mmol) of sodium hydroxide in a THF/ethanol mixture (20 ml/20 ml), 214 mg (58%) of a pink powder are obtained. m.p.=217° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.C(OCC)C.[C:25]([CH2:28][C:29](=O)[CH3:30])(=[O:27])[CH3:26]>>[C:25]([CH:28]=[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1)[CH3:30])(=[O:27])[CH3:26]
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Solvent: CCOCC
Product: COc1ccc(NC(C)=CC(C)=O)cc1C1=NC(=O)C2=NN=NC2=N1

Procedure:
A stirred suspension of 2-(5-amino-2-methoxyphenyl)-8-azapurin-6-one (1.34 g) in acetylacetone (15 ml) was heated at reflux for one hour. The mixture was then cooled and poured into diethyl ether (100 ml). The precipitated solid was filtered off and recrystallised twice from ethanol with the aid of charcoal to give 2-[5-(1-acetylprop-1-en-2-ylamino)-2-methoxyphenyl]-8-azapurin-6-one (1.2 g), m.p. 239°-240° C. (with decomposition).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[N:22]([CH3:23])[CH:21]=[CH:20][C:18]=2[N:19]=1>CN1C(=O)CCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[N:22]([CH3:23])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cn1ccc2nc(Cl)nc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3ccn(C)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred suspension of NaH (8.9 mg, 0.22 mmol) in dry NMP (1.0 mL) was added 2,4,6-trimethyl phenol (30.2 mg, 0.22 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (44.6 mg, 0.22 mmol) in dry NMP (1.0 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1-2:1), to give the product as a light yellow solid (52.7 mg, 80%).
Reaction SMILES: C([O:8][C:9]([C:11]1[NH:15][C:14]([CH2:16][C:17]2[NH:18][C:19]([CH2:26][C:27]3[NH:28][C:29]([C:39]([O:41]CC4C=CC=CC=4)=[O:40])=[C:30]([CH3:38])[C:31]=3[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:20]([CH2:24][CH3:25])[C:21]=2[CH2:22][CH3:23])=[C:13]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[C:12]=1[CH3:55])=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[C:39]([C:29]1[NH:28][C:27]([CH2:26][C:19]2[NH:18][C:17]([CH2:16][C:14]3[NH:15][C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:55])[C:13]=3[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[C:21]([CH2:22][CH3:23])[C:20]=2[CH2:24][CH3:25])=[C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:30]=1[CH3:38])([OH:41])=[O:40]
Reactant: CCOC(=O)Cc1c(Cc2[nH]c(Cc3[nH]c(C(=O)OCc4ccccc4)c(C)c3CC(=O)OCC)c(CC)c2CC)[nH]c(C(=O)OCc2ccccc2)c1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(Cc2[nH]c(Cc3[nH]c(C(=O)O)c(C)c3CC(=O)OCC)c(CC)c2CC)[nH]c(C(=O)O)c1C
Yield: 98.3 %

Procedure:
2,5-Bis(5-benzyloxycarbonyl-3-ethoxycarbonylmethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole (11) (0.75 g, 1 mmol) was dissolved in 85 ml of dry THF and hydrogenated over 10% palladium-charcoal (41 mg) at 1 atm H2 until the reaction was deemed complete as judged by TLC. The catalyst was then separated by filtration, the solvent reduced in volume on the rotary evaporator, and the product precipitated by trituration with n-heptane. The white precipitate was collected by filtration and dried in vacuo to yield 0.56 g (98%) of 12 (m.p. 149° C. (dec.)), which was then used directly in the next step (the synthesis of 3, vide infra) without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH:20]=[O:21])[CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:32]=[C:33]([N:38]=[C:39]=[S:40])[CH:34]=[C:35]([Cl:37])[CH:36]=1>CC(N(C)C)=O>[Cl:29][C:24]1[CH:23]=[C:22]([N:19]([C:4]2[CH:3]=[C:2]([NH:1][C:39]([NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)=[S:40])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=3)[CH:5]=2)[CH:20]=[O:21])[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: Nc1cc(Nc2cccc(C(F)(F)F)c2)cc(N(C=O)c2cc(Cl)cc(Cl)c2)c1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CC(=O)N(C)C
Product: O=CN(c1cc(Cl)cc(Cl)c1)c1cc(NC(=S)Nc2cc(Cl)cc(Cl)c2)cc(Nc2cccc(C(F)(F)F)c2)c1
Reaction time: 8 h

Procedure:
To a solution of N-(3-amino-5-{[3-(trifluoromethyl)phenyl]amino}phenyl)(3,5-dichloro-phenyl)formamide (0.54 g, 1.2 mmol), in DMA (10 mL) was added 3,5-dichlorophenylisothiocyanate (0.30 g, 1.5 mmol) and the mixture stirred overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1Br
Yield: 93.9 %

Procedure:
A mixture of 2-bromo-4-nitrophenol (Description 40, 2.5 g), 2-iodopropane (2.2 g) and potassium carbonate (5 g) in acetone (30 ml) was heated under reflux for 18 h. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10) to give the title compound (2.8 g, 94%). 1H NMR (250 MHz, CDCl3) δ8.46 (1H, s), 8.20 (1H, m), 6.93 (1H, m), 4.75 (1H, m), and 1.42 (6H, d, J 7.5 Hz).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12](C(OC(C)(C)C)=O)[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[ClH:28].CCOCC>>[ClH:28].[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOCC
Product: CCCCOc1cccc(CCNCC(=O)N(C)C)c1
Yield: 95 %

Procedure:
A solution of 2-[2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide (9.6 g, 25.3 mmol) in HCl/Et2O (127 ml) was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure, the residue was ground with a mixture of Et2O/iPr2O 50/50, filtered and washed with Et2O/iPr2O to obtain the title compound as white solid (1.71 g, yield 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=O)[CH2:6]Br.[NH2:12][C:13]([NH2:15])=[O:14].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:12][C:13](=[O:14])[NH:15][CH:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: NC(N)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cc(-c2cccc(Br)c2)[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 3-bromophenacyl bromide (0.5 g, 1.8 mmol), urea (0.32 g, 5.3 mmol), and ammonium acetate (0.40 g, 5.4 mmol) in water (10 mL) was added glacial acetic acid (0.32 g, 5.4 mmol). The reaction mixture was heated at reflux overnight. After cooling to room temperature, the mixture was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give a brown residue which was triturated with diethyl ether to afford the desired product. LC/MS 238.9 and 240.9 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:23]([CH:27]6[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]6)[N:24]=[CH:25][CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:42]([CH3:49])([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C)C=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:23]([CH:27]6[CH2:32][CH2:31][CH2:30][N:29]([C:42]([CH3:49])([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:28]6)[N:24]=[CH:25][CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCCC(n2nccc2-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)C1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-9-[2-(3-piperidyl)pyrazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine; I; 100 mass % in N,N-Dimethylformamide; 100 mass % was added Cesium Carbonate; 2.00 equiv.; 1.090 mmol; 100 mass % followed by ethyl 2-bromo-2-methyl-propanoate; G; 3.00 equiv.; 1.635 mmol; 100 mass %. The reaction mixture was heated to 90° C. and was stirred for 12 hours. LC-MS analysis of the reaction mixture showed almost complete conversion to the desired product. The solvent was removed and the residue was purified on silica gel (0→10% MeOH/DCM) to yield ethyl 2-(3-(5-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylpropanoate as a light yellow foam.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[C:20]([F:37])([F:36])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc(F)cc1)c1ccccc1C(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: Fc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (7.5 mmol) and 2-(trifluoromethyl)-4′-fluorobenzhydrol (160) (15 mmol) using the procedure described for compound (3). After basic aqueous workup, the crude product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[F:20][C:21]([F:28])([F:27])[C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:9][C:8]1[C:3]([CH2:2][N:24]2[CH:25]=[CH:26][C:22]([C:21]([F:28])([F:27])[F:20])=[N:23]2)=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc(C(F)(F)F)n1
Yield: 67.3 %

Procedure:
The title compound of Step C (0.7 g, 2 mmol), 3-trifluoromethylpyrazole (0.27 g, 2 mmol) and potassium carbonate (0.83 g, 6 mmol) were suspended in 10 mL of acetonitrile and heated to reflux for 1 h. The salts were filtered and the acetonitrile was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (85:15) to afford 0.52 g of the title compound of Step D, a compound of this invention, as a white solid melting at 112-114° C. 1H NMR (CDCl3): δ2.39 (s, 3H), 5.53 (s, 2H), 6.62 (d, 1H), 7.6-7.8 (m, 3H), 8.44 (d, 2H), 8.6 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]([O-:13])=O)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[NH2:18].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:11](=[O:13])[CH:3]([O:2][CH3:1])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COC(C(=O)[O-])C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COC(C(=O)Nc1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Yield: 30 %

Procedure:
Mono-t-butyl methoxymalonate (5.42 grams, 0.03 mole), prepared in Part B, 3,5-dichloroaniline (4.62 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (5.88 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 2.92 grams (0.009 mole) of t-butyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-3-oxopropanoate having a melting point of 129.5° C.-131.5° C. Elemental analysis of the product indicated the following:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[CH2:12]([NH:11][C:9](=[O:10])[CH2:8][N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNC(=O)CBr
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCNC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
Potassium carbonate (1.52 g, 11 mmol) was added to a solution of this amide (2.36 g, 10 mmol) and 1-(2-hydroxyethyl)piperazine (1.30 g, 10 mmol) in acetonitrile (40 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the residue obtained by evaporation of the solvent was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20) to provide 2.39 g (yield 83%) of N-heptyl-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:26]([C:27]([O:29]CC=C)=[O:28])=[C:16]3[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1.C(O)=O.C(OC(C)C)(C)C>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:26]([C:27]([OH:29])=[O:28])=[C:16]3[C:17]([C:21](=[O:25])[N:22]([CH3:23])[CH3:24])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)N(C)C)c12
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: COc1cc(OC)nc(Oc2ccc3oc(C)c(C(=O)N(C)C)c3c2C(=O)O)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
1.40 g of allyl 5-(4,6-dimethoxypyrimidin-2-yl)oxy-3-dimethylcarbamoyl-2-methylbenzofuran-4-carboxylate and 0.29 g of formic acid were dissolved in 12 ml of tetrahydrofuran, and 37 mg of tetrakistriphenylphosphine palladium (0) was added thereto under a nitrogen atmosphere. The mixture was heated and stirred at 50° C. for 3 hours. The mixture was returned to room temperature, and then isopropyl ether was added to the reaction solution. Precipitated crystals were collected by filtration to obtain 1.02 g (yield: 80%) of the desired compound.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:20])C.[Li+].[OH-].CC#N.O.FC(F)(F)C(O)=O>O1CCCC1.O>[O:20]=[C:7]1[N:6]([CH2:5][C:4]([OH:21])=[O:3])[C:10]2[CH:11]=[C:12]([O:15][C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:14][C:9]=2[O:8]1
Reactant: CCOC(=O)Cn1c(=O)oc2ccc(OC(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)oc2ccc(OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
Ethyl[2-oxo-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-3(2H)-yl]acetate (0.96 g, 3.0 mmol) was dissolved in 10 mL of tetrahydrofuran and treated with a solution of LiOH (0.083 g, 3.5 mmol) dissolved in 1.0 mL of water. The reaction was stirred vigorously at room temperature for 18 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.3 min and m/e 278 [M+1]+. The solvent was removed by rotary evaporation and the residue was then dissolved in 100 mL of ethyl acetate. The organic layer was washed with a 10% hydrochloric acid solution (3×30 mL) and the organic phase was then dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by prep HPLC (Phenomenex, 30×75 mm, 40 mL/min, A: acetonitrile (0.1% TFA) B: water (0.1% TFA), A: 10 to 99% over 15 min, UV detection at 214 nm) to give [2-oxo-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-3(2H)-yl]acetic acid (0.39 g, 1.4 mmol, 47%) as an off-white amorphous solid. MS (ES) m/e 278 [M+H]+.