Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[O:12][N:11]=2)[CH:5]=1.[C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH3:25].[Li]>>[C:28]([O:27][C:24](=[O:26])[CH2:25][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[O:12][N:11]=2)[CH:5]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1

Procedure:
The title compound was prepared from (RS)-3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-benzoic acid methyl ester [prepared from (Z)-3-(hydroxyimino-methyl)-benzoic acid methyl ester [CAS-No. 91186-80-0] by treatment with NCS, cat. amount pyridine in CHCl3 followed by addition of (RS)-tetrahydro-2-(2-propynyloxy)-2H-pyran and slow addition of Et3N in CHCl3 at 23° C.] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (3.00 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O-:13])(=O)=[O:11])=[CH2:3].[K+].S(Cl)([Cl:17])=O>CN(C)C=O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([Cl:17])(=[O:13])=[O:11])=[CH2:3]
Reactant: C=C(C)c1ccccc1S(=O)(=O)[O-]
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)c1ccccc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A mixture of potassium 2-(1-methylethenyl)benzenesulfonate (7.8 g, 0.33 mmol) and 30 ml of thionyl chloride was contacted with 1.5 ml of N,N-dimethylformamide at 0°. The mixture was allowed to warm to room temperature over 45 minutes then evaporated in vacuo. Water and ether were added and the aqueous phase extracted with several portions of ether. The combined ether layers were washed with saturated sodium chloride solution, dried and evaporated under reduced pressure to yield the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[O:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34]>CN(C)C=O>[OH:34][CH2:33][CH2:32][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[O:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(O)cc3o2)cc1OC
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OCCO)cc3o2)cc1OC
Yield: 55 %

Procedure:
7-hydroxy-3',4',5-trimethoxy flavone (200 mg, 0.61 mmol) was dissolved in dimethylformamide and hereto was added potassium carbonate (253 mg, 3 equivalents) and 2-bromoethanol (65 μl, 1.5 equivalents). After the reaction mixture was refluxed for 3~4 hours, the solvent was removed under reduced pressure and the residue was diluted with chloroform and washed with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and the residue was column-chromatograped to give 125 mg of the product (55%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[NH2:21][CH:22]1[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][CH:22]([NH2:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: NC1CNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 57.7 %

Procedure:
A mixture of 1.2 g (4.53 mmoles) of 1-cyclopropyl 6,7-difluoro-1,4-dihydro-4oxo-3-quinolinecarboxylic acid, 1.3 g (9.05 mmoles) of 3-aminoazetidine hydrochloride and 0.5 ml of triethylamine heated in 15 ml of pyridine for 2 hours. The mixture is filtrated and washed with water and ethanol to obtain 0.83 g (58%) of 1-cyclopropyl-6-fluoro-7-(3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 246°-7° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16]1.FC1C=C(F)C=CC=1[C@]1([C@H](N2C3=NC=CC=C3N=C2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1cnc2nc[nH]c2c1
Agent: C[C@@H](n1cnc2cccnc21)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnc2ncccc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 22.7 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (981 mg) and 1H-imidazo[4,5-b]pyridine (472 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(3H-3imidazo [4,5-b]pyridyl)ethyl]oxirane (501 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1-imidazo[4,5-b]pyridyl) ethyl]oxirane (271 mg) were obtained by the same way as in Reference Example 2.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.[ClH:23]>C(O)C>[ClH:23].[CH2:21]([O:20][C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9][NH2:8])=[O:19])[CH3:22]
Reactant: CCOC(=O)Nc1cccc(CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Nc1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In ethanol (15 ml) was dissolved 14.96 g of 3-(2-t-butoxycarbonylaminoethyl)-ethoxycarbonylaminobenzene (Preparation Example 36). Under ice-cooling, hydrochloric acid (15 ml) was added thereto, followed by stirring at room temperature for 20 minutes. Hydrochloric acid (12 ml) and ethanol (15 ml) were further added thereto, followed by stirring at room temperature for 20 minutes. Then, hydrochloric acid (20 ml) and ethanol (30 ml) were further added thereto, followed by stirring at room temperature for 30 minutes. The solvent was evaporated (azeotropic distillation with toluene), to give the title compound (11.99 g) as pale yellow crystals.
Reaction SMILES: [C:1]([O-])(=[S:3])[CH3:2].[K+].I[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@H:30]3[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:39])=[CH:26][C:27]=2[CH2:28][CH2:29]3)=[CH:16][CH:15]=1>C(O)C>[C:1]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@H:30]3[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:39])=[CH:26][C:27]=2[CH2:28][CH2:29]3)=[CH:16][CH:15]=1)(=[S:3])[CH3:2]
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCCI)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=S)CCCCCCOc1ccc([C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1
Reaction time: 0.83 h
Yield: 96.5 %

Procedure:
150 mg of potassium thioacetate is added to a solution of 470 mg of the product obtained in Stage D in 6 cm3 of ethanol and agitation is carried out for 1 hour 50 minutes at 50° C. The ethanol is distilled off, the residue is taken up in ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. 400 mg of residue is obtained which is chromatographed on silica (eluant ethyl acetate-essence G 6/4 then 8/2). 265 mg of desired product is collected (M.p. #90° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCCC1=O>C(OCC)(=O)C.[Cu]I>[C:11]1([S:17]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cnccc1Br
Reactant: O=S([O-])c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=Cc1cnccc1S(=O)(=O)c1ccccc1
Temperature: 60 °C
Yield: 158.8 %

Procedure:
A mixture of 4-bromopyridine-3-carbaldehyde (0.90 g), benzenesulfinic acid sodium salt (4.0 g), copper (I) iodide (4.6 g) and 1-methyl-2-pyrrolidinone (50 mL) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a yellow oil (1.9 g).
Reaction SMILES: CN(CCN(C)C)C.N[C@H](C(O)=O)C[SeH].[Li]CCCC.[C:21]1([O:29][CH3:30])[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:23][CH3:24].[Cl:31][CH2:32][CH2:33][CH2:34][CH:35]=[O:36]>C1COCC1.[Cl-].[Na+].O>[CH3:24][O:23][C:22]1[C:21]([O:29][CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH:35]([OH:36])[CH2:34][CH2:33][CH2:32][Cl:31]
Reactant: O=CCCCCl
Reactant: COc1ccccc1OC
Agent: CN(C)CCN(C)C
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(O)CCCCl)c1OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of TMEDA (6.6 mmol) in dry THF (15 mL), was added Sec-BuLi (6.6 mmol) slowly at −78° C. The reaction mixture was stirred at −78° C. for 10 minute, veratrole (6.0 mmol) in THF (3 mL) was added slowly. The reaction was stirred at −78° C. for 30 minutes, 1-chlorobutan-4-al (6.6 mmol) was added and stirred at −78° C. for 2 hr. The reaction mixture was warmed to rt, added brine (1 mL), and filtered. The filtrate was dried over MgSO4, filtered and concentrated to a residue. The residue was purified by flash column chromatography (Silica gel; Ethyl acetate/Hexane: 3/7) to afford 1-(2,3-dimethoxyphenyl)-4-chlorobutan-1-ol in 20% yield. 1H NMR (300 MHz, CDCl3) δ7.05 (dd, J=8.0 Hz, 7.7 Hz, 1H), 6.94 (bd, J=7.7 Hz, 1H), 6.85 (bd, J=8.1 Hz, 1H), 4.91-4.97 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.56-3.60 (m, 2H), 2.44-2.45 (m, 1H), 1.81-2.00 (m, 4H) ppm. MS (CI, NH3) m/e 244 (base, M+H+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:20])=[O:19]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 17.5 g (84 mmol) of (R)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 150 ml of dry pyridine was cooled to 5° and treated dropwise with 11.5 g (0.1 mol) of methanesulfonyl chloride keeping the temperature at 5°. The reaction mixture was stirred at 5° for two hours and stored at 5° for 18 hours. The reaction mixture was allowed to warm to room temperature over three hours and the solvent was then removed in vacuo. The residue was partitioned between ethyl acetate/water (500 ml each) and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with water, dried (MgSO4) and evaporated in vacuo to give 21.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:25])[CH2:16][CH:17]([CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:34][CH2:35][CH3:36])=[O:33])[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccccc1OCc1ccccc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(2-benzyloxyphenyl)-3-(4-chlorophenyl)prop-2-en-1-one and diethyl malonate, diethyl 2-[3-(2-benzyloxyphenyl)-1-(4-chlorophenyl)-3-oxopropyl]malonate was obtained as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:31])(=[O:30])[N:21]=3)[C:10]2=[O:32])=[CH:5][N:6]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:30])(=[O:31])[N:21]=3)[C:10]2=[O:32])=[CH:5][N:6]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1cnc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 262A (0.040 g, 0.082 mmol) in tetrahydrofuran (1.7 mL) and methanol (0.007 mL, 0.164 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.064 mL, 0.128 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.22 (m, 2 H) 6.38 (t, J=6.25 Hz, 1 H) 7.07 (t, J=7.54 Hz, 1 H) 7.28 (t, J=8.09 Hz, 2 H) 7.59 (m, 5 H) 8.08 (dd, J=8.09, 1.47 Hz, 1 H) 16.19 (s, 1 H). MS (ESI−) m/z 486 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20]>>[OH:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)(CN)CO
Product: CC(C)(CO)CNC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 3-amino-2,2-dimethyl-1-propanol (CAN 26734-09-8) as starting materials and isolated (23 mg, 74%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 313.1315 (MH+).
Reaction SMILES: C(C([NH:7][C@H:8]([C:15]([NH:17][C@@H:18]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:19]([OH:33])[CH2:20][C@@H:21]([C:29]([OH:32])([CH3:31])[CH3:30])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[O:16])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=O)(C)(C)C.Cl.[CH2:42]([C@H:49]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[C:50]([OH:52])=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:42]([C@H:49]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[C:50]([NH:7][C@H:8]([C:15]([NH:17][C@@H:18]([CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C@@H:19]([OH:33])[CH2:20][C@@H:21]([C:29]([OH:32])([CH3:30])[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[O:16])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=[O:52])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)C(C)(C)C)C(C)(C)O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of 200.7 mg (0.336 mmole) of (2S, 4S, 5S)-5-[N-(t-butylcarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-butylhexanamide in 6 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then benzene was added to the residue. The solvent was removed by distillation under reduced pressure from the resulting solution. The same operation was repeated, in total, three times, and the residue was then dried by evaporation under reduced pressure for 8 hours. The dried material was then suspended in 10 ml of anhydrous tetrahydrofuran, and 98.2 mg (0.354 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension. 0.06 ml (0.396 mmole) of 95% diethyl cyanophosphate and 0.2 ml (0.143 mmole) of triethylamine were then added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from a mixture of ethyl acetate and diisopropyl ether, to give 229.8 mg of the title compound as white crystals, melting at 92°-95° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: Cc1ccccc1C(OC1CCNCC1)c1ccccc1
Product: Cc1ccccc1C(OC1CCN(CCCOc2ccccc2[N+](=O)[O-])CC1)c1ccccc1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(2-methylphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(2-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12](=[O:23])[NH:13][CH2:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[O:23][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][N:13]=1
Reactant: COC(=O)c1cc(C(=O)NCC(=O)c2ccccc2)c(SC)s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ncc(-c3ccccc3)o2)c(SC)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
To a cooled (0° C.) solution of 80.1 mg (0.229 mmol) of methyl 5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-carboxylate (as prepared in the previous step) in 2 mL of anhyd DMF was added 26.7 μL (0.286 mmol) of phosphorus oxychloride. After stirring for 20 h at room temperature, the mixture was concentrated in vacuo. The resulting yellow solid was recrystallized twice from MeOH to afford the title compound as a beige powder (48.8 mg, 64%). 1H-NMR (300 MHz, DMSO-d6) δ8.26 (s, 1H), 7.88 (s, 1H), 7.86 (d, 2H, J=7 Hz), 7.51 (m, 2H), 7.40 (m, 1H), 3.86 (s, 3H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H13NO3S2: 332.0 (M+H). Found: 331.9.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[CH:21]([C:23]1[N:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1)=[CH2:22].C(O)(=O)C>C(O)CC.O>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:21][CH2:22][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)=[N:28][CH:27]=1)(=[O:31])[CH3:30]
Reactant: C=Cc1ccc(C(C)=O)cn1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Solvent: CCCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(CCN2CCN(c3cccc4cc(C(=O)N(C)C)oc34)CC2)nc1
Temperature: 69 °C

Procedure:
A reaction mixture of N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.078 g, 0.29 mmol) (Example 39d), 1-(6-vinylpyridin-3-yl)ethanone (0.15 g, 1.00 mmol) and acetic acid (0.016 mL, 0.29 mmol) in n-propanol (1.5 mL) and water (0.10 mL) was heated at 69° C. for 2 days. The product was purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]([C:54]([F:57])([F:56])[F:55])=[N:41]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:44]4[N:40]([CH3:39])[N:41]=[C:42]([C:54]([F:57])([F:56])[F:55])[CH:43]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cn1nc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(C(F)(F)F)nn3C)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 45 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (58 mg, 0.21 mmol), sodium carbonate (22 mg, 0.21 mmols), and bis(triphenylphosphine)palladium(II) dichloride (6 mg, 0.01 mmol) in 1,2-dimethoxyethane (2.0 ml) and water (0.50 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane diethyl ether) to give 38 mg (45% yield, 66% purity) of the title compound.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[CH:16]1[C:26]2[CH2:25][NH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.O.ClCCl>CN(C)C=O>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([N:24]2[CH2:25][C:26]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]2=3)=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
4-Biphenyl-carbonyl chloride (1.19 g) dissolved in N,N-dimethylformamide (10 mL) was added dropwise to an ice cooled solution of 5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine (0.98 g) in N,N-dimethylformamide (10 mL). After stirring at room temperature overnight, the reaction mixture was poured into water and dichloromethane. The organic layer was sequentially washed with water and saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and eluted with additional dichloromethane. The combined eluate was refluxed with gradual addition of hexane until incipient crystallization occurred. Cooling and filtration provided the title compound (0.72 g), m.p. 180–182° C.