Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)=N1)(C)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=2)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[C:59]4[N:58]=[C:46]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[NH:45][C:43](=[O:44])[C:42]=4[N:41]=[CH:40]3)[C@H:36]([OH:60])[C@@H:35]2[OH:61])=[CH:27][CH:26]=1.[C:76]1([N:82]=[C:83]=[O:84])[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1.C([O-])([O-])=O.[K+].[K+].COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C4N=C(NC(=O)COC5C=CC=CC=5)NC(=O)C=4N=C3)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:75][O:74][C:71]1[CH:70]=[CH:69][C:68]([C:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[C:59]4[N:58]=[C:46]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[NH:45][C:43](=[O:44])[C:42]=4[N:41]=[CH:40]3)[C@H:36]([OH:60])[C@@H:35]2[O:61][C:83](=[O:84])[NH:82][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[CH:73][CH:72]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Cu+2]
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
The THF solution (33 ml) containing 2,6-bis[(4S)-isopropyl-2-oxazoline-2-yl]pyridine (0.06 mmol, 18.1 mg) and copper chloride (II) (0.06 mmol, 10.2 mg) was stirred for a day at room temperature. After the reaction mixture was cooled to −20° C., the THF solution (32 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-N2-phenoxyacetyl-guanosine (0.60 mmol, 431.8 mg) and the THF solution (1.6 ml) of phenyl isocyanate (0.60 mmol, 71.5 mg) and K2CO3 (0.60 mmol, 82.9 mg) were sequentially added thereto. After the mixture was stirred for 24.5 hours at −20° C., the THF solution (1.6 ml) of phenyl isocyanate (0.60 mmol, 71.5 mg) was added thereto. After the mixture was further stirred for 23.5 hours, the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-N2-phenoxyacetyl-2′-O-phenylcarbamoylguanosine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-N2-phenoxyacetyl-3′-O-phenylcarbamoylguanosine were produced at the ratio of 99:1, and the transformation ratio of the reaction was not less than 99%.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[C:5]([F:11])=[CH:4][N:3]=1.[H-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O:36][C@H:37]1[CH:41]=[CH:40][C@@H:39](O)[CH2:38]1)=O>CN(C=O)C.C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:40]3[CH2:41][C@H:37]([OH:36])[CH:38]=[CH:39]3)[C:6]=2[C:5]([F:11])=[CH:4][N:3]=1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Reactant: Fc1ncc(F)c2[nH]cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@@H]1C=C[C@H](n2cnc3c(F)ncc(F)c32)C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-4) (2.0 g, 12.9 mmol, 1 equiv) was dissolved in dry DMF (21 mL). Sodium hydride (542 mg, 13.5 mmol, 1.05 equiv) was carefully added. The resulting mixture was stirred at ambient temperature for 45 minutes at which point triphenylphosphine (507 mg, 1.9 mmol, 0.15 equiv), Pd-tetrakis (745 mg, 0.6 mmol, 0.05 equiv) and (1R,3S)-(+)-cis-4-cyclopentene-1,3-diol 1-acetate (3-1) (2.2 g, 15.5 mmol, 1.2 equiv) in dry THF (21 mL) were added. The mixture was stirred at 60° C. for 16 hours, then cooled to ambient temperature, diluted with 100 mL EtOAc and washed with 50 mL water. The aqueous layer was washed with EtOAc three additional times, and the combined washings were dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase chromatography (5-95% CH3CN/water with 0.1% TFA modifier) to afford (1S,4R)-4-(4,7-difluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enol (3-2) as a white solid. LRMS m/z (M+H) 238.0 found, 238.1 required.
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH2:15]([NH2:18])[CH2:16][CH3:17].[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30](NCC)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30]([NH:18][CH2:15][CH2:16][CH3:17])(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: CCCN
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: CCCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F

Procedure:
2.512 g (9.2 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 2.27 mL (27.6 mmol) propylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification. 1H NMR (300 MHz, DMSO-d6) δ8.19-8.22 (d, 1H, J=7.84 Hz), 8.12-8.16 (t, 1H, J=11.59 Hz), 7.85-7.88 (d, 1H, J=9.90 Hz), 2.80-2.87 (q, 2H, J=6.82), 1.33-1.45 (m, 2H), 0.77-0.82 (t, 3H, J=7.51 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:25]=3[O:34][CH2:35][CH2:36][CH2:37][OH:38])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]>C1COCC1.N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:25]=3[O:34][CH2:35][CH2:36][CH2:37][OH:38])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C#N)cc2)c(OCCCO)c(OC)c1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CN)cc2)c(OCCCO)c(OC)c1
Reaction time: 17 h
Yield: 70.7 %

Procedure:
1.15 g of 4-cyano-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-benzenesulfonamide in 5 ml of THF and 12 ml of methanolic ammonia solution (10%) are hydrogenated in a suitable pressure apparatus in the presence of 1.00 g of sponge nickel catalyst (Johnson-Matthey) at 50° C. and 5 bar for 17 hours. The catalyst is filtered off, rinsed with copious MeOH and THF, and the entire filtrate is evaporated, giving 819 mg of 4-aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-benzenesulfonamide having a content of 82.4% (yield 59.4%); MS-FAB (M+H+)=540.2; Rf (polar method): 1.75 min.
Reaction SMILES: [CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCC(C)S(N)(=O)=O
Reactant: OB(O)c1cccnc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCC(C)S(N)(=O)=O
Yield: 27.8 %

Procedure:
Methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.47 g, 0.97 mmol) was coupled with pyridine-3-boronic acid (0.14 g, 1.2 mmol) according to the methods described in Part J of Example 1 and Part H of Example 370. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) and then recrystallized from methanol, isolated by filtration, and dried for 5 days under high vacuum at 100-140° C. to provide 0.13 g of methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 191-192° C.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[CH:21]=[C:11]2[C:12](=[O:20])[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[CH2:14][CH2:15][N:10]2[N:9]=1)=O)C>C1COCC1.CO.O>[CH:17]1([CH2:16][N:13]2[CH2:14][CH2:15][N:10]3[N:9]=[C:8]([CH2:6][OH:5])[CH:21]=[C:11]3[C:12]2=[O:20])[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2cc(CO)nn2CCN1CC1CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
Sodium borohydride (0.23 mL, 6.1 mmol) was added dropwise to a stirred solution of 5-cyclopropylmethyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.32 g, 1.2 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) under N2 at 0° C. The reaction mixture was stirred at 80° C. for 30 minutes and then diluted with water and extracted with DCM. The aqueous layer was acidified with a 1N solution of HCl and extracted with DCM. The organic layers were combined, dried (NaSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in methanol in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-cyclopropylmethyl-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.21 g, 78% yield) as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:25])[CH2:11][CH2:12][CH2:13][N:14]2[C:19](=[O:20])[C@H:18]([CH3:21])[NH:17][CH2:16][C@H:15]2[C:22]([NH2:24])=[O:23])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:26][C:27]1[CH:32]=[C:31]([N:33]=[C:34]=[O:35])[CH:30]=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]>>[Cl:26][C:27]1[CH:32]=[C:31]([NH:33][C:34]([N:17]2[C@@H:18]([CH3:21])[C:19](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:4][CH2:5]4)[C@H:2]([OH:1])[CH2:9]3)=[O:25])[C@H:15]([C:22]([NH2:24])=[O:23])[CH2:16]2)=[O:35])[CH:30]=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: C[C@@H]1NC[C@@H](C(N)=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@H](C(N)=O)CN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 88 %

Procedure:
In analogy to the procedure described in the second part of example 120 step E, (2S,5S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-5-methyl-6-oxo-piperazine-2-carboxylic acid amide was reacted with 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) to give the titled compound in 88% yield as a colorless solid. MS: 574.3 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=4[Cl:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([O:41]CC)=[O:40].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][C:28]=4[Cl:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([OH:41])=[O:40]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C(F)(F)F)cc5Cl)nn4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.034 g, 0.054 mmol) in 3:1 THF/EtOH (1 ml) was added 1M sodium hydroxide (0.22 ml, 0.22 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated to dryness, taken up in water, and acidified with 1M hydrochloric acid. The reaction was extracted twice with EtOAc, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.030 g, 0.050 mmol, 92% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:17][OH:18].Cl>CCOC(C)=O.CN(C=O)C>[CH3:17][O:18][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1F
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)ccc1S(C)(=O)=O
Temperature: 100 °C
Yield: 95.7 %

Procedure:
To 3-fluoro-4-methylsulfonyl-benzoic acid (490 mg, 2.25 mmol), sodium hydride (270 mg, 6.74 mmol), methanol (1.55 g, 2.0 mL, 48.3 mmol) was added DMF (5 mL) and reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled and diluted with EtOAc and acidified using 1 M HCl solution. The organic layer was separated, washed with saturated aqueous brine solution (3×), dried over sodium sulfate and concentrated in vacuo to give 3-methoxy-4-methylsulfonyl-benzoic acid (496 mg, 95%). ESI-MS m/z calc. 230.0. Found 231.3 (M+1)+; Retention time: 0.49 minutes (3 min run).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[CH3:34]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=3)[C:32]2=[O:33])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1cc(N=C=O)ccc1F
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(F)c(C)c3)c(=O)n(C3CCCC3)c12
Yield: 59.6 %

Procedure:
1-Cyclopentyl-3-(4-fluoro-3-methyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-fluoro-4-isocyanato-2-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 420 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=NC=CC=1>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 5.7 mg (0.03 mmol) of p-toluenesulfonic acid.1H2O and 14.0 mg (0.15 mmol) of 3-methylpyridine, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:2]1([N:11]2[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A solution of 1-bromobenzene (1 g, 6.37 mmol, 1.00 equiv), t-butyl piperazine-1-carboxylate (2.35 g, 12.62 mmol, 2.00 equiv), BINAP (196 mg, 0.63 mmol, 0.10 equiv), Pd2(dba)3 (290 mg, 0.32 mmol, 0.05 equiv), and NaOt-Bu (1.89 g, 18.90 mmol, 3.00 equiv) in toluene (20 mL) was placed in a 100-mL 3-necked round bottom flask and stirred overnight at 100° C. in an oil bath under an inert atmosphere. The resulting mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate/petroleum ether (1:40)) yielding 1.3 g (78%) of t-butyl 4-phenylpiperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[O:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]=2[CH3:24])(O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.B(F)(F)F.CCOCC>ClCCl>[CH:1]([N:14]1[CH2:17][CH:16]([C:19]2[O:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]=2[CH3:24])[CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(C2CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 62.8 %

Procedure:
To a cooled (0° C.) solution of 1-benzhydryl-3-(3-methylbenzofuran-2-yl)azetidin-3-ol (406 mg, 1.099 mmol) in dichloromethane (50 mL) were added triethylsilane (1.775 mL, 10.99 mmol) and trifluoroacetic acid (1.630 mL, 22.01 mmol). The reaction mixture was warmed to rt and stirred for 23 h. After 18 h, boron trifluoride etherate (0.6 mL, 4.73 mmol) was added and the reaction was allowed to stir for an additional 5 h. The reaction mixture was partitioned between sat. NaHCO3 and DCM. The layers were separated, the organic layer was washed with sat. NaHCO3 and brine, dried on Na2SO4 and concentrated. The residue was purified by flash chromatography (heptane/EtOAc, 0%→30%), yielding the title product (244 mg, 63%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[F:29][C:30]([F:41])([F:40])[C:31]1[C:36]([C:37](O)=[O:38])=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:37](=[O:38])[C:36]3[C:31]([C:30]([F:41])([F:29])[F:40])=[CH:32][CH:33]=[N:34][CH:35]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1cnccc1C(F)(F)F

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 4-trifluoromethyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 570. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.4 (s, 1H)) 9.0 (d, 1H) 8.4 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.7 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.7 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:29]([NH:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:30].Cl>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][CH2:20][OH:21])[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:29]([NH:31][CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)=[O:30]
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Product: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(N3CCC[C@H](NCCO)C3)ccc12

Procedure:
Prepared according to the method of example 50(b) using 6-chloro-N-(cyclohexylmethyl)-2-[(3S)-3-[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]amino]-1-piperidinyl]-5-quinolinecarboxamide Example 52(a)) (190 mg) and hydrochloric acid (4M in 1,4-dioxane) (2.0 mL). Purification (SiO2, dichloromethane:methanol:ammonia in methanol (7 M) 96:3:1) and subsequent recrystallisation (acetonitrile) gave the title compound as a solid (53 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6]
Reactant: [H][H]
Reactant: CN(C)C=Nc1c(C(=O)CN=[N+]=[N-])ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Agent: [Pd]
Solvent: CO
Product: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Yield: 91.6 %

Procedure:
The compound (40) (35 mg) obtained in item (7) above was dissolved in methanol (3.5 ml) and the resulting solution was subjected to catalytical reduction by blowing hydrogen therein in the presence of palladium black as catalyst at room temperature for 30 minutes. The reaction solution was filtered and the filtrate was concentrated. The resulting solid was washed with ethyl acetate to yield the titled compound (41) (29.7 mg) as an insoluble solid. Yield: 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1.[CH3:13][NH2:14].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH2:10][CH:11]([NH:14][CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCCCOc1cncc(Cl)c1
Reactant: CN
Agent: Cl
Solvent: CO
Product: CNC(C)CCOc1cncc(Cl)c1
Temperature: 100 °C
Yield: 76.6 %

Procedure:
Crude 3-bromo-1-(5-chloro(3-pyridyloxy)butane (1.50 g, 5.67 mmol) from the previous step was dissolved in methanol (10 mL) and added to a 40 wt % aqueous solution of methylamine (40 mL) in a heavy-walled glass pressure-tube apparatus. The mixture was stirred and heated at 100° C. (oil bath temperature) for 14 h. After cooling, the mixture was concentrated by rotary evaporation, and the product was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give a pale-brown oil. The product was dissolved in cold, 15% aqueous HCl (15 mL), stirred at 0° C. for 45 min and extracted with chloroform (50 mL). The aqueous layer was cooled to 0° C., basified with 15% aqueous NaOH solution to pH 8-9 and extracted with chloroform (3×75 mL). The combined extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 0.929 g (76.6%) of a pale-yellow oil.