Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)([OH:12])[CH2:8][CH2:7]1)=O)C.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2([O:12][CH3:26])[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CI
Reactant: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid ethyl ester (2.0 g) was dissolved in dimethylformamide and the mixture was cooled to 0° C. Sodium hydride (250 mg) was added thereto, and the mixture was stirred for 30 min. Then, methyl iodide (0.4 ml) was added, and the mixture was further stirred for 30 min and warmed to room temperature. Water was added thereto, and the mixture was extracted three times with methylene chloride. The organic layer dried over magnesium sulfate and the solvent was evaporated under reduced pressure. Ethanol (20 ml) and a 6N aqueous sodium hydroxide solution (15 ml) were added to the obtained residue, and the mixture was heated under reflux for hr. The reaction mixture was allowed to cool to room temperature, neutralized with 12N aqueous hydrochloric acid, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-methoxypiperidine (1.56 g, yield 93%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCCl>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][N:1]1[CH2:2][CH2:3][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH2:7]2)[CH2:5][CH2:6]1
Reactant: N#CC1=CCC2(CCNCC2)c2ccccc21
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)CCN1CCC2(CC=C(C#N)c3ccccc32)CC1
Reaction time: 8 h

Procedure:
A solution of 2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (A4) (66 mg, 0.3 mmol), 3,3-dimethylbutanal (46 mg, 0.46 mmol) in 1,2-dichloroethane (5 ml) was stirred at 40° C. for 2 h. To the solution was added sodium triactoxyborohydride and the resulting mixture was stirred overnight, followed by treatment of MeOH (1 ml). Evaporation and the residue was dissolved in MeOH (2 ml) and purified by reverse phase C-18 HPLC to give 1′-(3,3-dimethylbutyl)-2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (Compound No. 51). LC-MS: m/e=309.1 (M+H). Rt=1.92 min. 1H-NMR (500 MHz, DMSO-d6): 9.03 (br. s, 1H), 7.49-7.40 (m, 4H), 7.12 (t, 1H), 3.45 (d, 2H), 3.22-3.11 (m, 4H), 2.78 (d, 2H), 2.03 (td, 2H), 1.88 (d, 2H), 1.58-1.54 (m, 2H), 0.92 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.C([Li])CCC.[C:21]([O:24]CC)(=[O:23])C>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([C:21]([OH:24])=[O:23])[C:5]=2[CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
A solution of 2-methoxyfluorene (2.7 g, 13.8 mmol) in 50 mL of THF at -78° C. was charged with n-butyl lithium (0.93 g, 14.5 mmol). The reaction mixture was stirred for 15 min then CO, gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred for additional 2 hr until a colorless solution was obtained. The reaction mixture was diluted with 100 mL of water and 100 mL of ethyl acetate. The layers were separated, the aqueous phase was washed with ethyl acetate (5×25 mL) and acidified to pH 1 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried to afford 2.2 g (66.7%) of 2-methoxy-9-fluorenecarboxylic acid as colorless solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]2[CH:26]=[C:25]3[C:21]([C:22]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]4)=[N:23][NH:24]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:45]Cl>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]2[CH:26]=[C:25]3[C:21]([C:22]([CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:32]4)=[N:23][N:24]3[CH2:45][C:44]3[CH:47]=[CH:48][C:49]([Cl:50])=[C:42]([Cl:41])[CH:43]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)c(Cl)c3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.42 h
Yield: 102.3 %

Procedure:
Sodium hydride (12.2 mg; 0.304 mmol) was added to a stirred solution of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl} piperidine-1-carboxylic acid tert-butyl ester (145 mg; 0.276 mmol) in dry DMF (5 ml) and the mixture was stirred at 23° under nitrogen for 25 min. 3,4-Dichlorobenzyl chloride (0.043 ml, 0.304 mmol; Aldrich) was added, and the mixture was stirred at 23° for 18 h. The solvent was evaporated in vacuo and the residue partitioned between water (25 ml) and ethyl acetate (3×20 ml). The organic layers were washed with 50:50 brine: water (30 ml) and brine, dried (MgSO4) and evaporated in vacuo to give a yellow oil (193 mg). Purification by flash chromatography on silica gel (Merck 9385), eluting with ether: cyclohexane 70:30 gave the title compound as a colourless oil (117 mg; 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26]N[C@@H](C3C=CC=CC=3)C)[N:9]=2)[CH:7]=1.Cl.[NH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44].CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:9]=2)[CH:7]=1
Reactant: COC(=O)CN
Reactant: C[C@@H](NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1

Procedure:
Using synthetic method analoguous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from methyl 2-aminoacetate hydrochloride and DIEA. LCMS (Method 28) [M+H]+=520.1, RT=0.85 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.8, 6.9 Hz), 8.69-8.67 (m, 2H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.22 (t, 2H, J=6.0 Hz), 3.62 (s, 3H), 3.37 (s, 2H), 2.98 (t, 2H, J=6.0 Hz), 2.27 (br, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[OH:13])([O-:3])=[O:2].[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1>N1C=CC=CC=1>[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:13][C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][N:8]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Solvent: c1ccncc1
Product: CC1CCN(C(=O)Oc2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 8 h

Procedure:
200 mg (1.12 mmol) of 5-nitro-1H-indazol-3-ol and 180.4 mg (1.67 mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 20 ml of pyridin were heated under reflux for 5 h and left to stand overnight. Pyridine was distilled off in vacuo, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 48 mg (14%), M+H+: 304.99.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH:22][S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][S:23](/[C:26](=[CH:13]/[C:9]1[S:10][CH:11]=[CH:12][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[C:27]#[N:28])(=[O:25])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Reactant: O=Cc1sccc1Oc1ccccc1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)NCc1ccccc1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and benzylaminosulfonylacetonitrile as in Example 1 gave (E)-2-(benzylaminosulfonyl)-3-(3-phenoxythien-2-yl)acrylonitrile
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:16][C@@:13]3([O:15][CH2:14]3)[CH2:12][CH2:11][CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[C-:18]#[N:19].[Na+].Cl([O-])(=O)(=O)=O.[Li+].CCOC(C)=O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@:13]([CH2:14][C:18]#[N:19])([OH:15])[CH2:16]2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: [C-]#N
Reactant: Fc1cnc(Cl)nc1NC1CCC[C@@]2(CO2)C1
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 100 °C

Procedure:
A suspension of 2-chloro-5-fluoro-N-[(3S)-1-oxaspiro[2.5]octan-7-yl]pyrimidin-4-amine, 49c, (0.50 g, 1.94 mmol), NaCN (0.11 g, 2.33 mmol) and lithium perchlorate (0.25 g, 2.33 mmol) in CH3CN was heated at 100° C. in a pressure tube for 3 h. The mixture was diluted into EtOAc and the organic phase was washed with aqueous saturated NaHCO3 solution, dried with MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc/hexanes) afforded the desired product: 1H NMR (300.0 MHz, CDCl3) δ 7.78 (d, J=2.7 Hz, 1H), 4.85 (d, J=6.6 Hz, 1H), 4.28 (qn, J=4.0 Hz, 1H), 2.45 (s, 2H), 2.16 (d, J=13.0 Hz, 1H), 2.05 (d, J=11.7 Hz, 1H), 1.80-1.71 (m, 3H), 1.46-1.28 (m, 2H) and 1.17-1.06 (m, 1H) ppm; LCMS RT=2.15 (M+H) 285.34.
Reaction SMILES: N1C=CC(C2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)=CC=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:20](Cl)=O>>[F:16][C:17]1[CH:18]=[C:19]([C:20]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Product: Fc1cc(F)cc(-c2nnc3n2CCCN3)c1

Procedure:
The title compound is prepared according to the procedure for 3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (example 17a) from 3,5-difluoro-benzoyl chloride.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([S:20]([N:23]2[CH2:27][CH2:26][S:25][C@H:24]2[C:28]([O:30][C@H:31]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]3[CH2:56][CH2:55]3)[CH:43]=2)[CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][N+:36]([O-:40])=[CH:35][C:34]=2[Cl:41])=[O:29])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)=[O:13])=O)(C)(C)C.C(OCC)(=O)C>Cl>[ClH:39].[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([S:20]([N:23]2[CH2:27][CH2:26][S:25][C@H:24]2[C:28]([O:30][C@H:31]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:50])[F:51])=[C:44]([O:52][CH2:53][CH:54]3[CH2:56][CH2:55]3)[CH:43]=2)[CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][N+:36]([O-:40])=[CH:35][C:34]=2[Cl:41])=[O:29])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 200 %

Procedure:
4-((S)-2-((S)-3-(3-(2-(tert-Butoxycarbonylamino)ethylcarbamoyl)phenylsulfonyl)-thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)-3,5-dichloropyridine 1-oxide (211 mg, 0.245 mmol) was dissolved in HCl 1N in Ethyl Acetate (5 ml, 165 mmol). The reaction was stirred at room temperature for 5 hrs to achieve completion. The reaction mixture was concentrated under vacuum, and the crude product was triturated with Et2O and filtered to give the crude 4-((S)-2-((S)-3-(3-(2-aminoethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride (195 mg, 0.245 mmol, 100% yield).
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.CN(C)[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16]>O1CCCC1.C(OCC)C>[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16]
Reactant: CN(C)C(=O)C1CC1
Reactant: Fc1ccccc1CCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccccc1F)C1CC1

Procedure:
A 1000 ml round-bottomed flask is filled with magnesium (10.7 g, 0.44 mol). Iodine (0.2 g) is sublimated to the magnesium, then diethyl ether (240 ml) is added and under reflux, a solution of 2-fluorobenzyl chloride (47.8 ml, 0.4 mol) and diethyl ether (80 ml) is added to the reaction mixture. The mixture is refluxed for 2 hours and at this temperature a solution of cyclopropanecarboxylic acid dimethylamide (36.2 g, 0.32 mol), prepared according to example 1, and tetrahydrofuran (200 ml) are added. The reaction mixture is stirred for half an hour and under cooling aqueous hydrogen chloride (160 ml, 1:1) is added dropwise to the mixture. The organic layer is dried and the residue is fractionated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[C:5](=[O:8])[NH:6][N:7]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:19][C:9]([C:4]1[C:5](=[O:8])[NH:6][N:7]=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: O=C(O)c1cc(Cl)n[nH]c1=O
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc(Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
30.5 g of 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 18 g of ortho-phenylenediamine and 2 g of DMAP are dissolved in 800 ml of DMF, at room temperature 32.2 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added, and the resulting solution is stirred at room temperature for 4 hours. For workup, the solvent is distilled off and the residue is suspended in water at 70° C. The precipitate is filtered off, washed several times with water and then dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Dissolve aniline (930 mg, 10 mmol) in anhydrous pyridine (25 mL) and cool to 5° C. Add, by dropwise addition, p-toluenesulfonyl chloride (2.1 g, 11 mmol) and stir overnight. Partition between water and ethyl acetate and separate the organic phase. Wash the organic phase with cold 1N hydrochloric acid, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21]CC[Si](C)(C)C)[C:18](=[O:19])[C:13]=2[C:12](O)=[C:11]1CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](OCN1C2C=NNC(=O)C=2C(C(O)(C)C)=C1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([C:12]1[C:13]2[C:18](=[O:19])[N:17]([CH2:20][OH:21])[N:16]=[CH:15][C:14]=2[N:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:11]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(O)c(Cc3ccccc3)n2COCc2ccccc2)c1=O
Reactant: CC(C)(O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Product: O=c1c2c(Cc3ccccc3)cn(COCc3ccccc3)c2cnn1CO
Yield: 71 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 21-(e) except for using 3.08 g (6.26 mmol) of 1-benzyloxymethyl-3-hydroxyphenylmethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Reference example 33-(e) in place of 1-benzyloxymethyl-3-(1-hydroxy-1-methylethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 1.68 g of the title compound was obtained as a pale yellowish solid. (Yield: 71%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3C(OC(C)(C)C)=O)[O:10][C:5]2=[CH:4][C:3]=1[Cl:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][NH:12]3)[O:10][C:5]2=[CH:4][C:3]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2nc(Cl)c(Cl)cc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2oc([C@H]3CCCN3)cc2nc1Cl
Reaction time: 1 h
Yield: 85.6 %

Procedure:
5,6-Dichloro-2-(1-t-butyloxycarbonyl-2-(R)-pyrrolidinyl)furo[3,2-b]pyridine (355 mg, 1.0 mmol) was dissolved in CH2Cl2 (3 mL) and TFA (3 mL) was added at ambient temperature. After stirring for 1 hour, the solvent was removed and the residue was redissolved in CH2Cl2 and washed with saturated K2CO3 solution, dried (MgSO4) and concentrated. The crude product was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a solid (220 mg, 87%): 1H NMR (CDCl3, 300 MHz) δ 1.81-2.05 (m, 3H), 2.15-2.29 (m, 1H), 3.04-3.20 (m, 2H), 4.39-4.42 (m, 1H), 6.70 (s, 1H), 7.80 (s, 1H); MS (CI/NH3) m/z: 257 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19]([Cl:28])=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][Si:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][O:39][CH2:40]Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:43])([CH3:42])[CH3:35])[C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19]([Cl:28])=[N:18][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298 g, 0.00075 mol) and potassium carbonate (0.311 g, 0.0023 mol), were taken in DMF (2 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (0.4 ml, 0.0023 mol) was added drop wise at 0° C. and the mixture was stirred at 20° C. for 4 hours. The mixture was cooled to 10° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate (2×10 ml). The organic layer was washed with saturated brine solution (2×15 ml) and dried over Na2SO4. Solvent was removed and the residue was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.278 g, 70%) as off white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[CH2:17]=O>[Pd].CO>[CH3:1][O:2][CH2:3][C@@H:4]1[N:9]([CH3:17])[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.7 %

Procedure:
To a mixture of tert-butyl (3R)-3-(methoxymethyl)piperazine-1-carboxylate (206 mg), methanol (3.09 mL), and a 36% aqueous formaldehyde solution (187 mg) was added 10% palladium-supported carbon (50% wet product) (76 mg), followed by stirring at room temperature for 4 hours under a hydrogen gas atmosphere (1 atm). The reactant was filtered through celite and then the solvent was evaporated under reduced pressure to obtain tert-butyl (3R)-3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (231 mg) as an oily material.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH2:16]([CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)[CH2:17][CH2:18][CH2:19][CH3:20].CN(C1C=CC=CN=1)C.[Br:45][CH2:46][CH2:47][CH2:48]O.C(O)(=O)C(O)=O>C(Cl)Cl>[Br:45][CH2:46][CH2:47][CH2:48][O:34][C:33]([CH:30]1[CH2:29][CH2:28][CH:27]([CH:24]2[CH2:25][CH2:26][CH:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]2)[CH2:32][CH2:31]1)=[O:35]
Reactant: CCCCCC1CCC(C2CCC(C(=O)O)CC2)CC1
Reactant: OCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: CCCCCC1CCC(C2CCC(C(=O)OCCCBr)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of DCC (11.3 g, 54.5 mmol) in DCM is added slowly to an ice cooled mixture of 4′-pentyl-bicyclohexyl-4-carboxylic acid (15.0 g, 53.5 mmol), dimethylaminopyridine (1.1 g) and 3-bromopropan-1-ol (7.5 g, 54.0 mmol) and DCM (100 ml). After addition is complete, the mixture is stirred at 25° C. overnight. Oxalic acid is added to mop up excess DCC, the mixture is filtered and then evaporated to dryness to afford 4′-pentyl-bicyclohexyl-4-carboxylic acid 3-bromo-propyl ester as a white solid which gave correct mass ion by GCMS (M+401). 1H NMR gave expected signals. The product is used without further purification in the preparation of preferred example 2.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[C@@H:16]([CH3:18])[NH2:17].C(N(CC)CC)C>CN(C=O)C>[NH2:9][C:6]1[C:5]([CH2:10][NH:17][C@H:16]([CH3:18])[C:15]([O:14][CH3:13])=[O:19])=[CH:4][C:3]([Br:2])=[CH:8][N:7]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: COC(=O)[C@@H](C)N
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2.5 g, 7.3 mmol) in DMF (10 mL) was added D-alanine methyl ester hydrochloride (1.67 g, 10.9 mmol) and triethylamine (5 mL, 36 mmol) and the reaction was stirred at room temperature overnight. The reaction is quenched with water (20 mL) and the product was extracted with ethyl acetate (4×20 mL), the combined organic layers dried over sodium sulfate and concentrated. The crude reaction mixture was purified using a silica gel column eluting with ethyl acetate to give the final product as a white solid (1 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.35 (s, 1H), 5.54 (bs, 2H), 3.73 (d, 1H, J=13.2 Hz), 3.54 (d, 1H, J=13.2 Hz), 3.36-3.34 (m, 1H), 2.96 (s, 3H), 1.35 (d, 3H, J=6.8 Hz).