Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:8]1[N:9]([CH3:44])[C:10]([NH:13][C:14]([C@@H:16]2[NH:20][C@@H:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@:18]3([C:33]4[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[C@H:17]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:15])=[CH:11][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:44][N:9]1[CH:8]=[CH:12][CH:11]=[C:10]1[NH:13][C:14]([CH:16]1[NH:20][CH:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]2([C:33]3[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH:17]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[F:43])=[O:15]
Reactant: Cn1c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 109.3 %

Procedure:
A solution of rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester (0.1 g, 0.16 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 20 h, then concentrated. To the residue was added aqueous saturated NaHCO3 solution until “pH” became 7-8, and the mixture was extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (1-methyl-1H-pyrrol-2-yl)-amide as a light brown solid (95 mg, 93%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)(O)[O-].[Na+]>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: BrCc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A mixture of 15.1 g (0.062 mol) 4-(4-fluorobenzoyl)piperidine hydrochloride, 13.77 g (0.062 mol) of 2-(bromomethyl)naphthalene and 13.6 g (0.16 mol) of sodium bicarbonate in 500 mL of absolute ethanol was stirred at room temperature for 16 hr. The solvent was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo. The residue was recrystallized from 400 mL of methanol to give 11.81 g (54.9%) of white crystalline solid, mp 131°-134° C. The filtrate was subjected to flash chromatography (silica gel, gradiently eluted with CH3OH/CH2Cl2) to give an additional 2.84 g (13.2%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl-:4].[Cl-].[CH3:6][C:7]1([Zr+2:13][C:14]2([CH3:20])[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15]2)[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8]1>C1(C)C=CC=CC=1>[CH3:6][C:7]1([Zr+2:13][C:14]2([CH3:20])[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15]2)[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8]1.[Cl-:4].[CH3:1][N-:2][CH3:3]
Reactant: CNC
Agent: CC1=CC(C)([Zr+2]C2(C)C=CC(C)=C2)C=C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[N-]C
Temperature: -10 °C

Procedure:
Into a 500 ml glass reactor thoroughly purged with nitrogen were charged 100 ml of dry hexane and n-butyl lithium (hexane solution of 1.62 M, 15.6 ml), and they were stirred at -10° C. To the reaction liquid was added 1.25 g of dimethylamine at -10° C. and stirred for 30 min. The temperature of the reaction system was raised to 0° C. After the reaction of 1 hour, nitrogen was blown into the reaction system to remove the residual dimethylamine. To the reaction liquid was dropwise added 200 ml of a toluene solution containing 3.66 g of bis (1,3-dimethylcyclopentadienyl) zirconium (IV)-dichloride over a period of 30 min, and the reaction liquid was stirred at 0° C. The temperature of the reaction system was raised to room temperature. After the reaction of 1 hour, the reaction liquid was heated at 95° C. for 6 hours, and the produced salt was removed by means of filtration. The filtrate was concentrated (about 20 ml). The precipitated solid was filtered, and the obtained brown solid was purified by means of sablimation (200° C., 0.5 mmHg), to obtain 0.60 g of a crystal of bis (1,3-dimethylcyclopentadienyl)-zirconium (IV)-(dimethylamide)chloride (yield: 18%).
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:42][Si](C(C)(C)C)(C)C)[CH2:25][C@@H:26]2[O:34][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[I-].[CH2:51]([Li])[CH2:52][CH:53]([CH3:55])[CH3:54].[Cl-].[NH4+]>C(OCC)C>[CH3:54][CH:53]([CH2:52][CH2:51][CH2:3][C@H:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([OH:42])[CH2:25][C@@H:26]2[OH:34])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH3:1])[CH3:55]
Reactant: [Li]CCC(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC(C)[C@H]2CC[C@H]3C4=CC=C5C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]5(C)[C@H]4CC[C@]23C)cc1
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 99 mg of 20-methyl-1α,3β-bis(t-butyldimethylsilyloxy)-21-p-toluenesulfonyloxypregna-5,7 -diene in 2 ml of diethyl ether was added dropwise, at -50° C. to -60° C., to a diethyl ether solution of iodide and 0.9 ml of a 1.1N diethyl ether solution of isoamyllithium in 2 ml of diethyl ether. After stirring at -30° C. for 1 hour, the reaction mixture was poured into a cold aqueous solution of ammonium chloride, followed by extraction with diethyl ether. The extract was washed with 10% aqueous ammonia, water and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was dissolved in 2 ml of tetrahydrofuran, 1 ml of a 40% aqueous solution of tetra-n-butylammonium fluoride was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The extract was washed with an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was washed with cold ethyl acetate to give 45 mg of cholesta-5,7-diene-1α,3β-diol, whose 1H NMR spectrum was identical with that obtained in Reference Example 8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[N:4][N:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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]>[CH3:25][C@H:14]1[CH2:13][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:3][N:4]=2)[CH2:17][CH2:16][N:15]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: OB(O)c1ccccc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
(S)-tert-butyl 4-(4-chlorophthalazin-1-yl)-2-methylpiperazine-1-carboxylate (2.10 g, 5.79 mmol), phenylboronic acid (1.06 g, 8.69 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.334 g, 0.289 mmol) were placed in a flask under argon. Degassed toluene (50 mL) and aqueous sodium carbonate (2.0 M, 5.0 mL) were added and the reaction heated at 100° C. for 16 hours. The reaction was allowed to cool, diluted with 150 mL of ethyl acetate, and then washed with aqueous K2CO3 (10%), and saturated sodium chloride. The dried organics (MgSO4) were evaporated to give yellow oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave an off-white solid. MS (M+H)+=405.2.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([OH:16])=O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][NH:42][CH2:43][C:44]([O:46][CH2:47]C)=[O:45])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([N:42]([CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:16])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc(CC(=O)O)c(=O)[nH]c2n1
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2ccc(C)nc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a precooled (0° C.) solution of (7-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetic acid (0.995 g, 4.60 mmol) and DhbtOH (0.744 g, 4.60 mmol) in DMF (25 mL)was added DCC (1.04 g, 5.00 mmol) and the mixture was stirred for 40 min at 0° before addition of ethyl N-(2-(tert-butyloxycarbonyl)aminoethyl)glycinate (1.10 g, 5.0 mmol). This mixture was stirred at rt overnight, evaporated in vacuo, redissolved in ethyl acetate (75 mL) and washed with 5% aqueous NaHCO3 (3×25 mL) and with brine (2×25 mL). The organic phase was dried over MgSO4, filtered and evaporated in vacuo. The crude product purified on silica using dichloromethane/methanol (90:10 v/v) as the eluent. Fractions containing the product were pooled and evaporated in vacuo to yield the desired product (790 mg, 41%) (mp 98-100° C.). 1H NMR (DMSO-d6; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.05 (s br, 1H), 7.91 (7.96) (d, 8.0 Hz, 1H), 7.74 (7.71) (s, 1H), 7.10 (d, 8.0 Hz, 1H), 6.90 (6.99) (m, 1H), 4.05 (4.36) (s, 2H), 4.09 (q, J=5.2 Hz, 3H), 3.63 (s, 3H), 3.47 (m, 2H), 3.17 (s, 2H), 3.16 (s, 3H), 1.36 (1.35) (s, 9H). 13C NMR (DMSO-d6): δ 170.44 (170.66), 170.11, 162.65 (162.73), 159.22, 155.83 (155.71), 148.99, 136.43 (136.77), 136.04 (136.17), 128.61 (128.29), 118.21, 112.00 (112.07), 78.04, 51.81 (52.20), 47.63 (48.20), 38.59 (38.45), 33.42 (33.75), 28.27, 24.22. FAB+ HRMS: 433.2086, calc. C21H29N4O6 433.2087.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:25](=[O:26])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
Proline methyl ester hydrochloride (3.3 g) and triethylamine (2.8 ml) were suspended in dry methylene chloride (30 ml). Under cooling, phenylacetylchloride (3.4 g) and triethylamine (3.1 ml) were simultaneously added dripwise to the suspension. Thereafter, the mixture was stirred at room temperature for 2 hours, and the reaction mixture was washed successively with water, 1N HCl, water, saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: carbon tetrachloride) to obtain the end compound an an oil (3.7 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:26][C:20]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=2[C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 2-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-5-chloro-phenol (Example 48, intermediate a) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Brown sticky solid (86%). MS (Turbo Spray): m/z=518.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:32][SH:33].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:36]([O:35][C:31](=[O:34])[CH2:32][S:33][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:37]
Reactant: OC(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCOC(=O)CS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CSC(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-1 -[4-(2-quinolylmethoxy)phenyl]butan-1-ol from Example 2 (830 mg; 2 mmol) and ethyl thioglycolate (0.283 ml; 2.5 mmol) in methylene chloride (20 ml) at 0° C. was added boron trifluoride etherate (0.62 ml; 5 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. After the mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel; hexane-ethyl acetate 3:1) to afford 820 mg of {[4-(4-chlorophenyl)-1-(4-[2-quinolinylmethoxy]phenyl)butyl]thio}acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCCCC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCCCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 55.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.86 g) and 5-amino-2-(4-piperidinopiperidin-1-yl)benzonitrile (0.8 g), the title compound (0.78 g) was obtained, melting point: 252° C./decomposition. b3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].C([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([N:16]1[CH2:17][CH2:18][C:5]2[C:20](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=2)[CH2:19]1)=[O:7]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)N2CCc3cc(O)ccc3C2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
B1 (345 mg, 1.5 mmol) and 3,5-dimethoxybenzoyl chloride (331 mg, 1.65 mmol) were dissolved in DCM (10 mL) and cooled to 0° C. Triethylamine (627 μL, 4.5 mmol) and the solution stirred for 30 minutes prior to warming to room temperature and stirring for 18 hours. The resultant solution was diluted with DCM and washed with NaHCO3 (sat.) and brine, dried over MgSO4 filtered and solvent evaporated under reduced pressure. Purification by column chromatography afforded B12 (146 mg, 31%). 1H NMR (270 MHz, CDCl3) δ 2.74-2.85 (2H, m), 3.58 and 3.91 (2H, m), 3.77 (3H, s), 4.48 and 4.77 (2H, s), 6.49-6.71 (5H, m), 6.72 and 6.98 (1H, d, J=7.7); HRMS (ESI+) calcd. for C18H20NO4 (M++H) 314.1387, found 314.1378; LC/MS (ES+) tr=2.09 min (>?%), m/z 314.3 (M++H); HPLC tr=1.476 min (>99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26]CC4C=CC=CC=4)[CH:22]=3)[CH:17]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)C>[OH-].[OH-].[Pd+2]>[OH:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:8]1([NH:7][C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)[CH:25]=[CH:24]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(OCc4ccccc4)ccc3c2)COC(C)(C)OC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
[5-(6-Benzyloxy-naphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (1.19 g, 0.00257 mol) and 20% Pd(OH)2 on carbon (20:80, palladium hydroxide:carbon black, 0.243 g; Aldrich) was suspended in ethanol (200 mL, 3 mol; Fisher), purged with N2 then stirred under H2 (balloon) at r.t. overnight. LCMS showed partial conversion. The mixture was transferred to a pressure vessel and continuously stirred under 50 psi of H2 for one day. The mixture was filtered, evaporated and dried in high vacuum to give a solid product (0.914 g, yield 95.3%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[O:21])=[CH:17][N:16]=1
Reactant: NCC(O)C(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(O)C(F)(F)F)cn1
Yield: 46 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-amino-1,1,1-trifluoropropan-2-ol instead of methylamine, to the title compound (124 mg, 46%) which was obtained as a white solid. MS: m/e=420.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[O:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH3:29]>>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:28][CH3:29])=[CH:31][CH:32]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Product: COc1ccc(CNCCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Yield: 57.8 %

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.5 g) as starting compound and 4-methoxylbenzaldehyde (0.56 g) were reacted and treated in the same manner as in Example 121 to give 1.13 g of 4-amino-5-chloro-N-((1-(6-(4-methoxybenzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:28])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.[CH3:30][O:31][C:32]([NH:34][CH:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.C(OCC)(=O)C.CN(C=O)C>[CH3:30][O:31][C:32](=[O:33])[NH:34][CH:35]([C:36]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:28])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:37])[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(Br)cc2)cc1)C(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
2-(4′-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (496 mg, 1.11 mmol) was dissolved in methanol and concentrated HCl (2 mL) was added. The solution was stirred at 60° C. for 30 min then concentrated. The resulting residue was treated with 2-methoxycarbonylamino-3-methyl-butyric acid (233 mg, 1.33 mmol), HATU (549 mg, 1.44 mmol) and DMF (10 mL). After cooling this mixture to 0° C., DIPEA (0.970 mL, 5.55 mmol) was added. The reaction mixture was Stirred for 5 hours then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (70% to 90% EtOAc/hexanes) to afford {1-[2-(4′-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (520 mg, 93% over 2 steps).
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[N:6]=2.[CH3:25][OH:26]>>[CH2:17]([O:16][CH2:15][CH2:14][O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:26][CH3:25])[N:4]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[C:9]([NH2:12])[N:8]=1)[CH3:18]
Reactant: CO
Reactant: CCOCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na]
Product: CCOCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
Sodium (1.25 g, 54.4 mmol) was dissolved in methanol (40 ml). After 10 min, 8-bromo-2-{[2-(ethyloxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7 g, 18 mmol) was added with stirring. The mixture was heated to reflux for 2 h. The solvent was removed. The residue on a silica column using DCM: MeOH 100:1 as eluent to give the product as a yellow solid (4.78 g, 78.4%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:19])[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH:25]([CH:30]=O)[CH2:24]2>>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH:25]([CH2:30][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=4[N:10]=[C:9]3[CH3:19])[CH2:6][CH2:7]1)[CH2:24]2
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Reactant: Cc1nc2cc(C#N)ccc2n1[C@H]1CC[C@@H](N)CC1
Product: Cc1nc2cc(C#N)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-1-(4-amino-cyclohexyl)-2-methyl-1H-benzoimidazole-5-carbonitrile and 5-chloro-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C25H27ClN4 (m/e) calcd 418.1924, obsd 419.2 (M+H).