Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:15][CH:14]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 3a using 3-oxo-pentanoic acid ethyl ester and 1-(4-bromomethylphenyl)-2,2-dimethylpropan-1-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)=[CH:30][CH:29]=2)[C:32]1=[O:36])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(Cn2ccnn2)cc1
Product: C[C@@H](n1ccn(-c2ccc(Cn3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 28).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([N+:21]([O-])=O)[CH:8]=1)[CH2:2][CH3:3].[H][H]>[Ni].CO>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([NH2:21])[CH:8]=1)[CH2:26][CH3:27]
Reactant: CCCN(CCC)C(=O)Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCCN(CCC)C(=O)Cc1ccc(OCc2ccccc2)c(N)c1
Reaction time: 4.5 h
Yield: 73.7 %

Procedure:
In the presence of Raney nickel, 36.0 g of 2-(4-benzyloxy-3-nitrophenyl)acetic acid dipropylamide is hydrogenated in 600 ml of methanol until 6.7 l of hydrogen has been absorbed, which takes about 4.5 hours. The crude product obtained after removing the catalyst by filtration and after evaporation is chromatographed on silica gel with cyclohexane/ethyl acetate (1:1), thus obtaining 24.4 g of pure 2-(3-amino-4-benzyloxyphenyl)acetic acid dipropylamide as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)CCC>[N:10]1([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=2[O-:9])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: [O-][n+]1cccc(F)c1Cl
Solvent: CCCCO
Product: [O-][n+]1cccc(F)c1N1CCNCC1

Procedure:
A solution of 2-chloro-3-fluoropyridine N-oxide (400 mg, 3.0 mmol) and piperazine (1.3 g, 15 mmol) in n-butanol, 15 ml, is stirred at reflux for 20 hours. After concentrating under reduced pressure at 55°-60° C., the residue is chromatographed over silica gel and the crude N-oxide eluted with a 50% methanol-methylene chloride solvent mixture. The appropriate eluate is concentrated to an oily residue of the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:37])=[C:34]([CH3:49])[NH:33][C:32]=1[CH:50]=O>N1CCCCC1.C(O)C>[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:37])=[C:34]([CH3:49])[NH:33][C:32]=1/[CH:50]=[C:23]1\[C:24](=[O:29])[NH:25][C:26]2[C:22]\1=[CH:21][C:20]([S:17]([CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])=[CH:28][CH:27]=2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Yield: 51.3 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (41 mg, 0.1 mmol) was condensed with 3,5-dimethyl-4-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (35 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solid was collected by vacuum filtration and purified on a silica gel column to give 36 mg (35%) of the titled compound.
Reaction SMILES: [CH:1]1([C:6]2([CH3:17])[C:14]3[CH2:13][CH:12]=[CH:11][C:10]=3[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:18][C:19]([CH3:21])=O.N1CCCC1>CO>[C:19](=[C:3]1[CH:4]=[CH:5][C:1]([C:6]2([CH3:17])[C:14]3[CH2:13][CH:12]=[CH:11][C:10]=3[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7]2)=[CH:2]1)([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: CC1(C)CCC(C)(C2C=CC=C2)C2=C1C=CC2
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)=C1C=CC(C2(C)CCC(C)(C)C3=C2CC=C3)=C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
7.70 g (34.0 mmol) of the cyclopentadienyltetrahydroindene (Example 5) are dissolved in 70 ml of methanol and cooled to 0° C. The orange-red reaction solution is subsequently treated successively with 2.96 g (51.0 mmol) of acetone and 4.83 g (68.0 mmol) of pyrrolidine. The mixture is stirred at 0° C. for 5 hours and then, in order to complete the reaction, at room temperature for a further 2 hours, before the reaction is terminated by addition of 4 ml of glacial acetic acid. The red, clear reaction solution is hydrolyzed by means of 200 ml of water, and the yellow suspension is extracted 3× with 50 ml of diethyl ether in each case. Repeated washing of the combined organic phases with saturated, aqueous sodium chloride solution and drying over magnesium sulfate give the fulvene as an orange-red, wax-like residue in a yield of 88% (8.00 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]=1)[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>O1CCCC1>[CH2:35]([N:37]([CH2:38][CH3:39])[C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:8]=1)[CH3:36]
Reactant: CCNCC
Reactant: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)C(C)Cc1nc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure is as in Example 85, starting with laevorotatory α-methyl-2-phenyl-4-quinazolinepropanoic acid (2 g) in tetrahydrofuran (20 cc), carbonyldiimidazole (1.65 g) and diethylamine (1.05 cc). After two recrystallizations in isopropyl ether, dextrorotatory N,N-diethyl-α-methyl-2-phenyl-4-quinazolinepropanamide (1.3 g), m.p. 93.8° C., is isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([OH:20])[C:14]=2[C:13]2[CH:21]=[C:22]([Br:25])[CH:23]=[N:24][C:12]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:20][CH:36]3[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]3)[C:14]=2[C:13]2[CH:21]=[C:22]([Br:25])[CH:23]=[N:24][C:12]1=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(OCc1ccccc1)n1c2cncc(O)c2c2cc(Br)cnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc3c2c2cc(Br)cnc2n3C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
A solution of 3-bromo-5-hydroxy-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid benzyl ester (234 mg, 0.59 mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (295 mg, 1.47 mmol) and triphenylphosphine (390 mg, 1.47 mmol) in anhydrous THF (7 mL) was treated dropwise with diethyl azodicarboxylate (295 mg, 1.47 mmol). On complete addition the mixture was heated at 50° C. for 1 hour. The mixture was concentrated in-vacuo and the resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-7% methanol in dichloromethane). The appropriate fractions were collected and evaporated to afford the title compound as an orange oil (0.34 g, 100%). LCMS (Method B): RT=4.76 min, M+H+=581/583. 1H NMR (400 MHz, CDCl3): 9.27 (s, 1H), 8.80 (d, J=2.3 Hz, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.32 (s, 1H), 7.60 (d, J=7.3 Hz, 2H), 7.43-7.36 (m, 3H), 5.64 (s, 2H), 4.89 (m, 1H), 3.40-3.39 (m, 2H), 3.02 (ddd, J=13.5, 9.8, 3.4 Hz, 2H), 2.21-1.80 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH3:19][N:20]([CH3:33])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][O:31][CH3:32])[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[CH3:33][N:20]([CH3:19])[C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:25])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][O:31][CH3:32]
Reactant: COCOc1ccc(C=O)cc1N(C)C
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C(O)c2ccccn2)cc1N(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromopyridine (3.05 g, 19.3 mmol) in dry tetrahydrofuran (100 ml) was added dropwise n-butyl lithium in hexane (1.6M, 12.0 ml, 19.2 mmol) under nitrogen atmosphere. After stirring at -78° C. for 30 minutes, thereto was added dropwise a solution of the aldehyde compound (Compound A) (3.00 g, 14.3 mmol) in dry tetrahydrofuran (20 ml), and the mixture was stirred at -78° C. for 2 hours. A saturated aqueous solution of ammonium chloride (10 ml) was added thereto, and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (200 ml) and extracted with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C@:7]([OH:18])([C:15]([OH:17])=O)[CH2:8]2.[CH3:19][Li].Cl>CCOCC.C(Cl)(Cl)Cl>[C:15]([C@@:7]1([OH:18])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)(=[O:17])[CH3:19]
Reactant: COc1ccc(OC)c2c1CC[C@](O)(C(=O)O)C2
Reactant: [Li]C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(OC)c2c1CC[C@](O)(C(C)=O)C2

Procedure:
To an ether solution (15 ml) of 12b having an optical purity of 100% (M.P. 117°-120° C.; [α]D20 -37.9° (c=1.01, chloroform)) (670 mg, 2.66 mmole), an ether solution of methyl lithium (0.84 mmole/ml, 33 ml, 28.3 mmole) is gradually added in 1 hour and 20 minutes in an argon stream. The resultant mixture is stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture is slowly poured into dilute hydrochloric acid (conc. hydrochloric acid: water=4:30) (270 ml) under stirring, and after saturation with sodium chloride, extracted with ether (150 ml×2). The ether extracts are combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (20 ml), a 10% aqueous solution of sodium thiosulfate (10 ml) and a saturated aqueous solution of sodium chloride (20 ml) in order and dried over anhydrous magnesium sulfate. After filtration and evaporation, pale yellow needles (615 mg) are obtained. Purification by column chromatography (silica gel, 60 g; ether-hexane (4:1)) affords the objective 13b having an optical purity of 100% as pale yellow needles (420 mg, 63%). M.P. 119°-126° C. [α]D20 -47.4° (c=1.06, chloroform). The product is recrystallized from chloroform-ether to obtain an analytical sample as colorless needles. M.P. 128°-129° C. [α]D20 -48.2° (c=0.982, chloroform). IRνmaxNujol cm-1 : 3480 (OH), 1700 (COCH3). NMR (in CDCl3): 1.87 (2H, broad t, J=6.5 Hz, CH2CH2CCH2), 2.29 (3H, s, COCH3), 2.52-3.02 (4H, m, CH2CH2CCH2), 3.52 (1H, s, OH), 3.76 (3H, s, OCH3), 3.78 (3H, s, OCH3), 6.62 (2H, s, aromatic proton).
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([CH:14]=1)[CH:12]=O.[C:21]([OH:33])(=[O:32])[CH2:22][NH:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(OC(=O)C)(=O)C>C(O)C>[C:26]1([C:24]2[O:33][C:21](=[O:32])[C:22](=[CH:12][C:11]3[CH:14]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=3[S:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[N:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cc(Cl)ccc1Sc1cccs1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: O=C1OC(c2ccccc2)=NC1=Cc1cc(Cl)ccc1Sc1cccs1
Reaction time: 2 h

Procedure:
8.4 g (0.1 mole) of sodium bicarbonate is added, with stirring, to the mixture of 25.5 g (0.1 mole) of 5-chloro-2-(2-thienylthio)-benzaldehyde and 17.9 g (0.1 mole) of hippuric acid in 34.7 g (0.34 mole) of acetic anhydride, and the reaction mixture is stirred at 90°-95° for two hours. It is thereupon cooled to 25°; to the thick crystal mass is added 300 ml of 50% ethanol, the solid substance is filtered off with suction and is washed with 150 ml of 50% ethanol. Drying in a vacuum chamber leaves 2-phenyl-4-[5-chloro-2-(2-thienylthio)-benzylidene]-2-oxazolin-5-one in the form of yellow crystals, m.p. 125°-127°.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]1[O:10][C:2](=[O:3])[S:4][N:11]=1
Reactant: NC(=O)c1ccccc1F
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccccc2F)ns1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Chlorocarbonyl sulfenyl chloride (11.24 g, 86 mmol) is added dropwise to a stirred suspension of 2-fluorobenzamide (10.80 g, 78 mmol) in dry toluene. The mixture is heated gradually over a period of 30 minutes to a temperature of about 80° C. (a clear solution is formed with evolution of gas), stirred for approximately 1 h at 80° C., heated to about 98° C., stirred at 98° C. for 5 h, and distilled to remove the toluene and excess chlorocarbonyl sulfenyl chloride. The resultant pot residue is redissolved in toluene, washed sequentially with water, 5% sodium bicarbonate and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. This residue is recrystallized from petroleum ether to give 5-(2-fluorophenyl)[1,3,4]oxathiazolin-2-one (13.2 g, 86%) as off-white crystals, mp 50° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[C:9]([CH3:12])=[C:10](I)[C:3]=12.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[C:9]([CH3:12])=[C:10]([C:21]3[CH:22]=[C:23]4[C:18]([CH2:17][CH2:16][N:15]4[CH3:14])=[CH:19][CH:20]=3)[C:3]=12
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Cc1c(I)c2c(Br)ccnc2n1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2ccc3c(c2)N(C)CC3)c2c(Br)ccnc2n1C
Temperature: 65 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
To a solution of 4-bromo-3-iodo-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine (D27) (580 mg, 1.653 mmol) in ACN (9 mL) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (557 mg, 2.148 mmol), bis(triphenylphosphine)palladium(II) chloride (116 mg, 0.165 mmol) and 9 mL of sodium carbonate (2N aqueous solution). The reaction mixture was stirred at 65° C. for 3 hours. The reaction mixture was diluted with water (30 mL), the aqueous layer was then extracted with ethyl acetate (50 mL×3). The organic layers were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give an impure material which was further purified by column chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane to afford the title compound (89 mg). LCMS (A): m/z (M+H)+ 356/358, C18H18BrN3 requires 355/357 (acidic).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH:26]=3)=[N:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:45]=CC=C[CH:41]=1.C(O)(C)C>ClCCl>[CH:40]([O:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:32][CH2:33][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]4)[CH:26]=3)=[N:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:45])[CH3:41]
Reactant: CC(C)N1CCN(c2cc(-c3ncc(-c4cccc(O)c4)[nH]3)ccn2)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1cccc(-c2cnc(-c3ccnc(N4CCN(C(C)C)CC4)c3)[nH]2)c1
Yield: 33 %

Procedure:
Diethyl azodicarboxylate (0.22 mL) was added via syringe to a solution of 1-{4-[5-(3-Hydroxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (304 mg) and triphenylphosphine (0.371 g) in a 1:1 mixture of isopropanol and dichloromethane (13 mL). The resultant solution was stirred at ambient temperature for 3 days and then washed with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (5% methanol in dichloromethane) to provide 1-{4-[5-(3-Isopropoxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (0.112 g). MS m/z 420 (M++1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O)(=O)=[O:16]>>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][OH:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)O
Product: CS(=O)(=O)c1ccc(C(=O)OO)cc1

Procedure:
A stirred mixture of 5 g of 4-(methylsulfonyl)benzoic acid and 50 mL of methanesulfonic acid froze when it was cooled in an ice bath. The ice bath was removed and when the mixture was partially melted, stirring was resumed and the addition of 2.83 g of 90% hydrogen peroxide was started. The 90% hydrogen peroxide was added gradually over ten minutes. When the addition of the hydrogen peroxide was completed, the reaction mixture was still partially frozen. A water bath of cold tap water was used to warm the reaction mixture. The temperature of the reaction mixture rose briefly to 28° C. One hour after the addition of the hydrogen peroxide was started, the reaction mixture was heated for 70 minutes within a temperature range of 40° C.-45° C. The stirred reaction mixture was then cooled in an ice bath. A solid precipitated from solution. When the temperature of the reaction mixture was between 10° C.-15° C., the solid product was filtered from solution. A second fraction of solid product was collected when the filtrate was poured onto ice prepared from deionized water and the solid which formed was filtered away from solution. Fraction one was washed four times with 60 mL each time of cold deionized water. Fraction two was washed four times with 150 mL each time of cold deionized water. Both fractions of the solid product were very easy to wash and to isolate by filtration. The two fractions were each transferred to a watchglass and dried overnight. The dried solids were fine, dry powders.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][NH2:20])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@H]2CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 100 %

Procedure:
Prepared from N-{(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-[(2S)-2-tert-butoxycarbonylaminomethylpyrrolidin-1-ylcarbonyl]propyl}-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 100%; Rf value: <0.1 (silica gel; ethyl acetate); C29H35ClN6O5 (551.09); mass spectrum: (M+H)+=551/553 (chlorine isotope).
Reaction SMILES: [CH3:1][NH2:2].CO.[Cl:5][C:6]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:7]=1[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]>CCO>[Cl:5][C:6]1[CH:19]=[C:18]([NH:2][CH3:1])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:7]=1[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]
Reactant: O=C(NC1CCCC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNc1cc(Cl)c(C(=O)NC2CCCC2)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
N-Methylamine in MeOH (2 M, 2.0 mL, 4.0 mmol) was added to 2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide (230 mg, 0.79 mmol) in EtOH. The mixture was heated at 50° C. for 12 h in a sealed vessel, cooled and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield: 150 mg (64%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[C:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O1CCCC1>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][C:32]([C:9]2[S:10][C:5]3[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)([OH:35])[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (1.22 g) in anhydrous tetrahydrofuran (20 ml) stirring at −78° C. was added 2.5M n-butyllithium in hexanes (2.3 mL). The reaction mixture was warmed gradually to −40° C. over 1 hour, cooled to −78° C., and 1-BOC-4-Piperidone (950 mg) was added. The reaction mixture was gradually warmed to room temperature and then left to stir for 2 hours, poured into ice/water and extracted into ethyl acetate. After the usual drying and evaporation of the solvent, the residue was purified by flash chromatography to give 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.