Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([OH:23])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H](C2C=CC=CC=2)C)[C:29](=[O:40])[CH2:28]1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([O:23][C@@H:25]([C@H:27]3[CH2:31][NH:30][C:29](=[O:40])[CH2:28]3)[CH3:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: COc1cc(-c2cc(O)c3cccnc3c2)cc(OC)c1OC
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3cccnc3c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
80 mg of 7-(3,4,5-Trimethoxyphenyl)quinolin-5-ol, 62 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one and 142 mg of triphenylphosphine was dissolved in 5 mL of DCM. 125.5 mg of DBAD was added and the mixture stirred for 6 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified via flash chromatography (10 SiO2; cyclohexane→cyclohexane:ethylacetate:MeOH 58:40:2). Product containing fractions were concentrated, dissolved in 1.5 mL of TFA and heated 75 min at 150° C. in the microwave. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 21 mg of Example 2 as solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12]([Cl:21])=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCC2(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCC2(C)C

Procedure:
20.0 g (0.075 mol) of 4,4,8-trimethyl-1,1-dioxothiochroman-7-carboxylic acid were dissolved in 200 ml of toluene and three drops of dimethylformamide and 10.7 g (0.09 mol) of thionyl chloride were added. After three hours of heating under reflux, the solvent was removed and the colorless oil that remained (yield 21.3 g) was directly used further.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C-:8].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([CH2:21][C:22](Cl)=[O:23])[CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([CH2:21][C:22]2[O:23][CH:8]=[N:7][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH:20]=1
Reactant: O=C(Cl)Cc1cc(Br)ccc1Cl
Reactant: [C-]#[N+]CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1Cc1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of potassium t-butoxide (1.35 g) in tetrahydrofuran (20 ml) was cooled to 0° C., and thereto was added methyl isocyanoacetate (1.33 ml). Then, a solution of the above 5-bromo-2-chlorophenylacetyl chloride in tetrahydrofuran (20 ml) was added thereto, and the mixture was stirred at 0° C. for 2 hours, and then at room temperature overnight. The mixture was cooled again to 0° C. 10% aqueous citric acid solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 5-bromo-2-chloro-1-(4-methoxycarbonyl-5-oxazolylmethyl)benzene (1.12 g) as a yellow solid. APCI-Mass m/Z 330/332 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].CI.[CH2:20]1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:20])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cc(O)c2ccccc2c1OC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(OC)c2ccccc2c1OC(C)=O

Procedure:
A solution of 1-acetyloxy-2-methoxy-4-hydroxynaphthalene (23.2 g) and methyl iodide (6.4 mL) in tetrahydrofuran (250 mL) was treated dropwise with a solution of DBU (16.5 mL) in tetrahydrofuran (50 mL). The resulting precipitate of DBU.HI was removed by filtration, and the filtrate evaporated. Recrystallization from methanol gave 1-acetyloxy-2,4-dimethoxynaphthalene, m.p. 116°-117° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2].Br[CH2:42][CH:43]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:44][CH:43]([O:45][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:47])[CH3:48])[CH3:42])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(CBr)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O[Si](C)(C)C(C)(C)C)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (500 mg, 0.86 mmol) in dry DMF (10 mL), was added (1-bromopropan-2-yloxy)(tert-butyl)dimethylsilane (327 mg, 1.3 mmol) and cesium carbonate (847 mg, 2.6 mmol). The reaction mixture was was stirred at 60° C. for 14 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (150 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Ethyl acetate:Pet. Ether) to afford title compound (350 mg, 53.8%) as white solid.
Reaction SMILES: [ClH:1].[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].S(Cl)([Cl:30])=O>>[ClH:30].[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([Cl:1])=[O:27])=[CH:21][C:20]=3[Cl:30])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)O)cc3)CC2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)Cl)cc3Cl)CC2)CC1

Procedure:
1-Isopropyl4-[1-(4-carboxy-phenyl)-piperidin-4-carbonyl]-piperazine hydrochloride (D9) (0.25 g) was dissolved in thionyl chloride (10 ml) and heated at reflux for 1.5 h. The reaction mixture was then evaporated to a minimum (co-evaporated with DCM, 3×10 ml) to give the subtitled compound as a yellow oil (0.25 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH:28]=[N:27][C:26]([NH2:29])=[N:25]1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:29][C:26]3[N:27]=[CH:28][N:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[C:17]([F:31])([F:16])[F:30])[N:25]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Nc1ncn(-c2ccccc2C(F)(F)F)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccccc4C(F)(F)F)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2-trifluoromethyl-phenyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a brownish solid (Yield=77%). MS ISP (m/e): 410.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=S)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.[H-].[Na+].C(I)C.[N:41]#[C:42][NH2:43]>O1CCCC1>[C:42]([NH:43][C:19](=[N:18][CH2:17][CH2:16][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)#[N:41]
Reactant: N#CN
Reactant: CN(CCCNC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CN(CCCN=C(NC#N)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of N-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-3,5-di-tert-butyl-4-hydroxybenzothioamide (1.0 g) obtained in Example 60 in dry tetrahydrofuran was added sodium hydride (0.16 g) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added ethyl iodide (0.31 g), followed by stirring at room temperature for 2 hours. The mixture was again cooled to 0° C., and cyanamide (0.84 g) was added thereto, followed by stirring at room temperature for 15 hours. After completion of the reaction, the mixture was poured into ice-water, and the product was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 99:1) to afford 0.70 g (69%) of the title compound as pale yellow crystals. mp 129-130° C. NMR (CDCl3) (200 MHz) δ: 1.45 (18H, s), 1.6-2.1 (2H, m), 2.20 (3H, s), 2.6-3.0 (4H, m), 3.6-3.8 (2H, m), 3.83 (2H, t, J=5.7 Hz), 5.56 (1H, s), 5.84 (2H, s), 5.8-6.8 (3H, m), 7.48 (2H, s), 8.44 (1H, brs)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[CH3:32][N:33]([C@H:43]([CH3:47])[C:44](O)=[O:45])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:44](=[O:45])[C@H:43]([N:33]([CH3:32])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH3:47]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: C[C@H](C(=O)O)N(C)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)N(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (397 mg, 0.945 mmol), EDC (362 mg, 1.891 mmol), and DMAP (289 mg, 2.364 mmol) in 10 ml of dry DCM was stirred for 15 minutes at room temperature, then (R)-2-(N-methylphenyl-sulfonamido)propanoic acid (345 mg, 1.418 mmol) was added. After stirring overnight at room temperature, the reaction was complete. The mixture was washed twice with 1N HCl, then with aq. NaHCO3, with brine and finally dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (AcOEt) to obtain 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(N-methylphenylsulfonamido)propanoyloxy)-ethyl)pyridine 1-oxide (430 mg, 0.666 mmol, 70.5% yield, MS/ESI+ 645.05 [MH]+, [αD]=+6.6, c=0.483, DCM).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][F:21])[C@@H:7]2[C@H:8]([O:11]C(OCC)C)[O:9][CH:10]=1)=[O:4].Cl.O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][F:21])[C@@H:7]2[CH:8]([OH:11])[O:9][CH:10]=1)=[O:4]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CF)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1=COC(O)[C@H]2C(CF)=CC[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
670 mg of the above (1S,4aS.7aR)-1-[1-(ethoxy) ethoxy]-7-(fluoromethyl)-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in tetrahydrofuran followed by addition of 2N aqueous hydrochloric acid and stirring for 2 hours at room temperature. The reaction mixture was neutralized after adding water, and then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a pale yellow oil from the hexane-ether eluate in the form of (4aS,7aR)-7-(fluoromethyl)-1-hydroxy-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (500 mg, yield: 98%). The physicochemical properties of this compound are described below.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([N:21]1[CH2:28][CH2:27][C@@H:26]([OH:29])[C@H:22]1[C:23]([OH:25])=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>O>[C:7]([O:29][C@@H:26]1[CH2:27][CH2:28][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:22]1[C:23]([OH:25])=[O:24])(=[O:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Pyridine (5 mL) and acetic anhydride (2 mL) were added to N-boc-cis-3-hydroxy-L-proline (400 mg, 1.73 mmol) and the reaction was stirred for 4 hours at room temperature. The reaction was diluted with water, acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (370 mg, 78%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1.[H][H]>C(OCC)(=O)C.[Pd].CO>[F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(CCF)CC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)CN(CCF)CC2
Yield: 99.6 %

Procedure:
2-(2-fluoroethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (assumed 1.07 mmol from previous reaction) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-(2-fluoroethyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (239 mg, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 2.80-2.93 (m, 6 H), 3.51 (bs, 2 H), 3.61 (s, 2 H), 3.80 (s, 3 H), 4.58-4.75 (dt, JHF=47.6, J=4.9 Hz, 2 H), 6.37 (s, 1 H), 6.50 (s, 1 H).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([CH2:23][CH2:24][CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.C1COCC1>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:14][CH:15]=2)[N:10]=[C:9]([CH2:23][CH2:24][CH3:25])[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 60 °C
Yield: 87.6 %

Procedure:
A 2M aq. LiOH sol. (44 ml) was added to a solution of 4.3 g (13.7 mmol) 4-methyl-2-propyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/THF mixture (in each case 44 ml) and the mixture was subsequently heated to 60° C. for 72 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with ether, set at pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 3.6 g (12.0 mmol, 88%) 4-methyl-2-propyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH3:27])[CH:23]([CH3:26])[CH2:24][CH3:25])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH3:27])[CH:23]([CH3:26])[CH2:24][CH3:25])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCNCc1ccccc1
Reactant: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCC(C)N(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
Sodium triacetoxyborohydride (2.0 g) was added to a solution of 3-chloro-5-[methyl(1-methylpropyl)amino]pyrazine-2-carbaldehyde (1.43 g), N-benzylethanolamine (1.14 g) and acetic acid (1.08 mL) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→80% ethyl acetate/hexane) to give the title compound (2.07 g, 91%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH:13]([C:19](=O)[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:12](=O)[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][NH2:32]>C(O)C>[CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[C:19]([C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])=[N:32][N:31]([CH3:30])[C:12]=3[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C(=O)C1CCc2cnc(SCc3ccccc3)nc2C1=O)c1ccccc1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(C(=O)c2ccccc2)c2c1-c1nc(SCc3ccccc3)ncc1CC2
Yield: 70.5 %

Procedure:
0.22 g (0.55 mmol) of 1-[2-(benzylthio)-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl]-2-phenylethane-1,2-dione were dissolved in 6 mL of ethanol and 0.03 g (0.66 mmol) of methyl hydrazine were added. The reaction mixture was maintained under stirring at refluxing temperature for 5 hours. After that time the solvent was removed under reduced pressure, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated, giving 0.16 g of the title compound (70% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:13]([NH:16][C:17]([NH2:19])=[S:18])=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:28][CH:29]=O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:13]([NH:16][C:17]3[S:18][CH:28]=[CH:29][N:19]=3)=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1NC(N)=S
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1Nc1nccs1
Temperature: 100 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
[5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-yl]-thiourea (0.28 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred three hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-yl]-thiazole-2-yl-amine (“A32”) is obtained after reversed phase column chromatography (acetonitrile/water+0.1% TFA) as yellow solid in a yield of 22%. HPLC (method C): 1.52 min; LC-MS (method A): 1.37 min, 422.15 (MH+); 1H-NMR (DMSO-d5, 500 MHz): δ [ppm] 10.272 (s, 1H), 7.906 (d, 2H, J=8.8 Hz), 7.853 (d, 1H, J=2.3 Hz), 7.462 (d, 1H, J=3.7 Hz), 7.44 (d, 1H, J=2.3 Hz), 7.201 (d, 2H, J=8.8 Hz), 7.087 (d, 1H, J=3.7 Hz), 4.261 (t, 2H, J=4.5 Hz), 3.764 (t, 2H, J=4.5 Hz), 3.333 (s, 3H), 3.184 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:23][C:24](OC2C=CC=CC=2)=[O:25])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:24]([NH:23][C:15]2[CH:14]=[C:13]([Cl:12])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(N)cc1
Yield: 131.1 %

Procedure:
From 2.7 g (15.7 mmol) of 4-aminobenzenesulfonamide and 4.8 g (15.7 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a manner similar to Preparation Example 1, 7.9 g (yield 94%) of methyl 2-{[(4-aminobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate was obtained. Property: colorless amorphous, PMR (δppm, DMSO-d6): 3.59 (3H, s), 5.37 (2H, s), 6.45 (2H, d), 6.83 (1H, dd), 7.41 (2H, d), 7.81 (1H, d), 8.66 (1H, d), 9.64 (1H, s).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18]>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
1,4-dioxa-8-azaspiro(4,5)decane (20.0 g, 0.14 mol), DCM (300 ml) and 1N aqueous sodium carbonate solution (200 ml) were charged to a flask and cooled to <10° C. A solution of 4-cyanobenzenesulfonyl chloride (26.8 g, 0.133 mol) in DCM (100 ml) was added dropwise, maintaining the temperature below 10° C. (typically addition takes 40-50 min). Cooling was removed and stirring at room temp continued for 2 h. The layers were separated, the organic layer was washed with water (2×100 ml) and concentrated in vacuo to approximately 100 ml. Hexane (about 300 ml) was added to initialise crystallisation. The precipitate was aged at 0-5° C. for 10-30 min, filtered and washed with hexane (2×100 ml) to yield 38.2 g (88%) of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzonitrile 7a as white solid.