Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH:13]([CH3:15])[CH3:14].[H-].[Na+].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1.C(OCC)(=O)C>[CH:13]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([B:23]([OH:28])[OH:24])[CH:3]=2)[NH:8][C:7](=[O:12])[CH2:6]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CC(=O)Nc2ccc(Br)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N1CC(=O)Nc2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of 6-bromo-4-isopropyl-3,4-dihydro-1H-quinoxalin-2-one (8.1 g, 30 mmol) in THF (200 ml) was added sodium hydride (60% dispersion in mineral oil, 1.2 g, 30 mmol). After stirring for 30 min. at room temperature, the mixture was cooled to −78° C. and butyl lithium (2.5 M in hexanes, 12.5 ml, 30 mmol) was added slowly. After 30 min. triisopropyl borate (19 ml, 83 mmol) was added and the mixture was allowed to warm to room temperature. After 2 hours, hydrochloric acid (1N, 350 ml) and ethyl acetate (350 ml) were added. After stirring for 30 min., the pH was adjusted to 6 and the layers were separated. The aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether, the precipitate filtered off and dried in vacuo to obtain the subtitled compound (3.5 g, 50%) as an off-white solid that was used without further purification. 1H-NMR (DMSO-d6) δ 1.15 (d, J=6.56 Hz, 6H), 3.51 (s, 2H), 4.04 (septet, J=6.57 Hz, 1H), 6.76 (d, J=7.65 Hz, 1H), 7.14 (d, J=7.66 Hz, 1H), 7.27 (s, 1H), 7.84 (s, 2H), 10.41 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1F)[C@@H:10](OS(C1C=CC(C)=CC=1)(=O)=O)[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:10]([S:35][C:33](=[O:36])[CH3:34])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](OS(=O)(=O)c1ccc(C)cc1)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1F
Reactant: CC([O-])=S
Agent: [K+]
Product: COC(=O)C(SC(C)=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Yield: 43.2 %

Procedure:
Methyl (2RS,3S)-3-tert-butoxycarbonylamino-2-acetylthio-3-(2-fluorophenyl) propionate may be prepared in a similar manner to that described in Example 1G, but starting with 30 g of methyl (2R,3S)-3-tert-butoxycarbonylamino-2-tosyloxy-3-(2-fluorophenyl)propionate and 17.2 g of potassium thioacetate. 9.8 g of methyl (2RS,3S)-3-tert-butoxycarbonylamino-2-acetylthio-3-phenylpropionate are thus obtained in the form of a red oil which is used without further purification in the subsequent syntheses.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][C:4]=1[CH2:11]Br.C[O:14][P:15]([O:18][CH3:19])[O:16][CH3:17]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17])[CH:8]=[CH:7][C:6]([CH2:9][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17])=[CH:5][C:4]=1[CH2:11][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17]
Reactant: BrCc1ccc(CBr)c(CBr)c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(CP(=O)(OC)OC)c(CP(=O)(OC)OC)c1)OC

Procedure:
A solution of 1,2,4-tris(bromomethyl)benzene (Preparation 4, 0.532 g, 0.0015M) and trimethylphosphite (15 mL, 0.126M) in dry toluene (25 mL) is stirred and heated at reflux temperature for 80 hours. Solvent and excess trimethylphosphite are removed under reduced pressure and the oily residue is chromatographed over silica gel (50 g, 40-63 μm, 10% CH3OH--CHCl3, 8 mL fractions) using 10% CH3OH--CHCl3 to elute the column. Fractions 16-22 contain the title compound (0.587 g, 0.00132M, 88%), which is a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14]CC#N)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:21]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:12](=[O:14])[C:11]1[CH:18]=[CH:19][CH:20]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCC#N)c1
Reactant: NCC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(=O)OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
Cyanomethyl 3-(t-butyloxycarbonylamino)-benzoate [compound of Example 61-(2)] (27.6 g), glycine benzyl ester.p-toluenesulfonate (33.7 g), triethylamine (20.2 g) and 4-dimethylaminopyridine (0.2 g) are mixed. The mixture is stirred at 80° C. two nights. The reaction mixture is extracted with ethyl acetate (200 ml). The extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a silica gel column chromatography (eluant, chloroform-ethyl acetate). The fractions containing the desired compound are collected, and the solvent is distilled off under reduced pressure. The residue is recrystallized from 70% aqueous acetonitrile to give N-[3-(t butyloxycarbonylamino)benzoyl]glycine benzyl ester (7.2 g). m.p.: 171°-173° C. (colorless needles) IR (KBr; cm-1): 1725, 1695, 1640
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([C:17]3[N:21]([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[N:20]=[N:19][N:18]=3)[C:14]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13][C:12]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH2:36]([O:35][C:12]1[CH:13]=[C:14]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[N:20]=[N:19][N:18]=2)=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)OC)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2′,4′-Bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid methyl ester (1 mmol) was dissolved in mixture of THF (5 ml) and water (5 ml). LiOH (72 mg, 3 mmol) was added, and the resulting mixture was stirred at 80° C. overnight. After the reaction was complete, the reaction was cooled to r.t., acidified with 1M HCl to pH=1. After extraction with ether (25 ml×3), the combined organics were washed with water (25 ml) and saturated brine (25 ml) and dried over Na2SO4. After filtration and concentration, 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid was obtained as white solid in quantitative yield. M.p.: 59-63° C.; 400 MHz 1H NMR (DMSO-d6) δ: 12.98 (br s, 1H), 8.18 (t, J=1.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.54-7.28 (m, 13H), 5.32 (s, 2H), 5.31 (s, 2H), 4.27 (t, J=7.2 Hz, 2H), 3.18 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 1.93 (pent, J=6.8 Hz, 2H); LCMS: 551 [M+H].
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][CH:32]([C:40]([OH:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:1]([NH:11][CH2:12][C:13]([NH:31][CH:32]([C:40]([OH:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: O=C(CNC(=O)OCc1ccccc1)NC(Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of 4.2 g (0.02 mole) of N-carbobenzoxyglycine and 2.2 g (0.022 mole) of N-methylmorpholine in 50 ml of dry toluene was cooled to -5° and 2.8 g (0.02 mole) of isobutyl chloroformate was added thereto. After 1 hour, a solution of 3.3 g (0.02 mole) of DL-phenylalanine in 20 ml of N-sodium hydroxide was added and the mixture was stirred vigorously overnight. The aqueous phase was isolated, extracted with ether and acidified with 4 N Hydrochloric acid to precipitate the product as a colorless oil which crystallized upon cooling. Recrystallization from ethanol-water yielded 5 g (70%) of N-carbobenzoxyglycyl-DL-phenylalanine, mp 158°-160° C., RfA 0.61.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:17][C:5]1[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#Cc1c(F)ccc(N)c1Nc1ccccn1
Yield: 54.3 %

Procedure:
6-Fluoro-3-nitro-2-(pyridin-2-ylamino)benzonitrile (1.3 g, 5.0 mmol), iron powder (1.12 g, 20.1 mmol), and ammonium chloride (1.55 g, 30.2 mmol) in methanol (20 mL) and water (7 mL) were heated at 90° C. for 3 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow solid (620 mg, 54%). 1H NMR 400 MHz δ (CDCl3): 9.05 (1H, ddd, J=7.5, 1.1, 0.8 Hz), 9.00-8.89 (1H, m), 7.34 (1H, ddd, J=9.1, 6.2, 1.7 Hz), 7.23-7.19 (1H, m), 6.83 (1H, s), 6.80 (1H, d, J=2.8 Hz), 6.65 (1H, ddd, J=7.6, 6.4, 1.4 Hz), 4.53 (2H, br s).
Reaction SMILES: C([O:8][C:9]([C@@H:11]([NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:23])=[O:15])[CH3:12])=[O:10])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:9]([C@@H:11]([NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[O:23])=[O:15])[CH3:12])([OH:10])=[O:8]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)O

Procedure:
A solution of 10.00 g (20.51 mmol) of the ester from example 22A in methanol (100 ml) is treated with Pd/C (1.00 g) (10 pc.) and hydrogenated at RT at a hydrogen pressure of 1 bar. Subsequently, the solution is filtered through silica gel and evaporated. 7.93 g (97% of th.) of the product are obtained, which is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15].[H-].[Na+].[NH4+].[Cl-]>O.C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(I)c[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
A 50-L jacketed reactor was flushed with nitrogen and charged with 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1437 g, 4578 mmol), anhydrous DMF (5.75 L) and SEM-Cl (1145 g, 6867 mmol). The reaction solution was cooled to 0-5° C. and treated with sodium hydride (60% dispersion in mineral oil, 275 g, 6867 mmol) portion wise over 2 h. The mixture was allowed to warm to room temperature over 1 h, after which time TLC analysis indicated complete reaction. The reaction mixture was treated with saturated aqueous NH4Cl (4.5 L), diluted with water (14 L), and stirred at room temperature for 16 h to give a brown precipitate. The precipitate was filtered and washed with water (3×3 L) and hexanes (2×3 L) to give 2065 g of a crude brown solid. The crude solid was dissolved in DCM (3 L), and the solution was filtered to remove insoluble material and concentrated to a solid. The solid was triturated twice from methanol/water (4 L, 5:1) and dried under reduced pressure at 45° C. for 64 h to afford 1100 g (Yield: 54%) of the title compound as a beige solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 5.54 (s, 2H), 3.52 (t, J=7.94 Hz, 2H), 0.84 (t, J=7.94 Hz, 2H), −0.08 (s, 9H). MS (ESI) m/z 443.9 [M+1]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1.C([Li])CCC.C([C:22]([O:24][CH3:25])=[O:23])#N.O>C1COCC1.C(OCC)(=O)C>[CH3:25][O:24][C:22]([C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:14][C:10]=2[CH:11]=1)=[O:23]
Reactant: COC(=O)C#N
Reactant: c1cc2cc(C3OCCO3)ccc2o1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc2cc(C3OCCO3)ccc2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled down to −78° C. Butyl lithium (180 uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25° C. Then the reaction mixture was cooled down to −78° C. and methyl cyanoformate (23 uL, 1.1 eq.) dissolved in 1 mL THF was added dropwise to the reaction mixture. After 1 h30 only small amount of starting material was detected and two major compounds were formed (expected product/dimer 73:27). The temperature was increased slowly to room temperature overnight. Water and ethyl acetate were added to the mixture and the aqueous layer was extracted 3 times. Combined organic phases was dried over MgSO4, filtrated and evaporated to give the 5-[1,3]Dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester (31.9 mg, 44%) mixed with the dimer (expected product/dimer 46:54). The mixture was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19]([OH:21])=O)=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19](=[O:21])[NH2:25])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)O)c2cc(Cl)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(Cl)ccc21
Reaction time: 16 h

Procedure:
To a mixture of 1-tert-butoxycarbonylmethyl-5-chloro-1H-indole-3-carboxylic acid (400 mg, 1.29 mmol) in CH2Cl2 (6 mL) were added successively NH4Cl (138 mg, 2.58 mmol), HBTU (1.22 g, 3.23 mmol) and DIPEA (0.902 mL, 5.17 mmol). Stirring was continued at RT for 16 h. Additional aliquots of NH4Cl (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture. After stirring for 4 h, the reaction mixture was diluted with CH2Cl2 and the solution was washed with water (2×), 0.1N aqueous HCl (2×), saturated aqueous NaHCO3 (2×) and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 2:1 to 1:0) to give the title compound as a white solid. TLC Rf (EtOAc/c-hexane 2:1)=0.20; MS (LC/MS): 309 [M+H]+, 617 [2M+H]+; tR (HPLC conditions b): 4.75 min.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[OH-].[Na+].C1(C)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ccc2ccccc2n1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(O)cc3CC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(Oc4ccc5ccccc5n4)cc3CC[C@@H]12
Yield: 11.4 %

Procedure:
A 50 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-hydroxy-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (300 mg, 1.22 mmol), tetrabutylammonium chloride (339 mg, 1.22 mmol), 2-chloroquinoline (200 mg, 1.22 mmol), 4 mL of 50% sodium hydroxide solution, and 4 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 100°, under nitrogen, for 24 h. The mixture was cooled, diluted with water (50 mL) and extracted with chloroform (3×100 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (60% ethyl acetate/hexanes eluent; followed by an additional chromatography on a short silica column, eluting with 10% ethyl acetate/dichloromethane) to give 52 mg (11%) of the title compound as a white solid. mp 172°-174°. FDMS: m/e=372. α[D]589 =+67.74 (c=0.43, chloroform).
Reaction SMILES: C([C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:11]=[C:10]2[C:6]=1[C:7]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[C:8]([Br:24])[C:9]2=[O:23])(C)(C)C.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Br:24][C:8]1[C:9](=[O:23])[C:10]2[C:6]([C:7]=1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[CH:5][CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:19][CH2:18]1)[CH:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(OCCC2CCNCC2)cc2c1C(c1cc(F)cc(F)c1)=C(Br)C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of t-butyl 6-(2-(piperidin-4-yl)ethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one (211 mg, 1.2 eq, 1.03 mmol) obtaind in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (58%).
Reaction SMILES: C(O[C:4]([NH:6][N:7]([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9])=[O:5])C.[CH3:13][NH:14][CH3:15]>C(O)C>[CH:10]([N:7]1[C:8]([N:14]([CH3:15])[CH3:13])=[N:9][C:4]([OH:5])=[N:6]1)([CH3:12])[CH3:11]
Reactant: CNC
Reactant: CCOC(=O)NN(C#N)C(C)C
Solvent: CCO
Product: CC(C)n1nc(O)nc1N(C)C
Temperature: 25 °C
Yield: 44 %

Procedure:
35.0 g of 2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester is added dropwise to a solution of 100 ml of 33% dimethylamine in absolute ethanol. The solution is maintained firstly for 15 hours at room temperature and afterwards for 1 1/2 hours at reflux temperature (65° C). After concentration by evaporation to dryness there remains an oily residue, which slowly crystallises on standing. The semisolid product is washed with ethyl acetate. There is obtained 15.5 g (44% of theory) of 1-isopropyl-5-dimethylamino-3-hydroxy-1,2,4-triazole, m.p. 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=2)[CH:5]=1.[CH2:21]([NH2:23])[CH3:22].[BH4-].[Na+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:23][CH2:21][CH3:22])[CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc(C=O)c2)c1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCNCc1cncc(-c2cc(C(=O)OC)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
4-Cyano-3-(5-formyl-pyridin-3-yl)-benzoic acid methyl ester (0.445 g, 1.67 mmol) was suspended in MeOH/dichloromethane (1:1; 8 mL) and a solution of ethylamine (2M in MeOH, 1.25 mL, 2.51 mmol) was added. The mixture was stirred for 16 hours at room temperature. The mixture was then was cooled to 0° C. and NaBH4 (76 mg, 2.01 mmol) was added in portions over 10 minutes. After allowing the mixture to warm to room temperature over 2 h, the reaction was quenched with 1 mL of water. The solution was concentrated in vacuo to ⅓ of its original volume and then it was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined organics were dried (Na2SO4) filtered and the solvent removed in vacuo to give 4-cyano-3-(5-ethylaminomethyl-pyridin-3-yl)benzoic acid methyl ester as a yellow oil (0.353 g, 72%). MS(ESI) m/z 296.0 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:16])[NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1>CO.[Ni].[H][H]>[Cl:15][C:8]1[N:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:12][C:3](=[O:2])[C@H:4]([CH3:16])[NH:5]2
Reactant: [H][H]
Reactant: COC(=O)[C@H](C)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: C[C@@H]1Nc2nc(Cl)ccc2NC1=O
Yield: 24.3 %

Procedure:
Compound A (9.0 g, 0.05 mol) was dissolved in 200 ml of methanol and hydrogenated with Raney nickel catalysis under 1 atm of hydrogen. After hydrogen uptake ceased, the catalyst was filtered off with suction, and the solvent was removed in vacuo. The solid product was stirred with diethyl ether, resulting in 2.4 g of pure product (melting point 236°-237° C.).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:31]1[N:36]=[C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:40][C:39]=2[O:50][CH3:51])[C:34]([Cl:52])=[CH:33][N:32]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:52][C:34]1[C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[CH:40][C:39]=2[O:50][CH3:51])=[N:36][C:31]([NH:29][C:27]2[CH:26]=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:32][CH:33]=1
Reactant: CCN1CCCOc2cc(N)ccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc21
Yield: 102.3 %

Procedure:
10-Camphorsulfonic acid (1.0E2 mg, 0.44 mmol) was added to 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (65 mg, 0.34 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (102 mg, 0.287 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 30 min). The mixture was conc. and purified by, conc., neutralized with MP-Carbonate (2.69 mmol/g loading; 0.50 g, 1.345 mmol), filtered and conc. to give 5-Chloro-N*2*-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as lavender solids (150 mg, 100%). MP: =185-188° C., LCMS: 511 (M+H); 1H-NMR (DMSO): 9.00 (s, 1H), 8.01 (s, 2H), 7.60 (d, 1H, J=7.8 Hz), 7.10 (d, 1H, J=8.8 Hz), 7.06 (s, 1H), 6.70 (s, 1H), 6.60 (d, 1H, J=8.6 Hz), 6.51 (d, 1H, J=8.7 Hz), 3.96 (t, 2H, J=5.3 Hz), 3.80 (s, 3H), 3.76 (t, 4H, J=4.5 Hz), 3.14 (t, 4H, J=4.5 Hz), 3.12 (m, 4H), 1.87 (m, 2H), 1.10 (t, 3H, J=6.9 Hz).