Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][N:6]([CH3:8])[CH:7]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:9]([C:4]5[C:3]([CH2:1][CH3:2])=[CH:7][N:6]([CH3:8])[N:5]=5)=[O:11])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCc1cn(C)nc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1cn(C)nc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 63.9 %

Procedure:
In the same manner as in Example 18-4 and using 4-ethyl-1-methyl-1H-pyrazole-3-carboxylic acid (150 mg, 0.970 mmol), tetrahydrofuran (7 mL), oxalyl chloride (93.0 μL, 1.07 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (184 mg, 64%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[NH2:16])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][N:7]1[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=2[NH:16][C:23]1=[O:24])[CH3:2]
Reactant: CCOC(=O)CCNc1cc(C#N)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCn1c(=O)[nH]c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-Amino-5-cyano-phenylamino)-propionic acid ethyl ester (0.65 g, 2.8 mmol) in CHCl3 (10 mL) was added CDI (0.68 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.6 g (83%) of the desired priduct as a brown solid. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:8][CH2:7]1)(=O)=O.[CH2:20]([N:27]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][C:32]([O:39][CH3:40])=[C:33](O)[CH:34]=2)[N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH2:20]([N:27]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][C:32]([O:39][CH3:40])=[C:33]([O:5][C@H:6]3[CH2:11][CH2:10][C@H:9]([N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]4)[CH2:8][CH2:7]3)[CH:34]=2)[N:29]=[CH:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN1CCN([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)CC1=O
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1

Procedure:
650 mg (cis)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane in 3 ml N-methyl-2-pyrrolidinone are added dropwise at 120° C. over two hours to 632 mg 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline and 1.09 g caesium carbonate in 4 ml N-methyl-2-pyrrolidinone. The product is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[O:23]1[CH2:28][CH2:27][N:26]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][C:39](OC)=O)=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:25][CH2:24]1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:39]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([S:29]([N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)(=[O:31])=[O:30])=[CH:37][CH:36]=3)[NH:22][C:20](=[O:21])[C:3]=2[N:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: COC(=O)Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(O)C(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N4CCOCC4)cc3)nc21

Procedure:
Analogously to the procedure of Example 29, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 30 mg (0.107 mmol) of methyl 4-morpholinosulphonylphenylacetate.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:19][O:20][CH2:21]Cl>C(OCC)(=O)C.O>[CH3:19][O:20][CH2:21][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[N:6]1
Reactant: COCCl
Reactant: O=[N+]([O-])c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCn1cc([N+](=O)[O-])nn1
Yield: 61.5 %

Procedure:
4-nitro-1H-1,2,3-triazole (6.468 g, 56.707 mmol) and potassium carbonate (15.683 g, 113.472 mmol) were added into 150 mL acetone. Chloromethyl methyl ether (4.74 mL, 62.407 mmol) was added dropwise into the above mixture under ice bath. After completion, water and ethyl acetate were added into the reaction solution. Phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, chromatographed on a silica gel column (ethyl acetate:petroleum ether=1:5) to obtain 1-(methoxymethyl)-4-nitro-1H-1,2,3-triazole, as 5.517 g of a light yellow liquid, at a yield of 61.5%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([C:8]([O:10]CC)=O)[CH2:7][CH2:6]1)=[O:4].[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>C1COCC1>[CH3:13][C@@H:14]([N:21]1[CH2:2][C:3](=[O:4])[C:5]2([CH2:6][CH2:7]2)[C:8]1=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(C(=O)CBr)CC1
Reactant: C[C@@H](N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1CC(=O)C2(CC2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a solution of ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate (4.7 g, 20 mmol) in THF (60 mL) was added (R)-α-methylbenzylamine (2.9 g, 24 mmol) and Et3N (4.04 g, 40 mmol). After stirring at rt for 3 days, the reaction mixture was concentrated in vacuo, and the residue was extracted with ethyl acetate (50 mL×2) and washed with water (30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to afford the title compound as a light yellow solid (3.66 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:11][C:4]1[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: NC(=O)c1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Yield: 69.9 %

Procedure:
5-Bromo-3-nitropyridine-2-carboxamide (400 mg, 1.63 mmol), ammonium chloride (435 mg, 8.15 mmol) and iron powder (273 mg, 4.89 mmol) were suspended in methanol (6 mL) and water (3 mL), and stirred at 100° C. for 20 hours. After cooled to room temperature, this was filtered through Celite, and the Celite was washed with methanol. The mother liquid was concentrated, and the residue was dissolved in chloroform and washed with water. The organic layer was concentrated under reduced pressure to obtain the intended compound (246 mg, 70%).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH2:28])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:26])(=[O:27])[NH2:28])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(Cl)ccc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(Cl)ccc1S(N)(=O)=O
Yield: 11.8 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.29 g), 2-(aminomethyl)-4-chlorobenzenesulfonamide hydrochloride (0.42 g) and potassium carbonate (0.52 g) were stirred in ethanol (10 ml) at 70° C. overnight. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-fluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].F[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[C:20]([Cl:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2>>[NH2:1][CH2:2][C@H:3]([CH3:4])[O:5][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[C:20]([Cl:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2
Reactant: C[C@H](O)CN
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 46 %

Procedure:
The procedure described in Example 1 (preparation of starting materials) was repeated using (S)-(+)-1-amino-2-propanol and 5-fluoro-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine in 46% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.96 (m, 2H), 4.79 (m, 1H), 5.28 (s, 2H), 7.17 (d, 1H), 7.21 (d, 1H), 7.29 (d, 1H), 7.35 (m, 1H), 7.56 (d, 1H), 7.64 (dd, 1H), 7.70 (t, 1H), 7.86 (dt, 1H), 8.20 (d, 1H), 8.48 (s, 1H), 8.58 (d, 1H), 10.60 (bs, 1H); Mass Spectrum MH+ 435.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.Cl.C(OC([NH:57][C@@H:58]([CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])[C:59]([NH2:61])=[O:60])=O)C1C=CC=CC=1.Cl.NCC(N)=O>>[NH2:57][C@H:58]([C:59](=[O:60])[NH2:61])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NCCCC[C@H](N)C(N)=O)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and (S)-2-benzyloxycarbonylamino-6-aminohexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[N:11]=[C:12]3[N:22]([CH:23]=2)[CH2:21][CH2:20][O:19][C:18]2[C:13]3=[CH:14][C:15]([CH:24]([OH:26])[CH3:25])=[CH:16][CH:17]=2)[N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:26][CH:24]([C:15]1[CH:14]=[C:13]2[C:18]([O:19][CH2:20][CH2:21][N:22]3[C:12]2=[N:11][C:10]([C:4]2[N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=[C:2]([CH3:1])[N:3]=2)=[CH:23]3)=[CH:17][CH:16]=1)[CH3:25])(=[O:30])=[O:29]
Reactant: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2cc(C(C)O)ccc2OCC3)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2cc(C(C)OS(C)(=O)=O)ccc2OCC3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 1-{4-[4-methyl-1-(propan-2-yl)-1H-imidazol-2-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethan-1-ol (10 mg, 0.028 mmol) in DCM (2 mL) at 0° C. was added TEA (14 mg, 0.139 mmol) and methanesulfonyl chloride (6.0 mg, 0.053 mmol). The reaction mixture was further stirred at 0° C. for 2 h. TLC showed the reaction was completed. After being quenched with aqueous NaHCO3 (5 mL), the resultant mixture was extracted with DCM (3×5 mL), washed with brine (2×5 mL). The organic phase was dried over Na2SO4 and concentrated to give 1-{4-[4-methyl-1-(propan-2-yl)-1H-imidazol-2-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (12 mg, 100% yield), which was directly used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:16](=O)[CH3:17])[C:10]([O:12]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C@@H:16]([CH3:17])[N:29]([CH2:28][C:27]([F:31])([F:30])[F:26])[C:10]1=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(CC(C(C)=O)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1[C@H](c2cccc(Cl)c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A slurry of methyl 2-[(tert-butoxycarbonyl)amino]-4-(3-chlorophenyl)-5-oxohexanoate as a 1:1 racemic mixture of diastereomers (11.1 g, 30.0 mmol), 2,2,2-trifluoroethylamine (9.59 mL, 120 mmol), acetic acid (10.3 mL, 180 mmol), sodium triacetoxyborohydride (25.4 g, 120 mmol), and flame-dried 4 Å molecular sieves (50 g) in 1,2-dichloroethane (300 mL) was stirred at 23° C. for 8 h. Additional 2,2,2-trifluoroethylamine (9.59 mL, 120 mmol), acetic acid (10.3 mL, 180 mmol), and sodium triacetoxyborohydride (25.4 g, 120 mmol) were added and stirring was continued for 20 h. The reaction mixture was diluted with dichloromethane (200 mL) then poured into water (500 mL). Molecular sieves were removed by filtration, and the organic layer was washed with water (3×500 mL), dried over sodium sulfate, and concentrated. A solution of the residue in ethanol (200 mL) was stirred in the presence of solid potassium carbonate (12.4 g, 90 mmol) at 60° C. for 2 h, then 23° C. for 16 h. The bulk of the ethanol was removed under reduced pressure and the remaining slurry was then partitioned between water (500 mL) and ethyl acetate (300 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was crystallized from a 2:1 mixture of hexane and ethyl ether to give the title compound as a racemate. The enantiomers were separated using normal-phase HPLC using a ChiralPak® AD column, eluting with 40% hexane in ethanol initially, stepping to 20% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second enantiomer to elute. MS: m/z=421.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[C:15](Br)[CH:16]=1)[NH:13][C:12]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)=[C:11]2[C@H:26]([CH3:29])[CH2:27][NH2:28])([CH3:7])[CH3:6])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1)=[C:11]2[C@H:26]([CH3:29])[CH2:27][NH2:28])([CH3:7])[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)c1cc(Br)c2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN)c2c1
Agent: [Pd]
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN)c2c1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
To a solution of (S)-2-[3-(2-amino-1-methylethyl)-7-bromo-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (79 mg in 1 mL methanol) was added 8 mg of 10% palladium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 7 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (chloroform:methanol, 92:8) to provide the title compound (68 mg).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([C@H:37]1[O:39][CH2:38]1)Cl>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:35][CH:37]2[CH2:38][O:39]2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: ClC[C@@H]1CO1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CO2)cc1

Procedure:
Analogously to Example 148e, 5.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 2.05 ml of (S)-(+)-epichlorohydrin are reacted. The title compound is obtained as a colourless oil. Rf=0.24 (1:2 EtOAc-heptane); Rt=5.66.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([OH:10])=O)([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C>C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:10])([CH3:2])[CH3:3]
Reactant: CN1CCC(N)CC1
Reactant: CC(C)Oc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)NC2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a mixture of 0.88 g (3.9 mmole) of 3-isopropoxy-4-nitro-benzoic acid, 2.8 mL (16 mmole) of ethyldiisopropyl amine, 0.54 g (4.7 mmole) of 4-amino-1-methyl-piperidine and 18 mL of dimethylformamide was added 1.63 g (4.3 mmole) of 1-[bis(dimethylamino)methylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 2 hours, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with ethyl acetate 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-40:60) gave 1.2 g of 3-isopropoxy-N-(1-methyl-piperidin-4-yl)-4-nitro-benzamide as a yellow solid.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:2]=12.Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][F:23])=[CH:16][CH:15]=1>>[F:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:2]3[C:3]([CH:6]=2)=[N:4][O:5][N:1]=3)=[CH:15][CH:16]=1
Reactant: FCCOc1ccc(Br)cc1
Reactant: OB(O)c1ccc2nonc2c1
Product: FCCOc1ccc(-c2ccc3nonc3c2)cc1

Procedure:
Starting from 5-benzo[1,2,5]oxadiazoleboronic acid and 1-bromo-4-(2-fluoro-ethoxy)-benzene. Yellow-beige powder. MS(ES+): 259 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].O[C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:1][CH2:2][CH2:3][C@H:4]([O:5][C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O[C@H](CCCl)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1cccc(O[C@@H](CCCl)c2ccccc2)c1
Reaction time: 8 h
Yield: 53.2 %

Procedure:
(1R)-3-Chloro-1-phenyl-1-propanol (1.000 g, 5.86 mmol), 1-(3-hydroxyphenyl)ethanone (0.797 g, 5.86 mmol), triphenylphosphine (1.54 g, 5.86 mmol) and diethylazodicarboxylate (1.53 g, 8.79 mmol) were combined in a flask, which was immediately flushed with argon. THF (20 mL) was added and the mixture was stirred overnight under argon. THF was removed in vacuo, the crude product was dissolved in 50 mL of CH2Cl2/H2O (1:1) and the organic layer was separated and dried over MgSO4. After removing the solvent in vacuo, the residue was purified by flash chromatography using 10% ethyl acetate/hexane to yield the desired product (900 mg, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.49–7.46 (m, 2H), 7.40–7.26 (m, 6H), 7.07–7.04 (m, 1H), 5.46–5.43 (dd, 1H, J=4.4 Hz, 8.8 Hz), 3.84–3.78 (m, 1H), 3.643.59 (m, 1H), 2.52 (s, 3H), 2.51–2.46 (m, 1H), 2.29–2.22 (m, 1H).
Reaction SMILES: CC1(C)[O:7][C@H:6]2[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][O:11][C@@H:5]2[CH2:4][O:3]1.Cl>CO>[OH:3][CH2:4][C@@H:5]1[C@@H:6]([OH:7])[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][O:11]1
Reactant: CC1(C)OC[C@H]2OC[C@@H](O)[C@@H](O)[C@@H]2O1
Agent: Cl
Solvent: CO
Product: OC[C@H]1OC[C@@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
To a solution of (−)-(4aR,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (42 mg, 0.21 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.6 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature and concentrated in vacuo.