Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])OCC(Cl)(Cl)Cl)=[CH:5][CH:4]=1.[C:18]1([C:24]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:26][N:25]=[C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:28]=3)[CH2:30][CH2:31]2)=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1

Procedure:
A solution of 2,2,2-trichloroethyl (6-methoxypyridin-3-yl)carbamate (300 mg, 1.00 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 5 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (84.0 mg, 21.2%) as a solid.
Reaction SMILES: C([CH:8]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)[CH2:9][N:10]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)C1C=CC=CC=1.ClC(OCC(C)C)=O.CO>ClCCCl>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:16]1[N:10]([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH2:9][CH2:8][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1
Reactant: c1ccc(CC(CN(c2nccs2)C2Cc3ccccc3C2)C2CCCCN2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1nccs1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 52 (0.688 g, 1.64 mmol) in DCE (15 mL) was added isobutyl chloroformate (0.53 mL, 4.94 mmol) at 0° C. and the solution was refluxed for 9.5 hours. Methanol (30 mL) was added and the mixture was allowed to stir at rt for 16 hours. The reaction mixture was concentrated under reduced pressure to provide compound 53.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: Nc1nccs1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3nccs3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)pyrimidineacetaldehyde, (uridinedialdehyde), (6.05 g) was dissolved in water (25 ml). To a solution was added 2-aminothiazole (2.50 g). The mixture was stirred at ambient temperature overnight to give a clear solution. The solution was subjected to column chromatography on HP-20 resine, which was eluted with water and then 50% aqueous acetone. The elution was condenced in vacuo and lyophilized to give white powder of 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolyl)morpholin-2-yl]uracil (8.09 g).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[C:12]2[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31]>>[CH2:24]([O:23][C:21]([N:11]([C:12]1[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=1)[S:8]([C:7]1[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][CH:34]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[O:22])[CH:25]([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Product: COC(=O)c1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1

Procedure:
reaction of 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide with 4-methoxycarbonylphenylboronic acid (or an anhydride or ester thereof) in the presence of a source of fluoride ion and under aqueous conditions to give N-(isobutoxycarbonyl)-2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=3)[CH:13]2[C:23]([NH:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[O:24])=[O:11])[CH:7]=1.[N+](C1C=CC(C(OC)=O)=CC=1)#[C-]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=3)[CH:13]2[C:23]([NH:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:24])=[O:11])[CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)C2c3ccc(C)cc3CCN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Agent: [C-]#[N+]c1ccc(C(=O)OC)cc1
Solvent: CO
Product: Cc1ccc2c(c1)CCN(C(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1)C2C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
(E)-Methyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate: To 20B (0.15 g, 1.033 mmol), methyl 4-isocyanobenzoate (0.166 g, 1.033 mmol), and Intermediate 2 (0.259 g, 1.033 mmol) was added MeOH (20 mL). The reaction was heated to reflux for 24 h. After cooling to rt the product was filtered off as (0.318 g, 55.3%) a yellow solid. MS (ESI) m/z: 557.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[H-].[Na+].C1(C)C(C([O:21][C@@H:22]2[C@@H:26]([CH2:27][O:28]C(C3C(C)=CC=CC=3)=O)[O:25][C@H:24](Cl)[CH2:23]2)=O)=CC=CC=1.O>CN(C)C=O>[O:10]([C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[C@@H:24]1[O:25][C@H:26]([CH2:27][OH:28])[C@@H:22]([OH:21])[CH2:23]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@H](Cl)C[C@@H]1OC(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(O[C@H]2C[C@H](O)[C@@H](CO)O2)cc1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
p-Nitrophenol (178 mg, 1.28 mmol) and sodium hydride (64 mg of a 60% dispersion in mineral oil, 1.6 mmol) were stirred together in dry dimethylformamide (4 ml) at room temperature for 30 minutes then the chloride (416 mg, 1.07 mmol) from Example 16 was added. The mixture was stirred for a further 3 hours, then water (100 ml) was added and the mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in hexanes) to give a pale yellow oil which crystallized from a mixture of chloroform and hexanes to give the title compound as a colourless solid (190 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(F)ccc3[nH]2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-fluoro-1H-benzimidazol-2-yl)piperidine-1-carboxylate (0.81 g, 2.53 mmol) in DCM (8 mL) is added a solution of 4M HCl in dioxane (2 mL). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is concentrated under reduced pressure to give 0.74 g of 5-fluoro-2-(piperidin-4-yl)-1H-benzimidazole. This product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine (19.4 mg, 0.068 mmol) in 1 mL of DMF cooled at 0° C. was added methyl iodide (100 uL, 1.61 mmol), followed by sodium hydride (60% oil suspension, 5 mg, 0.13 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched by adding 50 uL of water, diluted with 25 mL of ethyl acetate, washed with water (25 mL×3), saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (20% ethyl acetate/hexanes) to give the title compound (14.3 mg, 0.048 mmol, 70%). 1H NMR (CDCl3) 8.06 (d, J=2.7 Hz, 1H), 7.57-7.79 (m, 1H), 7.60 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 7.44 (dd, J=8.7 and 2.7 Hz, 1H), 7.09 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 6.99-7.02 (m, 1H), 6.82 (dd, J=8.7 and 0.6 Hz, 1H), 3.97 (s, 3H), 3.61 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:26])[C:13]([CH3:25])([S:15]([CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH3:4].[H-].[Na+].[CH3:29]I>C1COCC1>[CH3:29][O:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:26])[C:13]([CH3:14])([S:15]([CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:17])=[O:16])[CH3:25])[O:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 70 mg (0.18 mmol) of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide in anhydrous THF (2 mL) at 5° C. are added 9 mg (0.36 mmol) of sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred for 0.5 h and then 32 μL (0.54 mmol) of methyl iodide are added. The reaction is stirred at room temperature for 18 h and is then warmed to 35° C. for 6 h. The reaction is quenched by addition of methanol and concentrated under reduced pressure. The residue is dissolved in DCM and washed with water, saturated aqueous NaHCO3 solution and brine. The organic layer is dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: DCM, 10% ethyl acetate) followed by preparative HPLC (neutral conditions) to afford 20 mg of N-[3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide. Yield: 28%, ES-MS: m/z 403 [M+H]
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7]>C(O)C.[Pd]>[F:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1cccc(F)c1F
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1cccc(F)c1F

Procedure:
A solution of 2,3-difluorocinnamic acid (2.8 g, 15.2 mol) (commercially available from Lancaster) (Intermediate TWENTY-1) in ethanol (100 mL) was hydrogenated with H2 (balloon) and 10% Pd/C (0.3 g) at rt for 16 h. The mixture was filtered through Celite® and the solvent was evaporated to give 3-(2,3-difluoro-phenyl)-propionic acid as a solid, 2.68 g (98%). A mixture of 3-(2,3-difluoro-phenyl)-propionic acid (2.7 g, 14.4 mmol) in CH2Cl2 at 0° C. was treated with oxalyl chloride (8.7 mL, 2 M in CH2Cl2) and a few drops of DMF. The reaction mixture was stirred for 2 h at rt. The solution was decanted from the dark colored residues and the solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (20 mL) and added to a mixture of AlCl3 (1.92 g, 14.4 mmol) in CH2Cl2 (25 mL). The mixture was heated at 50° C. for 16 h. The entire mixture was poured into ice water. The aqueous phase was removed and extracted with CH2Cl2. The organic layers were combined, washed with sat. NaHCO3 solution, brine, and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel with 20% EtOAc:hexane to give 4,5-difluoro-indan-1-one (Intermediate TWENTY-2), 1.65 g (68%).
Reaction SMILES: [NH2:1][C:2]1([O:11][CH3:12])[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[Cl:13][CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23](=[N:27][O:28][CH3:29])[C:24](O)=[O:25])[N:22]=1)=[O:16].C(=O)([O-])O.[Na+:34].P(=O)(O)(O)O>O.O1CCCC1>[Cl:13][CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23](=[N:27][O:28][CH3:29])[C:24]([NH:1][C:2]2([O:11][CH3:12])[CH2:5][N:4]([S:6]([O-:9])(=[O:7])=[O:8])[C:3]2=[O:10])=[O:25])[N:22]=1)=[O:16].[Na+:34]
Reactant: COC1(N)CN(S(=O)(=O)O)C1=O
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1(OC)CN(S(=O)(=O)[O-])C1=O)c1csc(NC(=O)CCl)n1

Procedure:
In 1 ml of water is dissolved 30 mg of the above 3-amino-3-methoxy-2-oxoazetidine-1-sulfonic acid, and to the solution are added a solution of 89 mg of the acid chloride prepared from 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer) in 1 ml of tetrahydrofuran and 36 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. The mixture is further stirred at room temperature for 20 minutes and adjusted to pH 5.8 with phosphoric acid. After removal of tetrahydrofuran under reduced pressure, the water layer is washed with ethyl acetate and purified by Amberlite XAD-II chromatography. The above procedure yields 28 mg of sodium 3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-methoxy-2-oxoazetidine-1-sulfonate (syn-isomer) which is the same compound as the one described in Example 9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:15])=[CH:12][C:11]=2[C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Reactant: C1COCCN1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 4-{[(4-fluorophenyl)methyl]oxy}-3-[(3-pyridinylamino)carbonyl]benzoic acid (may be prepared as described in Description 111; 62 mg, 0.17 mmol) in N,N-dimethylformamide (DMF) (5 ml) was added morpholine (0.03 ml, 0.34 mmol), EDC (38.9 mg, 0.20 mmol), HOBT (41.5 mg, 0.27 mmol) and N-ethylmorpholine (0.04 ml, 0.34 mmol). The mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by MDAP.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH:14]1[C:26]2[CH:25]([CH2:27][O:28][C:29](=[O:108])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][O:99][CH2:100][CH2:101][O:102][CH2:103][CH2:104][C:105](O)=[O:106])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.ClCCl>CO>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:105](=[O:106])[CH2:104][CH2:103][O:102][CH2:101][CH2:100][O:99][CH2:98][CH2:97][O:96][CH2:95][CH2:94][O:93][CH2:92][CH2:91][O:90][CH2:89][CH2:88][O:87][CH2:86][CH2:85][O:84][CH2:83][CH2:82][O:81][CH2:80][CH2:79][O:78][CH2:77][CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][NH:30][C:29](=[O:108])[O:28][CH2:27][CH:25]2[C:26]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:4][CH:3]=1
Reactant: NCCCCOc1ccc(Br)cc1
Reactant: O=C(O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CO
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21)NCCCCOc1ccc(Br)cc1
Reaction time: 8 h
Yield: 71.6 %

Procedure:
4-(4-bromophenoxy)butan-1-amine (21.5 mg, 0.09 mmol), 1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16,19,22,25,28,31,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76-pentacosaoxa-4-azanonaheptacontan-79-oic acid (100 mg, 0.073 mmol), and N,N′-dimethylaminopyridine (5.4 mg, 0.044 mmol) were combined in a round bottom flask flushed with nitrogen and charged with a Teflon stirbar. Next 5 mL of anhydrous dichloromethane was added via syringe. N,N-Dicyclohexylcarbodiimide (23 mg, 0.11 mmol) is transferred to a second flask flushed with nitrogen and charged with a stirbar and 5 mL of anhydrous dichloromethane is added via syringe. While stirring the first solution, add the dicyclohexylcarbodiimide solution slowly, dropwise. The reaction is then allowed to proceed overnight. The following day solids from the reaction were filtered off and the filtrate was concentrated onto silica. Column chromatography in methanol and dichloromethane gave a clear thick oil (83.3 mg, 71% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH2:38]([O:40][C:41](=[O:47])[CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH3:39]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:43]([CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:47])(=[O:45])=[O:44])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: CCOC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
Prepared using General Procedure 14: To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 4 (177 g, 0.47 mmol) and DIEA (182 mg, 1.4 mmol) in DCM (8 mL) was added freshly prepared ethyl-2-(chlorosulfonyl)acetate (131 mg, 0.7 mmol). After 45 min, the crude reaction was partitioned between DCM and NaHCO3. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography (EA/hexanes) to provide 75 mg (30%) of (S)-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate as light yellow solid. LCMS-ESI (m/z) calculated for C25H26N4O5S2: 526.1; found 527.1 [M+H]+, tR=3.71 min. 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=8.9, 2.3 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.03 (d, J=9.0 Hz, 1H), 5.46 (t, J=7.9 Hz, 1H), 4.70 (dt, J=12.2, 6.1 Hz, 1H), 4.26-4.17 (m, 2H), 4.00 (d, J=8.2 Hz, 2H), 3.49 (ddd, J=17.4, 9.5, 3.9 Hz, 1H), 3.26-3.05 (m, 1H), 2.56 (ddd, J=12.9, 9.0, 4.4 Hz, 1H), 2.23-2.08 (m, 1H), 1.41-1.37 (m, 6H), 1.28 (dd, J=11.7, 4.6 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([CH3:23])([CH3:22])[CH2:16][C:17](=O)[NH:18]2)=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:22][C:15]1([CH3:23])[C:14]2[C:19](=[CH:20][C:11]([CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][OH:3])=[CH:12][CH:13]=2)[NH:18][CH2:17][CH2:16]1
Reactant: CCCCCC(C(=O)OCC)c1ccc2c(c1)NC(=O)CC2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCC(CO)c1ccc2c(c1)NCCC2(C)C
Temperature: 0 °C
Yield: 69.3 %

Procedure:
A solution of 2-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-heptanoic acid ethyl ester (3.657 g, 11 mmole) in 100 mL of ether was treated with 1.6 g of lithium aluminum hydride, heated at reflux for four hours and then cooled to 0° C. The reaction mixture was quenched by the successive addition of 1.6 mL water, 1.6 mL 15% sodium hydroxide solution and 4.8 mL water and stirred at room temperature until a white precipitate formed. MgSO4 was added and the mixture was filtered and concentrated in vacuo affording a yellow oil. The product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to yield 2.1 g of 2-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol as a pale yellow oil.
Reaction SMILES: [ClH:1].Cl.C([O:6][CH:7]([CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[C:29]4[O:28][CH:27]=[C:26]([Cl:30])[C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:31][CH3:32])(=O)C.N.Cl.C(OCC)C>C(Cl)Cl.C(O)(C)C>[ClH:30].[ClH:1].[Cl:30][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:20][C:14]3[C:13]4[C:18](=[CH:19][C:10]([O:9][CH2:8][CH:7]([OH:6])[CH2:33][N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)=[C:11]([O:31][CH3:32])[CH:12]=4)[N:17]=[CH:16][N:15]=3)[C:29]=2[O:28][CH:27]=1
Reactant: COc1cc2c(Nc3cccc4c(Cl)coc34)ncnc2cc1OCC(CN1CCOCC1)OC(C)=O
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3cccc4c(Cl)coc34)ncnc2cc1OCC(O)CN1CCOCC1
Yield: 157.7 %

Procedure:
A mixture of 7-(2-acetoxy-3-morpholinopropoxy)-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline dihydrochloride (0.15 g) and a saturated methanolic ammonia solution (3 ml) was stirred at ambient temperature overnight. The solvent was evaporated and the residue was dissolved in methylene chloride (3 ml) and adsorbed to the top of a pre-packed silica column (NH2-silica; Isolute sorbent from International Sorbent Technology Ltd, ref. no. 9470-0100) and eluted with a 19:1 mixture of methylene chloride and methanol. The material so obtained was dissolved in methylene chloride (3 ml) and a 6M solution of hydrogen chloride in isopropanol (0.3 ml) was added. Diethyl ether (10 ml) was added and the resultant precipitate was collected by filtration, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.11 g); Mass Spectrum: M+H+ 486.