Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:5][C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: Fc1ccc2scc(Br)c2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1sc2ccc(F)cc2c1Br
Yield: 26 %

Procedure:
A solution of 5.12 ml of fuming nitric acid and 4.5 ml of acetic acid was added dropwise, with stirring, to a cooled (5°-10° C.) mixture of 3-bromo-5-fluorobenzo[b]thiophene (5.35 g, 23.15 mmol) and 28.5 ml of acetic anhydride. The reaction mixture was stirred for 2 hours and poured onto ice water (350 ml) and extracted with CH2Cl2 (4×50 ml). The organic phases were combined, washed with water and dried over MgSO4. The solvent was evaporated and the residue was recrystallized from 90% ethanol to yield 1.7 g (26%) of 3-bromo-5-fluoro-2-nitrobenzo[b]thiophene. M.p. 129°-130° C. 1H-NMR(CDCl3): δ7.40 (ddd, 1H), 7.68 (ddd, 1H), 7.78 (dd, 1H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])[C@:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[C@@H:6]1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].[OH-].[K+]>C1COCC1.CO>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([C@H:8]2[CH2:9][N:5]([CH2:4][C:3]([OH:33])=[O:2])[C@@H:6]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@:7]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CN1C[C@H](c2cccc(Cl)c2F)[C@@](C#N)(c2ccc(Cl)cc2F)[C@@H]1CC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N(CC(=O)O)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 8, rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid methyl ester (115 mg, 0.23 mmol) in THF/MeOH (1.8/0.6 mL) was treated with 2N KOH (0.6 mL) at rt overnight to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (108.5 mg, 97.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[C:8]([OH:16])([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.[Br:24]Br.[OH-].[Na+]>O1CCOCC1>[Br:24][C:11]#[C:10][CH2:9][C:8]([CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=1)[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)([OH:16])[C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: BrBr
Reactant: C#CCC(O)(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)C(O)(CC#CBr)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
14 g (0.04 mol) of 4-((4-chlorophenoxy)-(1H-1,2,4-triazol-1-yl)-methyl)-5,5-dimethyl-hex-1-yn-4-ol (obtained as described in Example 1), dissolved in 75 ml of dioxane, were added dropwise to a solution of 7.7 g (0.048 mol) of bromine in 40 ml of 10% strength sodium hydroxide solution at 0° C. After five hours, the reaction mixture was stirred into ice water. The precipitated product was filtered off under suction, washed with water and dried. 14.2 g (86.1% of theory) of 1-bromo-4-((4-chlorophenoxy)-(1H-1,2,4-triazol-1-yl)-methyl)-5,5-dimethyl-hex-1-yn-4-ol of melting point 156° to 160° C. were obtained.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[F:10][C:9]1[C:2]([N:14]2[CH2:15][CH2:16][CH:12]([F:11])[CH2:13]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(F)c1F
Reactant: F[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1cccc(F)c1N1CCC(F)C1
Yield: 26.9 %

Procedure:
2,3-Difluorobenzaldehyde (1.0 g, 7.037 mmol) was taken up in dry dioxane (20 ml) in a tube and (S)-3-fluoropyrrolidine (627.1 mg, 7.037 mmol) and K2CO3 (676.4 mg, 10.56 mmol) were added and the mixture refluxed overnight. The reaction mixture was diluted with ethyl acetate, filtered, concentrated to dryness and purified on an ISCO system eluting with Hexane/ethyl acetate (10-100) to give 400 mg of 3-fluoro-2-(3-fluoropyrrolidin-1-yl) benzaldehyde.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][SH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CO.C(#N)C.C(OCC)(=O)C>[Cl:15][CH2:14][CH2:13][CH2:12][S:10][CH2:9][C:5]1[O:4][CH:8]=[CH:7][CH:6]=1
Reactant: ClCCCBr
Reactant: SCc1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: ClCCCSCc1ccco1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3.3 ml of a 30% sodium methylate solution in methanol is added in drops to 1.77 ml of furan-2-yl-methanethiol in 18 ml of anhydrous acetonitrile at 0° C. After 5 minutes, the drop-by-drop addition of 2.6 ml of 1-bromo-3-chloropropane is carried out. Then, the reaction solution is allowed to stir for 5 hours at room temperature. For working-up, the batch is diluted with ethyl acetate, washed with water and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 1.1 g of 2-(3-chloropropylthiomethyl)-furan as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH:12][C:25]([C:15]34[CH2:24][CH:19]5[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]5)[CH2:22]3)[CH2:16]4)=[O:26])[S:11][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc2nc(N)sc2c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2nc(NC(=O)C34CC5CC(CC(C5)C3)C4)sc2c1

Procedure:
Commercially available 6-methanesulfonyl-benzothiazol-2-ylamine, triethylamine, and adamantane-1-carbonyl chloride were processed as described for Example 17A to afford the title compound MS (ESI+) m/z 391 (M+H)+;
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][C:33]=1[C:41]([OH:43])=O.[NH2:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][N:51]2[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:47][CH:46]=1>CN(C=O)C.ClCCl>[Cl:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][C:33]=1[C:41]([NH:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][N:51]2[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:47][CH:46]=1)=[O:43]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Reactant: O=C(O)c1[nH]c2ccccc2c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(NC(=O)c3[nH]c4ccccc4c3Cl)cc21
Yield: 55 %

Procedure:
DIPEA (2.5 equiv.), EDCI (2.73 mmol, 1.2 equiv.) and HOBt (2.73 mmol, 1.2 equiv.) were added at 0° C. to a solution of 3-chloro-1H-indole-2-carboxylic acid (2.27 mmol, 1.0 equiv.) in DMF (6 ml), and the mixture was stirred for 15 min. tert-Butyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate A—for synthesis see above) (2.27 mmol, 1.0 equiv.) was dissolved in DMF (1 ml) and added, with stirring, and the reaction mixture was then stirred for 12 h at 25° C. The mixture was diluted with dichloromethane (50 ml), washed with sat. ammonium chloride solution (20 ml), water (20 ml) and sat. NaCl solution (20 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (10-15% ethyl acetate in hexane). Yield: 55%
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:4].[CH:31]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]([CH3:31])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[C:6]([OH:8])=[O:7])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Yield: 112.9 %

Procedure:
To a solution of 2-methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (4.10 g, 10.0 mmol) obtained in Example 1 in tetrahydrofuran (50 ml) was dropwise added lithium diisopropylamide (1.5 M cyclohexane solution, 15.0 ml, 22.5 mmol) at −78° C. under argon atmosphere. The mixture was stirred at said temperature and methyl iodide (2.5 ml, 40 mmol) was dropwise added. The mixture was stirred at said temperature for 2 hr and 10% aqeuous ammonium chloride (20 ml) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The obtained organic layers were combined, washed with saturated brine (10 ml), dried over magnesium sulfate and concentrated under reduced pressure to give the crude title compound (4.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.C(OC(OCC)[N:28]([CH3:30])C)C.[NH2:34]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:34][NH:28][CH:30]=[C:10]2[N:9]=1
Reactant: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: NN
Reactant: CCOC(OCC)N(C)C
Product: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NC1=CNNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-cyano-8-methoxy-pyrazolo[3,4-b][1,4]benzodiazepine (XXIIb) was prepared by reacting 0.00096 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IIb) with 1,1-diethoxy-N,N-dimethyl-methanamine and then hydrazine in a manner analogous to the example above. Recrystallization from ethyl acetate provided 5-(2-chlorophenyl)-1,2-dihydro-7-cyano-8-methoxy-pyrazolo[3,4-b][1,4]benzodiazepine (XXIIb) as a light red solid, mp 288-290° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][S:10][CH2:9][CH:8]1[C:13]([O:15]CC)=[O:14])=[O:6])[CH:2]=[CH2:3].CO.O1CCCC1.Cl>[OH-].[Na+]>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][S:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCSCC1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOC(=O)N1CCSCC1C(=O)O
Yield: 101.9 %

Procedure:
A solution of ethyl 4-(allyloxycarbonyl)thiomorpholine-3-carboxylate (15.4 g) in a mixture of 4N aqueous sodium hydroxide (30 ml), methanol (30 ml) and tetrahydrofuran (75 ml) was refluxed for 90 minutes. The organic solvents were evaporated to give an aqueous solution. The aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid, extracted with ethyl acetate (200 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give 4-(allyloxycarbonyl)thiomorpholine-3-carboxylic acid (14.0 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:18]([O:22][C:23]([C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:18]([O:22][C:23]([C@@H:25]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:27])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1cc(N)cc(-c2ccncc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)[C@H](Cc2ccccc2)C(=O)OC(C)(C)C)cc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of methyl 3-amino-5-(pyridin-4-yl)benzoate 45.1.C (4.70 g, 20.6 mmol) in DMF (50 mL) was added (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (6.56 g, 24.7 mmol, available from Aldrich), diisopropylethylamine (5.40 mL, 30.9 mmol) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate (9.36 g, 24.7 mmol). The resulting mixture is stirred overnight at room temperature. The mixture was then partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-100% EtOAc/hexane) to afford (S)-methyl 3-(2-(tert-butoxycarbonyl)-3-phenylpropanamido)-5-(pyridin-4-yl)benzoate 45.1.D (3.00 g, 31% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.C1(OC)C=CC=CC=1.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([OH:33])=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1=C(CSc2nnnn2-c2ccccc2)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3ccccc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylate (1.0 g, purity 80%, 1.42 mmol) in dichloromethane (50 ml) and anisole (0.93 ml) was cooled to 0° C. Titanium tetrachloride (0.62 ml, 5.6 mmol) was added in 1 min. After stirring for 2.5 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was dried over magnesium sulphate and evaporated to give 0.60 g of (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylic acid (purity 60%, yield 49.9%).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:29])[C:20]2=[O:39])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2]>C(O)(C(F)(F)F)=O.ClCCl>[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)=[O:29])[C:20]2=[O:39])=[O:2]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCOP(=O)(O)O)ccc21
Yield: 106.9 %

Procedure:
A solution of 77.8 mg of di(tert-butyl) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-6-quinolinyl)propyl phosphate from Example No. 32 in 1 mL of 1:1 TFA-dichloromethane is stirred for 1 h, then added slowly to 20 mL of rapidly stirred 1:1 ether-hexane. The precipitated solid is filtered, washed with hexane, and dried under vacuum to afford 67 mg of the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CC(O)=O.[C:13]([O:17][C:18](=[O:28])[NH:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOCC>[C:13]([O:17][C:18](=[O:28])[NH:19][C@H:20]1[CH2:21][CH2:22][C@H:23]([CH2:26][NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:24][CH2:25]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Reactant: Nc1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-phenylamine (1 g, 4.57 mmol) in DCM (25 ml) were successively added AcOH (0.523 ml, 9.13 mmol), (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.14 g, 5.02 mmol) and NaBH(OAc)3 (1.94 g, 9.13 mmol) at RT. The reaction mixture was stirred at RT for 1 h then diluted with Et2O and washed successively with a 2M aqueous HCl solution and a 2M aqueous Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/AcOEt 95:5→1:1) to yield the title compound (1.56 g, 3.62 mmol, 79%) as a colorless solid. TLC: RF=0.72 (heptane/AcOEt 1:1); HPLC: AtRet=2.64 min; LC-MS: m/z 431.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.87-1.03 (m, 2H), 1.03-1.17 (m, 2H), 1.32-1.48 (m, 1H), 1.37 (s, 9H), 1.70-1.86 (m, 4H), 2.76-2.86 (m, 2H), 3.08-3.25 (m, 1H), 5.77-5.89 (m, 1H), 6.34-6.46 (m, 2H), 6.59-6.71 (m, 1H), 7.24-7.35 (m, 2H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(O)(=O)C.[CH3:35][NH2:36].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:36][CH3:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNC)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (70 mg, 0.16 mmol; Example 91, Step C) and acetic acid (271 μL, 4.73 mmol) in ClCH2CH2Cl (2.6 mL) was added 2 M methylamine in THF (788 μL, 1.58 mmol) and sodium triacetoxyborohydride (100 mg, 0.47 mmol) at rt. After being stirred at rt for 3 h, the reaction was quenched (sat aq. NaHCO3), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the crude title compound as a pale yellow film. The product was used in the next step without further purification.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[C:36]4[N:35]=[CH:34][N:33]=[C:21]([NH:22]C(=O)COC5C=CC=CC=5)[C:20]=4[N:19]=[CH:18]3)[CH2:14][C@@H:13]2[OH:37])=O)=CC=1)([O-])=O.ClCCl.C(#N)C.C(N(P(N(C(C)C)C(C)C)OCCC#N)C(C)C)(C)C.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C>ClCCl>[C@@H:15]1([N:17]2[C:36]3[N:35]=[CH:34][N:33]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:12]([CH2:11][OH:10])[C@@H:13]([OH:37])[CH2:14]1
Reactant: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)O1
Agent: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reaction time: 2 h

Procedure:
5′-O-p-Nitrobenzoyl-6-N-phenoxyacetyldeoxyadenosine (1 eq) is dried in a dichloromethane/acetonitrile mixture and reacted with 1.2 eq of bisdiisopropylaminocyanoethoxyphosphine and 0.5 eq of diisopropylammonium tetrazolide in anhydrous dichloromethane. After reacting for 2 hours, the reaction mixture is diluted and washed successively with 0.5 M sodium bicarbonate and saturated sodium chloride. The organic phase is evaporated to dryness. After precipitation in hexane, the product is dried under vacuum and stored under argon. This amidite is soluble in acetonitrile, a solvent in which oligonucleotide syntheses are conventionally carried out.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:31][CH2:32]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1ccccc1Cl
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccccc1Cl

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(2-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 439.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].Cl.[N:15]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>O>[Cl:13][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][CH:11]=1)[NH:1][N:15]=[C:4]2[CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1C=CC(=O)O
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1n[nH]c2ccc(Cl)cc12
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a suspension of 2 -amino-5-chlorocinnamic acid (3.0 g) in water (35 ml), there is added conc. hydrochloric acid (11 ml). To the resulting solution cooled with ice, a solution of sodium nitrite (1.0 g) in water (2 ml) is dropwise added while stirring, and stirring is continued for 30 minutes. Anhydrous sodium sulfite (5.0 g) is portionwise added thereto. After stirring at room temperature for 1 hour, the resulting mixture is admixed with water (100 ml) and heated on an oil bath for 0.5 to 1 hour while refluxing. The reaction mixture is filtered. The collected material is washed with hot water. The washing water is combined with the filtrate and concentrated. The residue is crystallized from hot water to give 5-chloro-1H-indazole-3-acetic acid (0.7 g) as white needles melting at 205° C (decomp.)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:39]3[CH:38]=[CH:37][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:41][CH:40]=3)(=[O:44])=[O:43])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: CS(=O)(=O)c1ccc(S(N)(=O)=O)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(S(C)(=O)=O)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-(methylsulfonyl)benzenesulfonamide: 1H-NMR (CDCl3) δ 8.16-8.08 (4H, m), 7.47-7.20 (9H, m), 6.04 (1H, br.s), 3.46-3.41 (2H, m), 3.10 (3H, s), 2.87-2.82 (2H, m), 2.33 (3H, s), 2.22 (3H, s).