Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)(=O)=O.[C-:19]#[N:20].[Na+]>C(#N)C.C(OCC)(=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[CH:7][C:8]=1[C:19]#[N:20])([CH3:16])([CH3:15])[CH3:14]
Reactant: [C-]#N
Reactant: CC(C)(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)c1cccc(Cc2ccccc2C#N)c1
Yield: 151.3 %

Procedure:
To a solution of 3-tert-butylphenyl trifluoromethanesulfonate (6.17 g, 21.9 mmol) in acetonitrile (80 ml) were added sodium cyanide (2.15 g, 43.8 mmol) and copper iodide (0.42 g, 2.19 mmol). To the mixture was added tetrakis(triphenylphosphine)palladium (1.27 g, 1.10 mmol) under nitrogen stream and the mixture was heated under reflux for 5 hrs. The mixture was diluted with ethyl acetate, and insoluble material was filtered off with celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ether=1:0, 20:1) to give 3-tert-butylbenzylbenzonitrile (4.13 g) as a colorless transparent oil. The compound included impurities, but was directly used in the next reaction.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>>[Cl:8][C:7]1[C:2]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: NC1CC1
Product: Clc1nccnc1NC1CC1
Temperature: 130 °C
Yield: 87.9 %

Procedure:
2,3-Dichloropyrazine (1.013 ml, 9.73 mmol) and cyclopropylamine (3 ml, 42.8 mmol) were combined in a microwave vial and heated at 130° C. for 30 minutes. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 3-chloro-N-cyclopropylpyrazin-2-amine (1.45 g, 8.55 mmol, 88% yield) as an oil.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:11]([CH3:13])[CH:12]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O1CCCC1>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[B:20]([OH:23])[OH:21]
Reactant: COB(OC)OC
Reactant: Cc1cc(C)cc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(O)O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
tert-Butyllithium (1.7 M solution in hexanes, 36.2 ml, 62.6 mmol) is added dropwise to a solution of 3,5-dimethylbiphenyl (7.27 g; 28 mmol) in dry tetrahydrofuran (150 ml) at −78° C. and stirred under an atmosphere of nitrogen for 30 minutes. Trimethyl borate (9.54 ml; 84 mmol) is added and the resulting mixture is stirred at −78° C. for 30 min and then allowed to warm to room temperature. The reaction mixture is acidified with aqueous hydrochloric acid and extracted with ether (2×150 ml). The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give a yellow solid. The crude product is triturated with iso-hexane and filtered to give 3,5-dimethylbiphenylboronic acid (5.89 g) as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[CH3:12][C:9]1[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]2=[C:2]([O:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=3)[N:3]=[N:4][CH:5]=[C:6]2[C:10]=1[CH3:11]
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccc(C(F)(F)F)cc3)c21
Yield: 52.5 %

Procedure:
The title compound was prepared as pale yellow crystals in 52.5% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 4-trifluoromethylbenzyl alcohol.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.C(O)CCC.O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:19]2[N:18]=[N:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccc(Cl)nn1
Solvent: ClCCl
Solvent: CCCCO
Solvent: O
Product: Clc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A mixture of 4-amino-1-benzylpiperidine (4 g, 21 mmol) and 3,6-dichloro-pyridazine (1.56 g, 10.5 mmol) was stirred for 1 h at 120° C., before n-butanol (10 ml) was added and the reaction mixture stirred for a further 1 h at 120° C. After addition of water and dichloromethane, the organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was crystallized from acetonitrile and the resulting solid was filtered off and dried to yield D1 (1.3 g, 41%) as a solid. C16H19ClN4 requires 302. Found 303 (MH+); mp: 208.2-209.3° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C:53](=[O:64])[CH2:54][CH:55]([NH2:63])[C:56]1[CH:57]=[N:58][CH:59]=[C:60]([Br:62])[CH:61]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[Br:62][C:60]1[CH:61]=[C:56]([CH:55]([NH:63][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[CH2:19]2)=[O:25])[CH2:54][C:53]([O:52][CH3:51])=[O:64])[CH:57]=[N:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: COC(=O)CC(N)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 103.9 %

Procedure:
3.324 g (9.02 mmol) (3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (Bioorg. Med. Chem. 13 (2005) 4343-4352, Compound 10) were suspended in 52 ml N,N-dimethylformamide and cooled to 0° C. 3.694 g (9.71 mmol) HATU, a solution of 1.798 g (6.94 mmol) 3-amino-3-(5-bromo-pyridin-3-yl)-propionic acid methyl ester in 78 ml N,N-dimethylformamide and 3.56 ml (20.82 mmol) N-ethyl-diisopropylamine were added. The mixture was stirred at 0° C. for 5 minutes and at room temperature for 24 hours. 160 ml water were added and the mixture extracted with 280 ml dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuum. Chromatography over 55 g basic silica gel (dichloromethane/ethanol 100/0-97/3-94/6) gave 4395 mg (104%) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]Br)=[CH:4][CH:3]=1.[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CN
Reactant: Oc1ccc(CCBr)cc1
Solvent: CO
Product: CNCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 250 mg of 4-hydroxyphenethyl bromide in a round-bottomed flask, a 10 M excess of MeNH2 (6.2 mL of 2M in MeOH) was added and the solution was stirred at r.t. overnight. After filtration, the solvent was removed to give a brown oil in 80% yield. TLC (EtAc:MeOH, 9:1 v/v): RF=0.33. 1H NMR, δ: 9.42 (s, 1H), 7.10 (d, 2H), 6.75 (d, 2H), 3.60 (s, 3H), 2.84 (t, 2H), 2.60 (t, 2H), 1.90 (s, 1H). 13C NMR, δ: 167.5, 131.2, 128.3, 112.4, 41.5, 36.4, 35.0. Anal. calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26%. Found; C, 71.50; H, 8.80; N, 9.20%.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]#[C:14][Si](C)(C)C.CO.[F-].[Cs+]>O1CCCC1>[C:13]([C:3]1[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[F:12])#[CH:14]
Reactant: COc1cc(OC)c(F)c(C#C[Si](C)(C)C)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1c(F)c(OC)cc(OC)c1F
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a stirred solution of [(2,6-difluoro-3,5-dimethoxyphenyl)ethynyl](trimethyl)-silane (630 mg, 2.33 mmol) in tetrahydrofuran (2 mL)/methanol (2 mL), cesium fluoride (354 mg, 2.33 mmol) was added at room temperature. After 1 hour, the reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, concentrated to give the desired product (440 mg, 95%). 1H NMR (300 MHz, CDCl3): δ 6.62 (t, J=7.8 Hz, 1H), 3.89 (s, 7H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([Cl:13])[CH2:7][NH:8]C(C)(C)C)=[CH:4][C:3]=1[Cl:17].CO.Cl.[CH:21]([OH:24])(C)C>CCO>[ClH:13].[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([O:24][CH3:21])[CH2:7][NH2:8])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(C)O
Reactant: CC(C)(C)NCC(Cl)c1cc(Cl)c(N)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COC(CN)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under N2 atmosphere, 11 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl chloride is added to 75 ml of methanol at 0° C. After 20 minutes, the cooling bath is removed and the reaction mixture is stirred at ambient temperature. After the reaction is completed, the mixture is evaporated to dryness in vacuo. The residue is stirred in 75 ml of H2O and the mixture is made alkaline with 6 N NaOH solution and extracted with CH2Cl2 (3×50 ml). The organic phases are dried over MgSO4 and evaporated to dryness to afford an orange oil. This oil is dissolved in 150 ml of absolute EtOH and acidified with HCl/isopropyl alcohol solution to pH 2. The solution is evaporated to dryness and the residue is stirred in 75 ml of ethyl acetate. After cooling, this affords a pale yellow solid which is collected to give 6.97 g of the title compound, m.p. 195°-198° C. dec.
Reaction SMILES: Cl[CH2:2][C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].[SH:14][CH2:15][CH2:16]O.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(N(CC)CC)C>[O:4]1[C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][S:14][CH2:15][CH2:16]1
Reactant: OCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29 %

Procedure:
A solution of ethyl 2-chloroacetyl-2-methoxyiminoacetate (65 g.) in dry chloroform (130 ml.) was added to a stirred mixture of 2-mercaptoethanol (25 g.), triethylamine (35 g.) and dry chloroform (70 ml.) at 20° C. over 30 minutes, and stirred at the same temperature for 2.5 hours. After the solution was adjusted to pH 1.0 with 10% hydrochloric acid under ice cooling, the chloroform layer was separated, washed with water twice and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C. to give yellow oil. The oil was dissolved in toluene (600 ml.), and then p-toluenesulfonic acid (5.5 g.) was added to the toluene solution. The solution was heated under reflux for 2 hours while removing the produced water. The resultant solution was allowed to cool at room temperature and filtered. The filtrate was washed with water (100 ml.) three times, a saturated aqueous solution of sodium bicarbonate (100 ml.) twice and water (100 ml.) twice in turn, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel "Kieselgel 60" [Trademark: manufactured by E. Merck] (1 kg.) and eluted with benzene. After the eluate was concentrated under reduced pressure, the residue was washed with diisopropyl ether and dried to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (syn isomer, 21 g.), pale yellow crystals, mp. 64° to 66° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:15][CH2:16][NH2:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[C:13]C.C(N(C(C)C)C(C)C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([OH:39])([CH3:38])[C:35](O)=[O:36])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([OH:39])([CH3:38])[C:35]([NH:17][CH2:16][CH2:15][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:36])=[CH:32][CH:33]=1
Reactant: CC(O)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC#CCOc1ccc(CCN)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CCNC(=O)C(C)(O)c2ccc(Cl)cc2)cc1OC

Procedure:
To a stirred solution of 906 mg of 2-(3-methoxy-4-but-2-ynyloxy-phenyl)-ethylamine hydrochloride and 2.75 ml N-ethyldiisopropylamine are subsequently added 752 mg 2-(4-chlorophenyl)-2-hydroxy propionic acid and 1.875 g benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate. The resulting clear solution is stirred over night, extracted with ethyl acetate. The extracts are washed several times with water, dried over sodium sulfate, filtered and evaporated. The resulting oily residue is purified on silicagel (hexanc ethyl acetate) to obtain the 2-(4-chlorophenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]propionamide.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1>>[N:17]1([CH:13]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1ccccc1
Reactant: CC(C)(C)CC=O
Product: CC(C)(C)CC(NC(=O)c1ccccc1)n1nnc2ccccc21

Procedure:
A suspension of benzamide, 3,3-dimethyl-butyraldehyde, and benzotriazole were processed as described in Example 18B to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH3:1].[N:9]1[NH:10][N:11]=[N:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N
Product: Nc1ccc(-c2nn[nH]n2)cn1
Yield: 126.4 %

Procedure:
2-Amino-5-cyanopyridine (1.0 g), sodium azide (1.1 g), ammonium chloride (890 mg), and DMF (15 mL) were stirred for 2 hours and 15 minutes at 100° C. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol:concentrated aqueous ammonia=6:2:1) to obtain the titled compound (860 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>C(COC)OC.C(OC(=O)C)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:34]([C:33]3[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:15]2(=[O:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=S(=O)(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=S1(=O)c2ccccc2C(c2ccc(Cl)cc2)N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of 19.16 g (58.1 mmol) of N-(1-benzylpiperidin-4-yl)-benzene sulfonamide in 300 mL of dimethoxyethane at 0° C. was added 46.4 mL (116.1 mmol) of a n-butyllithium (2.5 M) slowly via addition funnel. The mixture was stirred using an overhead stirrer for 45 minutes at 0° C., then 9.61 g (63.9 mmol) of p-chlorobenzaldehyde was added in one portion. The mixture was allowed to warm to room temperature, diluted with 1 liter of ethylacetate and washed 2×500 mL of water followed by 500 mL of brine. The organic phase was separated, dried (MgSO4), and concentrated in vacuo. The residue was flash chromatographed over 300 g of silica gel (eluted with ethylacetate:heptane-2:1) to afford 17.3 g of product as an orange paste.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)#[N:4].[H][H].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:3]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[O:8][CH2:9][CH2:10][N:11]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)#[N:4]
Reactant: N#Cc1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Reactant: BrCc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N(CCOc2cccc(C#N)c2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28 mg (0.7 mmol) of sodium hydride (oily, 60%) was stirred in dimethylformamide under cooling with ice. A solution of 200 mg (0.69 mmol) of N-[2-(3-cyanophenoxy)ethyl]-4-cyanobenzamide in a small amount of dimethylformamide was added thereto. After the completion of the generation of hydrogen, 257 mg (1.5 mmol) of benzyl bromide was added to the mixture, and they were stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. 1N aqueous hydrogen chloride solution was added to the residue. The same procedure for the isolation as that of step 1 in Example 1 was repeated with ethyl acetate as the extractant to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:31]1([CH2:37][S:38][CH:39]([C:43](O)=[O:44])[C:40](O)=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:44][C:43]1[CH:14]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])[O:15][C:40](=[O:41])[C:39]=1[S:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: COc1ccc(C(C)=O)c(OC)c1OC
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c(OC)c1OC

Procedure:
The title compound was prepared by Method A using 2',3', 4'-trimethoxyacetophenone (1.5 g, 7.13 mmol), lithium bis(trimethylsilyl)amide (1.43 g, 8.56 mmol), chlorotrimethylsilane (1.8 mL, 10.67 mmol) and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(O)(=O)C.[CH3:22][NH2:23]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([NH:23][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CC1CCN(Cc2ccccc2)CC1=O
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC1CN(Cc2ccccc2)CCC1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a stirred solution of 1-benzyl-4-methyl-piperidin-3-one (2.3 grams, 11.5 mmol), prepared by the methods of Iorio, M. A. and Damia, G., Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the American Chemical Society, 107, 1768 (1985), (modified using 5% methanol as a co-solvent), both references are incorporated by reference in their entirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran was added 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirred in a sealed tube for 16 hours at room temperature. Triacetoxy sodium borohydride (4.9 grams, 23 mmol) was added and the new mixture stirred at room temperature in a sealed tube for 24 h, at which time, the reaction was quenched upon addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3×80 mL with ether, the combined ether layers dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 1.7 grams (69%) of the title compound as a white solid. LRMS: 219.1 (M+1).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([N-:40][S:41](N1C=CC(=[N+](C)C)C=C1)(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].O>ClCCl>[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH:27]3[CH2:32][CH2:31][N:30]([S:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])(=[O:42])=[O:43])[CH2:29][CH2:28]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)cs2)cc1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCC(c2csc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
3-Phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (0.075 g, 0.162 mmol) and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (0.0490 g, 0.162 mmol) were dissolved in dichloromethane (2 mL) and stirred at ambient temperature for 18 hours. Water was added and the reaction mixture was extracted with dichloromethane. The organic layer was dried, filtered and concentrated. The crude material was purified by silica gel chromatography (25-50% ethyl acetate in hexanes) provided tert-butyl 4(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-ylsulfonylcarbamate (0.0785 g, 75.4% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[N:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])=[C:17]([CH3:31])[CH:16]=3)=[O:14])[CH2:11][C:10]3=[CH:32][CH:33]=[CH:34][N:9]3[CH2:8][C:7]=2[CH:35]=1.[O:38]=[C:39](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C.[NH:53]1[CH2:58][CH2:57][C:56](=[O:59])[CH2:55][CH2:54]1>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[N:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])=[C:17]([CH3:31])[CH:16]=3)=[O:14])[CH2:11][C:10]3=[CH:32][CH:33]=[C:34]([C:39]([N:53]4[CH2:58][CH2:57][C:56](=[O:59])[CH2:55][CH2:54]4)=[O:38])[N:9]3[CH2:8][C:7]=2[CH:35]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OC)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1cccn1C2
Reactant: O=C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1ccc(C(=O)N3CCC(=O)CC3)n1C2
Reaction time: 8 h

Procedure:
A solution of the 7,8-dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone of Example 12, Step D (0.31 mmol), diphosgene (1.1 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (5 mL) was stirred at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (5 mL), and then triethylamine (1.5 equiv.) and 4-piperidone (1.5 equiv.) were added. The reaction mixture was stirred overnight, washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was first chromatographed on silica gel eluting with 2% methanol in dichloromethane and then chromatographed again with 2% methanol in ethyl acetate to provide the title compound as a yellow solid, m.p. 132–134° C.