Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]([O:28][CH2:29][O:30][CH3:31])[CH2:14][N:15]1[C:20](=[O:21])[CH:19]=[N:18][C:17]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[N:25][C:16]1=2.C(N(CC)CC)C>ClCCl>[CH3:31][O:30][CH2:29][O:28][CH:13]([CH2:14][N:15]1[C:20](=[O:21])[CH:19]=[N:18][C:17]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[N:25][C:16]1=2)[CH:12]=[O:11]
Reactant: COCOC(CO)Cn1c(=O)cnc2ccc(OC)nc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCOC(C=O)Cn1c(=O)cnc2ccc(OC)nc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.022 ml, 0.260 mmol) was dissolved in dichloromethane (1 ml), a solution of dimethyl sulfoxide (0.037 ml, 0.521 mmol) in dichloromethane (0.5 ml) was added to the solution at −78° C. and mixed for 30 minutes. While maintaining at −78° C., a solution of 4-[3-hydroxy-2-(methoxymethoxy)propyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (64 mg, 0.217 mmol) in dichloromethane (3 ml) was added to the reaction solution and the mixture was stirred for 1 hour. While maintaining the temperature at −78° C., triethylamine (0.181 ml, 1.302 mmol) was added to the reaction solution and the mixture was stirred for 30 minutes. The temperature was raised to 0° C., the reaction solution was stirred for 1 hour, then diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 67 mg (quantitative) of the title compound in the form of a yellow-orange oily product. The product was used as such for next reaction without purification.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]=[C:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12]([CH:13]=[CH:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2C(F)(F)F)=[O:30])=[CH:11]1>CS(C)=O>[CH3:28][C@:25]12[CH2:26][CH2:27][C:10](=[O:9])[CH:11]=[C:12]1[C@H:13]1[CH2:4][C@H:14]1[CH:15]1[CH:24]2[CH2:23][CH2:22][C@:20]2([CH3:21])[C@@H:19]([C:29]([NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:30])[CH2:18][CH2:17][CH:16]21
Reactant: C[S+](C)(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@]12CCC(=O)C=C1[C@H]1C[C@H]1C1C2CC[C@@]2(C)C1CC[C@@H]2C(=O)Nc1ccccc1
Reaction time: 1.5 h

Procedure:
To a suspension of NaH (0.25 g, 6.18 mmol) in 7.4 mL DMSO (dried over molecular sieves) at room temperature under N2 was added trimethylsulfoxonium iodide (1.50 g, 6.85 mmol). The mixture was stirred for 1.5 hr. A solution of (17β)-3-oxo-N-[2-(trifluoromethyl)phenyl]androsta-4,6-diene-17-carboxamide (5-1) (0.68 g, 1.49 mmol) in 10 mL DMSO was added slowly. The solution was stirred at room temperature overnight. The reaction was then quenched by dropwise addition of 10% KHSO4 solution and extracted with CHCl3. The organic phase was washed with 10% KHSO4 solution, saturated NaHCO3 solution, and brine, then dried with MgSO4. After removal of the solvent, the residue was purified by chiral preparative HPLC (Chiralpak AD, 85% Hexanes (0.1% diethylamine); 15% 2-propanol) to yield the desired resolved products 6-6and 6-2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:6]=[CH:7][C:8]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[C:22]([C:25]([OH:27])=O)=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].ON1C2C=CC=CC=2N=N1.Cl.[CH3:46][N:47]([CH3:56])[CH2:48][CH2:49][CH2:50][N:51]=[C:52]=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:52][N:51]([CH2:50][CH2:49][CH2:48][N:47]([CH3:56])[CH3:46])[C:25]([C:22]1[N:14]2[C:13]([CH2:12][N:11]([C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:4][C:3]=3[O:2][CH3:1])=[O:10])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15]2)=[CH:24][CH:23]=1)=[O:27]
Reactant: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)N(C)CCCN(C)C)n2Cc2ccccc21
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of 10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 10, Step F (0.40 g, 0.88 mmol), 3-(dimethylaminopropyl)-1-methyl amine (0.16 mL, 1.09 mmol) and 1-hydroxybenzotriazole (0.135 g, 0.96 mmol) in N,N-dimethylformamide (4 mL) was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.19 g, 1.09 mmol) followed by N,N-diisopropylethyl amine (0.24 mL, 1.35 mmol). The reaction mixture was stirred overnight, then diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in dichloromethane afforded 0.36 g of title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[C:33]#[N:34])=[N:19]S(C(C)(C)C)=O)[CH:15]=[CH:16][CH:17]=1.Cl>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:18]2([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:26]3[C:27](=[C:28]([F:32])[CH:29]=[CH:30][CH:31]=3)[C:33]([NH2:34])=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1
Yield: 94.8 %

Procedure:
4-Methoxyphenylmagnesium bromide (6.00 mL, 3.00 mmol) was added to a solution of N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.407 g, 1 mmol) in THF (10 mL) at 0° C. under an argon atmosphere. The resulting mixture was stirred and allowed to reach r.t. over night, then quenched with saturated aqueous NH4Cl, diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were passed through a phase separator (Sorbent) and concentrated. The residue was dissolved in MeOH (10 mL), and hydrogen chloride (2M in diethyl ether, 2 mL, 4 mmol) was added and the resulting mixture was stirred at r.t for 2.5 h. The mixture was concentrated in vacuo and purified on a silica gel column eluted with 0-5% 0.1M NH3 in MeOH in DCM to afford 0.39 g (95% yield) of the title compound: MS (ES+) m/z 411, 413 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](ON=C(C1C=CC=CC=1)C#N)=[O:7])([CH3:4])[CH3:3].Cl.Cl.[CH2:21]([O:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCCNOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCNOCc1ccccc1
Reaction time: 24 h

Procedure:
1 N NaOH (100 mL) was added to (6) (6.01 g, 21.4 mmol), followed by extraction with ether (5×50 mL). After a brine wash (50 mL), solvent was removed to give 4.39 g of (6) as the free amine. BOC-ON (5.10 g, 20.7 mmol ) in distilled THF (100 mL) was added to (6) (free amine, 21.1 mmol) in THF (165 mL) at 0° C. over 30 minutes. The reaction was stirred (0° C. to room temperature) for 24 hours and concentrated in vacuo. Cold 1N NaOH (100 mL) was added, followed by extraction with EtOAc (4×100 mL). The organic layer was washed with cold 1 N NaOH (3×80 mL), cold 0.5M citric acid (100 mL) and brine (2×100 mL). Removal of solvent gave 6.38 g (quantitative) of (7), which was used directly in the next step, as a liquid: NMR δ 1.2-1.7 (m+s, 15 H), 2.66-3.23 (m, 4 H), 4.5 (br s, 1 H), 4.67 (s, 2 H), 7.16-7.34 (m, 5 H) . An analytical sample was purified on a silica gel column, eluting with 15% EtOAc/CHCl3. Anal. calcd. for C17H28N2O3 : C, 66.20; H, 9.15; N, 9.08. Found: C, 66.13; H, 9.10; N, 9.05.
Reaction SMILES: [Cl:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:24])(=[O:23])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>C(Cl)Cl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[O:20][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:24])(=[O:23])[CH2:4][CH2:3]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(Cl)CCS3(=O)=O)c1O
Reactant: CCCS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1c(C(=O)c2ccc3c(c2C)C(Cl)CCS3(=O)=O)cnn1CC
Yield: 60.2 %

Procedure:
0.26 Gram (0.7 mmol) of 4-chloro-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide was dissolved in 3 ml of methylene chloride, and then a solution of 0.2 g (1.4 mmol) of potassium carbonate in 2 ml of water was added. Further, 0.16 ml (1.4 mmol) of n-propanesulfonyl chloride and 20 mg (0.08 mmol) of benzyltriethylammonium chloride were added, and the mixture was allowed to react at room temperature for 1 day. After the completion of the reaction, a methylene chloride layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 0.2 g (yield 60%) of 4-chloro-5-methyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH:42]1[CH2:47][CH3:48])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:3]=3[C:2]([F:32])([F:33])[F:1])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:43][CH:42]1[CH2:47][CH3:48])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCC1CNCCN1C(=O)OC(C)(C)C
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CCC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-ethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](=[S:42])[NH2:41]>CC(N(C)C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([C:39]([CH3:44])([CH3:43])[CH3:38])=[N:41][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.53 mmol) in 40 mL DMA, 1.0 eq. NBS (0.806 g, 4.53 mmol) was added and the solution was allowed to stir 15 min at rt. 2,2-dimethylpropanethioamide (0.531 g, 4.53 mmol) was then added at rt. The reaction was heated to 60° C. for 2 hours. The reaction was not complete by LC-MS. The reaction mixture was then heated to 80° C. for an additional hour. The reaction mixture was diluted with water and extracted×2 with EtOAc. The combined EtOAc washings were washed with water×3 to remove DMA, dried over MgSO4, filtered and concentrated onto silica gel. The crude material was chromatographed in 10-80% EtOAc in Hexanes to give the desired product, 1.6 g (64%). MS (ESI): 539.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][C:13]=1[OH:19]>B(F)(F)F.CCOCC>[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15]([OH:16])=[C:17]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1cc(Cl)c(O)cc1O
Reaction time: 2 h
Yield: 79.2 %

Procedure:
This compounds was synthesised in the same manner as described above. Phenylacetic acid (4.71 g, 34.6 mmol), 4-chlororesorcinol (5 g, 34.6 mmol), boron trifloride etherate (30 ml). After standing for two hours an orange precipitate formed. This was purified by flash chromatography to give the required compound as a white solid (7.2 g, 79.3%); Rf 0.9 hexane/ethyl acetate (20/80)].
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:10]=[C:11]([O:16][C:17]2[C:22]([F:23])=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=2N)[CH:12]=[C:13]([Cl:15])[CH:14]=1.[ClH:26].CCOC(C)=O>C(#N)C>[Br:8][C:9]1[CH:10]=[C:11]([O:16][C:17]2[C:22]([F:23])=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=2[Cl:26])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To an oven dried flask was added CuCl2 (4.06 g, 30.2 mmol). The flask was placed under high vacuum, flushed with nitrogen and acetonitrile (30 mL) was added. t-Butyl nitrite (4.50 mL, 37.8 mmol) was added dropwise. The stirred solution was placed in an oil bath at 50° C. under gentle stream of nitrogen, heated for 5 min and a solution of {2-[(3-bromo-5-chlorophenyl)oxy]-3-fluoro-4-methylphenyl}amine in acetonitrile (40 mL) was added dropwise. The reaction was stirred for 0.5 h, cooled in an ice bath and poured into ice cold, aqueous HCl (1 N, 125 mL). EtOAc (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. The crude material was purified by column chromatography (0% to 25% EtOAc/hexanes gradient) to afford the title compound (3.2 g, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.48-7.47 m, 1H), 7.41-7.38 (m, 1H), 7.32-7.28 (m, 1H), 7.11-7.10 (m, 1H), 7.04-7.03 (m, 1H), 2.27 (s, 3H).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:3]4[CH:2]=[C:1]([CH3:26])[CH:6]=[CH:5][CH:4]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1cccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-m-tolyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11](=[O:27])[C:10]=2[C:28](O)=[O:29])=[CH:5][CH:4]=1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11](=[O:27])[C:10]=2[C:28](=[O:29])[NH:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)Nc3ccncc3)c2-c2ccc(OC)cc2)cc1

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one and 4-aminopyridine as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[Mg][CH:21]=[CH2:22].[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:15]([OH:16])[CH:21]=[CH2:22])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(OCCCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-phenylpropoxy)benzaldehyde (10.4 g) in dry tetrahydrofuran (100 mL), a solution of bromo(vinyl) magnesium in tetrahydrofuran (14%, about 1 M) was added at 0° C. After stirring for 15 minutes, the reaction mixture was added to a cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 3:1) to give the title compound (10.01 g) having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][C:21](=[O:25])[C:20]2=[O:26])=[CH:13][CH:12]=1)=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]([O:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH:30]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:35]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH2:36][C:37]([O:39][CH:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:38])[C:21](=[O:25])[C:20]2=[O:26])=[CH:13][CH:12]=1)=[NH:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(C=Cc1cccnc1)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCNC(=O)C2=O)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
In 7.5 ml of N,N-dimethylformamide was dissolved 2.5 g of 4-[3-(4-tert-butoxycarbonylamidinophenoxy)propyl]-2,3-dioxopiperazine, and to the solution were added 6.1 g of diphenylmethyl 3-(3-pyridyl)acrylate and 0.48 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting mixture was stirred overnight at room temperature and distilled under reduced pressure to remove the solvent. To the resulting residue were added 80 ml of ethyl acetate and 60 ml of water and the pH was adjusted to 7 with 2N hydrochloric acid. The organic layer was separated, washed with water and then a saturated aqueous sodium chloride solution, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol 20:1) to obtain 2.34 g of diphenylmethyl 3-[4-[3-(4-tert-butoxycarbonylamidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as a colorless oil.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccccc1O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
In this reference example, 9.76 g of salicylaldehyde, 15.12 g of 1-benzyl-4-amino-piperidine and 100 ml of methanol are mixed and stirred at room temperature for one hour. While the resultant mixture is cooled with ice, 3.2 g of sodium borohydride is added thereto over a period of one hour and 30 minutes. Then, the mixture is stirred at room temperature for 2 hours. The resultant reaction mixture is poured into 1 l of ice water. The light yellow crystals deposited are separated by filtration and then dissolved in 200 ml of ethyl acetate. The ethyl acetate solution is washed with a saturated aqueous sodium chloride, dried and subsequently concentrated under reduced pressure to obtain 19.0 g of light yellow crystals. The crystals are recrystallized from ethanol to obtain 12.0 g of the desired product.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][CH3:16])=[O:4].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1COCC1>[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COc1cccc([N+](=O)[O-])c1NC(=O)CBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.6 %

Procedure:
To a solution of 2-bromo-N-(2-methoxy-6-nitrophenyl)acetamide (Step 1, 8.8 g, 30 mmol) in THF (240 mL) was added morpholin (11 mL, 122 mmol) at 0° C. and warmed to rt. After 2.5 h, the reaction mixture was quenched by addition of water (200 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with water (200 mL), brine (100 mL) dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to afford 6.7 g (75%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]3[CH:23]=[C:24]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)[C:25](OC)=[O:26])[CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:26][CH2:25][C:24]1[CH:23]=[C:22]([CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=1)[CH2:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20]2
Reactant: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
To (S)-methyl 3-((2-(benzyloxycarbonylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)benzoate (2.90 mmol, 1.4 g) at 0° C. in THF (29.0 mL) under an argon atmosphere was added Lithium aluminium hydride in THF (2.90 mmol, 2.90 mL) dropwise. The reaction was left to stir for 1.5 hrs at 0° C. The reaction was quenched with MeOH before the addition of 5N HCl (aq) to adjust the pH to 3. The reaction mix was diluted with DCM before washing with water (×1) followed by brine (×1). The DCM layer was dried over MgSO4 before removing the solvent in vacuo to give the product as a clear glassy solid (1.34 g, 102%). MS (ESI): m/z [M+H]+ 456.1