Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][C:5]=1[NH2:9])([O-:3])=[O:2].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[C:5]3[N:9]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1cc(-c2ccnc3c([N+](=O)[O-])cnn23)ccc1Cl)S(C)(=O)=O
Yield: 37.6 %

Procedure:
A mixture of 0.050 g (0.39 mmol) of 4-nitro-2H-pyrazol-3-ylamine and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 56 mg of N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:18]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:18])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 4-chloro-2-fluoro benzoic acid (1.5 g), THF (25 mL), oxalyl chloride (0.5 mL) and ammonia gas to afford 1.45 g of the product. 1H NMR (300 MHz, DMSO d6): δ 7.36 (d, J=6.3 Hz, H), 7.53 (dd, J=8.7 Hz, 1H), 7.64-7.76 (m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[CH:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)=[N:13][N:12]=[C:7]1[CH:6]=[CH:5]2
Reactant: NNc1ccc2cc(I)ccc2n1
Reactant: O=Cc1ccccn1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (6-Iodo-quinolin-2-yl)-hydrazine (2.99 g, 10.5 mmol) suspended in CH2Cl2 (30 mL) was added 2-pyridinecarboxaldehyde (1.2 mL, 12.6 mmol). The reaction was stirred at room temperature for 2 hours, followed by the addition of iodobenzene diacetate (3.39 g, 10.5 mmol). The reaction was stirred overnight at room temperature, during which time a precipitate formed. The mixture was concentrated to half the volume, and the precipitate was filtered and washed with minimal CH2Cl2 to give the desired product, 5k. The filtrate was concentrated and suspended in EtOH. After stirring overnight at room temperature, the mixture was filtered and rinsed with EtOH to obtain additional product, 5k.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH:25]=[CH:26][CH:27]=1.CC([O-])(C)C.[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C:12]1[CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:23]=[C:24]([NH:28][C:29]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])[CH:25]=[CH:26][CH:27]=3)[N:7]=2)[CH:9]=[CH:10][C:11]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)#[N:14]
Reactant: Nc1cccc(NC(=O)N2CCCC2)c1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)ccc1N1CCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(-c2ccnc(Nc3cccc(NC(=O)N4CCCC4)c3)n2)ccc1N1CCCC1
Temperature: 100 °C

Procedure:
5-(2-Chloro-pyrimidin-4-yl)-2-pyrrolidin-1-yl-benzonitrile (40 mg, 0.141 mmol), pyrrolidine-1-carboxylic acid (3-amino-phenyl)-amide (29 mg, 0.141 mmol), Pd2(dba)3 (6.4 mg, 0.007 mmol, 5 mol %), 2-dicyclohexylphosphino-2′-(N,N-dimethylaminobiphenyl) (55.5 mg, 0.141 mmol) and NaOtBu (20.3 mg, 0.211 mmol) were dissolved in 1,4-dioxane (1 mL) and the mixture heated at 100° C. in the microwave (300 W, stirring) for 10 minutes. The mixture was diluted with H2O (10 mL) and EtOAc (30 mL) and the layers separated. The aqueous phase was extracted with EtOAc (20 mL) and the combined organics dried (MgSO4), filtered and the solvent evaporated in vacuo. The mixture was dissolved in DMSO (1.5 mL) and the crude product purified by reversed phase preparative LC-MS. Fractions containing desired product were combined and the solvent evaporated in vacuo. The title compound was afforded as a yellow solid (13.1 mg, 21%); LC-MS, Rt=6.50 min (ANALpH2_MeOH_QC), m/z 453 (MH+).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C:33](=[O:39])[NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH2:8][C@H:7]([NH:22]C(=O)OCC2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C.CO>[C:1]([NH:4][C@@:5]1([C:33]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])[CH2:6][C@@H:7]([NH2:22])[CH2:8][C@@H:9]1[CH2:10][CH2:11][CH2:12][B:13]1[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)C[C@@H](N)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
While under nitrogen, a stirred solution of benzyl (1S,3S,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentylcarbamate (0.544 g, 1.00 mmol) in 4:1 ethyl acetate/methanol (20 mL) was treated with 20% Pd(OH)2/C (0.30 g), purged with hydrogen, and stirred under a balloon for 18 h. The mixture was purged with nitrogen and carefully filtered through a pad of Celite® (without letting filter pad dry) and the filtrate concentrated in vacuo to afford 0.409 g (100%) of the subject compound as a white solid. NMR (CDCl3): δ 6.72 (br s, 1 H), 6.67 (br s, 1 H), 3.63 (m, 1 H), 2.80 (m, 1 H), 2.57 (m, 1 H), 1.75-2.00 (m, 4 H), 1.93 (s, 3 H), 1.00-1.50 (m, 3 H), 1.25 (s, 9 H), 1.17 (s, 12 H), 0.60-0.75 (m, 2 H). MS (M+1): 410.5.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[NH:9][C:8]2=O)(=[O:3])[CH3:2].CN(C=O)C.O=S(Cl)[Cl:38]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[Cl:38])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Cl)c2cc1OC(C)=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of 2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.0 g, 7.42 mmol) in SOCl2 (60 mL) with DMF (1.4 mL) was heated at reflux for 5 h. the mixture was allowed to cool to RT and the volatiles were removed in vacuo. The residue was taken up in CHCl3 (300 mL) and washed with water (100 mL), sat. NaHCO3 (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the desired product 4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl acetate (3.14 g, 7.42 mmol, 100%). HPLC retention time 11.30 minutes (5-95-13 method).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:29]2[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (1.3 g, 3.4 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.77 g, 5.1 mmol) according to Reference R and the general procedure for reductive amination gave methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-azetidine-3-carboxylate as a light yellow solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:22](=O)=[O:23].C([Li])CCC.CCCCCC.CN(C)C=O.[Cl-].[NH4+]>O1CCCC1.CC(C)=O>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH:22]=[O:23])[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(C=O)c1
Yield: 30.6 %

Procedure:
Compound 78 (2.26 g; 6.53 mmol) was dissolved in tetrahydrofuran (25 ml), and the solution was cooled to −75° C. by use of a mixture of dry ice and acetone solvent under nitrogen atmosphere. n-butyl lithium in n-hexane (1.56 M: 4.2 ml; 6.53 mmol) was slowly added dropwise to the mixture, and the resultant mixture was stirred for 15 minutes. Subsequently, N,N-dimethylformamide (0.95 g; 13.1 mmol) was added dropwise to the mixture, and the resultant mixture was gradually brought to room temperature. Reaction was stopped by dropwise addition of saturated aqueous ammonium chloride solution, followed by extraction with ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.59 g of the target compound (yield: 30.6%).
Reaction SMILES: [OH:1][CH:2]([CH3:37])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:14][CH:13]=2)=[C:7]([CH2:30][CH2:31][CH3:32])[N:6]2[N:33]=[C:34]([CH3:36])[N:35]=[C:5]12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[CH3:36][C:34]1[N:35]=[C:5]2[N:4]([CH2:3][C:2](=[O:1])[CH3:37])[C:9](=[O:10])[C:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]4[NH:28][C:27](=[O:29])[O:26][N:25]=4)=[CH:16][CH:17]=3)=[C:7]([CH2:30][CH2:31][CH3:32])[N:6]2[N:33]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)O)c2nc(C)nn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
A mixture of 4-(2-hydroxypropyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.42 g), Dess-Martin reagent (0.71 g) and acetonitrile (10 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate-pentahydrate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.26 g, 62%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.C(Cl)Cl>[C:1]1([N:7]2[C:11]([NH:12][C:20](=[O:21])[O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccnn1-c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1ccnn1-c1ccccc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
1-Phenyl-1H-pyrazol-5-amine (1 eq) was dissolved in DCE (0.1M), phenylchloroformate (1.1 eq) was added. The reaction was stirred 1 h, then diluted with DCM and washed with water and brine, dried and concentrated under reduced pressure to afford the product in quantitave yield.
Reaction SMILES: C1(C2CC2C(Cl)=O)C=CC=CC=1.[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.C1(C)C=CC=CC=1>C(O)C>[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:43]=[CH:44][C:45]([NH:46][C:25]([NH:24][C:22]([CH:20]2[CH2:21][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])=[S:26])=[CH:47][CH:48]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)C1CC1c1ccccc1
Agent: O=C(N=C=S)C1CC1c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was prepared using commercially available 2-phenyl-1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 63%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.O[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][O:1][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: OCCc1ccccn1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(OCCc2ccccn2)c1

Procedure:
Prepared from 2-(2-hydroxyethyl)pyridine and ethyl 3-hydroxybenzoate. LC-MS (m/z): 245 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:9]([OH:10])[CH2:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:9]([O:10][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@H](O)CCCN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 77C (3.3 g, 12.7 mmol) in DCM (50 mL) was added DIPEA (6.63 mL, 38.1 mmol), tert-butyldimethylsilyl chloride (3.83 g, 25.4 mmol, 2.0 equiv) and DMAP (310 mg, 5.24 mmol, 0.2 equiv). The resulting mixture was stirred at rt overnight. TLC showed no completion and therefore another 2.2 mL of DIPEA and 1.91 g of tert-butyldimethylsilyl chloride were added and stirred at rt for 3 days. The mixture was concentrated and the residue was diluted with EtOAc (100 mL), washed with 0.5 N HCl (2×30 mL), brine (2×30 mL), dried (MgSO4) and evaporated to give the crude product as a light pink oil. Purification of the crude product by flash chromatography (5-10% EtOAc/hexane) gave the desired product 77D (3.8 g, 81%): Rf (10% EtOAc/hexane) 0.25; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.3 min (100%); MS (ES) m/z 374 [M+1]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([O:33][C:34]3[N:42]=[CH:41][CH:40]=[CH:39][C:35]=3[C:36]([OH:38])=O)=[CH:32][C:27]=2[O:26][CH2:25]1.C(N(CC)C(C)C)(C)C.[CH3:52][O:53][C:54](=[O:64])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=1>ClCCl.O>[CH3:52][O:53][C:54](=[O:64])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:36]([C:35]2[C:34]([O:33][C:31]3[CH:30]=[CH:29][C:28]4[O:24][CH2:25][O:26][C:27]=4[CH:32]=3)=[N:42][CH:41]=[CH:40][CH:39]=2)=[O:38])=[CH:58][CH:57]=1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Reactant: COC(=O)Cc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Reaction time: 0.5 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.71 g), 1-hydoxybenzo-triazole hydrate (1.24 g), and 2-(benzo[1,3]dioxol-5-yloxy)-nicotinic acid were combined and suspended in anhydrous dichloromethane (40 mL). N,N-diisopropylethylamine (5.93 mL) was added to the suspension, which was stirred for 0.5 h. The suspension was added to (4-aminomethyl-phenyl)-acetic acid methyl ester (1.22 g) and the reaction mixture stirred at ambient temperature overnight. Water (approx. 15 mL) was then added to the reaction mixture, and it was extracted with dichloromethane (7×30 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate:hexanes=3:2) to yield the title compound (1.41 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(O)=O)[CH2:11][CH2:10]2)=[C:4]([O:18][CH3:19])[CH:3]=1.C(OC(N1CCC(NC2N=NC(Cl)=CC=2OC)CC1)=O)(C)(C)C>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: COc1cc(Cl)nnc1NC1CCN(C(=O)O)CC1
Agent: COc1cc(Cl)nnc1NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: COc1cc(Cl)nnc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of 4-(6-chloro-4-methoxy-pyridazin-3-ylamino)-piperidine-1-carboxylic acid tent-butyl ester (D1) (0.44 g, 1.27 mmol) and Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (1.55 g, 6.35 mmol) in methanol (20 ml) was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a 7M solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D2 (0.25 g, 81%) as a white solid. C10H15ClN4O requires 242; Found 243 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ccccc12
Solvent: c1ccncc1
Product: O=C(Oc1ccc(-c2cc(=O)c3ccccc3o2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.5 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxyphenyl)chromen-4-one (100 mg, 0.419 mmol), pyridine (5 mL) and nicotinoyl chloride (223 mg, 1.25 mmol). The reaction mixture was stirred for 24 h at rt under nitrogen. The solvent was removed under reduced pressure and crude product was purified by column chromatography using 50% EtOAc in hexane to give 100 mg of 4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate (69%). MS (ES) m/z: 344.09 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13](=O)[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:16]([NH2:18])=[O:17]>C(O)=O>[CH:16]([NH:18][CH:13]([CH3:14])[CH2:12][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)=[O:17]
Reactant: NC=O
Reactant: CC(=O)CC1(c2ccc(Cl)cc2)CCC1
Solvent: O=CO
Product: CC(CC1(c2ccc(Cl)cc2)CCC1)NC=O
Temperature: 175 °C

Procedure:
1-[1-(4-chlorophenyl)cyclobutyl]propan-2-one prepared as described in Example 3 (25 g) and 98% formic acid (10 ml) were added to formamide (22 ml) at 160° C. The temperature was raised to 175° C. and maintained at this temperature for sixteen hours. The mixture was cooled, extracted with dichloromethane. The extract was washed with water and evaporated to give a gum which was crystallised from petroleum ether (b.p. 40°-60° C.) to give N-formyl-2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (m.p. 71°-73° C.).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:15])[NH:7][C:6]=2[CH:16]=1.[OH-].[K+].S([O-])(O[CH3:23])(=O)=O>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([S:15][CH3:23])=[N:7][C:6]=2[CH:16]=1
Reactant: COS(=O)(=O)[O-]
Reactant: S=C1Nc2cc(Cl)ccc2Nc2cscc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CSC1=Nc2cc(Cl)ccc2Nc2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.8 g. of 7-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepine-10-thione in 10 ml of dioxane is added dropwise and simultaneously at 30°-40°C., a solution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8 g. of methyl sulfate. After addition is complete, the reaction mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to 20 ml., diluted with water and extracted with chloroform. The chloroform solution is concentrated under reduced pressure to give a solid, which is recrystallized from methanol-water to give yellow crystals, m.p. 111°-113°C.