Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[N:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12].O.[BH4-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)NC(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Temperature: 25 °C

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid (2-amino-5-bromo-phenyl)-(4-chloro-phenyl)-methyleneamide (6.82 g, 0.02 mmol) dissolved in THF (196 mL) and H2O (4 mL) is added NaBH4 (1.57 g, 0.04 mol) at 0° C. The mixture is stirred at RT. The mixture is quenched with MeOH and H2O, MeOH and THF is removed. The mixture is extracted with ethyl acetate, dried over NaSO4 and concentrated. This provides the desired compound which is used without further purification.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[F:7][CH2:8][O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.O.CCOC(C)=O>C1COCC1>[F:7][CH2:8][O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC(=O)c1cnc(OCF)cn1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCF)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium trimethylsilanolate (18.6 mg) was added to a solution of methyl 5-fluoromethoxypyrazine-2-carboxylate obtained in Preparation Example 15-(1) (18.0 mg) in THF (1.0 mL). The reaction solution was stirred at RT for 1 h. Water and EtOAc were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made acidic with 1 M hydrochloric acid, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (10.2 mg). The compound was used for the next reaction without further purification. 1H-NMR (400 MHz, CDCl3) δ (ppm): 6.16 (d, J=50.8 Hz, 2H), 8.34 (d, J=1.4 Hz, 1H), 9.05 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:10][N:11]([CH2:13]N(C)C)[CH3:12]>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc[nH]1
Reactant: CN(C)CN(C)C
Solvent: C1CCOC1
Product: CCCCc1nccn1CN(C)C
Yield: 103 %

Procedure:
12.4 g of butylimidazole and 20.4 g of bis-(dimethylamino)methane were refluxed in 100 ml of tetrahydrofuran for 24 hours. The solvent was evaporated to give 18.64 g of product. The yield was quantitative. Other data concerning the product was:
Reaction SMILES: [CH3:1][C:2]([CH3:29])([P:26](=[O:28])=[O:27])[N:3]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][NH2:25])[CH:16]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:6])=[O:5].[Cl:30][C:31]1[N:32]=[N:33][CH:34]=[C:35](Cl)[C:36]=1[Cl:37].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:29])([P:26](=[O:28])=[O:27])[N:3]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][NH:25][C:35]2[C:36]([Cl:37])=[C:31]([Cl:30])[N:32]=[N:33][CH:34]=2)[CH:16]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:5])=[O:6]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCN)c1)C(C)(C)P(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2cnnc(Cl)c2Cl)c1)C(C)(C)P(=O)=O

Procedure:
940 mg N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-methoxy-benzene sulfonamide, 400 mg (2.2 mmol) 3,4,5-trichloropyridazine and 0.31 ml (2.2 mmol) triethylamine in 20 ml dry tetrahydrofuran were stirred for 2 h at 80° C., the solvent was removed in a vacuum, the residue was stirred with water, extracted three times with ethyl acetate, dried over sodium sulfate, filtered, the solvent was removed in a vacuum and 1.26 g (quant.) of a mixture of N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,5-dichloropyridazin-4-ylamino)-ethoxy]-5-methylphenyl-}-2-methoxy-benzenesulfonamide and N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,4-dichloropyridazin-5-ylamino)-ethoxy]-5-methylphenyl}-2-methoxy-benzenesulfonamide was obtained as an oil. MS (m/e)=573.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][NH:5][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Cl)cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNc1ccc(Cl)cc1OCc1ccccc1

Procedure:
A solution of [(2-benzyloxy-4-chlorophenyl)-tert-butoxycarbonylamino]-acetic acid methyl ester (14.95 g, 36.8 mmol) in 180 mL of TFA/methylene chloride (1:2) is stirred at RT for 45 min. The solvent is removed under reduced pressure and the residue is dissolved in EtOAc (500 mL). To this solution is added diisopropylethylamine (13.11 g) and the resulting precipitate is filtered. The filtrate is evaporated to give the title compound as a tan solid. (M+1)=306.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@H:14]([CH3:23])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>ClCCl>[CH3:23][C@@H:14]([CH2:13][O:12][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.5 %

Procedure:
p-Toluenesulphonyl chloride (13.2 g) was added portionwise to a stirred mixture of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g), triethylamine (21 ml) and dichloromethane (120 ml) and the mixture was stirred at room temperature for 20 hours. The mixture was washed in turn with water and with a dilute aqueous sodium carbonate solution. The organic solution was filtered through phase separating paper and evaporated to give tert-butyl (3R)-3-methyl-4-(p-toluenesulphonyloxy)-butyrate as an oil (20 g): NMR(CDCl3) δ 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s), 2.18.2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]=[CH:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of 3-fluoronitrobenzene (1.78 ml; 16.7 mmol), methyl imidazole-4-carboxylate and potassium carbonate (2.3 g; 16.7 mmol) in 10 ml NMP was heated to 120° C. in a nitrogen atmosphere overnight. The cooled mixture was poured into water (100 ml), the precipitate was filtered off, washed with water and dried to yield 6c (2.38 g; 58%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[C:26](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.O(C)S(C(F)(F)F)(=O)=O.Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH3:26])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: COS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OC)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Yield: 62.9 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1) (345 mg, 1.0 mmol), 2,6-di-tert.-butylpyridine (1.35 mL, 6.0 mmol) and methyl triflate (0.55 mL, 5.0 mmol) in DCM (2 mL) was stirred at 23° C. for 4 d. The reaction mixture was poured on ice, acidified with 1 N HCl and extracted with ether. After washing with sat. NaHCO3 -sol., brine and drying over MgSO4 the crude product was purified by silica gel column chromatography with hexane/EtOAc 4:1 to give (1S,2R,3R,5R,6S)-2-azido-3-methoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-1) (226 mg, 63%) as a yellow oil. 1H-NMR (250 MHz, CDC13) □1.26 (3H, t, J=7.1 Hz), 1.77 (1H, t, J=3.5 Hz), 2.05-2.18 (2H, m), 2.25 (1H, dd, J=7, 3.5 Hz), 2.34 (1H, dd, J=12, 7 Hz), 3.28 (3H, s), 3.42 (1H, bt,J=8 Hz), 4.12 (2H, q, J=7.1 Hz), 5.25 (1H, d,J=12 Hz), 5.34 (1H, d, J=12 Hz), 7.30-7.40 (5H, m); MS [EI] 258 [ (M--CO2Et-N2)+ ]; □D20 -48.02° (c=1.11, CHCl3).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][OH:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35].O>CN(C)C=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][O:20][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2cc(CO)ccc21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1ccc2c(c1)cc(-c1ccccc1)n2S(=O)(=O)c1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-benzenesulfonyl-5-hydroxymethyl-2-phenylindole (171 mg) in N,N-dimethylformamide (2.4 mL) were added imidazole (128 mg) and chlorotriisopropylsilane (0.150 mL) under cooling with ice, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (221 mg).
Reaction SMILES: Cl.[N:2]12[CH2:9][C@H:6]([CH2:7][CH2:8]1)[CH2:5][C:4](=O)[CH2:3]2.Cl.[NH2:12]O.O.O.O.C([O-])(=O)C.[Na+].[Na]>CS(C)=O.C(O)C>[N:2]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]([NH2:12])[CH2:3]2
Reactant: O=C1C[C@H]2CCN(C1)C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: NC1CC2CCN(C1)C2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a flask containing (5R)-1-azabicyclo[3.2.1]octan-3-one hydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g, 29.4 mmol), and ethanol (130 mL) is added sodium acetate trihydrate (9.23 g, 67.8 mmol). The mixture stirred for 3 h and is filtered and concentrated. The resulting white solid is taken up in n-propanol (100 mL) and sodium (˜13.6 g, 618 mmol) is added in 20-25 portions. The reaction spontaneously begins to reflux, and the reaction is heated in an oil bath (100° C.). The addition is complete in ˜20 min and the mixture solidifies after ˜40 min. The oil bath is removed and n-propanol (2×25 mL) is added dissolving the remaining sodium metal. The mixture is carefully quenched through the dropwise addition of H2O (100 mL). Saturated aq. NaCl (20 mL) is added, and the layers are separated. The organic layer is dried (MgSO4), filtered, treated with freshly prepared MeOH/HCl, and concentrated. The resulting solid is triturated with 30 mL EtOH, filtered and dried in vaccuo to afford 3.51 g as a white solid: [α]25D=−3 (c 0.94, DMSO); 1H NMR (400 MHz, DMSO-d6) δ 3.60-3.80, 2.95-3.10, 2.65-2.75, 1.90-2.15, 1.70-1.90; HRMS (FAB) calcd for C7H14N2 (M+H+) 127.1235, found 127.1235.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:34])[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14].I[CH3:36]>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:34])[S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1)([O:17][CH3:36])[C:13]([F:15])([F:14])[F:16]
Reactant: COCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1cccc1C(OC)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a suspension of 3.8 mg of NaH (0.10 mmol) in 3 mL of DMF at 0° C. was added 32 mg of N-(4-{1-[1-(2-methoxyethyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-1-hydroxyethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 79, 0.068 mmol) and the reaction mixture was stirred at 0° C. for 35 min. 6 μL of iodomethane (0.089 mmol) was added and the reaction mixture allowed to warm to room temperature and stirred for 2.5 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 9:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:34](=[O:36])[NH2:35])([CH2:20][C:21]([O:23][CH:24]1[CH:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:34](=[O:36])[NH2:35])([CH2:20][C:21]([O:23][CH:24]1[CH:29]([CH:30]([CH3:31])[CH3:32])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)=[O:22])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCC(C(C)C)C(OC(=O)CC(NC(=O)OCc2ccccc2)(C(N)=O)C(=O)OC(C)(C)C)C1
Solvent: CC(C)=O
Product: CC1CCC(C(C)C)C(OC(=O)C[C@@](NC(=O)OCc2ccccc2)(C(N)=O)C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 8.8 %

Procedure:
t-Butyl 2-benzyloxycarbonylamino-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (500 mg) was dissolved in acetone (2.5 g) under heating and placed in a freezer overnight. The precipitated crystals were filtered and dried to give t-butyl (2R)-2-benzyloxycarbonylamino-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (44 mg, yield 8.8%) as a white crystal. Optical purity of (2R)-derivative: 79.1% d.e.
Reaction SMILES: CI.[N:3]1[C:12]2[NH:11][C:10]3[CH:13]=[C:14]([CH:17]([OH:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[N:6]=[CH:5][CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:19][C:18](=[O:20])[CH:17]([C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:7]3[N:6]=[CH:5][CH:4]=[N:3][C:12]=3[NH:11][C:10]=2[CH:13]=1)[OH:21]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(O)c1ccc2c(c1)Nc1nccnc1S2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(O)c1ccc2c(c1)Nc1nccnc1S2
Yield: 64.7 %

Procedure:
150 mg of methyl iodide was added to a solution of 100 mg of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)hydroxyacetic acid in N,N-dimethylformamide (8 ml) in the presence of 260 mg of potassium carbonate. After purifying by silica gel column chromatography (eluted with dichloromethane/methanol) and recrystallizing from ethyl acetate/diisopropyl ether, 68 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CC(C)c1ccc(S)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(SCc2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of 4-(isopropyl)thiophenol (10 g, 65.68 mmol) in N,N-dimethylformamide (200 ml) sodium hydride (3.15 g, 131.35 mmol) was added. The exothermic reaction was allowed to cool down to room temperature. At 15° C. a solution of (4-bromomethyl-phenyl)-acetic acid (15.04 g, 65.68 mmol) in N,N-dimethylformamide (100 ml) was added. After stirring the reaction mixture at room temperature for 16 h the mixture was concentrated, diluted with water, and adjusted to pH=2 by adding HCl (2N). The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (19.5 g, 99%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: C=CCOc1ccc(C(C)=O)cc1
Reactant: COc1cccc(C=O)c1OC
Product: C=CCOc1ccc(C(=O)C=Cc2cccc(OC)c2OC)cc1
Reaction time: 23 h
Yield: 90 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 2,3-dimethoxy-benzaldehyde were under an inert atmosphere (argon) dissolved in 10 ml of dry freshly distilled ethanol, and 100 mg of sodium hydroxide was added to the solution. The mixture was left under stirring for 23 h and concentrated in vacuo. The crystalline residue was recrystallized from methanol-water to give 2.92 g (90%) of 2,3-dimethoxy-4′-prop-2-enyloxychalcone, m.p. 98-99° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][N:17](CC4C=CC(OC)=CC=4)[C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[Cl:46])[CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([O-])=O>>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][NH:17][C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[Cl:46])[CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NC4CCN(C(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(C)N1CCC(Nc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1

Procedure:
The 7-[(1-tert-butylpiperidin-4-yl)amino]-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 7-[(1-tert-butylpiperidin-4-yl)amino]-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one by a procedure analogous to that described in COMPOUND CCC3, STEP F. Mass spectrum (ESI) 557 (M+1). Trifluoroacetate salt 1H NMR (500 MHz, CDCl3): selected peaks δ 1.08 (s, 9H); 1.41 (m, 2H); 1.98 (d, J=4.6 Hz, 2H); 2.17 (brs, 2H); 2.96 (d, J=8.7 Hz, 2H); 3.05 (brs, 1H); 4.13 (dd, J=1.8 Hz, J=13.7 Hz, 1H); 4.31 (dd, J=1.1 Hz, J=13.7 Hz, 1H); 5.17 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16](COCC[Si](C)(C)C)[CH:17]=[CH:18][C:11]=12.Cl[C:28]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:31]=[C:30]([NH2:40])[N:29]=1.Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:28]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:31]=[C:30]([NH2:40])[N:29]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Nc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
70 mg (0.19 mmol) of 2-fluoro-N1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-yl)benzene-1,4-diamine and 41 mg (0.20 mmol) of 4-chloro-6-pyridin-4-ylpyrimidine-2-amine are suspended in 2.5 ml of water. 27 μl (0.28 mmol) of a 37% strength hydrochloric acid solution are then added, and the mixture is heated under reflux overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off, washed with a little water and then dissolved in DMSO and purified by preparative RP-HPLC.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[O:22])[CH2:11]1)=[O:7])(C)(C)C.[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37](C(O)=O)=[C:36]([O:44][CH3:45])[CH:35]=1>>[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH3:32])[CH:24]=3)=[O:22])[CH2:11]2)=[O:7])=[C:36]([O:44][CH3:45])[CH:35]=1
Reactant: Cn1cc(C(=O)NCCCCCN2CC[C@@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(5-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-pentyl)-1-methyl-1 H-indole-3-carboxamide (1.48 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.68 g) to give N-(5-((3S)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]4[C:23]([C:24]#[C:25][Si](C)(C)C)=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1.O.[OH-].[Li+].O1CCCC1>O>[C:24]([C:23]1[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@:10]3([C:9](=[O:30])[N:8]([C@H:5]4[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]4)[CH2:12][CH2:11]3)[CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:25]
Reactant: C[Si](C)(C)C#Cc1cccnc1N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-7-{3-[(trimethylsilyl)ethynyl]pyridin-2-yl}-2,7-diazaspiro[4.5]decan-1-one (10 mg, 0.00002 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 93), lithium hydroxide monohydrate (1.1 mg, 0.000026 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) and a couple of drops of water was stirred at rt for 30 min. The crude reaction mixture was purified by prep-HPLC to afford 7.2 mg of the desired product. LC-MS: 354.2 (M+H)+.