Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:2].[CH3:20]C(C)([O-])C.[K+].COS(OC)(=O)=O>O1CCCC1>[CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:20])=[O:2]
Reactant: Cc1ccsc1C(Cc1ccccc1O)N(C)C=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1ccccc1CC(c1sccc1C)N(C)C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To an ice-water chilled solution of 5.10 g of N-formyl-2-hydroxy-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 100 ml of tetrahydrofuran, was added 2.24 g of potassium t-butoxide and then a solution of 2.52 g of dimethylsulfate and 25 ml of tetrahydrofuran dropwise, with stirring. The mixture was stirred at ice-bath temperature for 30 min, at room temperature for one hr, and at reflux for 30 mins. Additional dimethylsulfate and potassium t-butoxide were added and the mixture was refluxed for 20 min. The reaction mixture was decanted into 40 ml of water and basified with 10% sodium hydroxide solution. The mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was combined with a previous sample. The combined residue Was purified by preparative H:PLC (Water Associates Prep LC/System 500, silica gel, material applied as a solution in dichloromethane, eluted with ethyl acetate-hexane (1:1,200 ml/min flow rate). The appropriate fractions were combined and concentrated. The residue crystallized during refrigerated storage. Recrystallization from cyclohexane afforded 3.5 g of the product, mp 80°-83° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[S:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[C:23]1[CH3:32]
Reactant: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Reactant: O=Cc1sccc1S(=O)(=O)c1ccc(F)cc1
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared by the method of Preparation 29a using 3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde and (5-chloro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[OH:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([O:19][CH2:20][C@H:21]3[CH2:24][C@H:23]([OH:25])[CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: OCC1CC(O)C1
Product: O[C@H]1C[C@H](COc2ncc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, yellow solid, MS: m/e=281.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and 3-(hydroxymethyl)cyclobutanol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C. and by separation of the received isomers-mixture using a chiral column (Lux2 Cellulose with heptane:isopropanol 85:15 as solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)\[CH:11](C(OC1C(C(C)C)CCC(C)C1)C([O-])=O)[C:12]([CH3:15])([CH3:14])[CH3:13].[OH-:36].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)\[CH:11]([OH:36])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: [OH-]
Reactant: CC1CCC(C(C)C)C(OC(C(=O)[O-])C(/C(=C\c2ccc(Cl)cc2Cl)n2cncn2)C(C)(C)C)C1
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of 1.6 g of (-)-[(E)-1-(2,4-dichlorphenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-yl]-(-)-menthoxyacetate and 30 cc of a 95% aqueous ethanol solution containing 0.2 g of potassium hydroxide was stirred at 25° C. for one hour. The reaction mixture was poured into 200 cc of ice water and extracted with 300 cc of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude crystals were recrystallized from a carbon tetrachloride-n-hexane mixture to obtain 0.8 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol: [α]D24 -31.7 (c=1, CHCl3), melting point 160°-161° C. The NMR spectrum was the same as that of the racemate described in Reference Example 2.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][CH2:21][CH:22](O)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:23]1([CH2:22][CH2:21][CH2:20][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCC(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.204 g (1.5 mmol) of phenylpropanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=2:1) to obtain the product as a oil (0.27 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]3=2)[C@H:7]([NH2:18])[CH2:6][C@@H:5]1[CH3:19])(=[O:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]3=2)[C@H:7]([NH:18][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:6][C@@H:5]1[CH3:19])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)N1c2c(ccc3ccccc23)[C@H](N)C[C@@H]1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1c2c(ccc3ccccc23)[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
[Step 5] 91 mg of the cis-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydrobenzo[h]quinoline and 84 mg of 4-chlorophenylboronic acid were dissolved in 2.5 mL of DMF followed by adding 130 mg of divalent copper acetate and 87 μL of pyridine and stirring for 30 minutes at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite followed by the addition of water and extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 25 mg of the target compound in the form of a yellow solid (19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][C@@H:14]([C:16]([O-:18])=[O:17])[NH2:15])=[O:11])=[CH:8][CH:7]=1>C1COCC1.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][C@@H:14]([C:16]([O:18][C:6]([CH3:20])([CH3:7])[CH3:5])=[O:17])[NH2:15])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1=CCCCC1
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1

Procedure:
128 mg of Pd(OH)2 on carbon is added to a solution of 10-4 (1.28 g, 2.64 mmol) in 35 ml of THF and 10 ml of cyclohexene, and the reaction medium is heated under reflux for 45 minutes. The temperature is brought down to approximately 20° C. followed by filtering, rinsing with ethyl acetate and evaporating under reduced pressure until a dry extract is obtained (724 mg) corresponding to the expected deprotected product.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([N+:23]([O-])=O)[CH:13]=[CH:12][C:11]=1[CH3:26]>O.C1COCC1>[F:9][C:10]1[C:15]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([NH2:23])[CH:13]=[CH:12][C:11]=1[CH3:26]
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N)c(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of sodium hydrosulfite (4.42 g, 21.45 mmol) in water (25 mL) was added dropwise to a solution of 2-fluoro-1-methyl-4-nitro-3-(phenyloxy)benzene (0.884 g, 3.58 mmol) in THF (10 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by chromatography (ethyl acetate:hexane) to give [3-fluoro-4-methyl-2-(phenyloxy)phenyl]amine (0.444 g, 51.4%) as a colorless oil, which crystallized after standing overnight. 1H NMR (400 MHz, chloroform-d) δ ppm 7.23-7.33 (m, 2H), 7.03 (t, 1H), 6.94 (d, 2H), 6.83 (t, 1H), 6.51 (dd, 1H), 3.40 (br. s., 2H), 2.18 (d, 3H). ES MS: m/z 217.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:31])[CH2:29]Br)[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:31])[CH2:29][N:42]3[C:41](=[O:43])[C:40]4=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]4[C:38]3=[O:48])[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CBr)c3ccccc32)cc1)OCc1ccccc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
(3aR*,10aS*)-9-[4-(Benzyloxycarbonylamino)benzyl]-4-(bromoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][l,4]diazepin-10(1H)-one (496 mg, 0.88 mmol) and potassium phthalimide (172 mg, 0.93 mmol) were suspended in DMF (3 mL) and the suspension was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with 3 portions of chloroform. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to provide 495 mg (yield 89%) of the title compound. m.p. 144°-147° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[N+:31]([C:27]1[CH:26]=[C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:30]=[CH:29][CH:28]=1)([O-:33])=[O:32]
Reactant: Nc1cccc(-c2cccc([N+](=O)[O-])c2)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: O=[N+]([O-])c1cccc(-c2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-3′-nitrobiphenyl (83 mg, 0.386 mmol) similar to Example 58 and isolated as a light tan solid (65 mg, 77%). 1H NMR (DMSO-d6): 13.00 (s, 1H), 11.94 (s, 1H), 11.23 (d, J=4.5 Hz, 1H), 11.11 (d, J=8.1 Hz, 1H), 10.97 (s, 1H), 10.78 (s, 1H), 10.75 (s, 1H), 10.69 (d, J 8.1 Hz, 1H), 10.35-10.28 (m, 2H), 10.14-10.04 (m, 3H), 9.67 (s, 1H).
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1.O>[C:2]1([C:1]([OH:9])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1
Reactant: CCCCCCCC[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(O)(CCCCCCCC)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl benzoate (14.34 g, 105.3 mmol) was dissolved in anhydrous THF (43 mL) and this mixture was cooled to 0° C. A solution of n-octylmagnesiumchloride in THF (200.0 mL, 2.0M, 400 mmol) was then added dropwise, keeping the temperature at less than 10° C. Upon completion of addition, the mixture was left to stir at 0° C. for 2 hours. A solution of hydrochloric acid in water (400 mL, 1.0 M) was then added dropwise keeping the temperature at less than 25° C. The mixture was diluted with iProAc (420 mL) and the resulting organic layer was washed with 1.0 M HCl (1×70 mL), washed with brine (1×70 mL), dried over sodium sulfate and evaporated to yield a colorless liquid. The crude material was purified by silica gel column chromatography to afford a clear colorless liquid (21.0 g). 1H NMR (300 MHz, CDCl3, δ): 7.41-7.30 (m, 4H), 7.28-7.20 (m, 1H), 1.90-1.70 (m, 4H), 1.35-1.20 (m, 23H), 1.11-0.96 (m, 2H) and 0.92-0.83 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: C#Cc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C#Cc1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethynyl aniline (1.05 mL, 10.0 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (857 μL, 1.10 eq.) at a temperature of 0° C. The resulting mixture was stirred overnight at room temperature and was then evaporated. The residue was treated with 2 N aq. HCl (25 mL) and subsequently extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over MgSO4 and evaporated to give the desired methanesulfonamide in quantitative yield. It was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].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>[F:9][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Ic1ccccc1
Reactant: Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 9.21 g of 4-bromo-2-fluorotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to -78° C. in a nitrogen atmosphere, and the mixture was then stirred at -78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at -78° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a solution of 6.63 g of iodobenzene and 0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.00 g of oily 3-fluoro-4-methylbiphenyl.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH:11]([CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9][CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:33])=[O:32]
Reactant: CCCCC/C=C\CCCC(O)CCC/C=C\CCCCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution (0° C.) of 6Z,15Z)-henicosa-6,15-dien-11-ol 4 (5.6 g, 18.2 mmol) and triethylamine (3.8 mL, 27.2 mmol) in anhydrous dichloromethane (50 mL) was slowly added methanesulfonyl chloride (2.1 mL, 27.2 mmol). The reaction mixture was stirred for 2 hours at room temperature then diluted with dichloromethane (50 mL). The solution was washed with saturated sodium bicarbonate (3×25 mL) then the combined aqueous washes were extracted with dichloromethane (50 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The pale yellow oil was filtered through a pad of silica (100% DCM) to afford (6Z,15Z)-henicosa-6,15-dien-11-yl methanesulfonate 5 as a crude colorless oil (7.6 g). Rf 0.8 (100% CH2Cl2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@H:10]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:14][C@H:11]1[CH2:12][CH2:13][C@@H:8]([NH:7][C:6](=[O:30])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:9][C@H:10]1[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(C)(=O)=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N)[C@H](CS(C)(=O)=O)C1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
(1R,3R,4S)-(4-Benzyloxycarbonylamino-3-(methyl)sulfonylmethylcyclohexyl)carbamic acid tert-butyl ester (300 mg) was dissolved in MeOH (5 ml) prior to the addition of 10% Pd/C (200 mg). A hydrogen balloon was added and the solution was stirred for 3 h. The palladium was filtered off and the solution was concentrated to give tert-butyl(1R,3R,4S)-4-amino-3-(methylsulfonylmethyl)cyclohexylcarbamate (201 mg). MS found: (M+H)+307.2.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2)[NH2:2].CO[CH:15](OC)[CH2:16][CH:17](OC)OC>CCO.C(Cl)Cl>[N:1]1([C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][N:7]=[CH:8]3)[CH:17]=[CH:16][CH:15]=[N:2]1
Reactant: NNc1cccc2cnccc12
Reactant: COC(CC(OC)OC)OC
Solvent: ClCCl
Solvent: CCO
Product: c1cc(-n2cccn2)c2ccncc2c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A suspension of 5-hydrazinylisoquinoline (22.0 g, 112 mmol) in EtOH (300 mL) was treated with 1,1,3,3-tetramethoxypropane (27.7 g, 169 mmol) and the mixture was heated to 100° C. for 10 h. The reaction mixture was then concentrated in vacuo and the residue obtained taken up in DCM (500 mL) and washed with a saturated aqueous solution of NaHCO3 gas formation. The aqueous layer was extracted twice with DCM and the combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 95:5 to DCM/MeOH 9:1) to give the title compound (16.1 g). UPLC-MS: MS 196.1 (M+H+); UPLC rt 0.62 min.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:15]=[CH:14][CH:13]=[C:4]([O:5][CH2:6][CH2:7][N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Ic1cccc(OCCN2CCCC2)c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3cccc(OCCN4CCCC4)c3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(3-iodo-phenoxy)-ethyl]-pyrrolidine (119 mg, 0.37 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:28]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CN(C)[C@H]1CCNC1
Product: CN(C)[C@H]1CCN(CCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)C1

Procedure:
The product from Example 1C and 3-(S)-(dimethylamino)pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) 67 7.88 (m, 1H), 7.80 (m, 4H), 7.58 (m, 2H), 6.80 (s, 1H), 4.43 (m, 1H), 3.6-3.9 (m, 4H), 3.35-3.45 (m, 4H), 2.95 (s, 6H), 2.6 (m, 1H), 2.35 (m, 1H); MS (DCI) m/z 360 (M+H)+;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
4-Nitrophenyl sulfonyl chloride (1.1 g, 5.4 mmol) was added in one portion to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.9 mmol) and diisopropylethylamine in THF (10 ml). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, after which time the solvent was removed under vacuum to give the title compound (1.92 g, 100% yield) as an orange solid which was used without further purification. Tr=2.00 min m/z (ES+) (M+Na+) 408.