Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7](=[O:17])([O-:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:1]1([P:7](=[O:16])([O:17][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P([O-])(OCc1ccccc1)c1ccccc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=P(OCCN1CCOCC1)(OCc1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 22 h
Yield: 74.6 %

Procedure:
A mixture of monobenzyl phenylphosphonate (115 mg, 0.46 mmol), N-(2-chloroethyl)morpholine hydrochloride (95 mg, 0.51 mmol) and potassium carbonate (140 mg, 1.0 mmol) in anhydrous DMF was stirred at 65° C. for 22 hours. Following dilution with ethyl acetate (40 ml), the mixture was washed with water four times and finally brine before being dried over magnesium sulfate, filtered and concentrated to leave 124 mg (74%) of the title compound as a pale yellow oil which was used without further purification. MS: 362 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.O[C:21]1[CH:22]=[C:23]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]=CC=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:32][O:31][C:29](=[O:30])[CH2:28][C:23]1[CH:22]=[CH:21][C:12]2[O:11][C:8]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:24]=1
Reactant: COC(=O)Cc1ccc(O)c(O)c1
Reactant: COC(OC)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2c(c1)OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)O2
Temperature: 60 °C
Yield: 37.7 %

Procedure:
A mixture of di(4-chlorophenyl)dimethoxymethane (26 g) (see Preparation 13) and methyl (3,4-dihydroxyphenyl)acetate (16 g) (see Preparation 12) in toluene (200 ml) was heated under reflux in a Dean-Stark apparatus for one hour. The reaction was cooled to 60° C. and p-toluenesulphonic acid was added (50 mg). After heating under reflux for 16 hours the solution was cooled, washed with aqueous sodium bicarbonate (100 ml), dried (MgSO4) and evaporated to a brown gum. Flash chromatography (silica, eluant=4:1 hexane/ethyl acetate) gave the title compound as a pale yellow gum (13.7 g). LRMS m/z=415(m)+.
Reaction SMILES: [NH2:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[O:6][C:7]([CH3:18])([CH3:17])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:14][CH2:13][CH2:12][C:11]3=[O:15])[C:4]=2[CH:3]=1.[N+](C1C(NC(=O)C)=C[C:30]2[O:31]C(C)(C)[C@@H](O)[C@H](N3CCCC3=O)[C:29]=2C=1)([O-])=O.[N+](C1C(N)=CC2OC(C)(C)[C@@H](O)[C@H](N3CCCC3=O)C=2C=1)([O-])=O.C(C1C(N)=CC2OC(C)(C)[C@@H](O)[C@H](N3CCCC3=O)C=2C=1)#N>>[C:30]([NH:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[O:6][C:7]([CH3:17])([CH3:18])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:14][CH2:13][CH2:12][C:11]3=[O:15])[C:4]=2[CH:3]=1)(=[O:31])[CH3:29]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Agent: CC1(C)Oc2cc(N)c(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Agent: CC1(C)Oc2cc(N)c([N+](=O)[O-])cc2[C@@H](N2CCCC2=O)[C@@H]1O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H](O)[C@@H]2N1CCCC1=O

Procedure:
6-amino-7-nitro-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically acceptable salt thereof; 6-nitro-7-acetamido-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol; 6-nitro-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically salt thereof; or 6-cyano-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically acceptable salt thereof.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccccc23)CC1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
(17.0 mg, 46%), from 3-(1-methyl-4-piperidinyl)-1H-indole (Example 5d, 21.5 mg, 0.1 mmol) and 4-fluorophenylsulfonyl chloride (29.2 mg, 0.15 mmol), HRMS-FAB+ for C20H21N2O2SF, calculated MH+ : 373.13861; found: 373.13669.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=[O:16].[Na+]>S(=O)(=O)(O)O.O>[OH:16][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(C2CCC(=O)CC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
200 ml of 4N sulfuric acid were heated to 80° C. in a sulfonation flask and then treated with about 5% of a solution of 37.9 g of 4-(4-aminophenyl)cyclohexanone in 200 ml of 4N sulfuric acid. Subsequently, the remaining solution of 4-(4-aminophenyl)cyclohexanone as well as a solution of 15.2 g of sodium nitrite in 45 ml of water were simultaneously added dropwise to the reaction mixture at 80° C. within 1.5 hours. Thereafter, the mixture was treated dropwise at 80° C. within 30 minutes with a solution of 9 g of sodium nitrite in 27 ml of water and stirred at 80° C. for a further 1 hour. After cooling the reaction mixture to 0° C. the separated crystals were removed by filtration under suction, washed with 200 ml of cold water and dried up to constant weight at 60° C. in a drying oven under a water-jet vacuum. The crystalline crude product (34.6 g) was suspended in 520 ml of ethyl acetate. The suspension was heated to reflux for 1 hour, then treated with 1.7 g of active carbon and then heated to reflux for a further 1 hour. The mixture was subsequently suction filtered (rinsing with 40 ml of warm ethyl acetate) and the filtrate was evaporated under a water-jet vacuum at a bath temperature of 40° C. Drying of the evaporation residue up to constant weight at 60° C. in a drying oven under a water-jet vacuum gave 32.2 g of 4-(4-hydroxyphenyl)cyclohexanone as yellow-brown crystals with m.p. 165°-166° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[C:16]1([C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6])[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C#CCCCO
Reactant: Ic1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCCC#Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
A solution of 0.59 g (7 mmol) of 4-pentyn-1-ol in 3 ml of acetonitrile is added dropwise under an argon atmosphere to a suspension of 1.78 g (7 mmol) of 1-iodonaphthalene, of 1.48 ml (10.5 mmol) of triethylamine, of 0.066 g (0.35 mmol) of cuprous iodide and of 0.147 g (0.21 mmol) of di(triphenylphosphine)palladium dichloride (Ph3P)2PdCl2 in 4 ml of acetonitrile. The mixture is stirred at ambient temperature for 3 hours, 4 g of silica are then added and the mixture is evaporated to dryness. The product is purified by chromatography on silica gel, elution being carried out with an 80/20 and then 60/40 mixture of cyclohexane and of ethyl acetate, to produce 1.22 g of product in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[CH2:19]([N:26]=[C:27]=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl>[CH3:13][N:12]([CH3:14])[C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[NH:1][C:27]([NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[C:27]([NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])=[CH:7][CH:8]=1
Reactant: CCCCCCCN=C=O
Reactant: CN(C)c1ccc(NCc2ccccc2N)cc1
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1CN(C(=O)NCCCCCCC)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of N-(2-aminobenzyl)-N',N'-dimethyl-1,4-phenylenediamine (0.6 g) in dichloromethane (10 ml) was added under ice-cooling heptyl isocyanate (0.4 g) and the mixture was stirred overnight while returning slowly to room temperature. The solvent was distilled off and the residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=20:1) to give 1-(4-dimethylaminophenyl)-1-[2-(3-heptylureido)benzyl]-3-heptylurea as a non-crystallizable solid (0.55 g, 44%).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](I)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([N:25]([CH2:33][C:34]#[CH:35])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24].C(N(CC)CC)C>[Cu]I.C(#N)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:35]#[C:34][CH2:33][N:25]([CH2:23][CH3:24])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ncc1Cl
Reactant: C#CCN(CC)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)C(=O)OC(C)(C)C
Yield: 66.5 %

Procedure:
The sub-titled compound was prepared from N-(1 adamantylmethyl)-5-chloro-2-iodoisonicotinamide (Example 2(i)) (0.40 g), tert-butyl ethyl(prop-2-ynyl)carbamate (Example 7(i)) (0.34 g), copper (I) iodide (0.004 g), bis-triphenyphosphine palladium dichloride (0.014 g), triethylamine (5 ml) and anhydrous acetonitrile (5 ml) by the method of Example 2(iii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (9:1 to 7:3) to afford the sub-titled compound (0.30 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:34](I)[CH3:35]>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([O:22][CH2:34][CH3:35])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c2cccc(OCc3ccccc3)c2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C)nc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a stirred mixture of 8-benzyloxy-4-carboxy-2-methylquinoline (700 mg), potassium carbonate (659 mg) and N,N-dimethylformamide (0.3 ml) was dropwise added ethyl iodide (409 mg) under ice-cooling and the mixture was stirred for 30 minutes at the same temperature and for 1 hour at ambient temperature. To the mixture was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, dried over magnesium sulfate. The solvent was removed, and the residue was crystallized from diisopropyl ether to give 8-benzyloxy-4-ethoxycarbonyl-2-methylquinoline (686 mg) as solid.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:22][C:21]([CH3:24])([CH3:23])[C@@H:20](O)[C@H:19]([NH2:26])[C:18]=2[CH:27]=1)[CH3:13]>CC(O)C>[C:1]([O:11][C@H:20]1[C@H:19]([NH2:26])[C:18]2[CH:27]=[C:14]([CH2:12][CH3:13])[CH:15]=[CH:16][C:17]=2[O:22][C:21]1([CH3:23])[CH3:24])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CCc1ccc2c(c1)[C@@H](N)[C@H](O)C(C)(C)O2
Solvent: CC(C)O
Product: CCc1ccc2c(c1)[C@@H](N)[C@H](OC(=O)C(O)c1ccccc1)C(C)(C)O2

Procedure:
(+)-Mandelic acid (0.57 kg) and trans-6-ethyl-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol** (0.75kg) were dissolved in warm 2-propanol (18 L). The solution was concentrated to 12 L and crystallised to give the title compound (0.523 kg).
Reaction SMILES: O[C@@H](C1C=CC=CC=1)C([O:5][C@@H:6]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@H:10]([CH2:20][O:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][N:8]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:7]1)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[CH2:41]([N:8]1[CH2:9][C@@H:10]([CH2:20][O:21][C:22]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:6]([OH:5])[CH2:7]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc([C@H]2[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)CN(Cc3ccccc3)C[C@@H]2OC(=O)[C@@H](O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@H]2[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)CN(Cc3ccccc3)C[C@@H]2O)cc1

Procedure:
33.3 (46.13 mmol) of (3R,4R,5S)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol (S)-hydroxy-phenyl-acetate were treated with a cold aqueous solution of 7.3 g (69.2 mmol) of sodium carbonate in 100 ml water and 600 ml of ethyl acetate. The aqueous phase was separated and extracted twice with 200 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure to yield 25 g of (3R,4R,5S)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol as a colorless oil which was directly used without further purification.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[S:19]1[N:23]=[CH:22][C:21]([S-:24])=[N:20]1.[K+].B(F)(F)F.CCOCC>FC(F)(F)C(O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:21]3[CH:22]=[N:23][S:19][N:20]=3)[CH2:15][S:14][C@H:9]12
Reactant: [S-]c1cnsn1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cnsn3)CS[C@H]12
Yield: 73 %

Procedure:
7-Aminocephalosporanic acid (0.272 g) was added to the solution of potassium 1,2,5-thiadiazole-3-thiolate (0.136 g) in trifluoroacetic acid (5 ml) and the mixture was stirred for a few minutes until the solution turned clear, and then, boron trifluoride etherate (0.434 g) was added thereto and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated under reduced pressure and the residue was adjusted to pH 3.0 with 2% aqueous solution of ammonium hydroxide. The precipitates were collected by filtration, washed with cool water, acetone and diethyl ether and dried to give 7-amino-3-(1,2,5-thiadiazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (0.210 g).
Reaction SMILES: OC[CH:3]([S:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1(C)C=CC=CC=1>>[C:9]1([CH:4]2[CH2:3][S:10][C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=3[O:18]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:19]=1
Reactant: OCC(Sc1cc(O)ccc1O)c1ccccc1
Reactant: Cc1ccccc1
Product: Oc1ccc2c(c1)SCC(c1ccccc1)O2

Procedure:
A solution of 2-(2-hydroxy-1-phenylethylsulfanyl)benzene-1,4-diol (0.83 g) in dry toluene (60 ml) was stirred with Amberlyst 15 (0.5 g) at 60° C. until disappearance of the starting material. After the mixture was filtered and solvent evaporated the crude product was purified by column chromatography using heptane-ethyl acetate (1:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 7.41 (m, 4H), 7.33-7.40 (m, 1H), 6.81 (d, 1H, J 8.7 Hz), 6.61 (d, 1H, J 3.0 Hz), 6.51 (dd, 1H, J 8.7, 3.0 Hz), 5.10 (dd, 1H, J 9.6, 1.9 Hz), 3.28 (dd, 1H, J 13.0, 9.6 Hz), 3.06 (dd, 1H, J 13.0, 1.9 Hz).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:15]([NH:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])([CH3:17])[CH3:16]>C(#N)C>[CH2:23]([O:22][CH2:21][CH2:20][O:19][N:18]([CH:15]([CH3:17])[CH3:16])[C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH3:24]
Reactant: CCOCCONC(C)C
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCON(C(=O)COC(C)=O)C(C)C
Temperature: 30 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
27.3 g (0.2 mole) of 2-acetoxyacetyl chloride were added to a mixture of 33.1 g (0.24 mole) of potassium carbonate, 200 ml of acetonitrile and 29.4 g (0.2 mole) of N-isopropyl-O-(2-ethoxyethyl)-hydroxylamine. During this addition, the temperature increased to about 30° C. The reaction mixture was subsequently stirred for a further 2 hours, without cooling, and was filtered and the solvent was distilled off in vacuo. 38 g (77% of theory) of acetoxy-acetic acid N-(2-ethoxyethoxy)-N-isopropyl-amide were thus obtained in the form of a colourless oil with a boiling point of 106°-107° C./0.1 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20](O)=[O:21])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:23])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([NH:57]/[C:58](/[NH2:61])=[N:59]/O)[CH:53]=[CH:54][C:55]=1[Cl:56].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[Cl:49][C:50]1[CH:51]=[C:52]([NH:57][C:58]2[N:61]=[C:20]([CH2:19][CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=3)[C:9](=[O:23])[CH2:10][CH2:11]4)[O:21][N:59]=2)[CH:53]=[CH:54][C:55]=1[Cl:56]
Reactant: N/C(=N\O)Nc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(CN2C(=O)CCc3cc(CCC(=O)O)ccc32)cc1
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)CCc3cc(CCc4nc(Nc5ccc(Cl)c(Cl)c5)no4)ccc32)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
To a solution of 3-(1-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid (200 mg, 0.589 mmol) in DMF (3 mL) were added HOBT (99 mg, 0.648 mmol), EDC (124 mg, 0.648 mmol), and DIPEA (0.154 mL, 0.884 mmol). The reaction mixture was stirred for 30 minutes, then (E)-1-(3,4-dichlorophenyl)-2-hydroxyguanidine (130 mg, 0.589 mmol) was added followed by sodium sulfate (419 mg, 2.95 mmol). The reaction mixture was heated at 110° C. for 12 h, then concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using 10-100% EtOAc/hexane to give 6-(2-(3-((3,4-dichlorophenyl)amino)-1,2,4-oxadiazol-5-yl)ethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one as a yellow solid (0.06 g, 11% yield). 1H NMR 400 MHz, DMSO-d6: δ 2.65-2.68 (m, 2H), 2.90 (t, J=15.20 Hz, 2H), 2.95 (t, J=12.40 Hz, 2H), 3.16 (t, J=15.20 Hz, 2H), 3.70 (s, 3H), 5.05 (s, 2H), 6.84-6.90 (m, 3H), 7.02-7.04 (m, 1H), 7.14-7.16 (m, 3H), 7.38-7.41 (m, 1H), 7.57 (d, J=8.80 Hz, 1H), 7.69 (s, 1H), 10.23 (s, 1H). LCMS (ES-API), RT: 2.20 min; m/z 523.0 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)CC2C=CC(OC)=CC=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:51])=[C:29]([N:35]2[CH2:43][C@H:42]3[C@H:37]([N:38](C(OC(C)(C)C)=O)[CH2:39][CH2:40][CH2:41]3)[CH2:36]2)[CH:30]=[C:31]([C:33]#[N:34])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:51][C:28]1[C:29]([N:35]2[CH2:43][C@H:42]3[C@H:37]([NH:38][CH2:39][CH2:40][CH2:41]3)[CH2:36]2)=[CH:30][C:31]([C:33]#[N:34])=[CH:32][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([NH:8][CH:18]2[CH2:19][CH2:20]2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CN(c3cc(C#N)cc(N)c3Cl)C[C@H]21
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2C[C@@H]3CCCN[C@@H]3C2)c1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (395 mg, 1.114 mmol), (4aS,7aS)-tert-butyl 6-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (420 mg, 1.114 mmol), palladium(II) acetate (66.3 mg, 0.295 mmol), XANTPHOS (64.5 mg, 0.111 mmol), DPPF (61.8 mg, 0.111 mmol) and cesium carbonate (944 mg, 2.90 mmol) in Dioxane (7 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 5 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system 40 g column, eluting with 0-5% MeOH in DCM (+/−)-(4aS,7aS)-tert-butyl (6-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (379 mg) was obtained as a brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].[N-:40]=[N+:41]=[N-:42].[Na+].O.C(OCC)(=O)C>CN(C=O)C>[N:40]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCCCCC=CCCCCCCCCCCC=CCCCCCCCCCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCCCCCCCCCC=CCCCCCCCCCCC=CCCCCCCCCCCC(=O)O
Temperature: 50 °C

Procedure:
To E5 (1.528 g, 2.693 mmol) in anhydrous DMF (70 ml) was added sodium azide (1.226 g, 18.851 mmol) and the reaction heated for 5 days at 50° C. under argon. The solvent was reduced to almost dryness and the residues taken up into water (150 ml) and ethyl acetate (150 ml). The aqueous layer was further extracted with ethyl acetate (4×150 ml), the fractions combined, washed (2×150 ml water), dried (MgSO4) and the solvent removed to quantitatively yield the title compound as a pale yellow waxy solid 1.465 g, 95%. C36H67O2N3 requires 573.5. Found ES−: (M−H+)−, 572.6. dH (CDCl3) 1.27 (46H, br, N3(CH2)2(CH2)8 CH2CH═CHCH2(CH2)8CH2CH═CHCH2 (CH2)7), 1.63 (4H, m, CH2CH2N3), CH2H2CO2H), 2.02 (8H, m, CH2CH═), 2.34 (2H, t, CH2CO). 3.35 (2H, t, CH2N3), 5.35 (4H, m, CH═CH).