Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]1[NH:10][C:9](=[O:11])[N:8]([Si](C)(C)C)[C:7](=[O:16])[C:6]=1[F:17])(C)C.FC1C(=O)NC(=O)NC=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[O:39][CH2:38][CH2:37][O:36]2)=[CH:31][CH:30]=1.COC1C=CC(C=O)=CC=1>C(O)CO>[OH:39][CH2:38][CH2:37][O:36][CH:35]([N:10]1[CH:5]=[C:6]([F:17])[C:7](=[O:16])[NH:8][C:9]1=[O:11])[C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: COc1ccc(C2OCCO2)cc1
Agent: COc1ccc(C=O)cc1
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: OCCO
Product: COc1ccc(C(OCCO)n2cc(F)c(=O)[nH]c2=O)cc1

Procedure:
Bis-trimethylsilyl-5-fluorouracil prepared from 5-fluorouracil (10 g) as in Example 1 was reacted with 2-(4-methoxyphenyl)-1,3-dioxolan prepared from p-methoxybenzaldehyde and ethylene glycol, and treated as in Example 8 to give 6.5 g of crystalline 1-[α-(2-hydroxyethoxy)-4-methoxybenzyl]-5-fluorouracil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C1COCC1.[OH:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([O:24][C:25](=[O:26])[C:20]=12)=[O:23]>CCOCC>[CH3:8][S:9]([O:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([O:24][C:25](=[O:26])[C:20]=12)=[O:23])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc2c1C(=O)OC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Triethylamine (0.83 g) and methanesulfonyl chloride (0.89 g) were added to a THF solution (10 mL) of 3-hydroxyphthalic anhydride (1.22 g) under ice cooling and the mixture was stirred at room temperature for 8 hours. After finishing the reaction, ether (20 mL) was added and the mixture was washed consecutively with water and saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crude product was washed with a mixed solvent of ether and n-hexane to obtain 3-methanesulfonyloxyphthalic anhydride (1.75 g) having the melting point of 134–140° C.
Reaction SMILES: [N:1]1([CH2:5][C:6]([O:8]C(C)(C)C)=[O:7])[CH2:4][CH2:3][CH2:2]1.[ClH:13]>>[N:1]1([CH2:5][C:6]([OH:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[ClH:13]
Reactant: CC(C)(C)OC(=O)CN1CCC1
Agent: Cl
Product: O=C(O)CN1CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
tert-Butyl 2-(azetidin-1-yl)acetate (688 mg) prepared in Step A mentioned above was added with 4 N hydrogen chloride (solution in 1,4-dioxane, 10 ml), and the mixture was stirred at room temperature for 20 hours. The deposited solids were taken by filtration, washed with diethyl ether, and then dried under reduced pressure to obtain the title compound as hydrochloride (574 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[CH2:14])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:19])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[CH2:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: C=CCn1c(=O)cc(O)c2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cc(OC)c2ccc(F)cc21
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 7-fluoro-4-hydroxy-1-(2-propen-1-yl)-2(1H)-quinolinone (see Example 130(c) for a preparation) (1.0 g, 4.56 mmol) in DMF (50 ml) at 0° C. was added sodium hydride (0.20 g, 5.0 mmol, 60% in paraffin). To the resulting solution was added methyl iodide (0.3 ml, 4.8 mmol) and stirring continued at 0° C. for 1 h, then at ambient for 18 h. The mixture was evaporated and the residues separated between dichloromethane and water. The organics were isolated, dried and concentrated. Chromatography over silica (50 g SPE, eluting with dichloromethane) provided the title compound (0.386 g, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[CH3:28][NH2:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:29][CH3:28])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CN
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Step F) (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (41 mg), which decomposed in the melting apparatus above 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][OH:35].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[S:16][C:13]=3[N:14]([CH2:33][CH2:34][OH:35])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: OCCBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CCCO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCO)c2sc(CCCO)cc2c1=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(3-hydroxypropyl)-thieno-[2,3-b]pyridine-5-carboxamide (Example No. 8) (0.330 g) in DMF (5 mL) are added K2CO3 (0.363 g) and 2-bromoethanol (0.19 mL). The reaction is heated to 100° C. and stirred for 18 h. An additional 0.19 mL of 2-bromoethanol is added and stirring is continued for 18 h. An additional 0.19 mL of 2-bromoethanol and 0.363 g of K2CO3 is added. After 5 h, 35 mg of NaH (60% oil dispersion) is added. The reaction is stirred for 1 h. The reaction mixture is cooled to rt and concentrated in vacuo. The residue is suspended in CH2Cl2 and H2O. The resulting off-white precipitate is filtered off and purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.145 g (39%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][N:17](C)[C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:5]=1)([O-:3])=[O:2]>C(Cl)Cl.CO.C(O)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18](=[O:24])[C:19]2[C:20](=[CH:13][CH:4]=[CH:5][CH:6]=2)[C:21]([OH:23])=[O:22])[CH:5]=1)([O-:3])=[O:2]
Reactant: CN(Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)C(=O)CCC(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccccc1C(=O)NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
N-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-N-methyl-succinic acid amide, FAB-MS: M+ =350; TLC: methylene chloride/methanol/acetic acid (80:18:2) Rf =0.46.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[N:26]=[CH:25]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37][CH2:36]2.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[C:35]5[C:40](=[CH:41][CH:42]=4)[NH:39][C:38](=[O:43])[CH2:37][CH2:36]5)[N:3]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Cl)nc32)cc1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Nc4ccc5c(c4)CCC(=O)N5)nc32)cc1
Yield: 12.4 %

Procedure:
A mixture of 2-chloro-N-(1-methyl-1H-indazol-5-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1158 mg, 0.349 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (113 mg, 0.697 mmol) and TMSCl (0.300 mL, 2.37 mmol) in nBuOH (3 mL) was stirred at 135° C. for 44 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give 6-(4-(1-methyl-1H-indazol-5-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (25 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[O:15])=[CH:9][C:8]=2[N+:25]([O-])=O)=[CH:5][C:4]([C:28]([F:31])([F:30])[F:29])=[N:3]1.Cl>CCO>[NH2:25][C:8]1[CH:9]=[C:10]([NH:13][C:14]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH:11]=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:5]=1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(NC(=O)c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(NC(=O)c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 34 (27 mg, 0.06 mmol) in 3 ml EtOH was added stannous chloride dihydrate (135 mg, 0.6 mmol) and aq. HCl (3 ml, 1N). The mixture was stirred at r.t. for 17 h. The solvents were evaporated and the residue was dissolved in 4N NaOH and then extracted with diethyl ether. The org. phase was concentrated and subjected to prep HPLC purification to give compound 35.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:43]4[CH:44]=[N:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=4)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(Cn3c([C@H]4CCCC[C@H]4C(=O)O)nc4cc(OCc5nc6ccccc6s5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using analogous conditions described in Step A of Example 97 using racemic cis-2-(5-(benzo[d]thiazol-2-ylmethoxy)-1-(4-bromobenzyl)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and (6-methoxypyridin-3-yl)boronic acid. MS (ESI): mass calcd. for C35H32N4O4S, 604.73; m/z found, 605.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38-8.28 (dd, J=2.6, 0.8, 1H), 8.06-7.96 (m, 2H), 7.96-7.88 (dd, J=8.7, 2.6, 1H), 7.63-7.57 (m, 2H), 7.57-7.52 (m, 2H), 7.49-7.43 (m, 1H), 7.43-7.42 (d, J=2.3, 1H), 7.37-7.28 (dd, J=9.2, 2.4, 1H), 7.27-7.18 (d, J=8.4, 2H), 6.91-6.82 (dd, J=8.7, 0.7, 1H), 5.92-5.73 (m, 2H), 5.72-5.63 (s, 2H), 3.97-3.90 (s, 3H), 3.71-3.60 (m, 1H), 3.03-2.94 (q, J=4.1, 1H), 2.41-2.26 (td, J=12.8, 9.2, 1H), 2.25-2.16 (d, J=13.7, 1H), 2.13-2.04 (d, J=12.6, 1H), 2.02-1.92 (d, J=9.7, 1H), 1.86-1.76 (m, 1H), 1.74-1.64 (d, J=10.0, 1H), 1.60-1.47 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1)=[O:5])[CH3:3].[C:23]([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])(=[O:25])[CH3:24].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:23]([NH:26][C@H:27]([C:29]([NH:1][C@H:2]([C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)=[O:5])[CH3:3])=[O:30])[CH3:28])(=[O:25])[CH3:24]
Reactant: C[C@H](N)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of 4.50 g (15 mM) of 6-[4-(L-alanylamino)-phenyl]-1,2-dihydro-2-oxonicotinic acid, Example 4, 1.97 g (15 mM) N-acetyl-L-alanine, 2.02 g (15 mM) 1-hydroxybenzotriazole, and 150 ml of DMF was stirred at room temperature and 3.09 g (15 mM) of dicyclohexylcarbodiimide was added. After 19 hours the reaction mixture was filtered and the filtrate evaporated to dryness. Water was added and the solids filtered, washed with hot ethyl acetate and ether, and dried, giving 5.01 g of 6-[4-(N-acetyl-L-alanyl-L-alanylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH3:9][O:10][CH2:11][CH2:12][CH2:13]C1C=CN=CC=1CO>>[CH3:9][O:10][CH2:11][CH2:12][CH2:13][C:3]1([CH2:7][OH:8])[CH:4]=[CH:5][CH:6]=[N:1][CH2:2]1
Reactant: O=Cc1cccnc1
Reactant: COCCCc1ccncc1CO
Product: COCCCC1(CO)C=CC=NC1

Procedure:
Following the general method of Example 1, 21.7 g (0.2 mol) of 4-chloro-1-methoxypropane and 21.4 g (0.2 mol) of pyridine-3-carboxaldehyde were converted to 18.87 g (52%) of (4-methoxypropyl-3-pyridinyl)methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1(C(OCC2C=CC=CC=2)=O)[C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1)[CH3:2].[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15]1=[O:16])[CH3:2]
Reactant: CCOC(=O)CCCCCCC1(C(=O)OCc2ccccc2)CCCC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCC1CCCC1=O
Temperature: 130 °C

Procedure:
The crude oil from (ii) above was dissolved in 50 ml. of toluene and reduced over 1 g. of 5% Pd on carbon under 50 psi of hydrogen for 20 hours. The catalyst was removed by filtration and the filtrate refluxed two hours to complete decarboxylation. The toluene was subsequently removed by evaporation and the residual oil distilled on the Kugelrohr apparatus. Heating to 130° C. removed the volatile impurities, and the bulk of the desired product was collected at 175°-180° C. Yield was 11.2 g. (79%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=O)[CH2:10]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)C.[BH4-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH:11]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:10]1
Reactant: C1CCNCC1
Reactant: O=C1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCC(N3CCCCC3)C2)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentanone (5 mg) in THF (0.10 mL) at room temperature was added piperidine (50 μL) followed by titanium(IV) isopropoxide and the resulting solution was heated at 65° C. in a sealed vial for 2 h. The solution was cooled to room temperature, 100 μL ethanol was added followed by sodium borohydride (4 mg), and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was then passed through a clean-up extraction column (2 g) and washed with methanol (0.3 mL). The filtrate was evaporated in vacuo, and the residue was purified by preparative TLC eluting with 10% MeOH/1% NH3.H2O/89% CH2Cl2 to give the title compound (1.2 mg). 1H NMR (400 MHz, CDCl3) δ 1.3-2.5 (m), 3.43 (d, J=8.8 Hz), 3.48 (d, J=8.8 Hz), 3.51 (d, J=8.0 Hz), 3.61 (d, J=8.0 Hz), 4.45 (s), 7.1-7.4 (m), 7.53 (s), 7.58 (s), 7.71 (s), and 7.74 (s). HPLC retention time (1.96 min, method A). MS: 486 (MH+).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].[H][H]>[Pt].CO>[S:9]([OH:13])([OH:12])(=[O:11])=[O:10].[NH2:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)/C=C(/C)N
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CC(C)N

Procedure:
5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of anhydrous methanol, 1.5 equivalent of sulfuric acid and 0.22 g of Pt/C catalyst (Heraeus K0129) were introduced into a 160 ml Parr autoclave. The hydrogenation was carried out for 2 hours at approximately 25° C. under 3-10 bar of hydrogen. The catalyst was then filtered off and the solvent was completely removed by distillation on a rotary evaporator. 6.13 g of pure methyl (RS)-3-aminobutyrate sulfate were obtained as an oil. The hydrogensulfate can be prepared correspondingly.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].CS(C)=[O:17].Cl>O.C(OCC)(=O)C>[F:11][C:10]1[C:2]([OH:17])=[C:3]([CH:7]=[CH:8][C:9]=1[CH3:12])[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1F
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)O)c(O)c1F
Temperature: 140 °C
Reaction time: 12 h

Procedure:
A mixture of 2,3-difluoro-4-methylbenzoic acid (25.0 g), sodium hydroxide (23.2 g) and DMSO (250 mL) was stirred at 140° C. for 12 hr, and then overnight at room temperature, under argon atmosphere. To the reaction mixture was added 6M hydrochloric acid (100 mL) under ice-cooling. Ethyl acetate and water were added thereto at room temperature, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (24.3 g). This compound was used in the next step without an additional purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[NH:3][C:2]=1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[OH-].[Na+].Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1

Procedure:
1 g of 1H -naphth[2,3-d)imidazole-2-thiol are suspended in 100 ml of alcohol in a 250 ml volume sulphonating flask equipped with a stirrer, thermometer, cooler and dropping funnel. A solution of 4.0 g. of sodium hydroxide in 50 ml of water was then added dropwise, and a clear solution formed. The solution was then heated to boiling, 8.2 g of 2-chloromethyl-pyridine-hydrochloride were added, and the resulting mixture was boiled under reflux overnight. The reaction mixture was then concentrated by evaporation, the residue was taken up in 600 ml of ethyl acetate and 200 ml of water, and the ethyl acetate phase was washed twice with 200 ml of water, dried over sodium sulphate, and concentrated by evaporation in vacuo. The residue was recrystallised once from ethyl acetate/petroleum ether and provided 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a melting point of 165°-167°; the hydrochloride melts at 230°-231°.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:36]([CH3:38])[CH3:37])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)Br
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC(N4CCCC4)CC3)ccc21
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a white solid (66%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19]C)=[O:18])[C@@H:14]([NH:21][C:22](=[O:45])[C@H:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]([O:43]C)=[O:42])=[CH:35][CH:34]=2)[NH:24]C(OC(C)(C)C)=O)[C@H:12]1[OH:13]>C(O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:21][C:22](=[O:45])[C@H:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:35][CH:34]=2)[NH2:24])[C@H:12]1[OH:13]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)OC)cc1
Solvent: O=CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)[C@@H](N)Cc2ccc(OCC(=O)O)cc2)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A mixture of methyl 1-(6-amino-9H-purin-9-yl)-3-(N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyroylamino)-1,3-dideoxy-β-D-ribofuranuronate (200 mg) prepared in Example 76 and formic acid (3 ml) was stirred for 3 hours at room temperature and evaporated to dryness. To the residue was added 1N aqueous sodium hydroxide to adjust the resulting solution to pH 7 and a further 1N aqueous sodium hydroxide (3 ml) was added thereto. The mixture was stirred for 15 minutes at room temperature and adjusted to pH 2 with 1N hydrochloric acid. The resulting precipitates were filtered, washed with water and dried to give 1-(6-amino-9H-purin-9-yl)-3-(O-carboxymethyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (125 mg), mp. 209°-212° C. (dec.).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=O)[CH2:31][C:32]1[O:36][CH:35]=[N:34][CH:33]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[O:36][CH:35]=[N:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: COC(=O)Cc1cnco1
Product: COc1ccc(N2CCN(C(=O)Cc3cnco3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 10 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and oxazol-5-yl-acetic acid methyl ester with heating for 5 days to afford the title compound as tan solid (13 mg, 10%). LC/MS (Method B) 3.84 min, [M+1]+ 476.