Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1
Product: Cc1cc(/C(CC(c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1

Procedure:
In analogy to example 39, from (E)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-(2-trifluoromethyl-phenyl)-propan-1-one oxime (example 132) and 1-methanesulfonyl-piperazine (CAS RN: [55276-43-2]) was prepared the title compound as a yellow foam, MS (ESI+): m/z=547.3 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I43) (0.570 g, 1.87 mmol) in EtOH (5 mL) and DMF (5 mL) was added to a solution of 10% Pd/C (200 mg) in DMF (10 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (130 mL). The solvent was removed in vacuo to yield a brown oil which was purified by column chromatography on silica gel (0-50% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I44) (0.46 g, 89%) as a crystalline solid; 1H NMR (400 MHz, CDCl3) δ 7.02-6.96 (m, 2H), 6.67-6.61 (m, 2H), 4.21 (bs, 2H), 3.57 (s, 2H), 2.77 (t, J=12.2 Hz, 2H), 2.53 (tt, J12.1, 3.5 Hz, 1H), 1.77 (d, J=13.3 Hz, 2H), 1.64-1.50 (m, peak obscured by solvent), 1.48 (s, 9H). LCMS Method C: rt 4.77 min; m/z 221 [M−tButyl+2H]+, 177 [M-Boc+2H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:42][C:43]1[CH:63]=[C:62]([S:64]([CH3:67])(=[O:66])=[O:65])[CH:61]=[CH:60][C:44]=1[O:45][C:46]1[C:51]([CH3:52])=[C:50]([O:53][CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[N:49]=[CH:48][N:47]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:57]2[CH2:58][CH2:59][CH:54]([O:53][C:50]3[C:51]([CH3:52])=[C:46]([O:45][C:44]4[CH:60]=[CH:61][C:62]([S:64]([CH3:67])(=[O:65])=[O:66])=[CH:63][C:43]=4[F:42])[N:47]=[CH:48][N:49]=3)[CH2:55][CH2:56]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
6-Amino-nicotinic acid (21.5 mg, 0.155 mmol), HATU (59 mg, 0.155 mmol) and triethylamine (0.05 mL, 0.359 mmol) were mixed in DMF and stirred at rt for 20 min. 4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine was then added and the mixture stirred at rt for 2 h. The crude was purified by HPLC to afford Compound C5 as a yellow solid (67 mg, 90.7%). 1H NMR (CDCl3, 400 MHz) δ 1.88-1.87 (m, 2H), 1.99-2.01 (m, 2H), 2.15 (s, 3H), 3.03 (s, 3H), 3.58-3.60 (m, 2H), 3.77-3.78 (m, 2H), 5.37-5.41 (m, 1H), 6.78-6.82 (d, 1H), 7.33-7.38 (m, 1H), 7.69-7.74 (m, 2H), 7.87-7.96 (m, 2H), 8.14 (s, 1H). Exact mass calculated for C23H24FN5O5S 501.15, found 502.4 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([O:18]C)=[O:17])[CH:8]=1.O1CCOCC1.[OH-].[Na+]>O>[CH3:1][NH:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[CH:8]=1
Reactant: CNC(=O)CNC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)CNC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
443.0 g. (1.5 moles) of N-(3-methoxycarbonyl-5-nitrobenzoyl)-glycine methylamide in 5.5 l. of dioxane is agitated for 2 hours at room temperature with the addition of 3.3 l. of 0.5 N sodium hydroxide solution. Thereafter, 400 ml. of water is added to the reaction mixture, the dioxane is distilled off under vacuum, and the acid is precipitated with concentrated hydrochloric acid, vacuum-filtered, washed free of salt with water, and dried under vacuum at 70° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][C:13]2([CH2:17][OH:18])[CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[F:1][C:2]([F:19])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][CH2:12][C:13]2([CH2:17][O:18][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1
Product: CS(=O)(=O)OCC1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1

Procedure:
In analogy to the procedure described in example 1G], {1-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-cyclobutyl}-methanol and methanesulfonyl chloride gave the title compound as yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][N:17]3[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:24]>O1CCCC1>[CH3:24][N:14]1[CH2:13][CH2:12][C:11]2([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:10]2)[CH2:16][CH2:15]1
Reactant: CI
Reactant: c1ccc(C2OC3(CCNCC3)N3CCCCC23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC2(CC1)OC(c1ccccc1)C1CCCCN12
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.2 g of a 50% dispersion in a mineral oil) is added in portions to a stirred solution of 5.4 g of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] in 100 ml of tetrahydrofuran at 25° C. The mixture is stirred 0.5 hours under nitrogen and 5 g iodomethane in 10 ml of tetrahydrofuran is added dropwise. The mixture is stirred at 45° C. for 3 hours, filtered and the filtrate is evaporated in vacuo. The residue is dissolved in methylene dichloride, washed with water, dried over magnesium sulfate and the solvent is evaporated. The residue is crystallized from ethyl acetate to obtain the desired hexahydro-1'-methyl-1-phenylspiro[3H-oxazolo-[3,4-a]pyridine-3,4'-piperidine]; mp 157°-159° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Cc1cccc(N)c1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1F
Yield: 60.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 250 mg of 2-fluoro-3-methylaniline in place of the 2,4-difluoroaniline. 208 mg of N-(2-fluoro-3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:20]1(N)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClC1C=CC=CC=1Cl>[CH:20]1([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:19])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)c2c(NC3CCCCC3)cccc21

Procedure:
1-Nitroanthraquinone is refluxed with an excess of cyclohexylamine in o-dichlorobenzene to yield 1-cyclohexylamino anthraquinone which is further brominated in aqueous pyridine to yield the corresponding 1-cyclohexylamino-4-bromoanthraquinone. This compound is further condensed with p-amino acetanilide to yield 1-cyclohexylamino-4-(p-acetaminoanilino)anthraquinone as a bright green pleochroic dye having an optical order parameter 0.7.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=12.[CH3:25]I>CN(C=O)C>[CH3:25][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:3]=[C:4]1[C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=12
Reactant: CI
Reactant: C#CCn1nnc2c(-c3nc4ccccc4[nH]3)ncn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCn1nnc2c(-c3nc4ccccc4n3C)ncn2c1=O
Reaction time: 8 h
Yield: 62.8 %

Procedure:
Sodium hydride (60% in mineral oil, 8 mg, 0.189 mmol, 1.1 eq.) was added in one portion to a slurry of 8-(1H-benzo[d]imidazol-2-yl)-3-(prop-2-ynyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (50 mg, 0.172 mmol) in DMF (4.5 mL) at 0° C. and the mixture, which became red, was stirred for 5 minutes before the addition of MeI (21 μL, 0.344 mmol, 2 eq.). The mixture was then stirred overnight and concentrated under high vacuum. The product was absorbed on silica and purified by flash chromatography using DCM:MeCN (80:20) as eluent to give the title compound as a bright yellow/green solid (33 mg, 62% yield). The product was then suspended in ethyl acetate, filtered and washed successively with water, ethyl acetate and diethyl ether to remove any trace of DMF. δH (DMSO-d6): 9.07 (1H, s), 7.76-7.79 (1H, m), 7.67-7.70 (1H, m), 7.35-7.39 (1H, m), 7.29-7.33 (1H, m), 5.17 (2H, d, J=2.5), 4.14 (3H, s), 3.53-3.54 (1H, t, J=2.5).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=[C:4]2[CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=[C:4]3[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)[N:7]=2)=[N:13][CH:14]=1)#[N:19]
Reactant: CCOC(=O)c1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(C(F)(F)F)cc3)cc3nc(C(=O)O)cn23)nc1

Procedure:
In analogy to the preparation of Example 109, the desired product is prepared by Pd-catalysed coupling starting from ethyl 7-chloro-5-({2-[(5-cyanopyridin-2-yl)amino]ethyl}amino)-imidazo[1,2-c]pyrimidine-2-carboxylate (Example 59A) and [4-(trifluoromethyl)phenyl]boronic acid.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9].Br.[OH-].[Na+].[C:19]1(C)[CH:24]=CC=C[CH:20]=1>>[C:10]1(/[CH:2]=[C:3]2/[CH:4]([N:9]3[CH2:24][CH2:19][CH2:20]3)[CH2:5][CH2:6][CH2:7][CH2:8]/2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1
Reactant: NC1CCCCC1C(O)c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: C(=C1\CCCCC1N1CCC1)\c1ccccc1
Yield: 30 %

Procedure:
A mixture of 2.5 g (9.5 mmoles) of cis-N-(3-hydroxypropyl)-N-[2-[hydroxy(phenyl)methyl][cyclohexyl]amine, 10 ml of toluene and 6.45 g of 48% v/v aqueous hydrogen bromide solution was stirred and heated on a steam bath for 3.5 hr. The resulting solution was cooled, basified with 20% sodium hydroxide solution and extracted with chloroform. The chloroform extract was washed with water, and saturated sodium chloride solution and then dried over magnesium sulfate and evaporated. The residue, 2 g, was chromatographed by high pressure liquid chromatography (HPLC) procedures using a Merck silica gel, size C column and 10% v/v methanol/in chloroform/1% v/v ammonium hydroxide mixture as eluting liquid, collecting 20 ml fractions. Fractions 1 to 14 gave no product material. Fractions 15 to 25 gave 0.686 g (30% yield) of (±)-(E)-1-[2-(phenylmethylene)cyclohexyl]azetidine, which was identified by NMR analysis comparison with the NMR of standard, authentic compound. Fractions 26 to 31 gave 0.25 g of a mixture, and fractions 32 to 50 gave 0.286 g of N-(3-hydroxypropyl)-N-[2-(phenylmethylene)cyclohexyl]amine which was identified by NMR comparison with a known standard sample, and also by conversion to its hydrochloride salt which was identical to a standard sample by NMR, UV and IR spectral analysis comparisons.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].S(Cl)(Cl)=O>CO>[CH:10]([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:15])[CH3:16])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:12]=1)([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:16])[CH3:15])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:12]=1)[C:25]1[C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:26]=1
Reactant: CC(C)c1cc(C(C)(C)C)ccc1O
Reactant: CC(C)c1cc(C(C)(C)C)cc(C=O)c1O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(C)c1cc(C(C)(C)C)cc(C(c2cc(C(C)(C)C)cc(C(C)C)c2O)c2cc(C(C)(C)C)cc(C(C)C)c2O)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Compound 3 was synthesized as described elsewhere with minor modifications.6 Briefly, a sample of 5-(tert-butyl)-2-hydroxy-3-isopropylbenzaldehyde (2) (5.08 g, 24.3 mmol) was combined with 2 equivalents of 4-(tert-butyl)-2-isopropylphenol (1) (9.17 g, 47.7 mmol) and 14 mL of methanol in a 100 mL schlenk flask. With a sodium carbonate trap connected to the reaction flask, the reaction mixture was cooled to 0° C. and thionyl chloride (11.4 mL, 157.7 mmol) was added dropwise causing an immediate change from orange/yellow to dark purple for the reaction mixture. The reaction was stirred overnight. The precipitate that was formed was collected by filtration. The residue was recrystallized from hexanes to afford 3 as a pale purple solid (6.88 g) in 48% yield with respect to the starting salicylaldehyde. 1H NMR (CDCl3-d) δ ppm 1.20 (27 H, s), 1.26 (18 H, d, J=6.9 Hz), 3.22 (3 H, spt, J=6.9 Hz), 4.91 (3 H, s), 5.83 (1 H, s), 6.81 (3 H, d, J=2.3 Hz), 7.18 (3 H, d, J=2.3 Hz). 13C-{1H} NMR, δ 22.7, 27.5, 31.4, 34.3, 41.8, 122.2, 123.7, 125.7, 135.0, 143.5, 148.9. Anal. calcd. for C40H58O3: C, 81.86; H, 9.96; N, 0.00. Found: C, 81.79; H, 10.32; N, 0.00.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:5].[OH:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[OH:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH:5][C@@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:12])[CH2:16][CH2:15]1
Reactant: O=C1CCC(O)CC1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)[C@@H](NC1CCC(O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35 %

Procedure:
(S)-(+)-2-Phenylglycine methyl ester (commercially available from Sigma-Aldrich, Milwaukee, Wis., 433 g, 2.146 mol) was added to a solution of 4-hydroxycyclohexanone (245 g, 2.146 mol) in DCE (8.5 L). Sodium triacetoxyborohydride was added (910 g, 4.292 mol), and the mixture was stirred at room temperature under nitrogen for 23 hours. Water (3 L) was added to quench the reaction, and the organic layer was separated. The aqueous phase was extracted with DCM (4 L×2) and the organic layers were combined, dried, filtered and concentrated. The residue was purified by column chromatography (gradient elution with 100% DCM to DCM/MeOH=25:1) to afford (S)-methyl 2-((4-hydroxycyclohexyl)amino)-2-phenylacetate (197 g, 35%) (mixture of cis and trans). m/z (ESI) 264 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:8][C:7]2=[O:26])([OH:3])=O.Cl.[NH2:28][CH2:29][C:30]([NH2:32])=[O:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([CH2:29][NH:28][C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]1)[CH2:8][C:7]2=[O:26])=[O:3])(=[O:31])[NH2:32]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)O)ccc1O2
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)NCC(N)=O)ccc1O2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
tert-butyl 6-carboxy-4-oxospiro(chroman-2,4′-piperidine)-1′ carboxylate (7.50 g, 20.8 mmol), glycinamide hydrochloride (2.76 g, 24.9 mmol), EDCI (4.78 g, 24.9 mmol), HOBT (3.78 g, 24.9 mmol), and TEA (5.80 ml, 41.6 mmol) were suspended in DMF (75 ml) and stirred at room temperature for 23 h. After removal of the solvent, the residue was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with saturated NaHCO3 aq. and brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was triturated with MeOH—Et2O and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([NH:26][C:44]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:45])([CH3:24])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 8 h
Yield: 84.2 %

Procedure:
2-(8-Benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine (2.19 g, 5.4 mmol), triethylamine (1.5 mL, 10.8 mmol), and dichloromethane (50 mL) were combined. Cyclohexanecarbonyl chloride (0.95 mL, 6.0 mmol) was added and the reaction was stirred overnight. Saturated sodium bicarbonate was added and the layers were separated. The organic fraction was sequentially washed with a second portion of saturated sodium bicarbonate and then brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide an orange foam. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 0-20% CMA in chloroform to provide 2.34 g of N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as a tan solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:11]1([C:16](=O)[CH2:17][C:18](OCC)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:16]2[CH:17]=[C:18]([OH:19])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CC(=O)C1CCCC1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(C3CCCC3)cc2O)c1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-cyclopentyl-3-oxopropanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].Cl.[CH3:6][O:7][C:8](=[O:23])[CH:9]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:10][NH2:11].C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8](=[O:23])[CH:9]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:10][NH:11][CH2:3][C:2]#[CH:1]
Reactant: COC(=O)C(CN)NC(=O)OCc1ccccc1
Reactant: C#CCBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCNCC(NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Propargyl bromide (1.6 mL, 14.4 mmol) is added to a solution of 3-amino-2-benzyloxycarbonylamino-propionic acid methyl ester hydrochloride (4.0 g, 13.9 mmol) and triethylamine (4.1 mL, 29.4 mmol) in THF (46 mL). The resulting mixture is heated to 50° C. and stirred overnight then cooled to RT and concentrated in vacuo. The crude residue is diluted with methylene chloride, washed with saturated NaHCO3 and brine then the organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude material (4.0 g) is taken on to the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ7.25-7.30 (m, 5H), 5.75 (bs, 1H), 5.20 (s, 2H), 4.45 (bs, 1H), 3.80 (s, 3H), 3.75 (m, 1H), 3.31 (s, 2H), 3.08 (dd, 1H), 2.98 (dd, 1H), 2.20 (t, 1H). EI MS, [M+H]+=291.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1.P([O-])(OCC)(SCC)=[S:14]>C1COCC1.O>[C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])(=[S:14])[NH2:11]
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: CCOP([O-])(=S)SCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(N)=S)c1
Temperature: 80 °C
Yield: 102.4 %

Procedure:
Preparation H11, Step 2: A solution of 2 g (0.01 mol) of methyl-3-cyanobenzoate in 32 ml of THF and 8 ml of water was charged with 2.3 g (0.012 mol) of diethyl dithiophosphate and heated at 80° C. for 24 h. THF was removed and the residue was taken in ethyl acetate. The extract was washed with water and concentrated to afford methyl 3-carbamothioylbenzoate (2.0 g) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].BrC[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27]>O1CCOCC1.[Ag]=O>[CH3:27][O:26][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:16]=1[CH2:15][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(CCBr)c(OC)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Yield: 55.6 %

Procedure:
Silver oxide (2.32 grams) was added to a solution of 5-nitroindole (1.62 grams) and methyl 4-bromoethyl-3-methoxybenzoate (2.6 grams) in 10 mL of dioxane. The mixture was heated at 60° for 20 hours. The dioxane was evaporated and ethyl acetate was added to the residue. The resulting suspension was filtered. The filtrate was evaporated and the residue was purified on silica with hexane/ethyl acetate to give 1.8 grams of title compound, m.p. 162°-163°.