Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:43][C@@H:42]2[C@:29]([CH3:46])([CH2:30][CH:31]=[C:32]3[C@H:41]2[CH2:40][CH2:39][C:38]2[C@:33]3([CH3:45])[CH:34]=[CH:35][C:36](=[O:44])[CH:37]=2)[C@H:3]1[C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=C(N3CCCC3)N=[C:14]([N:23]3[CH2:27][CH2:26]CC3)[N:13]=2)[CH2:8][CH2:7]1.CS(O)(=O)=O.[CH3:52][C@@H:53]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1.CS(O)(=O)=O.CS(O)(=O)=O.C[C@@H]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1.Cl.C[C@@H]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1>>[CH2:27]([NH:23][C:14]1[N:13]=[C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4](=[O:28])[C@@H:3]3[C@:29]4([CH3:46])[C@H:42]([C@H:41]5[C:32](=[CH:31][CH2:30]4)[C@:33]4([CH3:45])[C:38](=[CH:37][C:36](=[O:44])[CH:35]=[CH:34]4)[CH2:39][CH2:40]5)[CH2:43][C@H:2]3[CH3:1])[CH2:11][CH2:10]2)[CH:17]=[CH:53][CH:52]=1)[CH3:26]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Agent: CS(=O)(=O)O
Agent: Cl
Product: CCNc1cccc(N2CCN(CC(=O)[C@H]3[C@H](C)C[C@H]4[C@@H]5CCC6=CC(=O)C=C[C@]6(C)C5=CC[C@@]43C)CC2)n1

Procedure:
The preferred amino substituted steroid (XI) is 16α-methyl-21-[4[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione. More preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna1,4,9(11)-triene-3,20-dione monomethanesulfonate, 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4pyrimidinyl]-1-piperazinyl]pregna1,4,9(11)-triene-3,20-dione bismethanesulfonate and 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione hydrochloride. Most preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:40][N:41](C=O)C.O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:40]#[N:41])=[CH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(Br)ccc1CO
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1cc(C#N)ccc1CO
Temperature: 130 °C

Procedure:
A mixture of (4-bromo-2-methylphenyl)methanol (603 mg, 3.0 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), S-Phos (99 mg, 0.24 mmol) and zinc cyanide (421 mg, 3.6 mmol) was prepared in a mixture of DMF/water (99:1, 5 mL) under nitrogen atmosphere and heated at 130° C. for 30 minutes under microwave irradiation. The suspension was filtered through a Celite pad and the filter-cake washed with EtOAc. The filtrate was washed with water and brine. The organic phase was passed through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica, petrol ether/EtOAc) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.58-7.48 (2H, m), 7.44 (1H, s), 4.75 (2H, d, J=5.5 Hz), 2.33 (3H, s), 1.85-1.78 (1H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O-:26])=O)[CH:22]=4)[CH:17]=[CH:16]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:29][OH:30]>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]([NH:29][OH:30])=[O:26])[CH:22]=4)[CH:17]=[CH:16]3)=[CH:27][CH:28]=2)[CH2:5][CH2:6]1
Reactant: O=C([O-])c1ccc2ccn(CCOc3ccc(CN4CCOCC4)cc3)c2c1
Reactant: NO
Product: O=C(NO)c1ccc2ccn(CCOc3ccc(CN4CCOCC4)cc3)c2c1

Procedure:
1-(2-(4-(morpholinomethyl)phenoxy)ethyl)-1H-indole-6-carboxylate was activated and coupled with NH2OH as described in Example 4, Step 3 to provide 1-(2-(4-(morpholinomethyl)phenoxy)ethyl)-N-hydroxy-1H-indole-6-carboxamide as a tan solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[N:28]1([CH2:2][CH2:3][O:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[NH:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=4[O:23][CH3:24])[N:13]=3)=[CH:7][C:6]=2[CH3:27])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCn4ccnc4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-bromoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.12 g, 0.27 mmol) in acetone (5 mL) was added imidazole (0.18 g, 2.70 mmol) and Cs2CO3 (0.26 g, 0.80 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.04 g (35%). MP 218-219° C. 1H NMR (400 MHz, DMSO-d6): δ 11.80 (br s, 1H), 7.83 (s, 2H), 7.72 (s, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.36 (t, J=4.8 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.06 (s, 6H). MS (ES) m/z: 419.57 (M−1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:21][CH:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 3-(4-benzyloxyphenyl)-2-hydroxypropanoate (c.f. International Patent Appl. Publication No. WO9101337) (5.72 g) in methanol (120 mL) was added to an ice cooled suspension of 10% Palladium charcoal (1.90 g) in methanol (30 mL) under a nitrogen atmosphere. Solid ammonium formate (6.4 g) was added and the mixture heated at reflux for 15 minutes, then allowed to cool to room temperature. The catalyst was removed by filtering the reaction mixture through diatomaceous earth and the solvent evaporated. The residue was suspended in dilute hydrochloric acid (2M, 100 mL) and extracted with ethyl acetate (2×400 mL). The combined ethyl acetate solutions were washed with water (400 mL), brine (400 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with 1.5% methanol in dichloromethane as eluent to afford the title compound, mp 42°-43° C.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Na+].[CH3:15][C@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:39][C:37](=[O:38])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1>C1COCC1>[CH3:15][C@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:39][C@@H:37]([OH:38])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Yield: 96.6 %

Procedure:
N-Selectride® (0.64 ml, 1M in THF) was added to a solution of smilagenone (206 mg) in THF (10 ml) over 10 minutes at −78° C. The mixture was stirred and quenched with 10% aqueous citric acid (2 g in 20 ml water) and the product extracted into DCM (2×50 ml), dried (MgSO4) and evaporated to a colourless oil. The oil was taken up in acetone (20 ml) and water (50 ml) added. The precipitate was collected by filtration and dried to afford smilagenin (200 mg, 97%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH:23]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13]CC)=[O:12])[CH:7]=1.FC1C(C2C=CC(N3N=CC=N3)=CC=2)=CC(=O)N(CC[C@@](C)(S(C)(=O)=O)C(O)=O)C=1>>[F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH:23]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)S(C)(=O)=O
Agent: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)O)S(C)(=O)=O
Product: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)O)S(C)(=O)=O
Yield: 28.3 %

Procedure:
The title compound (144 mg, 28.4%) was prepared as an off-white solid from ethyl (2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate (538 mg, 1.09 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoic acid, Example 26, Step C. MS (LCMS) m/z 467.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.12-2.27 (m, 1 H) 3.17 (s, 3 H) 3.85-4.11 (m, 2 H) 6.55 (d, J=7.61 Hz, 1 H) 7.24-7.35 (m, 2 H) 7.44-7.66 (m, 4 H) 8.07 (d, J=6.44 Hz, 1 H).
Reaction SMILES: [Br-:1].C(O[C:7]([NH:9][CH2:10][CH2:11][N+:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:36])[C:22]([OH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13]2)=[O:8])(C)(C)C.Br>O1CCOCC1>[Br-:1].[C:7]([NH:9][CH2:10][CH2:11][N+:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:36])[C:22]([OH:35])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:13]2)(=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Agent: Br
Agent: [Br-]
Solvent: C1COCCO1
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (0.5 g, 1.04 mmol) in dioxane (25 ml) is added hydrogen bromide solution in dioxane (1 ml, prepared by bubbling HBr gas through dry, cooled dioxane). The reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound as a brown solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][PH:5]([CH2:7][CH2:8][CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6].[N:20](OCC)=[O:21].[O-]CC.[Na+]>C(O)C>[CH2:2]([O:3][CH2:4][PH:5]([CH2:7][CH2:8][C:9](=[N:20][OH:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6])[CH3:1]
Reactant: CCON=O
Reactant: CCOC[PH](=O)CCC(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC[PH](=O)CCC(=NO)C(=O)OCC
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a solution of the product of step (a) (32.2 g) in ethanol (90 ml) cooled to -10° C. was added ethyl nitrite (18 ml) followed by a solution of sodium ethoxide (from sodium (2.65 g) in ethanol (90 ml)), added dropwise over 90 min. The reaction mixture was then stirred at -10° C. for 16 hours evaporated in vacuo and the residue was dissolved in ethanol (150 ml) and acidified to pH 4.0 by the addition of conc. hydrochloric acid. The resulting solution was evaporated in vacuo and the residue treated with a mixture of ether and ethanol (10:1; 150 ml). Sodium chloride was filtered off and the filtrate evaporated in vacuo to give the oxime as a red oil (23.4 g). The n.m.r. spectrum supported the required structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[ClH:38]>O1CCOCC1>[ClH:38].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 16A; 580 mg; 1.11 mmol) in dioxane (3 mL) was added conc. aqueous HCl (3 mL; 36%). The reaction mixture was stirred for 0.5 hour and concentrated afford 580 mg (>100%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:25]1=[O:36])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2].O.NN>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][P:4]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:25]1=[O:36])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CN1CCC[C@H](NP(=O)(CCCCCCN2C(=O)c3ccccc3C2=O)OCC)C1=O
Agent: NN
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1CCC[C@H](NP(=O)(CCCCCCN)OCC)C1=O
Temperature: 25 °C

Procedure:
A solution of (S)-3-[[ethoxy(6-phthalimidohexyl)phosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After the reaction is completed, the mixture is diluted with toluene and the solvents decanted. The residue is triturated with methylene chloride and filtered. The combined filtrate is evaporated to dryness to give (S)-3-[[(6-aminohexyl)ethoxyphosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].O.NN>C(O)COCCO>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1ccc(-c2ccccc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCc1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Yield: 70 %

Procedure:
Thousand gram of 4-n-pentanoylbiphenyl, 2 l of diethylene glycol and 564 g of potassium hydroxide were introduced into a 5 l three neck flask and warmed with stirring to give a uniform solution at about 80° C, which was then cooled to about 50° C, followed by adding 738 ml of hydrazine hydrate, heating with stirring, distilling off low boiling fractions (mainly water) until the temperature of the reaction mixture reached 185° C, heating under reflux at 185°-190° C for 4 hours, cooling to room temperature, adding 1.5 l of water and 400 ml of hexane, stirring, washing hexane layer with aqueous solution of sodium chloride, and distilling, to give 659 g of 4-n-pentylbiphenyl (b.p. 166°-167°/6 mmHg) (Yield 70%).
Reaction SMILES: [N:1]1([C:11]2[C:12]([CH2:17][NH2:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](O[C:29]([CH3:31])=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC1C(C=O)=NC=C(C)C=1>[N:1]1([C:11]2[C:12]([CH2:17][NH:18][CH2:9][C:10]3[C:5]([CH3:6])=[CH:4][C:29]([CH3:31])=[CH:2][N:1]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NCc1ncccc1N1CCCc2ccccc21
Agent: Cc1cnc(C=O)c(C)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNCc2ncccc2N2CCCc3ccccc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of C-[3-(3,4-dihydro-2H-quinoline-1-yl)pyridine-2-yl]methylamine in CH2Cl2 and 3,5-Dimethyl-pyridine-2-carbaldehyde with NaBH(OAc)3 gave [3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:9][CH2:8]2.[Br:21]Br>CCO.C(Cl)Cl>[Br:21][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:11]2
Reactant: BrBr
Reactant: COc1cccc2c1CC(NC(C1CC1)C1CC1)CC2
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Br)c2c1CC(NC(C1CC1)C1CC1)CC2

Procedure:
8-Methoxy-2-(di-cyclopropylmethylamino)tetralin (OSU427) (311 mg, 1.09 mmol) was brominated in EtOH with 1.5 ml of a solution containing 0.6 ml Br2 in 10 ml CH2Cl2). After night in room temperature, the solvent was evaporated and the raw product (HBr salt) was recrystallized from acetone/ether to give 311 mg of white crystals melting at 153°-154° C. αD20 =-51.2°. GC/MS shows M+/M+2 at m/e=363.10 (43.1%) and 365.00 (41.9%) and the base peak at m/e=160.05.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]3[CH3:22])[CH:7]=[CH:8][CH:9]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[CH3:49][C:50]1([CH3:64])[O:54][CH:53]([CH2:55]OS(C(F)(F)F)(=O)=O)[CH2:52][O:51]1>CN(C=O)C>[CH3:49][C:50]1([CH3:64])[O:54][CH:53]([CH2:55][N:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[C:18]3[C:13]([N:14]([CH3:22])[C:15](=[O:21])[N:16]([CH3:20])[C:17]3=[O:19])=[CH:12]2)[CH2:52][O:51]1
Reactant: CC1(C)OCC(COS(=O)(=O)C(F)(F)F)O1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC3COC(C)(C)O3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil) (234 mg, 5.86 mmol) was added portionwise to a solution of 5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate Nf) (1000 mg, 3.66 mmol) and dibenzo-18-crown-6 (132 mg, 0.366 mmol) in DMF (28.1 mL) at 0° C. The solution was warmed to room temperature and stirred for 20 minutes, then re-cooled to 0° C. (2,2-Dimethyl-1,3-dioxolan-4-yl)methyltrifluoromethane sulfonate (Intermediate Sb) (1547 mg, 5.86 mmol) was added dropwise over 5 minutes. The mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with saturated NH4Cl(aq) (10 mL) and extracted with DCM (3×30 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum to afford the title compound as a red/brown amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:4].[OH:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(NC(=O)CCl)c1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)COc2ccc(C(=O)Oc3ccccc3)cc2)c1

Procedure:
To a solution of 2-chloro-N-m-tolyl-acetamide (580 mg, 3.16 mmol) and phenyl 4-hydroxybenzoate (677 mg, 3.16 mmol) in acetone (20 mL) was added potassium carbonate (502 mg, 3.63 mmol) and potassium iodide (26 mg, 0.16 mmol) and the mixture was heated to reflux overnight. The mixture was concentrated under vacuum, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to provide the desired product. MS (DCI-NH3): m/z 379 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1OB(O)O)#[N:14].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]2[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: N#Cc1ccccc1OB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(C=O)cc1[N+](=O)[O-]
Yield: 47 %

Procedure:
A mixture of 4-bromo-3-nitrobenzaldehyde (10.0 g), 2-cyanophenylboric acid (8.25 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (3.45 g), tetrabutylammonium bromide (1.36 g), 2M aqueous sodium carbonate solution (40 mL) and toluene (400 mL) was refluxed under an argon atmosphere for 3 days. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (5.15 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([OH:48])[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@@H:22]([NH:25]C(OC(C)(C)C)=O)[CH2:21]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:33]2[CH2:37][C@H:36]([NH:38][C:39]([CH2:41][O:42]C(=O)C)=[O:40])[C@@H:35]([OH:46])[C@H:34]2[OH:47])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[NH2:25][C@@H:22]1[CH2:23][CH2:24][N:20]([C:18]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[C@@H:33]3[CH2:37][C@H:36]([NH:38][C:39](=[O:40])[CH2:41][OH:42])[C@@H:35]([OH:46])[C@H:34]3[OH:47])=[C:11]([NH:10][CH2:9][C:8]([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[OH:48])[N:19]=2)[CH2:21]1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H]1CCN(c2nc(NCC(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic acid {(1S,2R,3S,4R)-4-[6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-2-((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate ZO1) in MeOH (˜0.5M) is treated with an equal volume of 4M HCl in dioxane and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by column chromatography/crystallisation to afford the title compound.