Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]12([NH2:32])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>C(O)C>[C:22]12([NH:32][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([C:6]4[C:5]5[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)=[CH:10][CH:11]=3)[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Product: O[C@H](CNC12CC3CC(CC(C3)C1)C2)COc1ccc(-c2noc3cc(F)ccc23)cc1
Yield: 88.4 %

Procedure:
Combine (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (29) (250 mg, 0.86 mmol), 1-adamantanamine (530 mg, 3.50 mmol), ethanol (4.0 ml) and heat (˜80° C.) for 16 hours. Cool reaction to room temperature and concentrate (in vacuo). Purify the compound by column chromatography (silica) eluting with 28% aqueous ammonia/ethanol/chloroform (1:19:180) to obtain a white solid. Dry (50° C. at 0.5 mm Hg) to give 332 mg (86% yield) of the title compound. Purity by LC/MS=92%, [M+H]+=437.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].OC[C:9]1([OH:20])[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH2:10]1>O1CCOCC1.O>[O:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH:14]=[CH:15][C:9](=[O:20])[CH2:10]1
Reactant: OCC1(O)C=Cc2ccccc2OC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1C=Cc2ccccc2OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
4×28.5 mg (0.55 mmol) of sodium periodate are added in four equal portions over 30 minutes to 106 mg (0.55 mmol) of 3-(hydroxymethyl)-2,3-dihydro-1-benzoxepin-3-ol, prepared according to example 24, in solution in 3 ml of a 3/7 dioxane/water mixture. After stirring at ambient temperature for 2 hours, the medium is filtered through celite and the solid is discarded. After the usual extracting and washing treatments, purification by chromatography on silica gel (dichloromethane) provides 61 mg (70%) of 1-benzoxepin-3(2H)-one; 1H NMR (300 MHz, CDCl3): 7.45–7.35 (m, 2H), 7.15–7.25 (m, 3H), 6.38 (d, J=8.7 Hz, 1H), 4.55 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH:17]=[CH:16]1>C1(C)C=CC=CC=1>[C:8]1([S:14][CH:17]2[CH2:16][C:15](=[O:21])[O:20][C:18]2=[O:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Sc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CC(Sc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.5 %

Procedure:
Triethylamine (0.8 ml) was added dropwise to a solution of benzenethiol (9.3 ml, 91 mmol) and maleic anhydride (8.9 g, 91 mmol) in toluene (125 ml). After stirring at room temperature for 12 hr the solvent was evaporated to leave 20 g of crude 3-phenylsulfanyl-dihydro-furan-2,5-dione as a brown oil. 1H NMR (CDCl3) δ 7.20-7.70 (5H, m), 4.20 (1H, dd), 3.40 (1H, dd), 2.90 (1H, dd).
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([OH:20])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH2:3])=[O:20]
Reactant: O=C(O)c1ccccn1
Reactant: CCN(CC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1ccccn1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 481.7 %

Procedure:
Diethylaniline (0.27 μL, 1.7 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (0.8 mg, 1.5 μmol, 1 equiv) in THF (0.15 mL) at 0° C. under an argon atmosphere and the solution was stirred for 10 min. Picolinic acid (0.24 mg, 2.0 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 mg, 2.0 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.25 mg, 1.8 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 17 h 45 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a yellow oil, which was purified by flash column chromatography (70% ethyl acetate-hexanes) to give the pyridine-2-carboxylic acid amide derivative (1.0 mg, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: CC(C)(C)c1cc(NC(=O)c2cc(Cl)ccc2O)cc(C(C)(C)C)c1
Yield: 34.1 %

Procedure:
Using 5-chlorosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]=[O:25])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH2:24][OH:25])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 3-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (40 mg, 0.119 mmol) in DCM (1 mL) at −78° C. under N2 was added 1M DIBAL-H in DCM (0.178 ml, 0.178 mmol). The reaction mixture was stirred at −78° C. for 2 h and then added CELITE® (250 mg). The reaction was quenched with sat′d aqueous NH4Cl (0.5 mL) at −78° C. and then stirred at rt for 30 min. MgSO4 (200 mg) was added and the mixture was stirred at rt for 1 h. The mixture was filtered. The solid was washed with DCM. The combined filtrates were concentrated in vacuo to afford the title compound (40 mg, 99% yield) as an oil. LCMS, [M+NH4]+=356.2.
Reaction SMILES: CC([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[C:15](=[O:17])[O-:16])(C)C.[CH:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[CH2:7]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:6]1[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:26]=[O:27])[CH:33]=2)=[CH:21][CH:20]=1)[C:15](=[O:17])[O:16][C:8]([CH3:13])([CH3:9])[CH3:7]
Reactant: CC(C)(C)C1c2ccccc2CC1N(Cc1ccc(Br)cc1)C(=O)[O-]
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2cccc(C=O)c2)cc1)C1Cc2ccccc2C1

Procedure:
The title compound was prepared from 1,1-dimethylethyl[(4-bromophenyl)methyl]2,3-dihydro-1H-inden-2-ylcarbamate (Example V-13) and 3-formylphenylboronic acid according to the procedure described in Example VI-16 Step 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9H), 3.00 (d, J=8.56 Hz, 4H), 4.51 (br. s., 2H), 7.06-7.19 (m, 4H), 7.34 (d, J=8.03 Hz, 2H), 7.69 (t, J=7.67 Hz, 1H), 7.72-7.77 (m, 2H), 7.86-7.91 (m, 1H), 8.01-8.06 (m, 1H), 8.19-8.24 (m, 1H), 10.10 (s, 1H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH:16]1[CH:21]=[N:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1([C:36]([N:38]2[CH2:42][CH2:41][C:40](=O)[CH2:39]2)=[O:37])[CH2:35][CH2:34]1.Cl>CCCCCC.C1COCC1>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1([C:36]([N:38]2[CH2:39][CH2:40][C:41]3([C:17]4[CH:16]=[CH:21][N:20]=[CH:19][C:18]=4[C:22](=[O:24])[O:23]3)[CH2:42]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3Cl)CC2)C1
Reactant: O=C(O)c1cccnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(Cl)cc4Cl)CC3)C2)c2ccncc21
Temperature: -55 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethyl-piperidine, (1.18 mL, 0.00700 mol) in tetrahydrofuran (30 mL, 0.4 mol) at −78° C. was added n-butyllithium in hexane (2.5 M, 3.7 mL). After stirring for 15 min., a suspension of niacin (0.287 g, 0.00233 mol) in THF was added and the mixture was stirred at −78° C. for 10 min. The reaction mixture was then warmed to −55° C. for 60 min. A solution of 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (580 mg, 0.0019 mol) in THF (2 mL) was added to the above mixture and stirring was continued at −55 degrees celsius for 20 min. The reaction mixture was then allowed to warm to rt for 1 h and then acidified (pH ˜1) using 6M HCl aq. solution. The reaction mixture was stirred at rt overnight and then neutralized (pH ˜7). The product from the mixture was extracted with AcOEt. The organic extract was washed with brine, dried with MgSO4, and concentrated in-vacuo. The crude product was purified by Combiflash followed by separation of the enantiomers using a chiral column. LCMS: m/z 402.0 & 404.0 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[N:2].[ClH:16]>O1CCOCC1>[ClH:16].[NH:5]1[CH2:6][CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C#N)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1CCCNC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with tert-butyl 3-cyanopiperidine-1-carboxylate (5.8 g, 27.07 mmol, 1.00 equiv, 98%) in 1,4-dioxane (60 mL). The mixture was cooled down to at 0° C. and treated with HCl (g). The mixture was stirred for 2 hours at 0° C. resulting in a precipitate that was collected by filtration to afford piperidine-3-carbonitrile hydrochloride as white solid (1.9 g, 48%).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[I:25]I.Cl>CCCCCC.C1COCC1>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([F:19])[C:15]([I:25])=[C:16]([F:18])[CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: II
Reactant: CCCCCC1CCC(c2cc(F)cc(F)c2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC1CCC(c2cc(F)c(I)c(F)c2)CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of (4-pentyl-cyclohexyl)-3,5-difluorobenzene (10 mmol) and 150 ml of THF, was added dropwise 7.5 ml of a solution of n-butyl lithium (corresponding to 12 mmol) in hexane while keeping them at a temperature lower than −70° C., and stirred at the same temperature for 30 min. While keeping the solution at a temperature lower than −70° C., iodine (30 mmol) was added thereto. Then, the solution was stirred for 1.5 hours, temperature of the solution was gradually backed up to room temperature, and then the solution was stirred for 2 hours. After 12 ml of 1N hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted once with toluene and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: heptane) to give a (4-pentyl-cyclohexyl)-3,5-difluoro-4-iodobenzene (8.3 mmol).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCC(N)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminobutanoate hydrochloride 56 (25 g, 0.163 mol) was suspended in CH2Cl2 (100 mL) and triethylamine (50 mL) and 4-chlorobenzenesulfonyl chloride (37.8 g, 1.1 eq) were added to the mixture. The mixture was stirred at room temperature overnight. Diluted with 200 mL of CH2Cl2 and washed with water (3×50 mL), sat. NaHCO3 (2×50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by rotary evaporation to give the product 57 as a yellow oil. LCMS 292.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]([CH2:28][C:29]2[CH:36]=[CH:35][CH:34]=[C:31]([CH3:32])[CH:30]=2)([C:3]([O:2][CH3:1])=[O:17])[CH2:5][CH2:6]1)=[O:11])([CH3:14])([CH3:16])[CH3:15]
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of methyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (5.0 g, 20.5 mmol; Example 3, Step B) in anhydrous THF (70 mL), a solution of sodium bis(trimethylsilyl)amide (20.5 mL, 1M, 20.5 mmol) was added over a period of 30 min. The resultant mixture was stirred at −78° C. for 1 h., and 3-methylbenzyl bromide (2.77 mL, 20.5 mmol) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>C(#N)C>[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:50])=[O:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccn3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 733 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0728 g, 0.158 mmol) was dissolved in acetonitrile (2.0 mL), and the solution was treated with triethylamine (0.0660 mL, 0.473 mmol) and 2-pyridinesulfonyl chloride (0.0680 g, 0.315 mmol) to obtain 4-(2-pyridinesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.698 g, yield 73%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH2:14]1[CH:18]2[CH2:19][CH:20]([NH2:21])[CH:16]([CH2:17]2)[CH2:15]1>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C@H:16]12[CH2:17][C@H:18]([CH2:14][CH2:15]1)[CH2:19][C@H:20]2[NH:21][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4]
Reactant: NC1CC2CCC1C2
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CN[C@@H]1C[C@H]2CC[C@@H]1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.152 mmol) in acetonitrile (1 mL) at room temperature was added exo-2-aminonorborane (0.036 mL, 0.305 mmol) and a catalytic amount of tetrabutylammonium iodide. The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (CI) m/z 271 (M+1)+; 1H NMR (300 MHz, MeOH-d4): δ ppm 4.7-4.8 (m, 2H), 3.61-3.8 (m, 2H), 3.2-3.3 (m, 1H), 3.02-3.11 (1H, s), 2.62-2.72 (m, 1H), 2.37-2.44 (m, 3H), 2.2-2.3 (br s, 2H), 1.0-1.7 (m, 8H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.B.[Na].Cl.[CH2:12](O)[CH3:13]>>[CH:12]1([CH2:13][NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:6][CH2:7][CH2:8][CH2:3][CH2:2]1
Reactant: CCO
Reactant: NCc1cccnc1
Agent: B
Agent: Cl
Agent: [Na]
Product: c1cncc(CNCC2CCCCC2)c1

Procedure:
To 100 ml of ethanol were added 7.0 g of cyclooctylaldehyde and 5.4 g of 3-aminomethylpyridine, and the mixture was subjected to a reaction for 4 hours at about 50° C. After cooling, 2.0 g of sodium boron hydride was added while 20° C. or below was kept by ice cooling, and the mixture was subjected to a reaction for 1 hour at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and concentrated to dryness. To the residue was added an aqueous potassium carbonate solution to make the residue alkaline. The mixture was extracted with chloroform. The extract was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was subjected to distillation under reduced pressure to obtain 6.4 g of N-(cyclohexylmethyl)-N-(3-pyridylmethyl)amine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([NH:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[N:3]=1.[NH2:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:43]([O:42][C:41]([NH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]1[NH:33][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([NH:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[N:3]=1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(Cl)nc1Nc1cccc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of ethyl 2-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)-6-(m-tolylamino)pyrimidine-5-carboxylate (96.3 mg, 0.214 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (58.14 mg, 0.271 mmol) and Et3N (0.030 mL, 0.214 mmol) in DMA (2 mL) was stirred at 80° C. for 3 h. Saturated aq NaHCO3 was added to the mixture, which was extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=3/1) to give the title compound as a yellow oil (123.8 mg, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 1.12-1.71 (m, 20H), 2.33 (s, 3H), 3.39-3.57 (m, 1H), 3.84-3.99 (m, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.55-4.79 (m, 1H), 5.16 (s, 2H), 5.41 (br s, 1H), 6.87-6.89 (m, 1H), 7.16-7.49 (m, 3H), 7.74-7.75 (m, 2H), 7.90-7.91 (m, 2H), 10.68-10.81 (m, 1H). [M+H] calc'd for C34H41N6O6, 629; found, 629.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][NH:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:12][N:13]2[CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH2:22][CH3:23])=[CH:8][C:7]=1[I:30].C1COCC1.[Li+].[OH-]>CO>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:24]([OH:26])=[O:25])=[CH:12][N:13]2[CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH2:22][CH3:23])=[CH:8][C:7]=1[I:30]
Reactant: CCOC(=O)c1cn(C[C@@H]2CCCN2CC)c2nc(NCCN(C)C)c(I)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN1CCC[C@H]1Cn1cc(C(=O)O)c(=O)c2cc(I)c(NCCN(C)C)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-ethyl 7-(2-(dimethylamino)ethylamino)-1-((1-ethylpyrrolidin-2-yl)methyl)-6-iodo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 40) was then taken up in methanol (2 mL) and THF (5 mL) and 1 ml of 2N LiOH was added and stirred at room temperature for 30 min. The solvent was removed in vacuo to give (S)-7-(2-(dimethylamino)ethylamino)-1-((1-ethylpyrrolidin-2-yl)methyl)-6-iodo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a light brown solid, material, which will be carried forward without further purification.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:19]2[C:10](=[NH+:11][CH:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[CH:9]=[CH:8][CH:7]=1.[C:20]1([C:26]([CH3:31])=[CH:27][C:28](=O)[CH3:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:29][C:28]1[N+:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:19]=3[C:18]3[C:13]([C:12]=2[CH:31]=[C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: c1ccc2c(c1)c[nH+]c1ccccc12
Reactant: CC(=O)C=C(C)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: Cc1cc(-c2ccccc2)cc2c3ccccc3c3ccccc3[n+]12

Procedure:
Phenanthridinium perchlorate (2 g) and 4-phenylpent-3-ene-2-one (4 g) were heated together at 150° for 16 hours. The reaction mixture was cooled and diluted with methanol. The product was isolated by filtration and recrystallized from acetonitrile. Yield 1.5 g, m.p. 252°-3°.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[CH3:20]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: CI
Reactant: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)CCN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 5 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
10-chloro-2-cyclohexyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 267; 5.87 g, 20.91 mmol) was suspended in DMA (450 mL) under nitrogen. Methyl iodide (3.26 g, 23 mmol) was added and the suspension cooled to 5° C. on an ice-water bath. Sodium hydride (60% mineral oil dispersion; 920 mg, 23 mmol) was added in a single portion and the resulting mixture stirred on the ice-water bath for 30 minutes allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and the solvent evaporated. The residue was partitioned between DCM (200 mL) and water (300 mL) and the aqueous phase re-extracted with DCM (100 mL). The combined organic phases were dried (MgSO4) and the evaporated. The residue was taken up in DCM and purified on a silica column eluting with a gradient of 10-50% EtOAc/isohexane over 10 column volumes. Fractions containing product were combined and evaporated to yield the title compound as a cream solid (5.02 g, 81%)