Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:25]1([S:31]([NH:34][CH2:35][C:36](O)=[O:37])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:36](=[O:37])[CH2:35][NH:34][S:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:33])=[O:32])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)CNS(=O)(=O)c1ccccc1
Product: Cl
Product: O=C(CNS(=O)(=O)c1ccccc1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and N-(phenylsulfonyl)glycine, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([O:9]CC)=O)([O-:3])=[O:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[NH4+:30]>C(O)C>[C:12]1([CH:5]2[CH:4]([N+:1]([O-:3])=[O:2])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:30][C:7](=[O:9])[CH2:6]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CC(c2ccccc2)C([N+](=O)[O-])C(c2ccccc2)N1
Temperature: 70 °C
Yield: 86.1 %

Procedure:
Under a nitrogen atmosphere in a round-bottom flask equipped with a reflux condenser were placed 21.1 g (89 mmol) of ethyl 4-nitro-3-phenylbutyrate (McMurray, J. E. et. al., Syn.Comm., 8, 53(1978)) and 90 mL of ethanol. To the system was added 9.04 mL (89 mmol) of benzaldehyde and 13.7 g (180 mmol) of ammonium acetate, and the reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled, a small volume of ethanol was added and the suspension was filtered. The collected solid was rinsed with a small volume of ethanol followed by ether to afford 22.7 g of 4,6-diphenyl-5-nitro-2-oxopiperidine.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCc2ccccc2O1
Product: O=C(Cl)C1CCc2ccccc2O1
Yield: 97.6 %

Procedure:
89.0 g (0.5 mol) chroman-2-carboxylic acid and 71.4 g (0.6 mol) thionyl chloride were heated to 80 for 4-5 hours (end of gas evolution). Destillation (77°-80°/0.1 torr) yielded 96.0 g (98%) chroman-2-carboxylic acid chloride
Reaction SMILES: C(C1N=C(C2(C)COC2)NC=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12])#N.I[C:25]1[NH:29][C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[C:36]([F:39])([F:38])[F:37].IC1NC(C2(C)COC2)=NC=1C#N>>[CH3:18][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:25]1[NH:29][C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[C:36]([F:39])([F:38])[F:37]
Reactant: FC(F)(F)c1nc(C2CCOCC2)[nH]c1I
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C#N)c1
Agent: CC1(c2nc(C#N)c(I)[nH]2)COC1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCOCC3)nc2C(F)(F)F)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 202.4, except 5-iodo-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole (compound 287.1) was used instead of 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>O1CCCC1>[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][C:13]1([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:15][CH2:16][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12]1
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2F)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
In a flask, lithium bis(trimethylsilyl)amide (LHMDS) (9.24 mL of 1.0 M solution in THF, 9.24 mmol) was added to tetrahydrofuran (20 mL). The reaction mixture was cooled to −78° C., and then a solution of 1-tert-butyl 3-methyl piperidine-1,3-dicarboxylate (1.5 g, 6.17 mmol) in tetrahydrofuran (5 mL) was added drop-wise to the reaction mixture at −78° C. The reaction was stirred at −78° C. for 30 minutes. Afterwards, 2-fluorobenzylbromide (1.12 mL, 9.24 mmol) was added, and the reaction was stirred for an additional 3 hours at 0° C. Upon reaction completion, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried with sodium sulfate, and concentrated to yield crude product. The crude product was purified using flash chromatography (0-60% ethyl acetate in hexane) to give the titled compound (1.41 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[S:31]([NH2:34])(=[O:33])=[O:32])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:12][C:11]([C:35]([F:38])([F:37])[F:36])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>CO.[Pd]>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[S:31]([NH2:34])(=[O:32])=[O:33])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:12][C:11]([C:35]([F:36])([F:37])[F:38])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(-n2nc(C(F)(F)F)cc2C(=O)N2CCc3cc(-c4ccccc4S(N)(=O)=O)ccc32)c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCc1cccc(-n2nc(C(F)(F)F)cc2C(=O)N2CCc3cc(-c4ccccc4S(N)(=O)=O)ccc32)c1
Yield: 15 %

Procedure:
1-[[1-[3-Cyanophenyl]-3(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]-5-[2-(aminosulfonyl)phenyl]-2,3-dihydro-1H-indole (0.2 g, 0.34 mmol), prepared according to Example 4, was reduced under an atmosphere of hydrogen gas (55 psi) in methanol (5 mL) and trifluoroacetic acid in the presence of 10% palladium on carbon catalyst for 18 h at ambient temperature. The reaction mixture was filtered through a pad of Celite® and washed with methanol (3×). This product was treated with trifluoroacetic acid (1 mL) at 80° C. over 1 h, then purified by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% of trifluoroacetic acid on a reverse phase C18 (60 angstrom) column to give the title product (28 mg, 15%). LRMS (ES+): 598.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>ClCCl>[CH3:35][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (550 mg, 2.30 mM) and triethylamine (0.4 mL) in dry dichloromethane (DCM, 10 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, o-tolyl isocyanate (428 mg/ml, 3.45 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8a as colorless oil. Yield: 700 mg, 81.78%.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][NH:22][C:23]([NH:25][CH3:26])=[S:24]>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:24][C:23](=[N:22][CH2:21][C:17]3[O:16][CH:20]=[CH:19][CH:18]=3)[N:25]2[CH3:26])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CNC(=S)NCc1ccco1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: CN1C(=NCc2ccco2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.55 g of 1-(2-furylmethyl)-3-methylthiourea were reacted according to the prescription of Example 23 and the end product was precipitated by adding 100 ml of diethyl ether. Colorless crystalline solid body: melting point: 168° C (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH3:16])[C:3]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CO>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH3:16])[C:3]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1
Reactant: COCn1c(-c2nccs2)c(Cl)c2cccc([N+](=O)[O-])c21
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCn1c(-c2nccs2)c(Cl)c2cccc(N)c21
Yield: 91.8 %

Procedure:
A mixture of 3-chloro-1-(methoxymethyl)-7-nitro-2-(1,3-thiazol-2-yl)-1H-indole (0.30 g), iron(III) chloride hexahydrate (15 mg), activated carbon (0.15 g), tetrahydrofuran (6 mL) and methanol (6 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (0.27 g) while heating under reflux. The reaction mixture was heated under reflux for 2 hr, filtrated, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (0.25 g, yield 91%) as a yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.N1CCCCC1>[CH:12](=[C:2]1[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reaction time: 24 h
Yield: 72.1 %

Procedure:
To a solution of 1,3-indandione (43.8 g) and piperidine (44 mg) in dry benzene (500 ml) was added benzaldhyde (31.8 g). The mixture was heated to reflux and the water generated was removed by Dean-Stark trap. After 24 hours, the mixture was evaporated to dryness. The residue was recrystallized from ethanol (200 ml) to give 2-benzylidene-1,3-indandione as a yellow solid (50.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(NC(C)C)(C)C.CCOC(C)=O>C1COCC1.[Cu]I>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(OCC)cc1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.60 g (11.0 mmol) 4-ethoxyphenylacetylene in 40 mL THF are added 3.10 g (11.0 mmol) 1-bromo-4-iodo-benzene under argon, followed by 0.18 g (0.22 mmol) Pd(dppf)Cl2CH2Cl2 as catalyst, 0.04 g (0.22 mmol) copper(I)iodide and 3.10 mL (21.9 mmol) diisopropylamine as base. The mixture is stirred at rt for 3 h. After that time, EtOAc is added and the organic layer is washed with ammonia (5%, 2×) and water (1×). The organic layer is separated, dried over magnesium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silicia gel; PE:EtOAc 9:1) to yield the desired product.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]([NH2:8])=[O:7].C([O:11][C:12](=O)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)C.FC(F)(F)C(O)=O>O.C(OCC)(=O)C>[CH3:39][N:37]([CH3:38])[C:36](=[O:40])[CH:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:12](=[O:11])[NH:5][C:6]([NH2:8])=[O:7])=[CH:20][CH:19]=2)=[CH:23][CH:24]=1)[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C(Cc3cccnc3)C(=O)N(C)C)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C(Cc1cccnc1)c1ccc(Oc2ccc(CCC(=O)NC(N)=O)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of sodium ethoxide (21% w/w, 8.10 mL, 21.8 mmol) and ethyl acetate (0.6 mL) was refluxed for 30 min. Urea (1.30 g, 21.8 mmol) was added and heated till it dissolved completely. 3-{4-[4-(1-Dimethylcarbamoyl-2-pyridin-3-ylethyl)-phenoxy]-phenyl}-propionic acid ethyl ester, 80 (1.74 g, 3.80 mmol) was added and heated for 5 min at 80° C. Reaction mixture was cooled to room temperature, neutralized by trifluoroacetic acid and water (50 mL) was added and extracted with ethyl acetate (3×50 mL). Organic layer was washed with water (2×20 mL) and brine (50 mL). The compound was purified by silica gel chromatography and product was eluted with chloroform-methanol (97:3). Yield: 0.30 g (16.7%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH:22]1([CH2:27][CH2:28]Br)[CH2:26][CH2:25][CH:24]=[CH:23]1>>[CH:22]1([CH2:27][CH2:28][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:26][CH2:25][CH:24]=[CH:23]1
Reactant: BrCCC1C=CCC1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CCC2C=CCC2)c1
Yield: 32.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-(cyclopent-2-en-1-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound (123 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].CS(O[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][C:28]2[CH:37]=[CH:38][CH:39]=[CH:40][C:27]1=2)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:13][CH2:14][N:15]([CH2:23][CH2:24][CH:25]=[C:26]3[C:27]4[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=4[CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]3=4)[CH2:16][CH2:17]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCCC=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of 2-(1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester (4.6 g, 0.019 mol), 3-(10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl methanesulfonate (5.0 g, 0.015 mol) and potassium carbonate (4.8 g) in N,N-dimethylformamide (50 ml) was heated to 60° .C for 5 h. After standing overnight, the solid was filtered off and washed with benzene. The filtrate was diluted with benzene (200 ml) and washed with water (4×100 ml). The organic solution was dried (MgSO4) and the solvent evaporated in vacuo. The residue (7.8 g) was purified by column chromatography on silica gel using benzene and a benzene-ethyl acetate mixture as eluents, affording 2-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene) -1-propyl)-1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester (3.4 g, 48%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>CC(O)=O.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N:11]=[N+:16]=[N-:17])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2cc(N=[N+]=[N-])ccc2[nH]1
Yield: 65.7 %

Procedure:
In an oven dried, 250 mL round bottom flask flushed with argon, compound 33 (400 mg, 2.74 mmol, 146.19 MW) was dissolved in 90% AcOH (20 mL). After complete solvation, the reaction was placed at 0° C. and protected from light with foil. NaNO2 (1.1×, 3.01 mmol, 208 mg, 69.00 MW) dissolved in cold H2O (2 mL) was added dropwise and stirred for ten minutes. NaN3 (1.1×, 3.01 mmol, 196 mg, 65.01 MW) dissolved in cold H2O (2 mL) was added dropwise. After one hour the reaction was poured into water (40 mL), which was extracted 3 times with CH2Cl2 (40 mL each). The extracts were washed with sodium bicarbonate and brine (100 mL each), dried with sodium sulfate, filtered and concentrated. Purification by silica flash chromatography (100% CH2Cl2) yielded the azide as a light brown solid (310 mg, 66%). 1H NMR (600 MHz, d6-DMSO): δ 11.025 (s, 1H, N—H), 7.295-7.281 (d, J=8.4, 1H, indole-7H), 7.131-7.127 (d, J=2.4, 1H, indole-4H), 6.737-6.719 (dd, J1=8.4, J2=2.4, 1H, indole-6H), 6.108-6.106 (d, J=1.2, 1H, indole-3H), 2.369 (s, 1H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 137.5, 133.9, 130.0, 129.5, 111.7, 111.6, 108.5, 99.0, 13.4. Melting point: 57-60° C. TLC (in 1:1 ethyl acetate:hexanes) Rf=0.56. IR (film): 3409 cm−1, 2111 (aryl-azide). Elemental analysis calculated for C9H8N4: C, 62.78; H, 4.68; N, 32.54. found: C, 62.95; H, 4.68; N, 32.53.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)[C:55]1[O:59][CH:58]=[CH:57][CH:56]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[N:13]([C:58]3[O:59][CH:55]=[CH:56][CH:57]=3)[C:12]2=[O:23])[CH:24]([CH3:35])[CH2:25]1)=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccco1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NC(=O)N2c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1COCCO1
Product: CC1CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCC12C(=O)N(c1ccco1)C(=O)N2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
8-(3,5-Bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (200 mg, 0.41 mmol) was dissolved in dry dioxane (10 mL) and triphenylphosphin (145 mg, 0.54 mmol), furfuryl alcohol (53.1 mg, 0.54 mmol) and diethylazodicarboxylate (40% in toluene, 0.54 mmol) were added sequentially and stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (dichloromethane) to yield the desired product (143 mg, 61%), MS: m/e=566.1 (M+H+).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([C:14]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.C1(C)C=CC=CC=1>[CH3:1][O:22][C:21]([C:14]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C1(c2ccccc2)CCCCCC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCCCCC1

Procedure:
A 2.0 M solution of trimethylsilyl diazomethane (29.2 mL) was added dropwise to a solution of 1-phenyl-cycloheptanecarboxylic acid (Example 14c) (9.8 g) in methanol (85 mL) and toluene (300 mL) under an atmosphere of nitrogen.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-:10].[Na+].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]1([CH:7]([C:2]2[N:10]=[N:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:1]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: N#CCc1ccccc1
Reactant: [NH2-]
Agent: [Na+]
Product: N#CC(c1ccccc1)c1ccc(-c2ccccc2)nn1
Yield: 59 %

Procedure:
To a solution of 5.7 g. (0.03 mole) of 3-chloro-6-phenylpyridazinone and 4.1 g (0.035 mole) of phenylacetonitrile in 50 ml of dry benzene was gradually added 7.8 g (0.07 mole) of pulverized sodium amide. The mixture was slowly heated to 80° to 90° C. and maintained at this temperature for one hour. The resulting precipitate was filtered off, thoroughly washed with benzene and water, giving 4.8 g (59% yield) of 2-phenyl-2-(6-phenyl-3-pyridazinyl)acetonitrile in the form of pale yellow crystals, m.p. 201°-203° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:31][CH2:30][N:29](C(OCCCC)=O)[CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.ClCCl>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CCCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Tert-butyl 4-((3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamido)methyl)-4-phenylpiperidine-1-carboxylate (˜1.80 g, ˜2.84 mmol, described in Example 1) was dissolved in trifluoroacetic acid/dichloromethane (1:5, mL). This mixture was stirred at 23° C. for 2 hours, then neutralized with sat. sodium carbonate to pH˜7. The aqueous phase was then extracted with ethyl acetate/THF and the combined organic layers were dried over anhydrous magnesium sulfate to give the title material (1.06 g, 70%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99-2.09 (2H, m), 2.28 (2H, br s), 2.31 (3H, s), 2.66-2.82 (2H, m), 3.25 (2H, m), 3.45 (2H, br d), 6.86 (1H, d, J=5.31 Hz), 6.93 (1H, s), 7.05 (1H, t, J=5.18 Hz), 7.26-7.34 (1H, m), 7.38-7.46 (4H, m), 7.81 (1H, s), 8.17 (1H, d, J=5.31 Hz), 8.23 (1H, d, J=5.05 Hz), 8.37 (1H, t, J=6.44 Hz), 11.84 (1H, s). LC/MS (M+H)+: 535. HPLC ret. time (Condition C): 4.085 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:25]1[N:33]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O.NN>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([NH:25][NH2:33])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g of (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester were dissolved in 30 ml DMF. 5 g HATU and 2.2 ml DIPEA were added and the reaction mixture cooled to 0° C. 4 eq. of Hydrazine-Monohydrate in 30 ml DMF were added and the reaction warmed to rt and stirred for 1 h. The crude product was extracted from ethylacetate/aq. NaHCO3.