Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]1[C:15](=[O:16])/[C:14](=[CH:17]/[C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[N:22]=[CH:21]3)/[S:13][C:12]1=[O:39].C(CN)O>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:23]2[C:24]3[C:20](=[CH:19][C:18](/[CH:17]=[C:14]4/[C:15](=[O:16])[N:11]([CH2:10][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[C:3]([OH:40])=[O:2])[C:12](=[O:39])[S:13]/4)=[CH:26][CH:25]=3)[CH:21]=[N:22]2)=[C:29]([C:35]([F:37])([F:36])[F:38])[CH:30]=1
Reactant: COC(=O)c1ccccc1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Solvent: NCCO
Product: O=C(O)c1ccccc1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid was prepared from 2-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid methyl ester following General Procedure 0 and converted to the corresponding ethanolamine salt following General Procedure T.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[NH2:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[F:17][C:18]([F:29])([F:28])[C:19]1[S:20][CH:21]=[C:22]([C:24](=[O:27])[CH2:25]Br)[N:23]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:15][CH2:25][CH:24]([OH:27])[C:22]2[N:23]=[C:19]([C:18]([F:29])([F:28])[F:17])[S:20][CH:21]=2)[CH3:16])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carbomethoxymethoxyphenyl)-1-methyl-ethanamine with 2-trifluoromethyl-4-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel column with methylene chloride/methanol=20:1 as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][OH:22])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:22][CH2:21][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:23][CH3:24])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])([CH3:18])[NH:14]2)=[O:30]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CO)C(C)=CC(C)(C)N2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1cc(F)ccc1-c1ccc2c(c1COC(=O)c1cccc(N)c1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
6-(4-Fluoro-2-methoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-3, 49.7 mg, 0.15 mmol), 3-aminobenzoic acid (49.0 mg, 0.35 mmol), tri-n-butylphosphine (87.0 μL, 0.35 mmol), and 1,1′-(azodicarbonyl)dipiperidine (89.4 mg, 0.35 mmol) were dissolved in anhydrous benzene (2 mL), and then the mixture was stirred under argon atmosphere at room temperature overnight. Hexane (3 mL)-ethyl acetate (3 mL) were added to the reaction mixture, and unsoluble materials were filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.0 mg) as a colorless amorphous product. (Yield 42%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](OC)(=[O:19])[C:17]#[CH:18]>CN(C)C=O>[CH3:14][C:12]1[NH:13][C:16](=[O:19])[CH:17]=[CH:18][C:11]=1[C:10](=[O:15])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: C#CC(=O)OC
Reactant: CC(N)=CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)ccc1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
m.p. 282°-284° C., 5.0 g, was obtained following the procedure described in Example A-2 using 20 g of 3-(4-nitrophenyl)-1-methyl-3-oxo-1-propenamine, 9.5 ml of methyl propiolate and 100 ml of dimethylformamide.
Reaction SMILES: C(O[CH:5]1[CH2:31][C:30](=[O:32])[CH:29]([CH2:33][CH:34]=[CH2:35])[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][C:50]2([O:62][SiH:63]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:55][CH2:54][CH:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]([O:60][CH3:61])[CH2:51]2)[CH:6]1[CH3:77])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C>[CH2:33]([CH:29]1[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][C:50]2([O:62][SiH:63]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH2:55][CH2:54][CH:53]([C:56]([CH3:58])([CH3:59])[CH3:57])[CH:52]([O:60][CH3:61])[CH2:51]2)[CH:6]([CH3:77])[CH:5]=[CH:31][C:30]1=[O:32])[CH:34]=[CH2:35]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3(O[SiH](c4ccccc4)c4ccccc4)CCC(C(C)(C)C)C(OC)C3)C(C)C(OC(C)=O)CC1=O)C(C)CC2OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3(O[SiH](c4ccccc4)c4ccccc4)CCC(C(C)(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 14-acetoxy-17-allyl-12-[2-(4-tertbutyl-diphenylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (43.8 mg) in tetrahydrofuran (1.5 ml) was added potassium carbonate (ca 100 mg) at room temperature and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was diluted with diethyl ether and the resulting solution was washed with a saturated aqueous ammonium chloride, water and an aqueous sodium chloride successively, and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified on silica gel thin layer chromatography (developing solvent: diethyl ether and hexane, 3:2 v/v) to give 17-allyl-12-[2-(4-tertbutyl-diphenylsilyloxy-3-methoxycyclohexyl)-1methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (30 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](Cl)=[O:9])[C:4]([CH3:11])=[N:3]1.[CH2:12]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[C:23]([O:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])[NH2:19])[CH:13]([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:12]([C:16]1[CH:17]=[C:18]([NH:19][C:8]([C:5]2[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[O:9])[CH:20]=[CH:21][C:22]=1[C:23]([O:32][CH3:33])([C:24]([F:27])([F:25])[F:26])[C:28]([F:29])([F:30])[F:31])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(c1ccc(N)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: Cc1nn(C)c(C)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(c1ccc(NC(=O)c2c(C)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Yield: 79.4 %

Procedure:
1,3,5-trimethylpyrazole-4-carbonyl chloride (3.93 g, 22.8 mmol), 3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (5.0 g, 15.2 mmol), and triethylamine (3.07 g, 30.4 mmol) were dissolved in tetrahydrofuran (100 ml), and the mixture was heated under reflux for 5 hr. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were washed with ether to give the desired compound (5.62 g).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[NH:17][C:18]1[C:19](=O)[CH2:20][CH2:21][CH2:22][CH:23]=1)([CH3:7])[CH3:6]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:4])/[N:3]=[C:19]1\[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]\1[NH:17][C:9]1[C:10]([CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=[CH:13][C:8]=1[CH:5]([CH3:7])[CH3:6]
Reactant: CN(C)N
Reactant: CC(C)c1cccc(C(C)C)c1NC1=CCCCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC1=CCCC/C1=N\N(C)C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Follow a procedure similar to that of Example C except use toluene (12 mL); 1,1-dimethylhydrazine (0.81 mL, 10.6472 mmol); a solution of titanium(IV) chloride (0.2011 g, 1.0600 mol) in toluene (5 mL); stir for 1 hour; then add 2-(2,6-diisopropylphenylamino)cyclohex-2-enone (0.4889 g, 1.8014 mmol, Preparation 3); followed by 1 mL of rinse toluene; stir the resulting reaction mixture overnight; to give after isolation 0.5222 g (92.5%) of the product (K) as a yellow oil containing about 7% of a minor isomeric product.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: O=CCC1Cc2ccc(F)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 1.92 g of (RS)-2-(2-oxo-ethyl)-6-fluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.73 g (75%) of (R)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([P:3]([Cl:6])([Cl:5])=[S:4])[CH3:2].[CH3:7][CH:8](S)[CH3:9].N1C=CC=CC=1>C(#N)C>[CH2:1]([P:3]([Cl:6])([Cl:5])=[SH:4][CH:8]([CH3:9])[CH3:7])[CH3:2]
Reactant: CC(C)S
Reactant: CCP(=S)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCP(Cl)(Cl)=[SH]C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a mixture of 326 g (2.0 moles) ethylphosphonothioic dichloride in 500 ml acetonitrile, a mixture of 152.3 g (2.0 moles) 2-propanethiol and 158.2 g (2.0 moles) pyridine were added over a period of 20 minutes. The reaction mixture was stirred overnight at room temperature and then heated at reflux for four hours, resulting in the formation of solids. The reaction mixture was cooled to room temperature and then filtered. The filtrate was combined with 500 ml hexane, washed twice with 75 ml water and then stripped to give 373 g of the aboveidentified product as a yellow oil.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:44])([CH:39](OC)[O:40]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][C:9]([CH3:44])([CH:39]=[O:40])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(SCc3ccccc3)C(OC)OC)cc2c1
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(C=O)SCc3ccccc3)cc2c1
Yield: 86.2 %

Procedure:
To a mixture of N-[2-(benzylthio)-3,3-dimethoxy-2-methylpropyl]-5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (1.95 g), water (0.16 mL) and acetone (30 mL) was added Amberlyst (registered trade mark) 15 ion exchange resin (500 mg) at room temperature, and the mixture was added overnight at room temperature. The insoluble substance was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the title compound (1.56 g, yield 87%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([O:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1OC(C)=O
Yield: 82 %

Procedure:
Use compound 8 and acetyl chloride as materials, and follow the method described in Example 180 to obtain a white solid as the target product (82%). 1H NMR (400 MHz, DMSO-d6): 1.79 (s, 3H), 1.83 (s, 3H), 2.08 (s, 3H), 332 (d, J=7.6 Hz, 2H), 3.73 (s, 3H), 3.89 (s, 3H), 5.23 (t, J=7.6 Hz, 1H), 6.72 (s, 1H), 6.79 (d, J=16.0 Hz, 1H), 719 (d, J=16.0 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O:38]CC)=[O:37].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)c(Cl)c5)n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2ccc(Cl)c(Cl)c2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 16 h
Yield: 65.9 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(3,4-dichlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.051 g, 0.085 mmol) in 3:1 v/v THF/ethanol (1 ml) was added 1M sodium hydroxide (0.20 ml, 0.20 mmol), and the reaction was stirred for 16 hours. The reaction was concentrated, taken up in water, and acidified with 1M hydrochloric acid. The reaction was extracted twice with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel preparative thin-layer chromatography, eluting with 95:5:1 DCM/MeOH/glacial acetic acid to yield the desired compound (0.032 g, 0.056 mmol, 66% yield). MS (apci) m/z=569.0 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[O:12][N:11]=2)[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:22])=[O:2])[CH:14]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(-c2cc(-c3ccc(C)cc3)on2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(-c3cccc(C(=O)O)c3)no2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 25 ml round flask, 330 mg (1.13 mmol) of 3-[5-p-tolyl-isoxazol-3-yl]-benzoic acid methyl ester is dissolved in 10 ml of dioxane and subsequently 1.69 ml of aqueous lithium hydroxide (1M, 1.69 mmol, 1.5 eq.) are added and the resulting solution stirred for 20 h at room temperature. Then, the dioxane is removed in vacuo, 10 ml of water are added and the pH adjusted to 2 with hydrochloric acid (1M). The precipitate is filtered and dried to yield the title compound as a white solid. Mass spectrum: m/z (M−H)+: 278.2
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24]C)[N:13]2[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:26][C:9]1[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:24])[N:13]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC[C@@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a solution of 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(tetrahydro-3-furanyl)propyl]-9H-purin-6-amine (52 mg, 0.143 mmol) in methanol (5 ml) at room temperature was added 4M HCl in dioxane (0.894 ml, 3.58 mmol). The reaction mixture was stirred at room temperature for 18 hrs and concentrated in vacuo to give a white solid. This material was dissolved in methanol and loaded onto a 2 g aminopropyl SPE cartridge, eluting with methanol. The solvent was removed to give the title compound as a white solid (36 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:6]=2[CH:7]=1.[CH:15]1[C:27]2[N:26]([C:28]3[CH:29]=[CH:30][C:31]4[NH:32][C:33]5[C:38]([C:39]=4[CH:40]=3)=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[K]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C(C)=CC=CC=1>[CH:30]1[C:31]2[N:32]([C:2]3[CH:3]=[CH:4][C:5]4[O:14][C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:8]5[C:6]=4[CH:7]=3)[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:40]=[C:28]([N:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:27]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:29]=1
Reactant: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4ccccc43)cc12
Reactant: Clc1ccc2oc3ncccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: c1cnc2oc3ccc(-n4c5ccccc5c5cc(-n6c7ccccc7c7ccccc76)ccc54)cc3c2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 60.3 %

Procedure:
The 300 mL round bottom flask, equipped with magnetic stirrer and refluxed condenser, was charged with 6-chlorobenzofuro[2,3-b]pyridine (2.04 g, 10 mmol), 3-(9-carbazolyl)carbazole (3.32 g, 10 mmol), Pd(OAc)2 (450 mg, 20 mol %), P(t-Bu)3 (10 mL of 1M solution in toluene, 10 mmol), potassium tert-buthoxide (1.92 g, 20 mmol) and 150 ml of xylene. The flask was filled with nitrogen, and the reaction mixture was heated to reflux and stirred under nitrogen atmosphere for 36 hours. Then the reaction was cooled down to room temperature, washed with water, filtered through silica plug and evaporated. The residue was subjected to column chromatography on silica gel, eluent hexane/ethyl acetate mixture 4:1, providing 3.01 g of 6-(9H-3,9′-bicarbazol-9-yl)benzofuro[2,3-b]pyridine as white solid, structure was confirmed by NMR and MS spectroscopy.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=[O:5])#[N:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[N:9]1([C:4](=[O:5])[CH2:3][C:1]#[N:2])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)CC#N
Reactant: C1COCCN1
Product: N#CCC(=O)N1CCOCC1
Yield: 76.9 %

Procedure:
Ethyl cyanoacetate (5.33 mL, 50 mmol) and morpholine (17.49 mL, 0.2 mol) were gently refluxed at 90° C. in an oil bath for 2 days. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with 50% acetone in n-hexane. 5.93 g of the compound was obtained. MS (DCI) m/e 155 (M+H)+, 172 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 4.03 (s, 2H), 3.53-3.59 (m, 4H), 3.42-3.45 (m, 2H), 3.32-3.35 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]=O>>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][N:10]([CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]1)[CH3:28])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=O
Reactant: CC(C)N1CCC(CNC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Product: CC(C)N1CCC(CN(C)C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Yield: 95.7 %

Procedure:
Using alkylation method B, N-[(R)-2-[(1-isopropyl-piperidin-4-ylmethyl)amino]-1-phenylethyl]carbamic acid tert-butyl ester (511 mg, 1.4 mmol) and paraformaldehyde (816 mg, 27 mmol) afforded 522 mg (98%) of the title compound as a crude residue that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: OC(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O
Product: O=C(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F

Procedure:
2.75g (0.01 mol) of 2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 25 ml of chlorobenzene at room temperature. 12.2 ml (0.012 mol) of an approximately 6% strength sodium hypochlorite solution are metered in within 10 minutes with vigorous stirring and the mixture is stirred for a further 8 hours during which the reaction temperature rises to 24° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.3 mbar, 100°-120° C. bath temperature), 2.0 g (73.3% of theory) of 2-(2,2,2-trifluoroethoxy)-5-trifluoroacetylpyridine are obtained.