Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH:16]=[CH:17][CH:18]=O)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[O:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].N1CCCCC1.C(O)C>O1CCCC1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][CH2:17][CH2:18][CH:26]2[O:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(CCOc1ccc(C=CC=O)cc1)c1ccccn1
Reactant: O=C1COC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCOc1ccc(CCCC2OC(=O)NC2=O)cc1)c1ccccn1
Yield: 21 %

Procedure:
A mixture of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamaldehyde (4.00 g), 2,4-oxazolidinedione (2.86 g), piperidine (0.60 g) and ethanol (50 ml) was heated for 2 hours under reflux. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. Fractions eluted with ethyl acetate-chloroform (1:4) gave crystals. The crystals were dissolved in tetrahydrofuran (100 ml). To the solution was added palldium-carbon (5%, 1.40 g). The mixture was subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:2), 5-[3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]propyl]-2,4-oxazolidinedione (1.10 g, 21%) was obtained. Recrystallization from dichloromethane-isopropylether gave colorless prisms. Melting point: 126-127° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:15])=[C:6]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]2[C:13]=1[CH3:14])(=[O:3])[CH3:2].CC(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)C>CC(C)=O>[CH3:21][N:22]([CH3:24])/[CH:23]=[CH:2]/[C:1]([C:4]1[C:5]([CH3:15])=[C:6]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]2[C:13]=1[CH3:14])=[O:3]
Reactant: CC(=O)c1c(C)c2n(c1C)CCNC2=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CC(C)=O
Product: Cc1c(C(=O)/C=C/N(C)C)c(C)n2c1C(=O)NCC2
Temperature: 95 °C
Yield: 76.5 %

Procedure:
7-Acetyl-6,8-dimethyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one (6.692 g, 32.49 mmol) was combined with Brederick's reagent (13.42 mL, 64.98 mmol) and heated to 95° C. for 10 hours. After cooling the reaction mixture was treated with acetone (2 mL) and the resulting yellow precipitate filtered off and washed with 2:1 EtOAc:Me2CO to provide the target compound (6.496 g, 24.86 mmol, 77% yield).
Reaction SMILES: [N:1]1([CH2:7][CH:8]([C:10]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CI.[C:32]([O-])(O)=O.[Na+]>C1COCC1>[CH3:32][O:9][CH:8]([C:10]1[C:19]2[C:14](=[C:15]([C:20]([F:21])([F:22])[F:23])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:24]([F:27])([F:25])[F:26])[CH:11]=1)[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(CN1CCCCC1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(CN1CCCCC1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To an ice-cold solution of α-piperidinomethyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol (60 mg, 0.15 mmol) in THF (1.5 mL) was added NaH (6 mg, 60% dispersion in oil, 0.15 mmol), the mixture stirred at 0° C. for 30 min, treated with methyl iodide (10 μL, 0.16 mmol), allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into saturated NaHCO3, extracted with EtOAc (2×20 mL), the combined extracts dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2, EtOAc] to give the title compound (62 mg, 100%) as a pale yellow oil: IR νmax (Nujol)/cm−1 2937, 2855, 2824, 1603, 1585, 1309, 1188, 1147, 1108 and 769; NMR δH (400 MHz, CDCl3) 1.40-1.45 (2H, m), 1.52-1.66 (4H, m), 2.44-2.61 (5H, m), 2.84 (1H, dd, J 13.9, 7.8 Hz), 5.14 (1H, dd, J 7.8, 3.3), 7.74 (1H, t, J 7.7 Hz), 7.92 (1H, s), 8.17 (1H, d, J 6.9 Hz) and 8.45 (1H, d, J 8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:25])=[CH:7][C:5]=2[N:6]=1.C([O-])(O)=O.[Na+]>C(OC(C)=O)(C)(C)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:9]([C@H:18]([O:24][C:8]([CH3:25])([CH3:9])[CH3:7])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:25])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.3 h

Procedure:
A suspension of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate (7.20 g, 16.9 mmol) in neat t-BuOAc (100 mL) was cooled to 0° C. in an ice bath. 70% w/v aqueous HClO4 (293 μL, 3.4 mmol) was added dropwise over 5 min. The reaction was warmed to 23° C., then stirred for 2.3 h. At this point the reaction was transferred to an addition funnel. The reaction was added to a 23° C. solution of sat aqueous NaHCO3 (400 mL) over 30 min. Once addition was complete, the reaction was stirred for another 15 min. The resulting system was extracted with EtOAc (2×150 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Some residual t-BuOAc remained. Hexane (200 mL) was added and the slurry was concentrated once more. The resulting residue (reasonably free of t-BuOAc) was treated with Benzene and loaded onto a 330 g “gold” ISCO silica gel column. The following gradient elution sequence was used: [100% Hexane (5 column volumes, isocratic)→10% EtOAc/90% Hexane (5 column volumes, linear gradient→10% EtOAc/90% Hexane (5 column volumes, isocratic ((S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate elutes))→100% EtOAc (10 column volumes, isocratic, (unreacted (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate elutes))]. Product-containing fractions were pooled, concentrated, co-evarporated with Et2O (100 mL) to give desired product. LCMS-ESI+ calc'd for C22H23BrClNO3S: 496.0, 498.0 and 500.0 (M+H+); found: 496.2, 498.2, and 500.1 (M+H+). 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.48 (m, 3H), 7.37 (m, 1H), 5.12 (s, 1H), 4.20 (m, 2H), 2.57 (s, 3H), 1.24 (t, 3H, J=7 Hz), 0.96 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Yield: 73.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-methoxyphenylboronic acid (119 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (EtOAc eluent), to give 160 mg (73%) of the title compound as a white solid. mp 152°-156°. FDMS: m/e=335. α[D]589 =+77.45 (c=0.64, chloroform).
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[N-:18]=[N+:19]=[N-:20].[Na+]>CCO.O>[N:18]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[N+:19]=[N-:20]
Reactant: CCOP(=O)(CCOCCOCCI)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCOCCOCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 2-(2-(2-iodoethoxy)ethoxy)ethylphosphonate (1 eq) in EtOH (0.2 M) was added sodium azide (5 eq) in water (1.4 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with EtOAc (3 times). The combined organic layers were washed brine, dried over anhydrous Na2SO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH™ system using 0-5% MeOH/DCM to give diethyl 2-(2-(2-azidoethoxy)ethoxy)ethylphosphonate as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][OH:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:30]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][OH:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)=[O:30])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (50 mg, 0.13 mmol) was added selenium dioxide (146 mg, 1.30 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (52 mg, 99% yield).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.C([O-])=O.[NH4+]>CO.[Pd]>[ClH:1].[F:21][C:3]([F:2])([F:20])[C:4]1[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: FC(F)(F)c1cc(C2=CCNCC2)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: FC(F)(F)c1cc(C2CCNCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 4-(3,5-bis(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (19, 452 mg, 1.37 mmol), ammonium formate (0.863 g, 13.7 mmol), and 10% Pd/C (0.332 g) in CH3OH (10 mL) was heated at reflux for 7 h. The mixture was cooled to ambient temperature and was filtered over Celite. The filtrate was concentrated and the resulting residue was diluted in CH2Cl2 (8 mL) and CH3OH (2 mL). To this solution was added HCl (2.0 N solution in Et2O, 6 mL). The resulting solids were collected by filtration to give 4-(3,5-bis(trifluoromethyl)phenyl)piperidine hydrochloride (20) as a white solid (376 mg, 82%): 1H NMR (300 MHz, DMSO-d6) δ 9.05-8.58 (m, 2H), 8.03-7.97 (m, 1H), 7.95-7.87 (m, 2H), 3.44-3.29 (m, 2H, overlaps with H2O), 3.19-2.88 (m, 3H), 2.09-1.80 (m, 4H); ESI MS m/z 298 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.[OH-].[Na+].CS(C)=O.[N+]([C:22]1[CH:23]=[C:24]([C:30]#[N:31])[C:25](=[CH:28][CH:29]=1)[C:26]#[N:27])([O-])=O>O.C1C=CC=CC=1>[C:26]([C:25]1[CH:28]=[C:29]([CH:22]=[CH:23][C:24]=1[C:30]#[N:31])[O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]#[N:31])[CH:23]=3)=[CH:7][CH:8]=2)[CH:3]=1)#[N:27]
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc3ccc(Oc4ccc(C#N)c(C#N)c4)cc3c2)cc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.2 %

Procedure:
A mixture of 4.0 g (0.025 mol) of 2,7-dihydroxynaphthalene (2.2 g, 0.054 mol) of 50% aqueous sodium hydroxide, 30 ml of dimethyl sulfoxide and 25 ml of benzene was heated at reflux under a nitrogen atmosphere for 4 hours. The water was azeotroped from the mixture with a Dean-Stark trap. The reaction content was cooled to room temperature and 8.7 g (0.05 mol) of 4-nitrophthalonitrile was added in one sum. The resulting mixture was stirred for 15 hours at room temperature and was then poured into 150 ml of water. The light-brown precipitate was collected by suction filtration, washed with water, dried at reduced pressure, and washed with hot absolute ethanol to yield 6.1 g (59%) of the desired product, m.p. 201°-204° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].[CH2:10]1C[O:13][CH2:12][CH2:11]1>O.C(O)(=O)C.C=O>[OH:13][CH:12]1[CH2:11][CH2:10][N:4]([CH2:5][C:6]2[C:2]([CH3:1])=[C:3]([CH:8]=[O:9])[NH:4][C:5]=2[CH3:7])[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: Cc1cc(C)c(C=O)[nH]1
Agent: C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1CN1CCC(O)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (2.5 g, 20 mmol) in THF (40 mL), water (20 mL), acetic acid (3 mL), formaldehyde (37% wt. % solution in water, 5 mL) and the appropriate amine (30 mL) was heated to reflux (oil bath 90-100° C.) for 6 hours and then stirred at rt for overnight. The reaction was concentrated to a volume of 30 mL, basified with 2N NaOH and extracted with ethyl acetate (2×150 mL) and DCM (4×100 mL). The combined organic layers were concentrated and the residue was purified on a silica gel column to give 2.3 g (49%) of 4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH:41]([CH3:43])[CH3:42])[C:38]([OH:40])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38](=[O:40])[CH:37]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH:41]([CH3:43])[CH3:42])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)C(C(=O)O)c1ccc(F)cc1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CC(C)C(C(=O)N(C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-3,N-dimethyl-butyramide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 2-(4-fluoro-phenyl)-3-methyl-butyric acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 616.4 [M]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[C:22]([C:30]#[N:31])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:34])=[CH:26][CH:27]=5)[C:22]([C:30]#[N:31])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(O)ccc54)ccc3o2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc2c(c1)c(C#N)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-tert-butyl-2-{5-[(3-cyano-5-hydroxyindol-1-yl)methyl]benzofuran-2-yl}thiazole (158 mg), methyl iodide (0.1 ml) and sodium carbonate (0.1 g) in N,N-dimethylformamide (1.5 ml) was stirred for 3 days at room temperature. The resulting mixture was diluted with brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[(3-cyano-5-methoxyindol-1-yl)methyl]benzofuran-2-yl}thiazole.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[NH2:26][CH:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1N1CCCC1=O
Temperature: 65 °C

Procedure:
A mixture of 1-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)pyrrolidin-2-one (20 mg, 0.07 mmol), ammonium acetate (55 mg, 0.71 mmol) and sodium cyanoborohydride (9.0 mg, 0.14 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (11 mg, 50%). LCMS calculated for C14H20ClN2O2 (M+H)+: m/z=283.1. found: 283.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([CH3:15])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]1[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>O.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([C:11]([F:13])([F:12])[F:14])=[C:9]([CH3:15])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)c(C)c(C(F)(F)F)n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)O)n(Cc2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a mixture of ethyl 1-(3-chlorobenzyl)-3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (737 mg, 1.6 mmol) in H2O (10 mL) and EtOH (10 mL) was added NaOH (1.29 g, 32 mmol) and the mixture stirred at reflux for 3 h. The reaction mixture cooled to room temperature and concentrated the next day. Aqueous 5N HCl was added and the solids which had been formed were filtered off and dried on air for 5 d to give 768 mg of compound ACI-05 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:27]([O:29]C)=O)[C:11]3[NH:25][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[C:12]=3[N:26]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:27]([NH2:31])=[O:29])[C:11]3[NH:25][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[C:12]=3[N:26]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Yield: 19 %

Procedure:
A solution of methyl 2-(3-chlorophenyl)-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (50 mg, 0.12 mmol) in a solution of 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated at 80° C. for 48 hr. Filtration gave 2-(3-chlorophenyl)-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxamide (10 mg, 0.022 mmol, 19% yield) as a yellow solid. MS (ESI) m/z 408 (M+H). 1H NMR (DMSO-d6) δ ppm 10.97 (s, 1H), 8.53 (br. s., 1H), 8.19-8.44 (m, 4H), 7.88 (br. s., 1H), 7.41-7.63 (m, 2H), 6.87 (br. s., 1H), 3.56-3.88 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([CH3:18])[C:10]=12.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([CH3:18])[C:10]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)Nc5ccccn5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)Nc4ccccn4)cc3F)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A 100 mL round-bottomed flask was charged with 1-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-(pyridin-2-yl)urea (21.3 mg, 0.0427 mmol) from Example 20, Step A and 2,2,2-trifluoroacetic acid (487 mg, 4.27 mmol). The reaction mixture was stirred at 80° C. for 8 hours. The CF3COOH was removed under reduced pressure and the residue was purified by column chromatography (Silica gel, DCM/7M NH3 in MeOH from 50/1 to 10/1, v/v) to provide the product (14 mg, 85%). LRMS (APCI−): 100% purity, 220 nm, m/z 377 (M−1) detected; 1H NMR (400 MHz, CD3OD-d4) δ 8.31 (m, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.83 (m, 1H), 7.75 (m, 1H), 7.36 (m, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.04 (m, 1H), 6.28 (d, J=5.6 Hz, 1H), 2.72 (s, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[C:13]([C:19](O)=[O:20])[NH:14]3)=[CH:6][CH:5]=1)[CH3:2].Cl.Cl.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@@H:33]([N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)[CH3:34])[CH2:28][CH2:27]1>>[OH:41][CH:38]1[CH2:37][CH2:36][N:35]([C@@H:33]([CH3:34])[CH2:32][N:29]2[CH2:28][CH2:27][CH:26]([NH:25][C:19]([C:13]3[NH:14][C:15]4[C:11]([CH:12]=3)=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=3)[CH:18]=[CH:17][CH:16]=4)=[O:20])[CH2:31][CH2:30]2)[CH2:40][CH2:39]1
Reactant: CCOc1ccc(-c2cccc3[nH]c(C(=O)O)cc23)cc1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: CCOc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(C[C@H](C)N5CCC(O)CC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-ethoxy-phenyl)-1H-indole-2-carboxylic acid, (preparation analogously to 128, see example 141) and amine 50.