Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH3:23])[C@@H:17]([CH:20]([CH3:22])[CH3:21])[CH:18]=O)=[O:15])=[CH:12][C:11]=1[CH3:26].[Na].[BH4-].[Na+]>CCO.C(Cl)Cl>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([CH2:18][C@@H:17]([N:16]([CH3:23])[C:14](=[O:15])[C:13]2[CH:24]=[CH:25][C:10]([F:9])=[C:11]([CH3:26])[CH:12]=2)[CH:20]([CH3:21])[CH3:22])[CH2:2][CH2:3]1)#[N:8]
Reactant: N#CC1CCNCC1
Reactant: Cc1cc(C(=O)N(C)[C@H](C=O)C(C)C)ccc1F
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC(C#N)CC2)C(C)C)ccc1F
Reaction time: 1 h
Yield: 4 %

Procedure:
TEA (0.552 mL, 3.98 mmol) was added to a mixture of piperidine-4-carbonitrile (0.132 g, 1.19 mmol) in EtOH (2 mL) and DCM (3 mL). To the mixture was added (S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.1) (0.2 g, 0.80 mmol). The resultant mixture was stirred at rt for 15 min before sodium triacetoxyhydroborate (0.337 g, 1.59 mmol) was added. The stirring was continued at rt over night. Sodium tetrahydroborate (0.015 g, 0.40 mmol) was added and the mixture was stirred for 1 h. The solvents were removed on a vacuum centrifuge. The residue was diluted with DCM and washed with NaOH (aq., 1M). The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak IC 5 μm 20×250 mm column and Heptan/EtOH/TEA 60/40/0.1, as mobile phase to give the title compound (11 mg, 4%). Enantiomeric excess: 98.2%. Mixture of rotamers: (400 MHz, CD3OD) δ 0.85-1.08, 1.69-2.02, 2.12-2.96, 3.37-3.50, 4.41-4.59, 7.07-7.16, 7.19-7.36.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][CH2:45][NH2:46]>>[C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:46][CH2:45][CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: NCCc1ccccn1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: O=C(NC(CCNCCc1ccccn1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method B as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-(2-pyridinyl)ethanamine, the title compound was obtained in 97.4% purity by HPLC.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:35]([C:29]2[N:30]([CH3:34])[C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)=[O:36])=[O:8])[N:6]=1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cn1c(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)cc2cc(F)ccc21

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 5-Fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=508.3.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1.[Br:20]C1C=C2C(C(C)=NN2)=CC=1.FC1C=CC=CC=1C#N>O>[Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([Br:20])=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Agent: N#Cc1ccccc1F
Solvent: O
Product: N#Cc1ccccc1-n1nc(CBr)c2ccc(Br)cc21
Yield: 64 %

Procedure:
In a similar manner to that described for the preparation of 2-(3-(bromomethyl)-1H-indazol-1-yl)benzonitrile except in Step 1 the mixture was diluted with H2O and in Step 2 the mixture was heated at reflux overnight, 6-bromo-3-methyl-1H-indazole (1 g, 4.74 mmol) and 2-fluorobenzonitrile (0.617 mL, 5.69 mmol) were converted to the title compound (800 mg, 64%) as an off white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C>[CH3:9][NH:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)=[N:3][CH:4]=1)=[O:7]
Reactant: OC1CCNCC1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCC(O)CC2)nc1
Yield: 86 %

Procedure:
A mixture of 8.51 g (49.9 mmol) 6-chloro-N-methyl-nicotinamide, 5.66 g (54.9 mmol) 4-hydroxypiperidine, 26.1 ml (150 mmol) N-ethyldiisopropylamine and 0.31 g (2.5 mmol) 4-(N,N-dimethylamino)-pyridine was heated at reflux over night. After cooling to room temperature the crude mixture was transferred to a flash chromatography column. Elution afforded 10.1 g (86.1%) of the title compound as a light yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16](C4OC=CC=4)=[CH:15][C:14]=3[N+:24]([O-])=O)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[NH4+].[OH2:29].O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].O>C(O)C>[N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:6]4[CH:11]=[CH:10][O:29][CH:7]=4)=[CH:15][C:14]=3[NH2:24])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc(-c2ccco2)ccc1Nc1cccc(-n2ccnc2)c1
Reactant: O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(-c2ccoc2)ccc1Nc1cccc(-n2ccnc2)c1
Yield: 146.3 %

Procedure:
To a solution of 7c from Example 11 (13 g, 37.6 mmol) in ethanol (25 ml) is added ammonium chloride (6.03 g, 113 mmol) and sodium sulfide nonahydrate (27.05 g, 113 mmol). The mixture is heated to reflux for 1 hour. After cooling the mixture is poured into 700 ml of water. The product is filtered off, washed with water and air-dried to yield 8c (8.7 g, 73%). Mp 188-189° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH2:12]([NH:19][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: OC(CNCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a cooled (0° C.) suspension of 2-bromo-1-(4-bromophenyl)ethanone (40.24 g; 0.14 mol) in EtOH (500 mL) and CHCl3 (100 mL) was added benzylamine (63 mL; 0.58 mol). After 30 minutes the ice-bath was removed and the mixture stirred for another 2 hours at RT. Subsequently the reaction mixture was cooled again to 0° C. and NaBH4 (6.26 g; 165.5 mmol) was added in small portions. The resulting mixture was stirred at 0° C. for 1 hour and thereafter another 4 hours at RT. The reaction mixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 1M aqueous NaOH. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo. The residue was crystallized from tort-butyl methyl ether/heptanes to afford 2-benzylamino-1-(4-bromo-phenyl)-ethanol (18.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15](O)=[O:16])=[CH:13][N:12]([CH3:18])[C:9]=32)=[CH:4][N:3]=1.C1C=CC2N(O)N=[N:25]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15]([NH2:25])=[O:16])=[CH:13][N:12]([CH3:18])[C:9]=32)=[CH:4][N:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(C(=O)O)c2c1-c1nc(N)ncc1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c2c1-c1nc(N)ncc1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 8-amino-1-methyl-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid M2 (0.08 mmol) in dry DMF (4 mL), HOBT.NH3 (0.164 mmol), TBTU (0.164 mmol) and DIEA (0.328 mmol) were added. The mixture was stirred at rt for 24 h then the solvent was evaporated. The residue was suspended in 10 mL of water, filtered, washed with water and dried in vacuo, providing the title compound (55% yield). ESI (+) MS: m/z 244 (MH+). 1H NMR: 2.73 (t, J=7.44, 2H), 3.00 (t, J=7.44, 2H), 4.04 (s, 3H), 6.94 (bs, 1H), 7.35 (bs, 1H), 7.73 (s, 1H), 7.96 (s, 1H), 7.76 (bs, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>C1COCC1>[CH:18]1[C:13]([C:22]([C:21]([F:28])([F:27])[F:20])=[O:23])=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Cl)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, 110 ml of n-butyllithium/hexane solution (0.95M solution) was added to a solution of 20 g of p-bromochlorobenzene in 200 ml of dry THF at -60° C. The reaction solution was stirred at -60° C. for 1 hour and at -20° C. for 30 minutes. A solution of 17.8 g of ethyl trifluoroacetate in 20 ml of dry THF was added to the reaction solution at -60° C., followed by stirring at that temperature for 1 hour. The reaction solution was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure to obtain 13.1 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:21][C:20]([OH:22])([CH2:19][CH2:18][NH:17][C:2]1[CH:7]=[N:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1)[CH3:23]
Reactant: Brc1cnc(C#Cc2ccccc2)cn1
Reactant: CC(C)(O)CCN
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(O)CCNc1cnc(C#Cc2ccccc2)cn1
Yield: 509.8 %

Procedure:
A solution of 2-bromo-5-(phenylethynyl)pyrazine (Example 168, step 1) (158 mg, 0.061 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (255 mg, 1.83 mmol, 30 equiv.) and triethylamine (185 mg, 255 ul, 1.83 mmol, 30 equiv.) in 3 ml pyridine was stirred overnight at 85° C. The reaction mixture was concentrated in vacuo. After workup with dichloromethane/water/brine, and drying over magnesium sulfate, the organic phases were concentrated in vacuo. The crude product was chromatographed over a prepacked 20 g silica column eluting with a 25% to 100% ethyl acetate in heptane gradient which yielded the title compound (87.5 mg, 51% yield) as an off-white solid, MS: m/e=282.2 (M+H+).
Reaction SMILES: C(N)CCCCCCCCCCCCCCCC.[CH:19]1([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.N(C(OC(C)(C)C)=O)(CC(O)=[O:38])C>C(Cl)(Cl)Cl>[C:26]([NH:25][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:38]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCCCCCCCCCCCCCCCCN
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
C17BocSar1 : the product C17BocSar1 is obtained by coupling heptadecylamine with BocSar1 in the presence of dicyclohexylcarbodiimide (DCCI). 3.78 g (0.02 mole) of BocSar and 2.06 g (0.01 mole) of DCCI are mixed cold (at 0° C.) in 100 ml of chloroform. A copious precipitate of dicyclohexylurea (DCU) is formed. The mixture is left for 30 minutes at 0° C., with agitation, and 2.55 g (0.01 mole) of heptadecylamine are added. The reaction is left to proceed for 20 hours. The precipitate is filtered off and washed, the filtrate is recovered, the chloroform is evaporated off, the residue is taken up in 50 ml of THF, the mixture is cooled to 0° C. and filtered to remove the maximum amount of dicyclohexylurea, and the precipitate is washed with the minimum amount of cold THF.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([NH:15][NH2:16])=[O:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[N:18]([O-])=O.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([N:15]=[N+:16]=[N-:18])=[O:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cc(-c2cccc(F)c2)on1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc(-c2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a suspension of 5-(3-fluorophenyl)isoxazole-3-carbohydrazide (22.5 g, 101 mmol) in H2O (2000 mL) and HCl (2 N, 101 mL, 2.0 equiv.) at 0° C. was added a solution of sodium nitrite (13.9 g, 202 mmol, 2.0 equiv.) in H2O (100 mL). The suspension was stirred at RT for 16 h. The precipitate was filtered and washed with H2O. The solid was dried under high vacuum to give 5-(3-fluorophenyl)isoxazole-3-carbonyl azide as a yellow solid (20 g, 85%). LRMS (M+H+)m/z 179.0.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1.[ClH:26].C(OCC)(=O)C>>[ClH:26].[ClH:26].[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]=2[N:18]=1
Reactant: C[C@@H]1CCC[C@H]1Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1CCC[C@H]1Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of the compound obtained in step 1 (0.46 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.18 g, 44%) as a white powder.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:24])([CH3:23])[CH2:10][N:11]([CH2:17][CH2:18][P:19]([CH3:22])([CH3:21])=[S:20])[C:12](=O)[CH2:13][O:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH3:22][P:19]([CH3:21])([CH2:18][CH2:17][N:11]([CH2:10][C:9]([S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:24])[CH3:23])[CH2:12][CH2:13][O:14][CH3:15])=[S:20]
Reactant: COCC(=O)N(CCP(C)(C)=S)CC(C)(C)SCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCN(CCP(C)(C)=S)CC(C)(C)SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a stirred solution of N-(2-benzylthio-2-methylpropyl)-N-(2-dimethylphosphinothioylethyl)methoxyacetamide (750 mg) in dry toluene (10 cm3) at 0° C., under an atmosphere of dry nitrogen was added a solution of boranetetrahydrofuran complex in tetrahydrofuran (5.25 cm3, 1M). The mixture was stirred for 30 min at 0° C. and then for 4 h at room temperature. Concentrated hydrochloric acid (1 cm3) was added carefully and the tetrahydrofuran then removed under reduced pressure. The remaining aqueous solution was made strongly basic by the addition of aqueous sodium hydroxide (6M) and then extracted with chloroform (3×10 cm3). The extracts were dried (Na2SO4) and the solvent removed to give the product (500 mg, 71%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:27][C:28](=[O:30])[CH3:29])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:31]Br>C(Cl)Cl>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:31])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:27][C:28](=[O:30])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C1CCCC1
Reactant: BrBr
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
To acetic acid 2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (2.9 g, 7.7 mmol) in anhydrous methylene chloride (68 mL) was added ferric chloride (66 mg, 0.41 mmol). The reaction mixture was placed under nitrogen and cooled to -78° C. The reaction mixture was protected from light and a solution of bromine (0.44 mL, 8.5 mmol) in anhydrous methylene chloride (11 mL) was added dropwise over a period of 15 min. After stirring at -78° C. for 45 min the reaction was quenched with dilute sodium bisulfite, and then poured into water (200 ML). The resulting mixture was extracted with diethyl ether (300 mL), and the diethyl ether layer was washed with water and then brine. Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (95:5) gave the title compound as a white solid (2.7 g, 79%): (CDCl3): δ 8.28 (d, 1 H), 7.58-7.52 (m, 2 H), 7.39-7.34 (m, 1 H), 7.29 (d, 1 H), 7.18 (dd, 1 H), 7.14 and 7.13 (d, 1 H), 3.18 (quintet, 1 H 2.44 (s, 3 H), 2.40 (s, 3 H), 2.06-2.02 (m, 2 H), 1.75-1.45 (m containing a singlet at δ 1.60, 9 H). MS(EI), [M+], 1 bromine isotope pattern, 492/494; Anal. Calc. for C27H25BrO2S: C, 65.72, H, 5.11, N, 0.00. Found: C, 63.18, H, 4.96, N, 0.00.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=O)[CH3:2].Cl[C:7]1[N:12]=[N:11][C:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[C:9]([CH3:21])[CH:8]=1>C(O)CCC>[CH3:2][C:1]1[N:12]2[N:11]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:9]([CH3:21])=[CH:8][C:7]2=[N:5][N:4]=1
Reactant: CC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Solvent: CCCCO
Product: Cc1cc2nnc(C)n2nc1-c1ccc(C#N)cc1

Procedure:
A 1.48 g. portion of acetic acid hydrazide is dissolved in 50 ml. of butyl alcohol with heating, then 4.58 g. of p-(6-chloro-4-methyl-3-pyridazinyl)benzonitrile (prepared as in Example 1) is added and complete solution occurs after heating for an additional 10 minutes. The solution is then heated at reflux for 18 hours. The reaction mixture is concentrated to afford 5.8 g. of orange solid which is washed with petroleum ether. This product is dissolved in 1:1 ethyl alcohol/acetone and is filtered through a pad of silica gel. The filter is washed copiously with acetone and the combined filtrates are concentrated to a yellow solid. The solid is dissolved in 100 ml. of acetone and the solution is cooled in dry ice-acetone to afford a tan solid which is collected by filtration, washed copiously with petroleum ether and air dried. This product is dissolved in methyl alcohol, is treated with activated charcoal and is filtered. The filtrate is used to recrystallize 1.06 g. of yellowish crystals. A 500 mg. portion of the above is recrystallized twice from methanol and the resultant product is dried in vacuo to give the product of the example, m.p. 242°-244° C.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)/C(=N\OC(=O)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 24.7 %

Procedure:
2-(2-Triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic acid (10 g) was suspended in 140 ml of anhydrous dichloromethane, and 6.7 ml of triethylamine was added to this suspension under ice cooling with stirring. To the resulting solution was added a solution of benzoyl chloride (3.2 g) in dichloromethane (20 ml). The mixture was stirred at room temperature for one hour, the insoluble matters were filtered off, and the filtrate was washed twice with 20ml 1N hydrochloric acid and 30 ml of saturated sodium chloride solution each and dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced pressure, and the brown viscous residue (12 g) was purified by silica gel column chromatography using chloroform containing 10 to 15% methanol as eluent, giving 3 g of the objective compound as light brown crystals.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21][CH:22]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:23][CH2:24]O.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:21][CH:22]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:23][CH2:24][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]12[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2)=[O:20]
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)=CCCC(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)=CCCC(C)CCOC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 12 h
Yield: 64.4 %

Procedure:
To a solution of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (0.10 g, 0.36 mmol), 4-(dimethylamino)pyridine (DMAP; 44 mg, 0.36 mmol), and 3,7-dimethyl-oct-6-en-1-ol (61 mg, 0.39 mmol) in methylene chloride (20 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI; 75 mg, 0.39 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with 1 N NaOH aqueous solution (15 mL) and water (30 mL), and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to give 798 (97 mg, 65%) as a solid: 1H NMR (CDCl3) 0.91 (3H, d, J=6.9 Hz), 1.34-1.37 (2H, m), 1.56-1.60 (9H, m), 1.67-1.69 (8H, m), 1.81 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.35 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05 (1H, s), 4.11 (2H, t, J=6.9 Hz), 4.21 (1H, s), 5.09 (1H, t, J=6.9 Hz); LC-MS (ESI) m/z calcd for C25H42N2O3 [M+H]+ 419.32. found [M+H]+ 419.22; mp 49 C. Anal. Calcd for C25H42N2O3: C, 71.73; H, 10.11; N, 6.69. Found: C, 70.27; H, 9.83; N, 6.39.