Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12>C1COCC1>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:49]3[C:45](=[O:55])[C:46]4[C:47](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:48]3=[O:50])[CH2:12][CH2:13]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 15 °C

Procedure:
40 g (−118 mmol) 2-[2-(4-diphenylmethyl-piperazin-1-yl)-ethoxy]-ethanol, 31.1 g (119 mmol) triphenylphosphine and 17.3 g (118 mmol) phthalimide are suspended in 200 ml THF and 24.2 ml (119 mmol) are azodicarbonic acid diethyl ester are added dropwise under protective atmosphere and light cooling (to Ca. 15° C.). The mixture is stirred without further cooling for three hours and subsequently, the solvent is removed under vacuum. The residue is taken up in 1N HCl and washed twice each with 50 ml acetic acid ethyl ester respectively. The aqueous phase is neutralized with ca. 50 g sodium hydrogen carbonate and extracted four times each with 125 ml chloroform. The combined chloroform phases are dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (99/1 to 90/10): Yield 11 g (19%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36]([C:29]5[C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:26]=[CH:27][CH:28]=5)=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (29.6 mg, 74.6%), MS (ISP) m/z=486.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a stirred solution of 85 mg (0.49 mmol) 2-methyl-isonicotinic acid hydrochloride in 10 ml THF were added 214 mg (0.56 mmol) HATU and 0.16 ml (0.94 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 1 h. 100 mg (0.38 mmol) (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine was then added and stirring continued at room temperature for 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Trituration in ether afforded 95 mg (66%) (±)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-methyl-isonicotinamide as a white solid. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.I[C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1C(O)=O.C(=O)(O)[O-].[K+]>CN(C)C=O.Cl.C(OCC)(=O)C.[Cu]I>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(I)c1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1
Yield: 17.1 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 412 mg, 2 mmol), 3-iodo-methoxy-benzene (264 μL, 2.2 mmol), copper(I) iodide (19 mg, 0.1 mmol), picolinic acid (49 mg, 0.4 mmol), and potassium bicarbonate (280 mg, 2.8 mmol) in N,N-dimethylformamide (10 mL) was irradiated in a microwave oven at 220° C. for 30 min. The reaction mixture was diluted with 0.1 M HCl (200 mL) and then extracted with ethyl acetate (200 mL). The organic layer was washed with 0.1 M HCl, 0.25 M NaOH, and brine, then dried (magnesium sulfate), filtered, evaporated and purified using an ISCO system, eluting with 5-60% ethyl acetate/dichloromethane to give a tan semi-solid. This was dissolved in ethyl acetate (30 mL) and washed with 0.1 M HCl (30 mL), then dried, filtered, evaporated and triturated with petroleum ether to give (4S,7R)-2-(3-methoxy-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (107 mg, 20%) as a white solid. ES(+)-MS (M+H) 313.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].O(CC)[C:14]([S-])=[S:15].[K+].C(O)C>O>[SH:15][C:14]1[O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc2oc(S)nc2c1
Yield: 31.9 %

Procedure:
A mixture of 2-amino-4-trifluoromethylphenol (8.85 g, 0.05 mole), potassium ethyl xanthate (8.8 g, 0.055 mole) and ethanol was heated under gentle reflux for a period of 24 hours. After cooling, the mixture was filtered and the filtrate was distilled under reduced pressure to remove the solvent and to give an orange solid. The solid was dissolved in water, the aqueous solution extracted with ethyl acetate and the organic phase evaporated to give a red wolid. The solid was triturated with boiling petroleum ether (bp 100°-120° C.) and the insoluble material collected by filtration to give the title compound (3.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C=Cc2ccc(C=Cc3ccc(N)cc3)cc2)cc1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
25.9 g of 1,4-bis(4-nitrostyryl)benzene were added to a mixture consisting of 50 g of iron powder, 12 ml of undiluted hydrochloric acid, 50 ml of water and 800 ml of N,N-dimethyl formamide and subjected to 1.5 hours' intense stirring at a temperature in the range of from 90° to 100° C. Thereafter, the pH value was adjusted to be 8 by means of 10% aqueous solution of sodium carbonate while thus heating, and the undissolved matter was filtered. From the resulting filtrate were separated yellow crystals, and these crystals were collected by filtering, washed in water, dried, and thereafter recrystallized from N,N-dimethyl formaldehyde, whereby there were obtained 20.9 g (yield rate: 95.7%) of 1,4-bis(4-aminostyryl)benzene in the form of yellow crystals (melting point: 300° C. or more).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[O:16][C:17](Br)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2].[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC(O)=O.CC(O)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[O:16][C:17]([C:27]3[CH:28]=[CH:29][C:24]([N:23]([CH3:33])[CH3:22])=[CH:25][CH:26]=3)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(N(C)C)cc3)o2)c1
Temperature: 70 °C
Yield: 74 %

Procedure:
To a previously degassed mixture of (3-[(5-bromo-furan-2-carbonyl)-amino]-phenyl)-acetic acid ethyl ester (11) (0.4 g), 4-(dimethylamino)phenylboronic acid (0.23 g), potassium carbonate (0.39 g) and tetra-n-butylammonium bromide (0.37 g) in water (2 ml) was added palladium II acetate (circa 10 mg). The mixture was heated to 70° C. for an hour, cooled and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulphate and evaporated in vacuo. Compound 13 (0.33 g) was obtained following silica gel column chromatography of the residue in 2:3 ethyl acetate:petroleum ether.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>CCOC(C)=O>[ClH:26].[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCC1CCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (10.2 g, 29.3 mmol) in EtOAc (100 mL) was cooled on an ice-bath and 4 M hydrogen chloride in EtOAc (100 mL) was added. The mixture was stirred at ambient temperature for 1 hr and concentrated. The residue was suspended in hexane (30 mL) and the mixture was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, and dried under reduced pressure to give piperidin-4-ylmethyl-carbamic acid benzyl ester hydrochloride (7.24 g, 87%) as a white solid.
Reaction SMILES: [C:1]1(S([O-])(=O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[K+].[NH2-:16].[Na+].N>>[C:1]1([NH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [NH2-]
Reactant: O=S(=O)([O-])c1cccc2ccccc12
Agent: N
Agent: [K+]
Agent: [Na+]
Product: Nc1cccc2ccccc12
Yield: 86.8 %

Procedure:
In a 200-ml autoclave were placed 28.3 grams (0.115 mole) of anydrous potassium 1-naphthalene sulfonate, 9.7 grams (0.241 mole) of sodium amide and 105 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 110° C for 10 hours. The reaction pressure in the autoclave was 75 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 1-naphthyl amine. Recrystallization from ethanol gave 14.3 grams of 1-naphthyl amine having a melting point of 48° to 49° C. Yield ws 87.0%.
Reaction SMILES: [N:1]([C@H:4]1[C@H:9]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C(OCC)(=O)C>[NH2:1][C@H:4]1[C@H:9]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](N=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A mixture of crude trans-tert-butyl 3-azido-4-(benzyloxycarbonylamino)piperidine-1-carboxylate (12 g, ˜32 mmol) and triphenylphosphine (41.9 g, 160 mmol) in THF (100 mL) and water (5 mL) was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (500 mL). The organic layer was washed with brine (50 mL) and directly evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1˜1:1) to afford trans-tert-butyl 3-amino-4-(benzyloxycarbonylamino)piperidine-1-carboxylate (5.0 g, 44%) as a yellow oil. MS (ES+) C18H27N3O4 requires: 349, found: 350 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[NH:33]1[C:34]2[C:30](=[C:29]([CH2:28][NH:27][C:26]([C:19]3[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:39])=[O:2])=[O:16])=[C:21]([C:22]([F:23])([F:25])[F:24])[CH:20]=3)=[O:38])[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-({5-[(1H-Indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (170 mg, 0.29 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (120 mg, 2.94 mmol) in water (8 mL). The mixture was then stirred at room temperature overnight. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 0.1089 g (67%). MS m/e 564.9 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]2[N:17]=[C:16]3[N:18]([CH3:27])[C:19](=[O:26])[N:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]3=[CH:14][CH:13]=2)[CH:5]=1)[CH3:3].[CH:28]([S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31])=[CH2:29]>C(O)C>[CH3:24][C:22]([CH3:23])([CH3:25])[CH2:21][N:20]1[C:15]2[C:16](=[N:17][C:12]([C:6]3[CH:5]=[C:4]([C@H:2]([N:1]4[CH2:34][CH2:33][S:30](=[O:32])(=[O:31])[CH2:28][CH2:29]4)[CH3:3])[CH:11]=[CH:10][C:7]=3[C:8]#[N:9])=[CH:13][CH:14]=2)[N:18]([CH3:27])[C:19]1=[O:26]
Reactant: C=CS(=O)(=O)C=C
Reactant: C[C@@H](N)c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Solvent: CCO
Product: C[C@H](c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1)N1CCS(=O)(=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 38-4 (20 mg, 0.055 mmol) in ethanol (0.3 mL) at room temperature was added (ethenylsulfonyl)ethene (0.011 mL, 13 mg, 0.11 mmol). After 1 hour, the reaction was filtered and purified by reverse phase chromatography (1-100%, 0.1% TFA in H2O/Acetonitrile) to give desired product. MS (M+H)+: observed=482.2212, calculated=482.2220.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]4[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=4)[CH2:9][C@@H:4]3[CH2:3]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(CO[C@@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
A solution of 0.75 g (3.15 mmol) of (7R,8aS)-7-hydroxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6) and 0.79 mL (6.3 mmol) of 4-fluorobenzyl bromide in 30 mL of dry DMF was treated with 0.15 g (3.8 mmol) of sodium hydride (60% oil dispersion), and the mixture was heated at 100° C. for 18 h. The mixture was cool, diluted with water, and extracted with diethyl ether (5×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatograph with 50:50 ethyl acetate:hexane gave 0.090 g (8%) of the title compound. mp (.HCl) 74°-79° C. 13C NMR (base, CDCl3): δ 35.6, 43.9, 48.9, 51.2, 60.4, 60.7, 70.7, 76.7, 115.1, 115.4, 129.35, 129.46, 133.9, 144.9, 145.2, 149.9, 153.2, 158.9, 164.0. HRMS calcd for C18H20F2N4O (MH+): 347.1683, found: 347.1671.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]([CH3:26])[CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32](Cl)[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]([CH3:26])[CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N(C)C1CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N(C)C2CN(C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (S)-3-((5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)(methyl)amino)azetidine-1-carboxylate (27.4 mg, 0.060 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (17.20 mg, 0.102 mmol) in DMSO (2 mL) was added triethylamine (0.046 mL, 0.330 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 5 hours. The solvent was removed with a stream of nitrogen. The crude title compound was used without further purification. ESI-MS m/z [M+H]+ calc'd for C25H33N9O2, 492. found 492.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([N+:15]([O-])=O)=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:3]=1>C1(C)C=CC=CC=1.[Pt]>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]([NH2:15])=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:3]=1
Reactant: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(NCCOCCCc2cccnc2)c(N)c(Oc2ccccc2)n1
Reaction time: 6 h
Yield: 98.1 %

Procedure:
Under a nitrogen purge, 5% platinum on carbon (2.0 g), toluene (5 mL), and 2-propanol (5 mL) were added to a Parr vessel. A solution of (6-methyl-3-nitro-2-phenoxypyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine (5.71 g, 14.0 mmol) in toluene (45 mL) was then added. The vessel was placed under hydrogen pressure (49 psi, 3.4×105 Pa) for three hours. An analysis by liquid chromatography/mass spectrometry indicated the presence of starting material, and additional 5% platinum on carbon (0.1 g) was added. The reaction was continued for an additional 6 hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to yield 5.2 g of 6-methyl-2-phenoxy-N4-{2-[3-(pyridin-3-yl)propoxy]ethyl}pyridine-3,4-diamine as a dark oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:13][CH:14]([C:21]#[N:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:13])[C:21]#[N:22])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C#N)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C#N)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
This compound is synthesized according to Makosza, et al with some modifications (Makosza, M., et al, Tetrahedron (1974), 30: 3723). A solution of 4-chloronitrobenzene (31.5 g, 0.2 mol) in pyridine (100 mL) is added dropwise to a vigorously stirred suspension of KOH (fine powder 70.0 g) and α-methylbenzylcyanide (26.2 g, 0.2 mol) in pyridine (150 mL), with the reaction temperature being maintained at 10° C. The reaction mixture is stirred for 24 hours at 25° C., and poured onto an excess of HCl-ice mixture. The acidic aqueous mixture is extracted with benzene, the organic phase washed with brine, dried (Na), and the benzene evaporated under vacuum. A crude product 42.5 g (84 wt %) results and is recrystallized from isopropanolpetroleum ether to give Compound 7 as white crystals,
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:25])[CH:10]([C:26]2[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](=[O:37])[NH:35][OH:36])=[CH:28][CH:27]=2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[OH:36][NH:35][C:34](=[O:37])/[CH:33]=[CH:32]/[C:29]1[CH:28]=[CH:27][C:26]([CH:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:25])=[CH:31][CH:30]=1
Reactant: Cc1[nH]c2ccccc2c1CCN1CCN(C(=O)OC(C)(C)C)CC1c1ccc(/C=C/C(=O)NO)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1[nH]c2ccccc2c1CCN1CCNCC1c1ccc(/C=C/C(=O)NO)cc1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
A solution of 3-[4-((E)-2-hydroxycarbamoyl-vinyl)-phenyl]-4-[2-(2-methyl-1H-indol-3-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (55.8 mg, 0.111 mmol) in dioxane (5 mL) was treated with a solution of hydrochloric acid in dioxane (0.03 mL, 4 M) and the resulting mixture was stirred at room temperature. A brown precipitate was collected and dissolved in water. The aqueous solution was washed with diethyl ether and concentrated to give (E)-N-hydroxy-3-(4-{1-[2-(2-methyl-1H-indol-3-yl)-ethyl]-piperazin-2-yl}-phenyl)-acrylamide (89, 49 mg, 99% yield). LCMS (m/z): 405.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[OH-].[K+]>C(O)COCCO>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=1[NH2:1]
Reactant: NN=C(c1cc(Cl)ccc1N)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(Cl)cc1Cc1ccccc1Cl

Procedure:
In the manner given in Preparation 11, 2-amino-2',5-dichlorobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-(o-chlorobenzyl)-4-chloroaniline, boiling point 140°-148° (0.15 mm Hg), melting point 64°-65° C.