Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](F)=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:41][C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 130 °C
Yield: 71.8 %

Procedure:
A mixture of (R)-[5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (100 mg, 0.21 mmol), sodium hydride (60% dispersed in mineral oil, 50 mg, 1.25 mmol) and 4-chlorophenol (315 mg, 2.45 mmol) in N,N-dimethylformamide (2 mL) was heated in a microwave oven at 130° C. for 15 minutes. The resulting mixture was then acidified with 0.1N hydrochloric acid to pH 5. The precipitate was collected by filtration and purified by preparative HPLC to afford (R)-{5-[3-chloro-4-(4-chloro-phenoxy)-benzenesulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (87.2 mg, 72%) as a white powder. MS cald. for C28H29Cl2NO6S 577, obsd. 578 (ESI+) [(M+H)+].
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: CCCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of 4-butoxybenzaldehyde (0.5 g, 2.8 mmol) and 3,5-dimethoxyacetophenone (0.5 g, 2.8 mmol) in methanol (10 ml) was added 50% w/v of aqueous sodium hydroxide (2.24 ml, 0.028 mol). The reaction mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. The product was recrystallised from ethanol to give 0.925 g (97%) of off-white crystals. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.35 (d, 1H), 7.1 (d, 2H), 6.9 (d, 2H), 6.7 (t, 1H), 4.0 (t, 2H), 3.85 (s, 6H), 1.75 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 191.1, 161.4, 160.8, 144.9, 140.8, 130.2, 127.3, 119.6, 114.9, 106.3, 104.8, 67.9, 55.6, 31.2, 19.2, 13.8. Mass Spectrum m/e (M+1) 341.
Reaction SMILES: Cl.[C:2]1(=O)[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].[OH-].[Na+]>>[NH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: Nc1ccccc1S
Reactant: O=C1CCCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCCCc1nc2ccccc2s1
Temperature: 0 °C

Procedure:
36.5 g of hydrogen chloride gas are introduced over a period of 30 minutes into a mixture of 113 g (1 mol) of caprolactam and 125 g (1 mol) of o-aminothiophenol, followed by the introduction of another 20 g of hydrogen chloride gas over a period of 3 hours at 160°C. The melt is then stirred into a mixture of 200 g of 45 % by weight sodium hydroxide and 200 g of ice, the supernatant oil separated off and the aqueous phase extracted by shaking with 200 ml of CH2Cl2. The combined organic phases are concentrated in vacuo and subsequently subjected to fractional distillation, giving 194 g (88 % of the theoretical) of 2-(5'-aminopentyl)-benzthiazole in the form of a yellowish oil with a boiling point of 131° to 133°C at 0.05 Torr.
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:11][CH:2]1[CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[O:4][C:13](=[O:15])[NH:1]1
Reactant: CC(N)C(O)c1cccnc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1NC(=O)OC1c1cccnc1
Yield: 32.5 %

Procedure:
A solution of 2-nitro-1-pyridin-3-yl-butan-1-ol (3.20 g, 17.6 mmol) in ethanol (90 mL) was purged with argon, and 200 mg of Raney-Nickel was added at room temperature. The reaction mixture was three times evacuated and refilled with hydrogen. The reaction was stirred for 16 hours under H2 at room temperature. Raney-Nickel was then filtered over Hyflo, and the Hyflo washed with EtOH. The filtrate was then concentrated in order to give 2-amino-1-pyridin-3-yl-propan-1-ol as a product (2.35 g, 88%), which was used in the next reaction step without purification. To a solution of 2-amino-1-pyridin-3-yl-propan-1-ol (700 mg, 4.60 mmol) in CH2Cl2 (20 mL) was added under argon Et3N (1.60 mL, 11.5 mmol) at 0° C., followed by triphosgene (819 mg, 2.76 mmol, dissolved in 5 mL of CH2Cl2). The reaction temperature was allowed to warm from 0° C. to room temperature within one hour. The reaction mixture was then quenched with ice cold water and a 2 M solution of Na2CO3, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in hexane from 0% to 100% in order to give the product (160 mg, 20%). LC-MS: [M+H] 179.1; Rt 0.31 min; (LCMS method 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])=[O:37])[CH:30]=[CH:29]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:42]2[CH2:41][CH2:40][N:39]([S:36]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[CH:34][CH:35]=[C:26]([Cl:25])[CH:27]=4)[CH:32]=3)(=[O:38])=[O:37])[CH2:44][CH2:43]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In dichloromethane (7 ml), trans-4-(N-tert-butoxycarbonylaminomethyl)cyclohexane carboxaldehyde (0.13 g) was dissolved, followed by the addition of 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate (0.24 g), triethylamine (78 μl) and sodium triacetoxyborohydride (0.17 g). The resulting mixture was stirred at room temperature for 11 hours under an argon gas atmosphere. To the reaction mixture, an aqueous solution of sodium bicarbonate was added, followed by dilution with dichloromethane. The organic layer so separated was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (0.29 g, 100%) was obtained.
Reaction SMILES: [NH2:1][N:2]([CH2:14][CH2:15][OH:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[S:4].C=O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[NH:5][C:3]([N:2]1[CH2:14][CH2:15][O:16][CH2:19][NH:1]1)=[S:4]
Reactant: NN(CCO)C(=S)Nc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: ClCCl
Product: S=C(Nc1ccc(Cl)cc1Cl)N1CCOCN1

Procedure:
1.72 g (6.20 mmol) N-amino-N-(2-hydroxyethyl)-N'-(2,4-dichlorophenyl)thiourea was suspended in 40 mL methylene chloride. 0.52 g (37% aqueous, 6.4 mmol) formaldehyde and a small quantity of p-toluenesulfonic acid were added before the reaction mixture was heated for 17 h in a Dean-Stark apparatus. The solvent was then removed and the desired product isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>ClCCl>[CH2:29]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCc1ccccc1
Yield: 73 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-phenyl-ethanol (18 mg, 0.15 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 49 mg (73%) of the titled compound. ESI-MS m/z 396 (MH+), 394 (M−H−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[Cl:11].[CH2:12]([OH:15])[CH:13]=[CH2:14].C([O-])(O)=O.[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH2:14][CH2:13][CH:12]=[O:15])[CH:7]=1
Reactant: C=CCO
Reactant: COc1cc(Cl)c(Br)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Br)cc1CCC=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
A mixture of 1-bromo-2-chloro-5-iodo-4-methoxybenzene (3.2 g, 9.2 mmol), prop-2-en-1-ol (1.3 g, 23.0 mmol), Pd(OAc)2 (206 mg, 0.9 mmol), TBAC (2.56 g, 9.2 mmol), NaHCO3 (2.3 g, 27.6 mmol) in DMF (50 mL) was stirred under Argon at 60° C. for 16 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:20) to afford the desired product (860 mg, 34% yield).
Reaction SMILES: Cl[C:2]1C=CC(OC(C2C=CC(OC3C=CC(Cl)=CC=3)=CC=2)(C)C(OC)=O)=C[CH:3]=1.[CH2:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH:39]([C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]4[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=4)=[CH:46][CH:45]=3)[C:40]([O:42][CH3:43])=[O:41])=[CH:35][CH:36]=2)[CH2:31][CH2:30]1.CN(C)P(N(C)C)(N(C)C)=O.C(I)C>O1CCCC1.O>[CH2:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][C:39]([C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]4[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=4)=[CH:46][CH:45]=3)([CH2:2][CH3:3])[C:40]([O:42][CH3:43])=[O:41])=[CH:35][CH:36]=2)[CH2:31][CH2:30]1
Reactant: COC(=O)C(Oc1ccc2c(c1)CCC2)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCI
Product: CCC(Oc1ccc2c(c1)CCC2)(C(=O)OC)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.015 mole of lithium N,N-diisopropylamide (prepared as in example 55) in tetrahydrofuran is chilled to -65° C. to -75° C. To the solution is added methyl (5-indanyloxy)[p-(p-chlorophenoxy)phenyl]acetate in tetrahydrofuran. To the mixture is added 4 ml of hexamethylphosphoramide and while chilling to -65° C. to -75° C., 4.68 g of ethyl iodide is added. After 2 hr., the mixture is allowed to warm to room temperature and stirr overnight. The mixture is poured into water and extracted with ether. The ether extracts are washed with 10% hydrochloric acid, water, saturated NaHCo3, saturated NaCl solution and dried (MgSO4). Evaporation of the solvent gives the product as an oil.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=O)[CH:5]=[C:6]2[C@:11]([C:13]([O:15][CH3:16])=[O:14])([CH2:12]\1)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:7]2.O.O.O.C([O-])(=O)C.[Na+].[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C(O)(=O)C.ClCCl>[C:33]1([N:39]2[C:4]3[CH:5]=[C:6]4[C@:11]([C:13]([O:15][CH3:16])=[O:14])([CH2:12][C:3]=3[CH:2]=[N:40]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:8][CH2:7]4)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@]12C/C(=C/O)C(=O)C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@]12Cc3cnn(-c4ccccc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
(R,Z)-2-tert-butyl 8a-methyl 7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (1.09 g, 3.23 mmol) was suspended in acetic acid (20 mL), and sodium acetate trihydrate (0.265 g, 3.23 mmol) and phenylhydrazine (0.318 ml, 3.23 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then water (20 mL) and dichloromethane (20 mL) were added and the phases were separated via a phase separator. The solvent was removed to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-50% ethyl acetate in isohexane) to afford (R)-6-tert-butyl 4a-methyl 1-phenyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (694 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.48 min, m+H=410.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[N:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>CCOCC>[ClH:22].[C:23]([N:18]1[C:17](=[O:21])[CH2:16][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[N:19]1[CH3:20])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C2CC(=O)N(C(C)=O)N2C)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (0.500 g) is dissolved in acetic anhydride (15 mL). The resulting solution is warmed to reflux for 2 hours, cooled to room temperature and concentrated in vacuo to afford an oil. This residue is dissolved in ether and treated with ethanolic HCl at room temperature. The resulting solid is stirred for 4 hours at room temperature, collected by suction and dried in vacuo to afford the title compound as a white powder (0.621 g; 98%) mp: 82°-85° C. 1H NMR (DMSO-d6, 400 MHz) δ6.88 (m, 3H); 3.85 (s, 3H); 2.82 (s, 3H); 2.52 (s, 3H); 2.00 (m, 2H); 1.84 (m, 3H); 1.64 (m, 2H). IR (KBr, cm-1) 1730.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]1[N:21]([CH3:27])[C:22](=[N:25][CH3:26])[S:23][CH:24]=1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:28]>C(O)(=O)C>[BrH:28].[CH2:1]([C@H:8]([CH2:19][C:20]1[N:21]([CH3:27])[C:22](=[N:25][CH3:26])[S:23][CH:24]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=c1scc(C[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)n1C
Agent: Br
Solvent: CC(=O)O
Product: CN=c1scc(C[C@@H](Cc2ccccc2)C(=O)O)n1C
Yield: 100 %

Procedure:
The resultant compound from Example 73 (315 mg, 0.828 mmol) was stirred for 2 h in 30% HBr in acetic acid (5 ml). The solvent was evaporated and the residue was dissolved in water which was washed with ether and lyophillized to afford 310 mg (100%) of the desired product as a foam. 1H NMR (CD3OD) δ7.20-7.35 (m,5H), 6.72 (s,1H), 3.44 (s,3H), 3.08 (s,3H), 2.70-3.20 (m,5H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[N+]([O-])([O-])=O.[O-2].[Bi+3:16]>O.N>[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[Bi+3:16].[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[Bi+3:16]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.3 %

Procedure:
A mixture of (+)-tartaric acid (27 g) and bismuth oxynitrate (8.61 g) in water (50 ml) was heated at 90°-100° with occassional stirring for 30 min, by which time a small portion of the product dissolved completely in weak aqueous ammonia. The mixture was cooled to room temperature then filtered and the filtrate washed well with water until free from water soluble materials. The residue was dried at 70°-80° in vacuo to give the title compound (14.78 g).
Reaction SMILES: C(O)(C)C.[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8].Cl(O)(=O)(=O)=O>[Ir](Cl)Cl.CC1C(C)=C(C)C(C)=C1C.O>[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][NH:16]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: Cl[Ir]Cl
Agent: CC1=C(C)C(C)C(C)=C1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(c1)NCCC2
Temperature: 85 °C
Reaction time: 17 h

Procedure:
1,2,3,4-Tetrahydro-quinoline-7-carboxylic acid methyl ester was obtained as follows: To a solution of his (pentamethyl-cyclopentadiene iridium dichloride) (32 mg, 0.02 equiv.) in a degassed mixture of isopropanol (9.5 ml) and water (0.5 ml) was added quinoline-7-carboxylic acid methyl ester (374 mg, 2.00 mmol) and perchloric acid (70% in water, 0.02 ml, 0.1 equiv.). The mixture was stirred at 85° C. for 17 hours, then the solvents were evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester as a white solid, 305 mg (80%). MS (ISP): m/e=192.4 (M+H+); δII (300 MHz; CDCl3) 7.23 (1H, d), 7.13 (1H, s), 6.98 (1H, d), 3.86 (3H, s), 2.52 (2H, m), 3.32 (2H, t), 2.79 (2H, t), 1.94 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[NH:24]1[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[N:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O.CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29]([C:28]5[NH:24][N:25]=[CH:26][CH:27]=5)=[O:30])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccn[nH]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccn[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
To a mixture of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), 1H-pyrazole-5-carboxylic acid (84 mg, 0.75 mmol), 1-hydroxybenzotriazole (101 mg, 0.75 mmol) and N,N-dimethylformamide (5 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol), triethylamine (0.279 mL, 2.0 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and crystallized from ethyl acetate to give the title compound (43 mg, yield 21%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].S([C:7]1[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12])(O)(=O)=O.Cl>O>[OH:1][C:7]1[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1C(=O)O
Temperature: 180 °C
Yield: 72 %

Procedure:
Sodium hydroxide (251.9 g, 6.30 mol) was added in portions to 4-sulphophthalic acid (50% in water, 258.4 g, 0.525 mol) in a steel vessel accompanied by stirring. After the addition of approx. one third NaOH the increasingly more viscous mixture was heated to 180° C. Once the addition had ended the mixture was stirred for a further 2 h at 200° C. During cooling, the residue was dissolved in water (1000 ml). Conc. hydrochloric acid (620 ml, pH=1) was added accompanied by ice cooling. The solution was extracted with ethyl acetate (5×400 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated on the rotary evaporator. The slightly yellow solid was recrystallized from ethyl acetate. 68.64 g (0.377 mol; 72% yield) of a white solid was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C2[N:46]=C(C3CC(=C)C3)N3C=CN=C(Cl)C=23)C=CC=1)C1C=CC=CC=1.B1C2CCCC1CCC2.[OH-].[Na+].OO>C1COCC1>[NH2:46][C:20]1[C:19]2[N:18]([C:17]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OCC1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Reactant: C=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CC(CO)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
{3-[1-(3-Benzyloxyphenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol: To a solution of 1-(3-benzyloxyphenyl)-8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazine (345 mg, 0.86 mmol) in dry THF (5 mL) was added 9-BBN (2.6 mL, 1.3 mmol, 0.5 M in THF) dropwise at 0° C. under nitrogen atmosphere. The temperature was slowly warmed to rt overnight. Upon which time TLC showed the reaction was complete. The mixture was cooled to 0° C., and 2 mL 1N aq. NaOH and 0.4 mL 30% aq. H2O2 were added, the resulting mixture was stirred at 0° C. for 10 min, then rt for 30 min. The resulting white solid was filtered off, the filtrate was diluted with ethyl acetate (60 mL), washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with 100% ethyl acetate), yielding the title compound as a yellow viscous oil, a mixture of cis and trans isomers. MS (ES, Pos.): MS (ES, Pos.): m/z 420/422 (3/1) [MH+]. 1H NMR (CDCl3, 400 MHz) δ 2.32 (br s, 1H), 2.60-2.85 (m, 5H), 3.88-4.11 (m, 3H), 5.36 (s, 2H), 7.27 (m, 1H), 7.48-7.69 (m, 9H), 7.77 (d, J=5.0 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][C:18]=2[O:25]CC2C=CC=CC=2)=[C:12]([F:33])[CH:11]=1)[CH2:6][CH2:7][CH2:8][NH2:9])(=[O:4])=[O:3].O1CCCC1>CO>[CH3:1][S:2]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][C:18]=2[OH:25])=[C:12]([F:33])[CH:11]=1)[CH2:6][CH2:7][CH2:8][NH2:9])(=[O:3])=[O:4]
Reactant: CCc1ccc(Oc2ccc(N(CCCN)S(C)(=O)=O)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2ccc(N(CCCN)S(C)(=O)=O)cc2F)c(O)c1
Yield: 68.8 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for N-Methanesulfonyl-N1-[4-(2-benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (90 mg, 0.19 mmol) and tetrahydrofurane for methanol (15 mL), the title compound (50 mg, 68%) was obtained as a brown liquid, after purification on silica gel (dichloromethane/ethyl acetate: 8/2)