Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]1([F:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:29][C:30]1([F:36])[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(F)(F)CC3)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4,4-difluoropiperidine via General Procedure E to give 19.3 mg of 278 following reverse phase purification. MS (Q1) 483.2 (M)+
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCN(C(C)C)C(C)C.[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29](Cl)=[O:30])=[N+:25]=[N-:26]>C(Cl)Cl>[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])=[O:30])=[N+:25]=[N-:26]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCCCCCCCCCCCNC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred ice cold solution of N-methyldodecanamine (5.0 g, 25.1 mmol) and DIEA (5.70 mL, 1.3 equiv, 32.6 mmol) in anhydrous DCM (150 mL) was added 3-azido-3-methylbutanoyl chloride (4.05 g, 1 equiv, 25.1 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. The content of the reaction was poured into a separatory funnel. The organic layer was washed with 1 M HCl (3×100 mL) and saturated NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.08 g, quant). This material was purified on an ISCO flash chromatography system with a gradient from 10-40% ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to give a pale yellow oil (7.28 g, 89.3%). 1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 3H), 1.26-1.35 (m, 6H), 1.47-1.48 (d, J=4, 6H), 1.50-1.59 (m, 2H), 2.51 (s, 2H), 2.94-3.04 (d, J=40, 3H), 3.30-3.40 (m, 2H). LRMS (ESI+) for C18H36N4O (324.3); Found: 325 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[C:5](=[O:19])[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:20][CH2:21][CH3:22])[N:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][N:6]2[C:5](=[O:19])[C:4]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:20][CH2:21][CH3:22])[N:3]=[C:2]2[CH3:1])=[CH:15][CH:14]=1
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc([N+](=O)[O-])cc2)C1=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2)C1=O
Temperature: 80 °C
Yield: 97.1 %

Procedure:
A mixture of (+/−)-2-methyl-3-[2-(4-nitro-phenyl)-2-oxo-ethyl]-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (528 mg, 1.4 mmol) and SnCl2.2H2O (1.92 g, 8.4 mmol) in 15 mL ethanol is heated to 80° C. for 2 hours. The reaction mixture is poured on to 1M sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases are tried and evaporated to yield (+/−)-3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (475 mg, 97%). LCIMS at 254 nm; [M+H] 350; Rt 2.506 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29](=[O:32])[CH2:30]Br>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:29](=[O:32])[C:28]1[CH:33]=[CH:34][CH:35]=[C:26]([O:25][CH3:24])[CH:27]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cccc(OC)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-methoxyphenacyl bromide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:35]=[N:36][NH:37][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4nn[nH]n4)cc32)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile (intermediate 54, 26 mg, 0.0534 mmol), sodium azide (17.4 mg, 0.267 mmol), and ammonium chloride (14.3 mg, 0.267 mmol) in DMF (1 mL) was heated in a microwave reactor at 130° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, and organic layer was separated, washed with aqueous NaHCO3, water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC to provide the title compound. LC/MS: m/e 530.0 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 8.15 (1H, s), 7.88 (1H, d), 7.65 (1H, d), 7.10-7.20 (4H, m), 6.93 (2H, d), 4.60-5.00 (2H, br s), 1.25 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[S:10][N:9]=[C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:7]=1)[CH3:2].[H-].[Na+].[C:19]([O:23][C:24](=[O:40])[N:25]([CH2:30][C:31]1[CH:39]=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)[CH2:26][CH2:27][CH2:28]Br)([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:6]1[S:10][N:9]=[C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:7]=1)[CH2:28][CH2:27][CH2:26][N:25]([CH2:30][C:31]1[CH:39]=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:40])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCBr)Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)Cc1nc(-n2ccnc2)ns1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of (3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-acetic acid ethyl ester (240 mg, 1.0 mmol) in DMSO (2 mL) was added NaH (70 mg of a 60% dispersion on mineral oil, 1.8 mmol) and benzo[1,3]dioxol-5-ylmethyl-(3-bromo-propyl)-carbamic acid tert-butyl ester (370 mg, 1.0 mmol) subsequently. The solution was stirred for 2 h at 60° C. Water (4 mL) was added and the solution was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave a residue which was purified by column chromatography to afford 370 mg (70%) of 5-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-pentanoic acid ethyl ester as a red oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[N:33]=[C:34]=[S:35]>CN(C=O)C>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[C:27]=1[NH:33][C:34]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)=[S:35]
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1cccc(C)c1N=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(NC(=S)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
A solution of 4-amino-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (150 mg) in DMF (4.5 ml) was added to sodium hydride (60% dispersion in mineral oil, 0.03 g) and the reaction mixture was stirred at ambient temperature for 20 minutes. 2,6-Dimethylphenyl isothiocyanate (0.162 g) was added and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was evaporated and the residual solid-was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia in methanol as eluent. There was thus obtained the title compound (0.112 g); NM Spectrum: (CDCl3) 1.44-1.61 (m, 2H), 1.87-2.08 (m, 5H), 2.32 (s, 3H), 2.36 (s, 6H), 2.94 (d, 2H), 4.04 (m, 5H), 7.1 (s, 1H), 7.19 (m, 3H), 7.29 (s, 1H), 8.69 (s, 1H), 8.9 (s, 1H), 13.37 (s, 1H); Mass Spectrum: M+H+ 466.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[N:3]=1.[CH3:36][O-:37].[Na+]>CO>[CH:23]([NH:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[C:4]2[N:3]=[C:2]([O:37][CH3:36])[CH:7]=[CH:6][N:5]=2)=[N:18][N:19]=1)([CH3:24])[CH3:25]
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(-c2c[nH]c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (50 mg, 0.098 mmol) and sodium methoxide (18.57 mg, 0.344 mmol, Alfa Aesar) in MeOH (1 mL). The reaction was stirred and heated in a Initiator microwave reactor at 85° C. for 30 min and 100° C. for 1 h. The solvent was removed and the residue was purified with RP-HPLC (eluent: 10-50% MeCN in water with 0.1% TFA). The fractions containing the product were combined and concentrated to remove AcCN. The remaining mixture was neutralized with NH4OH and filtered and dried to give N-isopropyl-5-(3-(4-methoxypyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (21.0 mg, 0.060 mmol, 61.0%) as an off-white solid. MS (ESI, pos. ion) m/z: 351.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (1H, br. s.), 9.04 (1H, s), 8.52 (1H, d, J=5.7 Hz), 8.32 (1H, s), 7.69 (1H, d, J=8.6 Hz), 7.58 (2H, dd, J=13.4, 7.9 Hz), 6.68 (1H, d, J=5.7 Hz), 4.09 (3H, s), 3.66-3.82 (1H, m), 1.23 (6H, d, J=6.5 Hz)
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][NH:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])([CH3:9])([CH3:8])[CH3:7].O>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(CNc1c(F)cccc1F)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(CN(C(=O)CBr)c1c(F)cccc1F)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
1.17 ml of bromoacetyl bromide (13.4 mmol) was added to a solution of 3.66 g of [2-(2,6-difluorophenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (60a) (12.2 mmol) in N,N-dimethylacetamide (61 ml) under ice-cooling, and the mixture was stirred at the same temperature for five minutes. Water was added to the reaction mixture, followed by extraction with diethyl ether. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1) to obtain 5.14 g of the title compound (yield: quant.).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CO>[CH2:1]([C:5]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[Cl:13])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: CCCCc1ncc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nccn1Cc1ccccc1Cl
Temperature: 50 °C
Yield: 61.3 %

Procedure:
2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 mL) and added dropwise to a solution of sodium methoxide (from sodium hydride (2.31 g, 0.0934 mol) in methanol (250 mL)). After one hour the solution was evaporated to dryness, and the sodium salt was taken up in dry dimethylformamide (150 mL) and 2-chlorobenzyl bromide (16.3 g, 0.079 mol) was added. The mixture was heated at 50° C. for 17 hours under argon, poured onto ice water and the product was extracted into ethyl acetate. The extract was washed, dried, and concentrated to give 18.5 g of crude product which was chromatographed over silica gel with 2:1 ethyl acetate/hexane to provide 11.9 g (61%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole as an oil. Thin layer chromatography on silica gel with 4:1 ethyl acetate/hexane gave an Rf value of 0.59.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[S:10](Cl)([CH3:13])(=[O:12])=[O:11]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
(2-Fluoropyridin-4-yl)methanol (1 g) was dissolved in DCM (40 ml), added with TEA (3.3 ml) and mesyl chloride (0.67 ml), and the mixture was stirred at 0° C. for 1 hr. The mixture was concentrated and then purified by silica gel column (n-hexane/ethyl acetate=4/1) to obtain the title compound (1.18 g, 77%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.N>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:2]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=3)=[CH:5][CH:4]=2)[CH:17]=[CH:18]1
Reactant: Nc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: O=c1ccn(-c2ccc(-c3ccc(=O)[nH]n3)cc2)cc1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-3(2H)-pyridazinone hydrochloride (1.5 g), 4H-pyran-4-one (0.71 g), and water (20 ml), was heated under reflux for 2 hours. The pH of the hot solution was adjusted to 8 with aqueous ammonia and the mixture was cooled to give the crude product, 1.84 g, m.p. 338°-340° C. Recrystallisation from aqueous ethanol gave the title compound, 1.4 g, m.p. 339°-341° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][C@H:13]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:35]O)=[N:8][CH:9]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1(=[O:66])[NH:60][C:59](=[O:61])[C:58]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:57]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][C@H:13]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:35][N:60]2[C:56](=[O:66])[C:57]3[C:58](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:59]2=[O:61])=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CO)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN2C(=O)c3ccccc3C2=O)nc1
Temperature: 0 °C
Yield: 96 %

Procedure:
1.0 g (2.0 mmol) (2S,4R)-[1-(5-Propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol in 15 ml THF were treated with 764 mg (2.82 mmol) triphenyl phosphine and 420 mg (2.82 mmol) phthalimide at RT. The solution was cooled to 0° C. and 615 μl (3.83 mmol) diethylazo dicarboxylate in 3 ml THF were added. The solution was stirred at RT over night, H2O was added and the inorganic layer was extracted with ETOAc. The combined layers were washed with 1M NaOH, sat. NaHCO3 solution and brine, and were dried over Na2SO4. Column chromatography with EtOAc:hexane 1:2 as eluent yielded 1.20 g (95%) (2S,4R)-2-[1-(5-Propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-isoindole-1,3-dione as white solid, MS: 625 (MH+).
Reaction SMILES: ClCCl.[Sn](Cl)(Cl)(Cl)Cl.[CH3:9][C:10]([CH3:14])([OH:13])[C:11]#[N:12].[Br:15][CH2:16][CH2:17]O>O>[Br:15][CH2:16][CH2:17][O:13][C:10]([CH3:14])([CH3:9])[C:11]#[N:12]
Reactant: OCCBr
Reactant: CC(C)(O)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)OCCBr
Temperature: 2.5 °C
Reaction time: 22 h
Yield: 31.6 %

Procedure:
Dichloromethane (42 mL) and tin tetrachloride (64.9 g, 249 mmol) were added to a 250 mL round bottom flask equipped with a magnetic stirrer, temperature probe, condenser and Argon inlet-outlet. The mixture was cooled to 0-5° C. Acetone cyanohydrin (21.2 g, 249 mmol) was added over 15 min, followed by slow addition of 2-bromoethanol (46.69 g, 373.6 mmol). The reaction mixture was stirred at 20-25° C. for 22 h. The mixture was cooled to 0-5° C., diluted with water (148 mL), and extracted with dichloromethane (3×64 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered and concentrated under vacuum to afford the crude product as a yellow liquid. The material was purified by vacuum distillation (10 mm Hg) using a Vigreux column. The fraction boiling between 75-85° C. was collected to afford 2-(2-Bromoethoxy)-2-methylpropanenitrile as a colorless oil (15.09 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH2:33]([OH:37])[CH2:34][CH2:35][OH:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:36][CH2:35][CH2:34][CH2:33][OH:37])[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCCO
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCCO

Procedure:
By reacting p-tert-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide with the monosodium salt of 1,3-propanediol, there was obtained p-tert-butyl-N-[6-(3-hydroxypropoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide as a white foam.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[O:25][C:24]2[C:17](=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=O)[O:16]1.CO.[BH4-].[Na+]>C(O)=O>[O:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:18]([CH2:19][NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17]=2[O:16][CH2:15]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: Nc1ccccc1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
A mixture of 2-phenoxy-phenylamine (410 mg, 2.22 mmol) and 2,3-(methylenedioxy)-benzaldehyde (500 mg, 3.33 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (253 mg, 6.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5% B, 80 g, 4.0 CV, 60 mL/min) to afford 360 mg (51%) of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl) amine as a white solid.
Reaction SMILES: CC1(C)CN2C(=[O:17])C=C(C3C=CN=CC=3)N=C2NC1.[H-].[Na+].N1[C:30]2[CH2:29][C@H:28]([CH2:31][N:32]3[C:37]4=[N:38][C:39]([C:43]5[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=5)=[CH:40][C:41](=[O:42])[N:36]4[CH2:35][C:34]([CH3:50])([CH3:49])[CH2:33]3)[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[O:17]1[C:30]2[CH:29]=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:27][CH:28]1[CH2:31][N:32]1[C:37]2=[N:38][C:39]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:40][C:41](=[O:42])[N:36]2[CH2:35][C:34]([CH3:49])([CH3:50])[CH2:33]1
Reactant: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Reactant: CC1(C)CN(C[C@@H]2Cc3cccnc3C2)c2nc(-c3ccncc3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(CC2Cc3ccccc3O2)c2nc(-c3ccncc3)cc(=O)n2C1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 22 %

Procedure:
A suspension of 0.51 g (2 mmol) of 7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred at 40° C. for 40 min. 0.52 g (2 mmol) of (+/−)2-iodomethyl-2,3-dihydro-benzofuran (prepared according to Synthesis 1997, (1), 23-25) in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at 60° C. for 20 min. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 99/1/0.1 to 98/2/0.2 to give 0.171 g of pure product obtained in the form of free base. Mp: 147-149° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]3[N:15]=[C:16]([CH3:21])[C:17]([C:18]([OH:20])=O)=[C:13]3[CH:12]=[C:11]([CH3:22])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:31][NH2:32])([CH3:26])([CH3:25])[CH3:24]>S(Cl)(Cl)=O.ClCCl>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:31][NH:32][C:18]([C:17]1[C:16]([CH3:21])=[N:15][N:14]2[C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:10][C:11]([CH3:22])=[CH:12][C:13]=12)=[O:20])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(OCC2CCCCC2)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 110 mg (0.364 mmol) of 7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 120A in 1 ml of thionyl chloride was stirred at 100° C. for 1 h. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was suspended in 3 ml of dichloromethane and then added to a solution of 102.3 mg (0.473 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A in 2 ml of dry dichloromethane. The resulting solution was stirred at room temperature overnight. The solvent was drawn off under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 40 mg (13% of theory, 59% pure) of the target compound.