Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](C1C=C2C(=CC=1)C(=O)CCC2(C)C)#[CH:2].Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][CH:20]2[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([O:29][CH:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([C:1]#[CH:2])[CH:18]=3)[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CC1(C)CCC(OC2CCCCC2)c2cc(Br)ccc21
Product: C#Cc1ccc2c(c1)C(OC1CCCCC1)CCC2(C)C

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K), 2.1 g (8.8 mmol) of 6-bromo-4-cyclohexyloxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound J) was converted into the title compound using 1 g (10.2 mmol) of trimethylsilyl acetylene, 0.14 g (0.20 mmol) of bis(triphenylphosphine)palladium(II) chloride, 19 mg (0.1 mmol) of cuprous iodide and 80 mg (0.6 mmol) of K2CO3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:12]3=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]([CH2:17]O)=[C:11]3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:27]>ClCCl>[Cl:27][CH2:17][C:16]1[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:9]=[N:10][C:11]=12
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cn2cnc3c(CO)cc(C(F)(F)F)nc32)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c(CCl)cc(C(F)(F)F)nc32)cc1

Procedure:
[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x199 (0.55 g, 1.63 mmol) is dissolved in dichloromethane (20 ml). SOCl2 (2 ml) is added dropwise. The reaction mixture is refluxed for 1 h. The volatiles are rotary-evaporated. Then 50 ml of chloroform is additionally distilled off from the residue. The resulting chloroform solution is added dropwise at 0° C. under vigorous stirring to saturated aqueous NaHCO3. The organic phase is separated, dried with anhydrous sodium sulfate, evaporated, and dried under 1 mmHg for 1.5 h at 40° C. 7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine x202 (0.55 g, 95%) sufficiently pure for the next step is obtained.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:3]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([C:2]2[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])=[O:7])=[C:4]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[CH:3]=2)[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 80 °C
Yield: 90 %

Procedure:
Using methods substantially equivalent to those described in example 4-F except that the reaction was heated to 80° C., 2-[4-(pyrrolidin-1-yl)-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (101 mg, 0.16 mmol, 90%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:11]2[NH:12][C:13](=[O:20])[N:14]([CH2:17][C:18]#[CH:19])[C:15](=[O:16])[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:23]>C(OCC)(=O)C.C(O)C>[ClH:23].[CH2:17]([N:14]1[C:15](=[O:16])[C:10]2[CH2:9][NH:8][CH2:22][CH2:21][C:11]=2[NH:12][C:13]1=[O:20])[C:18]#[CH:19]
Reactant: C#CCn1c(=O)[nH]c2c(c1=O)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: C#CCn1c(=O)[nH]c2c(c1=O)CNCC2

Procedure:
6-(tert-Butoxycarbonyl)-3 propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was suspended in 4 N hydrochloric acid in ethyl acetate (10 ml) and the resultant mixture was stirred at room temperature for 3 hours. A precipitate was obtained by filtration and dissolved in ethanol and the solvent was distilled away under reduced pressure. This was repeated three times to obtain the titled compound (790 mg) as a colorless amorphous substance. The resultant compound was subjected to a next reaction without further purifying.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[Br:13]N1C(=O)CCC1=O>CO>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Nc1cccc2c1C(=O)NC2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: Nc1ccc(Br)c2c1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74.5 %

Procedure:
3-Aminophthalimide (2.00 g, 12.3 mmol) was dissolved in methanol (200 mL), and the solution was added with N-bromosuccinimide (2.19 g, 12.3 mmol), followed by stirring at room temperature for 50 minutes. The obtained solid was collected by filtration and washed with methanol to obtain 3-amino-6-bromophthalimide (2.21 g, yield 74%).
Reaction SMILES: C(OCC)(=O)C=O.N[C@H](C)CO.CC1C=CC(N2N=CC=N2)=C(C=1)C(O)=O.[CH3:28][C@@H:29]1[CH2:33][O:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:30]1[C:39](=[O:52])[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[N:47]1[N:51]=[CH:50][CH:49]=[N:48]1>C1(C)C=CC=CC=1>[CH3:28][C@@H:29]1[CH2:33][O:32][C@@H:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:30]1[C:39](=[O:52])[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[N:47]1[N:51]=[CH:50][CH:49]=[N:48]1
Reactant: CCOC(=O)C1OC[C@@H](C)N1C(=O)c1cc(C)ccc1-n1nccn1
Agent: CCOC(=O)C=O
Agent: C[C@@H](N)CO
Agent: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC[C@@H](C)N1C(=O)c1cc(C)ccc1-n1nccn1

Procedure:
By using ethyl glyoxylate (polymer type, a solution of 47% toluene) (2.0 mL, 9.5 mmol), (2R)-2-aminopropan-1-ol (0.73 mL, 9.5 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.0 g, 4.9 mmol), the same procedure as in Reference Example 1 was carried out to obtain a diastereomer mixture of ethyl (2RS,4R)-4-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate. The obtained diastereomer mixture was purified by thin layer chromatography (1 mm, hexane/EtOAc=66/34) to obtain ethyl (2S,4R)-4-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate (colorless oil). By using the obtained colorless oil as the raw material, the same procedure as in Reference Example 4 was carried out to obtain the title compound (0.041 g) (colorless oil).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]([NH:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[C:23]([CH:38]3[CH2:40][CH2:39]3)=[N:24][N:25]4[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[O:19])=[CH:16][N:17]=[C:11]2[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH:38]1([C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[CH:29][C:21]=3[NH:20][C:18]([C:15]3[N:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]4=[N:17][CH:16]=3)=[O:19])[N:25]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)[N:24]=2)[CH2:40][CH2:39]1
Reactant: [H][H]
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCc6ccccc6)ccn45)cccc32)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(O)ccn45)cccc32)n1
Temperature: 55 °C
Yield: 39.1 %

Procedure:
A mixture of 7-(benzyloxy)-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.75 g, 1.4 mmol; prepared as in Example 157) and 10% Pd/C (Degussa type, 0.75 g, 0.35 mmol) was treated with THF (12 mL). The reaction vessel was heated at 55° C. with stirring while maintaining 100 psi of hydrogen in the headspace of the reaction vessel for 20 hours. The reaction mixture was cooled to ambient temperature and filtered to remove the catalyst. The filtrate was diluted with EtOAc (75 mL) and extracted with 2.5 N sodium hydroxide (2×50 mL). The pH of the combined aqueous extracts was adjusted to approximately 5 using 0.5 M monobasic potassium phosphate solution and 6 N HCl to induce precipitation. The resulting solid was collected by vacuum filtration and dried under vacuum to give the product (0.24 g). MS (ES+APCI) m/z=439.4 (M+H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1.[Cl-].[NH4+].[O:30]1CCC[CH2:31]1>CN(C)C=O>[Br:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[C:19]([CH:31]=[O:30])[CH:18]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(Br)c2ccccc12
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c2ccccc2c1F
Reaction time: 0.5 h

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (4.13 ml) in tetrahydrofuran (40 ml) was cooled to −78° C. under argon atmosphere, and added dropwise thereto was n-butyl lithium (2.44 M hexane solution, 10.0 ml). The mixture was stirred at the same temperature for 30 minutes, and added dropwise thereto at −78° C. was a solution of 1-bromo-4-fluoronaphthalene (5.0 g) in tetrahydrofuran (20 ml). The mixture was stirred at the same temperature for 1 hour, and added dropwise thereto at −78° C. was N,N-dimethylformamide (5.16 ml). The mixture was stirred at the same temperature for 1 hour, and added thereto was a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from diisopropyl ether and hexane to give 4-bromo-1-fluoro-2-naphthaldehyde (4.43 g) as pale yellow crystals. APCI-Mass m/Z 267/269 (M+NH4).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10]O)[C:6]([CH:12]=[CH2:13])=[CH:5][N:4]=1.S(Cl)([Cl:16])=O>O1CCCC1>[ClH:16].[CH3:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10][Cl:1])[C:6]([CH:12]=[CH2:13])=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: C=Cc1cnc(C)c(O)c1CO
Agent: Cl
Solvent: C1CCOC1
Product: C=Cc1cnc(C)c(O)c1CCl

Procedure:
A mixture of 1.65 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine hydrochloride, 1 ml. of thionyl chloride and 20 ml. of tetrahydrofuran is refluxed 6 hours. After cooling, the precipitate is collected on a filter, washed with ether and dried to give 2-methyl-3-hydroxy-4-chloromethyl-5-vinyl pyridine hydrochloride.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)=[CH:18][CH:19]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: N#Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(C#N)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.03 g (4.23 mmol) of the compound from Example 174A in analogy to the synthesis of the compound from Example 278. 248 mg (15% of theory) of the target compound were obtained.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[N:37]=[CH:36][C:35]3[C:38]([I:47])=[N:39][N:40]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:34]=3[CH:33]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C(#N)C>[F:21][C:25]1[C:24]([O:23][CH3:22])=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=1[C:32]1[N:37]=[CH:36][C:35]2[C:38]([I:47])=[N:39][N:40]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:34]=2[CH:33]=1
Reactant: COc1cc(OC)cc(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (0.84 g, 2.4 mmol) (Alfa Aesar Cat. No. L17003) was added to a stirring solution of 6-(3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.55 g, 1.2 mmol) in acetonitrile (15 mL). The mixture was stirred at r.t. for 1 h. The solid was filtered out. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.52 g) which contained some amount of the corresponding di-fluoride analogue, and was directly used in next step reaction without further purification. LCMS (M+H)+=484.0
Reaction SMILES: [OH:1][C:2]1([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:29][CH2:28][CH2:27][N:26]4[C:22](=[N:23][C:24]([C:30]([NH2:32])=[O:31])=[CH:25]4)[C:21]=3[CH:33]=2)[CH2:5][CH:4]([O:6]C(=O)C2C=CC=CC=2)[CH2:3]1>CO.ClCCl.O>[OH:1][C:2]1([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:29][CH2:28][CH2:27][N:26]4[C:22](=[N:23][C:24]([C:30]([NH2:32])=[O:31])=[CH:25]4)[C:21]=3[CH:33]=2)[CH2:3][CH:4]([OH:6])[CH2:5]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(OC(=O)c4ccccc4)C3)c(F)cc1OCC2
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(O)C3)c(F)cc1OCC2

Procedure:
In a 25-mL round-bottom flask, a suspension of 9-(1-hydroxy-3-benzoyloxy-cyclobutylethynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (190 mg, ˜0.4 mmol), lithiumol (96 mg, 4.01 mmol) in methanol (0.5 mL) and water (1 mL) was stirred at room temperature overnight. The resulting solution was diluted with 20 mL of dichloromethane and 10 mL water. The organic layer was washed with 10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:10). This resulted in 7 mg of 9-(1,3-Dihydroxy-cyclobutylethynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a light yellow solid (single undetermined diasteromer). LC-MS (ES, m/z):358[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm) δ: 8.570 (d, 1H), 7.783 (s, 1H), 7.591 (br s, 1H), 7.139 (br s, 1H), 7.015 (d, 1H), 5.982 (s, 1H), 5.200 (d, 1H), 4.520-4.496 (m, 4H), 4.000-3.949 (m, 1H), 2.760-2.716 (m, 2H), 2.164-2.115 (m, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[C:22]([CH3:34])([CH3:33])[O:23][C:24](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[C:25]=2[C:26]#[N:27])=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N+:2]=[N-:3].O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[O:42]=[C:37]1[CH2:38][CH2:39][C:40](=[O:41])[N:36]1[O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]2[C:22]([CH3:34])([CH3:33])[O:23][C:24](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[C:25]=2[C:26]#[N:27])[CH:17]=[CH:18][C:4]=1[N:1]=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc(N=[N+]=[N-])c(OCCCCCC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc(N=[N+]=[N-])c(OCCCCCC(=O)ON2C(=O)CCC2=O)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
The following procedure requires dark room conditions. To a cooled solution (5° C.) of 6-{2-Azido-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid (0.1 g, 0.21 mmol) in dichloromethane (20 ml) was added N-hydroxysuccinimide (0.027 g, 0.24 mmol) and DCC (0.052 g, 0.25 mmol). The resulting solution was allowed to stir at 5° C. for 2 hours and then at room temperature for 12 hours. The solvent was removed under reduced pressure and the resulting dark red solid was purified by column chromatography (70% EtOAc/30% Hexane) to give 6-{2-azido-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester as a dark red solid (0.084 g, 69%). 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, 1H, J=16.4 Hz), 7.24 (dd, 1H, J=8.4 Hz, J=1.6 Hz), 7.09 (d, 1H, J=1.6 Hz), 7.04 (d, 1H, J=8 Hz), 6.96 (d, 1H, J=16.4 Hz), 4.13 (t, 2H), 2.87 (s, br, 4H), 2.70 (t, 2H, J=7.2 Hz), 1.98 (m, 2H), 1.91 (m, 2H) 1.82 (s, 6H), 1.68 (m, 2H). 13C NMR (400 MHz, CDCl3) δ: 173.50, 169.25, 168.48, 152.61, 146.50, 133.66, 131.19, 123.40, 121.54, 114.10, 112.07, 111.62, 110.83, 110.29, 97.48, 69.18, 30.85, 29.71, 28.34, 26.55, 25.62, 25.22, 24.22. IR (neat): 3321, 2926, 2850, 2361, 2225, 2128, 2094, 1812, 1783, 1733, 1563, 1536, 1497, 1307, 1292, 1186, 1102, 1064, 1046, 849 cm−1.
Reaction SMILES: [CH3:1][CH:2]([OH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C.[Br:22][C:23](C)([CH3:27])[C:24](Br)=[O:25]>C1(C)C=CC=CC=1>[Br:22][CH:23]([CH3:27])[C:24]([O:14][C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH2:1])=[O:25]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CCCCCCCCCCCC(C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(CCCCCCCCCCC)OC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a stirred solution of tridecan-2-ol 68 (5 g, 24.9 mmol) in toluene (50 mL) was added triethylamine (3.5 mL, 27.45 mmol)) and followed by 2-bromo-2-methylpropionyl bromide 97 (6.31 g, 27.45 mmol) at 5-10° C. The reaction mixture was stirred for 3 hour at 55-60° C., and the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated. The organic layer was washed with brine, and the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 98 (8.1 g, yield: 96%) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=C)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].CO.CC[O:18]C(C)=O>CC(O)C.O.C(Cl)Cl.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=[O:18])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C=CCC1(C(=O)OC)CCOCC1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)C1(CC=O)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Allyl-tetrahydro-pyran-4-carboxylic acid methyl ester (11 g, 59.78 mmol) was dissolved in iPrOH (300 mL). To this was added a aqueous solution of NaIO4 (28 g, 130.4 mmol, 2.18 equiv.) in water (300 mL), followed by addition of OsO4 (50 mg, crystals, in one portion) at rt. The solution was stirred with a mechanical stirrer at rt (water bath). After 30 min, milky cloudy mixture was formed. Stirring was continued for an additional period of 4 h. TLC (1% MeOH in DCM, and 5% MeOH in DCM) did not detect the SM. An aliquot was taken, dissolved in CDCl3 and 1H NMR was run, which showed no alkene peak in the sample, and thus the reaction was judged to be complete. The reaction mixture was poured into ice water (200 mL) and EtOAc (200 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (5×50 mL). More water was added to dissolve the solid to result in a clear solution. The combined extracts were washed with brine, and concentrated to dryness to get a liquid product. The liquid product was then subject to a distillation under reduced pressure to remove isopropanol. The remaining liquid was purified on a 80 g silica gel column, eluted with MeOH in DCM: 0% 0-5 min; 5-10% 5-25 min. 10-12% 25-60 min. Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to yield a liquid 6.6 g (60% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:19]([C:21]1[NH:22][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=2[C:29]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=O>N1CCCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:19][C:21]4[NH:22][C:23]5[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=5[C:29]=4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c3c(c2CCC(=O)O)CCCC3)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of 103 mg 6-(4-methoxyphenyl)-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was heated to 90° C. in a sealed tube and held there for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. Ethyl acetate was added upon which a solid precipitated from the aqueous layer. The precipitate was collected by filtration, and washed with water and hexane to give 57 mg of 3-{2-[6-(4-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indol-3-yl}-propionic acid as a brown solid (30%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](/[C:10](=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:18]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)/C(=C\c2ccccc2)C(=O)OC(C)(C)C)c(O)c1
Yield: 45.5 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxy-4-methyphenyl)-3-oxopropanoate (250 mg, 1.0 mmol), benzaldehyde (100 μL, 1.00 mmol), 12.0 mL benzene, piperidine (10 μL, 0.10 mmol) and glacial acetic acid (5.7 μL, 0.10 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 154 mg (46%) of white solid. mp=92-95° C.; IR (film) 2977.9; 1718.2; 1627.9; 1155.0 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.95 (bs, 1H), 7.82 (s, 1H), 7.40 (d, J=9.6 Hz, 1H), 7.36-7.29 (m, 5H), 6.83 (s, 1H), 6.61 (d, J=8.0 Hz, 1H), 2.34 (s, 3H), 1.41 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 200.8, 163.9, 163.0, 149.0, 142.0, 133.0, 131.8, 131.7, 130.6, 130.3, 129.1, 120.9, 118.5, 118.0, 82.7, 28.1, 22.3; LRMS (electrospray): Mass calculated for C21H22O4 [M]+, 338.15. Found [M+23]+, 361.2. An NOE difference experiment was conducted for this compound and a positive NOE was seen for the alkene proton when the tert-butyl signal was irradiated and a positive NOE was seen for the tert-butyl signal upon irradiation of the alkene proton.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][C:32]([CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC(=O)C1CCNCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidine-4-carboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.50 (s, 1 H), 8.14 (s, 1 H), 8.01-7.98 (d, J=1.2 Hz, 1 H), 7.95-7.93 (d, J=7.2 Hz, 1 H), 7.84-7.82 (d, J=8.8 Hz, 1 H), 7.66-7.61 (m, 2 H), 7.52-7.51 (m, 1 H), 5.23 (s, 1 H), 4.59 (s, 2 H), 3.74 (s, 2 H), 3.57-3.54 (m, 2 H), 3.22-3.10 (m, 4 H), 2.50 (s, 3 H), 2.26-2.22 (m, 2 H), 2.14-2.08 (m, 2 H).