Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:22]([O:24]C)=[O:23].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:22]([OH:24])=[O:23]
Reactant: COC(=O)C(c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(C(C(=O)O)C3CCCC3)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 60 °C
Yield: 39.7 %

Procedure:
To a solution of methyl 2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylacetate (0.077 g; 0.18 mmol) in methanol (1.8 mL) was added a solution of sodium hydroxide 10 N (0.18 ml) and the mixture was heated to 60° C. for 18 h. After cooling, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.029 g (40%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[CH:7]=[N:6]2.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[CH:7]=[N:6]2
Reactant: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3)cnc2c1
Temperature: 30 °C
Reaction time: 8 h
Yield: 104.9 %

Procedure:
A mixture of methyl 4-(6-methoxyquinoxalin-2-yl)benzoate (80 mg, 0.272 mmol) and aqueous NaOH (5 mL, 2M) in MeOH (5 mL) was stirred at 30° C. overnight. The resulting mixture was concentrated in vacuo. The residue was acidified with aqueous HCl (2M) until pH=3 and concentrated. The solid was dissolved in MeOH (30 mL) and filtered. The filtrate was concentrated in vacuo to give crude product (80 mg), which was used for next step directly without further purification.
Reaction SMILES: ClC1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][C:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=2)[C:9]2[C:10]([C:24](O)=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH2:37]([Cl:39])Cl.CO>>[Cl:39][C:37]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:13]=3[CH3:14])[C:24](=[O:25])[N:27]2[C:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=2)=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: COc1ccc(Cn2nc(C(=O)O)c(C(Nc3cc(C)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)cc1
Solvent: CO
Product: COc1ccc(Cn2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(C)c(=O)n(C)c2)C3=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 27.2). tR: 4.54 min (HPLC 1); tR: 1.03 min (LC-MS 2); ESI-MS: 489 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[CH:5][NH:6]2.[NH:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:21]=4[CH:20]=[CH:19][NH:18]5)[CH2:28][CH2:29]3)[CH2:13][CH2:12]1)=[CH:5][NH:6]2
Reactant: O=C1CCC(c2c[nH]c3cccc(F)c23)CC1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1cccc2[nH]cc([C@H]3CC[C@@H](N4CCN(c5cccc6[nH]ccc56)CC4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone (0.88 g, 3.8 mmol), 1-(indol-4yl)piperazine (0.7 g, 3.5 mmol), sodium triacetoxyborohydride (1.1 g, 5.2 mmol) and acetic acid (0.4 ml, 7 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml), and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5-7% methanol-ethyl acetate) afforded 1.14 g (79%) of product as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH2:17]([CH:19]([CH2:25][CH3:26])[C:20](=O)[CH2:21][C:22]#[N:23])[CH3:18].CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH:19]([CH2:25][CH3:26])[CH2:17][CH3:18])[C:21]([C:22]#[N:23])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(CC)C(=O)CC#N
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCC(CC)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of (2-amino-5-chlorophenyl)(phenyl)methanone (700 mg, 3.02 mmol), 4-ethyl-3-oxo-hexanenitrile (505 mg, 3.63 mmol) and methanesulfonic acid (290 mg, 196 μl, 3.02 mmol) in toluene (40 ml) was stirred for 5 min at room temperature and then heated to reflux using a Dean-Stark-trap to remove water. After 2.5 h the mixture was cooled to room temperature, washed with saturated NaHCO3 solution and water and was evaporated. n-Heptane was added to the remaining residue and the off-white precipitate that formed was filtered off. The precipitate was again dissolved in EtOAc and the solution was washed with saturated NaHCO3 solution and water and was evaporated to yield the title compound (461 mg, 46%) as yellow solid. The filtrate was concentrated and the remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 100:0-0:100) to afford a second batch of the title compound (347 mg, 34%) as yellow solid. MS (ESI): 335.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][CH3:26].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][O:25][CH3:26])[CH2:11][CH2:10]1
Reactant: COCCBr
Reactant: OC1(c2cccc(Cl)c2Cl)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(O)(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidin-4-ol (0.44 g, 1.81 mmol), acetonitrile (20 ml), potassium carbonate (0.5 g, 3.6 mmol), 1-bromo-2-methoxyethane (0.17 ml, 2.0 mmol). Yield: 0.3 g, 54%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether. M.p. 135-137° C. MS m/z (relative intensity, 70 eV) 305 (M+, 1), 303 (M+, 1), 260 (63), 258 (bp) 240 (31).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][CH:16]2[CH2:20][N:19]([CH3:21])[CH2:18][CH:17]2O)=[C:13]([O:25][CH3:26])[CH:12]=1>ClCCl>[Br:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C@H:16]2[C@@H:17]([F:7])[CH2:18][N:19]([CH3:21])[CH2:20]2)=[C:13]([O:25][CH3:26])[CH:12]=1
Reactant: COc1cc(Br)ccc1OC1CN(C)CC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)ccc1O[C@@H]1CN(C)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
Add diethylaminosulfur trifluoride (0.173 mL, 1.31 mmol) to a solution of 4-(4-bromo-2-methoxy-phenoxy)-1-methyl-pyrrolidin-3-ol (0.329 g, 1.09 mmol) in dichloromethane (7 mL) at −78° C. Warm the mixture to room temperature and stir overnight. Evaporate the mixture and purify the resulting residue by silica gel chromatography, eluting with 0-70% ethyl acetate/hexane to give 130 mg (39%) of the title compound as a light brown oil. LC-MS/ES m/z (81Br) 306.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[N:29][CH:30]=1>>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:38])[F:39])=[CH:30][N:29]=4)=[CH:32][C:33]3=[O:37])[CH:10]=2)[C:6]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 76.8 %

Procedure:
tert-Butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (100 mg, 0.417 mmol) and 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (197 mg, 0.542 mmol), were reacted following the procedure of Example 30 (step g) to provide the title compound (168 mg, 66%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.07 (dd, J=8.3, 1.9 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.58 (overlapping dd, J=7.1 Hz, 2H), 7.37 (s, 1H), 7.26 (d, 1H under solvent), 7.08 (dd, J=8.3, 1.7 Hz, 1H), 7.03 (dd, J=7.1, 1.9 Hz, 1H), 4.66 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]=[O:2].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[OH:21].Cl>C(#N)C>[F:13][C:14]1[C:15]([OH:21])=[C:16]([C:17]([CH3:20])=[CH:18][CH:19]=1)[CH:1]=[O:2]
Reactant: C=O
Reactant: Cc1ccc(F)c(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(O)c1C=O
Temperature: 90 °C
Reaction time: 240 h

Procedure:
Paraformaldehyde (3.86 g, 133 mmol), magnesium chloride (6.32 g, 66.5 mmol) and triethylamine (11.6 ml, 83.3 mmol) were added to a solution of 2-fluoro-5-methylphenol (4.19 g, 33.3 mmol) in acetonitrile (100 ml), and the mixture was vigorously stirred at 90° C. for 10 days. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. After the organic layer was successively washed with 1N hydrochloric acid, water and a saturated aqueous NaCl solution, and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane/ethyl acetate=4/1) to obtain crude 3-fluoro-2-hydroxy-6-methylbenzaldehyde. According to a method similar to Example (28-3) and Example (28-4), from the crude compound obtained in the above, tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-fluoro-6-methylbenzoate was obtained (624 mg, three-step total yield: 6%).
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C@@H:9]1[C@H:13]2[N:14]([C:19](=[O:34])[C@@H:20]([NH:26]C(=O)OC(C)(C)C)[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][C@@H:16]([O:17][CH3:18])[C@H:12]2[O:11][CH2:10]1>>[ClH:1].[NH2:26][C@@H:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([N:14]1[CH2:15][C@@H:16]([O:17][CH3:18])[C@H:12]2[O:11][CH2:10][C@H:9]([OH:8])[C@@H:13]12)=[O:34]
Reactant: CO[C@@H]1CN(C(=O)[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Agent: Cl
Solvent: C1COCCO1
Product: CO[C@@H]1CN(C(=O)[C@@H](N)CC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 2 h

Procedure:
A solution of HCl in 1,4-dioxane (4.0M, 25 mL, 100 mmol) was added to tert-butyl (S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-ylcarbamate (1.73 g, 4.48 mmol). The solution was stirred for 2 hours then the solvents were removed in vacuo and the residue azeotroped with toluene (1×50 mL then 1×25 mL) to leave (S)-2-amino-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethylpentan-1-one hydrochloride as an off-white solid which was used without further purification. TLC (Rf=0.0, EtOAc:heptane 2:1), analytical HPLC main peak, Rt=4.047 min., HPLC-MS 287.2 [M+H]+, 595.3 [2M+Na]+; δC (125 MHz, CD3OH) 29.66 (C(CH3)3), 30.45 (C(CH3)3), 44.51/49.24 (NCH2CHOCH3 and CH2C(CH3)3), 50.03 (CHCH2C(CH3)3), 57.85 (OCH3), 70.64 (CHCHOH), 74.83 (CHCHOH), 75.56 (CH2CHOH), 78.13 and 79.11 (CHCHOCH3), 169.80/169.98 (NC═O).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.C(Cl)Cl.O>C(Cl)Cl>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 20 °C
Reaction time: 6 h
Yield: 19.6 %

Procedure:
A mixture of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (300 mg, 0.717 mmol, 1.0 eq), BCl3/CH2Cl2 (7.17 ml, 7.17 mmol, 10 eq. 1 M) in CH2Cl2 (20 ml) was stirred at 20° C. under a nitrogen atmosphere for 6 h. Water (50 ml) was added into the mixture. The mixture was extracted by EA (3×50 ml). The combined organic phases were washed (sat NaHCO3), brine, dried (Na2SO4), filtered and concentrated. The residue was purified by recrystallization (solvent: EA/PE and DIPE) to afford title compound 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 50) (50.9 mg, 19.6%) as a yellow solid. LC-MS (m/z)=363.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.72-0.74 (m, 2H), 0.94-0.99 (m, 2H), 1.89-1.94 (m, 1H), 6.41 (s, 1H), 6.84 (s, 1H), 7.58 (d, J=4 Hz, 1H), 7.49-7.81 (m, 3H), 8.29 (d, J=5.2 Hz, 1H), 10.08 (s, 1H), 12.14 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]C2CCCCO2)=[CH:6][C:5]=1[CH:21]=[C:22]1[NH:26][C:25](=[O:27])[NH:24][C:23]1=O)([O-])=O.CO.II>CN(C)C=O.[Pd]>[OH:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:1]=[C:23]3[NH:24][C:25](=[O:27])[NH:26][C:22]3=[CH:21][C:5]=2[CH:6]=1
Reactant: O=C1NC(=O)C(=Cc2cc(OCCCOC3CCCCO3)ccc2[N+](=O)[O-])N1
Agent: [Pd]
Agent: II
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2cc3cc(OCCCO)ccc3nc2[nH]1
Reaction time: 23 h
Yield: 33.2 %

Procedure:
A solution of 5-[[2-nitro-5-[3-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]phenyl]methylene]-2,4-imidazolidinedione (19.14 g, 49 mmol) in dimethylformamide (150 mL) was hydrogenated over 10% palladium on charcoal (2 g) at 55 p.s.i. in a low pressure hydrogenation apparatus. After 23 hours, the mixture was filtered through kieselguhr and concentrated in vacuo. The resultant yellow solid was dissolved in refluxing methanol (300 mL) and iodine (11.74 g, 49 mmol) added portionwise. After 15 minutes, the mixture was concentrated to dryness and the residue diluted with 10% sodium thiosulfate solution and 10% sodium carbonate solution. The solid was filtered off, washed with water and dried in air. Crystallization from aqueous dimethylformamide afforded 1,3-dihydro-7-(3-hydroxypropoxy)-2H-imidazo[4,5-b]quinolin-2-one (4.22 g, 33%), m.p. 343°-345° C. (dec.).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH:14]3[CH2:15][CH:11]4[CH:12]([CH2:13]3)[CH:10]24)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH:11]12[CH2:15][CH:14]3[CH2:13][CH:12]1[CH:10]2[C:9]3=[C:7]([O:8][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1C2CC3C(C2)C31
Reactant: ClCCN1CCOCC1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(C(OCCN2CCOCC2)=C2C3CC4C(C3)C24)cc1

Procedure:
A solution of 19.83 g. (0.1 mol) of tricyclo-(2.2.1.02.6)hept-3-yl phenyl ketone in 45 ml. of anhydrous toluene was added while stirring and boiling to a suspension of 3.9 g. (0.1 mol) of sodium amide in 45 ml. of anhydrous toluene, followed by etherification with a solution of 14.96 g. (0.1 mol) of N-(2-chloroethyl)-morpholine in 45 ml. of anhydrous toluene in the same way as in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:12])[C:10]#[N:11].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:12])[CH2:10][NH2:11]
Reactant: N#CC(F)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCC(F)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-2-fluoroacetonitrile (0.263 g, 1.29 mmol) in THF (2 ml) was added borane-DMS complex (0.134 ml, 1.42 mmol), and the reaction was heated to reflux under argon for one hour. The reaction was cooled to ambient temperature, and 0.4 ml of concentrated hydrochloric acid were added. The reaction mixture was again heated to reflux for 30 minutes, then cooled to ambient temperature and treated with 1M sodium hydroxide until the pH reached 13. The reaction was extracted three times with ether, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous potassium carbonate, filtered, and concentrated to yield 217 mg of the title compound (80.9% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([O:10]C)=[O:9])[CH:2]=[CH2:3].[OH-].[Li+]>CO.O1CCCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOc1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A solution of methyl 3-(allyloxy)-5-cyanbenzoate (1.5 g, 6.9 mmol) in methanol-tetrahydrofuran (1:2, 30 mL) was treated with 0.5 N lithium hydroxide (17 mL, 8.3 mmol). The reaction was stirred at 70° C. for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH ˜4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 1.0 g (74%) of 3-allyloxy-5-cyanobenzoic acid as a white solid.
Reaction SMILES: O[CH:2]([C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH2:3][N+:4]([O-:6])=[O:5]>C(Cl)Cl.C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1>[N+:4]([CH:3]=[CH:2][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])([O-:6])=[O:5]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(O)C[N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(C=C[N+](=O)[O-])cc(C(=O)OC)c1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.29 g (8.09 mmol) of dimethyl 5-(1-hydroxy-2-nitroethyl)isophthalate in 50 mL of DCM and 10 mL of acetic anhydride at 22° C. was added 100 mg of 4-dimethylaminopyridine. The solution was stirred at 22° C. for 1.5 h, evaporated and then coevaporated with xylenes (the material darkened slightly). The residue was partitioned between 100 mL of DCM and 50 mL of 1 N HCl. The organic layer was washed with water (50 mL), satd NaHCO3, dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography on silica gel eluting with DCM to give dimethyl 5-(2-nitrovinyl)isophthalate as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)=[CH:10][C:9]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=2)=[C:8]([Cl:61])[C:3]=1[O:4][CH2:5]CO.[C:62]([Cl:66])(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C>[CH2:35]([O:34][C@H:15]1[C@H:16]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:12]([C:11]2[CH:10]=[C:9]([CH2:51][C:52]3[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH3:60])=[CH:56][CH:57]=3)[C:8]([Cl:61])=[C:3]([O:4][CH2:5][CH2:62][Cl:66])[C:2]=2[Br:1])[O:13][C@@H:14]1[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCO)c2Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCCl)c2Cl)cc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of alcohol 79 (2.68 g, 2.95 mmol) in acetonitrile (30 mL) were added CCl4 (3.4 mL, 35.41 mmol) and PPh3 (1.9 g, 7.38 mmol) at 0° C. The mixture was stirred at 55° C. for 3 hours. The mixture was filtrated and concentrated in vacuo. The resultant was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 80 (2.59 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:30])[C@H:12]2[CH2:29][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:15]3[CH:14]=[CH:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:30])[C@H:12]2[CH2:29][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c2n(c3ccccc13)C[C@H](N(C)S(=O)(=O)c1ccc(F)cc1)C=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c2n(c3ccccc13)C[C@H](N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Reaction time: 24 h
Yield: 91 %

Procedure:
To a solution of methyl {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyeamino]-6,7-dihydropyrido[1,2-α]indol-10-yl}acetate (1 equiv.) from step 7 in EtOAc (0.25 M) was added 10% Pd-C (20 mg/mmol) and the flask thoroughly purged with nitrogen. The stirring black solution was purged with hydrogen gas, then left under 1 atmosphere pressure of hydrogen and protected from light. The reaction was stirred for 24 h and then filtered through a plug of Celite 545, the plug was washed with EtOAc (2×), and the combined organics were concentrated under vacuum to give a yellow foam. Purification by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (20:80 to 40:60) gave the title compound (91%) as a light yellow foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.C1(P(=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:2]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccsc1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccsc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of thiophene-3-carbaldehyde (10 g, 89.3 mmol) in THF (500 mL) at 0° C. was added ethyl (triphenylphosphoranylidene)acetate (35 g, 100.5 mmol) in portions. After stirring overnight, the reaction mixture was concentrated and purified by column chromatography to give the title compound (13.6 g, 83%).