Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH3:18]I>>[CH3:18][N:4]1[C:5]2[C:10](=[C:9]([O:11][CH3:12])[CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1
Reactant: CI
Reactant: COc1cc2ccccc2c2c1C(C)(C)CN2
Product: COc1cc2ccccc2c2c1C(C)(C)CN2C

Procedure:
1-Amino-3-methoxynapthalene 18 was acetylated with 2-bromo-2-methylpropionyl chloride according to the general amino group acylation procedure described above in Example 2 to give compound 23. Compound 23 was cyclized by the Friedel-Crafts cyclization procedure described above in Example 2 to give compound 24. Next, compound 24 was reduced with 3 equivalents LAH in THF to give the 4-methoxybenzoindoline 25. Compound 25 was alkylated using the general amino group alkylation procedure described above in Example 3 using methyl iodide as the alkylating agent to give a N-methyl-3,3-dimethyl-4-methoxybenzoindoline intermediate 26 (1HNMR: CD3Cl d 8.07 (bd, 1 H, J=8.4 Hz), 7.69 (bd, 1 H, J=8.1 Hz), 7.33 (bt, 1 H, J=7.8 Hz), 7.22 (bt, 1 H, J=8.1 Hz), 6.70 (s, 1 H), 3.92 (s, 3 H), 3.32 (s, 2 H), 3.32 (s, 3 H), 1.44 (s, 6 H). Subsequent methoxy group deprotection of compound 26 by the general boron tribromide procedure described in Example 1 resulted in the N-methyl-3,3-dimethyl-4-hydroxy-benzoindoline 27.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=[O:3].[Se](=O)=[O:13]>O1CCOCC1.O>[Br:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)c(Br)c1
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
To 3-bromo-4-fluoroacetophenone (11.0 g) in 1,4-dioxane (160 ml) and water (15 ml) was added selenium dioxide (8.8 g). The mixture was heated at reflux for 10 h, cooled to room temperature, and the solvent then removed at reduced pressure. The residue was suspended in 50% diethyl ether in isohexane, and residual solid removed by filtration. The filtrate was dried over Na2SO4, and solvent then evaporated to give (3-bromo-4-fluorophenyl)oxoacetaldehyde as a yellow oil, which was used without further purification in the next step.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][C:6](=[CH:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:19])=[C:12]([CH:20]([CH3:22])[CH3:21])[CH:11]=2)[C:5]1=[O:23])(=O)C.[OH-].[Na+].Cl>CO.C1COCC1>[CH:16]([C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:13]=1[OH:19])[CH:9]=[C:6]1[CH2:7][CH2:8][NH:4][C:5]1=[O:23])([CH3:18])[CH3:17]
Reactant: CC(=O)N1CCC(=Cc2cc(C(C)C)c(O)c(C(C)C)c2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(C=C2CCNC2=O)cc(C(C)C)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 810 mg (2.57 mmol) of the thus obtained 1-acetyl-3-(3,5-di-isopropyl-4-hydroxybenzylidene)pyrrolidin-2-one in 5 ml of methanol and 10 ml of THF was added 2 ml of 1N aq. sodium hydroxide at room temperature and the mixture was stirred for 3 hours. The reaction mixture was poured into ice-water containing ethyl acecate and 3 ml of 1N hydrochloric acid. The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated under reduced pressure to give a residue, which was crystallized from a ether/n-hexane mixture to give 800 mg of the objective compound as yellowish white crystal in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].ClCC[I:31]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:31])[N:8]2[CH2:11][CH3:12])=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:3]=1
Reactant: CCn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: ClCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(I)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To (S)-4-(2-chloro-9-ethyl-9H-purin-6-yl)-3-methylmorpholine (465.0 mg, 1.65 mmol) in anhydrous THF (6.7 mL) at −78° C. under N2 was added freshly prepared lithium diisopropylamide in THF (2.0 eq). The reaction was stirred at −78° C. under N2 for 2 hours, and 1-chloro-2-iodoethane (1.01 g, 5.78 mmol, 3.5 eq.) was added. The reaction mixture was then stirred at RT for 3 days and then quenched with saturated aqueous sodium ammonium chloride solution at 0° C. Volatile solvent was then evaporated in vacuo, and the crude was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in hexane) to give the desired compound as a foam (610.0 mg, 90.7%). 1H NMR (CDCl3, 400 MHz) δ ppm 5.28 (broad s, 2H), 4.17 (q, J=7.4 Hz, 2H), 4.00 (dd, J=11.3, 3.4 Hz, 1H), 3.75 (m, 2H), 3.59 (m, 1H), 3.48 (broad s, 1H), 1.37 (m, 6H); LC-MS m/z (method B2)=408 [M+H]+, RT=2.06 min.
Reaction SMILES: C#C.[CH:3](NC(C)C)(C)[CH3:4].C#C.C1COCC1.C([Li])CCC.[CH3:22][C@H:23]1[CH2:28][C@H:27]2[C@H:29]3[C:39](=[CH:40][CH2:41][C@:25]2([CH3:26])[C:24]1=[O:43])[C@:37]1([CH3:38])[C:32](=[CH:33][C:34](=[O:42])[CH:35]=[CH:36]1)[CH2:31][CH2:30]3>C1COCC1>[C:3]([C@:24]1([OH:43])[C@@H:23]([CH3:22])[CH2:28][C@H:27]2[C@H:29]3[C:39](=[CH:40][CH2:41][C@:25]12[CH3:26])[C@:37]1([CH3:38])[C:32](=[CH:33][C:34](=[O:42])[CH:35]=[CH:36]1)[CH2:31][CH2:30]3)#[CH:4]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O
Reactant: CC(C)NC(C)C
Agent: C#C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#C[C@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reaction time: 0.5 h

Procedure:
Dry THF (5 l) is cooled to -20° and acetylene (0.27 kg) is dissolved in the THF at -20°. Diisopropylamine (880 ml) is added to the acetylene/THF solution. n-Butyllithium (1.6M, 3.88 l) is added to the mixture maintaining the temperature at -20° and stirred for 30 min. 16β-Methylandrosta-1,4,9(11)-triene-3,17-dione (IB) in (THF) is added to the reaction mixture at or below -20° and stirred for 20 min to give the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: C1=COCCC1
Reactant: OCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: BrCCCCOC1CCCCO1
Reaction time: 4 h
Yield: 96 %

Procedure:
16.0 g (105.0 mmols) of 4-bromobutanol was dissolved in 140 ml of chloroform, and a solution prepared by dissolving 13.9 ml (1.5-fold equivalent weight) of 3,4-dihydro-2H-pyran in 40 ml of chloroform was dropwise added thereto at 0° C. in an atmosphere of argon. The solution obtained was stirred for 4 hours while keeping it at 0° C., followed by addition of an aqueous sodium hydrogencarbonate, and the resulting solution was extracted with chloroform (100 ml×2). The organic layer obtained was dried with anhydrous sodium sulfate, and thereafter concentrated under reduced pressure to obtain 24.0 g of 4-(tetrahydropyran-2-yl)oxybutyl bromide (yield: 96%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)(=[O:11])[CH3:10]>>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:9](=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:21]=[CH:20]2
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Reactant: O=Cc1ccccc1
Product: COc1ccc2cc(C(=O)C=Cc3ccccc3)ccc2c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and commercial 2-acetyl-6-methoxynaphthalene, 1-(6-methoxy-2-naphthalenyl)-3-phenylprop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([NH:16][C:17]1[C:25]([Cl:26])=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:27][CH2:28][CH2:29][CH3:30])[CH:18]=1)(=[O:15])[CH3:14]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([Cl:26])[C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:18][C:19]=2[O:27][CH2:28][CH2:29][CH3:30])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: CCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Product: CCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-acetylamino-5-chloro-2-propoxybenzoic acid.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C=O)[CH2:6][CH2:5]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][CH2:25][CH2:26]N.[O-]CC.[Na+]>C(O)C>[NH:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C:1]2[NH:2][CH2:26][CH2:25][CH2:24][N:23]=2)[CH2:9][CH2:8]1
Reactant: N#CCC1CCN(C=O)CC1
Reactant: NCCCN
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: C1CN=C(CC2CCNCC2)NC1
Temperature: 200 °C
Yield: 56.7 %

Procedure:
A mixture of 4-cyanomethyl piperidine-1-carboxaldehyde (4. g, 0.026M) and 1,3-diaminopropane mono p-toluenesulfonate (7.3 g, 0.052M) was heated at 100° C. for 1/2 hrs and 200° C. for 2 hrs. The reaction mixture was dissolved in ethanol (50 ml) and sodium ethoxide (0.052M) was added. The mixture was filtered and the filtrate was stripped to dryness and distilled from about 170° to about 190° C./0.2 mmHg to yield 1,4,5,6-tetrahydro-2-[(4-piperidinyl)methyl]-pyrimidine (2.7 g, 56.7% yield). This compound was characterized as dihydrochloride salt, mp 279°-281° C. (EtOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:21])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)Cc1ccccc1)CC2

Procedure:
First 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane (60 g, 0.2 mol) is heated to 130° C. with N-methyl-benzylamine (65 g, 0.54 mol) for 1.5 hours. After cooling the mixture is distributed between water and methylene chloride. The organic phase is separated off, dried and evaporated. The residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol=10:1). M.p. of the hydrochloride: 205°-208° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH:8]=[CH2:9].S(=O)(=O)(O)O>CCCCCC>[CH2:9]([O:6][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)[CH:8]=[CH2:7]
Reactant: O=CCCCO
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: C=CCOC1CCCO1
Yield: 69.2 %

Procedure:
The procedure of Example 1 is followed with 4-hydroxybutanal (250 g of 11.0 wt. % solution, 0.31 mol, 1.0 eq.), allyl alcohol (13.8 g, 0.24 mol, 0.80 eq.), and hexanes (500 mL). Concentrated sulfuric acid (0.5 mL) is used in place of the ion-exchange resin. After stirring for 18 h at room temperature the hexane phase contains 5.96% of 2-allyloxytetrahydrofuran (21.3 g, 70% yield). The aqueous phase contains 5.3% of 4-hydroxybutanal and 1.9% of allyl alcohol.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C:15]2=[O:2])=[CH:12][CH:13]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Brc1ccc(N2CCOCC2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1COCCN1c1ccc(Br)cc1

Procedure:
1.41 g (6.20 mmol) of benzyltriethylammonium chloride and 0.98 g (6.20 mmol) of potassium permanganate are added to a solution of 500 mg (2.07 mmol) of 4-(4-bromophenyl)morpholine (Example 15A) in 10 ml of dichloromethane. After 5 h under reflux, the contents of the flask are concentrated in vacuo, and the residue is purified by preparative HPLC. The concentrated product is dried under high vacuum. 217 mg (35.7% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.CC#N.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C1COCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnc2[nH]ccc2c1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cnc2[nH]ccc2c1)Oc1ccccc1
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridin-5-ylamine (0.50 g, 3.7 mmol, see Synthesis, 2005, No. 15, 2503-2506) in THF (4 mL) and CH3CN (6 mL) was added pyridine (0.36 mL, 4.4 mmol) followed by phenyl chloroformate (0.49 mL, 3.8 mmol) slowly. The reaction was stirred overnight. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (0-100% EtOAc/hexane) provided the desired product as a white solid (0.213 g, 23%). MS M+1: 254.15.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl.O.C(Cl)(Cl)Cl.[CH3:15][CH2:16][C@@H:17]([C:19](O)=[O:20])[CH3:18]>[Cl-].[Zn+2].[Cl-]>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:19](=[O:20])[CH:17]([CH3:18])[CH2:16][CH3:15]
Reactant: Oc1cccc(O)c1
Reactant: CC[C@H](C)C(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(C)C(=O)c1ccc(O)cc1O
Temperature: 110 °C
Yield: 31.7 %

Procedure:
16.3 g of anhydrous zinc chloride was dissolved in 10.3 g of S-(+)-2-methylbutanoic acid by heating to 110° C. 13.2 g of resorcinol was added to the mixture and then the temperature of the admixture was raised to 150° C. over a period of 30 minutes under stirring. The reaction mixture was then cooled to the room temperature, and a mixture composed of 25 ml of hydrochloric acid and 25 ml of water was added thereto. The reaction mixture was then subjected to extraction for three times, each by using 50 ml of ethyl ether. The extracts were joined together and rinsed with an aquesous solution of NaHCO3 for three times, and then rinsed with water for three times. Anhydrous Na2SO4 was added to the rinsed extract to dry the ethyl ether extract. Ethyl ether was removed to obtain a liquid reaction product which was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 6.2 g of 3-hydroxy-4 -(1-oxo-2-methylbutyl)phenol was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6]C)=[O:5])[CH3:3].Cl.[CH3:9][C:10]([O:13][C:14]([NH:16][C@H:17]([C:20](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:21])[CH2:18][OH:19])=[O:15])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)(Cl)Cl>[NH:16]([C:14]([O:13][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:15])[C@H:17]([C:18]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:19])[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
25 g of H-Ala-OMe, HCl and 66 g. of Boc-Ser-ONb are dissolved in 500 ml DMF. The product is cooled in an ice bath and 25 ml of NEM, 24 g of N-hydroxy benzotriazole are added with magnetic stirring and the pH is maintained at 6.5 or 7 by addition of NEM. The product is stirred for 18 hrs. at ambient temperature. After TLC monitoring, the medium is evaporated to 90% (0.1 mm Hg--35° C.). The oil obtained is dissolved in 1.500 ml of chloroform, the product is washed with a solution of saturated sodium chloride (twice), 5% sulfate/potassium bisulfate solution (3 times), saturated sodium bicarbonate (5 times). The solution is dried over Na2SO4 and evaporated to dryness. An oil is obtained which is dried to constant weight (30°--0.1 mm Hg).
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[C:3](Cl)=[O:4].[CH2:13]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1)[CH:14]=[CH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([N:17]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1)[C:3](=[O:4])[CH:2]([Cl:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[CH:14]=[CH:15][CH3:16]
Reactant: O=C(Cl)C(Cl)c1cccc(F)c1
Reactant: CC=CCNc1ccc(Cl)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCN(C(=O)C(Cl)c1cccc(F)c1)c1ccc(Cl)c(C(C)C)c1
Reaction time: 0.33 h

Procedure:
2.6 g of 2-chloro-2-(3-fluorophenyl)acetyl chloride were gradually added dropwise to 2.2 g of N-(2-butenyl)-N-(4-chloro-3-isopropylphenyl)amine and 2.0 g of anhydrous potassium carbonate in 40 ml of N,N-dimethylformamide with stirring at 20°-30° C. After the stirring was additionally continued for 20 minutes, potassium carbonate was removed by filtration, and extraction was then carried out with toluene. After drying over anhydrous sodium sulfate, the reaction solution was concentrated by means of an evaporator to quantitatively obtain the desired oily product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12](Cl)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C.O>[N:16]([C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=[CH:11]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](N=[N+]=[N-])CC1
Yield: 59.8 %

Procedure:
To a stirred solution of cis-1-(tert-butoxycarbonylamino)-4-chloro-2-cyclohexene (1.85 g, 8.00 mmol) in DMF (40 mL) was added sodium azide (1.17 g, 18.0 mmol) and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into brine (40 mL) and diluted with ethyl acetate (120 mL) and water (20 mL). The phases were separated and the organic phase was washed with brine (4×25 mL). The organic phase was dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (10:1 hexanes-ethyl acetate) provided 1.14 g (60%) of trans-1-azido-4-(tert-butoxycarbonylamino)-2-cyclohexene as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOCC>C1COCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]#[N:16])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1CCC(OCc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C#N)CCC(OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a solution of 4-(benzyloxy)cyclohexanecarbonitrile (1.26 g, 5.85 mmol, 1.0 equiv) in THF (dry, 30 mL) was added a solution of LDA (3.95 mL, 2.0 M Heptane/THF/toluene, 1.35 equiv) dropwise at −78° C. under N2. The resulting yellow solution was stirred at −78° C. for 2 hrs. Ethyl chloroformate (2.79 mL, 29.26 mmol, 5.0 equiv) was then added by syringe dropwise. The solution was stirred at −78° C. and allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched by addition of H2O (20 mL), HCl (1.0 N, 20 mL). It was then extracted with EtOAc (3×40 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4 and then concentrated to give pale yellow residue. Ether (40 mL) was added and stirred for 5 min, filtered to remove the white solid. The ethereal solution was concentrated to give the yellow oil which was purified by CombiFlash (25 g silica gel column, EtOAc/Hexane: 0-20%) to afford 565 mg (yield 33%) of ethyl 4-(benzyloxy)-1-cyanocyclohexanecarboxylate as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C:19]#[N:20].C(N(CC)CC)C>CN(C)C=O.O>[C:19]([CH2:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:10]=2)[NH:14][CH:13]=1)#[N:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 3 h

Procedure:
Dimethyl sulphamoyl chloride (1.2 ml) was added dropwise to a stirred solution 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry dimethyl-formamide (50 ml) containing triethylamine (2.8 ml). After 3 h, the resulting suspension was diluted with water (20 ml) and stirred for 30min. The resulting solution was poured into water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (100 ml) and brine (2×100 ml), dried (Na2SO4) and evaporated in vacuo, to give a dark brown oil which was purified by column chromatography (Kieselgel 60, 100 g) eluted with ether/ethyl acetate, (9:1) to give the title compound as white solid (0.75 g) m.p. 147°-150°.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1)(=O)=O.[CH2:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C.[CH2:30]([CH:37]1CCNCC1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:30]([CH:37]1[CH2:29][CH2:28][N:25]([CH2:23][C:6]2[N:7]=[C:8]([C:12]3[S:13][C:14]4[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=4[C:16](=[O:18])[N:17]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:26][CH2:27]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCN(CC)CC
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1nc(-c2cccc(CN3CCC(Cc4ccccc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-benzylpiperidine (0.17 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.25 g, 67%) as pale yellow crystals.