Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:14]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].[Cl:22]S([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[ClH:22].[C:27](=[O:28])([O:1][CH2:2][CH:3]([NH2:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:11])([F:12])[F:13])[NH2:26]
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccccc1C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cl
Product: NC(=O)OCC(N)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 570 mg (1.87 mmol) of the compound from Example 62A in 100 ml of acetonitrile was cooled to −15° C. and admixed with 325 μl (3.73 mmol) of chlorosulphonyl isocyanate. After 10 min, 50 ml of water were added and the mixture was heated at 60° C. for 4 h. After cooling to RT, the solution was rendered alkaline (pH 9-10) by addition of saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvents on a rotary evaporator. For complete deprotection of the amino group, the residue was admixed with 15 ml of a 4M solution of hydrogen chloride in dioxane, and the mixture was stirred at RT for 5 min and the volatile components were removed on a rotary evaporator. The residue corresponded to the title compound (630 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:30])(=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified by HPLC. 1H-NMR (CDCl3) δ 10.75 (br s, 1H, NH), 8.64 (dm, 1H, J=4.8 Hz), 7.79 (dd, 1H, J=9.2 Hz, J=1.1 Hz), 7.75 (d, 2H, J=7.3 Hz), 7.49 (dm, 1H,J=9.2 Hz), 7.1-7.3 (m, 5H), 3.65 (s, 3H), 2.97(t, 2H, J=7.6 Hz), 2.61 (t, 2H, J=7.6 Hz), 2.35 (s, 3H). MS: m/z 473 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[F:15])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[CH:19][C:20]([N:27]2[C:31]([NH2:32])=[CH:30][C:29]([CH3:33])=[N:28]2)=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2.[N:34]1C=CC=CC=1>>[NH2:34][C:17]1[CH:18]=[CH:19][C:20]([N:27]2[C:31]([NH:32][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[C:6]([F:15])[CH:7]=3)(=[O:13])=[O:12])=[CH:30][C:29]([CH3:33])=[N:28]2)=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2
Reactant: Cc1cc(N)n(-c2ccc(Br)c3ncccc23)n1
Reactant: c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1F
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)c(F)c2)n(-c2ccc(N)c3ncccc23)n1
Temperature: 80 °C
Yield: 62 %

Procedure:
A stirring mixture of 4-t-butyl-3-fluorobenzene-1-sulfonyl chloride (prepared from Example 27 step c, 1.1 g, 4.2 mmol) and 1-(8-bromoquinolin-5-yl)-3-methyl-1H-pyrazol-5-amine (0.97 g, 3.2 mmol) in pyridine (5 mL) was heated at 80° C. for 15 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude solid was recrystallized from hot ethanol (5 mL) and the resulting solid was collected by filtration to give the desired compound (0.10 g, 0.19 mmol, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([C:12]([CH2:21][CH3:22])([C:18]([OH:20])=[O:19])[CH:13]([OH:17])C(O)=O)[CH3:11].N1CCCCC1.C(O)(=[O:31])C>CCOCC.C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:22][CH2:21][C:12]([CH2:10][CH3:11])([C:13]([OH:17])=[O:31])[C:18]([OH:20])=[O:19]
Reactant: O=Cc1ccccc1Br
Reactant: CC(=O)O
Reactant: CCC(CC)(C(=O)O)C(O)C(=O)O
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(CC=Cc1ccccc1Br)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
A 500-ml three-necked round flask (Dean & Stark) equipped with a stirring bar, a Dimroth condenser and a thermometer was charged with 74.0 g (400 mmol) of 2-bromobenzaldehyde, 70.48 g (440 mmol) of diethylmaloic acid, 1.6 ml of piperidine, 4.8 ml of acetic acid and 80 ml of benzene. The mixture was subjected to azeotoropic dehydration for 7 hours in an oil bath of 110° C. under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature and 300 ml of ether was added, followed by washing with 100 ml of water two times. The organic phase was dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure and the concentrate of a orange liquid was distilled under reduced pressure to obtain 117.2 g of the desired product as a yellow liquid (yield: 90%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C1C=CC2N(O)N=NC=2C=1.[OH:22][CH2:23][C:24]([NH:26][CH2:27][CH:28]([OH:43])[CH2:29][O:30][C:31]1[C:36]([CH3:37])=[CH:35][C:34]([C:38](=[NH:41])[NH:39]O)=[CH:33][C:32]=1[CH3:42])=[O:25].CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:41]=[C:38]([C:34]3[CH:33]=[C:32]([CH3:42])[C:31]([O:30][CH2:29][CH:28]([OH:43])[CH2:27][NH:26][C:24](=[O:25])[CH2:23][OH:22])=[C:36]([CH3:37])[CH:35]=3)[N:39]=2)[CH:9]=[CH:10][CH:11]=1)=[O:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of 3-formyl-benzoic acid (170 mg, 1.13 mmol), HOBt (184 mg, 1.36 mmol) and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide (352 mg, 1.13 mmol) in THF (4 mL) and DMF (6 mL) was cooled to 0° C. before EDC hydrochloride (239 mg, 1.24 mmol) was added in portions. The mixture was stirred at rt for 1 h before it was diluted with THF (4 mL) and heated to 80° C. for 16 h. The mixture was concentrated and then separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 5 μm, 90% to 10% water (containing 0.5% of formic acid) in MeCN) to give the title compound as a white solid (130 mg). LC-MS*: tR=0.75 min; [M+1]+=425.90, 1H NMR (D6-DMSO): δ 2.35 (s, 6H), 3.20-3.29 (m, 1H), 3.40-3.49 (m, 1H), 3.71-3.82 (m, 2H), 3.84 (d, J=5.0 Hz, 2H), 3.92-4.00 (m, 1H), 5.30 (d, J=4.8 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.70 (br t, J=4.8 Hz, 1H), 7.81 (s, 2H), 7.91 (t, J=7.8 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.49 (d, J=7.8 Hz, 1H), 8.69 (s, 1H), 10.18 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH:16][C:18]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[O:19])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)c1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(C(C)(C)C)c1
Reaction time: 4 h
Yield: 91.1 %

Procedure:
A mixture of 5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-ylamine (Step 1.2) (1 g, 4.05 mmol) and 1,1′-carbonyldiimidazole (0.984 g, 6.07 mmol, 1.5 eq) in DCM (50 mL) is stirred for 4 h at reflux and allowed to cool. The resulting precipitate is collected by filtration to provide 1.26 g of the title compound as white solid: ESI-MS: 340.2 [M−H]−; tR=2.85 min (System 1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccncc3)cc(Cl)n2n1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccncc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (7E, 100 mg, 0.305 mmol) and N-(piperidin-4-yl)acetamide (87 mg, 0.610 mmol) in NMP (1 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (10-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12 mg, 9%). 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.45 (d, J=5.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=6.1 Hz, 2H), 6.08 (s, 1H), 4.28 (br. s., 2H), 3.88 (br. s., 2H), 3.15 (d, J=3.0 Hz, 2H), 2.40-2.47 (m, 2H), 2.30-2.37 (m, 3H), 1.85-1.96 (m, 2H), 1.81 (s, 3H), 1.46-1.62 (m, 3H). ESI-MS: m/z 434.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([N:8]2[C:12](I)=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([N:8]2[C:12]([C:20]#[N:21])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1I
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1C#N
Temperature: 200 °C
Yield: 33.8 %

Procedure:
To a stirred solution of 1-(3-chloro-2-methoxyphenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (0.2 g, 0.49 mmol, 1.0 eq) in NMP (5 mL) was added CuCN (0.044 g, 0.49 mmol, 1.0 eq) and heated to 200° C. for 2 h. The reaction mixture was passed through celite pad and washed with excess of ethyl acetate. The filtrate was washed with water and ethyl acetate layer was separated, dried (Na2SO4), and the solvent evaporated. The resulting residue was purified by CC using ethyl acetate/PE (1:19) to get 1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (0.05 g, crude, yellow solid; TLC system: EtOAc/PE (1:9) Rf: 0.5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[O:21][CH2:22][CH2:23][C:24]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2c(c1)CCO2
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)CCO2

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 2,3-dihydro-benzofuran-5-carboxylic acid. MS: 420.3 (M+H).
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:12]([Li])[CH2:13]CC>O>[CH:2]1([CH2:12][CH3:13])[C:7]2[C:5](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3]1
Reactant: [Li]CCCC
Reactant: CCCCCC
Reactant: C1CCOC1
Solvent: O
Product: CCC1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 500 mL three-neck flask replaced with nitrogen was charged with 21.6 g (purity 72%, 42 mmol) of the yellow oily product and 274 mL of tetrahydrofuran, and cooled in an ice bath, and then 88.5 mL (1.59 M, 141 mmol) of a hexane solution of n-butyllithium was added dropwise. The color of the solution was turned from colorless to yellow. The temperature of this solution was gradually raised to room temperature, and the solution was further stirred for 1 hour. While this solution was cooled in a water bath, 137 mL of distilled water was added dropwise. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The separated organic layer and the extract were combined, washed with an aqueous saturated sodium chloride solution two times, and dried with sodium sulfate. Volatile components were distilled off under reduced pressure, and the resulting yellow oily product was purified by column chromatography (developing solvent: heptane/methylene chloride v/v=9/1), and recrystallized with ethanol/methylene chloride. Based on the following 1H NMR (400 MHz, CDCl3) data, the resulting pale yellow solid was identified to be (5,6,7,8-tetrahydro-5,5,8,8-tetramethylbenz-f-inden-3-yl) (inden-3-yl)ethane. Yield amount 9.1 g (purity>98%, 24 mmol, yield 57%).
Reaction SMILES: [C@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](Cl)=[O:16]>C1COCC1.C(Cl)Cl>[C@H:1]1([N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCCc2ccccc21
Yield: 73.2 %

Procedure:
To a solution of (R)-1,2,3,4-tetrahydro-1-naphthylamine (6.0 g) in THF (150 mL) at 0° C. was added TEA (18.5 mL) and phthaloyl chloride (8.2 g), and the resultant mixture was stirred at room temperature overnight and 70° C. for 3 h. The mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried over MgSO4, and concentrated in vacuo. The resulting crude was chromatographed on silica gel (EtOAc/hexane, 5/95 to 30/70) to afford 8.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:21]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:24])[CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:21]=1
Reactant: COc1ccc(N2C(=O)CCNc3ccc(Cl)cc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2C(=O)CCN(C)c3ccc(Cl)cc32)cc1

Procedure:
23 g 8-chloro-1-(4'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one is stirred in 150 ml dimethylformamide for about 2 hours on a boiling water bath to which has been added 15 g methyl iodide and 11 g anhydrous potassium carbonate. The reaction mixture is poured into 1 liter water whereby the product is thoroughly crystallized with stirring. The reaction mixture is filtered by suction, washed thoroughly with water, and crystallized from isopropyl alcohol. The yield is 19 g having an m.p.=144°-145° C. (79% of the theory).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[H-].[Na+].Br[CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][Br:21].C(OCC)C>CN(C)C=O.O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[O:12][CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][Br:21])=[CH:2]1
Reactant: Oc1cccc(-c2ccsc2)c1
Reactant: O=C(CBr)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCBr)COc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.4 %

Procedure:
0.25 g of 3-(3-thienyl)phenol was dissolved in 2.5 ml of dimethylformamide, and 28 mg of 60% oily sodium hydride was added. The mixture was stirred at room temperature for 15 minutes, and then a dimethylformamide solution (1 ml) of 0.45 g of 1,5-dibromo-2-pentanone [see J. Chem. Soc., 1948, 278] was added dropwise at -40° C. The mixture was stirred at this temperature for 2 hours, and ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane / ethyl acetate=30/1] to give 50 mg of the captioned compound as a colorless oil.
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH2:24][CH3:25])([C:19]([O:21]CC)=[O:20])[CH2:13][CH2:12]2)C1C=CC=CC=1.[OH-:26].[Na+]>C(O)(C)C>[CH2:12]([O:26][C:18]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14]([CH2:24][CH3:25])([C:19]([OH:21])=[O:20])[O:15]2)=[CH:10][CH:9]=1)[C:11]1[CH:16]=[CH:17][CH:18]=[CH:9][CH:10]=1
Reactant: [OH-]
Reactant: CCOC(=O)C1(CC)CCc2cc(OCc3ccccc3)ccc2O1
Agent: [Na+]
Solvent: CC(C)O
Product: CCC1(C(=O)O)CCc2ccc(OCc3ccccc3)cc2O1
Temperature: 70 °C

Procedure:
To a 2 L isopropanol solution of ethyl 6-benzyloxy-2-ethylchromane-2-carboxylate (155 g, 0.455 mol) was added 1 L of aqueous 5N sodium hydroxide. This solution was heated to 70° C. overnight. Isopropanol was removed under reduced pressure. The residue was acidified with conc. hydrochloric acid 300 ml and 2N hydrochloric acid to pH 1. The acidic solution was extracted three times with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to give a yellow oil, which crystallized upon standing: 130 g (91%).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[N:6]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: Cn1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)oc1=O
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)oc1=O
Temperature: 110 °C
Yield: 25.3 %

Procedure:
To a sealed vial is added 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3-methyl-3H-[1,3,4]oxadiazol-2-one (92 mg, 0.215 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (57 mg, 0.258 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) and 2M aq. Na2CO3 (0.45 ml, 0.9 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-4% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford the title compound (24 mg, 25%) as a off-white solid. LCMS (ESMS): m/z 442.43 (M++1).
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.O.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)CCC>[N+:12]([C:11]1[C:2]2[NH:19][CH2:16][CH2:17][NH:18][C:4](=[O:6])[C:3]=2[CH:8]=[CH:9][CH:10]=1)([O-:14])=[O:13]
Reactant: NCCN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Solvent: O
Solvent: CCCCO
Product: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 11.7 parts of methyl 2-bromo-3-nitrobenzoate, 8.1 parts of 1,2-ethanediamine monohydrate and 40 parts of 1-butanol was stirred for 1/2 hour at reflux temperature. The reaction mixture was evaporated and the residue was diluted with 50 parts of water. The precipitate was filtered off and washed with water and 2-propanol. It was then recrystallized from 2-methoxyethanol, yielding 6.5 parts of 2,3,4,5-tetrahydro-9-nitro-1H-1,4-benzodiazepin-5-one; mp. 191°-195° C. (interm. 1)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.C(O[Na])(C)=O.[CH:20]([C:22]1[N:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][C:26]([C:32]#[N:33])=[C:25]2[O:34][CH:35]([CH3:37])[CH3:36])=O>CC(O)=O>[CH:35]([O:34][C:25]1[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([CH:20]=[C:11]3[S:10][C:9]([NH:8][CH2:7][C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[N:13][C:12]3=[O:14])[N:23]=2)[N:28]=[CH:27][C:26]=1[C:32]#[N:33])([CH3:37])[CH3:36]
Reactant: Cc1ccsc1CNC1=NC(=O)CS1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: Cc1ccsc1CNC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(OC(C)C)c3n2)S1
Temperature: 80 °C
Yield: 31.4 %

Procedure:
To a mixture of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (36.2 mg, 0.16 mmol) (prepared as described below), AcONa (160 mg, 1.95 mmol), and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (50.2 mg, 0.21 mmol) (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 80° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in AcOEt (20 mL) and filtered through a glass. The solid was washed with AcOEt and dried to give 4-isopropoxy-6-{2-[(3-methyl-thiophen-2-ylmethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-[1,5]naphthyridine-3-carbonitrile as a light brown solid (22.6 mg, 32.4%). HR-ES (+) m/e calcd for C22H19N5O2S2 (M+H)+ 450.1053. found 450.1051.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:11]
Reactant: O=C1OCc2c1cc(F)cc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc2c1COC2=O
Yield: 92.1 %

Procedure:
A suspension of 6-fluoro-4-nitroisobenzofuran-1(3H)-one (9.6 g, 48.7 mmol) and Pd/C (10%, 1 g) in EtOAc (300 mL) was stirred at 25° C. under 1 atmosphere of hydrogen for 12 hr. TLC (petroleum ether/EtOAc=2:1) showed the reaction was complete. The mixture was filtered, and the cake was washed with EtOAc (100 mL×3). The filtrate was concentrated to give 4-amino-6-fluoroisobenzofuran-1(3H)-one (7.5 g, yield 92%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.85 (br s, 2H), 5.14-5.15 (d, 2H), 6.62-6.65 (dd, 1H), 6.98-7.00 (dd, 1H); LC-MS (ESI) m/z: 168 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:30]3[CH2:37][C:36](=[O:38])[NH:35][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:30]3[C:37](=[CH:18][C:9]4[NH:10][C:11]5[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=5[C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:36](=[O:38])[NH:35][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Yield: 77.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (80 mg, 77.4%) as a red solid.