Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccc(CC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Yield: 17.4 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-[2-(4-chloro-phenyl)-ethyl]-piperazine (4.74 g, 11.71 mmol) in dichloroethane (80 ml). Cool the solution to 0° and then add 1-chloroethyl chloroformate (7.95 g, 55.61 mmol) dropwise. Warm the solution to ambient temperature and then heat it at reflux for 15 hours. Remove the dichloroethane under vacuum and reflux the resulting residue in methanol for 1 hour. Remove the methanol under vacuum and dissolve the resulting precipitate in 1N NaOH. Extract the aqueous layer with dichloromethane and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90: 10) to give 459.0 mg (18%) of the title compound: mp 140°–144°; mass spectrum (ion spray): m/z=225.3 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[C:32]([O:34][CH2:35][CH3:36])[CH:31]=[CH:30][N:29]=3)[N:25]([C:37]3[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[N:24]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:35]([O:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([C:26]2[N:25]([C:37]3[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[N:24]=[C:23]([C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH3:13])[CH2:16][CH2:17]3)=[O:22])[CH:27]=2)[CH:33]=1)[CH3:36]
Reactant: CCOc1ccnc(-c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)nn2-c2ccc(OC)nc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccnc(-c2cc(C(=O)N3CCN(C)CC3)nn2-c2ccc(OC)nc2)c1
Reaction time: 0.5 h

Procedure:
At room temperature, trifluoroacetic acid (1.4 mL) was added to a solution of the above-obtained 4-[5-(4-ethoxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (0.135 g) in methylene chloride (2.7 mL), and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol (2.7 mL). To the mixture were added 35% aqueous formalin solution (0.114 g), acetic acid (0.076 mL) and sodium cyanoborohydride (50.0 mg). The resultant mixture was stirred for 100 minutes at room temperature. Sodium cyanoborohydride (33.3 mg) was further added thereto, and the mixture was stirred for 50 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol). Subsequently, the residue was purified through silica gel thin-layer chromatography (chloroform-methanol), to thereby give the title compound as an oily product (86.9 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[CH:13])[C:5]([O:7][CH3:8])=[O:6]>C1(C)C=CC=CC=1>[O:1]1[C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[CH:12]=[CH:13]1
Reactant: C#Cc1ccc(C(=O)OC)cc1O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2ccoc2c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-hydroxy-4-ethynylbenzoate (1 eq.) in dry toluene was added PtCl2 (0.1 eq.) under argon. The reaction mixture was stirred at 80° C. for 1.5 h, warmed to 20° C. and the solvents removed under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1) to afford methyl benzofuran-6-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2].Cl.O>CO.O1CCOCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:27])([CH3:28])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2cccc(CO[Si](C)(C)C(C)(C)C)c2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1(C)C=C(n2cccc(CO)c2=O)c2cc(C#N)ccc2O1
Yield: 73.8 %

Procedure:
In 9.00 ml of methanol, is dissolved 877 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzz[b]pyran obtained in Example 17. Then, 2.20 ml of 4N hydrochloric acid in dioxane is added to the solution at 0° C. and reacted at room temperature for one hour. After stopping the reaction by adding water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/20 mixture of methanol/methylene chloride as a developing solvent and further by silica gel column chromatography using 1/1 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 472 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-n2nccn2)nc1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. MS (ESI) 409.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[CH:12][N:11]=3)[S:9][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][N:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
tert-Butyl 3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (1.00 g, 2.4 mmol) was dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was recrystallized from hexane-tetrahydrofuran-methanol to give the titled compound (0.66 g, 76%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:18].CCN(CC)CC.C[C:28]1([CH3:37])N([O])[C:32](C)(C)[CH2:31][CH2:30][CH2:29]1.CO>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[CH:9]=2)[N:4]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:37]=2)[C:3]1=[O:18]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC1(C)CCCC(C)(C)N1[O]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(c1ccccc1)C(=O)C2(C)C
Temperature: 25 °C
Reaction time: 168 h
Yield: 54.3 %

Procedure:
To a solution of phenyl bronic acid (0.47 g; 3.9 mmol), N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.5 g; 1.9 mmol) and NEt3 (0.5 μl; 3.9 mmol) in CH2Cl2 (15 ml) is added molsieves (150 mg; 4 Å), Cu(OAc)2 (70 mg; 385 μmol) and finally TEMPO (0.33 g; 2.11 mmol). The reaction mixture is stirred in an open flask at RT for 7 days. After completion MeOH (20 ml) is added and the mixture is adsorbed on silica gel. Purification by chromatography gives N-(3,3-dimethyl-6-nitro-2-oxo-1-phenyl-2,3-dihydro-1H-indol-5-yl)-acetamide (0.35 g). The material is de-acetylated in MeOH (10 ml) using DBU (80 μl) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-phenyl-1,3-dihydro-indol-2-one (0.3 g) is obtained and used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:30])(=[O:29])[C:14]=2[CH:31]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:29])(=[O:30])[C:14]=2[CH:31]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCn3ccnc3)cc(Cl)c1O2
Temperature: 110 °C

Procedure:
Imidazole (0.118 g, 1.73 mmol) was added in an atmosphere of nitrogen, to a solution of Example 56k (1.3 g, 2.63 mmol) in dry DMF (10 mL) with stirring. The reaction mixture was then maintained at 110° C. for 18 h. It was cooled, concentrated and the solid obtained was filtered washed with water, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.120 g, (22.38%); 1H NMR (DMSO-d6): δ 2.7 (s, 3H, CH3), 3.2 (t, 2H, CH2), 3.9 (s, 3H, OCH3), 4.1 (t, 2H, CH2), 5.2 (s, 2H, CH2), 6.4 (s, 1H, NH), 6.6 (s, 1H, Ar), 6.75 (s, 1H, Ar), 6.9 (s, 1H, Ar), 7.2 (s, 1H, Ar), 7.6 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.2 (s, 1H, Ar); MS: m/e (ES+) 462 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13][OH:14])[C@H:11]([C:15](=[O:32])NC(C2C=CC=CC=2)CC2C=CC(C)=CC=2)[N:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O1CCOCC1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][O:14][C:15](=[O:32])[C@H:11]2[N:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC(NC(=O)[C@H]2[C@@H](CO)N(Cc3ccccc3)C(=O)N2Cc2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of the amide-alcohol (3.0 g) prepared in Example 8, dioxane (30 ml) and 20 % sulfuric acid (20 ml) is refluxed with stirring for 1 hour. After the reaction is completed, the mixture is concentrated to one third of the original volume and diluted with water (50 ml). The precipitate is filtered to give cis-1,3-dibenzyl-hexahydrofuro[3,4-d]imidazole-2,4-dione (1.53 g, 84.5 %). M.P. 106.5° to 109° C. [α]D20 + 2.6° (C = 2 in CHCl3). The infrared spectrum of the sample is identified with that of the authentic sample.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH2:10]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:6][CH2:5][CH2:9][CH2:10][CH2:2][CH:3]=[CH2:4]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: O=C(O)c1ccc(O)cc1
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
The procedures of Preparation Examples 18-20 were repeated except that 6 g 4-hydroxyl benzoic acid was replaced by 9.3 g 4-hydroxybiphenyl-4'-carboxylic acid, Yield: I-25: 67%; I-26: 89.8%; I-27: 80.6%. 1H-NMR:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:37])([F:36])[O:15][C:16]1[CH:17]=[C:18]([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1.Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>C1COCC1>[F:13][C:14]([F:36])([F:37])[O:15][C:16]1[CH:17]=[C:18]([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1.[C:23]([C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:36])([F:37])[F:13])[CH:17]=1)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])#[N:24]
Reactant: CC(C)(C)OC(=O)CBr
Agent: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(C#N)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
2,2-Bis(3-(trifluoromethoxy)phenyl)acetonitrile (100 mg, 0.3 mmol) was prepared as described in Example 10 (Procedure13 and 14). To a solution of diisopropyl amine (0.146 mL, 1.04 mmol) in THF (3 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexane, 0.675 mL, 1.08 mmol) and the reaction mixture was stirred for 5 min. A solution of (2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (300 mg, 0.83 mmol) in THF (0.5 mL) was added dropwise to the reaction mixture and stirred for 1 h. tert-Butyl 2-bromoacetate (0.159 mL, 1.08 mmol) was added dropwise, then the cooling bath was removed and the reaction mixture was stirred at rt for 45 min. The reaction mixture was poured into H2O (15 mL) and extracted with diethyl ether (2×15 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield crude tert-butyl 3-cyano-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate. The crude tert-butyl 3-cyano-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate was purified by a silica gel ISCO cartridge (12 g) with elution at 25 mL/min gradient 0 to 25% EtOAc in hexane to yield a white solid (84 mg, 63% yield). LCMS: RT=2.18 min [M+H] 476.02 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 75-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 1.30 (s, 9 H), 3.33 (s, 2 H), 7.21-7.24 (m, 4 H), 7.36 (d, J=8.35 Hz, 2 H), 7.45 (t, J=8.35 Hz, 2 H).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C1COCC1.CCCCCCC>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27]([OH:29])=[O:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (16.87 g, 0.071 mol) and (E)-3-(3,4-Dichloro-phenyl)-acrylic acid (7.71g, 0.036 mol) in THF (50 mL) was added trifluoroacetic acid (0.19 mL, 0.002 mol) at 0° C. The mixture was gradually warmed to room temperature and stirred overnight. It was then diluted with n-heptane (250 mL). The resulted white precipitation was collected and washed with heptane affording 11.6 g (94%) of the title compound as a white solid. ES-MS m/e: 350.2 (M+H+).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:24](C)=O.[Na+]>ClC(Cl)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:9]([N:3]1[CH2:4][C@@H:5]2[CH2:8][C@H:2]1[CH2:7][N:6]2[CH3:24])=[O:10]
Reactant: O=C(c1cc2ccccc2[nH]1)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1C[C@@H]2C[C@H]1CN2C(=O)c1cc2ccccc2[nH]1
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of (S,S)-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1H-indol-2-yl)-methanone hydrochloride (50 mg, 0.18 mmol), TEA (50 μL, 0.36 mmol), and formaldehyde (6 μL, 0.22 mmol) in dichloroethane (DCE)/MeOH (10:1, 3 mL) was added NaB(OAc)3H (115 mg, 0.54 mmol). After 2 h at rt, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with satd aq. NaCl, dried (Na2SO4), and concentrated to yield an orange solid (44 mg, 96%). MS (ESI): mass calcd. for C15H17N3O, 255.14; m/z found, 256.4 [M+H]+. 1H NMR (mixture of rotamers; CDCl3): 10.34-10.08 (m, 1H), 7.64-7.54 (m, 1H), 7.44-7.35 (m, 1H), 7.24-7.16 (m, 1H), 7.09-7.00 (m, 1H), 6.80 (s, 0.5H), 6.67 (s, 0.5H), 4.99-4.86 (m, 1H), 4.05-3.95 (m, 0.7H), 3.84-3.77 (m, 0.3H), 3.71-3.62 (m, 1H), 3.55-3.46 (m, 1H), 3.18-3.10 (m, 0.3H), 2.98-2.88 (m, 0.7H), 2.82-2.69 (m, 1H), 2.46-2.31 (m, 3H), 1.98-1.88 (m, 1H), 1.79-1.70 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[I:14](O)(=O)=O.II>C(O)(=O)C.S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(-c2ccc(I)cc2)cc1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 325.1 %

Procedure:
A 4-neck one liter round bottom flask equipped with mechanical stirrer, thermometer and reflux condenser topped with nitrogen bubbler inlet was charged with 4-bromobiphenyl (23.31 g, 100 mmol) in acetic acid (400 mL), sulfuric acid (10 mL) and water (20 mL). To this stirring mixture was added iodic acid (4.84 g, 27.5 mmol) followed immediately by addition of iodine chips (11.17 g, 44.0 mmol). The reaction flask was immersed in a preheated tri(ethylene glycol) heating bath and heated at 65° C. internal temperature. After 30 min the bath temperature was increased such that the internal temperature raised to 85° C. after 20 min. Heating at this temperature was continued for 4.5 hours at which point UPLC analysis showed the reaction to be complete. After stirring overnight at room temperature the reaction mixture was vacuum filtered through a coarse fritted funnel and the solids were rinsed with water. The resulting white solid (32.1 g, 89% yield) had mp 177-179° C. and was used without further purification in the next step. NMR analysis confirmed the structure of Intermediate Compound 3,4-bromo-4′-iodobiphenyl. Purity (UPLC): >99%.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(O)C>[OH:1][CH:2]([CH2:23][NH:27][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Yield: 73 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman (6.35g.), isopropylamine (16ml) and ethanol (16ml) was boiled under reflux for 2 days. Removal of the solvent in vacuo gave 7-(2-hydroxy-3-isopropylaminopropoxy)-2,2-dimethyl-4-phenylchroman (6.7g., 73%) isolated as the hydrochloride salt, m.p. 171-174° from ether-ethanol.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[OH:21][C:22]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.C(Cl)Cl>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH:18][C:30](=[O:31])[CH2:29][C:22]2([OH:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Reactant: O=C(O)CC1(O)CCCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)CC3(O)CCCCCC3)c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (100.00 mg, 0.36454 mmol), 2-(1-hydroxycycloheptyl)acetic acid (75.3 mg, 0.437 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (346 mg, 0.911 mmol), N,N-diisopropylethylamine (0.159 mL, 0.911 mmol), N,N-dimethylformamide (2 mL, 30 mmol) and methylene chloride (8 mL, 100 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken onto the next step without further purification.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:7]([CH2:18][CH3:19])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2.ClC1C(C2OCCO2)=CC2C(=CC=C(OC)C=2)N=1.Cl>C1COCC1>[CH2:18]([C:7]1[C:6]([CH:2]=[O:1])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[CH:13]=2)[N:8]=1)[CH3:19]
Reactant: CCc1nc2ccc(OC)cc2cc1C1OCCO1
Agent: COc1ccc2nc(Cl)c(C3OCCO3)cc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nc2ccc(OC)cc2cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 3-[1,3]dioxolan-2-yl-2-ethyl-6-methoxyquinoline SMA 44002 (400 mg, 1.54 mmol) in THF (10 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added a 1 N aqueous HCl solution (5 mL) and the mixture was stirred overnight at RT, then for 1 h at 70° C. A 6 N aqueous HCl solution (2.5 mL) was then added and the mixture was stirred for 26 h at 70° C. THF was removed at 40° C. under vacuum before addition of a conc. NH4OH solution (5 mL). The solution was extracted with CH2Cl2 (50 mL) and the organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum to give 2-ethyl-6-methoxyquinoline-3-carbaldehyde SMA 44004 as a brown oil (269 mg, 81% yield).
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][C:5]1([CH2:8][C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]1.C[O-].[Na+]>O1CCCC1.CO.C(OC)(C)(C)C>[CH2:6]1[C:5]2([CH2:4][C:3](=[O:12])[CH2:10][C:9](=[O:11])[CH2:8]2)[CH2:7]1
Reactant: COC(=O)CC1(CC(C)=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CO
Product: O=C1CC(=O)CC2(CC2)C1
Reaction time: 6 h

Procedure:
23.3 g of crude [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester (60% purity, from step 5) are dissolved in 135 ml of tetrahydrofuran and 17.1 g of a sodium methanolate solution in methanol (30% in methanol) are added at room temperature and the mixture is stirred for six hours. Then the solution is diluted with 135 ml of methyl tert-butyl ether and quenched with 135 ml of water. Stirring is continued for five minutes, then the phases are separated. The aqueous phase is extracted with 67.5 ml of methyl tert-butyl ether, then acidified to pH 2-3 with 37% HCl and washed twice with 67.5 ml of methyl tert-butyl ether each. The combined organic phases are washed with 18 ml of water and concentrated to dryness. The crude product is stirred with 18 ml of cold methyl tert-butyl ether and then the precipitate is isolated by filtration. The filter cake is washed with 18 ml of cold methyl tert-butyl ether to yield the product as an off-white solid.