Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:16][C:17]#[N:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: N#CCBr
Product: COc1cccc(N2CCN(CC#N)CC2)c1

Procedure:
The title compound is synthesized by coupling of 1-(3-Methoxy-phenyl)-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=232.2: AtRet=2.62.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12](=O)[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([C:7]2[C:8]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CC(=O)Nc1ccccc1-3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCNc1ccccc1-3
Yield: 67.9 %

Procedure:
To a solution of ethyl 12-cyclohexyl-6-oxo-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (111 mg, 0.28 mmol) in tetrahydrofuran (1 ml) was added 1M BH3 THF complex tetrahydrofuran solution (1.6 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:2) to give ethyl 12-cyclohexyl-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (74 mg, yield 69%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30][NH2:31]>C(#N)C>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30][NH:31][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1F

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3,4-difluorobenzylamine and acetonitrile essentially as described above in example 48. Purity by LC/MS (APCI)=98%, [M+H]+=401.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH3:9][C:10]1[N:11]([C@H:16]2[CH2:20][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17]2)[C:12]([CH3:15])=[CH:13][CH:14]=1.C(I)C.[NH4+].[Cl-]>O1CCCC1>[CH3:15][C:12]1[N:11]([C@H:16]2[CH2:20][C@@:19]([CH2:2][CH3:3])([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17]2)[C:10]([CH3:9])=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H]1C=C[C@@H](n2c(C)ccc2C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CC[C@]1(C(=O)OC)C=C[C@@H](n2c(C)ccc2C)C1
Reaction time: 0.67 h
Yield: 82 %

Procedure:
A −40° C. solution of 2M (in THF/ethylbenzene/heptane) LDA (68 ml, 138 mmol) in tetrahydrofuran (120 ml) was treated with methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (14.02 g, 63.9 mmol) while keeping the temperature less than −33° C. The cold reaction was stirred for 40 minutes and then a solution of ethyl iodide (13.63 g, 87.4 mmol) in tetrahydrofuran (5 ml) was added slowly while keeping the temperature less than −33° C. The reaction was stirred with the cold bath in place for four hours and allowed to slowly warm. The reaction was poured into NH4Cl soln (300 ml), then extracted with ethyl acetate (2×200 ml), washed with brine dried over MgSO4, and concentrated under reduced pressure. The resulting brown oil was passed through a column of silica gel with 10% ethyl acetate/hexanes to give methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethylcyclopent-2-ene-1-carboxylate as a brown oil (12.96 g, 82%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-10.45 (c=0.61, methanol).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][C:20]=1[O:27][CH3:28]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:26]([CH2:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([F:29])[F:15])=[C:20]([O:27][CH3:28])[CH:21]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: COc1cc(CN)ccc1OCC(F)F
Agent: Cl
Product: COc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 35 %

Procedure:
The title compound is prepared in 35% yield (74 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride (144 mg, 0.57 mmol, Amine-32) in a similar manner to Intermediate-2.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([CH:17]=1)[CH:15]=[O:16].O>CN(C)C=O>[CH3:3][O:9][C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (23.34 g, 0.165 mol) and potassium carbonate (22.73 g, 0.165 mol) are added to a solution of 5-hydroxy-2-nitrobenzaldehyde (25 g, 0.149 mol) in N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 18 hours and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a brown solid, mp 89°-90° C.
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][Si:20]([CH3:22])([CH3:21])[O:11][C:10]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:9]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=Cc2ccccc2CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Charge an oven dried, nitrogen flushed 100-mL round bottomed flask equipped with a stirring bar with β-tetralone (4.977 grams, 0.0340 moles), triethylamine (6.970 grams, 0.0689 moles), 4-dimethylamino pyridine (0.219 grams,0.0018 moles), trimethylsilyl chloride (7.704 grams, 0.0709 moles) and 30 mL methylene chloride. Stir at RT for 20 hours, filter, wash the solid with 1×20 mL methylene chloride, wash the combined organic layers with 1×5 mL saturated sodium bicarbonate solution, 1×5 mL water, dry over magnesium sulfate, concentrate on a Buchi rotavapor and distill (96°-99° C., 1 Torr) to yield the product as a viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])=[CH:13][C:12]([CH:25]=O)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=1.CO.[CH3:29][NH2:30].[BH4-].[Na+].[ClH:33].C(=O)([O-])O.[Na+]>CO>[ClH:33].[ClH:33].[CH3:29][NH:30][CH2:25][C:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[N:10]([S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: O=Cc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2cccnc2)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2cccnc2)c1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
1-(Pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (340 mg) was dissolved in methanol (34 mL), 40% methylamine methanol solution (695 mg) was added at room temperature and the mixture was stirred for 30 min. sodium borohydride (102 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (10 mL) was added and the mixture was stirred for 5 min. The reaction mixture was basified with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as pale-red crystals (yield 288 mg, 69%).
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:47][CH3:48])=[N:40][C:41]([CH3:46])=[CH:42][C:43]=2[O:44][CH3:45])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:59][C:60]1[O:61][C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[N:64]=1>>[O:61]1[C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[N:64]=[C:60]1[S:59][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:47][CH3:48])=[N:40][C:41]([CH3:46])=[CH:42][C:43]=2[O:44][CH3:45])=[O:36])[CH2:30][CH2:29]1
Reactant: Sc1nc2ccccc2o1
Reactant: COc1cc(C)nc(OC)c1NC(=O)CN1CCN(CCO)CC1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: COc1cc(C)nc(OC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-dimethoxy-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a colorless crystalline powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.O=S(Cl)[Cl:23].CO>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:23]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(2-quinolylmethoxy)benzyl alcohol (3.58 g, 13.5 mmol) in CHCl3 (100 ml) was added SOCl2 (2 ml). The mixture was stirred at room temperature for 24 hours. A small amount of methanol was added to the reaction mixture, and the solvent thereof was removed under reduced pressure, to thereby obtain the title compound as white powder.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(OC(C)C)(C)C>C(O)C>[N:18]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)CCl)cc1
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(C)c1ccc(-c2cn3ccccc3n2)cc1
Yield: 40.5 %

Procedure:
A mixture of 47 g of ethyl 2-[4-(chloroacetyl)phenyl]propionate, 100 ml of ethanol and 30 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with benzene, and the extract is washed with water, dried and concentrated to give a reddish brown oil. To the oil is added isopropyl ether, and the crystalline precipitate is filtered off and recrystallized from isopropyl ether to give 22 g of ethyl 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionate as colorless scales melting at 110°-112°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:25]([C@@H:10]1[CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH2:11]1)=[N+:26]=[N-:27]
Reactant: CCOC(=O)CC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 149.9 %

Procedure:
The mixture of tert-butyl (2R,4R)-2-(3-ethoxy-3-oxopropyl)-4-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (462 mg, 1.20 mmol, step 3 of Example 8) and sodium azide (228 mg, 3.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 14 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (150 mL), washed with water (50 mL×2) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 562 mg (100%) of the title compound as a colorless oil, which was used for the next step without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:27]([NH:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:18][O:19]CC1C=CC=CC=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)C)=O)CO)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:27]([NH:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[CH2:18][OH:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1ccccc1)C(=O)CCl
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1)C(=O)CCl

Procedure:
Z-Phe-Gly-Ser(Bzl)-LeuCH2Cl (0.98 g, 1.44 mmoles) was treated with anhydrous HF by a method substantially similar to that described for preparation of H-Phe-Ser-Ala-LeuCH2Cl.HF in Procedure F, yielding a hydrofluoride salt, H-Phe-Gly-Ser-LeuCH2Cl.HF (0.69 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].O.[NH2:11][NH2:12].O>CCO>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH:11][NH2:12])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)nnc1NN
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
3,6-Dichloro-4-methylpyridazine (Combi-Blocks) (60 g, 361 mmol) was dissolved in hydrazine monohydrate (Aldrich) (335 mL, 5411 mmol) and the solution was stirred at 80° C. for 1 h, forming a white precipitate. The reaction mixture is dilutes with water and the precipitated products isolated by filtration. The solid crude product is suspended in EtOH and left in an ultra sound bath for 1 h. The desired product (22.4 g) was obtained after filtration and drying under vacuum as a beige solid. tR: 0.31 min (LC-MS 2); ESI-MS: 160.0 [M+H]+ (LC-MS 2). 1H NMR (400 MHz; DMSO-d6) δ ppm 7.83 (br.s, 1H) 7.32 (s, 1H) 4.49 (br.s, 2H) 2.05 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:20](C(OC(C)(C)C)=O)[CH:19]=3)[N:15]=[N:14]2)=[CH:10][CH:9]=1>CO>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[N:15]=[N:14]2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(Cc3ccc(Cl)cc3)nn2)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Clc1ccc(Cn2cc(-c3c[nH]c4ncccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 295 mg (2.13 mmol) of potassium carbonate are added to a solution of 347 mg (0.85 mmol) of tert-butyl 3-[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-pyrrolo[2,3-b]pyridine-1-carboxylate in 4.2 ml of methanol, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is adsorbed onto kieselguhr and chromatographed on a silica-gel column with dichloromethane/methanol/ammonia water, giving 3-[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-pyrrolo[2,3-b]pyridine as colourless crystals; ESI 310;
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O.CC([O-])=O.[Na+]>CCCCCCC>[CH3:15][C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][C@H:2]([CH2:3][CH2:4][CH2:20][C:19]([CH3:21])=[O:18])[CH3:1]
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Reactant: C=C(C)OC
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCCCCCC
Product: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
56.1 g 3,7,11-trimethyl-1-dodecin-3-ol, 27.0 g isopropenyl methyl ether and 100 mL n-heptane were initially introduced into a 500 ml flask. 14.5 mg methanesulfonic acid were added, while stirring. The reaction mixture was stirred under reflux for 7.5 hours. During this period of time, 36.5 g isopropenyl methyl ether and 21.6 mg methanesulfonic acid were added in each case in two portions. The mixture was cooled to room temperature, neutralized with 3 ml methanolic NaOAc solution (10 g/1) and evaporated. The crude was hydrogenated with 10% Pd/C in isopropanol. Phytone was obtained in a yield of 91%.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>CN(C)C=O.O>[CH2:18]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: O=C1NC(=O)C2CC12
Reactant: C=CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCCCN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4dione (0.3 g) and 7-octenyl bromide (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH:7](/Br)=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(NCC)C>[C:9]1(/[CH:8]=[CH:7]/[C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCCCO
Reactant: Br/C=C/c1ccccc1
Solvent: CCNCC
Product: OCCCC#C/C=C/c1ccccc1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
Cuprous iodide (0.4 g, 2.1 mmol) and bis-triphenylphosphine palladium (II) chloride (0.8 g, 1.14 mmol) were added to a solution of pent-4-yn-1-ol (16 g, 193 mmol) (Jones, Eglinton, and Whiting, Org. Syn. Coll., 4, 755, (1963)) and E-styryl bromide (34.34 g, 188 mmol) (Feuerstein and Heimann, Ber., 34, 1468 (1901)) in anhydrous diethylamine (250 ml). The whole was stirred under an atmosphere of dry nitrogen with the exclusion of moisture and light for 16 hours. The diethylamine was removed at reduced pressure and the residue diluted with water (500 ml). The aqueous mixture was extracted with ether. The ethereal extracts were passed down a column composed of silica (100 g), Celite (trade name, from Koch-light Ltd) (100 g) and activated charcoal (20 g) at 3 psi (21 KPa) pressure. The column was washed with ether (200 ml) and the combined organic extracts dried over anhydrous magnesium sulphate. Removal of solvents gave 30.5 g of 7-phenyl-hept-4-yn-6E-en-1-ol as a pale brown oil. The material was not purified further.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][N:12]1[C:17](=[O:31])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28](=[O:30])[NH2:29])[CH:20]=1)=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[C:28]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:17]([N:12]2[CH2:13][C@H:14]([F:16])[CH2:15][C@H:11]2[C:9]([OH:10])=[O:8])=[O:31])=[CH:20]1)(=[O:30])[NH2:29]
Reactant: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2C(=O)O)c2ccccc21
Reaction time: 16 h

Procedure:
To a solution of (2S,4R)-1-(1-carbamoyl-1H-indol-3-ylcarbamoyl)-4-fluoro-pyrrolidine-2-carboxylic acid benzyl ester (2.5 g, 5.89 mmol) in THF (40 mL) was added Pd/C 10% (500 mg). Air was removed from the flask under high vacuum and replaced with nitrogen, this operation was repeated three times and finally nitrogen was removed and replaced with hydrogen. The mixture was stirred under a hydrogen atmosphere for 16 h. Hydrogen was removed under vacuum and replaced with nitrogen and the catalyst was removed by filtration over a pad of Celite and washed with THF. Solvents were concentrated to give the title product. MS (LC/MS): 335.0 [M+H]+, 691.2 [2M+Na]+, 333.1 [M−H]−; tR (HPLC conditions a): 2.22 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:20])[CH3:19])=[C:4]([I:9])[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Oc1cnc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
Cool a suspension of 6-fluoro-4-iodo-pyridin-3-ol (1.6 g, 6.69 mmol) and K2CO3 (2.8 g, 20.1 mmol) in DMF (10 mL) to 0° C. in an ice bath under nitrogen. Add chloroacetone (0.78 g, 8.03 mmol) during a period of 30 min. Stir the mixture at RT for 1.5 h. Add water and extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to afford the title compound (1.5 g, 76%). MS (ES) m/z 296 [M+1]+.