Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1>C(#N)C.O.[Li+].[OH-]>[F:1][C:2]([F:42])([F:43])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=2)[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:40][CH:41]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)Cc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a solution of ethyl(2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoate (0.662 g, 1.1 mmol) in acetonitrile (54 mL) was added aqueous 0.10 M LiOH (27 mL) and the solution was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 0.10 M LiOH (to a total volume of 300 mL, pH˜12) and washed with diethyl ether (2×100 mL). (The extraction process was complicated by the formation of emulsions.) The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.292 g (46%) of a colourless oil.
Reaction SMILES: C[O-].[Na+].[CH2:4]1[C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[CH2:5]1.[N+:13]([CH3:16])([O-:15])=[O:14]>CO>[N+:13]([CH2:16][C:9]1([OH:12])[CH2:10][CH2:11][C:6]2([CH2:5][CH2:4]2)[CH2:7][CH2:8]1)([O-:15])=[O:14]
Reactant: O=C1CCC2(CC1)CC2
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])CC1(O)CCC2(CC1)CC2
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To 4M solution of sodium methoxide (14 mL) in methanol (10 mL) was added a solution of spiro[2.5]octan-6-one (4.6 g, 0.031 mol) and nitromethane (2.3 mL, 0.042 mol) in methanol (20 mL) at room temperature and stirred overnight. The reaction was quenched with acetic acid (4.5 mL) and water (50 mL) and the volatiles were removed under reduced pressure. The residue was extracted with dichloromethane (2×50 mL), and the combined extracts were dried, filtered and evaporated. The residue was purified by flash chromatography to afford the desired product (3.2 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][NH:25][CH3:26])=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cc1F
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(C)c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of tert-butyl ({1-[(3-fluoro-4-methylphenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (287 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 125 mg, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])[CH2:31][CH:32]=[CH2:33].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:33]=[CH:32]/[CH2:31][CH2:30][N:34]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]2=[O:44])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/CCN3C(=O)c4ccccc4C3=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.184 mmol) in MeCN (5 mL) in a pressure tube is added 2-but-3-enylisoindole-1,3-dione (41 mg, 0.202 mmol), Pd(OAc)2 (3 mg) and triethylamine (186 mg, 1.84 mmol) then the mixture is heated at 100° C. for 10 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 20-40% EtOAc/hexane as eluent to give the title compound: (M+NH4)+=635.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[NH:10][C:11]([CH3:20])=[C:12]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[N:13]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]>C1(C)C=CC=CC=1>[N+:28]([C:25]1[CH:24]=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=[CH:27][C:26]=1[N:10]1[C:11]([CH3:20])=[C:12]([C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[N:13]=[C:9]1[Br:8])([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1[nH]c(Br)nc1C(=O)OC(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)OC(C)C)nc(Br)n1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
4.2 ml of triethylamine was added dropwise to 5 g (0.02 mol) of isopropyl 2-bromo-5-methyl-4-imidazolecarboxylate, 3.9 g of 1-fluoro-2,4-dinitrobenzene and 200 ml of toluene, and the mixture was refluxed for 16 hours. The toluene solution was then washed with water, dried and concentrated. The residue was stirred with diethyl ether and the solid obtained in this manner was isolated.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([NH:28][CH:29]=[O:30])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[CH:29]([NH:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1)=[O:30]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 96 %

Procedure:
The title compound II-aj was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-formamidoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.02-7.56 (2H, m), 3.74 (1H, m), 2.54-0.70 (20H, m), 1.04 (3H, s), 0.80 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:47]=[CH:46][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:48]>O1CCOCC1>[F:48][C:19]1[CH:20]=[C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([OH:45])([C:41]([F:42])([F:43])[F:44])[C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)[CH2:27][CH2:28]2)[CH:46]=[CH:47][C:18]=1[NH:17][C:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16]
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 130 °C
Yield: 35.9 %

Procedure:
Phenyl pyridin-4-ylcarbamate (1.933 mmol, 0.414 g) was added to a stirred solution of 2-(4-((4-(4-amino-3-fluorobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.292 mmol, 0.6 g) in dioxane (6 mL) and the mixture heated in a microwave for 10 minutes at 130° C. The mixture was washed with water (10 mL) and the organic phase dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 1% to 10% methanol/dichloromethane) to afford the title compound (271 mg). MS (ESI) m/z 585.3 [M+H]+
Reaction SMILES: C(O)C.Cl.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[CH:8][C:7]=1[C:23]([F:26])([F:25])[F:24]>[Fe].O>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([NH2:18])=[CH:15][C:16]=2[CH3:17])=[CH:8][C:7]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Yield: 79.5 %

Procedure:
A 250 ml two-necked round-bottomed flask equipped with a KPG-stirrer, a thermometer and a reflux condenser is charged with ethanol (100 ml), water (10 ml), iron (3.11 g) and hydrochloric acid 37% (0.3 ml). The reaction mixture is heated at 50° C. 2-(4-chloro-3-trifluoromethyl-phenoxy)-3-methyl-5-nitro-pyridine (5.81 g) is added portionwise. The mixture was heated at reflux for 2 hours. After cooling the mixture to 50° C. it is filtered through celite. The filtrate is poured into water (200 ml) and extracted with ethylacetate (2×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo to obtain 4.20 g of the compound as yellow solid (MP: 92-94° C.).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:17])([CH3:16])[C:12]3[S:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[F:23][C:3]1[C:2]([C:25]#[C:24][C@:26]2([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]2=[O:32])=[CH:7][C:6]2[C:8]3[N:9]=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:11][C:12]=3[C:13]([OH:17])([CH3:16])[CH2:14][O:15][C:5]=2[CH:4]=1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(Br)cc1-2
Product: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (415 mg) was reacted with methylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo{e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (272 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 23.3 mg and 27.4 mg (17.4% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]([CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]>>[CH3:16][O:17][C:18]([CH:20]1[CH2:25][N:24]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Product: COC(=O)C1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C

Procedure:
Intermediate 1 was coupled with piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 447.
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH:8]1[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1>CCCCCC.C1COCC1>[Li:5][C:8]1([Si:7]([CH3:19])([CH3:20])[CH3:6])[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: [Li]CCCC
Reactant: Cc1cnc2c(c1)CCCC2[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21

Procedure:
A mixture of a 1.55 molar solution of butyl lithium in hexane (6.45 ml, 1O mM) and THF (10 ml) maintained below 10° was treated with a solution of 5,6,7,8-tetrahydro-8-trimethylsilyl-3-methylquinoline (2.2 g, 10 mM) in THF (1O ml) to obtain 5,6,7,8-tetrahydro- -8-lithio-8-trimethylsilyl-3-methylquinoline. After 0.5 hour a 22% solution of t-butyldimethylsilyl isothiocyanate in benzene (6.9 g, 1O mM) was added dropwise. After 0.5 hour the reaction mixture was quenched with 2N hydrochloric acid (25 ml) and after 1 hour the aqueous layer was separated, basified (to pH9) and extracted with dichloromethane (2×50 ml). The organic extracts were dried and evaporated to give the title thioamide (2.1 g, c 100%). Recrystallisation from benzene gave analytically pure material (1.9 g, 88%) m.p. 153°, identical to authentic material (Found: C63.7; H,6.9; N,13.4% C11H14N2S requires: C64.0; H,6.8; N,13.6%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.08 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as a white solid (0.058 g, 11%). MS (ISN) 512.3 [(M−H)−]; mp 334° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: O=C1NCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1NCCc2ccc(OCCCCBr)cc21
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of intermediate 19 (196 mg, 1.2 mmol), 1,4-dibromobutane (0.43 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.22 mmol) was dissolved in EtOH (4 mL) and the solution was heated to reflux and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=3:1) to give 7-(4-bromobutoxy)-3,4-dihydroisoquinolin-1(2H)-one (intermediate 21) (230 mg, 63%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:16](=[O:17])[N:15]2[CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH2:21][CH:14]2[N:13]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])(=[O:36])=[O:35])[CH2:12]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:18]2[N:15]3[C:16](=[O:17])[CH:11]([NH:10][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:8])[CH2:12][N:13]([S:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])(=[O:36])=[O:35])[CH:14]3[CH2:21][N:20]([CH:22]([CH3:24])[CH3:23])[C:19]2=[O:25])=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1cnccn1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3cnccn3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using pyrazine-2-carbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=664.08 (calculated, monoisotopic); measured value (M+H)+: 665.05
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][C:12]2[NH:13][C:14](=[O:22])[C:15]3[CH2:21][O:20][CH2:19][CH2:18][C:16]=3[N:17]=2)[CH3:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([CH:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:37]([N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH2:21][O:20][CH2:19][CH2:18][C:16]=4[N:17]=3)=[O:38])[CH2:34][CH2:35]2)=[O:29])=[CH:40][CH:41]=1
Reactant: C[C@H](NCc1nc2c(c(=O)[nH]1)COCC2)c1ccc(F)cc1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: C[C@@H](c1ccc(F)cc1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (40.7 mg) from (S)-2-((1-(4-fluorophenyl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C30H32FN4O4 550.6. found 551.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.97 (dd, J=8.84, 5.31 Hz, 2H) 7.31 (dd, J=8.59, 5.05 Hz, 1H) 7.13-7.27 (m, 3H) 6.88 (t, J=7.83 Hz, 1H) 6.03 (q, J=7.07 Hz, 1H) 4.27-4.57 (m, 5H) 4.11 (br. s., 2H) 3.85-4.03 (m, 4H) 3.36 (br. s., 1H) 3.30 (br. s., 2H) 2.97 (s, 1H) 2.70 (br. s., 2H) 2.59 (d, J=4.04 Hz, 1H) 2.12 (s, 4H) 1.68 (d, J=7.07 Hz, 1H) 1.49 (d, J=7.07 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CC=C)(CC=C)CC=C)C=C.[OH2:25]>[Sc]>[C:1]1([CH:7]([OH:25])[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: O
Agent: C=CC[Sn](CC=C)(CC=C)CC=C
Agent: [Sc]
Product: C=CCC(O)c1ccccc1
Yield: 98 %

Procedure:
Water (0.25 ml) was added to this silica gel supporting scandium (75 mg), and while stirring, 4-phenyl-2-butanone (0.25 mmol) and tetraallyltin (0.125 mmol) were continuously added. The mixture was stirred at 40° C. for 24 hours. The mixture was returned to room temperature, and then was extracted four times by a decantation method using hexane. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel thin layer chromatography, to obtain the target product, 1-phenyl-3-buten-1-ol. Yield 98%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)=[O:8])[CH3:5].Cl[Sn]Cl>CO>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:12]=[C:13]([NH2:15])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Yield: 90.2 %

Procedure:
To a stirred solution of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (39 mmol) in 250 ml methanol was added SnCl2 (117 mmol) in one portion at room temperature. The reaction mixture was heated to reflux for 3 hours. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and treated with saturated NaHCO3 solution. Solids were filtered off and the filtrate was washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vaccuo to give 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow oil (10.5 g, 90.3%). MS (M+H)=299.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].Cl.[C:20]1(=[O:37])[N:24]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23](=[O:32])[C:22]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:21]12.C(N(CC)CC)C>O1CCOCC1>[C:23]1(=[O:32])[N:24]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=4)=[CH:4][C:3]=3[N+:16]([O-:18])=[O:17])[CH2:30][CH2:31]2)[C:20](=[O:37])[C:21]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:22]12
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1CC(=O)NN=C1c1ccc(N2CCC(CN3C(=O)c4ccccc4C3=O)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
2.68 g (10 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 2.81 g (10 mmol) of 4-phthalimidomethyl-piperidine hydrochloride are suspended in 30 ml of dioxane. After the addition of 2.8 ml (20 mmol) of triethylamine, the mixture is boiled under reflux for 4 hours. After it has cooled to room temperature, the solution is filtered from the residue and concentrated by evaporation under vacuum. After recrystallization of the solid residue from acetonitrile, 3.76 g (79%) of an orange yellow solid, m.p. 256°-258° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][C:14]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])([OH:17])[CH2:13][CH2:12]1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccccc1CCl
Product: CN1CCC(O)(Cc2ccccc2F)CC1

Procedure:
A sample of 2-fluorobenzyl chloride is converted to its Grignard reagent as described in Example 1 and is reacted with a sample of N-methyl-4-piperidone to provide 1-methyl-4-(2-fluorobenzyl)-4-piperidinol, mp 93°-95° C., after two recrystallizations.