Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)=[N:4][O:5][CH2:6][CH3:7].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=[P:23](=[O:25])[O-:24].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=[P:23](=[O:24])[O:25][CH2:2][C:3]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)=[N:4][O:5][CH2:6][CH3:7]
Reactant: Cc1ccccc1S(c1ccc(Br)cc1)=P(=O)[O-]
Reactant: CCON=C(CCl)OC(=O)NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCON=C(COP(=O)=S(c1ccc(Br)cc1)c1ccccc1C)OC(=O)NC1CC1
Temperature: 25 °C

Procedure:
1-Chloro-2-(N-cyclopropylcarbamoyloxy)-2-ethoxyiminoethane (11 grams; 0.05 mole), methyl ethyl ketone (80 ml), potassium 2-methylphenyl(4-bromophenyl)thionophosphinate (17 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 8 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvents in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[2-(N-cyclopropylcarbamoyloxy)-2-ethoxyiminoethyl] 2-methylphenyl(4-bromophenyl)thionophosphinate.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=1)[C:3]#[C:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1/[C:7](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:8](=[O:14])[NH:9]2.O.[Cl-].[NH4+]>CO.[Zn]>[NH2:29][C:25]1[CH:24]=[C:23]([CH:2]([OH:1])[C:3]#[C:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2/[C:7](=[CH:15]/[C:16]2[NH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])/[C:8](=[O:14])[NH:9]3)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccc([N+](=O)[O-])c3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccc(N)c3)c21

Procedure:
rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-nitrophenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (25 mg, 0.068 mmol) (from Example 60) was added to 10% H2O in methanol (2 mL) and to this mixture was added zinc dust (35 mg, 0.53 mmol) and ammonium chloride (10 mg, 0.19 mmol). The reaction was heated at reflux for 3 h, at which time the reaction was cooled and the solid was filtered off. The solids were washed extensively with ethyl acetate, and the ethyl acetate and methanol were evaporated in vacuo. The resulting precipitate was filtered off, dried and recrystallized from ethyl acetate/hexane to give rac-(Z)-4-[3-(3-aminophenyl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 19 mg, 73%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[F:19]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.C([O-])(O)=O.[Na+]>O1CCCC1.O>[F:19][CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[C:12]#[N:13]
Reactant: N#CCc1ccc2ncccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(F)c1ccc2ncccc2c1
Yield: 44.4 %

Procedure:
A solution of quinolin-6-yl-acetonitrile (1.06 g, 6.3 mmol) in tetrahydrofuran (40 mL) was cooled to −78° C. to which tert-butyl lithium (0.8 M in pentane, 7.6 mmol, 7.9 mL) was added in a dropwise fashion over 10 minutes. After the addition was complete the mixture was stirred at −78° C. for 30 min before a solution of N-fluorodi(benzenesulfonyl)-amine (1.5 eq., 9.45 mmol, 3.0 g) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred for 2 hours at −78° C. before water was added followed by aqueous NaHCO3. The mixture was extracted with dichloromethane (3×80 mL), dried (Na2SO4) and concentrated in vacuo onto silica gel and purified via flash column chromatography (SiO2, hexane:ethyl acetate 100/0-50/50) to return the title compound as a red solid (520 mg, 2.8 mmol, 44%). 1H NMR 500 MHz (DMSO-d6) δ 6.05 (1H, d), 7.66 (1H, dd), 7.95 (1H, dd), 8.19 (1H, d), 8.32 (1H, t), 8.55 (1H, d), 9.03 (1H, dd); MS (m/z) 187 [M+H+]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:33]([C:39]([F:42])([F:41])[F:40])([C:35]([F:38])([F:37])[F:36])[OH:34])=[N:10]1.[ClH:43]>C(OCC)(=O)C>[ClH:43].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:33]([C:35]([F:36])([F:37])[F:38])([C:39]([F:41])([F:40])[F:42])[OH:34])=[N:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(4-BOC-piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (340.0 mg, 0.6 mmol) prepared in Example 404 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 300.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH:31]([OH:37])[C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(OC(=O)C)(=O)C>[C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH:31]([O:37][C:33](=[O:34])[CH3:32])[C:32]([CH3:35])([CH3:36])[CH2:33][O:34][C:1](=[O:19])[CH3:2])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCNC(=O)CCNC(=O)C(O)C(C)(C)CO
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCNC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O
Yield: 164.2 %

Procedure:
N-(4-Oleoylaminobutyl)-3-[N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)amino]propanamide (0.55 g) and 10 ml of acetic anhydride were reacted in the same manner as in Example 36 to obtain 0.52 g of the title compound (yield: 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=O.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>O>[Cl:18][C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: COc1cc(OC)c2cn[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)c2cnnc(Cl)c2c1
Temperature: 25 °C
Yield: 91 %

Procedure:
1 g (4.9 mmol) of 5,7-dimethoxy-2H-phthalazin-1-one and 10 mL of phosphoryl chloride are heated at 80° C. for 2 hours. After cooling to room temperature, the reaction medium is poured dropwise into 50 mL of water and the mixture is then basified with 6N sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water and with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. 1 g of a beige-coloured solid is obtained (91% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]=2[C:28]([O:30]CC)=[O:29])=[CH:5][CH:4]=1.[OH-].[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]=2[C:28]([OH:30])=[O:29])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cccnc2n1Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)O)n(Cc3ccc4c(c3)OCO4)c3ncccc23)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 3-(4-methoxyphenyl)-1-(3,4-methylenedioxybenzyl)-pyrrolo[2,3-b]pyridine-2-carboxylate in EtOH with aqueous 1 N NaOH is stirred under an argon atmosphere first at room temperature then at reflux temperature. The reaction mixture is cooled to room temperature then poured into H2O and the solvent volume reduced in vacuo. The aqueous solution is extracted with Et2O and the Et2O extract discarded. The aqueous layer is acidified with 6 N HCl and the product extracted into EtOAc. The organic extract is washed with H2O then saturated aqueous NaCl, dried (Na2SO4) and the solvent removed in vacuo to afford the title compound.
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[S:8][C:7]=1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1S(C)(=O)=O)=[O:5].[OH2:35]>>[O:35]=[C:23]1[N:22]([CH2:21][C:7]2[S:8][C:9]3[N:10]([CH:18]([CH3:20])[CH3:19])[C:11](=[O:17])[N:12]([CH3:16])[C:13](=[O:15])[C:14]=3[C:6]=2[C:4]([OH:3])=[O:5])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24]1
Reactant: O
Reactant: COC(=O)c1c(Cn2c(S(C)(=O)=O)nc3ccccc32)sc2c1c(=O)n(C)c(=O)n2C(C)C
Agent: [Na]
Product: CC(C)n1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cn3c(=O)[nH]c4ccccc43)sc21

Procedure:
Sodium hydrogenocarbonate (0.55 g) was added to a suspension of the product from example 32 part b) (0.54 g) in water. The reaction mixture was heated at reflux for 17 h. The reaction mixture was washed with ethyl acetate and the aqueous layer was freezed dried to give the sub-title compound (0.7 g). MS(ES)(M++H) 415
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[C:12](OCC)(=[O:14])C>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:14][CH3:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: OC/C=C/c1cccc(Br)c1
Product: COC(=O)/C=C/c1cccc(Br)c1
Yield: 73 %

Procedure:
The title compound was prepared from trans-3-(3-bromophenyl)-2-propenol by a sequence analogous to that described above for compound (9a) but using D-(-)-diethyl tartrate. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 3:7) provided the title compound (73%) as a pale yellow oil. Distilled at 160-185° C. at 0.1 mmHg. using a Kugelrohr short path distillation apparatus as a colourless oil; [α]D25 +37.6 (c=0.020 gml-1, CHCl3).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21]>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[CH3:16])=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: CN(C)CCCN
Solvent: CC#N
Product: CN(C)CCCNCC(=O)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.77 cm3 of 3-(dimethylamino)propylamine. The reaction medium is refluxed for 3 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (90/10/1 by volume). The fractions containing the expected product are combined, concentrated under reduced pressure and then dried (90 Pa; 45° C.) to give 300 mg of N-(6-chloro-1H-indazol-3-yl)-2-[[3-(dimethylamino)propyl]amino]acetamide in the form of light-brown foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH3:18][C:19]1[C:23]([NH2:24])=[C:22]([CH3:25])[O:21][N:20]=1>>[CH3:18][C:19]1[C:23]([NH:24][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[C:22]([CH3:25])[O:21][N:20]=1
Reactant: Cc1noc(C)c1N
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Product: COCc1cc2c(C(=O)Nc3c(C)noc3C)ccc(OC)c2o1
Yield: 69.4 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.19 g) and 3,5-dimethylisoxazol-4-ylamine (88 mg). Purification by column chromatography on silica eluting with ethyl acetate afforded the title compound as a cream solid (0.18 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:18])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([F:18])[C:9]#[CH:10])[N:7]=1
Reactant: C#CC(O)c1cccc(Br)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C#CC(F)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(6-Bromopyridin-2-yl)prop-2-yn-1-ol (1.06 g, 5.00 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. Diethylaminosulfur trifluoride (925 μL, 7.00 mmol) was added dropwise, and the brown solution was stirred at 0° C. for 1 h. The reaction was quenched with saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (0-15% EtOAc/hexanes) afforded the title compound as an orange oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[C:60]([CH2:62][CH3:63])=[CH2:61].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:60]([CH2:62][CH3:63])=[CH2:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C=C(CC)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=C(CC)OC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33% methylene chloride in cyclohexane) sec-butenyl trichloroacetimidate (62 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 13 mg 3"-ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1sc2ccccc2c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1sc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To an ice cold solution of 10.0 g (47.0 mmol) of 3-chloro-benzo[b]thiophene-2-carboxylic acid (11) in 200 mL of THF was added 47 mL of LiAlH4 (47 mmol, 1 M/THF). After 3 h, the reaction was quenched by addition of MeOH (ca. 40 mL). The volatiles were evaporated and the residue was treated with 50 mL 1 M HCl. After stirring for 10 min., the mixture was extracted with CH2Cl2 (3×150 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (10-20% ethyl acetate/hexane) gave 4.32 g (21.6 mmol, 46%) of the alcohol (12).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]([C:41]([OH:44])([CH3:43])[CH3:42])[CH:38]=[CH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O>[OH:44][C:41]([C:37]1[CH:36]=[C:35]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)[CH:40]=[CH:39][CH:38]=1)([CH3:43])[CH3:42]
Reactant: CC(C)(O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)c1cccc(-c2ncc3c(n2)N2CCOC[C@H]2CN3CC(=O)NCC2CCOCC2)c1
Temperature: 120 °C
Yield: 68.7 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 50 mg, 0.131 mmol), 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (51.5 mg, 0.196 mmol), tetrakis(triphenylphospine)palladium (0) (15.13 mg, 0.013 mmol) and sodium carbonate (27.8 mg, 0.262 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.25 mL) was heated to 120° C. in a microwave for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (amine-functionalized silica, 0-10% MeOH gradient in CHCl3) to afford the title compound as an off-white solid (43.4 mg, 0.090 mmol, 68.8%). 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.26 (m, 2 H), 1.45 (s, 6 H), 1.48-1.71 (m, 3 H), 2.91-3.05 (m, 3 H), 3.11-3.36 (m, 5 H), 3.50-3.67 (m, 2 H), 3.73-3.93 (m, 4 H), 3.96-4.09 (m, 2 H), 4.56 (d, J=11.87 Hz, 1 H), 5.04 (s, 1 H), 7.31 (t, J=7.71 Hz, 1 H), 7.40-7.47 (m, 1 H), 7.51 (s, 1 H), 7.99-8.12 (m, 2 H), 8.34 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C26H35N5O4, 481.27; found 482.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13]C(C)=O)[C:10]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[C:10]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(S(=O)(=O)O)c(NC(C)=O)cc1OC
Solvent: CO
Product: COC(=O)c1cc(S(=O)(=O)O)c(N)cc1OC
Reaction time: 24 h

Procedure:
75 liters of methanol is placed in a 100 liter reactor. It is agitated and 24.5 kg of finely ground methyl 2-methoxy-4-acetamino-5-sulfobenzoate is added. The sulfonic acid dissolves; the deacetylated derivative crystallises shortly afterwards. The reaction mixture is left at room temperature for 24 hours, with agitation, so as to complete precipitation. The product is drained in a centrifugal drier, washed twice, with 6 liters of methyl alcohol each time, and dried in a ventilated oven at 50° C.; it has the following properties:
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)(Cl)Cl>[CH3:29][S:30]([O:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:24]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) was dissolved in chloroform (30.0 mL) and the mixture was cooled at 0° C. To this mixture was added TEA (1.4 mL, 0.010 mol) and methanesulfonyl chloride (0.68 mL, 0.0088 mol) and the resulting mixture was stirred at 0° C. for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and the concentrated in vacuo. 1H NMR (CDCl3): δ 7.43 (m, 6H), 7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m, 2H), 1.93 (m, 2H), 1.09-1.60 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH:2]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9])=[O:1]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a solution of 2-(hydroxymethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (1.75 g) in acetonitrile (50 mL) was added Dess-Martin reagent (2.1 g). The reaction mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (790 mg, yield 46%) as pale-yellow crystals.
Reaction SMILES: OO.NC(N)=[O:5].C1(=O)OC(=O)C2=CC=CC=C12.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:44])[N:27]([C@H:29]2[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH2:31][CH2:30]2)[CH3:28])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26](=[O:44])[N+:27]([O-:5])([C@H:29]2[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]([CH3:42])[CH3:43])[CH2:31][CH2:30]2)[CH3:28])=[CH:23][CH:24]=1
Reactant: NC(N)=O
Reactant: CN(C)CCCCCO[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: O=C1OC(=O)c2ccccc21
Agent: OO
Solvent: ClCCl
Product: CN(C)CCCCCO[C@H]1CC[C@H]([N+](C)([O-])C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.39 g (4.4 mmol, 2.2 eq) Hydrogen peroxide.Urea adduct in CH2Cl2, 338.5 mg (2.2 mmol, 1.1 eq) phthalic anhydride were added and stirred for 15 min at RT. 800 mg (2.01 mmol) trans-[4-(5-Dimethylamino-pentyloxy)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in CH2Cl2 was added and the mixture was stirred at RT for 2 h. 5% aqueous K2CO3 solution was added and the inorganic phase was extracted with CH2Cl2. The organic phases were washed with water and brine and dried over MgSO4. Column chromatography yielded 525 mg (63%) trans-[4-(5-Dimethylamino-pentyloxy)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester N-oxide as colourless oil, MS: 413 (MH+, 1Cl).