Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC1CCC(CCc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Yield: 80.6 %

Procedure:
6.41 g (17.4 mmol) of 4-{4-[2-(4-propyl-cyclohexyl)-ethenyl]-phenyl}cyclohexane carboxylic acid methyl ester produced in Example 5-1 was dissolved in a mixture of toluene and ethanol (1:1 by volume %). 0.4 g of Pd/C was added to 200 mL of the resultant solution and reacted in hydrogenation reactor for 12 hours. After reaction, Pd/C was removed by filtration and concentrated under reduced pressure to obtain 5.2 g (80%) of 4-{4-[2-(4-propyl-cyclohexyl)-ethyl]-phenyl}-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([N:11]([CH3:23])[C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:8]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[OH:28])([CH3:4])[CH3:3].C([Li])CCC.[C:34](Cl)(=[O:36])[CH3:35].O>O1CCCC1>[C:34]([O:28][C:6]1[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:10][C:9]([N:11]([CH3:23])[C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:36])[CH3:35]
Reactant: CN(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccn(-c2ccccc2)n1
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc(N(C)c2ccn(-c3ccccc3)n2)cc1C(C)(C)C
Reaction time: 16 h

Procedure:
To 2,6-bis (1,1-dimethylethyl)-4-(N-methyl-N-[1-phenyl-1H-pyrazol-3-yl]amino)phenol (0.6 g) in dry tetrahydrofuran (15 ml) at -78° under nitrogen was added butyl lithium (1.29 ml of 1.4M hexane solution). After 10 minutes acetyl chloride (0.2 ml) was added. The reaction was left for 16 hours, poured into water and extracted with ethyl acetate. Evaporation, and chromatography (silica, dichloromethane/hexane [1:1]) of the residue, followed by recrystallisation from hexane at -20° gave the title compound (0.35 g), mp 102°-103°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[F:40][C:41]1[CH:54]=[CH:53][CH:52]=[CH:51][C:42]=1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:40][C:41]1[CH:54]=[CH:53][CH:52]=[CH:51][C:42]=1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:45]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(Oc2ccccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Oc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.15 mmol, 74.3 mg), HCl salt of 3-(2-fluorophenoxy)cyclohexanamine (0.15 mmol, 37 mg), HATU (0.15 mmol, 57 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(2-fluorophenoxy)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(=O)O[CH2:13][CH2:12][O:11]1>[Br-].C([N+](CC)(CC)CC)C>[OH:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: O=Cc1ccc(OCCO)cc1
Yield: 66 %

Procedure:
Synthesized from 30 g of 4-hydroxybenzaldehyde, 21 g of ethylene carbonate and 62 g of tetraethylammonium bromide as described in Example XIIa. Purified by distillation (boiling point 0.1 140°-150° C.). Yield 66%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].N1C=CC=CC=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[S:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 84.9 %

Procedure:
In 50 ml of methylene chloride, methyl 18-hydroxyoctadecanoate (4.5 g, 14.3 mmoles) was dissolved. To the obtained solution was added pyridine (4.53 g, 57.2 mmoles), and then was gradually added p-toluenesulfonyl chloride (5.46 g, 28.6 mmoles) with ice-cooling over a period of 1 hour. Thereafter, reaction was carried out for 16 hours in a refrigerator. The reaction mixture was washed with a 10% aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution in this order, dried, and then concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (eluent: benzene) to give methyl 18-tosyloxyoctadecanoate (5.69 g, 85%) having the following properties.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].Br[C:14]1C=CC(C(O)=O)=NC=1.Cl.N1CCC1>>[N:2]1([C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=2)=[O:4])[CH2:12][CH2:14][CH2:1]1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Agent: C1CNC1
Agent: Cl
Product: O=C(c1ccc(Br)cn1)N1CCC1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyridine-2-carboxylic acid (1.50 g, 7.43 mmol) and azetidine hydrochloride (954 mg, 10.2 mmol) to give a yellow solid (1.38 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=2.02 Hz, 1 H) 7.93-7.99 (m, 1 H) 7.90 (d, J=2.27 Hz, 1 H) 4.65 (t, J=7.71 Hz, 2 H) 4.20 (dd, J=8.34, 7.33 Hz, 2 H) 2.27-2.36 (m, 2 H); LCMS for C9HgBrN2O m/z 241.00 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].Br[C:9]1[C:10](=O)[CH2:11][CH2:12][C:13]=1[O:14]C.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH3:2][CH:3]([C:4]1[NH:5][C:10]2[CH2:11][CH2:12][C:13](=[O:14])[C:9]=2[N:6]=1)[CH3:7]
Reactant: CC(C)C(=N)N
Reactant: COC1=C(Br)C(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCC2=O
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A mixture of 2-methylpropanimidamide hydrochloride (0.770 g), 2-bromo-3-(methyloxy)-2-cyclopenten-1-one (1 g) and potassium carbonate (2.17 g) in N,N-dimethylformamide (15 mL) were heated at 100° C. for 4.5 hr and then heated at 110° C. for 1 hour. The reaction mixture was cooled down to room temperature and dichloromethane was added. The white suspension (potassium carbonate) was filtered off and the filtrate concentrated under vacuum. The residue was purified by reverse phase chromatography using an acetonitrile—0.1% NH3:water—with an ammonium carbonate buffer modifier using a 5%-95% gradient. The desired fractions were combined and concentrated under vacuum to yield the title compound (531 mg). LC/MS MH+ 165, Rt 0.36 min (2 minute run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:32][CH2:31][CH2:30][O:29][C:25]2[C:24]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[C:23]([NH:22][S:19]([C:16]3[CH:15]=[CH:14][C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:18][CH:17]=3)(=[O:20])=[O:21])[N:27]([CH3:28])[N:26]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: Clc1ncc(Br)cn1
Product: COc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (60 mg) of 5-bromo-2-chloropyrimidine was used and 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-4-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl]benzenesulfonamide (Example 21) (85 mg) was used in place of 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (30.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[N:7]=[C:6]([NH:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[CH:5]=1.[N-:18]=[N+:19]=[N-:20].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[N:18]=[N:19][NH:20][N:11]=2)[N:7]=[C:6]([NH:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[CH:5]=1
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(C#N)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
Heat a suspension of (S)-2-sec-butylamino-6-cyano-isonicotinic acid methyl ester (932 mg, 4.0 mmol), sodium azide (780 mg, 12 mmol), and triethylamine hydrochloride (1.65 g, 12 mmol) in toluene (13 mL) at 90° C. for 2 days. Cool to room temperature and extract with water (3×30 mL), acidify the combined aqueous layers to about pH=2 using 1 N HCl, extract the desired product with ethyl acetate (4×50 mL), dry (sodium sulfate) and concentrate to give the title compound (720 mg, 65%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=O>>[CH2:2]([C:1]1[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:4]=1)[CH3:3]
Reactant: O=C(CBr)c1ccccn1
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Br
Product: CCc1nc(-c2ccccn2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 2-bromo-1-(2-pyridinyl)ethanone hydrobromide (J. Org. Chem., 1996, 61, 4623). MS (ESI) m/z 393 [M+H]+.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]2[N:27]=[C:26]([CH3:28])[C:25]([C:29](=O)[CH2:30][CH2:31][CH3:32])=[C:21]2[O:22][C:23]=1[CH3:24]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]2[N:27]=[C:26]([CH3:28])[C:25]([C:29](=[CH2:1])[CH2:30][CH2:31][CH3:32])=[C:21]2[O:22][C:23]=1[CH3:24]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCC(=O)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(CCC)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (0.814 g, 2.278 mmol) in THF (8 ml) is added 1.0M NaHMDS (in THF) (2.278 ml, 2.278 mmol) generating a yellow reaction mixture. After stirring at RT for 10 minutes, 1-[3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-yl]-butan-1-one (0.400 g, 1.139 mmol) is added and the reaction mixture is stirred at RT for 16 hours: a tan solution turning brown O/N. The reaction is quenched with ammonium chloride (sat. aq. 2 ml). The reaction mixture is partitioned between EtOAc (50 ml) and H2O (50 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts are washed with brine (1×50 ml), dried Na2SO4, filtered and concentrated in vacuo. The resulting residue is purified via Flashmaster SiO2 150 ml/50 g column eluting with 12:1 Iso-hexane/EtOAc to yield the title compound as a white crystalline solid; MS: 349.08 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.77 (1H, d), 7.59 (1H, d), 7.51 (1H, dd), 4.94 (1H, d), 4.85 (1H, d), 2.30 (3H, t), 2.18 (3H, s), 2.14 (3H, s), 1.35 (2H, m), 0.79 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([CH:27]([OH:30])[C:28]#[CH:29])=[CH:20][C:21]=3[C:22]([CH3:26])([CH3:25])[CH2:23][CH:24]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([CH:27]([OH:30])[C:28]#[C:29][C:32]4[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=4)=[CH:20][C:21]=3[C:22]([CH3:26])([CH3:25])[CH2:23][CH:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC1(C)CC=C(c2ccc(OCc3ccccc3)cc2)c2ccc(C(O)C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
In a manner similar to that of Example 16b, by reacting 0.28 g (0.71 mmol) of 1-[5-(4-benzyloxyphenyl)-8,8-dimethyl-7,8-dihydro-2-naphthyl]prop-2-yn-1-ol with 0.146 g (0.6 mmol) of 4-iodobenzoic acid, 0.010 g (0.015 mmol) of trans-dichlorobis(triphenylphosphine)palladium and 0.006 g (0.003 mmol) of copper iodide, a yellow solid is obtained (0.03 g; yield=10%; m.p.=171° C.).
Reaction SMILES: O1CCOCC1.[ClH:7].C([NH:11][CH:12]([CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=3[O:36][CH3:37])[CH:24]=2)[CH:19]=1)[C:13]([O:15]C)=[O:14])(=O)C>C(OCC)C>[ClH:7].[NH2:11][CH:12]([CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:29]([O:36][CH3:37])=[CH:30][CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[CH:24]=2)[CH:19]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C(Cc1ccc2cc(-c3c(OC)cccc3OC)ccc2c1)NC(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cccc(OC)c1-c1ccc2cc(CC(N)C(=O)O)ccc2c1
Yield: 81 %

Procedure:
To a solution of 1,4-dioxane (1 ml) are added successively 6 N HCl (3 ml) and methyl 2-(acetylamino)-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoate 207 (0.135 g). The solution is stirred and heated at reflux for 4 hours, then cooled, and diethyl ether (5 ml) is added. The aqueous phase is extracted with diethyl ether (35 ml). The organic phase is concentrated under vacuum. The resulting residue is dried overnight under high pression to give 2-amino-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoic acid hydrochloride 208.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:31]([NH:33][CH3:34])=[O:32])[C:16](=[O:30])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:18]=2[CH3:19])=[O:12])=[CH:6][CH:5]=1>C(O)(=O)C.C1COCC1>[Br:1][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:11]([C:13]1[CH:14]=[C:15]([C:31]([NH:33][CH3:34])=[O:32])[C:16](=[O:30])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:18]=1[CH3:19])=[O:12]
Reactant: CNC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: BrBr
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)c1cc(C(=O)C(Br)c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of bromine (30 mg, 19 mmol) in acetic acid—THF was added dropwise to a solution of 5-[(4-chlorophenyl)acetyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (75 mg, 0.162 mmol). After the addition, stirring was continued at RT overnight. The solvents were removed and the residue was purified on an Xterra C8 column using a gradient of acetonitrile/water. Freeze drying of the mixture afforded the title compound (86 mg, 95%).
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6]([O:22][CH3:23])([CH:19]=2)[CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1.[OH-].[K+]>C(O)C.O>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6]([O:22][CH3:23])([CH:19]=2)[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1
Reactant: CCOC(=O)C(CC1(OC)C=C2OCOC2=CC1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC1(OC)C=C2OCOC2=CC1)C(=O)O
Yield: 87.9 %

Procedure:
To a solution of the diethyl 2-(4,5-methylenedioxy-1-methoxybenyl)-malonate (20.0 g, 0.066 mol) of in ethanol (50 ml) was added a solution of potassium hydroxide (3.5 g, 0.066 mol) in water (25 ml). The solution stirred at reflux for 6 h. After concentrating the aqueous layer was washed with ether and acidified with concentrated HCl to pH 1 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a yellow solid (17.3 g, 89%).
Reaction SMILES: [CH3:1][S:2][C@H:3]1[CH2:7][NH:6][C@@H:5]2[C@@H:8]([OH:11])[CH2:9][O:10][C@H:4]12.C(=O)([O-])[O-].[Na+].[Na+].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](Cl)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCOCC1.O>[OH:11][C@@H:8]1[C@H:5]2[N:6]([C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:7][C@H:3]([S:2][CH3:1])[C@H:4]2[O:10][CH2:9]1
Reactant: CS[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of (3R,3aR,6S,6aS)-6-(methylthio)hexahydro-2H-furo[3,2-b]pyrrol-3-ol in 1,4-dioxane (5 mL) was added whilst stirring to a solution of sodium carbonate (123 mg, 1.16 mmol) in water (1.5 mL) at 0° C. A solution of 9-fluorenylmethoxycarbonyl chloride (150 mg, 0.58 mmol) in 1,4-dioxane (1.5 mL) was added dropwise over 5 minutes then the mixture allowed to warm to ambient temperature over 2 hours. Water (20 mL) was added and the product extracted into dichloromethane (3×10 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 2:1 gave alcohol (55) as a white solid (130 mg, 60%). TLC (Rf=0.19, Et2O:pentane 2:1); HPLC-MS 398.2 [M+H]+, 420.1 [M+Na]+, 817.3 [2M+H]+; analytical HPLC single main peak, Rt=16.096 min., [α]D17 −59.4° (c=2.78, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 4:3; 1.06 (0.57H, d, J=3.63 Hz, OH major), 2.04 (1.71H, s, SCH3 major), 2.14 (1.29H, s, SCH3 minor), 2.57 (0.43H, d, J=2.83 Hz, OH minor), 3.10 (0.57H, d, J=5.40 Hz, FmocNCH2 major), 3.21-3.24 (0.43H, m, FmocNCH2 minor), 3.41 (0.57H, dd, J=12.18 and 5.57 Hz, OCH2CHOH major), 3.52-3.82 (4.43H, m, FmocNCH, CHSCH3 OCH2CHOH minor, 1×FmocNCH2 and 1 ×OCH2CHOH), 3.92 (0.43H, dd, J=9.85 and 4.41 Hz, OCH2CHOH minor), 4.23-4.84 (4.57H, m, Fmoc CH, OCHCHSCH3, Fmoc CH2 minor and 1×OCH2CHOH major), 7.28-7.80 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 14.574/14.768 (SCH3), 47.234, 47.445, 48.069 and 48.826 (Fmoc CH and CHSCH3), 50.417/50.633 (FmocNCH2), 65.752/67.282 (Fmoc CH2), 68.555/69.282 (FmocNCH), 74.361/74.600 (OCH2CHOH), 75.774/76.148 (OCH2CHOH), 85.505/86.026 (OCHCHOCH3), 119.848, 120.003, 120.029, 124.512, 124.593, 124.946, 127.030, 127.063, 127.427, 127.507, 127.755, 127.771 and 127.892 (Fmoc aromatic CH), 141.196, 141.320, 141.378, 141.428, 143.581, 143.818, 143.890 and 143.964 (Fmoc quaternary), 154.115/154.849 (Fmoc C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Cl:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:11][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1ccc2nccn2n1
Solvent: ClC(Cl)Cl
Product: Clc1ccc2ncc(Cl)n2n1
Reaction time: 16 h
Yield: 85.5 %

Procedure:
6-Chloroimidazo[1,2-b]pyridazine 41 (6.53 mmol) was dissolved in chloroform (12 mL) and N-chlorosuccinimide (6.53 mmol) added under N2. After stirring for 16 h, the mixture was partitioned between saturated sodium hydrogensulfate solution (25 mL) and chloroform (12 mL). The organic layer was removed, washed with water (2×), dried and concentrated to provide 3,6-dichloroimidazo[1,2-b]pyridazine 5 (1.05 g, 85%) as an orange solid; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=9.5 Hz, 1H), 7.74 (s, 1H), 7.12 (d, J=9.5 Hz, 1H). 3,6-Dichloroimidazo[1,2-b]pyridazine 5 (150 mg, 0.8 mmol) and the desired amine (1 mL) were heated in a sealed tube for 16 hr at 120° C. Upon cooling the reaction mixture was concentrated and purified by column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) to provide the desired product 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:14]([OH:16])=O)[C:4]=12.C1C[N:26]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:25]C1.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:14]([NH:26][CH3:25])=[O:16])[C:4]=12
Reactant: COc1ccnc2[nH]cc(C(CC(=O)O)c3ccccc3)c12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2nccc(OC)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a RT suspension of 3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propionic acid (635 mg, 2.14 mmol) in DCM (20 mL) was added TEA (0.45 mL, 3.21 mmol). To this mixture was added PyBOP (1.22 g, 2.35 mmol) and MeNH2 (2 M in THF, 1.60 mL, 3.21 mmol). The resulting mixture was stirred at RT for 30 min, and the white precipitate was collected by filtration to afford 3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide in 72% yield (477 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N+:3]=1[O-:12].OS(O)(=O)=O.[OH-].[Na+].[N+:20]([O-])([OH:22])=[O:21]>>[Br:1][C:2]1[CH:11]=[C:10]([N+:20]([O-:22])=[O:21])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N+:3]=1[O-:12]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1c(Br)ccc2c1CCCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c2c1CCCC2
Temperature: 90 °C
Yield: 83 %

Procedure:
With efficient ice bath cooling 2-bromo-5,6,7,8-tetrahydro-quinoline 1-oxide (8.0 g, 35 mmol) (S. Zimmermann et al., J. Am. Chem. Soc., 1991, 113, 183) was treated with conc. H2SO4 (65 ml), followed by conc. HNO3 (10 ml). The resulting mixture was heated to 90° C. for 90 min, cooled and poured on crushed ice (200 g). NaOH (28%) was added to reach pH 7 and the aqueous phase extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated to yield 7.9 g (83%) of the title compound as a yellow oil. MS: m/e=272 (M+).