Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([F:40])[CH:42]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Nc1cccc(F)c1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(F)c4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (8 mL) was added 3-fluoroaniline (68.4 mg, 0.615 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (97 mg) as a yellow solid. LC-MS (ES) m/z=434 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12](=[O:16])[O:13][CH2:14]I.[CH3:17][O:18][C:19]([NH:21][O:22][CH2:23][C:24]([O-:26])=[O:25])=[O:20].[Na+].CCOCC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12]([O:13][CH2:14][O:26][C:24](=[O:25])[CH2:23][O:22][NH:21][C:19]([O:18][CH3:17])=[O:20])=[O:16]
Reactant: COC(=O)NOCC(=O)[O-]
Reactant: N#Cc1cc(Br)c(OC(=O)OCI)c(Br)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)NOCC(=O)OCOC(=O)Oc1c(Br)cc(C#N)cc1Br
Reaction time: 16 h

Procedure:
A solution of carbonic acid iodomethyl ester 2,6-dibromo-4-cyanophenyl ester (0.20 g, 0.43 mmol) in DMF (2 mL) was added sodium methoxycarbonylaminooxyacetate (0.89 g, 0.52 mmol). The mixture was stirred for 16 h. Ether was added to the reaction and washed with water then brine then dried over sodium sulfate, filtered, and concentrated to an oil. Silica gel chromatography (2:1 EtOAc:hexanes) afforded the desired product as a clear oil. 1H-NMR (300 MHz, CDCl3) δ (ppm): 3.80 (s, 3H), 4.57 (s, 2H), 5.99 (s, 2H), 7.90 (s, 2H), 8.02 (bs, 1H). Mp=110-111° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]3[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=3[N:3]=2)[CH2:19][CH2:18]1
Reactant: CN1CCCNCC1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (22.3 g, 99.4 mmoL), 1-methyl[1,4]diazepane (19 mL, 152.8 mmol), and triethylamine (75 mL). Heat to 70° C. After 18 hours, add 1-methyl[1,4]diazepane (10 mL) and continue to heat at reflux. After 96 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 50% ethyl acetate/hexane and then 10% methanol/dichloromethane to give 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.52 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia, 90/10/0.1).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([O:16]C)OC.[Mg+2].[Br-].[Br-].C(Br)C=C.Cl>CCOCC.[Cu]I>[CH2:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[O:16])[CH:3]=[CH2:2]
Reactant: COC(OC)c1ccccc1Br
Reactant: [Li]CCCC
Agent: [Cu]I
Agent: Cl
Agent: [Br-]
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCc1ccccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
BuLi (1.55 M in hexane, 14.7 mL, 22.7 mmol) was added to a sol. of 1-bromo-2-(dimethoxymethyl)benzene (5.00 g, 21.6 mmol) in Et2O (50 mL). The mixture was stirred for 30 min at −78 ° C. and MgBr2.Et2O (5.87 g, 22.7 mmol) was added. The mixture was allowed to warm up to 0° C. over 15 min and CuI (420 mg, 2.16 mmol) was added. The mixture was stirred at 0° C. for 5 min and allyl bromide (1.92 mL, 22.7 mmol) was added. The mixture was stirred overnight while warming up to rt. Aq. 1M HCl (1 mL) was added and the mixture was diluted with Et2O, and washed with aq. 1M HCl (1×). The org. Extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was dissolved in acetone (20 mL) and water (10 mL), and TosOH (cat. amount) was added. The mixture was stirred for 5 h at rt, and the solvents were partially removed under reduced pressure. The residue was diluted with Et2O, and washed with aq. 1M HCl (1×), and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (Et2O/petroleum ether 1:49→24:1) yielded 2-allylbenzaldehyde (1.06 g, 34%). This compound was transformed into the title compound following typical procedure J with cyclopropylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:27])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]2[C:5]([Cl:27])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:10]=1)=[O:26]
Reactant: O=C(Nc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(C(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-3-nitrobenzamide (50.0 mg, 0.124 mmol) in water (0.09 mL), methanol (0.48 mL) and acetic acid (0.19 mL) was added iron (17 mg, 0.31 mmol) powder in small quantities. When the addition was completed, the mixture was stirred at 0° C. for 3 h, 3 eq additional iron powder was added. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a light brown powder (32 mg, 69%). LCMS for C17H13Cl2N5O (M+H)+: m/z=374.0, 376.0. 1H NMR (400 MHz, CD3OD): δ 9.57 (s, 1H), 9.42 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.29 (dd, J=7.9, 7.6 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.10-7.05 (m, 2H), 6.90 (dd, J=8.2, 0.9 Hz, 1H), 6.84-6.81 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:20][C:19]1[C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Clc1cccnc1Cl
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1

Procedure:
The title compound may be prepared from 4-carboxybenzeneboronic acid and 2,3-dichloropyridine using the procedure outlined in Description 29 (D29), for the synthesis of 4-(6-methyl-2-pyridyl)-benzoic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCN(C(C)=O)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (160 mg, 0.53 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 1-Acetylpiperazine (Aldrich) (81.5 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (45) as a pale yellow powder (127.9 mg; 61%). 1H NMR (DMSO-d6, 300 MHz) δ 2.04 (s, 3H), 2.13 (s, 3H), 2.49 (s, 3H), 3.57 (m, 4H), 3.65 (m, 1H), 3.70 (m, 1H), 4.25 (m, 1H), 4.35 (m, 1H), 8.01 (s, 1H), 12.16 (s, 1H). M− (ESI): 392.14; M+ (ESI): 394.15. HPLC (method A), Rt: 2.41 min (purity: 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:30][CH2:29][C:26]3[CH:27]=[N:28][C:23]([N:20]4[CH2:21][CH2:22][S:17][CH2:18][CH2:19]4)=[CH:24][CH:25]=3)=[O:16])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)cc1
Reactant: NCc1ccc(N2CCSCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(N2CCSCC2)nc1)c1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3′-fluorobiphenyl-4-carboxylic acid 8-5 (51 mg, 0.24 mmol), (6-thiomorpholinopyridin-3-yl)methanamine 8-4 (45 mg, 0.21 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (91 mg, 0.24 mmol) in DMF (1.0 mL) was added DIEA (0.1 mL, 0.64 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give 3′-fluoro-N-((6-thiomorpholinopyridin-3-yl)methyl)biphenyl-4-carboxamide 8-6. MS m/z 408.2 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(SC2Cc3ccccc3C2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(SC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(p-methoxyphenylthio) indane (5 g) in dry dichloromethane (40 ml) was cooled to -70°. Boron tribromide (6 g) was added slowly with stirring at -70°. When addition was complete, the reaction mixture was kept at -70° for a further 10 minutes and then allowed to warm to room temperature. The mixture was left overnight and water (70 ml) then added slowly with stirring. The mixture was then poured into water (65 ml) and a further quantity (95 ml) of dichloromethane added, and the mixture agitated. The dichloromethane solution was separated and extracted with 2 molar sodium hydroxide. The cloudy extract was allowed to stand until it cleared and was then decanted from a residue. The solution was acidified with dilute hydrochloric acid and extracted with ether. The ether solution was washed with water, dried, and evaporated to give 2-(p-hydroxyphenylthio)indane.
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)[CH:3]=[CH2:4]
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1
Yield: 96.2 %

Procedure:
3-Bromo-1-propene (2.95 mL, 34.06 mmol) was added dropwise under argon to a stirred mixture of 7-hydroxy-4-methylcoumarin 1 (2.0 g, 11.35 mmol) and anhydrous potassium carbonate (K2CO3) (2.35 g, 17.03 mmol) in acetone (50 mL). The resulting mixture was then refluxed for 4 h, after which it was allowed to cool, and the K2CO3 filtered off and washed with fresh acetone. The solvent was removed in vacuo and the residue was crystallized from methanol to afford 2 as white-cream crystals (2.36 g, 96%). TLC (hexane/ethyl acetate, 1:3): Rf=0.63. mp 110° C. 1H NMR (CDCl3, 500 MHz) δ 2.39 (s, 3H, CH3), 4.60 (d, J=5.0 Hz, 2H, CH2), 5.33 (d, J=10.5 Hz, 1H), 5.44 (d, J=17.5 Hz, 1H), 6.05 (m, 1H), 6.12 (s, 1H), 6.80 (s, 1H), 6.87 (dd, J=1.5, 9.0 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 18.70, 69.29, 101.84, 112.05, 112.79, 113.75, 118.51, 125.64, 132.31, 152.61, 152.26, 161.26, 161.65. ESIMS calcd for C13H13O3 [M+H]+ 217.1, found 217.1.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](SC)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:31]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:37][CH:36]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)c1
Temperature: 250 °C
Yield: 19.7 %

Procedure:
The title compound was prepared in the following manner from N-tert-Butyl-3-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.1 g, 0.3 mmol), 4-(4-morpholino)aniline (90 mg, 0.5 mmol), N,N-Diisopropylethylamine (0.124 mL, 0.712 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were heated in the microwave at 250° C. for 30 minutes. An LCMS showed product and left over amine. The reaction was concentrated and redissolved in 3 ml of DMSO and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate and extracted with DCM, dried filtered and concentrated to give N-tert-Butyl-3-[2-(4-morpholin-4-yl-phenylamino)-pyrrolo-[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a yellow solid (30 mg, 20%). MP 225-226 C. LCMS (E/I+) 507 (M+H). NMR 1H (DMSO-d6)-9.40 (bs, 1H), 8.96 (bs, 1H), 8.52 (bs, 1H), 7.77 (d, 1H, J=7.40 Hz), 7.50-7.45 (m, 2H), 7.22-7.05 (m, 4H), 6.93 (s, 2H), 6.54 (d, 1H, J=7.91 Hz), 4.45-4.40 (m, 1H), 3.18-3.25 (m, 2H), 3.04-3.11 (m, 2H), 1.98-2.06 (m, 2H), 1.74-1.84 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:21][CH:20]2[C:8]([CH3:33])([CH:9]3[CH:17]([CH:18]([OH:22])[CH2:19]2)[CH:16]2[C:12]([CH3:31])([CH:13]([CH:23]([CH3:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:15]2)[CH:11]([OH:32])[CH2:10]3)[CH2:7][CH2:6]1.[OH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[OH:22][CH:18]1[CH:17]2[CH:9]([CH2:10][CH:11]([OH:32])[C:12]3([CH3:31])[CH:16]2[CH2:15][CH2:14][CH:13]3[CH:23]([CH3:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]2([CH3:33])[CH:20]([CH2:21][CH:5]([O:4][CH2:3][CH2:2][NH:1][C:42](=[O:43])[CH2:41][C:38]3[CH:39]=[CH:40][C:35]([OH:34])=[CH:36][CH:37]=3)[CH2:6][CH2:7]2)[CH2:19]1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN)CCC4(C)C3CC(O)C12C
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCNC(=O)Cc5ccc(O)cc5)CCC4(C)C3CC(O)C12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
700 mg of methyl 4-[3-(2-aminoethoxy)-7,12-dihydroxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl]pentanoate, 230 mg of 4-hydroxyphenylacetic acid and 305 mg of HOBT are dissolved in 10 ml of THF and a solution of 342 mg of DCC in 10 ml of THF is injected at 0° C. The mixture is stirred at 0° C. for one hour and then at RT for 25 hours. The precipitate is filtered off, the filtrate is diluted with 150 ml of a 10% aqueous NaHCO3 solution and the mixture is extracted three times with 100 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/MeOH 10:1 yields 660 mg of a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1nccs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: c1ccc(-c2nccs2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
A solution of 2-bromothiazole (1.0 g, 6.1 mmol, Aldrich) in dioxane (25 mL) was treated with phenylboronic acid (0.82 g, 6.4 mmol), Pd(PtBu3)2 (0.16 g, 0.3 mmol, Strem) and Cs2CO3 (3.97 g, 12.2 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure, and purified by column chromatography (SiO2, 1:1 hexanes/ethyl acetate) to give provide the title compound (0.69 g, 4.3 mmol, 70%). 1H NMR (CDCl3, 300 MHz) 7.33 (m, 1H), 7.41-7.48 (m, 3H), 7.87 (d, 1H, J=3.4 Hz), 7.95-8.00 (m, 2H); MS (DCl/NH3) m/z 162 (M+H+).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([S:12]SCC)[CH3:11].N(OC(C)(C)C)=O>C(Cl)Cl>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([S:12][CH2:10][CH3:11])=[CH:3][N:4]=1
Reactant: Nc1cnc(Cl)c(Cl)c1
Reactant: CCSSCC
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CCSc1cnc(Cl)c(Cl)c1

Procedure:
24.45 g (0.15 mol) of 3-amino-5,6-dichloropyridine in 280 ml of methylene chloride were reacted with 36.6 g (0.3 mol) of diethyl disulfide and 23.2 g (0.225 mol) of tert-butyl nitrite in 130 ml of methylene chloride by a method similar to Example 1, Precursor α. After working up and subsequently washing the crude product with ethanol, 13.3 g of product of value were obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4cc(F)ccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.73 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.51 mmol) and methylamine (0.155 g, 5.1 mmol). mp 185-187° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19]C)=[O:18])[CH2:13][CH2:12]1)([O-:3])=[O:2].O.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.Cl>C1COCC1.C(OCC)(=O)C.CO>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:12][CH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]1)([O-:3])=[O:2]
Reactant: COC(=O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Agent: Cl
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylate (250.0 mg, 0.8920 mmol) (prepared according to methods similar to the one depicted in Step 1 of preparation O-1) in THF (2.748 mL), Water (2.748 mL) and MeOH (1.5 mL) solution was stirred at RT and treated with Lithium hydroxide monohydrate (Water (1)) (224.6 mg, 5.352 mmol). The mixture was stirred at RT overnight, then was concentrated under reduced pressure to remove the organics. The aqueous solution was cooled in an ice bath then acidified with HCl (5.352 mL of 1 M, 5.352 mmol) to pH 4-5. Ethyl acetate was then added and the layers separated. Aqueous layer was extracted further with ethyl acetate (2×5 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to leave the 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylic acid as a yellow oil. Used in the next step without further purification. MS (ES+) 267.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:9]([C:10]1[CH:5]=[C:4]([C:2]2[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]3[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=3[CH:11]=2)[CH:3]=[CH:2][CH:11]=1)#[N:8]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Br)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3cccc(C#N)c3)cc2C1=O
Temperature: 150 °C

Procedure:
Added to a solution of 0.3 g of methyl 7-bromo-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate in 9.4 cm3 of dioxane and 1.8 cm3 of water, at a temperature close to 20° C., are 147 mg of sodium bicarbonate. The reaction medium is then degassed under an argon atmosphere, then 111 mg of 3-cyanophenylboronic acid and 72 mg of tetrakis(triphenylphosphine)palladium are added. The mixture is heated at 150° C. in a microwave oven for 4 minutes, cooled to a temperature close to 20° C. and filtered. The filtrate is dried over anhydrous magnesium sulfate then filtered; added to the filtrate is 1 g of silica and the absorbed residue is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm, eluent: 80% heptane/20% ethyl acetate then 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 103 mg of methyl 7-(3-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained in the form of an orange oil.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][O:13][CH:12]([C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][CH:9]1[CH2:14][O:13][CH:12]([C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]1
Reactant: COC(=O)C(C)(C)C1CCC(OCc2ccccc2)CO1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)C1CCC(O)CO1
Yield: 108.7 %

Procedure:
To a solution of 5-(benzyloxy)tetrahydro-2H-pyran-2-yl acetate (281 mg, 1.123 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (783 mg, 4.49 mmol) in DCM (5 mL) at −78° C. was added BF3.OEt2 (0.228 mL, 1.796 mmol). The reaction mixture was gradually allowed to warm to rt and stirred at rt for 18 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL) and diluted with DCM (20 mL). The organic layer was separated, washed with water, brine, dried (MgSO4) and concentrated. The crude product was purified by silica gel FCC (10-20% EtOAc in hexanes) to afford methyl 2-(5-(benzyloxy)tetrahydro-2H-pyran-2-yl)-2-methylpropanoate as a colorless oil (253 mg). To a solution of methyl 2-(5-(benzyloxy)tetrahydro-2H-pyran-2-yl)-2-methylpropanoate (250 mg) in MeOH (20 mL) was added 10% Pd—C (59.7 mg) and the reaction mixture was hydrogenated at 40 psi overnight. The suspension was filtered and the filtrate was evaporated to dryness to afford methyl 2-(5-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate as a clear oil (188 mg).