Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCNCC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 43.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-ethylaminomethylpyrrolidine (100 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound (120 mg) as colorless prisms, mp 217°-219° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.N1(O)C2C=CC=CC=2N=N1.[C:41]([CH2:43][C:44](O)=[O:45])#[N:42].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:44](=[O:45])[CH2:43][C:41]#[N:42])[CH2:3]1
Reactant: N#CCC(=O)O
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCNC4)c3n2)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN(C(=O)CC#N)C4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of (3-methyl-piperidin-3-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (11 mg, 0.27 mmol), benzotriazol-1-ol (4.0 mg, 0.03 mmol), 2-cyanoacetic acid (3 mg, 0.04 mmol), and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrogen chloride (6.0 mg, 0.03 mmol) in anhydrous dichloromethane was treated with triethylamine (0.01 ml, 0.08 mmol) and allowed to stir at room temperature overnight. The reaction mixture was partitioned between dichloromethane/water and the organic layers were collected, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography using 0.25:4.75:95 concentrated aqueous NH4OH: MeOH: dichloromethane as eluant to provide 5 mg (42%) of 3-{3-methyl-3-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-piperidin-1-yl}-3-oxo-propionitrile as a light yellow solid. M+H 578.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]2[N:18]=[C:17]([CH2:19][C:20]3([CH2:25][C:26]([OH:28])=[O:27])CCCC3)[O:16][N:15]=2)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1.[C:29]1(C2CCC(=O)OC2=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]2[N:18]=[C:17]([CH2:19][CH2:20][CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]([OH:28])=[O:27])[O:16][N:15]=2)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: O=C1CCC(c2ccccc2)C(=O)O1
Reactant: Cc1nc2c(cc1CCc1noc(CC3(CC(=O)O)CCCC3)n1)CCCN2
Product: Cc1nc2c(cc1CCc1noc(CCC(C(=O)O)c3ccccc3)n1)CCCN2

Procedure:
The procedure for the preparation of the product of EXAMPLE 8 was repeated using 2-phenylglutaric anhydride (Aldrich) in the place of 3,3-tetramethyleneglutaric anhydride to provide a 55:45 mixture of the title products as a gum. 1H (CD3OD) δ 1.90 (2H, m); 2.15-2.35 (2H, comp. band); 2.32/2.40 (3H, s); 2.42-2.53 (1H, comp. band); 2.69/2.76 (2H, t); 2.85 (1H, m); 2.92-3.04 (4H, comp. band); 3.45 (2H, t); 3.66/4.39, (1H, t); 7.23-7.40 (5H, comp. band), 7.44/7.52 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(N(CC)CC)C.[CH2:19]([OH:22])[C:20]#[CH:21]>CN(C=O)C.[Cu](I)I.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>[OH:22][CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: C#CCO
Reactant: O=C1CCc2cc(Br)ccc21
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C#CCO)ccc21
Yield: 71.2 %

Procedure:
5-Bromo-2,3-dihydro-1H-inden-1-one (1.68 g, 7.99 mmol) was dissolved in DMF and treated with triethylamine (1.61 g, 15.98 mmol), copper iodide (152 mg, 0.79 mmol) and prop-2-yn-1-ol (2.24 g, 39.96 mmol) in the presence of Pd(PPh3)4 (462 mg, 0.39 mmol) at ambient temperature. After being refluxed for 16 h, the reaction mixture was extracted with ethyl acetate (100 mL×3) and washed with brine. The combined organic layers were dried over MgSO4. Solvent removal under vacuum gave crude tan oil. Purification by preparative thin-layer chromatography afforded 5-(hydroxyprop-1-yn-1-yl)-2,3-dihydro-1H-indene-1-one (1.06 g, 72% yield): 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.59 (s, 1H), 7.42 (d, 1H), 4.45 (s, 2H), 3.18 (m, 2H), 2.69 (m, 2H); MS (EI) for C12H10O2: 187.20 (MH+).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:10])=[CH:28][CH:27]=1
Reactant: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)NCCCCc1cccnc1
Yield: 81.4 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (6.35 g) and 3-pyridinebutanamine (2.7 g) in tetrahydrofuran (75 mL) was stirred for 2 hours at 25° C. and was worked up in the usual fashion. The crude material was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to give 5.3 g of (E)-5,5-bis(4-chlorophenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 146°-147° C. Anal. Calculated for C26H24Cl2N2O: C, 69.18; H, 5.36; Cl, 15.71; N, 6.21 Found: C, 69.00; H, 5,57; Cl, 15.71; N, 6.21.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:23]2[CH2:24][NH:25][CH2:26][CH2:27][N:22]2[CH2:21][CH2:20][OH:19])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: OCCN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Bromo-5-octylbarbituric Acid (23.52 g) in 70 ml of dimethylsulfoxide, kept under nitrogen atmosphere and at a temperature of 5-10° C., is dropped N-(2-hydroxyethyl)piperazine (36.2 ml), then the mixture is stirred at room temperature for 2 hours 30 minutes. The reaction mixture is poured into water (1 l) under stirring and cooling with an ice bath. The white solid which separates is recovered by filtration, washed with water and dried under vacuum at 40° C. to give, after crystallization from ethanol (140 ml) 10.91 g of the product as a white solid, m.p. 183-184° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].C([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=O)C.[OH-].[K+].O>C(O)C>[NH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:13][C:12]([C:3]2[C:4]([O:10][CH3:11])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[OH:1])=[O:14])=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(O)c(C(=O)C=Cc2ccc(N)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
A mixture of 98 mg of 2'-hydroxy-4',6'-dimethoxyacetophenone, 85 mg of 4-acetamidobenzaldehyde and 1 g of potassium hydroxide in 4 ml of 50% aqueous ethanol was stirred at room temperature for 3 days. The mixture was poured into 30 ml of cold water and then extracted with three 30 ml portions of ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography using a silica gel plate (Kiesel gel 60 F254, Merck Co.) and cyclohexane/ethyl acetate (1:1, v/v) as the developing solvent, whereby 12 mg of 4-amino-2'-hydroxy-4',6'-dimethoxychalcone as a yellow powder were obtained: Rf value 0.22; 1H-nmr spectrum (in CDCl3): δ3.6(2H), 3.72(3H), 3.82(3H), 5.90(1H), 6.06(1H), 6.56(1H), 6.70(1H), 7.50(1H), 7.62(1H) and 14.4 ppm (1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[N:26][N:27]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:35][C:36]([C:44]#[N:45])([CH2:40][CH2:41][CH2:42][CH3:43])[C:37](O)=[O:38]>ClCCl>[C:44]([C:36]([CH3:35])([CH2:40][CH2:41][CH2:42][CH3:43])[C:37]([O:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[S:24][C:23]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:27][N:26]=2)=[CH:33][CH:32]=1)=[O:38])#[N:45]
Reactant: CCCCC(C)(C#N)C(=O)O
Reactant: CCCCCCCc1nnc(-c2ccc(O)cc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCc1nnc(-c2ccc(OC(=O)C(C)(C#N)CCCC)cc2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
With exclusion of moisture, 0.1 mol of dicyclohexylcarbodiimide in dichloromethane is added to a mixture of 0.1 mol of 2-heptyl-5-p-hydroxyphenyl-1,3,4-thiadiazole and 0.1 mol of optically active 2-methyl-2-butylcyanoacetic acid in 200 mL of dichloromethane, while cooling with ice. The mixture is stirred for a further 12 hours at room temperature, the dicyclohexyl urea is filtered off and 2-[4-(2-cyano-2-methylhexanoyloxy)-phenyl]-5-n-heptyl-1,3,4-thiadiazole is isolated by working up in the usual way.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[N:19]=[N:20][C:21]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:22][CH:23]=2)=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:21]2[N:20]=[N:19][C:18]([CH2:17][C:10]3[C:11]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:8][CH:9]=3)=[CH:23][CH:22]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cc(Cc2ccc(NCc3ccc(Cl)cc3)nn2)c2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (523, 50.0 mg, 0.111 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid (P-0092, 7.3 mg, 19.0%). MS (ESI) [M+H+]+=350.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[N:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:11]1[N:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1)[CH:16]=[CH2:17]
Reactant: C=CCOc1cnc(NC(=O)OC(C)(C)C)cn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 5-allyloxy-pyrazin-2-yl-carbamic acid tert-butyl ester (400 mg, 1.59 mmol) in methylene chloride (2 mL) was treated with a 25% solution of trifluoroacetic acid in methylene chloride (5 mL). The mixture was stirred at 25° C. for 90 min, poured with stirring into a saturated aqueous sodium bicarbonate solution (50 mL) and then sodium chloride (3 g) was added. The resulting mixture was extracted with methylene chloride (3×25 mL), and each of the organic extracts was washed with a small portion of a saturated aqueous sodium chloride solution. The combined organic extracts were dried over potassium carbonate, filtered, and concentrated in vacuo to afford 5-allyloxy-pyrazin-2-ylamine (240 mg, 100%) as pale yellow crystals.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH2:19]>>[OH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: NCCNCCO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OCCNCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and N-(β-hydroxyethyl)-ethylenediamine comparable as in Example A. A wax-like, colorless product was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:10][C:11]([S@@:14](/[N:16]=[CH:8]/[C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cc1cccnc1C=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: Cc1cccnc1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-methyl-2-pyridinecarboxaldehyde (3.243 g, 26.8 mmol) in DCM (18 mL) was added (S)-2-methylpropane-2-sulfinamide (6.55 g, 54.0 mmol) and copper(II) sulfate (8.72 g, 54.6 mmol). The suspension was stirred at rt for 17 hours, filtered, and the solid was washed with DCM (2×35 mL). The filtrates were concentrated, and the resulting product was purified by silica gel flash column chromatography (using a 80G ISCO cartridge) and eluted using DCM/MeOH gradient to yield the desired product (S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:22](Cl)([Cl:24])=[O:23]>C(OCC)C>[C:9]1([N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:22]([Cl:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=1
Reactant: Cc1ccccc1N=C1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccccc1N(C(=O)Cl)C1=CCCCC1

Procedure:
187 parts of cyclohexanone-o-methylphenylimine and 120 parts of triethylamine are added in portions and at 0° to 10° C. to a solution of 120 parts of phosgene in 400 parts of diethyl ether over a period of 1 hour in a manner analogous to that employed in Example 10. The mixture is stirred for another hour. The end product is then isolated analogously to Example 10. 216 parts (87% of the theory) of N-1-cyclohexenyl-N-o-methylphenylcarbamyl chloride is obtained having a boiling point of 132° C. at 0.3 mm.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][C@@:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@:8]([CH2:7][C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:22][CH:21]=1
Reactant: CC(=O)NNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nnc(C[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(Br)cc3)C(=O)O2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of N′-acetyl-2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetohydrazide (100 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added pyridine (37 mg, 0.46 mmol). The reaction mixture was cooled to −10° C. and triflic anhydride (125 mg, 0.44 mmol) was added. The reaction mixture was stirred at −10° C. for 1 h and at 0° C. for 1 h. The mixture was warmed to rt and quenched by addition of satd aq NaHCO3. The aqueous layer was washed with CH2Cl2 and the combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (56 mg, 58%). 1H NMR (400 MHz, CDCl3): δ=1.51 (d, 3H), 2.32-2.41 (m, 2H), 2.48 (s, 3H), 2.73 (m, 2H), 3.16 (m, 2H), 5.49 (m, 1H), 6.78 (d, 2H), 7.24 (m, 2H), 7.32 (m, 2H), 7.41 (m, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1
Product: Cc1ccccc1C(=O)c1ccccc1

Procedure:
Methylbenzophenone was prepared from mixtures of toluene and benzoyl chloride using essentially the method described in Example 1, with the following modifications in the distillation scheme.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH3:17].CC([O-])=O.[K+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][N:12]1[C:16]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=2)=[CH:15][N:14]=[C:13]1[CH3:17]
Reactant: COc1nc(Br)ccc1N
Reactant: Cc1nccn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1nc(-c2cnc(C)n2C)ccc1N
Reaction time: 8 h
Yield: 16.5 %

Procedure:
A suspension of 6-bromo-2-methoxypyridin-3-amine (96 mg, 0.473 mmol), 1,2-dimethyl-1H-imidazole (91 mg, 0.946 mmol), Pd(OAc)2 (4.3 mg, 0.019 mmol), KOAc (93 mg, 0.95 mmol) in DMA (3 mL) was stirred at 1500 under microwave irradiation for 8 hours. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The organic layer was purified by eluting through an SCX-2 column using 2M NH3/MeOH followed by Biotage silica gel column chromatography eluting with 0-4% MeOH/EtOAc to give the title compound as pink solid (17 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[O:7])=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1.[O-]CC.[Na+].O>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[CH:8]([C:9]#[N:10])[C:12]([CH:13]2[CH2:15][CH2:14]2)=[O:11])=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1cc(Cl)ccc1C(=O)C(C#N)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-[4-chloro-2-(methylsulphonyl)benzoyl]-5-cyclopropylisoxazole (2.2 g) in ethanol was added to a solution of sodium ethoxide in ethanol (prepared from sodium (0.2 g) and ethanol). The mixture was stirred at room temperature for 2 hours then poured into water and acidified to pH 1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallised from ethyl acetate and cyclohexane to give 1-[4-chloro-2-(methylsulphonyl)phenyl]-2-cyano-3-cyclopropylpropan-1,3-dione, COMPOUND 612, (1.7 g) as a light brown solid, m.p. 116° C.
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1.Cl.[C:20](=O)(O)[O-:21].[Na+]>O1CCCC1.CN(C)C=O>[Cl:6][C:7]1[C:12]([CH2:20][OH:21])=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: Clc1ccc(-c2ccccc2)nc1
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCc1nc(-c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
tert-Butyl Lithium (1.7M pentane solution, 15 ml) was added slowly to a solution of 5-chloro-2-phenylpyridine (4.70 g) in tetrahydrofuran (50 ml) at −78° C. under a nitrogen atmosphere, which was stirred for 1 hour. N,N-Dimethylformamide (2.3 ml) was added to the mixture slowly, which was stirred for 1 hour while raising the temperature to room temperature. After addition of dilute hydrochloric acid the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Sodium borohydride (946 mg) was added slowly to a mixture of the residue, tetrahydrofuran (50 ml) and methanol (50 ml) at room temperature, which was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloro-6-phenyl-2-pyridylmethanol (2.35 g, yield 43%) as pale yellow crystals from the fraction eluted with ethyl acetate-hexane (1:6, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 69–70° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3Cl)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[CH:31]3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C(C)=O)CC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc2ncnc(Oc3ccc4[nH]ncc4c3)c2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 67.7 %

Procedure:
A mixture of 6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-7-methoxyquinazoline (235 mg, 0.62 mmol), 5-hydroxyindazole (100 mg, 0.75 mmol), (prepared as described for the starting material in Example 29), and cesium carbonate (303 mg, 0.93 mmol) in acetone (20 ml) was heated at reflux for 2 hours. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indazol-5-yloxy)-7-methoxyquinazoline (200 mg, 68%) as a pale green solid.