Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]4[S:33][C:32](=[O:34])[NH:31][C:30]4=[O:35])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17]C)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C(Cl)Cl>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]4[S:33][C:32](=[O:34])[NH:31][C:30]4=[O:35])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COc1ccc(-c2ccc3cc(C4SC(=O)NC4=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Product: O=C1NC(=O)C(c2ccc3cc(-c4ccc(O)c(C56CC7CC(CC(C7)C5)C6)c4)ccc3c2)S1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of 5-[6-(3-[1-adamantyl]-4-methoxyphenyl)-naphthalen-2-yl]-2,4-thiazolidinedione (0.130 g, 0.27 mmol) in 10 mL of anhydrous CH2Cl2 cooled to −78° C. under argon was added borontribromide (0.31 mL, 3.23 mmol). The cooling bath was removed and the reaction mixture was stirred for 18 hours at RT. The resulting mixture was carefully poured onto ice and extracted with CH2Cl2 (2×50 mL). The combined organics were washed with water, brine and dried over magnesium sulfate. The mixture was filtered, evaporated and the residue was purified on silica gel (eluent: hexane:EtOAc, 3:2) to give 5-[6-(3-[1-adamantyl]-4-hydroxyphenyl)-naphthalen-2-yl]-2,4-thiazolidinedione as a solid (0.090 g, 72% yield); mp 312–314.5° C., 1H NMR (300 MHz; DMSO-d6): δ 1.74 (s, 6H), 2.05–2.15 (m, 9H), 5.97 (s, 3H), 6.88 (d, J=8.1 Hz, 1H), 7.43–7.51 (m, 3H), 7.81 (dd, J1=8.7 Hz, J2=1.8 Hz 1H), 7.94–8.02 (m, 3H), 8.10 (s, 1H), 9.52 (s, 1H), 12.35 (brs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[NH:5][CH:6]([CH3:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17]#[N:18])[CH:16]=1)[N:13]([CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:12][CH2:11]2)[CH3:2].OO.[OH-].[Na+].C(O)(=[O:38])C>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:31])[NH:5][CH:6]([CH3:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17](=[O:38])[NH2:18])[CH:16]=1)[N:13]([CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH2:12][CH2:11]2)[CH3:2]
Reactant: CCOC(=O)NC(C)Cc1cc(C#N)c2c(c1)CCN2CCCO[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(C)Cc1cc2c(c(C(N)=O)c1)N(CCCO[Si](C)(C)C(C)(C)C)CC2
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2-{1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-7-cyano-2,3-dihydro-1H-indol-5-yl}-1-methyl-ethyl)-carbamic acid ethyl ester compound (V) (6 g, 0.01 mole) in DMSO (100 ml) was added 30% H2O2 (15 ml) and the mixture was stirred at 25-30° C. for 15 min. To the reaction mixture was then added 5 N NaOH solution (15 ml) and the mixture was stirred at above temperature for further period of 3 h. Acetic acid (18 ml) was added and reaction mixture was diluted with water. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure to give 3.68 g of (VI) as pale yellow waxy solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]12.[CH:21](=O)[CH3:22].CC(O[Na])=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH:21](=[C:15]1/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[C:4]/12)/[CH3:22]
Reactant: CC=O
Reactant: O=C(O)c1ccc2c(=O)n3c(nc2c1)CCCCCC3
Agent: CC(=O)O[Na]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C/C=C1\CCCCCn2c1nc1cc(C(=O)O)ccc1c2=O
Temperature: 25 °C

Procedure:
A solution of 13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (100 mg, 0.37 mmol), acetaldehyde (5 mL) and CH3COONa (1 g) in acetic acid (10 mL) was stirred at 110° C. for 24 hours. After it was cooled to room temperature, the mixture was adjusted to pH around 8 with Na2CO3 and extracted with a mixture of dichloromethane/methanol (10/1) (3×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product obtained was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>N1CCCCC1.ClCCl>[C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH2:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccccn2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccn2)cc1
Reaction time: 2 h

Procedure:
The product from Example H (3.90 g, 8.42 mmol) was suspended in 50 mL of 20% piperidine in dichloromethane at room temperature with stirring (2 h). The solution was concentrated under reduced pressure and partitioned between ethyl acetate and water (100 mL each) and separated. The organic layer was washed with 5% sodium bicarbonate (2×50 mL), brine (2×50 mL), dried with magnesium sulfate, filtered and concentrated under reduced pressure to an oil. The oil was purified by silica gel chromatography with ethyl acetate and methanol (3:1). Appropriate fractions were combined and concentrated under reduced pressure to a solid (1.34 g).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7](OC)[C:8]=1[C:9]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1.C(B1C2CCCC1CCC2)C1C=CC=CC=1.C1COCC1>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]([C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cn1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccccc2)cn1
Temperature: 60 °C

Procedure:
A sealable tube was charged with S-phos (0.22 g, 0.53 mmol), palladium acetate (0.060 g, 0.27 mmol), potassium phosphate (8.5 g, 40 mmol) and 5-bromo-2-methoxypyridine (1.8 mL, 13 mmol) under argon. 9-Benzyl-9-bora-bicyclo[3.3.1]nonane 0.5M in THF (53 mL, 27 mmol) was added, the vessel was sealed and heated to 60° C. overnight. The mixture was diluted with diethyl ether and was filtered through a pad of celite. Evaporation of the filtrate and purification by flash chromatography (0-40% EtOAc/hexanes) gave 5-benzyl-2-methoxypyridine. MS (ESI) m/z: Calculated: 199.1; Observed: 200.1 (M++1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH3:11])=[C:2]=[O:3].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10][CH3:11])=[O:3])[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: CSc1ccccc1N=C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CSc1ccccc1NC(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isocyanato-2-(methylsulfanyl)benzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 469.1 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][O:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:15][CH2:14]1.IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:13]1([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][C:21]([CH3:1])([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:15]1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)[C@H]1CC[C@H](OCC2CC2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCC(OCC2CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (15 mL, 105 mmol) in THF (100 mL) was cooled to 0° C. under Ar. n-Butyllithium (38 mL, 95 mmol, 2.5M in hexane) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D43, 9.47 g, 43.0 mmol) in THF (50 mL) was added and the resulting yellow solution was heated at 50° C. for 2 h. The reaction mixture was cooled to 0° C. and iodomethane (8 mL, 128 mmol) was added dropwise, the reaction was then allowed to warm to rt and left to stir for 3 days. 10% Citric acid (200 mL) was then added and the reaction mixture was concentrated by rotary evaporation. The residual mixture was diluted with H2O and extracted with Et2O (2×). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D44, 10.0 g, 93%) as a brown oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:22][CH:21]2[O:23][CH:17]([CH2:18][NH:19][CH2:20]2)[CH2:16]1)[C:7]#[N:8].[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33]Br)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][N:19]1[CH2:20][CH:21]2[O:23][CH:17]([CH2:16][N:15]([CH2:14][CH2:13][O:12][C:11]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=3[F:3])[CH2:22]2)[CH2:18]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(OCCN2CC3CNCC(C2)O3)c(F)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A suspension of 3-Fluoro-4-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitrile hydrochloride hydrochloric acid salt (5 g, 0.0137 mol, from step N (vii) above ), (3-Bromo-propyl)-carbamic acid tert-butyl ester (4.24 g, 0.0178 mol, from step (i) above) and potassium carbonate (7.57 g, 0.0548 mol) in dry acetonitrile (100 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered through celite and solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 5% methanol in dichloromethane as eluent to give the sub-title compound (5.8 g) as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11]>C(Cl)Cl>[CH:10]([NH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])=[O:11]
Reactant: NCc1ccccc1N
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: Nc1ccccc1CNC=O

Procedure:
The amine component employed is prepared by reaction of 2.6 g of 2.6 g of 2-(aminomethyl)aniline, dissolved in 50 ml of methylene chloride, with 3.91 g of 4-nitrophenyl formate at room temperature for 4 h. Purification over 250 g of silica gel (mobile phase N) gives 2-(formylaminomethyl)aniline: Rf (N)=0.22.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH:16]=2)=[C:7]([NH:37][C:38]([NH:40][C:41]2[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=2[CH:50]([CH3:52])[CH3:51])=[O:39])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:16]=2)=[C:7]([NH:37][C:38]([NH:40][C:41]2[C:42]([CH:50]([CH3:51])[CH3:52])=[CH:43][CH:44]=[CH:45][C:46]=2[CH:47]([CH3:49])[CH3:48])=[O:39])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCN3CCN(C(=O)OC(C)(C)C)CC3)c2)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCN3CCNCC3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 571.4 %

Procedure:
To a solution of N-[1-butyl-4-[3-{2-(4-tert-butoxycarbonyl-1-piperazinyl)-ethoxy}phenyl]-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (26 mg, 0.035 mmol) in methylene chloride (5 ml) was added trifluoroacetic acid (1 ml, 13 mmol), and the mixture was stirred at room temperature for two hours. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue was added 5% aqueous ammonia (50 ml), and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (20% methanol in chloroform) to give the title compound (13 mg, 0.20 mmol).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[O:7]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCBr
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: BrCCCCCCOc1ccccc1
Yield: 77 %

Procedure:
Preparation analogously to Example 38 by the reaction of sodium phenolate with 1,6-dibromohexane to give 6-phenoxy-1-bromohexane (b.p.11 =172°-5°; yield 77%), which is reacted with excess 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate. Isolation as hydrochloride. Yield, after recrystallisation from isopropanol: 53%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2SCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7.5 g (0.032 mole) of 3-tert.-butoxycarbonyl-thiazolidine-2-carboxylic acid and 5.2 g (0.032 mole) of N,N'-carbonyl-diimidazole are heated under reflux in 50 ml of tetrahydrofuran for 15 minutes. After addition of 6.1 g (0.03 mole) of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone, the mixture is stirred at room temperature for 18 hours and concentrated and the residue is crystallised with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: CO[C@@H](C)COc1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H](C)COc1ccc(C(C)N)cc1

Procedure:
tert-Butyl [1-(4-{[(2S)-2-methoxypropyl]oxy}phenyl)ethyl]carbamate (0.29 g, 0.94 mmol) was treated with trifluoroacetic acid (2 mL) in dichloromethane (18 mL) for 25 minutes, the volatiles removed under reduced pressure and the residue purified by silica gel column chromatography using dichloromethane:methanol:triethylamine 98:1:1 giving the title compound in 0.12 g (59%) yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 2 H) 7.34-7.41 (m, J=8.78 Hz, 2 H) 6.97-7.03 (m, 2 H) 4.35 (q, J=6.78 Hz, 1 H) 3.93 (d, J=5.02 Hz, 2 H) 3.60-3.70 (m, 1 H) 3.30 (s, 3 H) 2.96 (q, J=7.11 Hz, 1 H) 1.45 (d, J=6.78 Hz, 3 H) 1.16 (d, J=6.27 Hz, 3 H)
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][C@H:18]3[CH2:34][C@@H:21]4[O:22]C(C5C=CC(OC)=CC=5)[O:24][CH2:25][C@@H:20]4[CH2:19]3)[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.CC(O)=O>C1COCC1>[C@@H:1]1([NH:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([CH2:17][C@H:18]3[CH2:34][C@H:21]([OH:22])[C@H:20]([CH2:25][OH:24])[CH2:19]3)[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](Cc4cc(N[C@H]5CCc6ccccc65)ncn4)C[C@@H]3O2)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@H](Cc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 60 h
Yield: 91.8 %

Procedure:
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-6-{[(4aS,6S,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]methyl}pyrimidin-4-amine (0.280 g, 0.61 mmol) was dissolved in THF (2 mL), water (2 mL) and AcOH (6 mL, 0.106 mmol) were added. The mixture was stirred under an atmosphere of argon for 60 h. The mixture was concentrated under reduced pressure and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (0.190 g, 91%). LC/MS: Rt=1.29 min, ES+ 340 (AA standard).
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[NH:12][CH:11]=[N:10][C:9]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>O>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:12]2[CH:11]=[N:10][C:9]([N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[N:8][C:7]2=[O:6])=[CH:35][CH:34]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc[nH]c(=O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
To an N,N-dimethylformamide solution (200 mL) of the crude product of tert-butyl 4-(4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)piperazine-1-carboxylate synthesized in Reference Synthesis Example 7 and potassium carbonate (7.46 g, 54.0 mmol), 4-chlorobenzyl bromide (10.2 g, 49.5 mmol) was added at room temperature and the resultant reaction solution was stirred at room temperature for 1 day. After completion of the reaction, water was added to the reaction solution and a deposited solid was collected by filtration. The filtered residue was suspended in ethyl acetate and the suspended solid was collected by filtration and dried under reduced pressure to obtain the title compound (12.4 g, two step yield 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH3:22][C:23]1([CH3:43])[C:27](=[O:28])[C:26]2[CH:29]=[C:30]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=2[O:24]1>C1COCC1.O>[OH:28][C:27]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[C:26]2[CH:29]=[C:30]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=2[O:24][C:23]1([CH3:43])[CH3:22]
Reactant: Cc1c(NC(=O)OC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Reactant: CC(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(NC(=O)OC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1ccc(C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromocumene (6.25 g, 31.4 mmol) in THF (50 mL) was added dropwise a solution of n-butyllithium in hexane (1.60 M, 19.6 mL, 31.4 mmol) under argon atmosphere at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction solution was added dropwise a solution of tert-butyl (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Reference Example 59 (500 mg, 2.02 mmol) in THF (5 mL) at the same temperature, and the reaction solution was stirred at room temperature for 1 hour, followed by addition of water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain oily tert-butyl (3-hydroxy-3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate. A mixture of said compound with trifluoroacetic acid (10 mL) was added triethylsilane (1.0 mL, 6.4 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added a saturated sodium hydrogen carbonate solution to alkalify the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the free salt of the title compound. Then, it was made hydrochloride in a 4 N hydrochloric acid/methanol solution to obtain 2.03 g (yield 37%) of the title compound. Melting point: 166-168° C. (decomp.) (methanol).
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[N:21]1CCC[C:22]1=[O:26]>>[C:22](=[O:26])([S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[NH2:21]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCCCSC(N)=O
Yield: 60 %

Procedure:
As described in Example 17, but using 63 g of 1-octadecylmercaptan (0.22 mol) dissolved in 30 ml of N-methylpyrrolidone, S-octadecyl thiocarbamate was obtained in a yield of 60% of theory.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CC[CH2:39][O:38]5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CCC[C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Agent: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCCOC)c4)cc23)CC1
Yield: 56.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-(methyloxy)ethanamine (39 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 31 mg of the title compound (56.5%).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([O:19]C)[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([OH:19])[C:8]2=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(O)c(Cc2c[nH]nn2)ccn1-c1ccccc1
Yield: 61.1 %

Procedure:
Reaction of 151a (0.212 g, 0.75 mmol) and 1M BBr3 in CH2Cl2 (1.5 equiv) within 48 h as described for the synthesis of 148a gave compound 152a (0.123 g, 61%) as light brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 5.27 (2H, s), 6.13 (1H, t, J=6.4), 6.67 (1H, d, J=7.2), 7.30 (1H, d, J=5.6), 7.45-7.49 (1H, m), 7.57 (2H, t, J=7.6), 7.87 (2H, d, J=8.0), 8.73 (1H, s), 9.08 (1H, s); 13C NMR (101 MHz, CDCl3) δ 136.59, 129.60, 128.94, 122.29, 120.62, 107.99, 29.29. (quaternary carbons were not seen). HRMS (EI) calcd for C14H12N4O2 [M]+ 268.0960. found 268.0967.