Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH:3]([F:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=[O:5].[F:15][N+]1C=CC(C)=CC=1S([O-])(=O)=O.CCCCCC.C(Cl)(Cl)Cl>ClC(Cl)CCl>[CH3:1][S:2][C:3]([F:15])([F:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=[O:5]
Reactant: CSC(F)C(=O)c1ccc(F)cc1F
Reactant: Cc1cc[n+](F)c(S(=O)(=O)[O-])c1
Solvent: ClCC(Cl)Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CSC(F)(F)C(=O)c1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
In a 20 ml solution of 0.5 g (2.3 mmol) of 2-methylthio-2,2',4'-trifluoroacetophenone [Compound (2b-1)] in 1,1,2-trichloroethane, 0.7 g (3.7 mmol) of N-fluoro-4-methylpyridinium-2-sulfonate ("MEC-02", trade name; Daikin Industries, Ltd.) was added at an internal temperature of 80° C., followed by stirring at an internal temperature of 100° C. for 20 minutes. After cooling, the reaction mixture was added to n-hexane. The insoluble matter so precipitated was filtered off. The insoluble matter was then washed with ethyl ether, followed by combination with the hexane layer. The layers so combined were washed successively with water and saturated saline, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column using chloroform, whereby 0.26 g of the title Compound (2c-1) was obtained in the form of a light yellow oil (yield: 48.1%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[CH:29][C:28](=[O:31])[N:27]([CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>C(Cl)Cl.CO>[ClH:37].[CH:32]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[CH:29][C:28]2=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(=O)n(C5CCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=c1ccc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
A solution of 4-[6-(8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (143 mg, 0.29 mmol) in CH2Cl2/MeOH (6 mL/1.5 mL) was treated with HCl gas at room temperature for ˜3 min. The solution was stirred at room temperature for ˜6 hours then filtered to collect the solid. This solid was washed with CH2Cl2 and dried in vacuo to yield 8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (98 mg, 66%). mp 213–215° C. Anal Calc'd for C21H25N7O2O HCl 2.5 H2O: C, 49.51; H, 5.90; N, 15.74; N, 15.74; Cl, 13.92. Found: C, 49.64; H, 6.12; N, 19.23, Cl, 14.20.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:20][C:18]2[N:19]=[C:12]3[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:16][CH:15]=[CH:14][N:13]3[N:17]=2)=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)cc1

Procedure:
(4-Methanesulfonyl-phenyl)-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-bromo-4-methanesulfonyl-benzene (75.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as tan solid (0.063 g, 55%). MP=280-282° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.56 (d, J=5.7 Hz, 1H), 8.22 (d, J=8.0 Hz, 2H), 8.10 (d, J=7.6 Hz, 2H), 7.92 (d, J=7.8 Hz, 2H), 7.77 (d, J=7.3 Hz, 2H), 7.72 (d, J=7.3 Hz, 1H), 7.32 (s, 1H), 7.14-7.09 (m, 1H), 3.11 (s, 3H), 3.06 (s, 3H). MS=443 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[Br:13]Br>C(O)(=O)C>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(C=O)c(Br)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
3,5-dimethoxybenzaldehyde (12.6 g, 76 mmol) was dissolved in acetic acid (350 mL). The resulting colourless solution was cooled to 0° C. A solution of bromine (3.9 mL) in ethanoic acid (50 mL) was added dropwise over 1 h. Once the addition was complete the ice bath was removed and the resulting pale green solution was stirred overnight at room temperature. Cold water was added to the solution. The resulting white solid was collected by vacuum filteration and rinsed with water. The solid was then redissolved in EtOAc and adsorbed on silica gel. The product was purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 1 (12.5 g, 66%) as a white solid. m/z=345.98 (M+H). 1H NMR (500 MHz, CDCl3): δ: 10.43 (1H, s, CHO), 7.06 (1H, s, ArH), 6.73 (1H, s, ArH), 3.93 (3H, s, CH3O), 3.86 (3H, s, CH3O). 13C NMR (500 MHz, CDCl3): δ: 192.09 (CHO), 159.92 (C-5), 157.02 (C-3), 134.67 (C-1), 109.12 (C-2), 105.83, 103.37 (C-4 & C-6), 56.60 (OMe), 55.82 (OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH2:11].CN([CH:15]=[O:16])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]([OH:16])=[O:11]
Reactant: CN(C)C=O
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O
Product: O=C(O)c1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g (33.0 mmol) of commercially available 5-chloro-1H-indole in 50 ml dry DMF was kept at 0° C., while 7.35 g (35.0 mmol) trifluoroacetanhydride was added dropwise. After 3 h stirring at room temperature the mixture was poured into 200 ml water, and the precipitate was filtered with suction and heated with reflux overnight in 200 ml 20% NaOH. It was extracted twice with dichloromethane, and the aqueous layer was acidified with hydrochloric acid. The crystalline title compound was collected by filtration and dried in vacuo.
Reaction SMILES: [CH:1]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:17])[C:13]([C:18]([OH:20])=[O:19])=[CH:12][CH2:11]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[CH:1]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:17])[CH:13]([C:18]([OH:20])=[O:19])[CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)C1=CCc2cc(C3CCCCCC3)c(Cl)cc21
Agent: [Ni]
Solvent: CCO
Product: O=C(O)C1CCc2cc(C3CCCCCC3)c(Cl)cc21

Procedure:
A solution of 1 g of 5-cycloheptyl-6-chloro-ind-1-ene-1-carboxylic acid in 40 ml of absolute ethanol is hydrogenated with 100 mg of Raney nickel at room temperature and normal pressure until 1 equivalent of hydrogen has been taken up. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo and the residue is crystallised from ether/petroleum ether. 5-Cycloheptyl-6-chloro-1-indanecarboxylic acid, thus obtained, melts at 138°-140° C.
Reaction SMILES: N.[Ca].C([O:5][C:6]([C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13])=O)C.[Cl-:14].[NH4+]>C(O)(C)C.CO.C(O)(C)(C)C>[ClH:14].[OH:5][CH2:6][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13]
Reactant: [Cl-]
Reactant: CCOC(=O)c1nc[nH]c1C
Agent: N
Agent: [Ca]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: CC(C)O
Solvent: CO
Product: Cc1[nH]cnc1CO
Product: Cl
Reaction time: 0.67 h
Yield: 47.7 %

Procedure:
A 2 liter flask, fitted with an overhead stirrer and a nitrogen inlet, was charged with 700 ml. of anhydrous ammonia. Calcium (29.0 g., 0.723 m.) was added carefully in portions. t-Butanol (25 ml., 0.266 m.) was added in one portion and 5-methyl-4-imidazolecarboxylic acid ethyl ester (50 g., 0.32 m.) was added in portions over 30 minutes. The blue solution was stirred for 40 minutes and methanol (120 ml.) added dropwise. Ammonium chloride (80.0 g., 1.48 m.) and isopropanol (800 ml.) were added and the ammonia removed. Hydrogen chloride gas was added (pH about 1) and the solids filtered off. The filtrate was concentrated to 100 ml. and acetone (500 ml.) was added. The product was collected and dried to give 4-hydroxymethyl-5-methylimidazole hydrochloride (23.0 g. of 65% pure material; yield 30%).
Reaction SMILES: [CH3:1][CH:2]([C:4](/[C:6](/[C:15]([O:17][CH3:18])=[O:16])=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)[CH3:3].[NH2:19][C:20]([CH:27]([CH3:29])[CH3:28])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH:30](O)(O)C>>[CH:2]([C:4]1[NH:19][C:20]([CH:27]([CH3:28])[CH3:29])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:6]=1[C:15]([O:17][CH2:18][CH3:30])=[O:16])([CH3:3])[CH3:1]
Reactant: CC(O)O
Reactant: CCOC(=O)C=C(N)C(C)C
Reactant: COC(=O)/C(=C/c1ccc(F)cc1)C(=O)C(C)C
Product: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)OCC)C1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
528 g (2 mol) of (E/Z)-4-carboxymethyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one and 350 g (2 mol) of 90% ethyl 3-amino-4-methyl-pent-2-enoate are stirred in 1800 ml ethanediol overnight at a bath temperature of 200° C. The mixture is cooled slowly and poured into a large glass beaker at approx. 80° C. After further cooling to 0° C., the solution is drawn off by suction from the precipitated sediment, then the sediment is washed well with ice cold ethanol and dried in a desiccator. The ethanol solution is concentrated, and the residue together with the ethanediol mother liquor is extracted four times with 1.5 l ether each time. The combined ether phases are washed three times each with 500 ml of 10% hydrochloric acid and once each with 500 ml of saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered, and allowed to stand overnight at room temperature. The solution is drawn off by suction from the precipitated sediment, subsequently washed with ice cold ethanol, and dried in a desiccator. The ethanol solution and the ether mother liquor are concentrated together in a vacuum to a volume of approx. 2 l, allowed to stand overnight again, and drawn off by suction from the precipitated sediment.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].B(F)(F)F.[Cl:16][CH2:17][C:18]([CH3:22])(O)[CH:19]=[CH2:20]>ClC1C=CC=CC=1.CCCCCC.C(OCC)C>[Cl:16][CH:17]([C:8]1[C:2]([CH3:1])=[C:3]([OH:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[OH:7])[C:18]([CH3:22])=[CH:19][CH3:20]
Reactant: C=CC(C)(O)CCl
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: CC=C(C)C(Cl)c1c(C)c(O)c(C)c(C)c1O
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Trimethylhydroquinone (2.01 g, 14 mol) was suspended at room temperature in a mixture of chlorobenzene (10 ml) and hexane (5 ml). Boron trifluoride diethyl ether complex (3.60 ml of a 48 percent strength solution of boron trifluoride in diethyl ether, 1.95 g of boron trifluoride, 28 mmol) was then added in the course of 15 min. 1-Chloro-2-methylbut-3-en-2-ol (2.42 g, 20 mmol) was then added dropwise in the course of 15 min. After 30 min., the reaction mixture was filtered, and the filtrate was washed with chlorobenzene (10 mol) and dried at 40° C./20 mbar for 8 hours. 2.24 g (62.9 percent) of 2-(1-chloro-2-methylbut-2-en-yl)-1,4-dihydroxy-3,5,6-trimethylbenzene were obtained. The melting point of the product Was 118 to 122° C. (decomposition). Other data regarding the product was:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:6]#[N:7].S(=O)(=O)(O)[OH:20].N>ClCCl>[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:6]([NH2:7])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: CC(NC(C#N)CCC(F)(F)F)c1ccccc1
Agent: N
Solvent: ClCCl
Product: CC(NC(CCC(F)(F)F)C(N)=O)c1ccccc1
Temperature: -2.5 °C

Procedure:
5,5,5-Trifluoro-2-(1-phenylethylamino)pentanenitrile (crude mixture of diastereomers from Step B, 1.10 kg) was dissolved in dichloromethane (5.5 L) in a suitable vessel equipped with mechanical stirring, ice bath for cooling and maintained under a blanket of nitrogen. Stirring was started and the reaction mixture was cooled to 0 to −5° C. Concentrated sulfuric acid (1.75 L) was added dropwise over a period of 1 hour into the above mixture, maintaining the temperature below 0° C.; a clear solution was obtained after the addition was complete. The temperature of the reaction mixture was raised to 25 to 27° C. and stirred overnight (12-14 h). Completion of the reaction was determined by HPLC. The reaction mixture was poured slowly over crushed ice (˜15.0 kg) and was neutralized with aqueous ammonia (˜25% by volume). The aqueous layer was separated and extracted with dichloromethane (2×3.0 L). The combined dichloromethane layer was washed with water (1×12.0 L) followed by brine (1×3.0 L). The product rich organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 0.85 kg (72.0%) of the crude title compound 1H NMR (CDCl3) (400 MHz) (Mixture of diasteromers) δ 1.36 (d&m, 4H, CH3 (J=8.0 Hz & 1H of CH2), 1.90 (m, 1H of CH2), 2.15 & 2.35 (two m, 1H each of CH2—CF3), 2.80-2.90 (m, 1H, CH-Ph), 3.60-3.70 (m,1H, —(CONH2)CH(NH), 5.90 & 6.45 (1H each of CONH2 with minor peaks for other diasteromer), 7.20-7.40 (m, 6H, Ar+NH).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:20][C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24](=[O:34])[C:23]=3[CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3c(c2)C(=O)c2ccccc2-3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5 Step A and 2-hydroxy-9-fluorenone in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H20O5 [M−H]−: 411.2
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:33])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH2:14][NH:15][S:16]([C:19]1[C:28]2[C:23](=[C:24]([N:29]([CH3:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C.CCOCC>O1CCOCC1>[ClH:1].[CH3:30][N:29]([CH3:31])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][CH:20]=[C:19]2[S:16]([NH:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:7]([OH:33])=[O:6])=[O:32])(=[O:17])=[O:18]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCC(=O)N3CCC[C@H]3C(=O)OC(C)(C)C)cccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)c1cccc2c(S(=O)(=O)NCC(=O)N3CCC[C@H]3C(=O)O)cccc12
Reaction time: 1 h
Yield: 99 %

Procedure:
A cold (0° C.), saturated solution of hydrogen chloride in dioxane (400 mL) was added to N-(5-dimethylamino-1-naphthalenesulfonyl)-glycyl-L-proline tert-butyl ester (7.20 g, 15.6 mmol). The mixture was stirred at about 0° C. for about 2 hours and at room temperature for about 2 hours before ether (100 mL) was added. After refrigeration for about 1 hour, the mixture was suction-filtered and afforded 8.30 g (99%) of the title compound as a dense, white solid, m.p. 115°-135° C. (sealed tube); 1H NMR (D2O) δ 8.53 (d, J=8.8 Hz, 1H), 8.30 (d, J=8.7 Hz, 1H), 8.10 (d, J=7.4 Hz, H), 7.95 (d, J=7.8 Hz 1H), 7.74-7.67 (m, 2H), 3.84-3.67 (m, 2H), 3.61 (s, 6H), 3.32-3.17 (m, 2H), 1.96-1.87 (m, 1H), 1.77-1.67 (m, 3H); --C NMR (D2O) ppm 178.17, 178.03, 170.68, 170.34, 141.10, 137.84, 137.61, 133.07, 132.88, 131.39, 130.65, 129.57, 129.24, 128.50, 128.41, 128.11, 122.13, 61.88, 49.52, 49.27, 46.82, 33.44, 31.34, 26.84, 24.32; IR (KBr, cm-1) 3432, 3070, 2960, 1736, 1654, 1440, 1328, 1178, 1146, 1120, 872, 772, 586; MS m/z (MH+ -HCl) calcd 406.1437, obsd 406.1450.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]([NH:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)=[O:39])=[CH:31][CH:30]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([O:19][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][C:38](=[O:39])[NH:40][O:41][C@@H:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:33][CH:34]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCc1ccc(O)cc1)NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OCc2ccccc2)cn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)Oc1ccc(CCCC(=O)NO[C@@H]2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(R)-3-(5-(Benzyloxy)pyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (0.19 g, 0.5 mmol), 4-(4-hydroxyphenyl)-N-(tetrahydro-2H-pyran-2-yloxy)-butanamide (0.14 g, 0.5 mmol), and DMAP (0.06 g, 0.5 mmol) were added into DCM (10 mL) and stirred at 0° C. for 10 min. A solution of DCC (0.12 g, 0.6 mmol) in DCM (5 mL) was added to the above-mentioned solution dropwise. The mixture was stirred from 0° C. at room temperature for 1 h (monitored by TLC). The white solid was removed and the filtrated was then evaporated in vacuo. Ethyl acetoacetate was added and the solid was again removed. The solution was evaporated in vacuo. The residue was purified by chromatography (EA:Hex=1:5) to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:23])[C:11]2[CH:17]=[C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:23])[C:11]2[CH:17]=[C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCCCC3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCCCC3
Yield: 96.7 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.23 mL, 2.1 mmol) was added to a stirred solution of chloride 187 (178 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 188 (204 mg, 95%) as a yellow solid: mp (MeOH) 149-152° C.; 1H NMR δ 7.96 (s, 1H, H-11), 7.31 (s, 1H, H-5), 5.84 (br s, 1H, NH), 3.52-3.57 (m, 2H, CH2N), 2.85-2.90 (m, 4H, H-6, H-10), 2.58 (br t, J=6.0 Hz, 2H, CH2N), 2.28 [s, 6H, N(CH3)2], 1.79-1.85 (m, 2H, H-8), 1.65-1.74 (m, 4H, H-7, H-9); 13C NMR δ 159.0, 153.4, 148.0, 142.1, 129.0, 125.0, 118.8, 57.6, 45.1 (2), 38.7, 36.8, 36.2, 32.0, 28.7, 28.4. Anal. calcd for C16H23N5O.½H2O: C, 61.9; H, 7.8; N, 22.6. Found: C, 62.0; H, 7.8; N, 22.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])(=[O:25])=[O:24])[CH:7]=1
Reactant: COc1ccccc1/C=C/S(=O)(=O)Cl
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Product: COc1ccccc1/C=C/S(=O)(=O)Nc1cc(Cl)ccc1S(N)(=O)=O

Procedure:
The title compound was synthesized as described for Example 226 a) starting from 2-amino-4-chlorobenzenesulfonamide and (E)-2-(2-methoxyphenyl)ethenesulfonyl chloride.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:22]>>[BrH:22].[OH:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C2CNCc3ccc(C)cc32)cc1OC
Agent: Br
Product: Cc1ccc2c(c1)C(c1ccc(O)c(O)c1)CNC2

Procedure:
To 450 mg of 4-(3,4-dimethoxyphenyl)-6-methyl-1,2,3,4 -tetrahydroisoquinoline, was added 9 ml of 48% hydrobromic acid, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction solution was cooled, and the crystals which separated out were collected by filtration, giving 390 mg of 4-(3,4-dihydroxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:25])[CH2:6][NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][N:11]=1)=[O:9])[CH3:3].O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>O>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([F:40])[CH:46]=2)=[CH:12][N:11]=1)=[O:9])[CH3:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)CNC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CNC(=O)c1ncc(-c2cccc(F)c2)cc1O
Temperature: 80 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a 5 L round-bottomed flask was charged [(3-hydroxy-5-trifluoromethanesulfonyloxypyridine-2-carbonyl)-amino]-acetic acid ethyl ester sodium salt, 4, (310 g, 0.78 mol), 1,4-dioxane (3 L) and water (150 mL). The solution was subjected to a vacuum-nitrogen purge cycle, followed by the addition of potassium phosphate (50 g, 0.234 mol) and 3-fluorophenylboronic acid (163 g, 1.17 mol). After addition, the vacuum-nitrogen purge cycle was repeated once. 1,1-Bis(diphenyl-phosphino)ferrocenepalladium (II) chloride CH2Cl2 complex (72 g, 0.088 mol, 0.11 eq.) was then added. After another vacuum-nitrogen purge cycle, the reaction mixture was then heated to 75 to 85° C. The progress of the reaction was monitored by TLC. The reaction was complete after 14-16 hours. The reaction was cooled to 15 to 25° C. and concentrated by rotary evaporation at up to 45° C. bath temperature until solvent collection had ceased. The residue was treated with an aqueous solution of HCl (1M, 1.5 L) and ethyl acetate (1.5 L) and stirred for 30 minutes at room temperature. The layers were then separated. The organic layer was washed with water (1.5 L), brine (1.5 L), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethylacetate/acetic acid: 3:1:0.01 by vol/vol) to afford 226 g (90% yield) of the desired product. MS (ESI+): m/z 319 (M+1); 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H), 8.44 (s, 1H), 8.32-0.31 (d, J=1.5 Hz, 1H), 7.51-7.44 (m, 2H), 7.40-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.17-7.13 (t, J=6.6 Hz, 1H), 4.33-4.25 (m, 4H), 1.36-1.31 (t, J=7.2 Hz, 3H).