Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 86.5 %

Procedure:
A mixture of 6.8 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.02 g of 2-(dimethylamino)ethyl chloride hydrochloride, 6.1 g of potassium carbonate and 150 ml of acetone is refluxed for 20 hours. After the reaction is completed, insoluble materials are removed by filtration and washed with ethanol. The washings are added to the filtrate, and the combined solution is evaporated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then evaporated to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 7.13 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][O:30]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:33]2[CH2:34][C:29]([CH3:28])([CH3:38])[O:30][CH2:31][C@H:32]2[C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC1(C)CN[C@H](C(=O)O)CO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 60.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.26 g, 0.51 mmol) was reacted with (S)-6,6-dimethylmorpholine-3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.18 g, 63%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a mixture of 0.40 g (1.55 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.188 g (1.86 mmol) of triethylamine and 15 ml of tetrahydrofuran at 0° C. is added 0.275 g (1.55 mmol) of 4-cyanobenzoyl chloride dropwise and the reaction mixture is allowed to stir overnight while slowly reaching room temperature. A precipitate is formed overnight which is collected by filtration, washed with water and ether and dried to yield a crude product which is triturated with methanol/chloroform to yield 0.14 g (23%) of the title compound as a white solid: m.p.>300° C.; m/e 386.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[C:7]1=[O:30])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]=3[N:21]=2)[C:7]1=[O:30])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3cccnc3n2)C[C@H]1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3c(n2)NCCC3)C[C@H]1Cc1ccccc1

Procedure:
A mixture of 12-6 (220 mg, 0.5270 mmol) and 10% Pd/carbon (100 mg) in EtOH (4 mL) was stirred under a balloon of hydrogen for 2 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH to give 12-7 as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4Cl)noc3N)CC2)c1
Yield: 67.9 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (516 mg, 1.25 mmol, 68%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Br[CH:20]1[CH2:23][CH2:22][CH2:21]1.[I-].[Na+]>CN(C=O)C>[CH:20]1([S:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)(=[O:11])=[O:10])[CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCC1
Reactant: O=S(O)c1ccc(F)c(F)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)c(F)c1)C1CCC1
Temperature: 100 °C

Procedure:
To 5.6 mmol 3,4-difluoro-benzenesulfinic acid and 6.2 mmol triethylamine in 10 ml DMF were added 8.4 mmol bromocyclobutane and 0.2 mmol sodium iodide and the mixture heated at 100° C. for 48 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 233.1 (M+H+, 100%)
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#N)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.Cl.[OH-:33].[Na+]>O1CCCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:21]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:33])=[CH:26][CH:25]=1
Reactant: N#Cc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: [OH-]
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 0 °C

Procedure:
To a cooled (ice bath) and stirred suspension of 2-((R)-indan-1-ylamino)-quinoline-6-carbonitrile (example 53, step B) (230 mg, 0.81 mmol) in tetrahydrofurane (4 ml) was added drop wise a 1M solution of 4-fluorophenyl-magnesium bromide (2.4 ml, 2.43 mmol), the reaction mixture was heated under reflux conditions for 20 h and poured into ice-water (20 ml). 2N hydrochloride solution (5 ml) was added, the mixture was stirred at room temperature for 10 min, 3 N sodium hydroxide solution (5 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield (4-fluoro-phenyl)-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-methanone as light yellow foam (220 mg, 71%). MS: m/e=383.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:9]([CH:8]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Oc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Yield: 76.9 %

Procedure:
Finely ground 3-ethoxycarbonyloxybenzoic acid (10.5 g) was added with stirring to concentrated sulphuric acid at 2°. A mixture of concentrated sulphuric acid (10 ml) and 70% nitric acid (4.5 g) was then added dropwise with stirring, keeping the temperature at 5° or below. When addition was complete, the solution was stirred for another 30 minutes and then poured into ice and water (200 ml). The white solid which separated was washed with water and taken up in chloroform. The solution was dried (MgSO4) and concentrated to yield 5-ethoxycarbonyloxy-2-nitrobenzoic acid (9.8 g) with a melting point of 126°-130°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[H-].[Na+].I[CH:14]([CH2:16][CH3:17])[CH3:15].C(N1C=CC(C2SC=CC=2)=N1)(CC)C>CN(C)C=O.CC(OC)(C)C.O>[CH:14]([N:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:9]=[N:8]1)([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)I
Reactant: c1csc(-c2cc[nH]n2)c1
Agent: CCC(C)n1ccc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)n1nccc1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13 %

Procedure:
3-(2-thienyl)-1H-pyrazole (23.2 mmol) was dissolved in 100 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (28.0 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, 2-iodobutane (35.0 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. 650 mg of a mixture of 1-sec-butyl-3-(2-thienyl)-1H-pyrazole and 1-sec-butyl-5-(2-thienyl)-1H-pyrazole (82:18; 13% yield) were obtained.
Reaction SMILES: [CH2:1]([CH:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O)[CH2:2][CH3:3].[BrH:14].S(=O)(=O)(O)O>O>[Br:14][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH3:3]
Reactant: Br
Reactant: CCCC(CCC)CCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCC(CCC)CCCCCBr
Temperature: 95 °C
Yield: 89.2 %

Procedure:
To a 50 mL flask containing 6-propylnonan-1-ol (4.92 g, 26.4 mmol) was added hydrobromic acid 48% (12 mL, 105.6 mmol, 4 eq.) and conc. sulfuric acid (1.4 mL, 26.4 mmol, 1 eq.) and the mixture was heated to reflux (95° C.) for 14 h. The reaction was cooled to room temperature before adding H2O (40 mL). The mixture was extracted with dichloromethane (3×120 mL) and the combined organic phases were washed with aqueous sodium bicarbonate (40 mL, 1M). Drying over magnesium sulfate and evaporation gave 1-bromo-6-propylnonane (5.87 g, 89% yield) as a brown liquid. 1H NMR (CDCl3, 400 MHz) d?(ppm): 3.40 (t, J=6.8 Hz, 2H); 1.86 (tt, J=6.8 Hz, J=6.8 Hz, 2H); 1.45-1.35 (m, 2H); 1.34-1.15 (m, 13H); 0.88 (t, J=6.8 Hz, 6H). 13C NMR (CDCl3, 129.9 MHz) d?(ppm): 36.9; 36.0 (2C); 34.0; 33.5; 33.9; 28.7; 25.8; 19.8 (2C); 14.5 (2C).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1>CC#N.C(Cl)(Cl)Cl>[Br-:23].[CH3:37][C:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:33][CH:32]=1)([CH3:35])[CH3:36]
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: CC(C)(C)c1ccc(COCCBr)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(COCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)cc1
Product: [Br-]
Temperature: 60 °C
Yield: 15.6 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) was added to a solution of 1-{[(2-bromoethyl)oxy]methyl}-4-(1,1-dimethylethyl)benzene (25 mg, 0.143 mmol) in 2:3 CH3CN/CHCl3 (3 mL), and the reaction was heated at 60° C. for 96 h. The reaction was concentrated, and the crude product was washed with EtOAc (3×1 mL). The product was dried under high vacuum to give the title compound (9 mg, 16%). LC/MS ESI RT 2.28 min M+484
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.NC(N)=[S:15].[OH-].[Na+].[Cl:19][CH2:20][CH2:21][N:22]([CH2:46][CH2:47][Cl:48])[P:23]([N:39]([CH2:43][CH2:44][Cl:45])[CH2:40][CH2:41][Cl:42])(=[O:38])[O:24][CH2:25][CH2:26]OS(C1C=CC(Br)=CC=1)(=O)=O>C(O)C.CO>[Cl:19][CH2:20][CH2:21][N:22]([P:23]([N:39]([CH2:43][CH2:44][Cl:45])[CH2:40][CH2:41][Cl:42])([O:24][CH2:25][CH2:26][S:15][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:38])[CH2:46][CH2:47][Cl:48]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: NC(N)=S
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: O=C(O)c1ccc(CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)cc1

Procedure:
4-(Thiomethyl)benzoic acid was prepared from methyl 4-(bromomethyl)benzoate using the procedure of Org. Syn. Coll. Vol. 3, page 363 (reaction with thiourea in ethanol, followed by hydrolysis of the ester with aqueous sodium hydroxide). 4-(Thiomethyl)benzoic acid, 2 g, was alkylated with 2-(4-bromobenzenesulfonyloxy)ethyl tetrakis(2-chloroethyl)phosphorodiamidate, 15.8 mL of 0.83 M, in 10 mL methanol and 6.25 mL of 4 M sodium hydroxide in methanol. The resulting product after filtration and concentration was a pale yellow oil, which was dissolved in saturated aqueous sodium bicarbonate and washed twice with 100 mL isopropyl acetate. The aqueous extracts were combined, acidified to pH ˜1 with sulfuric acid, and back extracted twice with into 100 mL isopropyl acetate. The isopropyl acetate layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to give α-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-4-carboxytoluene as a pale yellow oil, 5.4 g, with product identity verified by LC-MS.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1I.[F:12][C:13]([F:18])([F:17])C([O-])=O.[Na+]>CN1CCCC1=O.O.[Cu]I>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:18])([F:17])[F:12]
Reactant: Cn1c(I)cc2ccccc21
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1c(C(F)(F)F)cc2ccccc21
Temperature: 160 °C
Yield: 37 %

Procedure:
A mixture of 1-methyl-2-iodoindole (4.40 g, 17.3 mmole), sodium trifluoroacetate (24.0 g, 176.5 mmole) and copper(I) iodide (17.1 g, 89.8 mmole) in N-methylpyrrolidone is heated at 160° C. for 6 hours, cooled to room temperature, diluted with water and filtered through diatomaceous earth to remove copper salts. The filtrate is extracted with ether. The extracts are combined, washed with water, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and 4:1 hexanes:ethyl acetate as eluent to give the title product as a pale yellow oil which crystallized on standing, 119 g (37% yield), mp 28°-32° C., identified by IR, 1HNMR and 19FNMR analyses.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C.C(OCC)(=O)C>[N:1]1([CH:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: BrCCOCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(N2CCOCC2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of tert-butyl N-(4-aminocyclohexyl)carbamate (1.07 g, 4.99 mmol, 1.00 equiv) in DMF (10 mL) was added triethylamine (1.26 g, 12.48 mmol, 2.50 equiv) and 1-bromo-2-(2-bromoethoxy)ethane (1.4 g, 6.04 mmol, 1.20 equiv). The resulting solution was stirred overnight at 70° C. The resulting solution was diluted with ethyl acetate (100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.2 g (crude) of tert-butyl N-[4-(morpholin-4-yl)cyclohexyl]carbamate as a light yellow solid. MS (ES): m/z 285 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:24])[CH2:22][OH:23])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].[C:25](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[OH:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([O:9][CH2:25][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:24]
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCc2ccccc2)cc(O[C@@H](C)CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
Benzyl bromide (1.89 g, 7.20 mmol) was added to a mixture of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (1.55 g, 6.86 mmol) and potassium carbonate (1.89 g, 0.014 mol) in DMF (16 mL) and the reaction stirred at RT for 20 hours. Ethyl acetate (40 mL) was added and the mixture washed with water (40 mL), saturated sodiumbicarbonate solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a red oil which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (1.7 g).
Reaction SMILES: [I-:1].[CH3:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[N+:7]=1[CH3:8].[C:13]1([NH:19][CH:20]=NC2C=CC=CC=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[C:32](=[O:34])[CH3:33])(=O)C>CC(C)=O>[I-:1].[CH3:8][N+:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[CH:2]=[CH:20][N:19]([C:32](=[O:34])[CH3:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1oc2ccccc2[n+]1C
Reactant: CC(=O)OC(C)=O
Reactant: C(=Nc1ccccc1)Nc1ccccc1
Agent: [I-]
Solvent: CC(C)=O
Product: CC(=O)N(C=Cc1oc2ccccc2[n+]1C)c1ccccc1

Procedure:
A mixture of 27.7 g (0.1 mole) of 2,3-dimethylbenzoxazolium iodide, 21.6 g (0.11 mole) of N,N'-diphenylformamidine, and 100 ml of acetic anhydride was made and was then refluxed. After cooling the mixture refluxed, 300 ml of acetone were added and were then filtrated to take crystals. The resulted crystals were washed with acetone, so that the objective matter was obtained. The yield thereof was 26.0 g (62%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][CH3:19])[CH:12]=1)[CH:5]=[O:6].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[C:30]2[N:26]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:27]=[CH:28][CH:29]=2)=[CH:12][C:13]=1[CH2:18][CH3:19]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CCc1cc(Oc2ccc(C=O)cc2Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Oc2ccc(C=O)cc2-c2ccnn2C2CCCCO2)ccc1Cl
Temperature: 75 °C
Yield: 49.1 %

Procedure:
3-bromo-4-(4-chloro-3-ethylphenoxy)benzaldehyde (Preparation 9, 336 mg, 1.08 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.08 mmol) and cesium carbonate (1.05 g, 3.24 mmol) were suspended in dioxane (4 mL) and water (2 mL). The suspension was degassed 40 minutes with nitrogen then tetrakis-triphenylphosphine palladium (62 mg, 0.054 mmol) was added and the reaction mixture was heated for 18 hours at 75° C. The solution was concentrated in vacuo to a quarter of its volume then diluted with water (20 mL) and extracted by ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with a gradient from 15% diethyl ether in heptane to 50% diethyl ether in heptane to afford the title compound as a colourless oil (218 mg, 49%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].[C:23](#N)C>>[C:11]1(=[O:21])[N:15]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[C:4]=2[CH3:23])[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: CC#N
Reactant: BrCc1cccc(CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: Cc1c(CBr)cccc1CN1C(=O)c2ccccc2C1=O

Procedure:
α,α′-Dibromo-m-xylene is refluxed with potassium phthalimide (1.0 equivalent) in acetonitrile to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C>Cl.CO>[NH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)n1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(-c2cccc(N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A mixture of {6-[4-(methanesulfonylamino-methyl)-phenyl]-pyridin-2-yl}carbamic acid tert-butyl ester (11 g, 29 mmol) in HCl/MeOH (4M, 300 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was filtered and washed with ether to give N-(4-(6-aminopyridin-2-yl)benzyl)methane sulfonamide (C-3) (7.6 g, 80%) 1H NMR (300 MHz, DMSO-d6) δ 14.05 (br s, 1 H), 8.24 (br s, 2 H), 7.91-7.98 (m, 3 H), 7.70 (t, J=6.0 Hz, 1 H), 7.53 (d, J=8.1 Hz, 2 H), 7.22 (d, J=6.9 Hz, 1 H), 6.96 (d, J=9 Hz, 1 H), 4.23 (d, J=5.7 Hz, 2 H), 2.89 (s, 3 H). MS (ESI) m/z (M+H)+: 278.0,