Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25](F)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:37][CH:34]3[CH2:36][CH2:35]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(F)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4CC4)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 56.4 %

Procedure:
A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (325b) (218 mg, 0.480 mmol), cyclopropanamine (82 mg, 1.44 mmol) and DIEA (0.17 mL, 0.96 mmol) in 3 mL of DMSO was heated in an oil bath at 80° C. for 5 h. It was diluted with 50 mL of EtOAc, washed with 5 mL of water. The organic solution was concentrated and the residue was stirred in 5 mL of ether. The insoluble yellow solid was filtered, rinsed with 2×2 mL of ether to give 133 mg of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate, as a yellow crystalline solid. The filtrate was concentrated and the residue was purified on a silica gel column (25-70% EtOAc in Hexanes) to give 67 mg ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.31 (1H, br.), 8.05 (1H, m), 7.61 (1H, dd, J=8.0, 1.2 Hz), 7.42 (1H, d, J=3.5 Hz), 7.35 (1H, t, J=7.8 Hz), 7.26 (1H, br.), 7.02 (2H, br.), 4.28 (2H, q, J=7.0 Hz), 2.56 (3H, s), 1.35 (4H, m), 1.32 (9H, s), 1.03-1.19 (5H, m), 0.63-0.78 (2H, m). m/z (ESI, +ve) 492.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9]Br>O.C(O)C>[C:11]1([CH:8]([CH3:9])[CH2:7][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(CBr)c1ccccc1
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: CC(CN1CCNCC1)c1ccccc1

Procedure:
A solution of piperazine (344 g), β-bromoisopropylbenzene (199 g) in water (1 liter) and ethanol (0.35 liter) is refluxed for 24 hours. After cooling, the resulting amine is extracted with 3×0.5 liter methylene chloride. After washing with water and evaporation of the solvent in vacuo, the resulting 2-phenylpropyl piperazine is distilled; b.p.=163°-165° C./15 mm Hg.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28](F)=[C:27]([Br:32])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12CC(CC1)CC2NC(=O)[C@H](C)C[C@H:45]([OH:55])[C@@H](N)CC1C=CC=CC=1.BrC1C=C(C=C(OC)C=1)C(O)=O>>[CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[C:29]([O:55][CH3:45])[CH:28]=[C:27]([Br:32])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: COc1cc(Br)cc(C(=O)O)c1
Product: COc1cc(Br)cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)c1

Procedure:
Prepared as for D3 from (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29) and 3-bromo-5-methoxybenzoic acid.
Reaction SMILES: [O:1]=[C:2]([NH:11][C@H:12]([C:28]([O:30]C)=[O:29])[CH2:13][C:14]1[N:18](COCC2C=CC=CC=2)[CH:17]=[N:16][CH:15]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].Cl.O=C(N[C@H](C(O)=O)CC1N(C[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)C=NC=1)CCC1C=CC=CC=1.[CH3:65]O>O>[O:1]=[C:2]([N:11]([CH3:65])[C@H:12]([C:28]([OH:30])=[O:29])[CH2:13][C:14]1[N:18]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:17]=[N:16][CH:15]=1)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CO
Reactant: O=C(CCc1ccccc1)N[C@@H](Cc1cncn1COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1cncn1COCc1ccccc1)NC(=O)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C(=O)CCc1ccccc1)[C@@H](Cc1cncn1OCc1ccccc1)C(=O)O
Reaction time: 6 h

Procedure:
A mixture of N-(1-oxo-3-phenylpropyl)-3-[(phenylmethoxy)methyl]-L-histidine, methyl ester (17.2 g., 40.8 mmole) and aqueous sodium hydroxide solution (52 ml. of 1.0N solution, 52 mmole) in methanol (42 ml.) was stirred at 25° for 6 hours, after which it was diluted with water (500 ml.) and washed with ethyl acetate. The aqueous phase was neutralized by the addition of 1.0N hydrochloric acid (52 ml., 52 mmole, resulting pH of 5) and the mixture was extracted with ethyl acetate (5 times). Both the extracts and the aqueous wash were concentrated in vacuo. Each of the concentrates was stirred with hot isopropanol (500 ml. each) and filtered while hot. The filtrates were combined and partially concentrated until crystals formed. The crystals were collected and dried to give 6.5 g. of N-(1-oxo-3-phenylpropyl)-3-[(phenylmethoxy)-methyl]-L-histidine as a white powder; m.p. 163°-165°.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([OH:18])=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].[C:19](Cl)(=O)[C:20](Cl)=O.C[N:26]([CH:28]=O)C>C(Cl)Cl>[CH:20]12[CH2:19][CH:10]3[CH2:9][CH:8]([CH2:13][CH:12]([CH2:11]3)[CH:28]1[NH:26][C:16]([C:11]13[CH2:10][CH2:9][C:8]([CH2:7][CH2:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])([CH2:15][CH2:14]1)[CH2:13][CH2:12]3)=[O:18])[CH2:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Solvent: ClCCl
Product: CCS(=O)(=O)CCC12CCC(C(=O)NC3C4CC5CC(C4)CC3C5)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Carboxylic acid 1-4 (810 mg, 3 mmol) was dissolved in methylene chloride (5 ml) and treated with oxalyl chloride (4 eq.) and 0.050 ml of DMF. The reaction was stirred at room temperature for 45 min, then the solvent was removed under reduced pressure to give a quantitative crude yield of 4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]octane-1-carboxyl chloride (1-5).
Reaction SMILES: [NH:1]1[C:10]2C(=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.Cl.[NH2:13][OH:14].[OH-].[Na+].[CH2:17](O)[CH3:18]>O>[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:1](=[N:13][OH:14])[CH2:2][CH2:3][CH2:4][C:18]=2[CH:17]=1
Reactant: NO
Reactant: CCO
Reactant: O=c1ccc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc2c(c1)CCCC2=NO

Procedure:
The quinolinone (30g), hydroxylamine hydrochloride (14g), sodium hydroxide (9g), ethanol (165ml) and water (65ml) were stirred and refluxed for 2 hours. Water (100ml) was added and the product was allowed to crystallise overnight. The crystals were removed by filtration and washed with water and dried to give 3-methyl-8-oximino-5,6,7,8-tetrahydroquinoline (27.5g) mp 188° C. Found: C,68.5; H,6.9; N,15.4, C10H12N2O requires C,68.2; H,6.9; N,15.1%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(N1CCOCC1)C>[CH3:15][C:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1
Reactant: C1CNCCN1
Agent: CCN1CCOCC1
Product: CC(C)(C)Nc1cc(N2CCNCC2)nc(NC(C)(C)C)n1

Procedure:
A mixture containing 10.0 g (38.9 mmoles) of 4-chloro-2,6-bis(1,1-dimethylethylamino)pyrimidine, 13.42 g (155.8 mmoles) of piperazine and 150 ml of N-ethylmorpholine is boiled under reflux under nitrogen for 25 hours, then the solvent and piperazine are distilled off under atmospheric pressure. Water is added to the residue and distilled off until the head temperature reaches 100° C. After cooling down the residue is distributed between 200 ml of chloroform and 30 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 50 ml of water each, then dried and evaporated. The residue is purified by chromatography on a silica gel column by using a 9:1 mixture of chloroform and methanol. After recrystallizing the eluted product from hexane, the title compound is obtained in a yield of 7.65 g (64%), m.p.:142°-145° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[CH:33]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=2[C:40]2[C:45]1=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: BrC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(C2c3ccccc3-c3ccccc32)[C@H](Cc2ccccc2)C1)C(F)(F)F
Yield: 47.4 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 25a with 138 mg (0.561 mmol) of 9-bromofluorene and 155 mg (1.12 mmol) of potassium carbonate in 2.5 ml of acetone. The title compound (131 mg, 47%) is obtained as oil. TLC: toluene/ethyl acetate (1:1) Rf =0.43; FD-MS: M+ =591.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH2:21][O:22][CH3:23])[O:17][C:16]=3[CH:24]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36](F)=[C:37]([CH:40]=1)[C:38]#[N:39].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:20]2[CH2:19][CH:18]([CH2:21][O:22][CH3:23])[O:17][C:16]3[CH:24]=[C:12]([S:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=4)[C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]2=3)=[C:37]([C:38]#[N:39])[CH:40]=1
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: COCC1CNc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CN(c2ccc(Cl)cc2C#N)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (150 mg, 0.324 mmol) and 5-chloro-2-fluorobenzonitrile (50.55 mg, 0.324 mmol, Aldrich) in DMF (5.0 mL) was added Cs2CO3 (210 mg, 7.95 mmol) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel 100-200 mesh and 0-30% ethyl acetate in hexane) to obtain 4-(4-chloro-2-cyanophenyl)-N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (170 mg, 87.6%) as an off white solid. m/z (ESI) 596.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.C(=O)([O-])[OH:14].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[O:14][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(=O)O2
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of 5-methoxy-indan-1-one (4.2 g, 25.9 mmol) in 240 ml of dichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g, 51.8 mmol). 3-Chloro-perbenzoic acid (11.61 g, 51.8 mmol) was added portionwise, and the reaction mixture was stirred at 0° C. for 2 h and at room temperature overnight. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed with saturated solution of sodium hydrogencarbonate and dried with sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) was obtained as an orange oil which was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.[CH2:11]([O:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=O)[CH2:27][CH2:28][C:29](O)=[O:30])[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C@@:26]23[CH2:27][CH2:28][C:29](=[O:30])[N:10]2[C@@H:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:8][O:9]3)[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CCC(=O)[C@H]1CC[C@H](COCc2ccccc2)CC1
Reactant: N[C@H](CO)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC[C@@]2([C@H]3CC[C@H](COCc4ccccc4)CC3)OC[C@H](c3ccccc3)N12

Procedure:
To a stirred solution of (S)-(+)-phenylglycinol (6.85 g, 50 mmol) in toluene (150 mL) is added trans-4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyric acid (15.2 g, 50 mmol), and the resulting mixture is heated to reflux for 4 hours with continuous water removal by using Dean-stark apparatus. The resulting mixture is concentrated, and the resulting residue is purified by silica gel column chromatography to afford trans-(3S,7aS)-7a-[4-(benzyloxymethyl)cyclohexyl]-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5-one.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[ClH:19].O1CCOCC1>>[ClH:19].[CH2:1]([O:4][C:5]1([CH3:18])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC1(C)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A mixture of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate (3.10 g, 12.1 mmol) and 4N HCl/dioxane (15 mL, 60.0 mmol) was stirred at rt for 3 h. It was then concentrated in vacuum to obtain 2.2 g (95%) of 4-(allyloxy)-4-methylpiperidine hydrochloride as a light brown solid. 1H NMR (500 MHz, METHANOL-d4) δ 6.02-5.92 (m, 1H), 5.33 (dd, J=17.2, 1.7 Hz, 1H), 5.15 (dd, J=10.6, 1.7 Hz, 1H), 3.96 (dt, J=5.1, 1.6 Hz, 2H), 3.23-3.18 (m, 4H), 2.06 (dd, J=15.3, 2.5 Hz, 2H), 1.77-1.69 (m, 2H), 1.31-1.28 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:20][OH:21]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[N:20][OH:21])[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOCCCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCCOCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Butoxyhexyl)-4-piperidone oxime is prepared from 1-(6-butoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][CH:6]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:1]([OH:7])[CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12].[C:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][CH:6]([OH:7])[CH:1]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(O)C(NCc2ccccc2)C1

Procedure:
To a solution of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (500 g, 2.5 mol) in H2O (5 L) was added BnNH2 (294 g, 2.75 mol) at room temperature. The mixture was heated to reflux overnight. The mixture was extracted with DCM (1 L), dried over sodium sulfate, and concentrated under reduced pressure to give tert-butyl-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate and tert-butyl-3-(benzylamino)-4-hydroxypiperidine-1-carboxylate, which were used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]([OH:30])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])=[S:10])=[C:6]([O:31][CH3:32])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH3:32][O:31][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[S:10][C:9]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][C:17]([OH:30])([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=[O:13])=[N:8][C:7]=12
Reactant: COc1ccnc(Cl)c1NC(=S)NC(=O)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccnc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Yield: 20 %

Procedure:
To a magnetically stirred mixture of 1-(2-Chloro-4-methoxy-pyridin-3-yl)-3-[4-hydroxy-4-(3-trifluoromethylphenyl)-piperidine-1-carbonyl]-thiourea (100 mg, 0.20 mmol) in THF (10 mL) was added sodium hydride (10 mg, 0.25 mmole, 60% dispersion in mineral oil). The reaction is stirred at reflux overnight. TLC (80% ethyl acetate/hexane) indicated complete consumption of starting material. The reaction was poured into water and the aqueous layer was extracted with ethyl acetate. The resulting organic layers were washed with 2N HCl (2×) and saturated sodium chloride solution and then dried over magnesium sulfate. Purification by flash chromatography gave 4-Hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-b]pyridine-2-yl)-amide (20 mg, 0.04 mmole, 22% yield) as a light yellow solid. (LRMS for C20H19F3N4O3S (M+H)+ at m/z=452.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[Sn:29](Cl)([CH3:32])([CH3:31])[CH3:30]>C(OCC)C.C1COCC1>[CH3:23][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=3[Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)c4ccccc4nc3c2)c1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2ccc3c([Sn](C)(C)C)c4ccccc4nc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 9-bromo-3-(3,5-dimethylphenyl)acridine, 29, (0.6 g, 1.6 mmol) in 10 ml anhydrous diethyl ether:THF (1:1) was cooled to −78° C. To the solution was added 1.6 M n-BuLi in hexanes (2.4 mmol, 1.5 mL) dropwise over a period of 15 min and then a 1.0 M solution of Me3SnCl in hexanes (3 mL, 3 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 18 hours and concentrated in vacuo. Purification of the orange residue by flash chromatography (100:30:1 hexanes:ethyl acetate:triethylamine) afforded 30 (0.65 g, 91%) as a yellow solid. GC-MS revealed contamination of the product with 5-10% 3-(3,5-dimethylphenyl)acridine that could not be separated by chromatography. The stannane was therefore employed in the Stille cross-coupling with 1,8-dibromonaphthalene without filter purification. 1H-NMR δ=0.70 (s, 9H), 2.44 (s, 6H), 7.08-7.10 (m, 1H), 7.49-7.56 (m, 3H), 7.76 (ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz, 1H), 7.88 (dd, J=1.9 Hz, 9.1 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.22 (d, J=9.1 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.49 (m, 1H). 13C-NMR δ=−4.2, 21.8, 125.3, 125.4, 125.5, 127.7, 129.6, 129.8, 130.1, 130.4, 130.8, 132.8, 133.5, 138.4, 139.8, 142.0, 148.2, 148.2, 156.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C)C=O.S(Cl)([Cl:20])=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:20])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2[nH]1

Procedure:
A mixture of indole-2-carboxylic acid (2.18 g), N,N-dimethylformamide (52 mg) and thionyl chloride (1.0 ml) in dry dichloromethane (22 ml) was refluxed for 1 hour to give a solution of 2-indolylcarbonyl chloride.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].I[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1.O>C(O)C.O1CCCC1>[C:1]([NH:4][C:5]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C(CCCCc1ccccc1)c1ccc(CCI)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)(NC(C)=O)C(=O)OCC
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
A solution of diethyl 2-acetamidomalonate (30.6 g), sodium ethoxide (7.6 g) and molecular sieves 3A (5.5 g) in ethanol (80 ml) was stirred at room temperature for 20 hours. A solution of 1-[4-(2-iodoethyl)phenyl]-5-phenylpentan-1-one (18.4 g) in tetrahydrofuran (60 ml) was added thereto over 10 minutes and the mixture was refluxed under heating for 15 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (40 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=2:1) to give diethyl 2-acetamido-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}malonate (13.8 g) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18]O)[C:6]=2[CH:20]=1.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18][Cl:23])[C:6]=2[CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCn1c(C2CCCCC2)nc2ccc(Cl)cc21
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCCn1c(C2CCCCC2)nc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
To a stirred mixture of 50 parts of 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol in 375 parts of trichloromethane are added dropwise 60 parts of sulfinyl chloride (exothermic reaction). Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is evaporated and the semi-solid residue is dissolved in hot water. The solution is stirred with activated charcoal. The latter is filtered hot over hyflo and the filtrate is stirred in an ice-bath. The precipitated product is filtered off and dried, yielding 6-chloro-1-(3-chloropropyl)-2-cyclohexyl-1H-benzimidazole hydrochloride; mp. 227.5° C.