Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (508 mg, 3.6 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (671 mg, 3.6 mmol) in N,N-dimethylformamide (7 mL) was heated at 55° C. for 1.5 hours and then stirred overnight at room temperature. The reaction mixture was poured into water and the suspension was filtered with water washes to provide the title compound after drying.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17](O)=[O:18])=[CH:7]1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:17]([C:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=2)[CH:7]=1)=[O:18]
Reactant: O=C(O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(3-Chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 2.21 g (22.6 mmol) of N,O-dimethylhydroxylamine hydrochloride, 14.3 mL (10.4 g, 103 mmol) of triethylamine and 14.6 mL (15.6 g, 24.5 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 100 mL acetonitrile to give 3.10 g of the product as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.[Br:14]Br.Cl.Cl[Sn]Cl>O.C(O)(=O)C>[Br:14][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=2
Reactant: N#Cc1cccc2ccc(O)cc12
Reactant: BrBr
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(Br)cc2ccc(O)cc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 38.4 %

Procedure:
To a mixture of 7-hydroxy-1-naphthonitrile (26.03 g, 154.0 mmol) and glacial acetic acid (400 mL) was added bromine (51.8 g, 323 mmol). The mixture was stirred at 100° C. for 6 hr. HCl (400 mL of 12 N solution) and SnCl2 (69 g, 308 mmol) were added and the mixture was stirred at 100° C. for 1 hour. The resulting solution was cooled to room temperature and poured into water (1 I). The resulting yellow precipitate was collected by filtration, dried under vacuum, and triturated with ethyl acetate to yield 14.68 g (38%) of the title compound as an off-white solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 222–224° C.;1H NMR (DMSO-d6): δ 7.28–7.35 (2H, m), 7.97 (1H, d, J=8.73 Hz), 8.26 (1H, s), 8.47 (1H, s), 10.65 (1H, s); MS (ESI) m/z 246/247 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=O)[CH2:28][C:29](=[O:31])[CH3:30])[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=[S:44])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)CC(=O)NC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Solvent: Cc1ccccc1
Product: CC(=O)CC(=S)NC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21

Procedure:
A solution of the product of Step A (136 mg, 0.26 mmol) and Lawesson's reagent (106 mg, 0.26 mmol) in 5.0 mL of toluene was stirred at 120° C. for 3 h and then concentrated. Chromatography on a Biotage 40+S cartridge using 1:3 v/v EtOAc/hexanes as the eluant afforded the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])[C@@H:9]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)C1C=CC=CC=1.Cl.[H][H]>CN(C)C=O.[Pd]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C@H:9]2[C@@H:10]([C:14]([CH3:22])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[OH:15])[CH2:11][CH2:12][CH2:13][NH:8]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(C[C@H]2[C@@H](C(C)(O)c3ccccc3)CCCN2Cc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H]2NCCC[C@@H]2C(C)(O)c2ccccc2)cc1

Procedure:
A solution of 41.5 g. of cis-1-benzyl-2-(p-methoxybenzyl)-α-methyl-α-phenyl-3-piperidinemethanol in 8.3 ml. of concentrated hydrochloric acid is diluted with dimethylformamide to a volume of 400 ml. and catalytically hydrogenated under 10 atmospheres of hydrogen in the presence of palladium-on-carbon catalyst. The catalyst is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure. The resulting residue is taken up in ethanol and diluted with diethyl ether to yield cis-2-(p-methoxybenzyl)-α-methyl-α-phenyl-3-piperidinemethanol.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:13].Cl.CO>>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: CC(C)(c1ccccc1)N1Cc2c(Cl)c(O)cc(I)c2C1=O
Agent: Cl
Solvent: CO
Product: O=C1NCc2c(Cl)c(O)cc(I)c21
Yield: 57.9 %

Procedure:
In a similar manner to Step 6 of Example 139, 4-chloro-5-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (97.1 mg, 0.206 mmol) was treated with 10% hydrogen chloride-methanol solution (3 mL), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-hydroxy-7-iodoisoindolinone (36.9 mg, yield 58%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]1)[N:17]=2)[C:7](OC)=[O:8])([O-:3])=[O:2].CO.[BH4-].[Li+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)[N:17]=2)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoate (1.10 g, 2.5 mmol) in THF and methanol (0.31 mL, 7.6 mmol) was added lithium borohydride, 2.0 M solution in tetrahydrofuran (1.9 mL, 3.8 mmol). The reaction mixture was stirred at ambient temp, and upon completion the reaction mixture was cooled to 0° C. was quenched with ice and sat'd aq. NH4Cl carefully. The reaction mixture was partitioned between DCM and sat'd aq. NH4Cl and extracted with DCM. The combined organics were purified by silica gel chromatography, EA/hexanes gradient, to give (3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol as an orage solid. MS (ESI) m/z: Calculated: 403.1; Observed: 403.8 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][S:15][CH:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][O:19][C:18]3[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]=4)=[CH:30][C:17]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N-:43]=[N+:44]=[N-:45].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[CH2:32][O:31][C:29]1[CH:28]=[CH:27][C:18]2[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]([S:15][CH2:14][CH2:13][NH:12][S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]4[NH:45][N:44]=[N:43][N:2]=4)=[CH:8][CH:7]=3)(=[O:10])=[O:11])[C:17]=2[CH:30]=1
Reactant: N#Cc1ccc(S(=O)(=O)NCCSC2c3ccccc3COc3ccc(OCc4ccc5ccccc5n4)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(NCCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21)c1ccc(-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
0.89 g of 11-[2-(4-cyanophenylsulfonylamino)ethylthio]-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 34, 0.29 g of sodium azide and 0.24 g of ammonium chloride suspended in 5 ml of dimethylformamide were stirred at 120° C. for 1 hour. The reaction mixture was added to ice water and adjusted to about pH 3 with 1N-hydrochloric acid. Crystals precipitated were collected by filtration, dried and then washed with methylene chloride to obtain 0.69 g of the title compound as slightly yellow powder.
Reaction SMILES: [C:1]([P:6](Cl)[C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu].C1(C)C=CC=CC=1>[C:1]([P:6]([C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)P(Cl)C(C)(C)CC
Reactant: Clc1ccccc1
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(C)(C)P(c1ccccc1)C(C)(C)CC
Reaction time: 3 h
Yield: 95.9 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 20 ml of tetrahydrofuran, 10.4 g (0.050 mol) of di-tert-amylphosphinous chloride and 0.13 g (0.0005 mol (corresponding to 1% by mol)) of copper(II) acetylacetonate were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 6.8 g (0.060 mol) of chlorobenzene and 1.9 g (0.080 mol) of metallic magnesium in 45 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 40° C. to 45° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 3 hours. After the temperature of the reaction solution was returned to room temperature, gas chromatography analysis was carried out, and as a result, di-tert-amylphosphinous chloride was present in trace amounts. Thereafter, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 12.0 g (purity: 94.4%) of the aimed di-tert-amylphenylphosphine as a viscous oily substance. The yield was 90.5%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C(O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1)[CH3:18]
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCC1CN(C)C(=S)c2cccnc2O1

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione and diethylamine in ethanol are heated together to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)=[C:11]([F:13])[CH:12]=1)=[O:5])[CH3:2].C[C:28](C)([O-:30])C.C(OC(=O)CCC)[C@@H]1OC1.CO>O1CCCC1>[F:13][C:11]1[CH:12]=[C:7]([N:6]2[CH2:2][C@H:1]([CH2:28][OH:30])[O:3][C:4]2=[O:5])[CH:8]=[CH:9][C:10]=1[N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15]1
Reactant: CCOC(=O)Nc1ccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)c(F)c1
Reactant: CC(C)(C)[O-]
Agent: CCCC(=O)OC[C@H]1CO1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Reaction time: 0.08 h

Procedure:
5-Ethoxycarbonylamino-2-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene (33.6 g, 0.092 M) was dissolved in dry tetrahydrofuran (300 ml) under nitrogen. cooled to −70°, and treated dropwise over 30 minutes with a solution of lithiun t-butoxide (1 M in tetrahydrofuran, 100.7 ml), keeping the temperature below −65°. After stirring for 5 minutes, (R)-glycidylbutyrate (14.52 g, 0.101 M) was added, and stirring continued at −65° for 1 hour, before allowing the temperature to rise to ambient over 16 hours. The mixture was treated with MeOH (50 ml), stirred at ambient temperature for 1 hour, and the precipitate collected and washed well with tetrahydrofuran to give the desired product (21.8 g).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[CH:1]1([NH:6][C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 21.3 g (0.25 mol) cyclopentylamine in 50 ml tetrahydrofuran was added dropwise at −5 to 0° C. to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 31.4 g (0.19 mol, 78% yield) as a white solid.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.CCCCCC>CCO>[Br:26][C:27]1[CH:28]=[N:29][C:30]([N:9]2[CH2:10][CH2:11][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:8]2)=[N:31][CH:32]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(S(C)(=O)=O)CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1(S(C)(=O)=O)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a solution of ethyl 4-(methylsulfonyl)piperidine-4-carboxylate hydrochloride (0.20 g, 0.74 mmol) in EtOH (7.0 mL) was added DIPEA (0.03 mL, 1.86 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.12 g, 0.62 mmol). The reaction was then heated up to 70° C. for 1 h. After completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 15% EtOAc:hexane to obtain the desired product as a yellow solid (0.108 g, 45% yield). 1H NMR (DMSO-d6): δ 1.20 (t, J=7.20 Hz, 3H), 1.62 (m, 2H), 2.07 (m, 2H), 2.69 (m, 2H), 3.69 (s, 3H), 4.62 (q, J=7.20 Hz, 2H), 4.86 (m, 2H) and 8.46 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Br[CH2:16][CH:17]1[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:16][C@@:2]2([CH3:1])[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:7]2)[CH2:20][CH2:19][CH2:18]1
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Reactant: BrCC1CCC1
Product: C[C@@]1(CC2CCC2)N[C@@H](c2ccccc2)COC1=O

Procedure:
The title compound was prepared from (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) and (bromomethyl)cyclobutane according to the procedure outlined in Preparation 1. The total amount of compound synthesised was 0.445 g.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:35])[N:25]([CH3:34])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:37]>CCOC(C)=O>[ClH:37].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:25]([CH3:34])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:35])=[CH:11][N:10]=1
Reactant: COc1cc2c(CC(=O)N(C)CCc3ccccn3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(CC(=O)N(C)CCc3ccccn3)cnc(CN)c2cc1OC
Yield: 100 %

Procedure:
As described in Example 1, 78 mg of (6,7-dimethoxy-4-{[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-methyl}-isoquinolin-1-ylmethyl)-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 86 mg (>100%) of 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-N-methyl-N-(2-pyridin-2-yl-ethyl)-acetamide hydrochloride. MS: APCI (M+H) calc'd for C22H26N4O3+H 395.5; found 395.1.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([O:7][C:8]2[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Nc1ccccc1OC1CCCCC1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCCCC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To 20 ml of an acetic acid solution containing 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide was added dropwise 1.5 g of 61% nitric acid on heating at 110° C. over a 30-minute period, and then the mixture was stirred for 1 hour. The reaction solution was poured into ice water and neutralized with a dilute aqueous sodium hydroxide solution. The crystals which formed were collected by filtration, washed with water and dried to give 4.5 g of the crude crystals, which were then recrystallized from ethanol-n-hexane to give 3.3 g of N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][CH2:22][N:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][C:25]([OH:27])=[O:26])[CH2:10][CH2:11][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])#[N:2]>C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][CH2:22][N:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:28][C:29]([OH:31])=[O:30])[CH2:10][CH2:11][N:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: N#CCCCCCCN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NCCCCCCCN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Yield: 82.1 %

Procedure:
A solution of [((6-cyanohexyl)imino)bis(ethylenenitrilo)]tetraacetic acid (0.85g, 0.0019 mol) in acetic acid (50 ml) was treated with platinum oxide (0.15g) and hydrogenated at 45 psi overnight. The catalyst was removed by filtration through celite and the filter pad was rinsed with water. The solvent was removed under reduced pressure to yield crude product, which was chromatographed on a Bio Rad AG 1×8 ion exchange resin in the formate form. Elution with water gave pure [((7-aminoheptyl)imino)bis(ethylenenitrilo)]tetraacetic acid (0.70g, 82%). The product was one spot on tlc. The proton and carbon nmr spectra were consistent with the assigned structure.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][CH2:63][C:64](O)=[O:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][CH2:63][C:64]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:65]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: NCC(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (220 mg, 0.57 mmol), DCC (142 mg, 0.69 mmol) and DMAP (7 mg, 0.057 mmol) in ethyl acetate (10 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]glycine (171 mg, 0.57 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (8 mL) and cooled to 0° C. Dimethylamine (8 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 130 mg (56%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[N:20]([CH2:27][C@:28]([OH:32])([CH3:31])[CH2:29][OH:30])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:30][CH2:29][C@@:28]([OH:32])([CH3:31])[CH2:27][N:20]2[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=[C:19]2[Cl:18])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@](O)(COC(=O)Nc1ccc(Cl)cc1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 83 %

Procedure:
A THF solution (15 ml) of 4-chlorophenylisocyanate (1.3 g, 85 mmol) and triethylamine (0.1 ml) were added to a suspension of (R)-2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (1.5 g, 6.5 mmol) in THF (30 ml) followed by stirring at room temperature for 19 hours. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-chlorophenylcarbamate (2.1 g, yield 83%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2].O.NN>C(Cl)Cl.CCO>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([CH2:24][NH2:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CN)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [(S)-5-benzyloxycarbonylamino-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pentyl]-carbamic acid tert-butyl ester (0.63 g, 1.27 mmol) in DCM (5.1 ml) and EtOH (5.1 ml) is treated with hydrazine hydrate (0.318 g, 6.35 mmol) and the reaction mixture is stirred at room temperature overnight. A white precipitate forms which is removed by filtration and washed with DCM (3×10 ml). The filtrate is concentrated in vacuo and redissolved in DCM (15 ml) and MeOH (2 ml). Undissolved material is removed by filtration and the filtrate is concentrated in vacuo. The resulting oily yellow solid is purified by chromatography on silica eluting with 10-50% MeOH in DCM (1% TEA) to afford ((S)-1-Aminomethyl-5-benzyloxycarbonylamino-pentyl)-carbamic acid tert-butyl ester as a clear oil; [M+H]+ 366