Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:23])=[O:22].[CH2:24]([N:27]=[C:28]=[S:29])[CH:25]=[CH2:26]>CN(C=O)C.[Cl-].[Na+].O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:7]1[N:8]([CH3:9])[C:4]2[C:3]([C:21]([NH2:23])=[O:22])=[C:2]([NH:1][C:28]([NH:27][CH2:24][CH:25]=[CH2:26])=[S:29])[CH:20]=[CH:19][C:5]=2[N:6]=1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Reactant: C=CCN=C=S
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNC(=S)Nc1ccc2nc(Nc3c(Cl)cccc3Cl)n(C)c2c1C(N)=O
Temperature: 45 °C
Yield: 51.4 %

Procedure:
A mixture of 100 mg (0.286 mmol) of 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylic acid amide (Example 7) and 114 mg (1.15 mmol) of allyl isothiocyanate in DMF was warmed at 45° C. for 48 h. The reaction was diluted with 30 mL of brine and extracted with four 15 mL portions of EtOAc. The combined organic layers were washed with five 15 mL portions of brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel (MeOH-methylene chloride, first 2:98, then 4:96, then 5:95) to afford 66 mg (51%) of 2-(2,6-dichlorophenylamino)-3-methyl-5-(3-allyl-thioureido)-3H-benzimidazole-4-carboxylic acid amide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:8]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]3=[O:23])=[N:9][C:5]=2[CH:4]=1.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[CH:20]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:10][C:8]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]3[CH:29]=[CH:30][C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])=[CH:4][C:5]=3[N:9]=2)[C:12]1=[O:23])([CH3:21])[CH3:22]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CN)ccc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
To a solution of 1-[5-aminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (20 mg, 0.05 mmol) and TEA (10 mg, 0.10 mmol) in THF (2 ml) was added acetyl chloride (5 mg, 0.06 mmol) at room temperature and the reaction mixture was stirred for 12 h. After evaporation, the residue was purified by prep-HPLC (gradient 10%-100% B) to afford 18 mg (80%) of N-[2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-acetamide as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]=[C:24]=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:15][C:24]([NH:23][CH3:22])=[O:25])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(N)=O)cc1Cl
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 100 °C
Yield: 41.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (160 mg, 0.49 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.12 mL, 1.94 mmol). The reaction mixture was then heated at 100° C. for 16 h. At this time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded 1-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (79 mg, 42%) as a white foam: [α]23589=−8.9° (c=0.09, chloroform); FAB-HRMS m/e calcd for C17H23ClN2O4S (M+H)+387.1145, found 387.1142.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:46])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:46])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(CCO)CC4)cc3)cc12
Yield: 2.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)ethanol (200 mg, 0.259 mmol) was hydrolyzed by lithium hydroxide (108 mg, 2.59 mmol), THF/Methanol/water (5/5/2.5 ml) to yield 3 mg (2.2% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.34 (s, 1H), 7.75-7.74 (d, 1H), 7.44-7.41 (m, 2H), 7.28-7.27 (m, 2H), 7.00-6.7 (m, 4H), 6.52-6.51 (d, 1H), 5.26 (s, 2H), 3.73-3.69 (t, 2H), 3.26 (m, 4H), 2.91 (m, 4H), 2.79-2.77 (t, 2H), 2.12-2.08 (m, 6H). MS: m/z=525.2 (M+1), HPLC: 80.69% in method A.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[N:27][CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)NC(C)C)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc(NC(=O)NC(C)C)nc2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
A stirred solution of 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-isopropylurea (0.104 g, 0.168 mmol) in TFA (2 mL) was treated with trifluoromethanesulfonic acid (TCI) (0.02 mL, 0.2 mmol) and the reaction mixture was stirred at 70° C. for 2 h, then 80° C. for 2 h. TFA (2 mL) and trifluoromethanesulfonic acid (0.05 mL) were added. The heating was resumed at 75° C. for another 2 h. The mixture was cooled to rt, and some of the TFA was removed in vacuo. Sat'd NaHCO3 was added slowly until effervescence was no longer observed. The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give 1-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-isopropylurea (0.0312 g, 49% yield) as a yellow powder. 1H NMR (300 MHz, d6-DMSO) δ 11.77 (s, 1H); 8.92 (s, 1H); 8.77 (d, J=7.75 Hz, 1H); 8.65 (br. s., 1H); 8.31 (br. s., 1H); 8.10 (br. s., 1H); 7.85 (br. s., 2H); 7.71 (br. s., 1H); 7.38 (d, J=8.92 Hz, 1H); 6.80-6.99 (m, 1H); 3.77-3.91 (m, 1H); 2.43 (s, 3H); 1.15 (d, J=6.28 Hz, 6H). m/z (ESI, +ve ion) 380.1 (M+H)+.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[N:9](/[C:12](=[CH:17]\[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)/[C:13]([O:15][CH3:16])=[O:14])=[N+]=[N-]>>[NH:9]1[C:19]2[C:18](=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][NH:23]3)[CH:17]=[C:12]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)/C(=C/c1ccc2[nH]ccc2c1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2ccc3[nH]ccc3c2[nH]1
Yield: 62 %

Procedure:
To a boiling solution of 36 ml of xylene 1.09 g (4.5 mmol) of methyl (Z)-2-azido-3-(1H-indole-5-yl)acrylate is added in small portions. The reaction mixture is refluxed till the end of the nitrogen gas formation, then concentrated and the residue is crystallized with hexane, the product is filtered and washed with hexane to yield 0.6 g (62%) of the title compound. Mp.: 183-184° C. (hexane).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].Cl.CO[C:10](=[NH:12])[NH2:11]>>[O:5]=[C:4]([CH2:3][N:1]([C:10](=[NH:11])[NH2:12])[CH3:2])[OH:6]
Reactant: CNCC(=O)O
Reactant: COC(=N)N
Agent: Cl
Product: CN(CC(=O)O)C(=N)N

Procedure:
The reaction of sarcosine with O-methylisourea hydrochloride, described by E. Schutte in Hoppe-Seylers Z. Physiol. Chemie 279 (1943) 52-59, affords creatine in a yield of only 21%.
Reaction SMILES: Br[CH2:2][CH:3]([OH:19])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH:3]([OH:19])[CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CN1CCN(c2ccc(F)cc2)CC1
Temperature: 20 °C
Yield: 46.9 %

Procedure:
2-(3-Bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (26.8 g), triethylamine (11 cc) and 4-(4-fluorophenyl)piperazine (14.1 g) in toluene (280 cc) are heated at boiling point for 8 hours. The mixture is then cooled to a temperature of about 20° C. and stirring is maintained for 15 hours at this temperature. The precipitate formed is separated by filtration and washed with toluene (2×50 cc). The filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by chromatography on a silica column, with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (120 cc). 2-{3-[4-(4-Fluorophenyl)-1-piperazinyl]-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (16.2 g) is obtained, m.p. 130° C.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]>C1COCC1>[CH2:3]([O:7][C:8]1[C:13]([CH:14]([CH3:1])[OH:15])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Reactant: [Li]C
Solvent: C1CCOC1
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C(C)O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
Methyl lithium (0.67 ml, 1.5M in diethyl ether, 1.02 mMol) was added by syringe to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carboxaldehyde [Example 30](0.38 g, 0.88 mMol) in 50 mL THF cooled to -75° C. The cold bath was removed and the reaction mixture was allowed to come to room temperature. Acetic acid (10%, 5 ml) was added. After stirring for 30 minutes, the layers were separated. The organic layer was washed with 50 ml water, dried over sodium sulfate, filtered and concentrated to an oil. The titled material was purified by silica gel chromatography and recrystallized from ethyl acetate-hexane. Anal. Calc'd. C24H26NO4SF; C, 64.99; H, 5.91; N, 3.16. Found: C, 64.96; H, 6.07; N, 3.07.
Reaction SMILES: [NH2:1][N:2]([CH:10]([CH3:12])[CH3:11])C(=O)OC(C)(C)C.O/[CH:14]=[C:15]1\[C:16](=O)[C:17]2[C:22]([O:23][C:24]3\1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:26][CH2:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2.C(O)(C(F)(F)F)=O>ClCCl>[CH:10]([N:2]1[C:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[O:23][C:24]3([CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH2:25]3)[C:15]=2[CH:14]=[N:1]1)([CH3:12])[CH3:11]
Reactant: O=C1/C(=C\O)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Reactant: CC(C)N(N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of tert-butyl N-amino-N-isopropyl-carbamate (530.4 mg, 3.0 mmol), (Z)-benzyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (1.10 g, 2.9 mmol) and TFA (223.4 μL, 2.9 mmol) in dichloromethane (10 mL) was stirred 2 h. The reaction was concentrated to ⅓ volume, then TFA (˜1.5 mL) was added. The mixture was stirred for 30 min, then concentrated, neutralized with excess Et3N, re-concentrated, and purified by column chromatography (0-60% EtOAc/hexanes) to give benzyl 1-isopropyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.1 g, 91%) as a pale yellow oil. ESI-MS m/z calc. 417.2, found 418.3 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].F[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: O=Cc1ccc(O)c(F)c1
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)c2ccccc12

Procedure:
4-(2-Fluoro-4-formyl-phenoxy)-naphthalene-1-carbonitrile was prepared from 3-Fluoro-4-hydroxybenzaldehyde and 4-Fluoro-naphthalene-1-carbonitrile following General Procedure A. 1H NMR (400 MHz, CDCl3) δ 9.99 (d, J=1.95 Hz, 1H), 8.38 (d, J=8.6 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.77-7.84 (3H), 7.69-7.74 (2H), 7.29 (d, J=7.43 Hz, 1H), 6.83 (d, J=7.83 Hz, 1H).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH:51]([N:58]([CH3:60])[CH3:59])[C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH3:59][N:58]([CH3:60])[CH:51]([C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)[CH2:50][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)C(CN)c1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCC(c3cccnc3)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and (2-Amino-1-(3-pyridyl)ethyl)dimethylamine (0.055 g, 0.334 mmol). The mixture was stirred at rt for 2 h then sodium triacetoxyborohydride (0.177 g, 0.835 mmol) was added and it was stirred at rt for three days. The mixture was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step with no additional purification. LCMS: m/e 748.3 (M+H)+, 3.47 min (method 6).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(Cl)Cl>C(N(CC)CC)C>[CH3:9][S:10]([O:8][CH:4]([CH:5]([CH3:7])[CH3:6])[CH:2]([CH3:3])[CH3:1])(=[O:12])=[O:11]
Reactant: CC(C)C(O)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(OS(C)(=O)=O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a four-neck flask having an inner volume of 100 ml, 5.81 g (50 m.mols) of 2,4-dimethyl-3-pentanol, 6.30 g (55 m.mols) of methane sulfonyl chloride, and 50 ml of methylene chloride were placed and cooled to 0° C. To the cooled mixture, 7.59 g (75 m.mols) of triethyl amine was added dropwise over a period of one hour with the reaction temperature retained meanwhile. The reactants in the resultant reaction mixture were left reacting at 0° C. for one hour. After the reaction, the reaction mass was thrown into 50 ml of ice water to obtain an organic layer by separation. The organic layer thus obtained was washed with 50 ml of a diluted aqueous hydrochloric acid solution, 50 ml of water, 50 ml of a saturated aqueous sodium hydrogen carbonate solution, and 50 ml of a saturated saline solution. Then, by removing the solvent from the organic layer, 8.94 g (46 m.mols) of (2,4-dimethyl-3-pentyl) methanesulfonate was obtained as the product aimed at.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)O1>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([C:37]2[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][CH:38]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2ccnc3ccccc23)OC1(C)C
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-c3ccnc4ccccc34)nc21

Procedure:
Following General Procedure A for Suzuki coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline were reacted to give 475. LCMS: M+H+=501.3
Reaction SMILES: [OH-].[K+].Br[CH:4]1[CH2:9][N:8]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:7](=[O:14])[N:6]=[C:5]1[NH2:15]>CO>[CH:11]1([CH2:10][N:8]2[CH:9]=[CH:4][C:5]([NH2:15])=[N:6][C:7]2=[O:14])[CH2:12][CH2:13]1
Reactant: NC1=NC(=O)N(CC2CC2)CC1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccn(CC2CC2)c(=O)n1
Reaction time: 8 h

Procedure:
To a solution of 4.55 g. of 85% potassium hydroxide in 93 mml. of methanol cooled to 5°, was added 17.0 g. of 5-bromo-1-cyclopropylmethyl-5,6-dihydrocytosine. The mixture was stirred and allowed to warm spontaneously. When the initial reaction, which had warmed the mixture to 30°, subsided, the mixture was refluxed for 5 minutes and allowed to cool and stand at room temperature overnight. The suspension was evaporated under reduced pressure on a water bath at 86°. The residue was triturated was 300 ml. of water on a steam bath and chilled in ice before filtering. The resulting 1-cyclopropylmethylcytosine was washed with cold water and dried in a vacuum desiccator over potassium hydroxide; yield, 9.50 g., m.p. 264°-266°. A sample for analysis was recrystallized from ethanol; m.p. 265°-267°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:4]=1[C:5]([OH:24])=[C:6]([C:19](OCC)=[O:20])[C:7](=[O:18])[C:8]12[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:24][C:5]1[C:4]2[C:14](=[CH:15][CH:16]=[CH:17][C:3]=2[O:2][CH3:1])[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:7](=[O:18])[C:6]=1[C:19]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2c(OC)cccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cccc2c1C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C21CCOCC1
Temperature: 86 °C
Reaction time: 14 h
Yield: 63.5 %

Procedure:
A mixture of ethyl 5-methoxy-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (44 mg, 132 μmol), tert-butyl 2-aminoacetate hydrochloride (33 mg, 199 μmol) in 2 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (51 mg, 397 μmol). The mixture was warmed to 86° C. and stirred for 14 hours, M+1=418. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 35 mg of the title compound as a yellow oil. MS (m/z) 418 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:14][N+:15]([O-])=O)[CH2:10][N+:11]([O-])=O)=[CH:5][CH:4]=1.[H][H]>CO.[Pt](=O)=O>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][NH2:15])[CH2:10][NH2:11])=[CH:7][CH:8]=1
Reactant: CNc1ccc(C(C[N+](=O)[O-])C[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CNc1ccc(C(CN)CN)cc1

Procedure:
A mixture of N-methyl-4-[2-nitro-1-(nitromethyl)ethyl]aniline (42.7 mg, 0.178 mmol, 83 mol % purity) and 25 mg platinum (IV) oxide in 4 mL MeOH contained in a pressure tube was reacted under 65 PSI hydrogen. After 20 hours the mixture was filtered past Celite and rinsed with MeOH. The MeOH solution of crude product was stored under N2 in the freezer and used as is for the next reaction (contained 16 mol % [4-(methylamino)phenyl]methanol impurity). 1H NMR (CD3OD) δ: 7.00-7.05 (m, 2H), 6.62-6.68 (m, 2H), 2.83-2.91 (m, 2H), 2.70-2.79 (m, 5H), 2.57-2.67 (m, 1H)
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni].CO>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCOc1ccc(N)cc1
Reaction time: 30 h

Procedure:
A reaction mixture of 110.52 g (0.464 mol) of diethyl-[2-(4-nitrophenoxy)ethyl]amine and 17 g of Raney nickel in 700 mL of methanol is hydrogenated for 30 hours at 20° C. and 3 bar hydrogen. The catalyst is filtered off and the filtrate is evaporated down. Yield: 93 g (96.2% of theory); C12H20N2O (M=208.30); calc.: molecular ion peak (M)+: 209; found: molecular ion peak (M)+: 209.