Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[H-].[Na+].[CH:33]([C:35]1[C:36]([NH:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34]>O1CCCC1>[OH:34][CH:33]([C:35]1[C:36]([NH:41][C:42](=[O:47])[C:43]([CH3:45])([CH3:44])[CH3:46])=[N:37][CH:38]=[CH:39][CH:40]=1)[CH:16]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]1)[C:15]([O:14][CH3:13])=[O:30]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccnc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A solution of diisopropylamine (6.0 mL, 43 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. A 2.5M solution of n-butyllithium in hexanes (17.0 mL, 43 mmol) was added to the mixture drop-wise. Mixture was held at −78° C. with stirring for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (9.3 g, 36 mmol) in tetrahydrofuran (35 mL) was added to the mixture drop-wise. Mixture was held at −78° C. for 1.5 hours. In a separate flask, 60% sodium hydride in mineral oil (1.57 g, 39 mmol) was washed in hexanes and then suspended in tetrahydrofuran (70 mL). Mixture was cooled to 0° C. A solution of N-(3-formylpyridin-2-yl)pivalamide (6.74 g, 33 mmol) in tetrahydrofuran (20 mL) was added to the mixture drop-wise. Reaction was held at 0° C. with stirring for 2 hours. Mixture was warmed to room temperature and then added to the butyllithium containing solution drop-wise. Reaction mixture was held at −78° C. with stirring for 2 hours. Mixture was allowed to slowly warm to room temperature. Mixture stirred at room temperature for 14 hours. Reaction was quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2×100 mL). Organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as white foam in 93% yield. (M+H)+=464.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[C:33](=[CH:44][CH:45]=1)[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH:28][C:47]([NH:46][C:32]2[CH:31]=[C:30]([Cl:29])[CH:45]=[CH:44][C:33]=2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[O:48])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)cc1NC(=O)OCc1ccccc1
Yield: 77.1 %

Procedure:
2.84 g (6.99 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 2.67 g (6.99 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 8 to obtain 3.74 g (yield 77%) of benzyl 2-{[(3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 1.54 (9H, s), 5.19 (2H, s), 5.34 (2H, s), 7.05 (1H, m), 7.34-7.58 (10H, m), 7.60 (1H, d), 7.90 (1H, d), 7.98 (1H, d), 8.50 (1H, br), 8.62 (1H, s), 10.00 (,1H, br), 10.41 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[Na+]>C1COCC1.C(O)C>[OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cn3)c(O)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 400 mg (0.92 mmol) of ethyl 6-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)nicotinate with 357 mg (8.9 mmol) of sodium hydroxide in a THF/ethanol mixture (20 ml/20 ml), 60 mg (16%) of a yellow powder are obtained. m.p.: 250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=CC(=O)O
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 17 g (96 mmol) of (E)-4-(4-methoxyphenyl)but-3-en-2-one and 8.9 g (96 mmol) of glyoxylic acid monohydrate in 25 ml of glacial acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether/hexane yielded (E,E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 138°-139°.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:33])[N:6]2[CH2:28][C:29]([F:32])([F:31])[F:30].[CH3:34]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:34])[C:5](=[O:33])[N:6]2[CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1[nH]c(=O)n2CC(F)(F)F
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)n(CC(F)(F)F)c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
80 mg (0.175 mmol) of the compound from example 36 and 48 mg (0.175 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 25 mg (0.175 mmol) of iodomethane in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 30 mg of the title compound were obtained (35% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[NH:9][N:8]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[N:9]([CH2:34][CH2:33][CH2:32][O:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:8]=1
Reactant: BrCCCOC1CCCCO1
Reactant: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nn(CCCOC3CCCCO3)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone (0.20 g) prepared in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, followed by the addition of 0.24 g of 3-bromopropyl 2-tetrahydropyranyl ether and 0.24 g of potassium carbonate. The obtained mixture was stirred at 50° C. for 4 hours and poured into water, followed by extraction with ethyl acetate. The organic phase was washed with water twice and with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] to give 0.20 g of the title compound as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1>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>[N+:21]([C:18]1[CH:17]=[N:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cn1
Yield: 78.9 %

Procedure:
In a similar manner to that described in Reference example 14(a), a reaction was carried out using 4-methoxycarbonylphenyl boronic acid (3.24 g), 2-bromo-5-nitropyridine (4.75 g) and tetrakis(triphenylphosphine)palladium (1.04 g) and treated to afford the desired compound (3.67 g) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.N12CCCN=C1CCCCC2.[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24]>ClCCl>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[NH:2][S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Yield: 164.3 %

Procedure:
2-Aminoindan hydrochloride (5.16 g, 30 mmol, Sigma Aldrich Company Ltd.) was suspended in dry dichloromethane (100 ml), and cooled with stirring under argon to 0° C. To the suspension was added 1,8-diazabicyclo[5.4.0]undec-7-ene (14 g, 92 mmol) followed by the dropwise addition of isopropylsulfonyl chloride (8.56 g, 60 mmol). The cooling bath was removed and the mixture stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane (50 ml) and washed with 1 M hydrochloric acid (2×50 ml). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to give a yellow oil (11.8 g). The crude product was purified by chromatography on a 50 g Isolute™ Flash silica-gel column eluting from 20-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a pale yellow solid (6.88 g, 96%); 1H-NMR (400 MHz, CDCl3) δ 1.39 (6H, d, J=7 Hz), 2.91 (2H, m), 3.18 (1H, m), 3.31 (2H, m), 4.31 (2H, m), 7.21 (4H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([CH3:20])=[CH:14][C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:28][CH3:29]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:20])=[N:16][C:17]=3[O:19][CH2:28][CH3:29])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2cc(C)[nH]c(=O)c21
Agent: O=S(=O)(O)O
Product: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C)N2
Temperature: 130 °C

Procedure:
1920 mg (5.77 mmol) of 4-(4-cyano-2-methoxyphenyl)-2,7-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile are suspended in 40 ml (240 mmol) of anhydrous triethyl orthoformate. The reaction mixture is heated to 130° C. Then 10 drops of concentrated sulfuric acid are added each hour. After complete reaction has been detected (analytical HPLC; reaction time about 36 h), the reaction mixture is cooled to room temperature, and the volatile components are removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). The product obtained in this way is crystallized from ethyl acetate. 451 mg (22% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[CH2:26][C@H:25]4[N:21]([CH2:22][CH2:23][CH2:24]4)[C:20]4[N:27]=[C:28]([S:31][CH3:32])[N:29]=[CH:30][C:19]=4[C:18]3=[O:33])[CH:12]=2)[N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[OH:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]([N:17]3[CH2:26][C@H:25]4[N:21]([CH2:22][CH2:23][CH2:24]4)[C:20]4[N:27]=[C:28]([S:31][CH3:32])[N:29]=[CH:30][C:19]=4[C:18]3=[O:33])[CH:14]=[CH:15][CH:16]=2)[N:7]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(COC(C)=O)n3)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(CO)n3)c1)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
(S)-{3-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5-yl}methyl acetate (529 mg, 1.13 mmol) obtained in Step 1 was dissolved in ethanol (6.0 mL), and the mixture was stirred at 60° C. for 2 hours after adding a 3 mol/L aqueous sodium hydroxide solution (4.0 mL). After concentrating the mixture under reduced pressure, water was added to the resulting residue. The precipitated white solid was filtered off, and purified by silica gel column chromatography to give (S)-5-[3-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (234 mg, 49%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]2([NH2:32])[CH2:31][CH2:30][CH2:29]2)[N:24]=1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:32][C:28]3([C:25]4[N:24]=[C:23]([CH3:22])[O:27][N:26]=4)[CH2:31][CH2:30][CH2:29]3)=[O:20])=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C2(N)CCC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3ccc(C4CC4)c(OCc4ccccn4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine hydrochloride (1:1) (CAN 1170897-28-5) as starting materials, MS (EI): m/e=406.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:27]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([CH3:29])[CH3:28]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH:27]([CH3:29])[CH3:28])[CH:36]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)Oc1cccc(B(O)O)c1
Product: CC(C)Oc1cccc(-c2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-isopropoxyphenylboronic acid in analogy to Example 2b): MS (ISN): 512.3 and 514.3 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O.CN(C=O)C>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.COCCOC>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18])/[C:6](=[O:11])[NH:7]2
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)c(OC)c1

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 2,4-dimethoxyphenylboronic acid (61.7 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 2 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-1,3-Dihydro-4-(2,4-dimethoxyphenyl)-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 15 mg, 29%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=3[N:14]=2)=[O:7])=[C:4]([OH:24])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>CC(C)=O.C(OCC)(=O)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:24][C:4]1[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=1[C:6](=[O:7])[NH:8][CH2:9][C:10]1[S:11][C:12]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=2[N:14]=1)[CH3:37]
Reactant: O=C(NCc1nc2c(F)c(F)cc(F)c2s1)c1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 45 °C
Yield: 80.7 %

Procedure:
A solution of 4-fluoro-2-hydroxy-N-(4,5,7,-trifluoro-benzothiazol-2-ylmethyl)-benzamide (1.0 g, 2.8 mmol) in acetone (14 mL) was treated with aq 2 N K2CO3 (2.1 mL, 4.2 mmol) and ethyl bromoacetate (2 mL, 19 mmol) and heated to 45° C. for 5 h. After cooling to room temperature, the solution was acidified to a pH 1 with aq 2 N HCl. The resulting solution was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC (10-100% ethyl acetate in heptane 23 mL/min, 75 min) provided {5-fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid ethyl ester (1.0 g, 81%) as a white crystalline solid: 1H NMR (DMSO-d6 300 MHz) δ 9.32 (t, J=5.9 Hz, 1H), 7.94 (dd, J1=9.0 Hz, J2=7.2 Hz, 1H), 7.80-7.70 (m, 1H), 7.13 (dd, J1=11.1 Hz, J2=2.4 Hz, 1H), 6.95 (dt, J1=8.4 Hz, J2=2.5 Hz, 1H), 5.02 (s, 2H), 4.94 (d, J=6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:29]5[CH2:30][CH2:31][O:27][CH2:28]5)=[O:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCOC1

Procedure:
The title compound, off-white solid (80 mg, 75%), MS (ISP) m/z=427.3 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-3-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46](B(O)O)=[CH:45][N:44]=1>>[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:39][CH:40]=2)=[CH:45][N:44]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Product: COc1ncc(-c2ccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 2-methoxypyrimidine-5-boronic acid in Step A. MS (ESI): mass calcd. for C36H33N5O4, 599.25; m/z found, 600.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 2H), 8.21-8.16 (m, 1H), 8.09-8.04 (m, 1H), 7.83-7.79 (m, 1H), 7.74-7.69 (m, 1H), 7.69-7.64 (m, 1H), 7.56-7.51 (m, 1H), 7.48-7.41 (m, 3H), 7.18-7.13 (m, 1H), 7.13-7.08 (m, 2H), 7.08-7.03 (m, 1H), 5.40 (s, 2H), 5.38 (s, 2H), 4.05 (s, 3H), 3.25-3.18 (m, 1H), 2.31-2.21 (m, 2H), 1.84-1.79 (m, 2H), 1.54-1.42 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]([NH:19][NH2:20])=[CH:17][C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH3:23])[C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=S.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]2[NH:19][N:20]=[C:24]([NH:25][CH3:26])[C:17]=2[C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH3:23])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)cc(NN)n(CCOCc2ccccc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(CCOCc2ccccc2)c1=O
Reaction time: 20 h

Procedure:
A solution of 1-(2-benzyloxyethyl)-6-hydrazino-3-propyluracil (2.0 g, 6.3 mM) and methyl isothiocyanate (1.2 ml, 18 mM) in DMF (20 ml) was stirred at 60° C. for 1 hour and then at 100° C. for 20 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless prisms (1.39 g, 62%), m.p. 224°-226° C.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:7]=1[C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9].[CH3:22]O>>[OH:5][C:6]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:7]=1[C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])=[O:9]
Reactant: CO
Reactant: O=C(O)CCCNC(=O)c1cc(O)ccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCNC(=O)c1cc(O)ccc1O
Temperature: 25 °C

Procedure:
After dropwise adding 8.5 g (71 mmol) of thionyl chloride to 30 ml of anhydrous methanol at 10° C. during 30 minutes under cooling by ice while stirring, the solution was stirred at the same temperature for additional 45 minutes, then 5.1 g (20 mmol) of 4-[N-(2,5-dihydroxybenzoyl)amino]butyric acid (compound of Example 36) were portionwise added. The reaction mixture was allowed to warm to room temperature and stirred at 80° C. for 8 hours. After filtering the precipitate by and washing with methanol 3.7 g (68%) of the aimed compound were obtained, m.p.: 155°-159° C.