Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[OH-].[Na+]>CCO.C1COCC1>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A solution of ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinate (300 mg, 0.770 mmol) in EtOH (6 mL) and THF (6.00 mL) was treated with 30% aqueous sodium hydroxide (2 mL, 26.0 mmol) and stirred at rt for 3 hrs. Remove most of the solvent on rotary evaporator and acidified with 1N HCl (no precipitate formed) and extracted into CH2Cl2 several times and the combined extracts were concentrated to give 240 mg of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid. LCMS: (M+H)+=362.02, 363.93 (Cl pattern).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[K+].[C:37]([O:43][CH2:44]Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C)C=O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 81.6 %

Procedure:
3-Methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylic acid (69.6 g., 0.2 mole) was dissolved in 300 ml. of dimethylformamide and reacted in sequence with triethylamine (20.2 g., 0.2 mole), potassium bicarbonate (40 g., 0.4 mole) and chloromethyl pivalate (33 g., 0.22 mole) according to procedures detailed in Preparation B 1. To isolate the product, the reaction mixture was diluted with 3 l. of ether, and the organic solution washed, dried and evaporated to dryness, as detailed in Preparation 1, affording pivaloyloxymethyl 3-methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylate [75.5 g., 82%; ir (CH2Cl2) 1776, 1750, 1685 cm-1 ].
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.C(=O)(O)O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1>C(O)CC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:29]=[C:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:30])([F:31])[F:18])[CH:21]=3)[N:28]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Agent: O=C(O)O
Solvent: CCCO
Product: FC(F)(F)c1cccc(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
A 7.04 g amount of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one (U.S. Pat. No. 4,281,000) and 18.72 g of [3-(trifluoromethyl)phenyl]guanidine carbonate in 500 ml of n-propanol was heated at reflux temperature for 16 hours. The solvent was evaporated to near dryness, then water was added and the precipitate which formed was collected by filtration, then recrystallized from hexane to give 5.55 g of the desired product, mp 170°-171° C.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([Cl:27])=[O:4])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of CBZ-L-Pro-OH (0.62 g, 2.49 mmol) and a drop of DMF in methylene chloride (10 ml) under argon was added oxalyl chloride (0.26 ml; 2.99 mmol) which resulted in a vigorous evolution of gas. After the evolution of gas ceased, the reaction was stirred for an additional 30 minutes. The reaction was then concentrated to give, as a light yellow oil, N-carbobenzoxy-L-prolyl chloride (CBZ-L-Pro-Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:19](=[O:21])[CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc2cccnc12
Yield: 101.3 %

Procedure:
To a stirred solution of 8-aminoquinoline (33.37 g, 0.231 mol), DMAP (4-dimethylaminopyridine) (1.40 g, 0.011 mol) and triethylamine (Et3N) (37 mL, 0.265 mol) in CH2Cl2 (methylene chloride) (275 mL) was added acetic anhydride (Ac2O) (26.5 mL, 0.281 mol). After 20 hours the reaction mixture was poured into a saturated aqueous solution of NaHCO3 (sodium bicarbonate). The phases were separated and the aqueous phase was extracted with ether (3×150 mL). The combined organic phases were dried (Na2SO4) (sodium sulfate), filtered and concentrated in vacuo to provide 43.56 g (100%) of N-(quinolin-8-yl)-acetamide as a beige solid. This material was used without further purification in subsequent steps. 1H NMR (CDCl3) δ 2.35 (s, 3H), 7.42–7.56 (m, 3H), 8.15 (dd, 1H, J=1.5, 8.4 Hz), 8.76 (dd, 1H, J=1.8, 7.2 Hz), 8.79 (dd, 1H, J=1.5, 4.2 Hz), 9.78 (br s, 1H); 13C NMR (CDCl3) δ 25.5, 116.8, 121.8, 122.0, 127.8, 128.3, 134.9, 136.8, 138.6, 148.5, 169.2. ES-MS m/z 187 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[C:34]1[CH:39]=[CH:38][N:37]=[N:36][CH:35]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:34]4[CH:39]=[CH:38][N:37]=[N:36][CH:35]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccnnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Agent: Br
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnnc4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 4-bromopyridazine hydrobromide following a procedure analogous to that described in Example 1. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=382 [M+H]+.
Reaction SMILES: [OH:1][NH:2]/[C:3](/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[N:4]\[H].Cl.C(N=C=NCCCN(C)C)C.[O:27]=[C:28]1[C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][N:29]1[CH2:46][C:47](O)=O.CN(C)C=O>ClC(Cl)C>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:3]3[N:4]=[C:47]([CH2:46][N:29]4[CH2:30][CH2:31][CH2:32][C:33]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:27])[O:1][N:2]=3)=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc4[nH]ncc4c3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
(Z)—N-hydroxy-1H-indazole-5-carboximidamide (0.055 g, 0.312 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.120 g, 0.624 mmol) and 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.097 g, 0.312 mmol; Example 68E) were stirred together in dichloroethane (1 mL) at room temperature for 20 minutes. N,N-Dimethylformamide (0.2 mL) was added and stirring was continued for 2 hours and a dark solution resulted. The reaction was heated to 85° C. and stirred overnight. The reaction was cooled, concentrated, loaded onto a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=18 mL/minute) over 30 minutes. The material obtained was subjected to a second chromatography on a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 0.5% methanol/dichloromethane to 7.5% methanol/dichloromethane (Flow=18 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.30 (s, 1H), 8.01 (dd, J=1.2, 8.8, 1H), 7.75 (d, J=8.7, 1H), 7.45-7.07 (m, 10H), 4.92 (s, 2H), 3.66 (t, J=6.3, 2H), 2.76-2.57 (m, 2H), 1.78 (s, 2H).
Reaction SMILES: C[O:2][C:3]([CH2:9][C@@H:10]1[CH2:13][C:12](=[O:14])[NH:11]1)=[CH:4][C:5]([O:7][CH3:8])=[O:6].[Cl-].[Na+]>Cl>[O:2]=[C:3]([CH2:9][C@@H:10]1[CH2:13][C:12](=[O:14])[NH:11]1)[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C=C(C[C@@H]1CC(=O)N1)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)CC(=O)C[C@@H]1CC(=O)N1
Yield: 86.1 %

Procedure:
A solution of methyl 3-methoxy-4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate [(E,Z)-isomeric mixture](35 mg) in 1 N hydrochloric acid (2 ml) was stirred at 25° C. for two hours. The resultant solution was saturated with sodium chloride and extracted three times with chloroform. The combined extracts were dried over magnesium sulfate and evaporated. The residue (29 mg) was chromatographed on silica gel (1.5 g) eluting with 2% methanol in dichloromethane to give methyl 3-oxo-4-[(2R)-4-oxoazetidin-2-yl]butanoate (28 mg), mp. 45.0°-46.5° C.:
Reaction SMILES: [Cl:1][CH2:2][Si:3]([Cl:6])(Cl)[Cl:4].[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[Cl:1][CH2:2][Si:3]([Cl:6])([Cl:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC[Si](Cl)(Cl)Cl
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: ClC[Si](Cl)(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
A solution of 25.1 ml (36.8 g, 0.200 mol) of chloromethyltrichlorosilane in 400 ml dry tetrahydrofuran was cooled to -78° under nitrogen and stirred vigorously while 48.0 ml (0.100 mol) of 2.1 molar phenyllithium was slowly dripped in over 1 hour. After stirring another 30 minutes at -78° the solution was allowed to warm to room temperature and evaporated to about 200 ml. Addition of 500 ml ether, filtration to remove precipitated lithium chloride, and evaporation of the filtrate left 25.0 g of liquid. Distillation gave 6.5 g (29%) of the title compound as a colorless liquid: bp 62°-82° (0.15 mm); nmr (CDCl3): δ 3.3 (s, 2) and 7.1-7.9 (m, 5).
Reaction SMILES: [CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[C:6]1[CH3:17])([CH2:3][CH3:4])[CH3:2].C1C=C2N=NN(O)C2=CC=1.N.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl>[CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:36][CH2:37][C:38]2[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])=[O:16])=[C:6]1[CH3:17])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1c(C)c(C(=O)O)c2ccccc21
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)n1c(C)c(C(=O)NCc2c(C)cc(C)nc2O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
A mixture of 1-sec-butyl-2-methyl-1H-indole-3-carboxylic acid (97 mg, 0.42 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol), N-hydroxybenzotrizole (85 mg, 0.63 mmol) and triethylamine (127.26 mg, 1.26 mmol) in dichloromethane (30 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (63.8 mg, 0.42 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (20 mL×3). The organic layer was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (57 mg, 30%). LRMS (M+H+) m/z: calcd 365.2. found 365. HPLC purity (214 nm): 99%. 1H.NMR (300 MHz, CD3OD): δ 7.72-7.69 (m, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.11-7.06 (m, 2H), 6.10 (s, 1H), 4.53-4.51 (m, 3H), 2.62 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.95-1.93 (m, 2H), 1.59 (d, J=6.9 Hz, 3H), 0.72 (t, J=7.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CCO>[CH2:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
76B (1.20 g, 5 mmol) was suspended in EtOH (4 mL) and aqueous NaOH (1 M, 10 mL) and was heated to 75° C. for one hour. Upon cooling to room temperature, the solution was acidified with HCl (conc.), was cooled to 0° C., and was filtered. The white crystalline precipitate was dried under vacuum (835 mg, 74%). NMR 1H (ppm, CDCl3): 8.00 (d, J3=8.2 Hz, 2H), 7.29-7.13 (m, 9H), 3.01-2.91 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[Cl:24])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:27]([Mg]Br)[CH3:28]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([Cl:24])=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=4[Cl:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([OH:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1cc(Cl)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(OC)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
To a solution of 9-chloro-1-(2,6-dichloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (146 mg, 0.356 mmol) in tetrahydrofuran (4 mL) was added dropwise ethylmagnesium bromide (3 M solution in diethyl ether, 0.237 mL, 0.711 mmol) at 0° C., and the mixture was stirred at 0° C. for 5 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (137 mg, 0.311 mmol, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:30][C:31]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]([OH:40])[CH:34]=[CH:33][C:32]=1[C:41](=[O:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:40][C:35]3[CH:34]=[CH:33][C:32]([C:41](=[O:43])[CH3:42])=[C:31]([OH:30])[C:36]=3[CH2:37][CH2:38][CH3:39])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(OCCOCCOCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 72.5 %

Procedure:
A mixture of 2 g of [[8-acetyl-7-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.9 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 14 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. The solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an oil which was purified by high pressure liquid chromatography (60% ethyl acetate-hexane) to yield 1.8 g (73%) of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
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: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
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) δ9.08 (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: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([NH:8][C:9]1([CH2:12][CH:13]=[O:14])[CH2:11][CH2:10]1)=[O:7])C.[Na]>C1(C)C=CC=CC=1.CO>[CH3:1][O:3][C:4]([CH:5]1[C:13](=[O:14])[CH2:12][C:9]2([CH2:11][CH2:10]2)[NH:8][C:6]1=[O:7])=[O:15]
Reactant: CCOC(=O)CC(=O)NC1(CC=O)CC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)CC2(CC2)NC1=O

Procedure:
N-[1-(2-Oxo-ethyl)-cyclopropyl]-malonamic acid ethyl ester (200 mg; 0.823 mmol) in toluene (3 ml) is added to a solution of sodium (18.9 mg; 0.823 mmol) in MeOH (1 ml). The reaction mixture is refluxed for 45 minutes, poured on water and washed with TBME. The aqueous phase is acidified with 2N HCl (0.2 ml) and evaporated to dryness to yield the title compound as yellow resin (162 mg; 100%). 1H-NMR (400 MHz; DMSO-d6): 8.39 (s, 1H); 3.73 (s, 3H); 3.18 (s, 1H); 2.48 (s, 2H); 0.76 (m, 2H); 0.64 (m, 2H). MS (m/z) ES+: 198 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([NH2:26])=[O:25])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[F:15])=[CH:11][C:10]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:9][CH:8]=3.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:11]=3)[NH:6][C:5]=2[C:4]([C:24]([NH2:26])=[O:25])=[CH:3][C:2]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-c2ccccc2)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 105 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
3-Bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (25 mg, 0.059 mmol), phenylboronic acid (10.88 mg, 0.089 mmol), Pd(Ph3P)4 (6.87 mg, 5.95 μmol) and Na2CO3(2M) (0.074 mL, 0.149 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was stirred at 105° C. for 3 hrs. The mixture was filtered through a ACRODISC® PTFE membrane (0.45 um) and purified using preparative HPLC to give 9.7 mg of 4-fluoro-6-(morpholine-4-carbonyl)-3-phenyl-9H-carbazole-1-carboxamide. MS (ESI) m/z 418.06 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.9 (bs, 1H), 8.32 (bs, 1H), 8.19 (d, 1H, J=7.1), 8.15 (s, 1H), 7.84 (d, 1H, J=8.6), 7.72 (d, 2H, J=7.3), 7.62-7.53(m, 4H), 7.43 (t, 1H, J=7.3), 3.7-3.5 (bm, 8H).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][C:17]1([CH2:23]Br)[CH2:22][O:21][CH2:20][O:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[O:1][CH2:23][C:17]3([CH2:22][O:21][CH2:20][O:19][CH2:18]3)[CH2:16][O:12][C:11]=2[C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Reactant: BrCC1(CBr)COCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2c1OCC1(COCOC1)CO2

Procedure:
Following the general procedure, dialkylation of compound 513 (198 mg, 1 mmol) with compound 523 (301 mg, 1.1 mmol) in DMSO (5 mL) in the presence of K2CO3 (345 mg, 2.5 mmol) afforded compound 524 as a white solid material after purification by column chromatography (50-65% EtOAc in light petroleum). LC-MS: RT=2.65 min.; m/z 311.23 (M+H)+. 1H NMR (DMSO-d6): 7.37 (1H, d, J 8.8), 6.81 (1H, d, J 8.8), 4.80 (1H, d, J 6.4), 4.78 (1H, d, J 6.4), 4.07 (2H, s), 4.01 (2H, s), 3.81 (7H, s), 3.76 (3H, s).
Reaction SMILES: COC[N:4]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20](COC)[C:19]([C:25]1[N:29]=[CH:28][NH:27][N:26]=1)=[CH:18]2)[S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6].Cl.CO>O>[NH:27]1[CH:28]=[N:29][C:25]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:4][S:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)(=[O:6])=[O:7])=[N:26]1
Reactant: COCN(c1cccc2cc(-c3nc[nH]n3)n(COC)c12)S(=O)(=O)c1cccs1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cccc2cc(-c3nc[nH]n3)[nH]c12)c1cccs1
Yield: 59.6 %

Procedure:
A mixture of N-(methoxymethyl)-N-[1-(methoxymethyl)-2-(1H-1,2,4-triazol-3-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.40 g), concentrated hydrochloride (1 mL) and methanol (10 mL) was heated under reflux for 3 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.19 g, yield 60%) as colorless crystals. The crystals were recrystallized from ethyl acetate. melting point>280° C. (decomposition).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:3]1.[N:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:2]([O:1][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:22])[N:3]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2ccn(O)n2)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: COc1ccc(-c2ccn(OC(=O)N3CCOCC3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(4-methoxyphenyl)pyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (62%, crystals).