Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH2:28][CH2:29][OH:30])[CH:20]=2)([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:32])[C:3]=1[C:33]([O-:35])=[O:34].[ClH:36]>CCO>[ClH:36].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH2:28][CH2:29][OH:30])[CH:20]=2)([CH3:15])[CH3:16])[N:5]=[C:4]([CH3:32])[C:3]=1[C:33]([OH:35])=[O:34]
Reactant: COc1cc(OCCO)cc(C(=O)NC(C)(C)COc2cccc3nc(C)c(C(=O)[O-])c(N)c23)c1
Agent: Cl
Solvent: CCO
Product: COc1cc(OCCO)cc(C(=O)NC(C)(C)COc2cccc3nc(C)c(C(=O)O)c(N)c23)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of 4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate acid (Example 38, 263 mg, 0.544 mmol) in EtOH (2 mL) was added HCl in EtOH (1.25 N, 479 uL, 1.1 equiv.). The mixture was stirred at room temperature until it became a clear solution (0.5 h). The solution was concentrated under reduced pressure to give the title compound as a white solid, which was further purified by re-crystallization from EtOH/H2O and dried under vacuum overnight (248 mg, 87%). 1H NR (400 MHz, DMSO-d6) δ 1.51 (s, 6H), 2.80 (s, 3H), 3.68 (t, J=5.2 Hz, 2H), 3.74 (s, 3H), 3.97 (t, J=5.2 Hz, 1H), 4.53 (s, 2H), 6.59 (s, 1H), 6.92 (s, 1H), 6.94 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.86 (t, J=8.4 Hz, 1H), 8.03 (s, 1H), 9.40 (s, 1H), 9.98 (s, 1H). 484 (MH+—HCl).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:9][CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(=O)Sc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Sc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A solution of 1.0 g (3.7 mmol) of 4,4-dimethyl-7-bromo-2-oxo-thiochroman in 1 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 2.0 g (2.75 ml, 20.0 mmol) of trimethylsilylacetylene and a powdered mixture of 0.038 g of cuprous iodide and 0.084 g of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 55 degrees C. for 24 hours, and thereafter allowed to cool to room temperature. Solvent was removed in-vacuo to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:16]([NH:20][OH:21])([CH3:19])([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N+:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[O-:21])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)NO
Reactant: CCCCCCOc1ccc(C=O)cc1
Solvent: c1ccccc1
Product: CCCCCCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1
Yield: 55.8 %

Procedure:
A solution of 4-hexyloxybenzaldehyde (3.83 g, 18.6 mmol) in 120 mL of benzene was refluxed with N-tert-butylhydroxylamine (3.32 g, 37.2 mmol) for 18 hours. The reaction mixture was then concentrated by rotary evaporation and the resulting residue was purified by silica gel column chromatography using 50:50 ethyl acetate/hexane to afford the title compound (2.88 g, 55.8% yield) as a solid, m.p. 69.0° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:8][CH2:7]1)C.[BH4-].[Li+].O>O1CCCC1.CO.CCCCCC.C(OCC)(=O)C>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:33][CH:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COCCOC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a solution of ethyl{2-[5-({6-[(2-methoxyethoxy)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (190 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) was added at room temperature lithium tetrahydroborate (22 mg) 3 times at 30 min intervals, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and further to silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio). The obtained crude product was purified by preparative HPLC to give the title compound (52 mg, yield 30%) as a pale-yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[C:15]4[C:22](=O)[CH2:21][CH2:20][CH2:19][N:16]43)=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[C:15]4[C:22](=[N:25][OH:26])[CH2:21][CH2:20][CH2:19][N:16]43)=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: NO
Reactant: O=C(Nc1cccnc1)c1ccc2cc3n(c2c1)CCCC3=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: O=C(Nc1cccnc1)c1ccc2cc3n(c2c1)CCCC3=NO
Yield: 77.6 %

Procedure:
9-Oxo-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-3-carboxylic acid pyridin-3-ylamide (150 mg, 0.491 mmol), hydroxylamine hydrochloride (1.50 g, 21.6 mmol), and pyridine (3 mL) were combined in MeOH (40 mL) and heated to 60 □C for 20 h. The reaction was cooled and diluted with water (200 mL). The resulting precipitate was filtered, washed with water, then hexanes, and dried in a vacuum oven to give the title compound (122 mg, 78%) as an analytically pure mixture of oxime regioisomers (2:1).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C([O:32]CCOCCO)C>O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([NH2:27])=[O:32])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCCOCCO
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
A mixture of 35.5 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-cyanoindole [m.p. 167°; obtainable from the corresponding 5-formyl compound via the oxime], 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether is stirred for 3 hours at a bath temperature of 140°. The mixture is cooled and worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxamide, m.p. 200°-205°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:11][CH2:12][O:13]C(C)=O.O(C(C)C)C(C)C.[NH4+].[OH-]>C(Cl)Cl.CO>[O:1]1[C:5]2[C@H:6]([NH:10][C:12](=[O:13])[CH3:11])[CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: NC1CCCc2ccoc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H]1CCCc2ccoc21
Reaction time: 17 h

Procedure:
Following the general procedure, 4,5,6,7-tetrahydrobenzofuran-7-ylamine (150 mg, 1.09 mmol), CALB (45 mg), EtOAc (0.43 mL) and iPr2O (4.0 mL) were stirred for 17 hours. The conversion determined from 1H NMR by integration of the peaks at 5.09 ppm (CHNHAc) and 3.95 ppm (CHNH2) was 55%. Flash chromatography of the material on silica gel using 1:20 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished (R)—N-(4,5,6,7-tetrahydrobenzofuran-7-yl)acetamide ((104 mg, 53%) in 79% ee (chiral GC method: 120° C. for 15 min, ramp rate of 2° C./min to 160° C., hold 20 min at 160° C., (S)-(−)-enantiomerrt43.6 min (R)-(+)-enantiomerrt=45.8 min); [α]D=+58° (c 1.04, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.65–1.86 (m, 3H), 1.90–1.2.04 (m, 1H), 1.94 (s, 3H), 2.30–2.50 (m, 2H), 5.09 (br s, 1H), 6.16 (s, 1H), 7.24 (s, 1H); 13C NMR (CDCl3) δ 20.6, 22.4, 23.6, 31.0, 43.6, 110.7, 120.9, 142.2, 148.8, 170.1; MS m/z: 180 (M+H+). The unreacted (S)-4,5,6,7-tetrahydrobenzofuran-7-ylamine (was isolated in 39% yield (59 mg) and 94% ee (chiral GC, (S)-enantiomerrt=12.6 min, (R)-enantiomerrt=13.5 min); [α]D=−18° (c 0.59, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 1.50–1.75 (m, 4H), 1.76–1.90 (m, 1H), 2.01–2.20 (m, 1H), 2.30–2.50 (m, 2H), 3.94 (t, 1H, J=5.7 Hz), 6.17 (d, 1H, J=1.5 Hz), 7.26 (d, 1H, J=1.5 Hz); 13C NMR (CDCl3): δ 21.1, 22.6, 34.0, 45.5, 110.5, 117.9, 141.3, 153.6; MS m/z: 160 (M+Na+).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:26])=[O:2])[C:13](=[O:25])[CH:14]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Br)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Br)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a stirred solution of (S)-2-[4-(3-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (450 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (134 mg, 0.006 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-2-[4-(3-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (320 mg, 74%) as a off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([C:12](O)=[O:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(COC)OC.O>[OH:13][CH2:12][C:9]1[N:10]=[N:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(C(=O)O)nn1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(CO)nn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
435 mg of 6-(ethoxycarbonyl)pyridazine-3-carboxylic acid was dissolved in 11.0 mL of dimethoxyethane, and 0.424 mL of 4-methylmorpholine and 0.531 ml, of isobutyl chloroformate were added thereto at 0° C. After stirring at 0° C. for 2 hours, a suspension of 294 mg of sodium borohydride in water (2.50 mL) was added to the reaction liquid, followed by further stiffing at 0° C. for 20 minutes. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=97:3 to 90:10) to obtain 184 mg of ethyl 6-(hydroxymethyl)pyridazine-3-carboxylate.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:28]=3)[C:23]([OH:25])=O)=[C:17]([F:43])[CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:44][C:45]1[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:35])[CH3:34])[CH:28]=3)[C:23]([NH:44][C:45]3[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=3)=[O:25])=[C:17]([F:43])[CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 11 h
Yield: 101.6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.86 g, 6.56 mmol) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (3 g, 5.96 mmol) in DCM (100 mL) and stirred at RT for 11 hour. 2-Amino-5-methylpyrazine (1.3 g, 11.9 mmol) and pyridine (0.94 mL, 11.9 mmol) were added and the reaction stirred for a further 30 mins. The solvent was removed in vacuo. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The extracts were combined and washed with water (1100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (3.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[Br:15][C:16]1[C:17]([NH2:31])=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](=[O:12])[NH:31][C:17]1[C:16]([Br:15])=[CH:21][N:20]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=[C:19]2[CH:18]=1)=[O:5])[CH3:2]
Reactant: Nc1cc2nc(-c3ccccc3)cn2cc1Br
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A solution of 5-chlorocarbonyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (as prepared in Example 14, Step 2, 2.35 g, 10.8 mmol) in dichloromethane (5 ml) was added dropwise over 20 min to a cooled (0° C.) solution of 6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-ylamine (1.56 g, 5.4 mmol) and triethylamine (877 mg) in dichloromethane (20 ml); the mixture was then stirred for at r.t. (30 min). The mixture was washed (water), and the organic layer was dried (Na2SO4), and evaporated. The title compound (460 mg, 23%) was isolated by filtration over a column of silica gel with dichloromethane as an eluent, and was used without further purification in the next step. MS (m/e)=470.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([O:21][CH3:22])[N:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:20][C:18]2[CH:17]=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:13][CH3:12])[CH:19]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)cc(OC)n1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cc(OC)n1
Yield: 75.6 %

Procedure:
The title compound (623 mg, 1.89 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 2,6-dimethoxy-4-pyridinamine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH:44]=O.Cl>O1CCCC1>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:44]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C=O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cccc(C=CCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution was formed by adding (5-carboxypentyl)triphenylphosphonium bromide (1.67 g, 3.67 mmol), under an atmosphere of argon, to a 1 M solution of LiHMDS (in tetrahydrofuran) (7.34 mL, 7.34 mmol). The resultant dark red solution was allowed to stir at ambient temperature for 30 minutes. Commercially available 3-methoxybenzaldehyde (0.100 g, 0.734 mmol) was dissolved in 5 mL anhydrous tetrahydrofuran and subsequently added to the reaction solution. Stirring continued for 6 hours until 6 N hydrochloric acid was carefully added to quench the reaction solution to a pH 2. Ethyl acetate was added and the organic layer was separated. The aqueous phase was washed thrice with ethyl acetate. The combined organic layers were washed once with brine and dried over sodium sulfate. The solvent was removed in vacuo and the olefin acid product was purified as a off-white oily solid in 99% yield (0.170 g) as a 85E:15Z mixture of isomers using flash column chromatography (silica) (25% ethyl acetate:hexanes mobile phase): 1H NMR (500 MHz, CDCl3) δ 7.29-7.36 (m, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.95-6.98 (m, 1H), 6.85-6.91 (m, 1H), 6.49 (d, J=11.5 Hz, 0.15H), 6.45 (d, J=15.5 Hz, 0.85H), 6.27-6.32 (m, 0.85H), 5.71-5.76 (m, 0.15H), 3.90 (s, 3H), 2.44-2.50 (m, 2.4H), 2.31-2.35 (m, 1.6H), 1.77-1.82 (m, 2H), 1.60-1.66 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 180.65, 160.21, 139.62, 139.42, 132.95, 130.98, 130.62, 129.88, 129.64, 129.55, 121.72, 119.09, 114.77, 113.01, 112.50, 111.74, 55.61, 34.37, 33.00, 29.70, 29.11, 28.69, 24.73, 24.64.
Reaction SMILES: C([O:4][C:5](=[O:44])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@H:13]1[CH2:31][O:32][C:33](=[S:43])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)C=C.[OH-].[Li+]>C1COCC1.O>[Cl:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:33]([O:32][CH2:31][C@@H:13]1[C@@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:15][C@@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@H:12]1[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:5]([OH:44])=[O:4])=[S:43]
Reactant: C=CCOC(=O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Yield: 72.6 %

Procedure:
A solution of ester 6 (614 mg, 0.97 mmol) and lithium hydroxide (62 mg, 1.5 mmol) in THF/H2O (1:1, 20 mL) was stirred at 23° C. for 72 h. The mixture was acidified with 1N HC1 and extracted with EtOAc. The organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 430 mg of the above titled compound.
Reaction SMILES: [CH2:1]([C:4]1([CH3:29])[C:9]2[N:10]([CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH2:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:28])[CH2:5]1)C=C>C(Cl)Cl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH2:18][N:10]3[C:11]4[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=4[C:8]4[CH2:7][N:6]([CH3:28])[CH2:5][C:4]([CH3:1])([CH2:29][CH:20]=2)[C:9]3=4)=[CH:26][CH:25]=1
Reactant: C=CCC1(C)CN(C)Cc2c1n(CC(=C)c1ccc(F)cc1)c1ccc(C)cc21
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c3n2CC(c2ccc(F)cc2)=CCC3(C)CN(C)C1

Procedure:
To a solution of the 4-allyl-5-[2-(4-fluoro-phenyl)-allyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 0.64 mmol) in degassed DCM (7 mL) was added dropwise a solution of Grubbs'2nd generation catalyst (27.61 mg, 0.0325 mmol, 5 mol %) in degassed DCM (3 mL) under an nitrogen atmosphere. The resultant solution was heated at 115° C. for 1 h in a microwave. The solvent was evaporated in vacuo and the residue was purified by reverse HPLC to obtain 6-(4-fluoro-phenyl)-2,3a,10-trimethyl-1,2,3,3a,4,7-hexahydro-2,7a-diaza-cyclohepta[jk]fluorene as an off white solid (50 mg). 1H NMR (Freebase, CDCl3) δ (ppm): 7.40 (m, 2H), 7.30 (d, 1H), 7.10 (d, 1H), 7.04-6.98 (m, 2H), 5.99 (d, 1H), 4.96 (d, 1H), 3.99 (d, 1H), 3.96 (s, 2H), 2.70 (d, 2H), 2.55 (s, 3H), 2.42 (s, 3H), 2.30 (d, 1H), 2.21 (m, 1H), 1.50 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([OH:23])[CH2:19][N:20]([CH3:22])C)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH2:33](NCC(O)COC1C=CC(N)=CC=1)[CH:34](C)[CH3:35]>CN1C(=O)CCC1>[Br:2][C:3]1[C:4]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]([OH:23])[CH2:19][NH:20][CH2:22][CH:34]([CH3:35])[CH3:33])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC(C)CNCC(O)COc1ccc(N)cc1
Reactant: COc1ccc(Oc2nc(Nc3ccc(OCC(O)CN(C)C)cc3)ncc2Br)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2nc(Nc3ccc(OCC(O)CNCC(C)C)cc3)ncc2Br)cc1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
Ethereal hydrogen chloride (2.0M; 0.57 ml, 1.14 mmol) was added to a solution of 5-bromo-2-chloro-4-(4-methoxyphenoxy)pyrimidine (Method 1, 200 mg, 0.63 mmol) and 4-[3-(isobutylamino)-2-hydroxypropoxy]aniline (Method 10, 136 mg, 0.57 mmol) in NMP (4 ml). The solution was heated at 100° C. for 6 hours and silica (1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (76 mg, 26%). MS (MH+): 517, 519; HPLC (RT): 6.48.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([C:15](C(C)(C)C)([C:19]([OH:21])=[O:20])[C:16]([OH:18])=O)(C)(C)C>C(O)(C)(C)C.N1CCCCC1>[C:3]([O:21][C:19]([C:15]1[C:16](=[O:18])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:20])([CH3:6])([CH3:4])[CH3:2]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CC(C)(C)C(C(=O)O)(C(=O)O)C(C)(C)C
Solvent: CC(C)(C)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)c1cc2ccc(O)cc2oc1=O
Yield: 53.4 %

Procedure:
2,4-dihydroxylbenzaldehyde (0.27 g, 2 mmol) and di-tert-buty malonic acid (0.43 g, 2 mmol) are dissolved in tert-butanol (5 mL), and three drops of piperidine are added. The mixture is refluxed for 16 hours to obtain a suspension. After being placed for cooling, insoluble material is removed by filtrating. The mother liquor is concentrated, and the ethyl acetate is added with stirring. The supernatant is separated, concentrated, and chromatographed over silica gel column with petroleum/ethyl acetate (3:4) as eluent to obtain 0.14 g of 7-hydroxyl-3-coumarin carboxylic acid tert-butyl ester, yield: 22.5%.