Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].[C:20]([OH:24])(=[O:23])[CH2:21][SH:22].C(=O)(O)[O-].[Na+]>C(O)C>[C:20]([CH2:21][S:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19])([OH:24])=[O:23]
Reactant: O=C(O)CS
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=CC1=C(SCC(=O)O)c2ccccc2OC1c1ccccc1

Procedure:
A solution containing 2.7 g 4-chloro-3-formyl-flav-3-ene, 0.85 ml thioglycolic acid and 2.5 g sodium bicarbonate in 30 ml absolute ethanol is refluxed for 15 hours. After evaporation, one adds water and extracts with methylene chloride. The aqueous phase is acidified to pH 1. Extraction with methylene chloride is followed by washing the organic solution with water, drying over magnesium sulfate and evaporation. The residue is purified by column chromatography on silicagel using a mixture of methylene chloride and ethanol as eluant. The best fractions are crystallized in a mixture of hexane and toluene. Pure 4-(S-carboxymethylthio)-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(O)ccc21
Product: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(OCCCCBr)ccc21

Procedure:
In analogy to example 1.4, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 438 (MH+, 1Br, 1Cl);
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[C:22]([F:24])[CH:23]=1.C(O)(=O)C.ClC(Cl)C.C([BH3-])#N>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]2[CH2:26][CH2:27][N:28]([CH2:1][C:3]3[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]4[C:12]=3[CH:11]=[CH:10][CH:9]=[CH:8]4)[CH2:29][CH2:30]2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: O=Cc1cc(C(=O)O)c(=O)n2ccccc12
Reactant: Fc1cc(F)cc(C2CCNCC2)c1
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(O)c1cc(CN2CCC(c3cc(F)cc(F)c3)CC2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
In a 2-5 mL Emrys™ process vial, a mixture of the 1-formyl-4-oxo-4H-quinolizine-3-carboxylic acid (35 mg, 0.16 mmol), 4-(3,5-difluorophenyl)piperidine (45.4 mg, 0.23 mmol), glacial acetic acid (0.055 mL, 0.97 mmol) and 0.80 mL of dichloroethane was stirred vigorously. To the stirring mixture was added resin-bound MP-cyanoborohydride (20.3 mg, 0.32 mmol). The mixture was heated via Emrys Optimizer™ microwave to 120° C. for 30 minutes. The reaction was filtered, providing material, which was purified by reverse phase HPLC to yield the title compound that gave a high resolution mass spectrum (ES+) m/z of 399.1512 calculated for M+H+ [C22H20F2N2O3: 399.1515].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21]([OH:23])=O)=[CH:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C(Cl)(=O)C(Cl)=O.[NH:40]1[CH2:45][CH2:44][CH:43]([N:46]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][C:47]2=[O:55])[CH2:42][CH2:41]1>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21]([N:40]2[CH2:45][CH2:44][CH:43]([N:46]3[C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH2:48][C:47]3=[O:55])[CH2:42][CH2:41]2)=[O:23])=[CH:12]1)[CH3:24])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1Cc2ccccc2N1C1CCNCC1
Reactant: CN(CCn1cc(C(=O)O)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of 0.20 g (0.57 mmol) 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-carboxylic acid, 0.11 ml (0.63 mmol) N,N-diisopropylethylamine and 2 drops of N,N-dimethylformamide in 4 ml dicholormethane were added 0.060 ml (0.74 mmol) oxalyl chloride at 0-5° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 3 h. A solution of 0.15 g (0.68 mmol) 1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and 0.11 ml (0.63 mmol) N,N-diisopropylethylamine in 2 ml dicholormethane was added. After stirring for 15 min at room temperature silica gel was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was transferred to a silica gel column. Elution gave 0.26 g (82%) of the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:21]1([CH:27]2[CH2:29][O:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:29][CH:27]([OH:28])[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(CC(O)c1ccccc1)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
A mixture of 34.6 mg (0.128 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 23 mg (0.192 mmol) 2-phenyl-oxirane and 38 mg (0.384 mmol) NEt3 in 2 mL DCM were stirred at 50° C. for 2 h and concentrated. The residue was taken up in methanol and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 7.1 mg (14%) of the title compound. MS m/e: 391.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[N:13]1[CH:18]=[C:17]([CH:19]=O)[CH:16]=[N:15][CH:14]=1>>[N:13]1[CH:18]=[C:17](/[CH:19]=[N:10]/[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[CH:16]=[N:15][CH:14]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: O=Cc1cncnc1
Product: FC(F)(F)c1cccc(N/N=C/c2cncnc2)c1
Yield: 87 %

Procedure:
In analogy to the procedure described in Example 167A], 3-(trifluoromethyl)phenylhydrazine and pyrimidine-5-carbaldehyde gave the title compound as a yellow solid (87%). MS: 267.1 (MH+).
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][C@H:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27])[C:14]([CH3:17])([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]([N+:26]([O-:28])=[O:27])=[C:18]([C@@H:13]([OH:12])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:23]=1
Reactant: COc1ccc([N+](=O)[O-])c([C@@H](OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c([C@@H](O)C(C)(C)C)c1
Yield: 99.4 %

Procedure:
A mixture of (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (590 mg, 1.4 mmol) and K2CO3 (389 mg, 2.8 mmol) in methanol (MeOH, 25 mL) was heated to reflux for one hour, then cooled down, concentrated in vacuo, and diluted with CH2Cl2 (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield enantiopure (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (333 mg, 99%). 1H NMR was identical with that of the racemic alcohol.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:16]1([NH:19][C:20]([C:22]2[S:23][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:26]=2)=[O:21])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[N:11]=[C:10]([C:24]3[S:23][C:22]([C:20](=[O:21])[NH:19][CH:16]4[CH2:18][CH2:17]4)=[CH:26][CH:25]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)NC3CC3)s2)OC1(C)C
Reactant: CCOc1nc(N)nc2ccc(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1nc(N)nc2ccc(-c3ccc(C(=O)NC4CC4)s3)nc12
Temperature: 90 °C
Yield: 80.9 %

Procedure:
To a solution of 2-amino-4-ethoxy-6-chloropyrido[3,2-d]pyrimidine (50 mg) in 1,4-dioxane (7 ml) and water (2.5 ml) was added N-(cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarboxamide (72 mg), K2CO3 (77 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg). The reaction mixture was heated to 90° C. for 1 hour. The reaction mixture was extracted with dichloromethane after which the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography, the mobile phase being a 3:97 MeOH/CH2Cl2 mixture, resulting in the pure title compound as a white powder (64 mg, yield: 81%) which was characterized by its mass spectrum as follows: MS (m/z): 356 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12])[CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1NC(=O)C(C)C(=O)O

Procedure:
The acid was prepared according to procedure B using ethyl 3-(5-fluoro-2-methylphenylamino)-2-methyl-3-oxopropanoate (2.45 g, 9.67 mmol) in THF (9.67 mL). The crude product was used without further purification. Mass Spectrum (ESI) m/e=226.0, (M+1).
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.[Cu](C#N)[C:30]#[N:31]>CN(C=O)C.O>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:11]2[C:12]3[N:13]=[C:5]([CH2:4][C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[C:30]#[N:31])[S:6][C:7]=3[N:8]=[CH:9][N:10]=2)=[CH:16][CH:17]=1
Reactant: N#C[Cu]C#N
Reactant: FC(F)(F)c1ccc(Nc2ncnc3sc(Cc4ccccc4I)nc23)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Cc1nc2c(Nc3ccc(C(F)(F)F)cc3)ncnc2s1
Temperature: 100 °C
Yield: 93.5 %

Procedure:
To a solution of [2-(2-iodo-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (0.20 g, 0.39 mmol) in anhydrous DMF (3.9 mL) was added copper cyanide (0.24, 2.73 mmol). The resulting suspension was heated to 100° C. in a sealed tube for 5 h. The reaction mixture was cooled to rt, diluted with H2O (20 mL) and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with 10% aq. HCl (2×5 mL) and satd. aq. NaCl (2×5 mL), dried, filtered, concentrated and purified by FCC to provide the title compound as a colorless solid (0.15 g, 94%). MS (ESI): mass calcd. for C20H12F3N5S, 411.1; m/z found 412.1 [M+H]+. 1H NMR (CDCl3): 8.63 (s, 1H), 8.18 (s, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.75-7.72 (d, J=8.5 Hz, 2H), 7.65-7.61 (m, 1H), 7.52-7.49 (m, 1H), 7.48-7.44 (m, 2H), 4.66 (s, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C@@H:24]1[CH2:28][C@@H:27](O)[CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23].C(Br)(Br)(Br)[Br:38].C(O)C>ClCCl>[CH3:20][O:21][C:22]([C@@H:24]1[CH2:28][C@H:27]([Br:38])[CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
Add triphenylphosphine (0.88 mol, 231 g) in portions to a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.58 mol, 144 g) and CBr4 (0.88 mol, 292 g) in dry dichloromethane (1.44 L) at 0° C. Upon complete addition, warm the reaction mixture to room temperature and stir for 4 h. Add ethanol (1.44 L) and stir for an additional 2 h. Add diethyl ether (1.44 L) to the reaction mixture, filter the precipitated triphenylphosphine oxide, and concentrate the filtrate under reduced pressure. Purify by column chromatography using 5% ethyl acetate in hexanes as eluent to obtain the title compound (155 g, 85%) as a thick oil. ES-MS m/z 308 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[CH3:26].[C:29](OC(=O)C)(=O)[CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:23](=[O:28])[CH:24]=[C:25]([CH3:26])[N:27]=[C:29]1[CH3:30]
Reactant: CC(=N)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: CC(=O)OC(C)=O
Product: Cc1cc(=O)n(-c2cc(S(=O)(=O)N3CCCCc4ccccc43)ccc2Cl)c(C)n1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-imino-butyramide (42 mg, 0.1 mmol) in acetic anhydride (1 mL) was added 4-dimethyl-aminopyridine (6 mg, 0.1 mmol). The mixture was heated at 85° C. under stirring for 16 hrs. The mixture was then subjected to purification by prep. LCMS to afford 3-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-2,6-dimethyl-3H-pyrimidin-4-one 14-1. MS: 443.8 (M+H)+; tR=6.94 min (method 2).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[CH:14]1([CH2:19][N:20]2[C:24]3=[N:25][CH:26]=[C:27]([F:29])[CH:28]=[C:23]3[C:22]([C:30](=[NH:33])[NH:31][NH2:32])=[N:21]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH:14]1([CH2:19][N:20]2[C:24]3=[N:25][CH:26]=[C:27]([F:29])[CH:28]=[C:23]3[C:22]([C:30]3[N:31]=[N:32][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:33]=3)=[N:21]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: N=C(NN)c1nn(CC2CCCC2)c2ncc(F)cc12
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(CC3CCCC3)c3ncc(F)cc23)nc1O

Procedure:
841 mg (4.473 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 20 ml of ethanol, and the mixture was heated to reflux. Subsequently, 1.070 g (2.982 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide suspended in 26 ml of ethanol were added, and the mixture was boiled under reflux overnight. After cooling, the mixture was concentrated, taken up in acetonitrile and filtered. The filtrate was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 30:70→100:0). This gave 396 mg of the target compound (32% of theory).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:24]([O:25][CH3:26])[CH3:23])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(Br)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Br)n1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a slurry of 6-bromopicolinic acid (5.44 g, 26.93 mmol) in DCM (100 mL) was added a solution of CDI (5.67 g, 34.97 mmol) in DCM (70 mL) drop-wise over 15 minutes under nitrogen. The solution cleared a little during the addition but remained cloudy and after 1 hour at rt the mixture was treated drop-wise over 15 minutes with N,O-dimethylhydroxylamine [solution in DCM prepared by treating N,O-dimethylhydroxylamine hydrochloride (5.35 g, 53.82 mmol) with aqueous NaOH (2M, 100 mL) and extracting with DCM (2×100 mL)]. The mixture cleared during the addition and the resulting clear pale yellow solution was left to stir under nitrogen for 20 hours. The mixture was then reduced under vacuum and the residue partitioned between EtOAc (125 mL) and saturated aqueous NaHCO3 (125 mL). The layers were then separated and the organic layer washed with brine (125 mL), dried (MgSO4), filtered and reduced to give the title compound as a yellow oil (5.29 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:10][C:4]=2[CH:3]=1.C([Li])CCC.Cl[CH2:23][C:24]1[CH:25]=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][C:5]3[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]2=3)=[CH:25][N:26]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Reactant: ClCc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1ccc2c(c1)N(Cc1ccc(Br)nc1)Cc1ccccc1O2
Temperature: -23 °C
Reaction time: 0.42 h
Yield: 80.7 %

Procedure:
To a stirred solution of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (2 g) in THF (25 mL) at -78° C. was added 1.6 M hexane solution of n-butyl lithium (5.4 mL). After 25 minutes, 3-chloromethyl-6-bromopyridine (1.79 g) in THF (5 mL) was added. After 30 minutes, the temperature was raised to -23° C. After 30 minutes, an excess saturated solution of NH4Cl was added and the mixture was extracted with ether. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel using 10% ethyl acetate in hexane as eluant. Appropriate fractions were pooled to give the title compound (2.8 g) as a thick gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:20]>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1cc(Br)cc(N2CCC(C(=O)O)CC2)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CCN(c2cc(Br)cc(C#N)c2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-bromo-5-cyanophenyl)piperidine-4-carboxylic acid (1.1 g, 3.6 mmol) in toluene (4 mL) and methanol (2 mL) was added TMSCHN2 (2 M in Et2O, 3.5 mL, 7.0 mmol) dropwise at room temperature. After 1 h, the reaction was quenched with acetic acid (˜0.1 mL), diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was separated, dried (MgSO4), and concentrated to give methyl 1-(3-bromo-5-cyanophenyl)piperidine-4-carboxylate in ˜100% yield.
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15]C)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[Br-].[Al+3].[Br-].[Br-].Cl.C(OCC)C>C1C=CC=CC=1>[CH2:1]([C:5]1([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OC)cccc2C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCC1(CCCC)CCc2c(O)cccc2C1=O
Yield: 119.7 %

Procedure:
A mixture of 2,2-dibutyl-3,4-dihydro-5-methoxy-1(2H)-naphthalenone (2.321 g) and aluminium bromide (7.0 g) in dried benzene (40 ml) was refluxed for 40 minutes and allowed to cool in an ice-water bath. The cooled mixture was poured into a mixture of 1N aqueous hydrochloric acid (150 ml) and diethyl ether (100 ml) with stirring. The organic layer was washed with brine, dried, and concentrated in vacuo to yield 2,2-dibutyl-3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (2.643 g) as a crude syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[C-]#N.[Na+].C[C:35](O)=[O:36]>CO.C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]([O:36][CH3:35])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a solution of the aldehyde of Step 6 (17.26 g, 41.7 mmol) in 1.5 L of MeOH:THF 2:1, NaCN (20 g, 408 mmol), AcOH (5.7 mL, 98.9 mmol) and activated MnO2 (90 g, 1.01 mol) were added and the mixture was stirred for 16 h. The inorganic solid was then removed by filtration and washed with EtOAc. To the combined organic phases, 25% aq NH4OAc (1.7 L) was added. The two phases were separated and the aqueous layer was reextracted with EtOAc. The organic phases were washed with brine and dried over Na2SO4. Flash chromatography of the residue on silica with toluene and EtOAc:toluene 2.5:97.5 afforded 15.63 g (84%) of the title ester.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:26](=[O:28])[NH2:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:26](=[O:28])[NH2:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2CC1CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2CC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of [9-[(cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (20 mg, 0.065 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture stirred at room temperature for 2 hours. The reaction was acidified with 0.2 N HCl, and the organics were removed in vacuo. The white precipitate was filtered away from the aqueous layer and rinsed with Et2O to afford 15 mg (0.0409 mmol; 63%) the title acid as a white powder. MS (ES) m/e 367 (M+1), 350 (M+H−NH3), 365 (M−1).