Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc(N)cc1
Yield: 102.9 %

Procedure:
A solution of crude 5-(2-methyl-[1,3]dioxolan-2-ylmethyl)-1-(4-nitrobenzyl)-1H-indole-2-carboxylic acid ethyl ester (2.4 g, ≈5 mmol) in dry tetrahydrofuran (20 ml) was shaken in a Parr apparatus with 10% palladium on carbon (200 mg) under 40 psi hydrogen for about four hours. The mixture was filtered and evaporated under reduced pressure to give the title compound (2.03 g), which was reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2Cl.[CH3:26][O:27][Na]>CO>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[O:27][CH3:26]
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC
Reactant: CO[Na]
Solvent: CO
Product: COc1cc(Cn2cnc3c(OC)nc(N)nc32)c(Br)c(OC)c1OC

Procedure:
A solution of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (see example 51) in MeOH was treated with MeONa at reflux for 1 h. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 5.229 min. 1H-NMR (CDCl3): δ 7.69 (s, 1H), 6.58 (s, 1H), 5.33 (s, 2H), 4.88 (s, 2H), 4.11 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:27][CH2:26][C@H:25]3[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24]3)[C:19]=2[CH:28]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@@H:20]([C:19]5[CH:28]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1ccc2c(c1)[C@H]1CCCN[C@H]1CC2
Product: COc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 69 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-9-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 69% of theory; LC (method 1): tR=2.55 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:15][C:14]([F:17])([F:16])[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)[OH:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-nitro-benzaldehyde (2.5 g, 17 mmol) in tetrahydrofuran (35 ml) was treated with trimethyl-trifluoromethyl-silane (2N in tetrahydrofuran, 10 ml, 20 mmol, 1.2 equiv.) and cooled to 0° C. A solution of tetrabutylammonium fluoride (1N in tetrahydrofuran, 1.70 ml, 2 mmol) was added, upon which the solution turned bright orange and then black. The mixture was stirred at 0° C. for 10 min, then at room temperature for 1 hour. The mixture was quenched with HCl 3N (6 ml), and stirred at room temperature overnight. The reaction was then diluted with ethyl acetate and brine and the two phases separated. The organic phase was washed with water, dried with Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethanol as a yellow solid, 2.1 g (57%). MS (ISP): m/e=220.1 (M−H), δH (300 MHz; CDCl3) 8.28 (2H, d), 7.70 (2H, d), 5.19 (1H, m), 2.84 (1H, d).
Reaction SMILES: Cl.C(O)C.[F:5][C:6]([F:41])([F:40])[C:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]([CH3:34])([CH3:33])[N:29]([CH3:35])[C:28]2=[O:36])=[C:18]([CH2:37][CH2:38][CH3:39])[CH:17]=1)([O:12]COC)[C:8]([F:11])([F:10])[F:9]>>[F:41][C:6]([F:5])([F:40])[C:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]([CH3:33])([CH3:34])[N:29]([CH3:35])[C:28]2=[O:36])=[C:18]([CH2:37][CH2:38][CH3:39])[CH:17]=1)([OH:12])[C:8]([F:11])([F:10])[F:9]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCCN1C(=O)N(C)C(C)(C)C1=O
Agent: Cl
Solvent: CCO
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCCCCN1C(=O)N(C)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Hydrochloric acid-ethanol (2 mol/L, 2 mL) was added to 3-[4-[4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenyloxy]butyl]-1,5,5-trimethylimidazolidine-2,4-dione (55.7 mg, 0.11 mmol), followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel preparative thin-layer chromatography (hexane:ethyl acetate=2:1) to obtain 41.8 mg of the title compound (yield: 82%) as a colorless crystalline powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([Cl:11])[CH:3]=1.P(Br)(Br)Br.[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([CH2:9][O:10][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:7]=1[F:8]
Reactant: OC1CCCCC1
Reactant: OCc1cc(F)c(Br)cc1Cl
Agent: BrP(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cc(COC2CCCCC2)c(Cl)cc1Br
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanol (5.00 g, 21.00 mmol) in dichloromethane (150 mL) was added phosphorous tribromide (8.53 g, 31.50 mmol) at 0° C. The clear reaction solution was stirred at the same temperature for 1 hour, then at an ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to dryness to obtain viscous yellow liquid which was added to a stirred mixture of cyclohexanol (1.68 g, 16.80 mmol) and sodium hydride (60% dispersion in mineral oil, 1.93 g, 21.00 mmol,) in N,N-dimethylformamide (15 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with addition of saturated ammonium chloride (100 mL). The organic layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered the solid. The filtrate was concentrated in vacuo to dryness. The residue was purified by flash column chromatography with ethyl acetate in hexanes (10%) to afford the title compound (2.60 g, 38%) as a viscous liquid: MS (ES+) m/z 320.9, 318.9 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])(=O)=O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([SiH](CCCCCCCC)CCCCCCCC)CCCCCCC.CN(C)[CH:93]=[O:94]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:26][C:22]1[C:21]([F:27])=[C:20]([NH:19][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:7]([CH:93]=[O:94])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCC[SiH](CCCCCCCC)CCCCCCCC
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Temperature: 70 °C
Yield: 41 %

Procedure:
A high pressure vessel was charged with 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl trifluoromethanesulfonate (10 g, 22.1 mmol), palladium (II) acetate (700 mg, 3.12 mmol), triethylamine (7.6 ml, 54.5 mmol), 1,3-bis diphenylphosphinopropane (1.46 g, 3.54 mmol), trioctylsilane (13.2 ml, 29.4 mmol) and N,N-dimethylformamide (110 ml). The reaction mixture was heated at 70° C. under a carbon monoxide atmosphere (13 Bar) for 3 hours. The mixture was cooled and the lower N,N-dimethylformamide layer was separated, filtered and concentrated under reduced pressure. The residue was suspended in methanol, filtered, washed with isohexane and dried to give 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde (3.0 g, 41%) as a pale orange solid; 1H NMR spectrum: (DMSO d6) 4.07 (s, 3H), 7.29 (t, 1H), 7.36 (s, 1H), 7.51 (t, 2H), 8.52 (s, 1H), 8.95 (s, 1H), 10.36 (s, 1H), 10.45 (s, 1H); Mass Spectrum: (M+H)+ 332.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4][CH2:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.[C:21]1([C:27]2[C:28]3[O:33][CH2:32][O:31][CH:30](Cl)[C:29]=3[CH:35]=[CH:36][C:37]=2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>O.O1CCCC1>[C:21]1([C:27]2[C:28]3[O:33][CH2:32][O:31][CH:30]([CH:5]([N:6]=[CH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]#[C:3][Si:2]([CH3:14])([CH3:1])[CH3:15])[C:29]=3[CH:35]=[CH:36][C:37]=2[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)C#CCN=Cc1ccccc1
Reactant: ClC1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(N=Cc1ccccc1)C1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Yield: 109.3 %

Procedure:
To a stirred solution of 1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne (7.609 g.; 34.4 mmol) in 106 ml. of tetrahydrofuran maintained at -78° under N2 was added dropwise 19.5 ml. of 1.63 N n-butyl lithium. To the stirred deep red solution was then added dropwise 11.43 g. (35.4 mmol) of 3,4-diphenylmethylenedioxybenzyl chloride in 35 ml. of tetrahydrofuran. After an additional 30 minutes at -78° water (25 ml.) was added dropwise, the mixture was warmed to 20°, 10% aqueous NH4Cl solution was added and the layers were separated. The aqueous layer was washed twice with benzene, the combined organic phases were washed twice with cold 10% aqueous NH4Cl, once with saturated NaCl solution, dried over Na2SO4 and concentrated to dryness to give 3-(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne as a viscous orange oil (18,86 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH2:3][CH2:2]1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][CH:11]=[C:8](/[CH:9]=[CH:17]/[N+:14]([O-:16])=[O:15])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(OCC2CC2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cccc(OCC2CC2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of 3-cyclopropylmethoxy-benzaldehyde (4.32 g, 24.5 mmol) described in Manufacturing Example 66-1-1, nitromethane (2.64 mL, 49 mmol), ammonium acetate (2.83 g, 36.8 mmol) and acetic acid (40 mL) was stirred for 5 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (3.73 g, 69%).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(BC(C(C)C)C)(C(C)C)C.[Br:41]Br>>[Br:41]/[CH:11]=[CH:10]/[CH:9]([O:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C#CC(CCCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrBr
Agent: CC(C)C(C)BC(C)C(C)C
Product: CCCCCCC(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 3-triphenylmethoxy-1-nonyne (Example 128) with disiamylborane and the bromine by the procedure described in Example 1173 is productive of the title compound.
Reaction SMILES: N#N.[CH3:3][N:4]([CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N:21]([CH3:23])[CH3:22])=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:5]>C(O)C.[Pd]>[CH3:5][N:4]([CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N:21]([CH3:23])[CH3:22])=[C:15]([NH2:18])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:3]
Reactant: CN(C)CC(=O)N1CCc2cc(N(C)C)c([N+](=O)[O-])cc21
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CN(C)CC(=O)N1CCc2cc(N(C)C)c(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To an N2 degassed solution of 1-[(dimethylamino)acetyl]-N,N-dimethyl-6-nitro-2,3-dihydro-1H-indol-5-amine (1.00 g, 3.42 mmol) and 10% Pd/C (3.64 g, 3.42 mmol) in ethanol (100 ml) was added H2 and the reaction was stirred at rt overnight on the Fisher Porter at 50 psi. The reaction was filtered through celite, rinsed with methanol (100 ml), concentrated by rotary evaporation, and high vacced prior to the next reaction to give the title compound (0.9 g, 100%). ESIMS (M+H)+=263.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH2:25]1>>[CH3:13][C:12]1[C:7]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH2:25]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCCC(O)C1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCC(O)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3-aminocyclohexanol instead of cyclopentanamine. The crude material was purified by crystallization from ethanol to afford to afford the titled compound as a hydrochloride salt as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.35-1.65 (m, 11H), 2.33 (s, 3H), 3.90-4.15 (m, 2H), 4.80-4.95 (m, 2H), 7.68-7.75 (m, 2H), 8.20-8.26 (m, 1H), 8.66 (d, J=11.15 Hz, 1H); MS (ESI) m/z 328.8 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.B.C1C[O:17]CC1.OO>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][CH2:12][OH:17])=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: C1CCOC1
Agent: B
Agent: OO
Product: OCC[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the alkene from Example 28D (1-bromo-4-[(1S,2R)-2-vinylcyclopropyl]benzene) in anhydrous THF (50 mL) under N2 was added borane-THF at 0° C. The mixture was stirred at room temperature for two hours and then chilled to 0° C. Aqueous hydrogen peroxide (30%) solution was added, the ice bath was removed, and the mixture was allowed to warm to room temperature with continued stirring for 10 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on silica gel with 4:1 hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH2:4][CH2:3]1>Cl>[C:22]1([C:2]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]3[CH:10]=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)[CH:14]=3)[CH2:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC1(c2ccccc2)CCN(Cc2cncc(-c3ccc(F)cc3)c2)CC1
Agent: Cl
Product: Fc1ccc(-c2cncc(CN3CC=C(c4ccccc4)CC3)c2)cc1

Procedure:
3.62 g of 3-(4-hydroxy-4-phenyl-1-piperidyl-methyl)-5-p-fluorophenyl-pyridine (obtainable by reaction of 3-bromomethyl-5-p-fluorophenyl-pyridine with 4-piperidone, subsequent reaction with C6H5Li and hydrolysis) are heated at 50° with 40 ml of 1N hydrochloric acid for 2 hours and the mixture is worked up in the customary manner to give 3-(4-phenyl-1,2,3,6-tetrahydropyridyl-methyl)-5-p-fluorophenyl-pyridine, melting point: 128°-129°.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[N:3]=1>[OH-].[Pd+2].[OH-]>[OH:15][C:12]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]([C:4]2[N:3]=[CH:2][NH:7][C:6](=[O:8])[N:5]=2)[CH2:14][CH2:13]1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)nc(Cl)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Product: O=c1nc(N2CCC(O)(c3ccccc3)CC2)nc[nH]1

Procedure:
6-Chloro-4-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-1,3,5-triazin-2(1H)-one (341 mg, 1.00 mmol) synthesized in Reference Synthesis Example 21 and palladium hydroxide-activated carbon catalyst (34.1 mg) were used to obtain a mixture of compounds of Reference Synthesis Example 22a and Reference Synthesis Example 22b being the title compounds (424 mg, quantitative) by synthesis in a similar manner to Reference Synthesis Example 3.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[C:31](=O)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[O-]CC.[Na+]>C(O)C>[CH2:32]([C:31]1[C:19]2[CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][C:18]=2[N:15]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:16]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2)C1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 54.2 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (224 mg, 1.04 mmol), tert-butyl 4-oxo-3-(2-phenylacetyl)piperidine-1-carboxylate (330 mg, 1.04 mmol) and sodium ethoxide (70.8 mg, 1.04 mmol) in ethanol (5 mL) were heated to 110° C. in a microwave reactor for 1 h 20 min. The reaction was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and the solvent evaporated under reduced pressure yielding tert-butyl 4-benzyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (280 mg, 54.2%) which was used in the subsequent step as such.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[S:15][C:16]([CH3:19])=[CH:17][N:18]=1)=[O:12].[F:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1F)[C:32]([N:34]1[CH2:37][CH2:36][CH2:35]1)=[O:33]>C(#N)C>[N:34]1([C:32]([C:31]2[CH:38]=[CH:39][C:40]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=3)[C:11]([NH:13][C:14]3[S:15][C:16]([CH3:19])=[CH:17][N:18]=3)=[O:12])=[C:29]([F:28])[CH:30]=2)=[O:33])[CH2:37][CH2:36][CH2:35]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)s1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO)c2)s1
Temperature: 160 °C
Yield: 11.9 %

Procedure:
Potassium carbonate (143 mg, 1.04 mmol) was added to a mixture of 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methyl-1,3-thiazol-2-yl)benzamide (160 mg, 0.52 mmol) and 1-(3,4-difluorobenzoyl)azetidine (102 mg, 0.52 mmol) in acetonitrile (5.0 mL), and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 15 hours. The mixture was allowed to reach ambient temperature and pressure and reduced in vacuo. The residual oil was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in ethyl acetate, to give the desired compound (30 mg)
Reaction SMILES: C([O:5][C:6](=[O:31])[CH:7]([N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.Cl>CO.O>[NH2:17][CH:7]([CH2:8][CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:31])=[O:5]
Reactant: CC(C)(C)OC(=O)C(CC1CCCCCCC1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(CC1CCCCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.1 %

Procedure:
To a solution of 2-(Benzhydrylidene-amino)-3-cyclooctyl-propionic acid tert-butyl ester (2.00 g) in methanol (15 mL) was added 10N HCl solution (30 mL) and the mixture heated to reflux. After 20 h, the mixture was allowed to cool to room temperature, diluted with 20 mL of water, transferred to a separatory funnel and washed with ethyl acetate. The aqueous layer was then neutralized with 10N sodium hydroxide solution and further cooled to 0° C. The white solid was filtered off and air dried to give 590 mg of 2-Amino-3-cyclooctyl-propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Br:8].[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=O>FC(F)(F)CO>[Br:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]2[N:9]([CH2:11][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]3)[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)c(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Cn2c(C3CCN(C(=O)OC(C)(C)C)CC3)nc3cc(Br)c(Br)cc32)CC1

Procedure:
4,5-dibromobenzene-1,2-diamine (100 mg, 0.38 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (160 mg, 0.76 mmol) were stirred for 1 hour in 2,2,2trifluoroethanol. Then Solvent was evaporated and product was purified on silica gel using EA/hex (1/1). Yield: 20 mg. m/z 657.1, rt. 4.2 min.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C@@H:10]([OH:14])[C:11]([NH2:13])=[O:12]>C1(C)C(C)=CC=CC=1>[OH:14][C@H:10]1[C:11](=[O:12])[NH:13][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Solvent: Cc1ccccc1C
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
A mixture of (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (159 mg) and xylene (3 ml) is refluxed for 29 hours. After allowed to cool to room temperature, the mixture is stirred to crystallization. The precipitated crystals are collected by filtration, washed with xylene, and dried at 60° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (1 15 mg).