Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([S:22]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H](CCc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a suspension of homophenylalanine (Synthetech) (7 g, 39.1 mmol) in distilled water (21.5 mL) was added a 2 M aqueous NaOH (21.5 mL). After 5 minutes, the suspension had cleared and phenylsulfonyl chloride (5.48 mL, 43 mmol) was added. After 2 hours, the reaction mixture's pH was adjusted to 12 with 2 M aqueous NaOH (5 mL), and extracted with Et2O (2×100 mL). The aqueous layer's pH was adjusted to 1 with 6 M HCl (10 mL), and the product was extracted with EtOAc (100 mL), dried over MgSO4 filtered, and the solvent was removed under reduced pressure. The residue was triturated with Et2O (2×100 mL), filtered, and pumped to dryness, giving 8.74 g (70%) of phenylsulfonylhomophenylalanine.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=O)[C:6]([CH3:19])([CH3:18])[NH:7]2>O1CCCC1>[Br:1][C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6]([CH3:19])([CH3:18])[NH:7]2
Reactant: CC1(C)Nc2ccc(NC3=NCCN3)c(Br)c2NC1=O
Solvent: C1CCOC1
Product: CC1(C)CNc2c(ccc(NC3=NCCN3)c2Br)N1
Temperature: 0 °C

Procedure:
A suspension of 5-bromo-1,2-dihydro-2,2-dimethyl-6-(2-imidazolin-2-ylamino)-3-(4H)-quinoxalinone (150 mg, 0.45 mmol) and LiALH4 (17 mg, 0.45 mmol) in tetrahydrofuran (3 ml) is heated and maintained at a temperature of 50°-80° C. until the starting material is consumed, The mixture is cooled to 0° C., 2-3 drops of H2O is added and the mixture is filtered. The solution is concentrated in vacuo to yield a residue which is chromatographed on silica gel with CHCl3 :CH3OH saturated with NH3 (g) elution to produce the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C#Cc2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1ccc(C#Cc2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1
Yield: 97 %

Procedure:
Prepared from (2-nitro-4-p-tolylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example F4) (640 mg, 1.82 mmol) by reduction with SnCl2.2H2O (2.0 g, 9.1 mmol) according to the general procedure G (method b). Obtained as a beige solid (569 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:5])[CH3:2].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17](=[O:18])[C:16]([Cl:21])([Cl:20])[Cl:15])[N:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn2c1CCCC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ethyl ester (Comp. No. 2b) (2 g, 10.3 mmol) in anhydrous dichloromethane (5 ml) was added trichloro-acetyl chloride (4.7 g, 25.9 mmol). The resulting mixture was stirred at room temperature for 3 days, and then evaporated to dryness. The crude product was purified by silica gel chromatography (eluting with 5 to 50% ethyl acetate in heptane) to give 2.74 g of 3-(2,2,2-trichloro-acetyl)-5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ethyl ester. LC/MS (method 5): Rt=5.05 min; m/z=338.02 (M+H+).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(C(F)(F)F)cc4)c3c2s1
Yield: 61 %

Procedure:
Prepared from VII and 4-aminobenzotrifluoride. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 61%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2851, 2229, 1649, 1604, 1582, 1512, 1457, 1382, 1318, 1272, 1252, 1221, 1165, 1117, 1101, 1062, 1011, 979, 863, 830; 19F NMR (282 MHz, DMSO-d6) δ −60.01; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, 1H, J=9.0 Hz), 8.22 (s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.39 (d, 2H, J=8.4 Hz); HRMS calcd for C17H9N5SF3 (M+H+): 372.0529, found 372.0535.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=O.[C:15]([NH:18][C:19]1[C:36]([Cl:37])=[CH:35][C:22]([CH2:23][NH:24]/[C:25](/[NH2:34])=[N:26]\[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21][C:20]=1[Cl:38])(=[O:17])[CH3:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[C:15]([NH:18][C:19]1[C:20]([Cl:38])=[CH:21][C:22]([CH2:23][NH:24]/[C:25](=[N:26]\[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])/[NH:34][C:4](=[O:6])[CH2:3][CH:2]([OH:1])[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:35][C:36]=1[Cl:37])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(Cl)cc(CN/C(N)=N\C(=O)OC(C)(C)C)cc1Cl
Reactant: COc1ccc(C(O)CC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(O)CC(=O)N/C(=N/C(=O)OC(C)(C)C)NCc2cc(Cl)c(NC(C)=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
A mixture of 3-hydroxy-3-(4-methoxyphenyl)propanoic acid (13.7 mg, 0.07 mmol), (Z)-tert-butyl (4-acetamido-3,5-dichlorobenzylamino)(amino)-methylenecarbamate (26.3 mg), PyBop (36.4 mg), and triethylamine (0.01 mL) in dichloromethane (0.35 mL) was stirred at room temperature for 12 h. The crude reaction mixture was purified directly by preparative TLC eluting with 30% ethyl acetate/70% hexanes to give the title compound as a clear sticky oil (30 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 1.48 (m, 9 H) 2.21 (s, 3 H) 2.70 (m, 2 H) 3.78 (m, 3 H) 4.55 (m, 2 H) 4.95 (m, 1 H) 6.80-7.00 (m, 3 H) 7.24-7.38 (m, 4 H), 9.10 (m, 1 H), 12.30 (m, 1 H). HPLC retention time: 2.493 min (method A). MS (ESI) (M+H)+ 553.08.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].N[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[Cl:14]>O.Cl>[Cl:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[N+:1]([O-:3])=[O:2])[C:10]#[N:11]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Sodium nitrite (6.78 g in water (40 mL) at 0° C.) was slowly added to a solution of 4-amino-3-chloro-benzonitrile (10.5 g) in water (30 mL) and concentrated hydrochloric acid (30 mL) also at 0° C. After 10 minutes the solution was poured onto a suspension of cuprous oxide (3.48 g) and sodium nitrite (31.69 g) in water (100 mL) at 0° C. The ensuing mixture was stirred at 0° C. for 1 hour then at 23° C. for 1 hour. The resulting mixture was extracted with dichloromethane and the organic layer washed with saturated sodium chloride. The separated organic layer was dried over sodium sulfate and then concentrated to give 3-chloro-4-nitro-benzonitrile (11.31 g).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[N:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.Br[CH2:30][C:31](=[O:33])[CH3:32]>>[CH3:18][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:16][O:15][C:12]1[CH:13]=[N:14][C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([O:1][CH2:30][C:31](=[O:33])[CH3:32])[CH:28]=[CH:27][C:5]=3[N:6]=2)=[CH:10][CH:11]=1
Reactant: C[C@@H](COc1ccc(-c2nc3ccc(O)cc3o2)nc1)NC(=O)OC(C)(C)C
Reactant: CC(=O)CBr
Product: CC(=O)COc1ccc2nc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn3)oc2c1

Procedure:
Using tert-butyl [(1S)-2-{[6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate and 1-bromopropan-2-one, and in the same manner as in Example 2, step E, the title compound was obtained.
Reaction SMILES: N1CCCC1C(OC1C=CC=CC=1)=O.C(O)(C(F)(F)F)=O.[O:22]([CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:22]([CH2:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccccc2)CC1
Agent: O=C(Oc1ccccc1)C1CCCN1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OCCCN2CCNCC2)cc1

Procedure:
The compound 30 was prepared according to the method described for compound 23 employing TFA (6 mL) and compound 28 (550 mg, 1.72 mmol) to give white solid compound. The compound was used without further purification after solvent removal.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:29]1[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=1)[C:12]([NH:14][CH:15]1[C:27](=[O:28])[N:17]2[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:12]([NH:14][CH:15]1[C:27](=[O:28])[N:17]2[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: COC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Yield: 79.8 %

Procedure:
7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 3.7 g), methanol (40 ml) and conc. hydrochloric acid (2.1 ml) were treated in a similar manner to that of Example 5 to give 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 2.8 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 103.3 %

Procedure:
Dibenzylamine (1.95 mL, 10 mmol), triethylamine (1.37 mL, 10 mmol), 4-amino-6-chloro-5-nitro-pyridine-3-carboxylic acid ethyl ester (2.45 g, 10 mmol) and toluene (73 mL) were combined and heated at reflux over night. The reaction mixture was cooled to room temperature and filtered through a short column of silica gel (eluting first with dichloromethane then ethyl acetate). The organics were concentrated to provide 10 as a yellow oil (4.2 g). 1H NMR (400 MHz, d6-DMSO) δ: 1.28 (t, J=7.1 Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.60 (s, 4H), 7.14-7.31 (m, 10H), 8.35 (s, br, 2H), 8.54 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[NH:6][CH:7]=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)([Br:14])=O>>[Br:14][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)(C)c1cc(=O)cc[nH]1
Product: CC(C)(C)c1cc(Br)ccn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
A mixture of 2-tert-butyl-1H-pyridin-4-one (Step 1.5) (4.25 g, 28 mmol) and POBr3 (8.88 g, 31 mmol, 1.1 eq) is heated to 120° C., stirred for 15 min, allowed to cool, quenched by addition of a saturated solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 95:5) to afford 5.18 g of the title compound as a yellow oil: ESI-MS: 214.0/216.0 [M+H]+; tR=2.49 min (System 1); TLC: Rf=0.35 (Hex/EtOAc, 1:1).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH2:26])[CH:20]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH3:26])[CH:20]=2)[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1)c1ccccn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(c1cccc(-c2cccc(C(C)(C)C)c2O)c1)c1ccccn1
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A solution of 12 (0.13 g, 0.31 mmol) in methanol (10 mL) and ethyl acetate (30 mL) was treated with 20% palladium on activated carbon (50% wet, 0.05 g) and was hydrogenated at 10 psi in a Parr shaker for 2 hr. The catalyst was filtered out and washed with ethyl acetate. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (25 g) with 5% ethyl acetate in hexane (3 L). Pure B1 (0.08 g, 80%) was isolated.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:8][CH:7]=2)=[O:15])=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Anhydrous aluminum chloride (80.0 g, 0.60 mol) was added to a stirred solution of terephthaloyl chloride (50.8 g, 0.25 mol) dissolved in fluorobenzene (235 ml, 2.5 mol) over a 10-15 minute period. The mixture was stirred at room temperature for one hour and then maintained at 70°-80° C. for four hours. After cooling, the reaction mixture was poured onto approximately 1000 g of ice containing 100 ml of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue collected by filtration, washed with water, and dried at 100° C. The crude solid was recrystallized from approximately 2000 ml of toluene to afford 70.7 g (88% yield) of 1,4-bis(4-fluorobenzoyl)-benzene; mp 218.5°-219.5° C.; Anal. Calcd for C20H12F2O2 : C, 74.53%; H, 3.75%; F, 11.179%. Found: C, 74.60%; H, 3.80%; F, 11.83%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]([NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[OH:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C[CH2:27][O:28]CC.[OH-].[Na+].ClC(OC(Cl)(Cl)Cl)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH:9]([N:16]2[CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:19][C:27]2=[O:28])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6]1
Reactant: CCOCC
Reactant: OC(CNC(CCN1CCOCC1)c1ccccc1)c1ccccc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1OC(c2ccccc2)CN1C(CCN1CCOCC1)c1ccccc1
Yield: 16.5 %

Procedure:
2-(3-Morpholino-1-phenylpropyl)amino-1-phenylethanol (2.2 g, 6.46 mmol) prepared in the above (1), ether (100 ml) and 10% NaOH (50 ml) were mixed and stirred. To the obtained mixture, 20% toluene solution of trichloromethyl chloroformate [14 ml (14 mmol)] was dropwise added slowly for a period of 1 hour. After stirring at room temperature for 1 hour, ethyl acetate (200 ml) was added to the resulting solution, and then the ethyl acetate portion was collected. The obtained portion was washed with saturated aqueous sodium chloride (100 ml) and then dried over anhydrous sodium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=50/1) to obtain 510 mg of diastereomer A (yield: 21.5%) and 390 mg of diastereomer B (yield: 16.5%) of the titled compound as oily products, provided that the diastereoisomers showing the Rf values of about 0.6 and 0.5 in TLC (chloroform/methanol=10/1) were referred to as diastereoisomers A and B, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:23][CH:24]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCl
Reactant: O=C(NCCc1ccc(O)cc1)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(CCNC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Yield: 40 %

Procedure:
To a solution of 4′-chloro-N-[2-(4-methoxyphenyl)ethyl][1,1′-biphenyl]-4-carboxamide (700 mg, 1.91 mmol) obtained in Reference Example 22 in dichloromethane (10 ml) was added dropwise 1.0 mol/l solution (4.21 ml, 4.21 mmol) of boron tribromide in dichloroethane at 0° C., and the mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give a demethylated compound (620 mg). A solution of 4′-chloro-N-[2-(4-hydroxyphenyl)ethyl][1,1′-biphenyl]-4-carboxamide (620 mg), N-(2-chloroethyl)-N,N-diethylamine hydrochloride (364 mg, 2.11 mmol) and potassium carbonate (876 mg, 6.34 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 6 hrs and at 100° C. for 4 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by NH-silica column chromatography (developing solvent; chloroform:ethyl acetate:hexane=1:1:2), and powderized with isopropyl ether to give the title compound (318 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl.O>[CH2:12]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: Nc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
A solution of N-tert-butoxycarbonylaminoacetaldehyde (0.28 g, 1.76 mmol) in 1,2-dichloroethane (DCE, 5 mL) was added to a solution of [4-(4-aminophenyl)butyl]carbamic acid benzyl ester (0.48 g, 1.6 mmol) in DCE (10 mL) and acetic acid (0.108 mL, 1.6 mmol). The mixture was stirred at room temperature for 20 min. NaB(OAc)3H (0.48 g, 2.26 mmol) was then added into the mixture which was further stirred at room temperature overnight. Water (10 mL) was added and the mixture was acidified to pH 7 by 10% aqueous HCl. The organic fraction was isolated and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, ethyl acetate/hexane, 1:2, v/v) to afford the protected diamine 600 (0.33 g, 47%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.54 (m, 2H), 2.51 (m, 2), 3.18 (m, 4H), 3.36 (m, 2H), 3.89 (br s, 1H), 4.69 (br s, 1H), 4.78 (br s, 1H), 5.51 (s, 2H), 6.54 (d, 2), 6.96 (d, 2H), 7.33 (m, 5H). m/z (ESI) 442 [C25H35N3O4+H]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]2[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:20][C:21]1[C:26]([CH2:27]O)=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:20][C:21]1[C:26]([CH2:27][O:14][C:12]2[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:19])=[CH:6][S:7][C:8]=3[CH:13]=2)=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=1
Reactant: Cc1ccc(CO)c(C)n1
Reactant: COC(=O)Cc1csc2cc(O)cc(C(F)(F)F)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(COc2cc(C(F)(F)F)c3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a mixture of methyl(6-hydroxy-4-(trifluoromethyl)-1-benzothiophen-3-yl)acetate (60 mg) and THF (dry) (2 mL) were added (2,6-dimethylpyridin-3-yl)methanol (31.2 mg), ADDP (62.6 mg), and tri-n-butylphosphine (0.153 mL) at room temperature. After stirring at room temperature for 16 h, the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). To the mixture of crude material and THF (1 mL) was added 1N NaOH (1 mL) at room temperature, and the mixture was stirred at room temperature for 13 h. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residual solid was crystallized from EtOAc-hexane to give the title compound (71.0 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH:36]1[CH2:38][CH2:37]1)[C:6]1[C:7]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[CH3:24])=[CH:15][CH:14]=2)[N:11]=1)#[N:2].Cl>CO>[CH:36]1([N:5]([C:6]2[C:7]3[CH2:28][NH:27][CH2:26][CH2:25][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][N:21]=[C:20]4[CH3:24])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][C:1]#[N:2])[CH2:37][CH2:38]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CNCC3)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-((2-cyanoethyl)(cyclopropyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (240 mg, 0.47 mmol) was dissolved in methanol (5 mL). Hydrochloric acid (0.014 mL, 0.47 mmol) was added and the reaction mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the crude 3-(cyclopropyl(2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)propanenitrile (189 mg, 98%) was used as such in the subsequent step. MS (ES+) m/z 415.0 (M+H)+