Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[N:33]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH2:33])=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCOCC1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 1.15 g (2.49 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) in THF (12.5 mL) was added 383 μL (3.48 mmol) of N-methylmorpholine and 392 μL (2.98 mmol) of isobutyl chloroformate. The resulting off-white slurry was stirred at 0° C. for 2 h, and then 336 μL (28% ammonia in water, 4.97 mmol) of ammonium hydroxide was added. After an additional 3 h at 0° C., the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound was used directly in the next step.
Reaction SMILES: C(NCC)C.C[Al](C)C.[CH2:10]([C:12]1[N:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16](=[O:24])[NH:17]2)[CH3:11].Cl.C[OH:32]>ClCCl>[CH2:10]([C:12]1[N:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[C:14]([OH:32])=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16](=[O:24])[NH:17]2)[CH3:11]
Reactant: CO
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2[nH]c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O

Procedure:
Diethylamine (0.63 ml) was added dropwise to a stirred solution of trimethylaluminum (2M solution in toluene; 3 ml) in dichloromethane (5 ml) under an atmosphere of argon. The mixture was stirred for 30 minutes than a solution of ethyl 5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-carboxylate (548 mg) in dichloromethane (5 ml) was added dropwise. The resulting mixture was heated at reflux for 4 hours then cooled in ice. A mixture of 2M hydrochloric acid (1 ml) and methanol (1 ml) was added dropwise. The mixture was filtered and the filtrate was concentrated by evaporation to give a brown oil which was purified by flash chromatography, eluting with methanol/ethyl acetate (1:24 v/v), to give 5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-N,N-diethylcarboxamide (B) (391 mg) as a solid, m.p. 56°-59° C.; NMR (CDCl3) 1.17(t, 3H), 1.25-1.4(complex m, 9H), 2.85(q, 2H), 3.07(q, 2 H), 3.32(q, 2H), 3.63(q, 2H), 6.95(s, 1H), 8.08(s, 1H), 12.28(s, 1H); mass spectrum (CI, ammonia): 302 (M+H)+ ; microanalysis, found: C, 66.4; H, 7.6; N, 13.6%; C17H23N3O2.0.25H2O requires: C, 66.7; H, 7.7; N, 13.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([Si](C(C)C)(C(C)C)C(C)C)[CH:20]=2)O)=[C:11]([F:38])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[C:11]([F:38])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cc2c[nH]c3ncccc23)c(F)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
(4-Benzyloxy-2-fluoro-5-methoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (655, 1.49 g, 2.79 mmol) was dissolved in acetonitrile (50 mL) and trifluoroacetic Acid (1.1 mL) was added. The reaction was stirred for 5 minutes. Triethylsilane (2.2 mL) was added to the reaction. The reaction was heated at 80° C. for 6 hours. The reaction was concentrated and the crude material was dissolved into ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate, and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. The solid obtained was used in the next reaction without further purification (656, 833 mg, 83%). MS (ESI) [M+H+]+=363.4.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:41]=1[C:42](O)=[O:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1(/[CH:11]=[C:12]2/[CH:13]([O:22][C:42](=[O:43])[C:41]3[CH:45]=[C:46]([O:49][CH3:50])[CH:47]=[CH:48][C:40]=3[O:39][CH3:38])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Reactant: COc1ccc(OC)c(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)OC2C#CCCCCC#C/C2=C\c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of Compound 20b (18.6 mg, 6.50×10−2 mmol), DCC (13.4 mg, 6.50×1031 2 mmol), and DMAP (15.8 mg, 0.13 mmol) in dry CH2Cl2 (4 mL) cooled in an ice-water bath was added 2,5-dimethoxybenzoic acid (17.8 mg, 9.76×10−2 mmol) followed by stirring at room temperature for 24 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 21.7 mg (74 percent) of Compound 40: pale yellow oil; Rf32 0.33 (20 percent EtOAc in hexane); IR (neat) 2958, 2235, 1721, 1640, 1189, 1064 cm−1; 1H NMR (300 MHz, CDCl3) δ8.32 (d, J=7.26 Hz, 1H), 8.08-8.04 (m, 1H), 7.88-7.78 (m, 2H), 7.60 (s, 1H), 7.54-7.42 (m, 4H), 7.03 (dd, J=9.03 and 3.39 Hz, 1H), 6.92 (d, J=9.03 Hz, 1H), 6.45 (s, 1 H), 3.84 (s, 3H), 3.80 (s, 3H), 2.46-2.25 (m, 4H), 1.95-1.70 (m, 4H); 13C NMR (75 MHz, CDCl3) δ169.9, 154.5, 153.7, 134.2, 133.3, 132.2, 129.5, 129.2, 127.0, 126.9, 126.4, 126.0, 124.3, 123.7, 120.3, 117.1, 114.6, 103.1, 93.5, 81.0, 79.5, 69.6, 57.6, 56.6, 28.3, 28.1, 22.6, 21.5; MS (+CI) m/z (relative intensity) 451 (M+, 3), 164 (100).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.C1(=O)O[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:13][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH:10]=[CH:11][N:12]=3)[CH2:17][CH2:16][O:15][C:2]=2[N:3]=1
Reactant: Clc1ccc(-c2ncc[nH]2)c(Cl)n1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Clc1ccc2c(n1)OCCn1ccnc1-2
Temperature: 90 °C

Procedure:
A mixture of 0.856 g (4.00 mmol) of 2,6-dichloro-3-(1H-imidazol-2-yl)pyridine, 704 mg (8.00 mmol) of ethylene carbonate and 2930 mg (9.00 mmol) of cesium carbonate was heated in 25.0 ml of N,N-dimethylformamidefor 13 hours at 90° C. The mixture was filtered, the filtrate concentrated in high vacuum, the residue purified on 10 g of silica column eluting with 80% of ethyl acetate in heptane to give 9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. Yield 0.359 g (41%). M/z 222.0, calc. 221.04. 1H NMR (500 MHz, CDCl3) δ 8.84 (d, J=8.2, 1H), 7.18 (s, 1H), 7.15 (d, J=8.2, 1H), 7.02 (s, 1H), 4.63-4.57 (m, 2H), 4.47-4.41 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][O:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Solvent: ClCCl
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reaction time: 1 h

Procedure:
A solution of [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (15.2 g, 53.1 mmol) in dichloromethane (50 mL) was treated with thionyl chloride (40.0 mL, 54.8 mmol). The reaction was stirred for 1 hour once vigorous bubbling ceased. The solvent and excess reagent were removed in vacuo. Yield=15.96 g. (99%) of 4 (chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10](Cl)[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Na+].[CH3:18][N:19]([CH3:23])[C:20](=[S:22])[S-:21].[I-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([S:22][C:20](=[S:21])[N:19]([CH3:23])[CH3:18])[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=c1cc(Cl)sn1Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=S)Sc1cc(=O)n(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 6.76 g. (0.03 mole) of 2-benzyl-5-chloro-4-isothiazolin-3-one in 25 ml of ethanol was added a solution of 5.37 g. (0.03 mole) of N,N-dimethyldithiocarbamic acid sodium salt dihydrate in 30 ml of ethanol followed by 0.1 g. of sodium iodide. A yellow solid separated spontaneously. The mixture was stirred at room temperature for 3 hours, then cooled and filtered. The solid was triturated with 50 ml of water and recrystallized from 250 ml of boiling EtOH to give 5.6 g. (60% yield) of the named product, mp 184°-186°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[N:5]=[C:4]([S:12][CH2:13][CH3:14])[N:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:8]([C:7]1[C:2]([N:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[N:3][C:4]([S:12][CH2:13][CH3:14])=[N:5][C:6]=1[S:10][CH3:11])#[N:9]
Reactant: COC(OC)N(C)C
Reactant: CCSc1nc(N)c(C#N)c(SC)n1
Product: CCSc1nc(N=CN(C)C)c(C#N)c(SC)n1

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-ethylsulfanyl-6-methylsulfanyl-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13]COC)=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COCOc1ccc(-c2cc(Cl)nn2-c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(O)cc2)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-chloro-5-[4-(methoxymethoxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazole obtained by Example 21 (2.35 g) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 36% hydrochloric acid (0.34 ml) . The reaction mixture was stirred at room temperature for 1 hr, at 50° C. for 1.5 hrs, and at 60° C. for 1.5 hrs.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][NH2:45])=[CH:40][CH:39]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21]/[C:22](/[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[N:45]\[NH:44][C:41]3[CH:42]=[CH:43][C:38]([O:37][C:36]([F:35])([F:47])[F:46])=[CH:39][CH:40]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC/C(=N\Nc3ccc(OC(F)(F)F)cc3)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 626.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[CH3:22][N:23]([CH2:25][CH:26]([OH:28])[CH3:27])[CH3:24]>C(Cl)(Cl)Cl>[C:1]([O:28][CH:26]([CH3:27])[CH2:25][N:23]([CH3:24])[CH3:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(O)CN(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OC(C)CN(C)C

Procedure:
The (N,N-disubstituted amino)-alkanol alkanoates are readily prepared by reacting the corresponding aminoalkinol with lauroyl chloride in the presence of triethylamine. A solvent such as chloroform is optional but preferred. For example, 1-(N,N-dimethylamino)-2-propanol can be reacted with lauroyl chloride in chloroform and in the presence of triethylamine to form 1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH3:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=1[O:32][CH3:33].Cl.C(=O)([O-])[O-].[NH4+:39].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH3:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[NH:39])[NH2:31])=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: COc1cc(C#N)ccc1NCc1nc2cc(N(C)S(=O)(=O)c3ccccc3)ccc2n1C
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: COc1cc(C(=N)N)ccc1NCc1nc2cc(N(C)S(=O)(=O)c3ccccc3)ccc2n1C

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-5-(N-methyl-benzenesulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[O-])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[CH2:17]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>CCCCCC>[CH2:17]([N:21]([CH2:22][CH2:23][CH2:24][CH3:25])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:11])[CH2:18][CH2:19][CH3:20]
Reactant: O=C([O-])Nc1cccc(Br)c1
Reactant: CCCCNCCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCN(CCCC)C(=O)Nc1cccc(Br)c1

Procedure:
A solution of 1.46 g. of phenyl N-(3-bromophenylcarbamate in 15 ml. of tetrahydrofuran is added to a solution of 1.52 g. of di-n-butylamine in 20 ml. of tetrahydrofuran and the mixture is stirred under reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords 1,1-di-(n-butyl)-3-(3-bromophenyl)urea, m.p. 80°-81° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1.[C:18](Cl)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[C:18]([NH:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
As shown in step 10-ii of Scheme 10, to Compound 1033 (10.0 g) in pyridine (80 mL) was added acetyl chloride (4.2 mL). After stirring at 50° C. for 30 min, water (200 mL) was added. The resulting solid was collected by filtration and washed with water (2×) gave tert-butyl 2-acetamido-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (Compound 1034, 10.873 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH2:26])[CH:22]=[CH:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH:26][C:29](=[O:31])[CH3:30])[CH:22]=[CH:21]4)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1

Procedure:
This material was prepared according to the method described in Example 66 using 8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine, (Example 2(d), Method B), (0.79 g, 2.1 mmol) and acetic anhydride (2.5 mL, 2.6 mmol). Purification by silica gel chromatography (2:1 hexanes: EtOAc) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 425 (M+1). Mp: 203.8–206.0° C. Anal. Calcd for C22H15F3N4O2: C, 62.26; H, 3.56; N, 13.20. Found: C, 62.28; H, 3.51; N, 13.15.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([NH:12]C(=O)C(F)(F)F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[F:8]>C([O-])([O-])=O.[K+].[K+].CO.O>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[F:8])[NH2:12]
Reactant: O=C(Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F
Yield: 6.9 %

Procedure:
A solution of 6.35 g (20.8 mmol) of 3-chloro-2,4-difluoro-6-nitro-(trifluoroacetamido)benzene in 60 mL of 7% K2CO3 methanol/water (3:2) was stirred at 25° C. for 4 h. The solution was evaporated to remove the methanol. Solid was observed in the residue. It was filtered, washed with water, and dried to leave 301 mg of a crystalline yellow solid; mp 96-97° C.; 1H NMR (CDCl3), 6.07 (mb, 2), 7.815 (dd, 1, J=1.92, 9.13). More solid was observed after the mother aqueous solution was allowed to stand at room temperature overnight. It was filtered, washed with water, and dried to leave a yellow solid (1.01 g). More solid was crystallized from the mother solution. It was collected three more times to provide 2.48 g of a yellow solid. 1H NMR is identical with above, total yield 3.80 g (87%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:12][C:13]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(O)(C)C>[Cl:12][C:13]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[CH:18][C:14]=1[C:15]([C:5]1[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[C:6]=1[OH:7])=[O:16]
Reactant: Cc1c(Cl)ccc(C(=O)Cl)c1Cl
Reactant: Cc1cc(=O)n(C)[nH]1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)c(C)c1Cl
Yield: 49.8 %

Procedure:
11.2 g (0.1 mole) of 1,3-dimethyl-5-pyrazolone and 9.6 g (0.13 mole) of calcium hydroxide were suspended in 165 ml of isopropanol, and with stirring, the suspension was heated under reflux for 30 minutes. The reaction mixture was cooled, and 22.4 g (0.1 mole) of 2,4-dichloro-3-methyl-benzoyl chloride was added dropwise. After the addition, the mixture was heated under reflux for 10 hours. The solvent was distilled off from the reaction mixture, and 40 ml of water was added. The mixture was acidified with 65 ml of 2 N hydrochloric acid, and extracted with 100 ml of chloroform twice. The extracts were washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from toluene to give 14.9 g of colorless crystals (yield 49.8%; melting point 148.9°-149.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.[N+:26]([O-])([OH:28])=[O:27]>>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[C:6]([N+:26]([O-:28])=[O:27])=[C:5]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3
Reactant: CCOC(=O)COc1cc(OC)c2c(c1)OC1(CCCCC1)CC2=O
Reactant: O=[N+]([O-])O
Product: CCOC(=O)COc1cc(OC)c2c(c1[N+](=O)[O-])OC1(CCCCC1)CC2=O
Yield: 74.2 %

Procedure:
Ethyl 2-{(5-methoxy-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl) oxy}acetate prepared in Preparation 49) (1.3 g, 3.92 mmol) is added by portions to fuming nitric acid (d=1.50, 10 ml) at -60° C. with stirring. After one hour stirring at -60° to -40° C., the reaction mixture is poured into ice-cold water. The mixture is extracted with diethyl ether. The ether layer is separated, washed with water and then aqueous sodium bicarbonate, dried and concentrated. The residue is washed with diethyl ether. Recrystallization from a mixture of ethyl acetate and hexane gives the title compounds as a crystalline solid (1.05 g, yield 74.2%, m.p.=142°-143° C.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:30][C:29]2=[O:44])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:25]([O:24][C:22]([NH:21][C:18]1([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:35])[CH2:30][C:29]2=[O:44])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCNCC1
Yield: 60 %

Procedure:
Trifluoroacetic acid (78 ml) was added to a solution of benzyl 4-[[1-(tert-butoxycarbonyl)-4-[(ethoxycarbonyl)amino]-4-piperidinyl]methyl]-3-oxo-1-piperazinecarboxylate (26 g) obtained in Reference Example 7 in toluene (78 ml) at room temperature while stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate/diethyl ether=5/1) to obtain the title compound (16 g, 60%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 60 °C
Yield: 31.2 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (described in Example 27B, 235 mg, 0.446 mmol) in DMF (3 mL) was added thiomorpholine 1,1-dioxide (181 mg, 1.338 mmol) followed by diisopropyl ethylamine (0.233 mL, 1.338 mmol) and tetrabutyl ammonium iodide (164 mg, 0.446 mmol). The reaction mixture was heated at 60° C. for 4 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea as a white solid (87 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.35 (brs, 2H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 3H), 7.25 (d, 1H), 6.92 (d, 1H), 6.45 (s, 1H), 4.25 (m, 2H), 3.95 (s, 3H), 3.10 (s, 4H), 2.80 (s, 4H), 2.60 (s, 2H), 1.95 (s, 1H), 1.20 (s, 9H); LC-MS (ESI) m/z 625 (M+H)+.