Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:29]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:28])[CH:22]=3)[C:13]=12>N1C=CC=CC=1>[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:29]3[CH2:30][CH2:31][C:32](=[O:35])[CH2:33][CH2:34]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:8]([NH:7][C:3]4[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=4)=[O:9])=[C:23]([F:28])[CH:22]=3)[C:13]=12
Reactant: Nc1ccc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)cc1F
Reactant: Cc1cccc(N=C=O)c1
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCC(=O)CC4)c4ncnc(N)c34)cc2F)c1
Reaction time: 16 h
Yield: 81.4 %

Procedure:
m-Tolyl isocyanate (1.2 equiv., 37.7 mg, 0.283 mmol) was added to a solution of 4-[4-amino-3-(4-amino-3-fluorophenyl) 1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (80.3 mg, 0.236 mmol) in pyridine. After 16 h at 40° C., the reaction was quenched with water (2 mL) and evaporated to dryness. Purification by preparative RP-HPLC (10% to 40% CH3CN in 0.1 N aqueous ammonium acetate, buffered to pH 4.5, over 60 min at 10 mL/min using a Waters Deltapak C18, 15 μm, 100×40 mm column, λ=254 mm) gave N-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea (91 mg, 84%); 1H NMR (DMSO-d6, 400 MHz) δ 2.26 (2H, br t), 2.30 (3H, s), 2.43 (4H, m), 2.69 (2H, m), 5.26 (1H, m), 6.82 (1H, d), 7.18 (1H, t), 7.25 (1H, br d), 7.32 (1H, br s), 7.45 (2H, m), 8.26 (1H, s), 8.36 (1H, t), 8.72 (1H, d) and 9.05 (1H, s) and RP-HPLC (10 to 90% CH3CN in 0.1 N aqueous ammonium acetate, buffered to pH 4.5, over 12 min at 2 mL/min using a Waters Symmetry C18, 5 μm, 250×4.6 mm column) Rt=15.433 min, 97.9%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:34]1[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]1)=[O:20])=[N:5]2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(Cl)c(Cl)cc4nc3OC)CC2)c1
Yield: 68 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-di methoxyphenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 68%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.74-3.78 (m, 4H), 3.79 (s, 6H), 4.15 (s, 3H), 6.07 (s, 1H), 6.11 (s, 2H), 7.33 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12]3)=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1
Reactant: CNC(=O)c1c(C2CC2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C2CC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a suspension of compound 5-bromo-2-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.5 g, 3.9 mmol) and K2CO3 (1.6 mg, 7.8 mmol) in DMF (15 mL) was added dropwise CH3I (1.1 mg, 7.8 mmol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 2 hours. After concentration in vacuum, the residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O, brine and dried over Na2SO4. The mixture was filtered and concentrated to give the product of compound 5-bromo-2-cyclopropyl-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1 g, yield: 65%). 1H-NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.98 (s, 1H), 5.63 (s, 1H), 3.05 (s, 3H), 2.79 (s, 6H), 2.39˜2.43 (m, 1H), 0.95˜0.97 (m, 2H), 0.89˜0.91 (m, 2H). MS (M+H)+: 401/403.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]2[NH:9][C:10]([CH2:12][N:13]([CH3:27])[S:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[CH:19][C:18]=3[CH3:26])(=[O:16])=[O:15])=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl.[N:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:52][CH2:51][C:45]3([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1>CC(C)=O>[CH3:25][O:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([S:14]([N:13]([CH3:27])[CH2:12][C:10]2[NH:9][C:8]3[C:3]([CH2:2][N:48]4[CH2:47][CH2:46][C:45]5([CH2:51][CH2:52][N:42]([C:39]6[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=6)[CH2:43][CH2:44]5)[CH2:50][CH2:49]4)=[CH:4][CH:5]=[CH:6][C:7]=3[N:11]=2)(=[O:16])=[O:15])=[C:18]([CH3:26])[CH:19]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CCl)c3[nH]2)c(C)c1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CN4CCC5(CC4)CCN(c4ccncc4)CC5)c3[nH]2)c(C)c1
Yield: 25 %

Procedure:
A mixture of N-((7-(chloromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (0.74 mmol, 1.0 eq.), K2CO3 (2.5 eq.) and 9-pyridin-4-Yl-3,9-diazaspiro[5.5]undecane dihydrochloride (AMN-01) (0.88 mmol, 1.2 eq.) in abs. acetone (20 ml) was heated under reflux for 16 h. The reaction mixture was filtered off and the filtrate was concentrated in order to obtain the crude product, which was purified by column chromatography over neutral aluminium oxide. Yield: 25%
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnc(Br)s1
Reactant: NCCCCOc1cccc(CN2CCCCC2)c1
Product: Nc1nnc(NCCCCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 4-[3-(1-piperidinylmethyl)phenoxy]1-butanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:15])[CH:8]=2)[N:3]=1.[NH3:16]>>[NH2:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:15])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cc2cc(Br)ccc2nc1Cl
Reactant: N
Product: Nc1nc2ccc(Br)cc2cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
0.8 g of 2-chloro-6-bromo-3-nitroquinoline (compound C4) are dissolved in 12 ml of ethanolic ammonia solution and stirred at 120° C. for 2.5 h in an autoclave. Under cooling in an ice bath, 0.55 g of the title compound precipitate from the reaction mixture as red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cccc(Cl)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-chloroaniline (49 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 47% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.79 (1H, s), 9.01 (2H, s), 8.75 (1H, s), 7.86 (1H, s), 7.67 (1H, m), 7.39 (1H, m), 7.20 (1H, m). MS m/z: 458.11, 460.09, 462.03 [M+H]+.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1C=CC=CC=1>[O:12]1[CH2:13][CH2:14][N:9]([C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCCC(=O)C1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: O=C1C=C(N2CCOCC2)CCC1
Temperature: 25 °C

Procedure:
In 700 ml benzene was dissolved 40.0 g 1,3-cyclohexanedione and 62 ml morpholine. The resulting solution was heated at reflux under nitrogen atmosphere for 1.5 hours. The water present in the reaction mixture was collected using a Dean-Stark trap. Upon cooling to room temperature, the reaction mixture was filtered through alumina and the filtrate concentrated in vacuo. Trituration of the resulting oil with ether solidified 62.4 g of 3-morpholino-2-cyclohexen-1-one crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1)=[O:5])[CH3:2].C[Si]([C:23]#[N:24])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N>[C:23]([CH2:12][C:10]1[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1)#[N:24]
Reactant: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl-5-(bromomethyl)benzene-1,3-dioate (1.9 g, 6.0 mmol) in 69 mL MeCN was added trimethylsilyl cyanide (1.2 mL, 9.0 mmol) and tetrabutylammonium fluoride (1M in THF, 9.0 mL, 9.0 mmol). The reaction was stirred for 0.5 h and concentrated. Flash chromatography (silica gel, 0-30% EtOAc/hexanes) gave diethyl 5-(cyanomethyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.20 (app t, J=0.7 Hz, 2H), 4.43 (q, J=7.1 Hz, 4H), 3.86 (s, 2H), 1.43 (t, J=7.1 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:17]([F:20])([F:19])[F:18])=[N:7]2.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.Cl>C1(C)C=CC=CC=1.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>[C:13]([NH:12][C:9]1[C:8]([C:17]([F:20])([F:19])[F:18])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:26](=[O:28])[CH3:27])[CH:3]=[CH:4][CH:5]=2)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2nc(C(F)(F)F)c(NC(C)(C)C)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of 8-bromo-N-(tert-butyl)-3-(trifluoromethyl)quinoxalin-2-amine (206 mg, 0.592 mmol), tributyl(1-ethoxyvinyl)stannane (300 μl, 0.888 mmol; Aldrich), and Pd(PPh3)4 (0) (68.4 mg, 0.059 mmol) in toluene (5.9 ml) was heated to 100° C. for 8 h; more Pd(PPh3)4 (0) (68.4 mg, 0.059 mmol) and tributyl(1-ethoxyvinyl)stannane (300 μl, 0.888 mmol) were added and the reaction was stirred at 100° C. for another 16 h. Concentrated HCl (61.6 μl, 0.740 mmol) was then added, and the resulting mixture was concentrated onto silica gel. Chromatographic purification (silica gel, 100% hexanes to 10% EtOAc in hexanes) provided 1-(3-(tert-butylamino)-2-(trifluoromethyl)quinoxalin-5-yl)ethanone (224e, >99% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 312.2 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][CH2:31][OH:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)CCO
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (99 mg, 98%), MS (ISP) m/z=403.5 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-hydroxy-propionic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[NH2:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][CH:26]=1
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(N)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-aminopyridine-5-boronic acid pinacol ester (Apollo Scientific, Cheshire, United Kingdom, 29 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 1.99 min (Method A); M+H=386 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.16-8.05 (m, 2H), 7.94-7.89 (m, 1H), 7.81-7.74 (m, 2H), 7.54-7.48 (m, 1H), 7.04-6.98 (m, 1H), 5.45 (s, br, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: C(OCC[C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)(=O)C.[CH2:18]1COC[CH2:19]1>>[CH2:7]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:19][CH:18]=1
Reactant: C1CCOC1
Reactant: CC(=O)OCCC1(c2ccsc2)C=CC=CC1
Product: c1ccc(CCc2ccsc2)cc1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1-(3-thienyl)phenylethyl acetate dissolved in THF (20 ml) was added carefully to dry liquid ammonia (300 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min and the reaction was quenched by addition of solid ammonium chloride. The residue, after the complete evaporation of liquid ammonia, was dissolved in water (100 ml) and was extracted with methylene chloride (4×50 ml). The combined organic layers was dried over MgSO4 and filtered. Removal of the solvent gave a crude product, which was purified by column chromatography using hexane followed by mixture of ethyl acetate in hexane as eluent to give 3-phenethylthiophene (3.2 g, 34% yield) and 1-(3-thienyl)phenethyl acetate (starting material, 7g).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:41][O:42]C)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:44]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:31]([I:44])=[C:32]([CH:33]2[CH2:36][CH:35]([CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:34]2)[O:42][N:41]=1)[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: CON=C(C#CC1CC(CC(C)C)C1)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-(3-isobutylcyclobutyl)-4-methoxyimino-5-hexynoate (53.6 g) and acetonitrile (320 mL) were mixed. To the mixture was added iodine (49.6 g) at ice temperature and the reaction mixture was stirred for 3 hr. After pouring the mixture into the solution of aqueous 20 w/v % sodium thiosulfate (380 mL) at ice temperature, the mixture was extracted with chloroform (1 L) and dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (80 g) and ethyl acetate/hexane=1/20 (600 mL) to the residue, the mixture was stirred at RT for 1 hr. The silica gel was filtered off and the filtrate was concentrated in vacuo. The residue was purified twice by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/60→1/50→1/45) to give the title compound (38.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][S:23](=[O:30])(=[O:29])[NH:24][CH:25]3[CH2:28][O:27][CH2:26]3)[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38]C)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][S:23](=[O:29])(=[O:30])[NH:24][CH:25]3[CH2:26][O:27][CH2:28]3)[C:11](=[O:33])[C@:10]([CH2:35][C:36]([OH:38])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetate (41.1 mg, 0.069 mmol; Example 372, Step C) in THF (2.0 ml) and MeOH (1.0 ml) was added 1 N lithium hydroxide (3.0 ml, 3.0 mmol). The suspension was stirred at room temperature for 15 hours, then acidified to pH 4 using 1 N HCl, and then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g SiO2, 5 to 25% gradient of a 1:6.5 MeOH/acetone mixture in hexanes) provided the title compound. The material was purified further by reversed phase preparatory HPLC (Eclipse Plus C1s, 30×250 mm, 5 μm column; Agilent, Santa Clara, Calif.) (eluent: 0.1% TFA in acetonitrile/water, gradient 30% to 60% over 25 min) to provide the title compound, as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([O:15]C)=[O:14])=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]3[CH2:29][CH2:28][CH2:27][C:7]=3[CH:8]=2)[N:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:11]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:9]2[C:8]3[CH2:29][CH2:28][CH2:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2cc3c(cc2c1-c1ccc(C)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2ccc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 60 °C
Yield: 1 %

Procedure:
To a solution of methyl 2-(2-methyl-4-p-tolyl-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl)pentanoate and methyl 2-(3-methyl-4-p-tolyl-8,9-dihydro-6H-cyclopenta[g]quinolin-3-yl)pentanoate (0.316 g; 0.81 mmol) in a mixture methanol-ethanol (2:1) (24 mL) was added a 5% sodium hydroxide solution (24.46 mmol; 19.5 mL) and the reaction mixture was heated to 60° C. for 18 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified to pH 2 with a 1N hydrochloric solution and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC (method 1) furnished 0.003 g (1%) of 2-(3-methyl-1-p-tolyl-8,9-dihydro-7H-cyclopenta[f]quinolin-2-yl)pentanoic acid. ESI/APCI(+): 374 (M+H). 1H NMR (CDCl3) δ 7.90 (d, J=8.35 Hz, 1H, H-9); 7.53 (d, J=8.35 Hz, 1H, H-8); 7.27 (bs, 1H, H-6′); 7.26 (bs, 1H, H-5′); 7.25 (d, J=8.2 Hz, 1H, H-3′); 7.06 (d, J=8.2 Hz, 1H, H-2′); 3.83 (t, J=6.7 Hz, 1H, H-12); 2.89, (m, 2H, H-7); 2.72 (s, 3H, H-10); 2.47 (s, 3H, H-7′); 2.22 (m, 1H, H-5); 2.18 (m, 1H, H-13); 2.02 (m, 1H, H-5); 1.84 (m, 1H, H-6); 1.76 (m, 1H, H-6); 1.63 (m, 1H, H-13); 1.19 (m, 1H, H-14); 0.97 (m, 1H, H-14); 0.737 (t, J=7.3 Hz, 3H, H-15). 13C NMR (CDCl3) δ 177.4 (C-11); 155.7 (C-2); 148.1 (C-4); 145.4 (C-9a); 143.1 (C-7a); 139.8 (C-4b); 137.9 (C-4′); 136.6 (C-1′); 131.5 (C-3); 129.8 (C-2′); 129.7 (C-3′); 128.9 (C-6′); 128.5 (C-5′); 126.7 (C-9); 126.6 (C-8); 124.1 (C-4a); 46.04 (C-12); 34.12 (C-5); 33.12 (C-7); 32.77 (C-13); 25.25 (C-6); 23.50 (C-10); 21.44 (C-14); 21.40 (C-7′); 14.14 (C-15).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH2:2][C:3]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])[N:7]([CH3:6])[CH2:16]2)=[O:4]
Reactant: CN1Cc2ccccc2NC1=O
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CN1Cc2cc(C(=O)CBr)ccc2NC1=O
Temperature: 25 °C

Procedure:
Bromoacetyl chloride (4.8 g) is added dropwise to a stirring solution of 3,4-dihydro-3-methyl-2(1H)-quinazolinone (2.5 g) and anhydrous aluminum chloride (4.9 g) in carbon disulfide (50 ml) under nitrogen. The reaction mixture is refluxed for five hours, cooled to RT and the carbon disulfide decanted. The residue is treated with hydrochloric acid (6N) and the acidic residue poured into ice water, stirred and filtered. The filtered solid is washed with water and dried in vacuo, affording the desired product, which is used in the next step without further purification, M.P. 190°-200° C. (dec).
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.O>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Reaction time: 0.42 h
Yield: 85 %

Procedure:
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4-fluoronitrobenzene and the mixture was stirred at 40° C. for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50° C., 10 mm Hg, 24 h) to the product in 85-95% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[OH:31])[C@@:23]2([CH:32]=[CH2:33])[C@H:14]1[C:15]1[CH:16]=[CH:17][C:18]([OH:34])=[CH:19][C:20]=1[CH2:21][CH2:22]2>>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@@:23]3([CH:32]=[CH2:33])[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:34])=[CH:19][C:20]=2[CH2:21][CH2:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCBr)C[C@@]1(C)[C@H]2CC[C@@H]1O
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCN1CCCCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with piperidine (10 equivalents) analogously to instructions 17.2, 50 mg of bromide 30a yields 41 mg of amine 34a as a colorless foam (GC-MS: m/z theor.: 451, pract.: 451).