Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.CN(C)[CH:24]=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:24]=[O:25])=[CH:9][N:10]=1
Reactant: CN(C)C=O
Reactant: c1csc(C2OCCO2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (10.00 g) in tetrahydrofuran (150 mL) was slowly added a 1.6M n-butyllithium hexane solution (44 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 1 hr and N,N-dimethylformamide (14 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.64 g, yield 56%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 186 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH:14]=[O:15])=[C:12]([C:16](Cl)=O)[O:11][N:10]=1.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:43])[CH:39]([CH2:41]C)[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([C:14]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:43])[CH:39]([CH3:40])[CH3:41])[CH:32]=3)[CH2:29][CH2:30]2)=[O:15])=[C:12]([CH3:16])[O:11][N:10]=1
Reactant: CCC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Reactant: O=Cc1c(-c2c(Cl)cccc2Cl)noc1C(=O)Cl
Solvent: C1CCOC1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
A mixture of 3-(2,6-dichlorophenyl)-4-formyl-5-isoxazolecarbonyl chloride (69.0 mg, 0.250 mmol), N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-ethylpropanamide (44.0 mg, 0.150 mmol), TEA (30.0 mg, 0.300 mmol) in THF (2 mL) was stirred for 12 h at room temperature. The crude product was purified by preparative TLC using CH2Cl2/MeOH/isopropyl amine (19:1:0.2) to give the desired product (52 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 7.52–7.49 (m, 2H), 7.49–7.41 (m, 2H), 7.39–7.31 (m, 2H), 7.29–7.21 (m, 2H), 6.92 (d, 1H, J=7.6 Hz), 3.25–3.11 (m, 5H), 2.81–2.74 (m, 4H), 2.58–2.44 (m, 4H), 2.30–2.19 (m, 2H), 1.93–1.78 (m, 4H), 1.56–1.44 (m, 2H), 1.31–1.28 (m, 2H), 1.24 (d, 6H, J=6.6 Hz); ESMS m/e: 585.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:25][NH:26][C:27](=[O:34])[CH:28]([CH2:32][CH3:33])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:25][NH:26][C:27](=[O:34])[CH:28]([CH2:32][CH3:33])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=505.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-ethyl-malonamic acid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCC1C=Cc2ccc(F)c(F)c2O1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCc2ccc(F)c(F)c2O1

Procedure:
51.0 g (0.21 mol) of 7,8-difluoro-2-pentyl-2H-chromene are hydrogenated for 1 h at room temperature in 510 ml of toluene in the presence of Pd/C (5% Pd). The batch is concentrated to dryness. The crude product (yellowish liquid) can be used directly for the next step.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CS(C)=O>[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][CH2:25]4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (180 mg, 0.46 mmol) and DIPEA (178 mg, 1.38 mol) in DMSO (2.0 mL) was added dropwise MeSO2Cl (53 mg, 0.46 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-91 (57.1 mg, 26.4%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH:25][C:34](=[O:36])[CH3:35])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C@@H:9]1[CH3:33])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccccc1C[C@H](N)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1C[C@H](NC(C)=O)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 53.3 %

Procedure:
Dissolve the diastereomeric mixture of amines from the previous reaction which contains (2R,3S,5R)-5-[(1S,2S)-2-amino-3-(2-ethylphenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (418 mg, 0.9 mmol) in dry dichloromethane (7 mL) under a nitrogen atmosphere and add acetic anhydride (90 μL, 0.95 mmol) and triethylamine (150 μL, 1.1 mmol). After 4 hours quench with methanol, concentrate and purify (silica gel chromatography) to give a mixture of amide diastereomers containing the title compound (243 mg). Purify the resulting mixture by HPLC, eluting with 65:35 acetonitrile:water with 8 μM hydrochloric acid, to give the title compound as a single diastereomer (47 mg, 10% overall).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2
Reactant: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(N[C@H]1Cc2ccc(CCl)cc2C1)OCc1ccccc1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To (S)-benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (5.72 mmol, 1.7 g) was added DCM (34.9 mL) followed by sulfurous dichloride (11.43 mmol, 1.360 g). The reaction was stirred for one hour before removing the solvent in vacuo. DCM was added (5 mL) before removing the solvent in vacuo, this procedure was followed a further twice to give a yellow solid (1.8 g, 100%). 1H NMR (400 MHz, CDCl3) δ 2.81 (m, 2H), 3.30 (m, 2H), 4.56 (m, 3H), 4.95 (brs, 1H), 5.12 (s, 2H), 7.19 (d, 2H), 7.25 (m, 1H), 7.33 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[S:29]([CH3:28])(=[O:31])=[O:30])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(C)(=O)=O)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-(3-{[(biphenyl-4-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12m, and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 4H), 7.44-7.23 (m, 6H), 7.14 (m, 3H), 4.35 (s, 2H), 4.33 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.78 (s, 3H), 2.59 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)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>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=3)=[CH:9][C:10]1=2
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol), tetrakis(triphenylphosphine)palladium (0) (0.17 g, 0.24 mmol), and cuprous (I) iodide (0.05 g, 0.28 mmol) in triethyl amine (20 mL) was heated under nitrogen at 80° C. for 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was taken up in ethyl acetate (50 mL) and washed with 1N aqueous HCl (3×20 mL) and brine (20 mL). The organic layer was separated and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.77 g, 92%): mp 240-242° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, J=7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349([M+], 50%); Anal. Calc. For C21H23NO2Si.0.2 EtOAc: C, 71.32; H, 6.75; N, 3.82. Found: C, 71.08; H, 6.64; N, 3.82.
Reaction SMILES: C[C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].[CH2:17]([OH:19])C>>[NH2:14][C:10]1[C:11]([O:19][CH3:17])=[CH:12][CH:13]=[CH:2][C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5]
Reactant: CCO
Reactant: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Product: C=CCOC(=O)c1cccc(OC)c1N

Procedure:
The above nitro compound was reduced by the method described in example 6 for the reduction of allyl 2-methyl-6-nitrobenzoate, except that the solvent was ethanol, to give allyl 2-amino-3-methoxybenzoate.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[C:5]2[C@@H:4]2[CH2:20][CH2:21][N:3]12.[Cl:22][CH2:23][C:24](=N)OCC>CN(C)C=O.C(O)C>[Cl:22][CH2:23][C:24]1[O:17][C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:21][CH2:20][C@H:4]4[C:5]=23)=[N:18][N:19]=1
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: CCOC(=N)CCl
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1c2ccccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Yield: 54.1 %

Procedure:
A solution of 5 g (17.64 mmol) of (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid hydrazide and 3.06 g (19.41 mmol) of ethyl chloroacetimidate in 40 ml of dimethylformamide and 10 ml of ethanol was stirred at 90° for 12 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and water. The aqueous phase was back-washed once with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol 93:3) yielded 3.26 g (55%) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colourless foam, RF=0.5 (methylene chloride/methanol 10:1).
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[CH2:16](Br)[CH3:17]>>[ClH:1].[CH2:16]([N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C:3]1[O:2][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1)[CH3:17]
Reactant: CCBr
Reactant: c1ccc2oc(-c3ncc[nH]3)cc2c1
Agent: Cl
Product: CCn1ccnc1-c1cc2ccccc2o1

Procedure:
This was prepared from 2-(benzofuran-2-yl)imidazole hydrochloride and ethyl bromide according to the procedure of example 2; m.p.=183°-185° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1([S:25][CH3:26])[CH2:16][N:15]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:14]1=[O:24].C(N(CC)CC)C.[N+:34]([C:37]1[CH:55]=[CH:54][C:40]([CH2:41][O:42][C:43]([CH:45]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[C:46](Cl)=[O:47])=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>ClCCl>[Si:17]([N:15]1[CH2:16][C:13]([S:25][CH3:26])([NH:12][C:46](=[O:47])[CH:45]([C:43]([O:42][CH2:41][C:40]2[CH:54]=[CH:55][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)=[O:44])[C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[C:14]1=[O:24])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: O=C(Cl)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)c1ccsc1
Reactant: CSC1(N)CN([Si](C)(C)C(C)(C)C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CN([Si](C)(C)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
A solution of (23) (418 mg) in dry dichloromethane (10 ml) containing triethylamine (222 mg) at 0° C. was treated with a solution of 2-(p-nitrobenzyloxycarbonyl)-2-thien-3-ylacetylchloride (407 mg) in dry dichloromethane (5 ml). The mixture was stirred at 0° C. for 15 minutes, then allowed to warm to room temperature. After 1 hour the mixture was washed successively with sat. NaHCO3, water, dilute HCl, water and brine. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography of the residue on silica gel gave the product (39) (496 mg) as a foam.
Reaction SMILES: O[CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[NH2:14]C1C2N=CC=CC=2CCC1>>[NH2:14][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccnc2c1CCCC2O
Reactant: NC1CCCc2cccnc21
Product: COc1ccnc2c1CCCC2N
Yield: 68 %

Procedure:
8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline was prepared in 68% yield from 8-hydroxy-4-methoxy-5,6,7,8-tetrahydroquinoline (preparation and characterization described by: Uchida, M.; Morita, S.; Chihiro, M.; Kanbe, T.; Yamasaki, K.; Yabuuchi, Y.; Nakagawa, K. Chem. Pharm. Bull. 1989, 37, 1517-1523.) using the same procedure employed to prepare 8-amino-5,6,7,8-tetrahydroquinoline (according to the procedures described in Bridger et al. U.S. patent application U.S. Ser. No. 09/535,314). 1H NMR (CDCl3) δ 1.59-2.15 (m, 6H), 2.60-2.65 (m, 2H), 3.84 (s, 3H), 3.95 (dd, 1H, J=6.0, 9.0 Hz), 6.61 (d, 1H, J=6.0 Hz). 8.32 (d, 1H, J=6.0 Hz); 13C NMR (CDCl3) δ 19.53, 22.89, 31.94, 51.57, 55.62, 104.04, 120.94, 148.52, 160.42, 163.71; ES-MS m/z 179 (M+H).
Reaction SMILES: CS(O[C@@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:17])=[CH:11][C:12]=2[F:16])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Li+]>CN(C=O)C>[N:18]([C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:17])=[CH:11][C:12]=2[F:16])[CH2:7]1)=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)O[C@@H]1CCc2c(F)cc(F)cc2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (54.0 g), prepared as in Example 7, and lithium azide (15.8 g, 0.322 mol) in 400 mL of DMF was stirred under argon at 50° C. for 16 hours. The reaction was quenched with 200 mL of water and the mixture extracted with 1 L of pentane. The extract was washed with 50 mL of water and dried over magnesium sulfate. Evaporation under reduced pressure at 35° C. gave crude-(S)-2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene as a yellow oil residue (59.8 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:16])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: [Li]CCCC
Reactant: Cc1cccc(-n2c(C)ccc2C)n1
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cccc(-n2c(C)ccc2C)n1
Temperature: -30 °C
Yield: 60 %

Procedure:
To a solution of the product from Example 2a (6.82 g, 36.6 mmol) in 75 mL of dry THF cooled to 40° C. under a N2 atmosphere was added dropwise n-BuLi as a 2.5M solution in hexanes (16 mL, 40 mmol). The resulting solution was stirred at low temperature for thirty minutes then treated with CH3I (2.4 mL, 38.6 mmol). On completion of the addition the mixture was allowed to warm to −30° C. and after 20 min to room temperature. The reaction was subsequently quenched by pouring into brine solution, the product isolated by extraction with EtOAc. Dried over MgSO4, filtered and concentration under vacuum. Purified by silica gel column chromatography eluting with EtOAc/hexane gave the title compound (4.42 g, 60%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a slurry of ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylate (1.04 g, 2.53 mmol) in THF (20 mL) was added 1.0 M of sodium hydroxide in water (20 mL). The reaction mixture was stirred at 80° C. overnight and was concentrated. The residue was diluted with 1 N HCl and a precipitate formed. The precipitate was filtered and dried to give 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (75) (0.88 g, 91%). LCMS: (FA) ES− 381.2. 1H NMR (400 MHz, d6-DMSO) δ: 13.00 (s, 1H), 7.65-7.72 (m, 2H), 7.36 (d, 1H), 3.73-3.79 (m, 4H) and 3.55-3.61 (m, 4H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([O:10]C)[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=2)=[CH:6][N:5]=1)[CH3:2].Br.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH2:1]([NH:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of N-ethyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.29 g, 0.7 mmol) and 48% aq. HBr (0.32 mL, 2.78 mmol) in acetic acid (5 mL) was heated at 90° C. for 6 h. The mixture was cooled to RT, diluted with water (60 mL), made basic with solid NaHCO3, extracted with 1:1 EtOAc/THF (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was stirred with MeCN for 1 h and the resulting solid was collected via filtration to afford 2-(ethylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one as white solid (210 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 11.20 (br s, 1H), 8.67 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.24-8.26 (m, 2H), 7.96 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.88 (br s, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.34-3.32 (m, 2H), 2.34 (s, 3H), 1.12 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(CC(F)(F)F)CC1
Yield: 44 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 14, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (250 mg, 0.54 mmol) was reacted with 2,2,2-trifluoroethyl trifluoromethanesulphonate (128 mg, 0.59 mmol) and purified by column chromatography, eluting with 5% methanol/methylene chloride to give a sticky solid. The sticky solid was dissolved in methanol and absorbed onto an Isolute SCX column. The column was washed with methanol and eluted with 7N ammonia in methanol. The product was triturated in ether/isohexane and filtered to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propoxy}quinazoline (130 mg, 44%).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[I:8][CH:9]([I:20])[S:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>C(O)(=O)C>[I:20][CH:9]([I:8])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([N:17]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])=[CH:18][CH:19]=1)(=[O:12])=[O:11]
Reactant: Nc1ccc(S(=O)(=O)C(I)I)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1ccc(S(=O)(=O)C(I)I)cc1

Procedure:
A mixture of 8.1 g. of maleic anhydride and 31.7 g. of p-(diiodomethylsulfonyl)aniline in 160 ml. of glacial acetic acid is treated in the fashion of Example 2 to produce crude N-[p-(diiodomethylsulfonyl)phenyl]maleimide. This material is washed with water, air-dried, and recrystallized from acetone to a pale, crystalline powder, m.p. 217° C.