Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1)=[O:16])[CH3:13]>ClC(Cl)C>[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH3:23])=[C:20]([CH3:22])[C:21]=1[C:5](=[O:7])[CH3:6])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c(C)c(C)c1C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of aluminum chloride (50.19 g, 0.376 mol) in dry dichloroethane (580 mL) at 25° C. was added slowly acetic anhydride (17.75 mL, 0.188 mol). The resulting mixture was stirred at room temp. for 10 minutes, then a solution of pyrrole 33 (10.49 g, 0.0627 mol) in dichloroethane (30 mL) was added and the reaction mixture was stirred at room temp. for 2 h. After an additional 3 h at 80° C., the mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried with anhy. sodium sulfate and concentrated in vacuo to an orange residue. Short plug filtration over silica gel (30% ethyl acetate/70% hexanes) gave 7.5 g (60%) of ethyl-3-acetyl-4,5-dimethyl-2-pyrrole carboxylate 34. 1H NMR (CDCl3) d 9.0 (bs,1H), 4.3 (q,2H), 2.7 (s,3H), 2.1 (s, 3H), 1.9 (s,3H), 1.3 (t,3H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Br[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:37]1[C:29]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])=[C:30]2[C:34]([NH:33][CH:32]=[N:31]2)=[N:35][CH:36]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 38.2 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 6-bromo-9H-purine (24 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 24 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 19 mg of the title compound (38% yield).
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29])=[NH:6]>[Ni].CO.O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])(=[NH:4])[NH2:6]
Reactant: Cc1ccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)cc1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cn(N=C3CCc4c(C(=N)N)cccc43)c(N)n2)cc1

Procedure:
Analogously to Example 2, 0.2 g of Raney nickel is added to a solution of 0.9 g (1.917 mmol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-tolyl)-imidazole dihydrochloride in 60 ml of methanol/water (1:1), and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, and the filtrate is acidified to pH 3 with 3N methanolic hydrochloric acid and is concentrated to a volume of approximately 20 ml. The product that has crystallized out is filtered off and recrystallized from ethanol/water, yielding the title compound with a water content of 11.81%, m.p. 220°-225° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.33 (d, 1H); 7.98 (s, 1H); 7.83 (d, 1H); 7.61-7.71 (m, 3H); 7.29 (d, 2H); 3.37 (s, 4H); 2.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:31]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:31][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:23][CH2:24]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ccccn3)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCN(c3ccccn3)CC2)c(N)cc1OCc1ccccc1
Yield: 139.9 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-pyridyl)piperazino]methanone (7b) (500 mg, 1.11 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (753 mg, 3.3 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (450 mg, 95% yield), This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 8b (650 mg, in 94% yield). 1H NMR (CDCl3) δ 3.15-3.30 (m, 4H), 3.70-3.80 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.20 (s, br,) 7.00-7.50 (m, 5H), 7.70 (s, 1H), 8.25-8.35 (d, J=9.05, 2H); FABMS: 418 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][CH3:12]>CCOCC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:12])[CH3:10])[N:7]=1
Reactant: CNC
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCOCC
Product: CN(C)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C

Procedure:
A suspension of cyanuric chloride (27.6 g.) in anhydrous ether (600 ml.) was kept at -30° C and treated with dimethylamine (13.5 g.). Following the addition the mixture was allowed to warm to 0° C and poured on to ice. The ether layer was separated, dried, and evaporated and the residue crystallised from light petroleum to give the product (26.0 g.) having a melting point of 123°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18]>>[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:21][C:20]=1[CH3:27])=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: O=C1Cc2cc(F)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN(C)C

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:31])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=3[CH:30]=2)=[CH:9][CH:8]=1)=[O:6].[ClH:32]>CO>[ClH:32].[F:31][CH:2]([F:1])[CH2:3][NH:4][C:5](=[O:6])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[CH:30]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)NCC(F)F)cc3)cc2C1
Agent: Cl
Solvent: CO
Product: O=C(NCC(F)F)c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a slurry of 1,1-dimethylethyl 7-(4-{[(2,2-difluoroethyl)amino]carbonyl}phenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.95 g, 2.2 mmol) and methanol (30 mL) was added hydrogen chloride (4 M in dioxane, 3.3 mL, 13 mmol). The reaction mixture was heated (50° C.) for 1.5 hours then concentrated. The resulting residue was suspended in ethyl ether (15 mL) and the solid collected by filtration to give N-(2,2-difluoroethyl)-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide hydrochloride salt (0.65 g, 80% yield) as a white solid. MS (EI) for C18H18F2N2O2: 333 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([OH:13])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:26]([NH:30][C:11](=[O:13])[CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: O=C(O)Cc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)Cc1ccc2[nH]ccc2c1
Yield: 77 %

Procedure:
A solution of indole-5-acetic acid (2.0 g), 4-dimethylaminopyridine (1.5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.4 g), and butylamine (1.2 ml) in methylene chloride was stirred under a nitrogen atmosphere for 18 hr. The reaction was diluted with methylene chloride, washed (10% (v/v) hydrochloric acid, water, brine), dried (MgSO4), and evaporated to give N-butylindole-5-acetamide (2.03 g, 77%) as an amber oil: NMR (300 MHz, CDCl3): 0.84(t, 3H, N(CH2)3CH3), 3.16(m, 2H, NCH2), 3.68(s, 2H, ArCH2), 5.44(br s, 1H, NH), 6.51(m, 1H, H2 -indole), 8.49(br s, 1H, NH).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[CH2:31][CH:32]=[CH2:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12BC(CCC1)CCC2.[OH-:43].[Na+].OO>O.C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[CH2:31][CH2:32][CH2:33][OH:43])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: [OH-]
Reactant: C=CCc1cc2ccc(-c3ccc(C(=O)OC)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3cc(CCCO)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.7 g (3.9 mmol) of methyl 4-[7-(1-adamantyl)-6-allyl-2-naphthyl]benzoate and 40 ml of THF were introduced into a round-bottomed flask under a stream of nitrogen. A solution of 23.5 ml (11.7 mmol) of 9-borabicyclo[3.3.1]nonane (0.5M in THF) was added dropwise at 0° C. and the reaction mixture was stirred for one hour at room temperature. 12 ml (12 mmol) of a sodium hydroxide solution (1 M) and 10 ml of a 30% hydrogen peroxide solution were then added successively and at 0° C. and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:13]([O:17][C:18](=[O:36])[C:19]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([Cl:34])[C:22](Cl)=[N:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>C(#N)C.CCOC(C)=O>[C:13]([O:17][C:18](=[O:36])[C:19]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([Cl:34])[C:22]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[N:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(O)CN
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Temperature: 25 °C
Yield: 74.6 %

Procedure:
1-Amino-propan-2-ol (2.44 g, 30.3 mmol) and triethylamine (0.42 mL, 3.03 mmol) were added to a solution of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloro-nicotinic acid tert-butyl ester (1.37 g, 3.03 mmol) in acetonitrile (30 mL). The reaction was heated to reflux. After 23 hours the reaction was cooled to room temperature and diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried over Na2SO4 and concentrated to a white solid. Purification by flash column chromatography (20:1 dichloromethane/methanol) provided the desired product as a white solid (1.11 g, 75%). MS APCI (+) m/z 492, 494 (M+, Cl, Br pattern) detected.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][N:8]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NC1CC(Oc2nccnc2Cl)C1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1nccnc1OC1CC(Nc2nc3ccccc3s2)C1
Temperature: 180 °C
Yield: 95.5 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yloxy)-cyclobutylamine hydrochloride (1.2 g, 6.28 mmol), 2-chloro-benzothiazole (purchased from ALDRICH™) (1.07 g, 6.28 mmol) and DIEA (1.8 g, 12.56 mmol) in NMP (12 mL) was heated to 180° C. for 2 hours in microwave. The reaction mixture was extracted with EtOAc (40 mL) and water, the organic phase was washed with brine and dried over Na2SO4. The organic layers were concentrated and purified by column chromatography on silica gel to give N-(3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine (3.0 g, 6 mmol, 95.5%). ESI-MS (M+1): 333 calc. for C15H13ClN4OS 332.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]#[C:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34](Cl)=[O:35]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:12]=[C:5]1\[C:6](=[O:11])[NH:7][C:8]2[C:4]\1=[C:3]([C:20]#[C:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)=[CH:10][CH:9]=2
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#Cc3cccnc3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(C#Cc3cccnc3)c21

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one (18 mg, 0.051 mmol) (from Example 69) was coupled with 2-thiopheneacetyl chloride (16.2 mg, 0.10 mmol) (Aldrich) in THF (2 mL) and saturated aqueous sodium bicarbonate (1 mL) at room temperature for 1 h, to yield (Z)-N-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-4-[(3-pyridinyl)ethynyl]-1H-indol-5-yl]-2-thiopheneacetamide. (Yield 7.7 mg, 32%).
Reaction SMILES: [C:1]([O:4][CH2:5]Cl)(=[O:3])[CH3:2].[Br:7][C:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C:9]=1[C:21]([OH:23])=[O:22].C(N(CC)CC)C>CN(C=O)C>[Br:7][C:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C:9]=1[C:21]([O:23][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:22]
Reactant: O=C(O)c1oc(-c2ccccc2)cc(=O)c1Br
Reactant: CC(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Temperature: 0 °C

Procedure:
Chloromethyl acetate (2.2 ml) was added to a stirred solution of 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylic acid (5.9 g) and triethylamine (2.9 ml) in dry DMF (40 ml). The solution was heated at 70°-80° C. for 3 hours, then poured on to ice-water and extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution, dried and evaporated, and the residue was crystallised from ethanolwater. The crude product was purified by chromatography on silica-gel and recrystallisation from ethyl acetate-petroleum ether 60°-80° C. gave the title product as white needles (mp 121° C.).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: C1CCNC1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(N4CCCC4)nc32)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.042 g) was treated with pyrrolidine (0.1 ml) in 1,4-dioxane (3 ml) at reflux for 6 h. The volatiles were removed under reduced pressure and the residue triturated with diethyl ether/isohexane mixtures to leave the subtitle product as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: Clc1nccc2[nH]cnc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nccc2[nH]cnc12

Procedure:
A mixture of 200 mg (1.3 mmol) of 4-chloro-1H-imidazo[4,5-c]pyridine [J. A. Montgomery and K. Hewson, J. Med. Chem., 8, 708 (1965)], 0.253 mL (261 mg, 5.2 mmol) of hydrazine hydrate, and 5 mL of ethanol was stirred at room temperature overnight. The precipitate was collected on a filter, washed with a little ethanol, and dried to give the title compound as a solid. LC-MS 150 (M+1).
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:31]=[C:32]3[S:36][C:35](=[S:37])[N:34]([CH2:38][C:39]([OH:41])=O)[C:33]3=[O:42])[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ON1C2N=CC=CC=2N=N1.[Cl-].[NH4+].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:31]=[C:32]3[S:36][C:35](=[S:37])[N:34]([CH2:38][C:39]([NH2:2])=[O:41])[C:33]3=[O:42])[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)CN1C(=O)C(=Cc2ccc(OCCc3ccccc3)c(OCc3ccccc3)c2)SC1=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)C(=Cc2ccc(OCCc3ccccc3)c(OCc3ccccc3)c2)SC1=S
Reaction time: 48 h
Yield: 91.7 %

Procedure:
N-methylmorpholine (0.17 mL, 1.58 mmol, 4 eq) was added to a solution of 5-[[3-(phenylmethoxy)-4-(2-phenylethoxy)phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid (200 mg, 0.40 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (108 mg, 0.79 mmol, 2 eq) and ammonium chloride (42 mg, 0.79 mmol, 2 eq) in N,N-dimethylformamide (5 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (152 mg, 0.79 mmol, 2 eq) and the reaction mixture was stirred for 48 h. It was diluted with ethyl acetate (50 mL), and the organic solution washed with 1M HCl, (3×100 mL), then water (100 mL), dried over sodium sulfate and concentrated in vacuo. A yellow powder precipitated from the concentrate which was collected by filtration, washed with ethyl acetate and petroleum ether and dried to give the product (185 mg, 93%) mp 212–214° C.: 1H NMR (d6 DMSO) 7.76 (s, 1H, C═C— 7.72 (broad s, 2H, exchanges with D2O, NH2), 5.16 (s, 2H, OCH2Ph), 4.60 (s, 2H, CH2CO2H), 4.30 (t, 2H, J 6.4 Hz, OCH2CH2), 3.07 (t, 2H, J 6.4 Hz, OCH2CH2).
Reaction SMILES: [CH3:1]N(C)CCO.[Li+].CCC[CH2-].[Si:12]([O:19][CH2:20][C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:22]1[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([Cl:42])[CH:37]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].CI>C1COCC1>[Si:12]([O:19][CH2:20][C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:22]1[CH2:35][C:36]1[CH:41]=[C:40]([CH3:1])[N:39]=[C:38]([Cl:42])[CH:37]=1)([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethylethanolamine (0.128 ml, 1.27 mmol) was added to anhydrous hexanes (1.4 L) and cooled to 0° C. N-BUTYLLITHIUM (2.5 M in hexanes)(1.02 ml, 2.55 mmol) was added dropwise and stirred for 30 minutes before being cooled to −78° C. (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.200 g, 0.425 mmol) in hexanes (1 mL) was added dropwise and the solution was stirred for 1 hour at −78° C. to give a dark orange solution. MeI (0.106 ml, 1.70 mmol) in THF (3.2 mL) was added dropwise and the reaction was allowed to slowly warm to 0° C. and was quenched with saturated aqueous ammonium chloride. The reaction was diluted with ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated to give the titled compound which was used directly for the next step without purification.
Reaction SMILES: [C:1]12([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]([OH:23])[CH2:15][CH2:14]3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:26]1COC[CH2:27]1>O>[C:1]12([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]([O:23][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(N1CCC(O)c2ccccc21)C12CC3CC(CC(C3)C1)C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC1CCN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 0.1 g (0.32 mmol) adamantan-1-yl-(4-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-methanone and 35 mg (55% in oil, 0.8 mmol) NaH in 5 mL THF at 0° C. was treated with 0.15 g (0.99 mmol) iododethane and allowed to stir to room temperature and subsequently heated to 50° C. overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and evaporated. The residue was subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 24.5 mg (22%) of the title compound as colourless solid. MS(m/e): 340.3 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.C([O-])=O.[Na+].O>CN(C=O)C.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>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2c(Cl)ccc(CN)c2F)c1

Procedure:
A solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.20 g, 0.56 mmol), sodium formate (0.057 g, 0.84 mmol) and Pd(Ph3P)4 (0.032 g, 0.028 mmol) in DMF (1.13 ml) was heated at 100° C. for 6 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and dried to afford 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile, which was used without further purification. The above amine (0.28 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.040 g, 0.25 mmol) were employed in a similar process described herein to prepare the title compound (0.042 g, 40%) as a white solid after purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) followed by neutralization. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.89 (br. s., 1H), 7.32-7.45 (m, 2H), 7.12-7.31 (m, 4 H), 7.08 (s, 1H), 4.70 (d, J=5.91 Hz, 2H), 2.37 (s, 3H). ES-LCMS: m/z 419.0, 421.0 (M+1).