Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1[CH:8]=[C:9]2[C:26](=CC=1)[O:25][C:12]1([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:29]>[C-]#N.[C-]#N.[Zn+2].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.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]2[C:26](=[CH:9][CH:8]=1)[O:25][C:12]1([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[CH2:11][C:10]2=[O:29])#[N:1]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 ml/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>CC(O)=O.O.[Fe]>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)Nc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Nc1cc(Br)ncc1N
Reaction time: 6 h

Procedure:
A solution of 2-bromo-N-isopropyl-5-nitropyridin-4-amine (intermediate 258, 4.5 g, 16.61 mmol) in HOAc (59 ml) was added dropwise to a mixture of iron powder (3.75 g, 66.4 mmol) in HOAc (59 ml) at 70° C. After stirring vigorously for 6 h, the reaction mixture was diluted with H2O and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and evaporated. The crude material was applied to a 80 g RediSep® silica column and purified by normal phase chromatography, eluting with a gradient from 5% to 100% EtOAc/heptanes. Product-containing fractions were combined and evaporated to give the title compound as a brown solid. (UPLC-MS 6) tR 0.56; ESI-MS 230.0/232.0 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]([C:9]1([S:13][C:14]2[CH:19]=[C:18]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)=[S:22])[C:17]([F:29])=[CH:16][C:15]=2[Cl:30])[CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:30][C:15]1[C:14]([S:13][C:9]2([C:7]([O:6][CH3:5])=[O:8])[CH2:12][CH2:11][CH2:10]2)=[CH:19][C:18]([N:20]=[C:21]2[N:23]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:1](=[O:2])[S:22]2)=[C:17]([F:29])[CH:16]=1
Reactant: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1(Sc2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)CCC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
While stirring at a temperature of +10° C., 12.5 ml of a 20% solution of phosgene in toluene are added dropwise to a solution of 10.4 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclobutanecarboxylic acid methyl ester and 10 ml of triethylamine in 100 ml of toluene. The reaction mixture is then stirred for 6 hours and then introduced into ice-water. The organic phase is then separated off and dried over sodium sulfate. Concentration by evaporation and subsequent chromatographic purification by means of silica gel chromatography yield 4.6 g of 9-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclobutylthio)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan-7one, ηD22 1.6010.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1([CH3:20])[CH3:19])(=[O:3])C.[OH2:21]>O1CCOCC1>[CH2:11]([O:10][C:9]([NH:8][C@H:6]1[CH2:7][C@@H:4]([C:1]([OH:3])=[O:21])[C:5]1([CH3:20])[CH3:19])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)C1(C)C
Solvent: C1COCCO1
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reaction time: 5 h
Yield: 92 %

Procedure:
To a stirred solution of benzyl (1S,3R)-3-acetyl-2,2-dimethylcyclobutylcarbamate (Step 2, 1.3 g, 4.72 mmol) in dioxane (90 ml): water (30 ml) aq. NaOBr solution (80 ml) was added slowly at about −5° C. and stirred at the same temperature for about 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was washed with methyl t-butyl ether and the aqueous layer was adjusted pH (2-3) with 1N HCl and extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated then the resulting crude was purified by silica gel column (100-200 mesh, elution: 20% EtOAc in Hexane) to afford the title compound as a semi solid. Wt: 1.2 g: Yield: 92%; 1H NMR (300 MHZ, CDCl3): δ 7.38-7.31 (m, 5H), 5.09 (q, 2H, J=10.8 Hz), 4.89 (d, 1H, J=8.4 Hz), 3.98-3.89 (m, 1H), 2.64-2.53 (m, 1H), 2.51-2.26 (m, 2H), 1.32 (s, 3H), 0.98 (s, 3H). IR (KBr, cm−1): 3411, 3351, 2961, 1705, 1532, 1456, 1412, 1343, 1256, 1044, 1003, 776, 697; Mass: [M+Na]+ 300 (100%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[O:24]=[C:25]1[C:34]2[CH:35]=[N:36][C:37]([C:39]3[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=3)=[CH:38][C:33]=2[O:32][C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=2.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C.C(Cl)Cl>[N:48]1([C:43]([C:42]2[CH:41]=[CH:40][C:39]([C:37]3[N:36]=[CH:35][C:34]4[C:25](=[O:24])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[O:32][C:33]=4[CH:38]=3)=[CH:47][CH:46]=2)=[O:44])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2cc3oc4ccccc4c(=O)c3cn2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(c1ccc(-c2cc3oc4ccccc4c(=O)c3cn2)cc1)N1CCOCC1
Reaction time: 0.08 h

Procedure:
HOBt (145 mg, 0.945 mmol), EDC (181 mg, 0.945 mmol) and Hunig's base (0.550 mL, 3.15 mmol) were added to a suspension of 4-(10-oxo-10H-chromeno[3,2-c]pyridin-3-yl)benzoic acid (200 mg, 0.630 mmol) in DMF (15 mL) and CH2Cl2 (10 mL) at room temperature. After 5 min, morpholine (0.110 mL, 1.261 mmol) was added. After 13 h at rt, the mixture was quenched with saturated NH4Cl (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined extracts were dried (MgSO4) and concentrated to give crude 3-(4-(morpholine-4-carbonyl)phenyl)-10H-chromeno[3,2-c]pyridin-10-one, which was taken to next reaction without purification. MS (ES+) m/z: 387 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].Br[C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:20])[C:16]([OH:30])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2>N1C=CC=CC=1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:19]([C:17]2[C:16]([OH:30])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([N:1]3[CH2:6][CH2:5][CH2:4][NH:3][C:2]3=[O:7])[N:18]=2)=[O:20])=[CH:28][CH:27]=1
Reactant: O=C1NCCCN1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: c1ccncc1
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCCNC2=O)c2cccnc2c1O
Temperature: 25 °C

Procedure:
To a mixture of tetrahydro-2-pyrimidone (0.040 g, 0.4 mmol), 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.050 g, 0.13 mmol), and Cu2O (0.0095 g, 0.07 mmol) under an atmosphere of argon was added pyridine (1.0 mL) and the suspension was stirred at reflux for 16 hr. Cu2O (0.005 g, 0.04 mmol) was added and the reaction heated at 115 C for a further 16 hr. The reaction was allowed to cool to room temperature and the solvent evaporated in vacuo. The residue was treated with DMF (2 mL) and filtered to remove the solids. TFA (0.5 mL) was added to the filtrate which was purified by reverse phase HPLC. (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Product: COC(=O)c1ccc(OCc2cccc(C)n2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except KI (1.3 eq.) is also added from 4-hydroxy-benzoic acid methyl ester and 2-(chloromethyl)-6-methyl-pyridine hydrochloride [CAS 3099-29-4]. MS (ES+) 258.2
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[C:11]([OH:13])=O.CN1CCCCC1.Cl.[CH3:22][NH:23][O:24][CH3:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:22][N:23]([O:24][CH3:25])[C:11]([C:3]1[CH:4]=[C:5]([S:7](=[O:9])(=[O:8])[NH2:10])[S:6][C:2]=1[Cl:1])=[O:13]
Reactant: CNOC
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCCC1
Product: CON(C)C(=O)c1cc(S(N)(=O)=O)sc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
1,1-Carbonyldiimidazole (7.70 g, 0.047 mol) was added portionwise to a solution of 5-chloro-4-carboxythiophene-2-sulfonamide (7.25 g, 0.03 mol) in DMF (60 mL). After two hours, N-methylpiperidine (6.0 mL, 0.05 mol) and N,O-dimethylhydroxylamine hydrochloride (5.2 g, 0.05 mol) were added to the reaction mixture. After an additional four hours at room temperature, the reaction mixture was poured into ice/water saturated with NaHCO3. The crude product was extracted into ethyl acetate, the extract was dried (anhydrous Na2SO4), filtered and evaporated. The crude residue was chromatographed on silica gel and eluted with 59% methanol/methylene chloride to give 3.45 g (40%) of white solid product, mp 223°-225° C.
Reaction SMILES: [CH3:1][S:2][C:3]([S:11][CH3:12])([CH2:7][CH2:8][S:9][CH3:10])[C:4]([OH:6])=[O:5].C([O-])(=O)C.[Ca+2:17].C([O-])(=O)C>O.CC(C)=O>[CH3:12][S:11][C:3]([S:2][CH3:1])([CH2:7][CH2:8][S:9][CH3:10])[C:4]([O-:6])=[O:5].[Ca+2:17].[CH3:12][S:11][C:3]([S:2][CH3:1])([CH2:7][CH2:8][S:9][CH3:10])[C:4]([O-:6])=[O:5]
Reactant: CSCCC(SC)(SC)C(=O)O
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CC(C)=O
Solvent: O
Product: CSCCC(SC)(SC)C(=O)[O-]
Yield: 98.4 %

Procedure:
16.6 g of 2,2,4-tris(methylthio)butanoic acid (4) (73.3 mmol) were dissolved in a mixture of 140 ml of H2O and 35 ml of acetone. Subsequently, a solution of 6.2 g of calcium acetate (93%) and 22 ml of H2O was slowly added dropwise at 20° C. with vigorous stirring. After a short time a white solid precipitated out which was filtered off after 30 minutes. The resulting white solid was washed twice with 200 ml of H2O each time, then with 200 ml of acetone and 200 ml of diethyl ether, and dried in a drying cabinet. A total of 17.7 g of calcium 2,2,4-tris(methylthio)butanoate (5) (M=490.8 g/mol, yield=98%) were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]3[CH2:25][C@H:24]3[N:26]([CH2:34][CH:35]3[CH2:37][CH2:36]3)C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[O:15])=[CH:10][CH:9]=1.Cl.COC1CCCC1>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C@@H:23]3[CH2:25][C@H:24]3[NH:26][CH2:34][CH:35]3[CH2:37][CH2:36]3)=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3Cl)cc2)cc1
Agent: Cl
Solvent: COC1CCCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCC2CC2)cc1)c1ccc(-c2ccccc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 128.9 %

Procedure:
tert-Butyl [trans-2-(4-{[(2′-chlorobiphenyl-4-yl)carbonyl]amino}phenyl)cyclopropyl](cyclopropylmethyl)-carbamate (115 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0° C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (5 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (65.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17](=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[ClH:33].O1CCOCC1>>[ClH:33].[ClH:33].[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17](=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)CCCCNC(=O)OC(C)(C)C)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)CCCCN)c1cccnc1

Procedure:
A 4M HCl/dioxane solution(10 mL) of 24-3 (101 mg, 0.24 mmol) was stirred under ambient conditions for 18 hr. The solution was concentrated to provide 24-4 as a pale yellow gum which was used in the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:19]([C:21]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(CC)CC.CC(O)=O>ClCCCl>[CH3:27][C:24]1([CH3:28])[O:23][CH2:22][C:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH2:19][N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:11]=3)[CH2:15]2)[CH2:26][O:25]1
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Reactant: CCCCCCCCc1ccc2c(c1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCCCCCCc1ccc2c(c1)CN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)C2
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of the product of Step E (0.03 g; 0.112 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.037 g; 0.115 mmol) and NaBH(OAc)3 (0.035 g; 0.17 mmol) in 1,2 dichloroethane (3 ml), Et3N (0.016 ml; 0.112 mmol) was added at room temperature, followed by AcOH (0.064 ml; 0.112 mmol). The resulting mixture was stirred overnight under N2. After dilution to 10 ml with Et2O, the mixture was washed with 1.M NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2; hexane/EtOAc 8:2) to give pure title compound (0.05 g; 92%) as colourless solid. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=7 Hz); 1.25 (m, 10H); 1.41 (s, 3H); 1.44 (s, 9H); 1.47 (s, 3H); 1.57 (m, 2H); 2.56 (tr, 2H, J=7.92 Hz); 3.18 (s, 2H): 3.79 (d, 2H, J=11.7 Hz); 4.05 (s, 4H); 4.14 (d, 2H, J=11.7 Hz); 5.03 (s, 1H); 6.98 (s, 1H); 6.99 (d, 1H, J=8.14 Hz); 7.06 (d, 1H, J=8.14 Hz).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:14]#[N:15]>CN(C=O)C.CCOCC>[F:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:9][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cc(F)cc(OC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (1.92 g, 48.0 mmol) is slowly added to a stirred solution of cyclohexanol (4.01 g, 40.0 mmol) in DMF (30 ml) at 0-5° C. under nitrogen. After 2.5 hours, 3,5-difluorobenzonitrile (5.56 g, 40.0 mmol) is slowly added over 5 min. The mixture is allowed to warm to room temperature and stirred for an additional 12 hours. The mixture is diluted with ether (150 ml), washed with water, brine (30 ml), dried over Na2SO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate:hexanes (1:10) to provide 3-fluoro-5-cyclohexyloxybenzonitrile as a yellow oil. MS: 220 (M+1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH2:30]([NH2:35])[CH2:31][CH:32]([CH3:34])[CH3:33]>>[CH3:33][CH:32]([CH3:34])[CH2:31][CH2:30][NH:35][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[CH2:12][C:10]3[CH2:11][N:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[C:2]([F:1])([F:29])[F:28])[CH2:8][C:9]=3[CH2:14]2)=[N:16][CH:17]=1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 34 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (40 mg, 0.099 mmol) was reacted with isoamylamine analogously to example 3d. Yield: 34%, M+H+: 473.18.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][C:7]=3[C:6]=2[C:5]([Br:34])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.C[Si]([N:49]=[C:50]=[O:51])(C)C>C1COCC1.O>[Br:34][C:5]1[CH:4]=[CH:3][C:2]([C:50]([NH2:49])=[O:51])=[C:10]2[C:6]=1[C:7]1[CH2:14][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:12][CH2:11][C:8]=1[NH:9]2
Reactant: Brc1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Reactant: C[Si](C)(C)N=C=O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 54.9 %

Procedure:
A solution of 6,9-dibromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (purity about 75%, 650 mg, 0.852 mmol) in THF (10 mL) was stirred at −78° C. and treated with tert-butyllithium, 1.7 M in pentane (2.505 mL, 4.26 mmol) over 2-3 min. After stirring for about 5-10 min at −78° C., the red-orange solution was stirred on an ice-water bath for 2 h. The solution was then cooled again to −78° C. and treated with trimethylsilyl isocyanate (0.922 mL, 6.81 mmol). Stirring was continued while allowing the cooling bath to warm slowly to room temperature. After 19 h, the mixture was treated with water (5 mL) and extracted twice with EtOAc. The combined organic phases were dried and concentrated. The residue was subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexane (gradient from 20:80 to 100:0) to provide the desired product as an off-white solid (251 mg, 55% yield). LCMS (M+H-trityl)+ m/z 294, 296.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21].C1COCC1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([NH:21][CH3:20])=[O:13]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (2-chloro-4-methoxy-phenyl)-acetic acid (49c) (500 mg, 2.50 mmol) in CH2Cl2 (10 mL) was added 2.0 M oxalyl chloride in CH2Cl2 (3.75 mL, 7.50 mmol), follow by 4 drops of DMF. The mixture was stirred at ambient temperature for one hour, concentrated, and further dried under high vacuum. The residue was re-dissolved in CH2Cl2 (10 mL), to this solution was added 2.0 M methylamine in THF (3.5 mL, 7.50 mmol). After stirring at ambient temperature overnight, the reaction was quenched with water, extracted with CH2Cl2 for three times. The combined organic phase was dried over Na2SO4, and concentrated to give 0.46 g white solid as the intermediate 70a. 1H NMR (300 MHz, CD3OD) δ 7.14 (d, 1H, J=8.66 Hz), 6.87 (d, 1H, J=2.64 Hz), 6.78–6.72 (m, 1H), 3.68 (s, 3H), 3.48 (s, 2H), 2.62 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 214, found 214.
Reaction SMILES: O=[C:2]1[C:6](=[CH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH:3]1[C:16]([O:18][CH3:19])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:21].CO.O>CCCCCC>[Cl:21][C:2]1[C:6](=[CH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCC(=CCCc2ccccc2)C1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: COC(=O)C1=C(Cl)C(=CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a mixture of methyl 2-oxo-3-(3-phenylpropyl-1-yl)cyclopentanecarboxylate (1 g, 3.8 mmol) in hexane (40 mL) is added phosphorus pentachloride (1.5 g, 7.6 mmol). The mixture is heated under reflux for 2.5 hours. The solution is cooled in ice and methanol (few mL) is added. The mixture is stirred at room temperature for 15 minutes. The mixture is poured into water and is extracted with hexane. The organic layer is washed with water and is dried over MgSO4. The organic layer is removed in vacuo and the residue is dissolved in dichloromethane. To this solution is added 2 M oxalyl chloride (few mL). The mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue is dissolved in dichloromethane and methanol (few mL) is added. The solution is stirred at room temperature for 15 minutes. The solvent is removed in vacuo and the residue is chromatographed on silica gel (20:1 hexane:ethyl acetate) to give methyl 2-chloro-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylate (0.2 g, 20%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.50-1.70 (m, 4H), 1.78-1.92 (m, 1H), 2.07-2.19 (m, 1H), 2.53-2.71 (m, 4H), 2.78-2.92 (m, 1H), 3.78 (s, 3H), 7.17-7.32 (m, 5H); MS (EI) m/e 278 (M+).