Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[N:29](COCC[Si](C)(C)C)[CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])=[CH:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[CH3:1][C:2]1([CH3:43])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:17])=[O:18])[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 60.3 mg of crude 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenyl}-amide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with EtOH (2 drops) and TFA (1 mL) and stirred at RT for 1.5 h. Solvents were evaporated in vacuo, and the residue was purified by RP-HPLC (C18) with 20-100% CH3CN in 0.1% TFA/H2O over 30 min to afford 11.2 mg (20% over three steps) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.4 Hz), 7.91 (s, 1H), 7.21 (dd, 1H, J=8.4, 2.4 Hz), 5.76-5.71 (m, 1H), 3.71-3.65 (m, 4H), 3.50-3.46 (m, 1H), 3.26-3.20 (m, 4H), 3.14-3.11 (m, 1H), 3.10-3.04 (m, 2H), 3.35-2.27 (m, 2H), 2.10-2.05 (m, 2H), 1.59 (t, 2H, J=6.4 Hz), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H31N5O4S, 498.2 (M+H). found 498.0.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: BrCC1CC1
Product: Cc1ccccc1C1=CN(CC2CC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=537.2 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and cyclopropyl methyl bromide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.O=[C:11]1[CH2:15][S:14][CH2:13][CH:12]1[C:16](OC)=[O:17]>>[CH2:13]1[C:12]2[C:16](=[O:17])[NH:9][C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=3[NH:8][C:11]=2[CH2:15][S:14]1
Reactant: COC(=O)C1CSCC1=O
Reactant: Nc1ccc(F)cc1N
Product: O=C1Nc2ccccc2NC2=C1CSC2

Procedure:
In a similar fashion 4-fluoro-o-phenylenediamine is condensed with methyl tetrahydro-4-oxo-3-thiophenecarboxylate to give a mixture of 7-fluoro- and 6-fluoro-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.Cl.[NH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[OH:31]>>[OH:31][C@H:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[NH:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N[C@H]2CCC[C@@H]2O)nc1
Yield: 78 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using trans-2-aminocyclopentanol hydrochloride instead of isopropylamine, to the title compound (100 mg, 78%), which was obtained as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([OH:38])=[C:28]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=1>>[C:30]([C:28]1[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=1[O:38][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=1)(=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(Cl)cc2C(=O)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (5-chloro-2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.244 g (38%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H25O5Cl 501.1469, found 501.1474.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([CH:27]1[CH2:31][C:30](=[O:32])[O:29][C:28]1=[O:33])[CH:22]=[CH:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:30]([CH2:31][CH:27]([CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])[C:28]([OH:33])=[O:29])=[O:32]
Reactant: CCCC=CCC1CC(=O)OC1=O
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: Cc1ccccc1
Product: CCCC=CCC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.1 g, 0.37 mmol; prepared in a manner similar to that described in Example 23), 3-hex-2-enyldihydrofuran-2,5-dione (0.068 g, 0.37 mmol) and toluene (10 ml) was heated under reflux for 20 hours, then the resulting solid was collected by filtration from the hot mixture, washed with ethyl acetate (3 ml) and dried in vacuo to give 2-{[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]methyl}oct-4-enoic acid (0.061 g) as an off-white solid, m.pt. 179–181° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.7–0.9 (t, 3H) (CH3), 1.1–1.35 (m, 2H) (—CH2CH3), 1.75–2.0 (m, 2H) (—CH2CH2CH3), 2.0–2.3 (m, 2H) (—CH2CH═CH—), 2.3–2.8 (2×m obscured by DMSO signal, 2H+1H) (—CH2CH(CO2H)CH2—), 4.2 (s, 2H) (ArCH2—), 5.15–5.5 (m, 2H) (—CH═CH—) 6.9–7.2 (m, 2H) (2×ArH), 7.65–8.0 (m, 4H) (4×ArH), 8.2 (d, 1H) (ArH), 12.1 (br s, 1H) (CO2H), 12.6 (s, 1H) (CONH); m/z (M+H)+. 452, 93.7% purity.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([CH:20]=[O:21])[CH:8]=2)[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([CH2:20][OH:21])[CH:8]=2)[CH3:2]
Reactant: CCn1c2ccc(C=O)cc2c2cc(NC(C)=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCn1c2ccc(CO)cc2c2cc(NC(C)=O)ccc21
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
To a solution of N-(9-Ethyl-6-formyl-9H-carbazol-3-yl)-acetamide (50 mg, 0.150 mmol) in EtOH (5 ml) at 0° C. was added NaBH4 (8.5 mg, 0.225 mmol), and after 10 minutes the cooling bath was removed. After 1 hour additional NaBH4 (2 mg) was added, and after stirring 90 minutes water was added, the EtOH removed in vacuo, and the aqueous layer extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated to afford the crude product. Chromatographic purification (silica, 50% EtOAc/Hex) afforded the product as a solid (28 mg, 56% yield). MS m/z @ 337 (m+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:6]=2)([O-])=O.[Cl-].[NH4+].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.[Fe].C(O)C.O>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH:1][C:4]2[C:5]3[C:9]([CH:10]=[CH:11][CH:12]=2)=[N:8][N:7]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=3)=[O:39])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1cccc2nn(CCN3CCCCC3)cc12
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Fe]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1cccc2nn(CCN3CCCCC3)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Nitro-2-(2-piperidin-1-yl-ethyl)-2H-indazole (0.160 g, 0.583 mmol), iron powder (0.326 g, 5.84 mmol) and ammonium chloride (0.0185 g, 0.346 mmol) was suspended in a 4:1 ethanol/H2O solution and heated to reflux for 3 hours. The mixture was cooled to room temperature, the solvents removed in vacuo and the residue stirred in triethylamine/ethyl acetate (1/4, 5 mL). The mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4) and the filtrate was concentrated to provide a pale white solid. The solid (40.0 mg, 0.164 mmol) was dissolved in 3 mL of N,N-dimethylformamide and (4-benzyloxy-phenyl)-acetic acid (0.0470 g, 0.194 mmol), PS-EDCI (1.30 mmol/g, 0.378 g, 3 equiv), N-Hydroxybenzotriazole (0.0330 g, 0.244 mmol) and diisopropylethylamine (0.0850 mL, 0.488 mmol) were added and the reaction vessel was placed on a shaker table for 6 hours. The mixture was concentrated under vacuo and the residue dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.37 (m, 2 H) 1.46 (m, 4 H) 2.39 (m, 4 H) 2.79 (t, J=6.61 Hz, 2 H) 3.68 (s, 2 H) 4.51 (t, J=6.61 Hz, 2 H) 5.08 (s, 2 H) 6.92 (m, 2 H) 7.14 (m, 1 H) 7.39 (m, 9 H) 8.47 (m, 1 H) 10.02 (s, 1 H); MS (DCI/NH3) m/z 469 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12](=[O:20])(=[O:19])[N:11]=2)=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12](=[O:19])(=[O:20])[N:11]=2)=[CH:2]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=S1(=O)N=C(c2c[nH]c3ccccc23)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(C2=NS(=O)(=O)c3ccccc32)c2ccccc21
Temperature: 80 °C

Procedure:
A solution of the product from example 1, step b (300 mg) was dissolved in DMF and treated with K2CO3 (166 mg, 1.2 mmol) followed by t-butyl bromoacetate (150 μL, 1 mmol). The reaction was heated to 80° C. for 1 h. Additional K2CO3 and t-butyl bromoacetate were added (1 mmol each) and the reaction was heated to 100° C. for 2 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed with water 3 times then dried over MgSO4 and concentrated to give the sub-title compound as a yellow solid. MS: ESI (positive): 397 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNc1c(C=O)c2ccccc2n1-c1ccc(C(C)(C)C)cc1
Yield: 26 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with N,N-dimethylethylenediamine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-(2-dimethylaminoethylamino)-1H-indole-3-carboxaldehyde (26% yield) as a light tan solid. ESI/MS 364 (M+H); RT 3.39 min. NMR 9.94 (1H, s); 7.84 (1H, br s); 7.67 (2H, d); 7.48 (2H, d, J=9 Hz); 7.10 (1H, t); 6.98 (1H, t); 6.66 (1H, d, J=9 Hz); 3.05 (2H, br s); 2.30 (2H, BR t); 2.03 (6H, S); 1.36 (9H, s).
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:46][O:47][CH3:48])[C:23]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:33]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1>C(OC(C)C)(C)C>[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:46][O:47][CH3:48])[C:23]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:33]([O:35][CH2:36][C:37]([OH:39])=[O:38])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)OC(C)(C)C)=CCS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of anisole (5 ml) and trifluoroacetic acid (6 ml) was added tert-butoxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.5 g) with stirring at ambient temperature. The reaction mixture was stirred for an hour at the same temperature. Then the resultant solution was dropwise added to diisopropyl ether (150 ml). The precipitates were collected by filtration and washed with diisopropyl ether. The precipitates were dissolved in an aqueous solution of sodium bicarbonate. The aqueous solution was adjusted to pH 2.5 with conc. hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give carboxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 0.85 g), IR and NMR spectra of which were the same as those of the object compound of Example 14.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21]OS(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].O>CN(C=O)C>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][N:6]1[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:16])([CH3:1])[C:7]1=[O:8]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
At 0° C., a solution of 2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (35.8 g, 0.161 mol) and 1-methoxy-3-(p-toluenesulfonyloxy)propane (47.6 g, 0.195 mol) in DMF (720 ml) is treated with Kl (5.49 g, 33.1 mmol). After adding 60% of NaH (7.80 g, 0.195 mol) over 10 min, the mixture is stirred at 0° C. for 30 min, warmed to 60° C., stirred for 14 h, and treated with H2O (3500 ml). After the extraction of the mixture with EtOAc (3×400 ml) and Et2O (3×400 ml), the combined org. layer is washed with H2O (2×250 ml), dried (Na2SO4), and evaporated. A SiO2 flash chromatography (2000 g, hexane/EtOAc 5:2) gives 4-(3-methoxy-propyl)-2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (39.0 g, 82%) as yellow oil. Rf (hexane/EtOAc 5:2) 0.45. 1H-NMR (400 MHz, CDCl3) 1.55 (s), 1.91-2.02 (m, 2 H), 3.36 (s), 3.43 (t, J=6.0), 4.07 (t, J=6.0), 7.04 (d, J=9.0), 7.93 (dd, J=9.0, 0.4), 8.09 (d, J=0.4). 13C-NMR (100 MHz, CDCl3) 167.6 (s), 148.9 (s), 143.0 (s), 129.5 (s), 119.8 (d), 117.7 (d), 110.4 (d), 78.9 (s), 69.4 (t), 58.7 (q), 39.7 (t), 27.5 (t), 23.7 (2q).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[NH:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[CH:13][C:12]=1[Cl:24])[C:6](=O)[CH2:7][CH3:8])C.[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([NH2:39])[CH:33]=1)[CH3:30]>>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]2[C:33]=1[C:4](=[O:3])[C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[NH:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)=[CH:13][C:12]=1[Cl:24])=[C:6]([CH2:7][CH3:8])[NH:39]2)[CH3:30]
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)NC2CCC2)cc1Cl)C(=O)CC
Product: CCc1[nH]c2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(=O)c1Cc1ccc(C(=O)NC2CCC2)cc1Cl

Procedure:
The title compound was prepared by the method of Preparation 65c using 2-(2-chloro-4-cyclobutylcarbamoylbenzyl)-3-oxopentanoic acid ethyl ester and (S)-2-(3-amino-4-fluorophenoxy)propionic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[N:38]=[CH:39][C:34]([F:33])=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2ncc(F)cn2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.03 g (57%). 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 2H), 8.04-7.93 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.31-7.25 (m, 2H), 7.15 (s, 1H), 4.07 (s, 3H), 3.00-2.92 (m, 3H), 2.37 (s, 3H), 1.80-1.72 (m, 2H), 1.54-1.43 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ−113.44, 146.33 LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: O1CCC(N2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)C=N2)CC1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[CH:50]=CC(B3OC(C)(C)C(C)O3)=[CH:47][CH:46]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[CH:46]=[CH:47][C:10]([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)=[CH:11][CH:50]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC1OB(c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)OC1(C)C
Reactant: Nc1cc(-c2cncc(-c3cnn(C4CCOCC4)c3)c2)cc(-c2ccccn2)n1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
This compound is prepared analogously to 5″-[1-(Tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-[2,2′;4′,3″]terpyridin-6′-ylamine (Example 2.156) by replacing 1-(tetrahydro-pyran-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Intermediate B18) with 4-[4-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@@H:13]1[O:23][CH2:24][CH:25]=[CH2:26])=[O:10].II.C[Si](C)(C)[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[O:23][CH2:24][CH:25]=[CH2:26])=[O:10]
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: Cc1ccccc1
Product: C=CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Yield: 36.4 %

Procedure:
To as solution of Ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 19, 2.5 g, 6.20 mmol) in toluene (450 mL) was added iodine (6.31 g, 24.8 mmol) followed by hexamethyldisilane (10.34 mL, 49.62 mmol and the reaction mixture was refluxed for 30 h. The reaction mixture was treated with 10% sodium thiosulphate (300 mL) and layers were separated. The aqueous layer was extracted with toluene and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica, 4% methanol in dichloromethane) afforded 750 mg (36.54%) of 3,4-dichloro-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][C@H:16]([C:28]([OH:30])=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(OCC)(=O)C.O.C(O)(=O)C(O)=O>CCCCCC>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:28]([OH:30])=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
10 g of crude N2-[1-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine rich in 1S-isomer (the molar ratio of the 1S- to the 1R-isomer was 80:20) was suspended in 10-fold volume mixed solutions of 80 ml of ethyl acetate and 20 ml of n-hexane. 1.46 g (0.5 eq.) of oxalic acid monohydrate was added, and the reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure at a temperature lower than 40° C. The filtered cake was dissolved in 80 ml water, and 1N sodium hydroxide solution was added to adjust the pH value to 4.0 to 6.0. The solution was cooled to 0 to 5° C., and stirred for 3 hrs. After filteration, and the solid was dried in vacuum at a temperature lower than 40° C. to give 5.8 g of pure N2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine. The yield is 58%, and the molar ratio of the 1S- to the 1R-isomer is 99.0:1.0.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[N:7]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(N(CC)CC)C>[N:7]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:4]([O-:5])(=[O:15])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Agent: OCCN1CCCCC1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)[O-]

Procedure:
Diketene (8.1 ml) was added dropwise to 2-piperidinoethanol (9.36 ml) and triethylamine (0.05 ml) under stirring, so as to keep the temperature at 60°-70° C. (exothermic reaction). When the addition was over, the mixture was stirred at 80° for 40'. 12.4 g of the product were obtained by vacuum (2 mmHg) distillation. The NMR spectrum was in agreement.