Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1.[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>[Na]>[CH:21]1([NH:27][C:28]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]3[O:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[O:13][CH2:12]3)[OH:10])[CH2:4][CH2:3]2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C=NC1CCCCC1
Reactant: NC1CCN(CC(O)C2COc3ccccc3O2)CC1
Agent: [Na]
Product: O=C(NC1CCCCC1)NC1CCN(CC(O)C2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine (2.0 g, 0.0072 m) prepared according to Example 3(c) in sodium dried benzene was treated with cyclohexyl isocyanate (0.99 g 0.008m) in sodium dried benzene (25 mls). The mixture was stirred at room temperature for 18 hours. The solid was filtered off and washed with benzene. The white solid was suspended in ethyl acetate and acidified with ethanolic hydrogen chloride until the solution was acidic. The title compound was filtered off, washed with ether and dried (1.47 g 46.5%)
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (102 mg, 0.30 mmol) in dichloromethane (15 mL) was added ethyl isocyanate (0.026 mL, 0.33 mmol), mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The solvent was removed under reduced pressure and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 15 to 20% EtOAc:Hexane to get 1-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-3-ethylurea (484) (120 mg 97%). 1H NMR (300 MHz, CDCl3) δ ppm 0.91 (t, J=7.18 Hz, 3H) 2.05-2.20 (m, 2H) 2.21-2.39 (m, 2H) 2.96-3.28 (m, 6H) 4.07-4.19 (m, 2H) 4.35 (br. s., 1H) 5.58 (s, 1H) 6.43 (s, 2H) 7.06-7.36 (m, 10H)
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC>CS(C)=O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:21]([C:28]2[NH:27][N:26]=[CH:25][C:24]=2[F:23])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Temperature: 100 °C

Procedure:
Pd(Ph3P)4 (17.33 mg, 0.015 mmol) was added to solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 4.2, 133 mg, 0.3 mmol) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole (101 mg, 0.270 mmol) in DMSO (1 mL) in a vial under an argon atmosphere. The vial was sealed and the RM mixture was heated at 100° C. for 18 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc from 10% to 50% EtOAc) to afford the title compound as an off-white powder. HPLC (Condition 4) tR=5.5 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=399.2 [M−H]−.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:7]1=[O:15]
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1Cc2ccccc2N1C1=NCCS1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(=O)N(C3=NCCS3)c3ccccc32)cc1
Yield: 53.7 %

Procedure:
To a warmed benzene solution of 1-(2-thiazolin-2-yl)-indolin-2-one (2.0 g, 7.2 mmol) and p-methoxybenzaldehyde (1.5 g, 11 mmole) is added piperidine (0.6 ml). The mixture is heated at reflux temperature for 2 hours. The reaction mixture is then washed with NaHSO3 solution, diluted HCl and water. The organic phase is dried over anhydrous MgSO4 and concentrated in vacuo. The residue is recrystallized once each from acetone/hexane, acetonitrile and CHCl3 /methanol and gives 1.3 g (43%) of the product (m.p. 164.5°-167° C, softens at 149° C).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH3:17])[C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19])#[N:2].[H-].[Na+].[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30]I)(=[O:24])[CH3:23]>CS(C)=O>[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][N:10]1[C:11](=[O:18])[C:12]2[N:13]([CH3:17])[CH:14]=[N:15][C:16]=2[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:9]1=[O:19])(=[O:24])[CH3:23]
Reactant: CC(=O)O[C@H](C)CCCCI
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2CCCCCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCC#N)c1=O
Reaction time: 0.42 h
Yield: 86.7 %

Procedure:
To a stirring solution of 0.31 g 3-(cyanopentyl)-7-methylxanthine (1.2 mmol) in 20 ml dimethyl sulfoxide was added 30 mg sodium hydride (1.3 mmol). After 25 minutes, 0.34 g of (R)-5-acetoxy-1-iodohexane (1.3 mol) was added and the mixture was stirred for 24 h. The mixture was then quenched with 70 ml water and extracted three times with 30 ml ethyl acetate. The combined extracts were washed two times with 35 ml saturated aqueous sodium chloride solution and dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel) eluting with 5% methanol-ethyl acetate to give 0.42 g (R)-1-(5-acetoxyhexyl)-3-(5-cyanopentyl)-7-methylxanthine (88% yield) as a viscous oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12](O)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:37]>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([NH2:37])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(N)=O)n1Cc1ccccc1[N+](=O)[O-]

Procedure:
(E)-3-[2-n-Butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5yl]-2-benzyl-2-propenoic acid, prepared in Example 58, is treated with thionyl chloride and then ammonium hydroxide, as described in Example 57, to give the title compound.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:10]([O:31][C:28]1[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
11.06 g (162.5 mmol) of imidazole in 30 ml of dimethylformamide are added dropwise at room temperature to 35.24 g (130.0 mmol) of tert-butylchlorodiphenylsilane and 11.25 g (65.0 mmol) of 4-bromophenol in 150 ml of dimethylformamide. After the reaction mixture has been stirred at room temperature for 1 hour, it is poured into 1000 ml of 5% strength aqueous sodium bicarbonate solution and extracted twice with 400 ml of dichloromethane, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is evaporated to dryness. Chromatographic purification (silica gel/hexane: ethyl acetate 8:2) gives 23.40 g of 4-bromophenyl tert-butyldiphenylsilyl ether. ##STR27##
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH3:21])[CH2:18][CH2:19]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Cl)cc2)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine and 4-chlorobenzenesulphonic acid chloride. Melting point: 105°-106° C.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH:23][CH2:24][CH2:25][NH2:26])[CH3:22]>CCOC(C)=O.CO>[C:1]([NH:26][CH2:25][CH2:24][NH:23][CH2:21][CH3:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNCCN
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Trityl chloride (˜3.45 g, ˜12.5 mmol) was slowly added into N-ethylethlenediamine (˜1.1 g, ˜12.5 mmol) DCM (methylene chloride) solution with stirring. After the reaction mixture was stirred at room temperature overnight (˜23 hours), HPLC indicated that the reaction was complete. After Biotage silica gel chromatography was performed (EtOAc/MeOH), Compound 2 was obtained as a white solid (˜3.5 g, ˜85% isolated yield), and the product was confirmed by proton NMR.
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:22][N:9]2[CH2:10][CH2:11][C:12]3[C:17]([C@H:8]2[CH2:7][C@H:6]1[O:23][C:24](=[O:40])[CH:25]([NH:29]C(OCC1C=CC=CC=1)=O)[CH:26]([CH3:28])[CH3:27])=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:2]([CH3:4])[CH3:3]>CO.[Pd]>[CH2:1]([C@@H:5]1[CH2:22][N:9]2[CH2:10][CH2:11][C:12]3[C:17]([C@H:8]2[CH2:7][C@H:6]1[O:23][C:24](=[O:40])[C@@H:25]([NH2:29])[CH:26]([CH3:28])[CH3:27])=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cc2c(cc1OC)[C@H]1C[C@@H](OC(=O)C(NC(=O)OCc3ccccc3)C(C)C)[C@H](CC(C)C)CN1CC2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1OC)[C@H]1C[C@@H](OC(=O)[C@@H](N)C(C)C)[C@H](CC(C)C)CN1CC2
Reaction time: 8 h
Yield: 86.2 %

Procedure:
1 (200 mg, 0.63 mmol) was dissolved in 3 mL anhydrous CH2Cl2 and DMAP (75.0 mg, 0.63 mmol) and Cbz-L-valine (190 mg, 0.75 mmol) were added and the mixture stirred for 5 min. DCC (155 mg, 0.75 mmol) was added and a white precipitate formed immediately. The mixture was stirred overnight then filtered and concentrated. Purification via flash column chromatography (0.2:9.8, MeOH:CH2Cl2) gave 360 mg (0.63 mmol) of 2-benzyloxycarbonylamino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester 2a as a pale yellow solid in quantitative yield. Compound 2a (163 mg, 0.29 mmol) was dissolved in MeOH (10 mL) and Pd/C was added and the mixture was purged with H2. The mixture was stirred overnight, filtered through celite and concentrated. Purification via flash column chromatography (0.5:9.5, MeOH:CH2Cl2) gave 105 mg (0.25 mmol) of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester 2-1 in 85% yield. MS calcd: (419). Found 419.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[OH:34][CH:32]([CH3:33])[CH2:31][NH:30][C:19]([C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:17]=1)=[O:21]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Reactant: CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (2.00 g, 4.83 mmol) in THF (50 mL), was added 1-aminopropan-2-ol (543 mg, 7.23 mmol), EDCI (1.12 g, 5.84 mmol), HOBt (800 mg, 5.92 mmol) and DIPEA (2.48 g, 19.2 mmol). The reaction was stirred for 12 hours at 25° C. and then concentrated in vacuo and quenched by addition of water. The reaction was extracted with DCM (×3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 33% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford N-(2-hydroxypropyl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide as a yellow solid. LRMS (ESI) calc'd for C22H30N5O5Si [M+H]+: 472, found 472.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:29])[F:28])=[N:22][C:23](Cl)=[N:24][CH:25]=1)=[O:19].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:28])[F:29])=[N:22][C:23]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH3:8])[C:6]=3[CH3:9])[CH2:11][CH2:12]2)=[N:24][CH:25]=1)=[O:19]
Reactant: Cc1c(Cl)nnc(N2CCNCC2)c1C
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a roundbottom flask is added 3-chloro-4,5-dimethyl-6-piperazin-1-yl-pyridazine (1 g, 4.41 mmol), 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (2.12 g, 8.82 mmol) and diisopropylethylamine (2.3 mL, 13.23 mmol) in a dioxane (9 mL) solution and stirred for 18 h at room temperature. Filter the reaction mixture and rinse with water and ethylacetate to give 1.35 g of 2-[4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (71%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:27])([F:28])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:29])[CH3:2]
Reactant: CC(=O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of 7-(3-acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole ((0.76 g, 2.0 mmol) in anhydrous tetrahydrofurane (5 ml) was added a solution of methylmagnesium bromide (1.0 ml, 3M) dropwise over 5 min. The ice-bath was removed and the mixture was stirred at ambient temperature for 4 hours. Aqueous ammonium chloride, and subsequently ethyl acetate, was added.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-methylphenyl isocyanate (0.150 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 158 mg (51.1%) of the desired product as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([OH:51])=O)[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[CH2:53]([CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[CH2:53]([CH:60]1[CH2:65][CH2:64][N:63]([C:49]([C:47]2[N:48]=[C:43]3[CH2:42][CH2:41][CH:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([O:32][CH3:31])=[C:34]([CH3:52])[CH:35]=4)[CH2:45][N:44]3[CH:46]=2)=[O:51])[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCC(Cc5ccccc5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 4-benzylpiperidine (116 μl; 116 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered out. Yield: 182 mg (81%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[OH:17])[CH3:2].[H-].[Na+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1OCCN1CCCCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 16.4 %

Procedure:
3-(4-tert-Butyl-2-hydroxyphenyl)acrylic acid ethyl ester (59.0 mg, 0.238 mmol) and NaH (47.5 mg, 60% disp. oil, 5 eq) were added in anhydrous DMF. The reaction mixture was cooled down to 0° C. 1-(2-Chloroethyl)piperidine hydrochloride (87.6 mg 0.476 mmol, 2 eq) was added. The mixture was heated to 90° C. The reaction was stirred for 12 hr at 90° C. The reaction was quenched by adding H2O. The reaction mixture extracted with EtOAc and then washed with H2O and brine. The residue was purified with column chromatography (EtOAc) to give a yellow liquid (14.0 mg, 16.4%).
Reaction SMILES: Br[C:2]1[C:3]([CH:14]([F:16])[F:15])=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:6]=1[CH3:7].[O:17]1CCC[CH2:18]1.C([Li])CCC.CN(C)C=O>CCCCCC>[F:15][CH:14]([F:16])[C:3]1[C:2]([CH:18]=[O:17])=[C:6]([CH3:7])[N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[N:4]=1
Reactant: Cc1c(Br)c(C(F)F)nn1C1CCCCO1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1c(C=O)c(C(F)F)nn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 4-bromo-3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.60 g, 2.0 mmol) in tetrahydrofuran (7.00 mL, 86.3 mmol) was cooled at −78° C. Into the reaction was added 1.6 M of n-butyllithium in hexane (2.00 mL) and was stirred at −78° C. for 5 min. N,N-Dimethylformamide (0.31 mL, 4.1 mmol) was added and stirred at −78° C. for 1 h. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR (CDCl3): δ 10.12 (s, 1H), 6.81-6.95 (t, 1H), 5.38 (m, 1H), 4.03 (m, 1H), 3.68 (m, 1H), 2.66 (s, 3H), 2.42 (m, 1H), 2.14 (m, 1H), 1.96 (m, 1H), 1.50-1.75 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][C:44](=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) in dry tetrahydrofuran (20 ml) was treated with triethylamine (0.1 ml, 0.72 mmol) and the mixture heated gently until all components had dissolved. The solution was then cooled to room temperature, treated with a solution of benzoyl chloride (28 mg, 0.20 mmol) in dry tetrahydrofuran (2 ml) and the mixture stirred for 1.5 hr. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5), to give the product which was then triturated with a mixture of diethyl ether and pentane, filtered off and dried to afford the title compound as a solid (80 mg). MS: 595 (MH+).