Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:16])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[H-].[Na+].C(N)CN>>[CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: CCCCCCCCCCCCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: NCCN
Product: C#CCCCCCCCCCCCCCO
Yield: 76.2 %

Procedure:
Isomerization of pentadec-2-yn-1-ol (12.5 g, 54.95 mmol) using NaH/ethylenediamine as described above furnished pentadec-14-yn-1-ol (9.4 g, 76%) as a white solid. M.P.: 54.2-54.8° C. TLC: 30% EtOAc/hexanes, Rf≈0.45; 1H NMR (400 MHz, CDCl3) δ 3.60-3.65 (m, 2H), 2.16 (dt, 2H, J=7.1 Hz, 2.4 Hz), 1.92 (t, 1H, J=2.4 Hz), 1.47-1.60 (m, 4H), 1.22-1.35 (m, 18H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14].[N:15]1[O:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]=12.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.O1CCCC1>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C@:19]12[CH2:20][O:21][CH2:22][CH2:23][C@H:18]1[CH2:17][O:16][NH:15]2
Reactant: C1C[C@H]2CON=C2CO1
Reactant: Fc1ccc(Br)c(F)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc([C@]23COCC[C@H]2CON3)c(F)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 3.95 mL, 9.88 mmol) was added to a solution of 1-bromo-2,4-difluorobenzene (0.558 mL, 4.94 mmol) in a 1:3 mixture of tetrahydrofuran and toluene (25 mL) at −78° C., and the reaction mixture was stirred at this temperature for 1 hour. In a separate flask, a solution of (3aR)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C9) (628 mg, 4.94 mmol) in toluene (15 mL) was cooled to −78° C. and treated with boron trifluoride diethyl etherate (1.22 mL, 9.88 mmol); this mixture was also allowed to stir at −78° C. for 1 hour, and then added via cannula to the aryllithium solution. The reaction mixture was stirred for 1 hour and was then quenched with saturated aqueous ammonium chloride solution. After dilution with ethyl acetate, the layers were separated, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 40% ethyl acetate in heptane) provided the product. Yield: 610 mg, 2.53 mmol, 51%. The cis ring fusion was assigned on the basis of analogy with compound C17, whose stereochemistry was confirmed via single crystal X-ray analysis (vide infra). LCMS m/z 242.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.75-1.93 (m, 2H), 3.03-3.10 (m, 1H), 3.53-3.76 (m, 4H), 3.95-4.02 (br m, 1H), 4.03 (dd, J=12.5, 1.8 Hz, 1H), 6.93-7.00 (m, 2H), 7.84-7.92 (m, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:32][CH3:33])[C:10]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][C:19]=3[CH:29]=[O:30])[N:15]([CH3:31])[CH2:14]1)=[O:11])[CH3:8].Cl.C(O)(=O)C(C(C(O)=O)O)O.N>C(OCC)(=O)C.O1CCCC1>[CH2:32]([N:9]([CH2:7][CH3:8])[C:10]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][C:19]=3[CH2:29][OH:30])[N:15]([CH3:31])[CH2:14]1)=[O:11])[CH3:33]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Agent: Cl
Agent: N
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(CO)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
Under argon, 320 mg (8 mmol) of lithium aluminum hydride is suspended in 20 ml of absolute, freshly distilled tetrahydrofuran. At room temperature, a solution of 1.40 g (4 mmol) of 1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea in 40 ml of freshly distilled, absolute tetrahydrofuran is added dropwise. Then the mixture is stirred for 11/4 hours at room temperature. The batch is then cooled in an ice bath and combined with 20 ml of 1N hydrochloric acid. To this mixture is added 20 ml of 2N tartaric acid and the batch is layered over the ethyl acetate. For neutralization, 80 ml of 1N ammonia solution is added dropwise. The ethyl acetate phase is separated, and the aqueous phase is reextracted with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate. The concentrated crude product is chromatographed on silica gel with methylene chloride/methanol 95:5 under pressure. The crude product (1.09 g) is crystallized from ethyl acetate, thus obtaining 0.94 g of 1,1-diethyl-3-(6-methyl-2-hydroxymethyl-8α-ergolinyl)urea (65% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][O:18][CH3:19])[CH:10]=2)[N:3]=1>[Pd]>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:10]=2)[N:3]=1
Reactant: COCC#Cc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Agent: [Pd]
Product: COCCCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 40 %

Procedure:
A mixture of an ethanolic solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.1 g, 0.25 mmol) and 10% palladium on charcoal (10 mg) was placed under a hydrogen filled balloon for 16 h and filtered thru celite. The filtrate was concentrated to dryness in vacuo. The resultant residue was purified by flash chromatography on silica gel, ethyl acetate as eluent, to give the title product as a white solid, 0.04 g (40% yield), mp 48-50° C.; 1H NMR (DMSO-d6) δ 2.4 (m, 2H); 2.95 (s, 3H); 3.2 (s, 3H); 3.3 (t, 2H); 6.6 (b, 2H); 7.1 (m, 3H); 7.2 (m, 4H); 7.4 (d, 2H); MS [(+)ESI] m/z=404 [M−H]+.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][S:12]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:14])=[O:13])=[CH:27][CH:26]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Product: CC(C)(C)OC(=O)NCc1ccc(CNS(=O)(=O)c2cccc3cnccc23)cc1
Yield: 82.7 %

Procedure:
According to Reference Example 5, Step B, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (10 g) and Intermediate 59 (8.96 g) to obtain the title compound (13.39 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.[C-:16]#[N:17].[Na+]>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:16]#[N:17]
Reactant: [C-]#N
Reactant: FC(F)(F)COc1c(Cl)cccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(Cl)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)-3-chlorobenzyl bromide (1.6 g, 5.4 mmol) from Step 2 above in DMF (12 mL) was added NaCN (0.28 g, 5.7 mmol). The solution was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 5-20% EtOAc:hexanes to give 2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetonitrile as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[N:15]O)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[O:17]1CCOCC1>>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:10](=[O:17])[NH:15][CH2:11][CH2:12][CH2:13][C:14]1=2
Reactant: C1COCCO1
Reactant: Cn1c2c(c3ccccc31)C(=NO)CCC2
Product: Cn1c2c(c3ccccc31)C(=O)NCCC2

Procedure:
1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one oxime (24 g) and polyphosphoric acid (600 g) in dioxan (500 ml) were treated according to the method described for Intermediate 6. The solid (22 g) obtained by evaporation of the organic extracts was recrystallised from ethyl acetate (300 ml) to give a solid (19.2 g). This was purified by FCC eluting with System A (200:8:1) to give the title compound (5.5 g), m.p. 212°-215°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21]>CN(C)C=O>[F:19][C:20]([F:22])([F:21])[CH:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[OH:12]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1c(C=O)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(O)C(F)(F)F)cc2ccccc21
Yield: 78.7 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-1H-indole-2-carbaldehyde (300 mg, 1.88 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (52 mg, 0.38 mmol) and (trifluoromethyl)trimethylsilane (0.416 mL, 2.82 mmol), the mixture was stirred and reacted at room temperature for 4 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 2,2,2-trifluoro-1-(1-methyl-1H-indol-2-yl)ethanol (Compound DQ) (339 mg, yield: 79%).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4](=[O:17])[N:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH2:10]([O:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:30][CH:29]=2)(=[O:32])=[O:33])[C:4]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccn(OCc2ccccc2)c1=O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Br
Product: O=c1c(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cccn1OCc1ccccc1

Procedure:
The titled compound was prepared from 3-amino-1-benzyloxy-1H-pyridin-2-one hydrogen bromide salt from Step E and 4′-chloro-biphenyl-4-sulfonyl chloride according to the procedure described in Example 32 Step A. MS 467 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[CH:26]=2)([C:15]2[N:16]([CH3:20])[CH:17]=[N:18][CH:19]=2)[CH3:14])=[CH:9][C:8]=1[F:34])#[N:6]>C(Cl)(Cl)Cl>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)([C:15]2[N:16]([CH3:20])[CH:17]=[N:18][CH:19]=2)[CH3:14])=[CH:9][C:8]=1[F:34])#[N:6]
Reactant: COc1cccc(CCC(=O)NC(C)(c2ccc(C#N)c(F)c2)c2cncn2C)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: Cn1cncc1C(C)(NC(=O)CCc1cccc(O)c1)c1ccc(C#N)c(F)c1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
BBr3 (1M in CH2Cl2 ) (4 mL) was added slowly to a solution of N-[1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-(3-methoxy-phenyl)-propionamide (0.123 g, 0.25 mmol) in CHCl3 (2 mL) at 0° C. After 10 min the ice bath was removed and the mixture stirred at 20° C. for 20 min. The mixture was cooled to 0° C., quenched with saturated NaHCO3 solution (25 mL), then extracted with EtOAc (3×50 mL). The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[OH:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=2)[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1Br
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 23, using 5-bromo-N-(trans-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide and 4-trifluoromethoxyphenylboronic acid (commercially available) as starting materials. MS (m/e): 455.3 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(O)C>[C:10]1([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]2[CH:8]=[C:4]([CH2:3][CH2:2][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:5]=[CH:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CNCCN1
Reactant: ClCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCO
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(CCN3CCNCC3)c2)cc1

Procedure:
A solution of 4-(2-chloroethyl)-1-(triphenylmethyl)imidazole (5.89 g, 15.8 mmol) and piperazine (27.2 g, 316 mmol) in ethanol (80 mL) were heated to reflux for 2 hours. The solvent was removed in vacuo and the residue partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[C:5]([S:9][CH3:10])[N:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:5]1[N:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[CH:8]=[N:7][CH:6]=1
Reactant: CSc1cncc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1cncc(-c2nc(=O)c3ccccc3s2)n1
Yield: 23 %

Procedure:
2-Cyano-6-methylthiopyrazine (0.80 g, 5.29 mmol) and methyl thiosalicylate (1.34 g, 7.94 mmol) were dissolved in toluene (100 ml), and triethylamine (1.48 ml, 10.6 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the tilted compound (0.35 g, 23%) as pale yellow crystals.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][O:29][CH3:30])[CH:22]=1)[C:3]([NH:5][C:6]1([O:19][CH3:20])[C:13](=[O:14])[N:12]2[CH:7]1[S:8][CH2:9][C:10]([CH3:18])=[C:11]2[C:15]([OH:17])=[O:16])=[O:4].[Na].Cl[CH2:33][O:34][C:35](=[O:48])[C@H:36]([CH:45]([CH3:47])[CH3:46])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][O:29][CH3:30])[CH:22]=1)[C:3]([NH:5][C:6]1([O:19][CH3:20])[C:13](=[O:14])[N:12]2[CH:7]1[S:8][CH2:9][C:10]([CH3:18])=[C:11]2[C:15]([O:17][CH2:33][O:34][C:35](=[O:48])[CH:36]([NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH:45]([CH3:47])[CH3:46])=[O:16])=[O:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: COCc1cc(C(N)C(=O)NC2(OC)C(=O)N3C(C(=O)O)=C(C)CSC32)ccc1O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1cc(C(N)C(=O)NC2(OC)C(=O)N3C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)=C(C)CSC32)ccc1O
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 7-[[amino[4-hydroxy-3-(methoxymethyl)phenyl]acetyl]amino]-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the general procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethylformamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water and aqueous bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to give 7-[[amino[4-hydroxy-3-(methoxymethyl)phenyl]acetyl]amino]-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[F:29][C:30]([F:35])([F:34])[CH2:31][NH:32][CH3:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:33][N:32]([CH2:31][C:30]([F:35])([F:34])[F:29])[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CNCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)CC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1.5 mL) were added 2,2,2-trifluoro-N-methylethanamine hydrochloride (60 mg, 0.40 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH:36]2[CH2:37][CH2:38][O:33][CH2:34][CH2:35]2)=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CCOCC4)C3)sc12
Yield: 54 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), tetrahydro-4H-pyran-4-one (0.11 mL, 1.19 mmol) and sodium (triacetoxy)borohydride (238 mg, 1.12 mmol), to obtain 19.1 mg of the title compound as a white solid (54%).
Reaction SMILES: [CH3:1][N:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:10]3[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=3)[N:8]=[CH:9][C:4]=2[C:3]1=[O:18].[Br:19]Br.O>CC(O)=O>[Br:19][C:16]1[C:5]2[N:6]=[C:7]([C:10]3[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=3)[N:8]=[CH:9][C:4]=2[C:3](=[O:18])[N:2]([CH3:1])[CH:17]=1
Reactant: Cn1cc(-c2ncc3c(=O)n(C)ccc3n2)cn1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(-c2ncc3c(=O)n(C)cc(Br)c3n2)cn1
Yield: 68.5 %

Procedure:
The title compound from step 3 (220 mg, 0.912 mmol) and Br2 (146 mg, 0.912 mmol) in HOAc (15 mL) were stirred at room temperature for 2 h. Water (150 mL) was added, and the resulting solid was collected and triturated with DCM: PE=10:1 (10 mL) to give the title compound (200 mg, yield: 69.0%). 1H NMR (CDCl3, 400 MHz) δ 9.54 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.77 (s, 1H), 4.01 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]([NH:15][NH2:16])=[S:13])[CH3:2]
Reactant: NN
Reactant: CCc1cc(OC)ccc1N=C=S
Solvent: CCO
Solvent: O
Product: CCc1cc(OC)ccc1NC(=S)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 2-ethyl-1-isothiocyanato-4-methoxybenzene (4.9 g, 25 mmol) in ethanol (22 mL), was added slowly, hydrazine-hydrate (1.3 g, 28 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and diluted with ethyl acetate (250 mL) and washed with water (2×50 mL), followed by brine (2×50 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent provided the title compound as a white solid (4.9 g, 86%): mp 113-115° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.89 (s, 1H), 7.20-7.19 (m, 1H), 6.77-6.71 (m, 2H), 4.71 (bs, 2H), 3.74 (s, 3H), 2.52-2.47 (m, 2H), 1.13-1.08 (m, 3H); ESIMS m/z 224 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]([C:21]#[N:22])([CH3:20])[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([CH2:12][C:13]([C:16]#[N:17])([CH3:15])[CH3:14])=[C:6]([CH3:18])[C:5]=1[CH3:19].[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1.CO>[CH3:14][C:13]([CH3:15])([CH2:16][NH2:17])[CH2:12][C:7]1[C:8]([CH3:11])=[C:9]([CH3:10])[C:4]([CH2:3][C:2]([CH3:1])([CH3:20])[CH2:21][NH2:22])=[C:5]([CH3:19])[C:6]=1[CH3:18]
Reactant: Cc1c(C)c(CC(C)(C)C#N)c(C)c(C)c1CC(C)(C)C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1c(C)c(CC(C)(C)CN)c(C)c(C)c1CC(C)(C)CN
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a 1-liter flask, equipped as described in Example 9(a), was put 6.17 g of 1,4-bis(2-methyl-2-cyanopropyl)tetramethylbenzene and 200 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 71.3 ml of a 24.1% solution of diisobutylaluminum hydride in toluene was added in 25 min. The mixture was refluxed for 22 hrs and allowed to stand at room temperature for 3 days. After the mixture had been cooled in an ice-water bath, a solution of 4 ml of water in 20 ml of methanol was added dropwise with stirring. This was followed by the dropwise addition of a solution of 20 ml of water in 40 ml of methanol. The mixture was then stirred at room temperature for several hours and allowed to stand at room temperature for 3 days. The mixture was filtered under nitrogen, the solid was washed thoroughly with toluene on the filter, and the combined filtrate and rinsings were distilled on the water pump. A solid residue resulted which, after further drying in a vacuum oven at room temperature, weighed 5.21 g and melted at 97°-99°. Sublimation of this material at 125°-145°/0.50 mm gave 1,4-bis(2,2-dimethyl-3-aminopropyl)tetramethylbenzene as a colorless crystalline solid melting at 97.5°-98.5°.