Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1)([O-])=O.FC1C=CC([N+]([O-])=O)=CC=1>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:16]2[CH:17]=[CH:18][C:13]([NH2:10])=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=[N+]([O-])c1ccc(F)cc1
Product: Nc1ccc(OCCCN2CCCC2)cc1

Procedure:
The target compound was obtained by the method according to Example 18, using 3-pyrrolidin-1-yl-propan -1-ol, and 4-nitrophenol or 1-fluoro-4-nitrobenzene as starting materials.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:14]=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(Nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccn2)n1
Yield: 54.6 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (18.2 mL, 7.27 mmol), tert-butyl 4-(2-chloropyridin-4-yloxy)piperidine-1-carboxylate (2.50 g, 8.00 mmol), potassium phosphate (1.70 g, 8.00 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.166 g, 0.182 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.116 g, 0.200 mmol) were reacted in toluene (20 mL) and water (5 mL), to provide tert-butyl 4-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)piperidine-1-carboxylate (1.55 g, 54.1% yield) as white solid. 1H NMR (CDCl3) δ 8.14 (d, 1H), 6.44 (d, 1H), 6.36 (bs, 2H), 4.51 (m, 1H), 3.68 (m, 2H), 3.34 (m, 2H), 2.34 (d, 3H), 1.92 (m, 2H), 1.75 (m, 2H), 1.47 (s, 9H); Mass spectrum (apci) m/z=291 (100) (M+H-Boc).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:34]([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45]Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:34]([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45][O:14][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCCC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
N-Boc-L-valine (1.3 g, 6 mmole) was dissolved in dioxane (5 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 3.8 ml, 6 mmole), and the solution was evaporated and coevaporated with toluene several times. The residue was dissolved in DMF (15 ml) and 4-bromobutyric acid benzyl ester (1.28 g, 5 mmole) was added to it. The reaction was kept for 18 hr, and then poured into sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was dried and the product was isolated with silica gel column chromatography, 1.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:11]([O-])([OH:13])=[O:12]>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1c(O)cc(Br)cc1[N+](=O)[O-]

Procedure:
In SCHEME 7 4-bromoguaiacol (28) is selectively nitrated with 70% HNO3 in AcOH to give 4-bromo-6-nitroguaiacol (29) which is further methylated with methyl iodide and K2CO3 in acetone to give the corresponding 5-bromo-3-nitroveratrol (30). 5-bromo-3-nitroveratrol (30) is reacted under inert conditions with a boronic acid of generell type (31) under Suzuki-type basic conditions (Pd(PPh3)4 and aqueous sodium bicarbonate in dimethoxyethane) to a biaryl of type (32). Biaryl (32) is further hydrolized with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (33) which is converted to a building block of type (34) by reaction with oxalyl chloride in anhydrous dichloromethane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CC(=O)CC>[CH3:21][O:20][C:18](=[O:19])[CH2:17][O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc(C)c(C)c1

Procedure:
A mixture of 3,4-dimethyl-phenol (5.000 g; 40.928 mmol), potassium carbonate (7.070 g; 51.160 mmol), and methyl bromoacetate (4.70 ml; 51.160 mmol) in butanone (280 ml) was heated at reflux for 4 h. Filtration, concentration to dryness under reduced pressure, and purification by FC (heptane/EA, 4/1) afforded (3,4-dimethyl-phenoxy)-acetic acid methyl ester as a pale yellow oil (7.400 g; 93%). LC-MS: tR=0.92 min.; [M+H]+: no ionisation.
Reaction SMILES: [NH2:1][C:2]([CH3:46])([CH3:45])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]=1)=[O:6].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:99]([NH:101][CH:102]3[CH2:107][CH2:106][N:105]([C:108]4[CH:113]=[CH:112][CH:111]=[CH:110][N:109]=4)[CH2:104][CH2:103]3)=[O:100])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH3:45][C:2]([NH:1][C:99]([NH:101][CH:102]1[CH2:103][CH2:104][N:105]([C:108]2[CH:113]=[CH:112][CH:111]=[CH:110][N:109]=2)[CH2:106][CH2:107]1)=[O:100])([CH3:46])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)=[O:6]
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CC(C)(N)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)NC(=O)NC1CCN(c2ccccn2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-2-methyl-propyl)-amide (first step a) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42). MS (ES+) m/e 829 (MH+)
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16]C(C)(C)C)=[O:15])=[O:8])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl.O>[C:1]([O:4][CH2:5][C@H:6]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of compound 2 (1 g, 2.30 mmol) in CH2Cl2 (5 mL) was added 20% TFA-DCM (10 mL) and stirred at RT for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×15 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield compound 3 (800 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.[N+:24]([O-])([O-:26])=[O:25].[K+]>>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:14]=[CH:15][C:16]([N+:24]([O-:26])=[O:25])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)[C@H]1[C@@H](c2ccc([N+](=O)[O-])cc2)CC(=O)N1C
Reaction time: 18 h
Yield: 32 %

Procedure:
To (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-phenyl-pyrrolidin-2-one (prepared according to the procedure of Intermediate T, Method 2, 1.00 g, 4.04 mmol) was added sulfuric acid (4.0 mL). To the resulting yellow solution was added potassium nitrate (0.50 g, 4.85 mmol) in portions, keeping the reaction temperature below 30° C. The reaction mixture was stirred for 18 h, then poured onto ice water (30 mL) and extracted with CH2Cl2, dried (MgSO4) and concentrated under reduced pressure. The oily residue was diluted with EtOAc and the resulting precipitate was collected by filtration. The solid was washed with Et2O to give (±)-(4R 5R*)-5-ethoxycarbonyl-1-methyl-4-(4-nitrophenyl)pyrrolidin-2-one (374 mg, 32%) as a white solid: mp 142-143° C.; TLC (33% EtOAc/hex) Rf 0.23; HPLC ES-MS m/z 293 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15]C.Br[C:33]1N=C(C2CC2)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]([CH3:15])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:31][CH2:33]1
Reactant: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.96-0.99, ,1.58, 1.81, 2.26, 2.85, 3.14, 3.26, 4.86, 5.44, 5.63, 7.26-7.50; MS (ESI+) for C23H21Cl2N3O m/z 426 (M+H)+.
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].ClCC(OC(=O)CCl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]>ClC(Cl)C>[C:4]([CH2:3][CH2:2][C:1]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([O:26][CH3:27])[CH:22]=1)=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)CCC(=O)O
Reactant: COc1ccccc1OC
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)CCC(C)=O)cc1OC
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 81.8 %

Procedure:
In 50 ml of dichloroethane were dissolved 5.8 g (0.05 mole) of levulinic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 8.98 g (0.065 mole) of 1,2-dimethoxybenzene and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 5.5 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 9.66 g of 4-(β-acetylpropionyl)-1,2-dimethoxybenzene.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[O:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21](Cl)=[N:22][O:23][CH3:24]>CCOCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[O:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[N:22][O:23][CH3:24]
Reactant: CON=C(Cl)c1ccccc1COc1cccc(Cl)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(c1ccccc1COc1cccc(Cl)c1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
N,N-Dimethylformamide (3 ml) and 60% sodium hydride (0.16 g, 3.9 mmol) were added to imidazole (0.27 g, 3.9 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl chloride (0.40 g, 1.3 mmol) was added, and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 1-[2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl]imidazole (0.29 g, 65.3%) as colorless crystals. mp. 96.5-97.5° C.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[CH:24]=[C:23](F)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32]>CN(C=O)C>[NH2:18][C:19]1[CH:24]=[C:23]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33]
Reactant: CC(C)C(=O)Nc1cc([N+](=O)[O-])c(F)cc1N
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cc([N+](=O)[O-])c(Sc2cccc3cnccc23)cc1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
5-Isoquinolinethiol 500 mg (3.1 mmol) was dissolved in DMF 20 ml, potassium carbonate 1.29 g (9.3 mmol) and N1-(2-amino-4-fluoro-5-nitrophenyl)-2-methylpropane amide) 750 mg (3.1 mmol) were added, and the mixture was heated with stirring at 100° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, ether was added to the resulting residue to crystallize. The crystals were collected and washed with methanol to obtain N1-[2-amino-4-(5-isoquinolylsulfanyl)-5-nitrophenyl]-2-methylpropanamide 380 mg (31.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:19](OC)=[O:20])[C:17]=2[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[OH:20][CH2:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[N:10]=[CH:11]2
Reactant: COC(=O)c1cccc2cnc(NC(=O)OC(C)(C)C)cc12
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc2c(CO)cccc2cn1
Temperature: 25 °C

Procedure:
A 10 mL round bottom flask with methyl 3-((tert-butoxycarbonyl)amino)isoquinoline-5-carboxylate (0.2 g, 0.662 mmol) in 6 mL THF was charged with DIBAL (3.3 mL, 3.31 mmol), The reaction mixture was stirred at rt. After stirring for 2 h, the reaction mixture was added with Rochelle's salt and stirred for 1 h and then extracted with EtOAc (3×20 mL). Combined organic layer was dried, filtered and then concentrated in vacuo. Purified by silica gel chromatography (0-100% EtOAc in hexane) yielded tert-butyl (5-(hydroxymethyl)isoquinolin-3-yl)carbamate (26-4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:5]2.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[NH:20][NH2:21]>CO.OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:21][NH:20][C:19]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:5]2
Reactant: CCOC(=O)NN
Reactant: O=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCOC(=O)NN=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Yield: 95 %

Procedure:
To a mixture of 1.5 g of 5-fluoro-2-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-one (prepared by a procedure analogous to Example 1, Step B) and 0.63 g of ethyl carbazate in 20 ml of methanol was added 1 drop of conc. H2SO4 and the reaction was refluxed under nitrogen overnight. The reaction was then partitioned between ethyl acetate and 5% aqueous NaHCO3, the aqueous extracts were washed with ethyl acetate and the combined organic extracts were dried over MgSO4. Concentration of the organic extract afforded 1.9 g of a yellow oil, which was triturated with ether to afford 1.27 g of a white solid, m.p. 139°-141° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH2:15])[CH2:4][CH2:3]1.[NH2:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([F:26])=[C:21]([CH:25]=1)[C:22](O)=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([F:26])=[C:21]([CH:25]=1)[C:22]([NH:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:23]
Reactant: CN1CCN(c2ccccc2CN)CC1
Reactant: Cc1cc(F)c(C(=O)O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising (2-(4-methylpiperazin-1-yl)phenyl)methanamine (413 mg, 2.010 mmol) and 5-amino-2-fluoro-4-methylbenzoic acid (step 2) (340 mg, 2.010 mmol) in DMF (3 ml) was treated with DIPEA (0.351 ml, 2.010 mmol) followed by HATU (764 mg, 2.010 mmol) and stirred at 25° C. for 24 hrs. The mixture was partitioned between water and EtOAc. The organic portion was washed with sat. aq. NaHCO3, 0.5 M LiCl and brine (each back extracted with EtOAc). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness to give a pink oil. Purification by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[C:37]1([N:43]2[CH:47]=[C:46](C(=O)C)[CH:45]=[N:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:20]=[CH:32][C:31]([C:33]([OH:35])=[O:34])=[CH:30][C:29]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:46]2[CH:45]=[N:44][N:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:47]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cnn(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cnn(-c5ccccc5)c4)ccc3c1)n2C1CCCCC1
Yield: 51 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(1-phenyl-1H-pyrazol-4-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (69 mg, 51% yield). MS: 514.23 (M+H+); HPLC Procedure B, retention time=6.36 min.
Reaction SMILES: I(Cl)(=O)=O.[I:5](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.Cl.Cl.[NH2:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][CH2:31][S:32]([N:35]2[CH2:52][CH2:51][C:38]3([N:42]=[C:41]([CH:43]4[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]4)[NH:40][C:39]3=[O:50])[CH2:37][CH2:36]2)(=[O:34])=[O:33])=[C:25]([CH3:53])[CH:24]=1.C(=O)([O-])[O-].[Ca+2].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.ClCCl>[NH2:22][C:23]1[CH:24]=[C:25]([CH3:53])[C:26]([CH2:30][CH2:31][S:32]([N:35]2[CH2:36][CH2:37][C:38]3([N:42]=[C:41]([CH:43]4[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]4)[NH:40][C:39]3=[O:50])[CH2:51][CH2:52]2)(=[O:34])=[O:33])=[C:27]([CH3:29])[C:28]=1[I:5]
Reactant: Cc1cc(N)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)c(I)c(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 61.8 %

Procedure:
Benzyltrimethylammonium dichloroiodate (324 mg, 0.930 mmol) was added to a mixture of 8-[2-(4-amino-2,6-dimethyl-phenyl)-ethanesulfonyl]-2-(4-methyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (530 mg, 1.03 mmol) and calcium carbonate (517 mg, 5.17 mmol) in methanol (6 mL)-dichloromethane (15 mL) at room temperature. The mixture was stirred at room temperature for 22 hours, and an aqueous sodium bicarbonate solution and ethyl acetate were then added. The organic layer and the aqueous layer were separated, and the aqueous layer was repeatedly extracted with ethyl acetate three times. The organic layers were combined and washed with saturated brine, and the insoluble matter was then filtered off through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 8-[2-(4-amino-3-iodo-2,6-dimethyl-phenyl)-ethanesulfonyl]-2-(4-methyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a pale yellow solid (337 mg, 62%).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=[O:4].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH:3]=[O:4]
Reactant: [H][H]
Reactant: CC(C=O)=CCC(C)CC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C=O)CCC(C)CC(C)(C)C
Reaction time: 2.5 h
Yield: 97.1 %

Procedure:
In a hydrogenation autoclave, 250 g (1.37 moles) of 2,5,7,7-tetramethyl-2-octenal, dissolved in 500 ml of methanol, were hydrogenated in the presence of 25 g of a 0.5% strength palladium/alumina catalyst at 80° C., initially under a hydrogen pressure of 25 bar, and after 2-3 h, under 55 bar. The total hydrogenation time was 10 h. The catalyst was filtered off, after which fractional distillation gave 245 g (1.33 moles) of 2,5,7,7-tetramethyloctanal (bp.=68° C./0.3 mbar; nD25 =1.4308), corresponding to a yield of 96% of theory. The compound was in the form of a diastereomeric mixture.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:25]3=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]3[CH2:23][CH2:22][O:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:25]5=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]5[CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: C1=CCC2CCOC3(CCNCC3)C2=C1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CC1)OCCC1CC=CC=C12

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1,5-dihydrospiro[4H-2-benzopyran-1,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 58% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-23.56 (c=0.51, methanol).