Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>N1C=CC=CC=1.O>[C:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:6]=[C:5]([CH3:7])[O:4][N:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)no1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Ex-1B: To a solution of 3-amino-5-methylisoxazole (0.27 g, 2.75 mmol) in pyridine (1 mL) at 0° C. was added a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.29 mmol) in 1 mL pyridine dropwise to the reaction. The resulting solution was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for an additional 18 h. The mixture was diluted with water (100 mL), cooled to 0° C., and stirred for 1 h. The resulting precipitate was collected on filter paper and rinsed with several portions of water. The filtrate was acidified with 3 N HCl and the resulting precipitate was collected and rinsed with water. The solids were combined and dried in vacuo to afford 0.50 g (80%) of 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide as a pale green solid, mp 189–190° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.14 (d, 2H, J=8.1 Hz), 7.98 (d, 2H, J=8.1 Hz), 6.16 (s, 1H), 2.62 (s, 3H), 2.30 (s, 3H). HRMS (EI) Calcd. for C12H12N2O4S: 280.0518 (M+); Found: 280.0514. Anal. Calcd. for C12H12N2O4S: C, 51.42; H, 4.32; N, 9.99; S, 11.44; Found: C, 51.73; H, 4.39; N, 10.12; S, 11.30.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@H:27]([C:37]3[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[OH:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)(C)c1ccc(I)cc1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-tert-butyl-4-iodobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[OH:22][C:23]1[CH:24]=[C:25]([C:32](O)=[O:33])[C:26](=[CH:30][CH:31]=1)[C:27](O)=[O:28].O>C(O)(=O)C>[OH:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:30][CH:31]=1)[C:27](=[O:28])[N:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]1)[C:32]2=[O:33]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1C(=O)c3ccc(O)cc3C1=O)C2
Temperature: 140 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A suspension of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.0 g) and 4-hydroxyphthalic acid (1.0 g) in acetic acid (10 ml) was stirred for 1 hour at 140° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.5 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[CH3:10][C:4]1[N:3]=[C:2]2[NH:11][N:12]=[CH:8][C:7]2=[CH:6][CH:5]=1
Reactant: Cc1ccc(C=O)c(Cl)n1
Reactant: NN
Solvent: C1COCCO1
Product: Cc1ccc2cn[nH]c2n1
Temperature: 150 °C
Yield: 51 %

Procedure:
In a microwave vial 2-chloro-6-methylpyridine-3-carbaldehyde (1.98 g, 12.7 mmol) was dissolved in 1,4-dioxane (12 mL) and hydrazine (6.0 mL, 191 mmol) was added. The vial was sealed and heated under microwave irradiation at 150° C. for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 863 mg (41%) of 6-methyl-1H-pyrazolo[3,4-b]pyridine as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.06 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 2.79 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1.[OH-].[NH4+]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:12][C:13]2[CH:14]=[C:15]3[C:19]4=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]4[C@H:17]4[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]34)[CH:21]=2)[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc2ncc(Nc3cc4c5c(c3)[C@@H]3CNCC[C@@H]3N5CCOC4)cc2c1

Procedure:
Using 3-bromoquinoline and following the procedures described in EXAMPLE 56, Part C, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into (7bR,11aS)-N-(3-quinolinyl)-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine, bis-trifluoroacetic acid salt. This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 114. 1H NMR(CDCl3) δ: 8.60 (d, 1H, J=2.9 Hz), 7.95 (d, 1H, J=1.9 Hz), 7.60-7.55 (m, 1H), 7.50-7.38 (m, 3H), 6.88 (d, 1H, J=1.9 Hz), 6.81 (s, 1H), 5.99 (s, 1H), 5.85 (broad s, 1H), 4.61 (ABq, 2H, JAB=14.7 Hz), 4.23 (app d, 1H, J=12.4 Hz), 3.74 (app t, 1H), 3.43 (broad s, 1H), 3.30-3.00 (m, 4H), 2.75 (app t, 1H), 2.65-2.55 (m, 1H), 2.20-1.90 (m 3H). LRMS (ES)+: 373.4 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].O.Cl>C(O)C>[OH:5][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
Sodium tetrahydridoborate (0.051 g) was added portionwise over 5 minutes to a solution of 2-(4-acetylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.135 g) in ethanol (5 ml). The mixture was stirred for 45 minutes at ambient temperature and was then poured into water (20 ml) and acidified to pH 3 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (3×20 ml). The extracts were combined, washed with water and saturated sodium chloride solution and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 10-70% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(1-hydroxyethyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.096 g) as a foam; 1H NMR (CDCl3 +CD3COOD): 1.55 (d, 3 H), 2.3 (s, 3 H), 3.85 (s, 3 H), 4.95 (q, 1 H), 7.25 (s, 1 H), 7.3 (d, 2 H), 7.35 (d, 2 H), 7.55 (dd, 1 H), 8.7 (d, 1 H), 8.85 (d, 1 H); mass spectrum (+ve ESP): 401 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)=[N:6][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=3)=[N:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Nc1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(Nc2ncc(-c3ccc(F)cc3)cc2[N+](=O)[O-])c1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
A mixture of PdCl2dppf (300 mg, 0.4 mmol), N-(5-bromo-3-nitro-pyridin-2-yl)-benzene-1,3-diamine (Preparation P1, 2.5 g, 8.2 mmol) and 4-fluorophenylboronic acid (1.4 g, 10 mmol) in DME (16 ml) and 2N Na2CO3 (16 ml) was deoxygenated by evacuate/fill N2 (×3), then stirred and heated at 80° C. under N2 for 4 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O and then filtered through Celite. The organic layer was washed with brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→50% EtOAc/petrol) to give the title compound (1.66 g) as a dark red/brown solid. 1H NMR (400 MHz, DMSO-d6): 9.85 (1H, s), 8.87 (1H, d), 8.70 (1H, d), 7.82 (2H, dd), 7.33 (2H, t), 7.02 (1H, t), 6.92-6.81 (2H, m), 6.40 (1H, d), 5.15 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:41]4[CH2:42][CH2:43][N:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=592.00 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[Cl:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=2)=[O:13])[CH:27]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cc(Cl)ncn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)ncn1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(Cl)ncn1
Yield: 12.3 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-amino-6-chloropyrimidine (1.51 g, 11.7 mmol) in 12 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol, filtered, and recrystallized from acetonitrile-DMF to yield 0.38 g of the title compound, mp 254°-256° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([CH3:19])([CH3:18])[CH2:11][N:12]1[CH2:17][CH2:16]C[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]1CCNCC1>>[CH3:18][C:10]([CH3:19])([CH2:11][N:12]1[CH2:17][CH2:16][N:22]([CH3:21])[CH2:14][CH2:13]1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: CC(C)(CN1CCCCC1)C(=O)OCc1ccccc1
Reactant: CN1CCNCC1
Product: CN1CCN(CC(C)(C)C(=O)OCc2ccccc2)CC1

Procedure:
The procedure for benzyl-2,2-dimethyl-3-piperidin-1-ylpropanoate was followed except for replacing piperidine with 1-methylpiperazine. Purification via silica gel chromatography (5% EtOAc in hexane) afforded the title compound as a yellow oil. MS (ES+): m/z: 291.20 (100) [MH+]. HPLC: tr=2.08 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=1.18 (s, 6H), 2.09 (s, 3H), 2.23-2.33 (m, 4H), 2.39-2.50 (m, 6H), 5.11 (s, 2H) 7.31-7.36 (m, 5H)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:42]([CH3:43])[C:34]=4[CH3:33])=[CH:18][CH:17]=3)=[O:23])[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4cc(Cl)ccc43)cc2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
As described for Example 136, a mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.131 g of triethylamine and 0.219 g of 2,3-dimethylbenzoyl chloride in 13 ml of dichloromethane is stirred at room temperature for 18 hours. Work-up gives a solid which is recrystallized from dichloromethane-hexane to give 0.38 g of crystals 191°-193° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH:12]=2)[CH2:7][C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH3:22][O:23][CH:24](OC)OC>CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[CH:22][O:23][CH3:24])[C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)CC2CCCC=C2N1C(C)=O
Reactant: COC(OC)OC
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: COC=C1C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a solution of 1,2-diacetyltetrahydrocinnolin-3-one (0.34 g, 1.5 mmol) in N,N-dimethylformamide (3.6 mL) is added acetyl chloride (5 mL) and trimethylorthoformate (0.64 mL, 6.0 mmol). The mixture is heated at reflux in a 130° C. oil bath for 12 hours under a nitrogen atmosphere and then is allowed to cool to room temperature. The reaction mixture is purified in three batches via semi-preparative HPLC (Prodigy ODS3 column, 5% MeCN/95% water/0.01% trifluoroacetic acid to 100% acetonitrile over 1 hour at 10 mL/min) to give 1,2-diacetyl-4-methoxymethylene-1,4-dihydro-2H-cinnolin-3-one (0.18 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[CH2:27][NH:28][C:29](=[O:31])[CH3:30]>>[C:29]([NH:28][CH2:27][C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:34]=[CH:33][CH:32]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)NCc1cccc(N)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CC(=O)NCc1cccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
N-[3-(Acetylaminomethyl)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-(3-aminobenzyl)acetamide using method J. NMR; δH [2H6]—DMSO 10.34,(1H, b), 8.38,(1H, t), 8.06,(2H, d), 7.91,(1H, dd), 7.79,(1H, d), 7.70,(2H, m), 7.57,(3H, m), 7.30,(1H, t), 7.00,(1H, d), 4.25,(2H, d), 2.57,(3H, s), 2.34,(3H, s), 1.88,(3H, s). LCMS; retention time 3.07 min, MH+ 441.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:22]2[CH3:25])=[CH:17][CH:16]=1
Reactant: CC1NCCc2ccc(Cl)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(Cl)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 54 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Reaction time: 20 h

Procedure:
A solution of 4-fluoro-2-nitro-benzoic acid tert-butyl ester (13 g, 54 mmol) and N-methyl-piperazine (17 mL) was stirred at room temperature for 6 hours. The reaction mixture was then diluted with water (800 mL) and maintained under magnetic stirring for 20 hours. The resulting solid was filtered, washed thoroughly with water and dried under vacuum at 40° C. The title compound was obtained as yellow solid (16.4 g, 94% yield), and was used in the next step without any further purification.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)C=CCOc1ccc(CC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCOc1ccc(CC(C)=O)cc1
Yield: 99.2 %

Procedure:
To a solution of 1-[4-(3-carbomethoxyprop-2-eneoxy)phenyl]propan-2-one (1.1 g) in ethanol (50 ml), was added 10% Pd/C (100 mg) and the mixture hydrogenated at ambient temperature and atmospheric pressure until hydrogen uptake was complete (approx. 10 minutes). The solution was filtered, evaporated to give the title compound (1.1 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:36]=[CH:35][S:34][C:33]=1[C:37](O)=[O:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:37]([C:33]4[S:34][CH:35]=[CH:36][C:32]=4[O:31][CH3:30])=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: COc1ccsc1C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2sccc2OC)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 3-methoxythiophene-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl>CS(C)=O.O>[CH2:7]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-butylamine (0.32 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 8 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to oily compound which was later crystallized by benzene hexane to get N-(n-butyl)-(4-(naphthalen-2-yloxy)butyl)amine, solid. m.p. oil, (yield 0.56 gm, 96.5%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C@H:3]([OH:36])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:7][CH:6]1[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].CCN(C(C)C)C(C)C.[CH3:48][NH2:49].C(N=C=NCCCN(C)C)C>CO>[CH3:48][NH:49][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([CH:6]2[CH2:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]2[CH2:4][C@@H:3]([OH:36])[C:2]([F:1])([F:38])[F:37])[CH:28]=1
Reactant: CN
Reactant: O=C(O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydroquinoxalin-2-yl}benzoic acid (100 mg, 0.185 mmol) (from Scheme A12) was dissolved in MeOH (925 μl), Hunig's Base (97 μl, 0.555 mmol), methylamine (93 μl, 0.185 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (106 mg, 0.555 mmol) were added, and the mixture was stirred at 25° C. overnight. The product was purified on a reverse phase column, 10-90% MeCN/H2O gradient, 0.1% TFA modifier, yielding Example 19, N-methyl-3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoro-methoxy)benzyl]-1,2,3,4-tetrahydro quinoxalin-2-yl}benzamide. MS m/z=554.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1F
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1F
Yield: 59.8 %

Procedure:
Ethyl 4-(2,4-difluorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.73 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.53 g, 60%). The compound was characterized by the following spectroscopic data: