Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-Bromo-pyridin-2-yl)-methanol (60 mg, 0.32 mmol) in dichloromethane (2 ml) was cooled in as ice bath. To the mixture was then added triethylamine (0.13 mL, 0.96 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.64 mmol). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate (5 mL). The organic phase was separated and the aqueous phase extracted further with dichloromethane (2×5 mL). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give the product as a pale brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:5])=[O:4].Cl[Sn]Cl>C(O)C>[NH2:12][C:8]1[CH:7]=[C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cccc(N)c1

Procedure:
To a solution of the above N,N-dimethyl-3-nitro-benzenesulfonamide (20.4 mmol, 4.7 g) in ethanol (50 mL) was added SnCl2 (105 mmol, 19.9 g) and the mixture was refluxed for 1 hour. Upon cooling, the solvent was removed in vacuo. Ethyl acetate (200 mL) and NaHCO3 (sat, 100 mL) were added to the residue followed by another 200 mL ethyl acetate and 500 mL water. The phases were separated and the organic phase was washed twice with water. The organic phase was filtered, washed with water (2×100 mL) dried over MgSO4 and evaporated to leave the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:39][C:40](OC(C)=O)=[O:41]>C(Cl)Cl>[C:40]([N:16]1[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]2[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:18]=2[CH2:17]1)(=[O:41])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2c(nc(C(C)C)c(C(OC(C)(C)C)C(=O)O)c2-c2ccc(F)cc2)C(C)(C)C1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1)(0.012 g, 0.028 mmol) and Et3N (0.139 ml, 1 mmol) in CH2Cl2 (5 mL) was added Ac2O (0.026 ml, 0.280 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-(6-acetyl-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (0.011 g, 76% yield) as white powder and mixture of rotomers. 1H NMR (500 MHz, CDCl3) δ ppm 7.41-7.54 (1H, m), 7.11-7.23 (3H, m), 4.91 (1H, br. s.), 4.49 (0.7H, d, J=17.4 Hz), 4.28 (0.3H, d, J=16.5Hz), 4.08 (0.7H, d, J=17.7 Hz), 3.93 (0.3H, d, J=16.8 Hz), 3.39-3.52 (2H, m), 3.15-3.27 (1H, m), 2.15 (2H, s), 1.95 (1H, s), 1.27-1.39 (9H, m), 1.15 (3H, d, J=5.5Hz), 0.90 (3H, s), 1.00 (6H, s). LCMS (M+H) calcd for C27H36FN2O4: 471.27. found: 471.3.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@H:10]([C@H:11]([OH:16])[C@H:12]([OH:15])[CH2:13][OH:14])[O:9][C@:8]([O:20]P(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)(O)=O)([C:17]([OH:19])=[O:18])[CH2:7][C@@H:6]1[OH:41])=[O:3].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)O)=O.CC(NC1C(C(O)C(O)CO)OC(OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)CC1O)=O.[Na+].[O:105]([C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O)[C@@H:106]1[O:114][C@H:113]([CH2:115][OH:116])[C@H:111]([OH:112])[C@H:109](O)[C@H:107]1[OH:108].O([C@H]1[C@@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O>>[OH:19][C:17]([C@@:8]1([O:9][C@@H:10]([C@@H:11]([C@@H:12]([CH2:13][OH:14])[OH:15])[OH:16])[C@H:5]([NH:4][C:2]([CH3:1])=[O:3])[C@@H:6]([OH:41])[CH2:7]1)[O:20][C@H:109]1[C@@H:111]([OH:112])[C@@H:113]([CH2:115][OH:116])[O:114][C@@H:106]([OH:105])[C@@H:107]1[OH:108])=[O:18]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@](OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Reactant: CC(=O)N[C@@H]1[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](CO)O[C@H]1O
Agent: CC(=O)NC1C(O)CC(OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)OC1C(O)C(O)CO
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@@H]2[C@@H](O)[C@H](O)O[C@H](CO)[C@@H]2O)(C(=O)O)C[C@@H]1O

Procedure:
The resulting CMP-sialic acid analogue (which in FIG. 3 is illustrated as the CMP derivative of Neu5Ac, i.e., CMP-Neu5Ac) is then combined with the derivatized βGal(1→3)βGlcNAc-OR compound in the presence of the βGal(1→3/4)βGlcNAc α(2→3)sialyltransferase or the βGal(1→3)GalNAc α(2→3)sialyltransferase under conditions wherein sialic acid is transferred to the 3 position of the galactose to form a αNeu5Ac(2→3)βGal linkage. Suitable conditions, known in the art, include the addition of the sialyltransferase to a mixture of the derivatized βGal(1→3)βGlcNAc-OR compound and of the CMP-sialic acid in a appropriate buffer such as 0.1M sodium cacodylate in appropriate conditions of pH and temperature such as at a pH of 6.5 to 7.5 and a temperature between 25° and 45° C., preferably 35°-40° C., while incubating for 12 hours to 4 days. The resulting sialylated product can be isolated and purified using conventional methodology comprising HPLC, ion exchange-, gel-, reverse-phase- or adsorption chromatography.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]=[CH:6]2)[O:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:12](Cl)([Cl:14])[Cl:13]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:13][C:12]1([Cl:14])[CH:9]2[CH:8]1[CH2:7][CH2:6][C:5]12[O:4][CH2:3][CH2:2][O:1]1
Reactant: C1=CC2(CC1)OCCO2
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: ClC1(Cl)C2CCC3(OCCO3)C21
Temperature: 45 °C
Reaction time: 72 h

Procedure:
To a solution of 1,4-dioxa-spiro[4.4]non-6-ene (25.23 g, 0.20 mol) in CHCl3 (200 mL) and CH2Cl2 (200 mL) was added triethylbenzylammonium chloride (100 mg) and 50% NaOH solution (200 mL) at rt. This solution was vigorously stirred at 45° C. over 3 days. The reaction mixture was diluted with H2O (300 mL) and extracted with CHCl3 (2×150 mL). The combined organic layer was concentrated in vacuo and the residue was purified by SiO2 column chromatography (0–50% CH2Cl2 in Hexanes) to the title compounds as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 4.06–3.93 (m, 4 H), 2.25–2.01 (m, 5H), 1.89–1.83 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:12]([O-])([O-:15])(=[O:14])=[O:13].[Na+].[Na+].Cl>O.C(O)C>[CH2:5]([O:4][CH2:3][CH2:2][S:12]([OH:15])(=[O:14])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)CCOCc1ccccc1
Yield: 75.8 %

Procedure:
A mixture of [(2-bromoethoxy)methyl]benzene (6.0 g) and sodium sulfate (3.9 g) in water (12 ml) and ethanol (36 ml) was refluxed overnight. The mixture was acidified with conc. hydrochloric acid under ice-cooling. The mixture was evaporated under reduced pressure. The residue was suspended in dichloromethane/methanol (4/1) and filtered off through Celite pad. The filtrate was evaporated to give 2-(benzyloxy)ethanesulfonic acid (4.5 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][F:27]>C(#N)C>[F:27][CH2:26][CH2:25][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1
Reactant: FCCBr
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1c(C2CCN(CCF)CC2)cccc1C(F)(F)F

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-fluoroethane (0.01 ml). MS m/z (relative intensity, 70 eV) 291 (M+, 29), 259 (15), 258 (bp), 194 (22), 167 (11).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]=[N:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1C(=O)CCC1=O.[CH2:20]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>CN(C=O)C>[C:1]1([C:7]#[C:8][C:9]2[CH2:20][C:21]3([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH2:22]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=CC#Cc1ccccc1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of Compound 1a (0.35 g, 2.41 mmol) in 3 mL of DMF stirred at r.t. was added N-chlorosuccinimide (0.386 g, 2.89 mmol) and the solution became orange coloured. After 2 h stirring, the solution became yellow and, after additional 2 h stirring, it was cooled to 0° C. and a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (143 mg, 0.73 mmol) in 0.5 mL of DMF was added, followed by a solution of TEA in 0.5 mL of DMF. The cooling bath was removed and the reaction mixture was stirred at r.t. for 2 days. Afterwards, the reaction mixture was diluted with cold water, extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, evaporated to dryness in vacuo. The crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 7:3) affording 210 mg of the title product. Yield: 85.5%.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][NH:36][CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]([OH:54])=O)[CH2:47][CH2:46]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:43][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][N:36]([CH3:37])[C:52](=[O:54])[CH2:51][N:48]3[CH2:47][CH2:46][O:45][CH2:50][CH2:49]3)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1
Reactant: CNCC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1
Reactant: O=C(O)CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1)C(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
Into a 50-mL vial, was placed N-(3-(trifluoromethyl)benzyl)-2-(2-(2-((methylamino)methyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (10 mL), 2-morpholinoacetic acid (28.9 mg, 0.20 mmol, 1.20 equiv), EDC.HCl (47.4 mg, 0.25 mmol, 1.50 equiv), and 4-dimethylaminopyridine (30.4 mg, 0.25 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×50 mL of aqueous NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 116 mg (59%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 9.12 (m, 1H), 8.86 (d, J=9.2 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.17 (m, 1H), 8.12 (m, 1H), 8.01 (m, 1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.60 (m, 3H), 4.96 (m, 2H), 4.72 (s, 2H), 4.50 (m, 2H), 3.98 (m, 4H), 3.70 (m, 4H), 3.1 (s, 3H), 2.10 (m, 4H), 1.98 (s, 2H). MS (ES, m/z): 730 [M+H]+.
Reaction SMILES: ClC(N(C)C)=C(C)C.[O:9]=[S:10]1(=[O:37])[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25](O)=[O:26])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][NH:11]1.[NH2:38][C:39]1[CH:43]=[CH:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:40]=1.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.O>[O:37]=[S:10]1(=[O:9])[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[CH:23]=[C:24]([C:25]([NH:38][C:39]4[CH:43]=[CH:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:40]=4)=[O:26])[CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][NH:11]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 1 h
Yield: 16 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.1 mL, 0.74 mmol) was added to a solution of 3-[(1,1-dioxido-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl)oxy]-5-{[(S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.21 g, 0.50 mmol) in DCM (5 mL) and stirred for 1 hour. 1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (137 mg, 0.74 mmol) then pyridine (0.08 mL, 0.99 mmol) were added and the reaction stirred for a further 45 minutes. The mixture was reduced in vacuo and ethyl acetate (50 mL) and water (50 mL) added. The aqueous layer was re-extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a golden oil which was chromatographed on silica, eluting with 30-60% ethyl acetate in isohexane, to give a colourless oil. The oil was dissolved in ethyl acetate (30 mL) and washed with 1M hydrochloric acid, dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a colourless oil (47 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[OH2:21]>>[CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:21])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 57.2 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-isopropyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.3 g, 4.15 mmol), NaH (60%, 500 mg, 12.45 mmol) and water (89 mg, 4.98 mmol) were reacted to form the desired product (0.7 g, 57%). EI- MS m/z 293.5 (M-H)−.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[CH:2].O1CCCC1.C([Li])CCC.C1(O[C:39]#[N:40])C=CC=CC=1>CCCCCC.O.CN(C)P(=O)(N(C)C)N(C)C>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16]2)[CH2:5][CH2:4]1)#[CH:2].[CH2:17]([C@H:14]1[CH2:13][CH2:12][C@H:11]([CH2:10][CH2:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[C:2][C:39]#[N:40])[CH2:4][CH2:5]2)[CH2:16][CH2:15]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: N#COc1ccccc1
Agent: C#C[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCCCC)CC2)CC1
Agent: C#C[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCCCC)CC2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C#CC#N)CC2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 750 mg of trans-1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane (prepared according to Example 14) in 75 ml of a 4:1 mixture of absolute tetrahydrofuran and hexamethylphosphoric acid triamide was placed at -45° C. in a sulphonation flask under argon gasification and treated within 2 minutes with 3.3 ml of a 1.0N solution of butyl lithium in hexane. The mixture was subsequently stirred at -20° C. for a further 1 hour, then cooled to -78° C. and treated with 490 μl of phenyl cyanate in a single portion. The mixture was then stirred at -78° C. for a further 2.5 hours, poured into 200 ml of water and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed twice with 150 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.6 g) on silica gel with hexane gave in sequence 194 mg (25.8%) of trans-1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane and 284 mg (34.8%) of trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexanepropiolonitrile (purity 98.9%). A recrystallization of the nitrile from methanol yielded colourless crystals (purity 99.4%); m.p. (C-N) 51.4% and cl.p. (N-I) 112.7° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)C=C>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:35])[C:10]=2[N:9]=[CH:8]1)[CH:2]=[CH2:3]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: C=CCN
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: C=CCn1cnc2c(-c3ccccc3F)csc2c1=O
Yield: 10.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), allylamine (86 mg, 0.92 mmol), and acetic acid (0.1 ml) were used to give 11.7 mg (0.04 mmol, 10.2% yield) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16](I)[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC[N:32](C(C)C)[CH:33]([CH3:35])[CH3:34].C(N)(C)C.C(Cl)Cl>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16]([NH:32][CH:33]([CH3:35])[CH3:34])[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)c(I)c1C#N)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCCCO
Solvent: CC(C)N
Product: CC(C)Nc1c(F)c(Nc2cc(C3CC3)[nH]n2)nc(N[C@@H](C)c2ccc(F)cc2)c1C#N
Temperature: 185 °C
Yield: 50.6 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile (Example 134, 0.07 g, 0.14 mmol) and DIEA (0.023 g, 0.18 mol) in n-BuOH (1.5 ml) was added isopropylamine (0.16 g, 2.7 mmol). The reaction was then heated to 185° C. under microwave conditions (1 hour×4 cycles). The reaction was then cooled to room temperature, DCM (10 ml) was added, and washed with 10% aqueous Na2S2O3. The organic layer was then dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.031 g, 51%). 1H NMR (400 MHz, CD3OD) δ 7.36-7.33 (m, 2H), 7.04-7.00 (m, 2H), 5.99-5.59 (br s, 1H), 5.14 (s, 1H), 4.29-4.23 (m, 1H), 1.87-1.83 (m, 1H), 1.52 (d, J=7.0 Hz, 3H), 1.25 (d, J=6.2 Hz, 6H), 0.95-0.94 (m, 2H), 0.65-0.63 (m, 2H). MS: Calcd.: 437. Found: [M+H]+ 438.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([SH:27])=[N:3][N:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Sc1nnc(-c2ccccc2)c2ccccc12
Reaction time: 1.5 h

Procedure:
1-Hydroxy-4-phenylphthalazine (0.31 g, 1.5 mmol) in toluene (30 ml) is allowed to react with Lawesson's reagent (0.6 g, 1.5 mmol) and the mixture is stirred in an oil bath. (80-90° C.) for 1.5 hour until all starting material is used up. Evaporation of the solvent gives a yellow solid which is stirred with isopropyl ether. Filtration gives the title compound as a yellow solid which is recrystallized from hexane/THF/toluene:7.5/2.5/2.0 (0.3 g)
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=C)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:43].[Na+]>CC(C)=O.O>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=[O:43])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC2
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1C=O)O2
Reaction time: 2 h

Procedure:
To a solution of the product from Step 1 (30 mg, 0.053 mmol) in acetone (1 ml) and water (1 mL) was added potassium osmate dehydrate (19.61 mg, 0.053 mmol). The reaction was stirred at room temperature for 10 minutes after which sodium periodate (114 mg, 0.532 mmol) was added. After stirring for 2 hours, an additional 15 mg of potassium osmate and 115 mg of sodium periodate were added. After stirring 16 hours, the reaction was filtered and the solid was washed with acetone. The filtrate was concentrated, diluted with EtOAc and washed with Na2S2O3 and NaHCO3 aq. soln. Purification by PTLC (30% EtOAc-hexane) provided the desired aldehyde.