Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH:7]=[CH:8][C:9]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[C:23]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]O)(=[O:27])[C:24]([CH3:26])=[CH2:25].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH3:26][C:24](=[CH2:25])[C:23]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:17][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9](=[O:10])[CH:8]=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=2)=[CH:20][CH:19]=1)=[O:27]
Reactant: C=C(C)C(=O)OCCCCCCO
Reactant: COc1ccc(C=CC(=O)Oc2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCOC(=O)c1ccc(OC(=O)C=Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
This step involved adding a polymerizable group and the remainder of the spacer group to the compound of Step 3. The compound of Step 3 (25.5 g=85 mmole) was slurried in 800 mL dichloromethane. The compound of Step 1 (15.8 g=85 mmole) was added in one portion, followed by dicyclohexylcarbodiimide (17.5 g=85 mmole) and 4-pyrrolidinopyridine (1.3 g=8.5 mmole). The mixture was stirred at room temperature for 4 hours, and then vacuum filtered. The filtrate was washed with 5% aqueous acetic acid, H2O, 3 portions 5% aqueous Na2CO3, H2O, and then dried over MgSO4 and freed of solvent on a rotary evaporator. The resulting solid was crystallized from low-boiling ligroin via a Soxhlet extractor. Fluffy white crystals, m.p. 65°-67° C. Yield 31.8 g. Elemental Analysis: C27H30O7, mol. wt. 466.5. Anal. Calcd: C, 69.5; H, 6.5, O, 24.0. Found: C, 69.5; H, 6.5; 1H NMR (CDCl3): δ (ppm) 4.4 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[OH:17])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[CH:9][C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=3[O:17][C:4]=2[CH:3]=1
Reactant: Cc1cccc(O)c1C=Nc1ccc(Br)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2c1C=Nc1ccc(Br)cc1O2
Temperature: 140 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 2-[(4-bromo-2-fluorophenyl)iminomethyl]-3-methylphenol (31.7 g, 102.9 mmol) in DMSO (0.27 L), K2CO3 (28.6 g, 206.9 mmol) and 18-Crown-6 (477 mg, 1.8 mmol) were added. The resulting mixture was stirred at 140° C. for 1 h and then allowed to cool to ambient temperature. Water was added and the mixture was extracted with toluene/ethyl acetate (8:2). The combined organic layers were washed with water and with brine, dried (Na2SO4) and evaporated to afford the crude compound which was purified by flash chromatography (SiO2, CH2Cl2) to give 7-bromo-1-methyldibenz[b,f][1,4]oxazepine (25.05 g, 84%). 1H-NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 7.01 (m, 2H), 7.18-7.37 (m, 4H), 8.77 (s, 1H). (m/z)=288+290 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[NH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1>CS(C)=O>[Cl:3][C:4]1[N:5]=[N:6][C:7]([O:19][C:15]2[C:14]([CH3:20])=[CH:13][C:12]([NH2:11])=[C:17]([CH3:18])[CH:16]=2)=[CH:8][CH:9]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(Cl)nn2)c(C)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.8 g of sodium hydride was added in portions to a stirred solution of 30 g of 3,6-dichloropyridazine and 27.4 g of 4-amino-2,5-dimethylphenol in 300 ml of dimethyl sulfoxide. The temperature of the mixture rose to 65° C. The mixture was then stirred for 18 hours at room temperature, poured over ice water and filtered. Recrystallization of the filter cake from methanol gave 4-(6-chloro-3-pyridazinyloxy)-2,5-dimethylbenzeneamine, as a brown solid (5A), mp: 138°-140° C.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]>[Rh].[O-2].[Al+3].[O-2].[O-2].[Al+3].C(O)C>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: [Rh]
Agent: [Al+3]
Agent: [O-2]
Solvent: CCO
Product: CC(C)(C)S(=O)(=O)C[C@@H](CC1CCCCC1)C(=O)O
Reaction time: 10 h
Yield: 78.7 %

Procedure:
A mixture of 2 g (7 mmol) of (S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamic acid (EPA 0236734) and 2 g of rhodium/aluminium oxide catalyst (5%) in 100 ml of ethanol is hydrogenated for 10 hours at 50° and 10 bar. After filtering off the catalyst the reaction solution is evaporated under reduced pressure and the residue is recrystallized from a 9:1 mixture of hexane and ethyl acetate. There are obtained 1.6 g of (S)-α-[(tert-butylsulphonyl)methyl]cyclohexanepropionic acid as colourless needles; MS: 308 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.Cl.[NH2:25][C:26]1([C:29]#[N:30])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:29]([C:26]1([NH:25][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:4]4[C:5]5[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=5)[N:2]([CH3:1])[N:3]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:22])[CH2:28][CH2:27]1)#[N:30]
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Reactant: N#CC1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C#N)CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and 1-aminocyclopropanecarbonitrile hydrochloride (46 mg, 0.39 mmol) in DMF (3 mL) was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered, the solid was washed with DMSO and MeOH then dried to give N-(1-cyanocyclopropyl)-2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (22 mg, 23%) as a white solid. MS: (M+H)+=372; 1H NMR (300 MHz, DMSO): δ 12.98 (s, 1H), 9.14 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 7.58 (s, 1H), 7.25 (d, 1H, J=8.4 Hz), 4.17 (s, 3H), 2.56 (s, 3H), 1.77 (d, 2H, J=6.0 Hz), 1.48-1.44 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][C:20]=2[O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:26])=[CH:21][C:20]=2[O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:17][CH:18]=1
Reactant: COCCOc1cc(C(=O)O)ccc1-c1ccc(F)cc1
Reactant: Nc1ccc2cccnc2c1
Product: COCCOc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccc(F)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (21 mg, 0.14 mmol) and 4′-fluoro-2-(2-methoxyethoxy)-1,1′-biphenyl-4-carboxylic acid (D77) (50 mg, 0.17 mmol) as an orange solid. MS(ES): MH+ 417, M-H+ 415
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([NH:28][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[N:9]=[CH:10][N:11]4[C:17]5[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=5[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=34)[N:4]=2)[CH2:27][CH2:26]1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CNC4CC4)n3)ncn2-c2ccc(F)cc2C1=O
Yield: 63.5 %

Procedure:
1.7 g (5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 2 hours with 5 ml (7.2 mmol) of cyclopropylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture the residue was taken up in methylene chloride and washed with aqueous ammonia. After drying the organic phase over magnesium sulfate, evaporation of the solvent and recrystallization of the residue from ethyl acetate and hexane there were obtained 1.17 g (65%) of 3-(5-cyclopropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 176°-178°, which was converted into the hydrochloride.
Reaction SMILES: [F:1][C:2]1([F:45])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[CH:38]=[N:39][N:40](COC)[CH:41]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[F:45][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[CH:41]=[N:40][NH:39][CH:38]=2)[CH2:4][CH2:3]1
Reactant: COCn1cc([C@H]2CCC(F)(F)C[C@@H]2Oc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)c(F)c2)cn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1ccc(O[C@H]2CC(F)(F)CC[C@@H]2c2cn[nH]c2)cc1F
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a solution of the 4-({(1S*,2R*)-5,5-difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.12 g, 0.19 mmol) prepared in Example 147d and triethylsilane (0.15 mL) in dichloromethane (4.0 mL), trifluoroacetic acid (3.0 mL) was added at room temperature, and the reaction solution was stirred for 2 hours. The reaction solution was concentrated, then ethanol (1.0 mL) and 2 M hydrochloric acid (4.0 mL) were added to the residue, and the mixture was stirred at 100° C. for 3 hours. After allowing to cool, the reaction solution was neutralized with sodium hydrogencarbonate, and the resulting solid was collected by filtration. The solid thus collected by filtration was purified with silica gel chromatography (dichloromethane/methanol=95:5) to yield the title compound (40 mg, 48%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH3:10])[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[CH2:17]([O:16][C:14]([NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH3:10])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C[C@H](N)C(=O)O)C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of the 5,5,5-trifluoro-L-leucine (12 g) in H2O (150 mL) at 0° C. was added benzyl chloroformate (4.8 mL, 34 mol), followed by dropwise addition of 1 M aqueous NaOH (120 mL, 120 mmol). More benzyl chloroformate (4.8 mL, 34 mmol) was added. The mixture was further stirred at 0° C. and the pH of the mixture became ˜7. The mixture was washed with Et2O (2×) and acidified with aqueous HCl. The aqueous layer was extracted with EtOAc (3×), dried (Na2SO4) and concentrated in vacuo to provide N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucine. The crude acid was dissolved in Et2O and treated with a solution of diazomethane in Et2O. Chromatography over silica gel and elution with hexanes:Et2O (7:3) gave methyl (4S)—N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucinate as the less polar fraction.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,4-dichloroquinazoline (2 g, 10.05 mmol) in THF (50 ml) at 0° C. was added tert-butyl 4-aminopiperidine-1-carboxylate (2.2 g, 11.05 mmol), followed by TEA (2.8 ml, 20.1 mmol) and catalyst DMAP (3 mg). The reaction mixtures was then warmed up to room temperature and stirred for 20 hours. The product was extracted with EtOAc (×2). The organic layers were combined and washed with water, and brine, and dried (MgSO4) and concentrated under vacuum. The product was isolated after silica gel column chromatography using 20% EtOAc and 80% hexane as eluent.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].Cl.[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31]>>[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared by saponification of 4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 204D, followed by coupling with methionine methyl ester hydrochloride and saponification as described in Examples 304E-G. 1H NMR (300 MHz, CDCl3) δ 8.40 (bs, 1H), 8.25 (dd, J=4.1, 1.9 Hz, 1H), 7.99 (dd, J=22.8, 8.1 Hz, 1H), 7.53-7.50 (m, 1H), 7.36-7.21 (m, 7H), 5.91 (bd, J=7.7 Hz, 1H (NH)), 5.18 (s, 2H), 4.70-4.58 (m, 1H), 3.66 (s, 3H, OMe), 2.18-2.00 (m, 5H), 1.95-1.82 (m, 1H), 1.65-1.55 (m, 4H, contains SMe). MS (CI) 465 (M+H)+. Anal calcd for C26H28O4N2S: 0.30H2O solvate: C, 66.45; H, 6.13; N, 5.96. Found: C, 66.45; H, 6.15; N, 5.97. HRMS FAB Calcd m/z MH+ for C26H28O4N2S 465.1848, found 465.1869.
Reaction SMILES: C([O:8][C:9](=[O:30])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:29])[C@H:16]([CH2:27][OH:28])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H].Cl>CO.[C].[Pd].O.C(OCC)(=O)C>[C:21]1([S:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:30])=[O:8])=[O:29])[CH2:27][OH:28])(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](CO)NS(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@H](CO)NS(=O)(=O)c1ccccc1
Yield: 85 %

Procedure:
N-benzenesulfonyl-L-seryl-L-proline benzylester (1.96 g, 4.5 mmole) was dissolved in methanol (40 ml), and water (5 ml) solution of sodium bicarbonate (0.42 g, 5 mmole) was added thereto. Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 3 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in water (20 ml) and 1N aqueous hydrochloric acid (10 ml) was added thereto. The solution was concentrated under reduced pressure to produce solid material, which is a white residue. The residue was dispersed in ethyl acetate (100 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid. It was recrystallized from ethyl acetate and petroleum to obtain N-benzenesulfonyl-L-seryl-L-proline (yield: 1.31 g, 66.9%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22](O)[CH2:21][CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19]2
Reactant: OC1CCCc2cc(F)ccc21
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OC2CCCc3cc(F)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.82-1.88 (1H, m), 1.99-2.10 (2H, m), 2.28-2.34 (1H, m), 2.74-2.94 (2H, m), 5.35 (1H, t, J=4.0 Hz), 5.85 (1H, d, J=1.6 Hz), 6.84-6.89 (2H, m), 7.29 (1H, dd, J=5.6 Hz, 8.4 Hz), 7.36 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.63 (1H, d, J=2.0 Hz), 7.86 (1H, s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H15FN4O, 335; Found, 335.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][N:12]=1
Reactant: CSc1ncc(Cc2ccccn2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccccn2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (3.4 g) was heated at 130°-135° for 7 hours. The cooled residue was triturated with hot water to give 2-[2-(5-methyl-4- imidazolylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone and this product was treated with dilute ethanolic HCl to give the title compound m.p. 207°-210° (aqueous ethanol)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([Si:15]([CH3:35])([CH3:34])[O:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:18]=1[CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]([Si:15]([CH3:35])([CH3:34])[O:16][C:17]1[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=1[CH2:25][P:26](=[O:33])([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])([CH3:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C)OCC
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalylchloride (0.6 g, 6.7 mmol) in 20 mL methylene chloride is cooled to -70° C. Dimethylsulfoxide (0.6 mL, 8.4 mmol) is added dropwise. The solution is warmed to -30° C. then cooled to -70° C. A solution of diethyl [[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(hydroxymethyl)phenyl]methyl]phosphonate (1.73 g, 4.45 mmol) from Preparation 18 in methylenechloride (15 mL) is added to the reaction mixture. The reaction mixture is stirred for 0.5 hours then warmed to -35° C. Triethylamine (4.7 mL, 33.5 mmol) is added and the mixture allowed to warm to room temperature. Methylenechloride (400 mL) is added and the organic phase is washed with 100 mL H2O. The organic phase is dried (MgSO4) and concentrated. The residue is passed through a 200-g silica gel plug using 5% MeOH/CH2Cl2 as the eluent. An oil of diethyl [[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-formylphenyl]methyl]phosphonate is obtained (1.67 g, 97%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:32]1([CH:38]([CH:43]2[CH2:47][CH2:46][CH2:45][O:44]2)[NH:39][C:40]([NH2:42])=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1.CCOC(C)=O>[CH3:31][NH:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:42][C:40]([NH:39][CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:43]3[CH2:47][CH2:46][CH2:45][O:44]3)=[O:41])=[CH:3][C:4]=2[N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]=1
Reactant: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: NC(=O)NC(c1ccccc1)C1CCCO1
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)NC(c3ccccc3)C3CCCO3)ncc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6-chloro-N-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (400 mg, 0.941 mmol), 1-(phenyl(tetrahydrofuran-2-yl)methyl)urea (228 mg, 1.035 mmol), cesium carbonate (920 mg, 2.82 mmol) and BrettPhos precatalyst (52.6 mg, 0.066 mmol) were taken up in dioxane (9.5 ml) in a 20 mL microwave vial. The vial was evacuated and back-filled with N2 (×3). The reaction mixture was stirred at 100° C. for two hours. Room temperature was attained. The crude reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo, taken up in 5 ml of DCM, and purified on silica gel 5-50% DCM/EtOAc to give 1-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(phenyl(tetrahydrofuran-2-yl)methyl)urea. MS ESI calc'd. for C38H37N6O2 [M+H]+ 609. found 609.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[C:18]([Cl:24])[CH:17]=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][C:18]=2[Cl:24])[C:6]=1[CH:7]=[O:8]
Reactant: Clc1cc(Br)ccc1CBr
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1Cl

Procedure:
The title compound was prepared by reaction of 4-chloro-5-formyl-2-phenylimidazole with 4-bromo-2-chlorobenzyl bromide according to the process mentioned in Example 1a). In this case, starting from 2.0 g (9.68 mmol) of 4-chloro-5-formyl-2-phenylimidazole, 2.6 g of the title compound was obtained.