Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][O:31][CH:32]2[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:25][CH:24]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=2[F:16])[S:3][C:2]=1[NH:1][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][O:31][CH:32]2[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:25][CH:24]=1)=[O:8]
Reactant: Cc1nc(Cl)ccc1COC1CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1COC1CN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and tert-butyl 3-[(6-chloro-2-methylpyridin-3-yl)methoxy]azetidine-1-carboxylate (150 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[O:13][C:11]=2[CH:12]=1.C1C(=O)N([Br:38])C(=O)C1.O>C(#N)C>[Br:38][C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH:2]([CH3:30])[CH3:1])=[CH:12][C:11]2[O:13][C:14](=[O:21])[C:15]3[C:20]([C:10]=2[CH:9]=1)=[CH:19][CH:18]=[N:17][CH:16]=3
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)oc(=O)c1cnccc12)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@@H](COc1cc2oc(=O)c3cnccc3c2cc1Br)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 67.4 %

Procedure:
To a stirred solution of (S)-tert-butyl (4-methyl-1-((5-oxo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (0.100 g, 0.242 mmol) (prepared as described in Example 11, Part E) in anhydrous acetonitrile (2 mL) was added NBS (0.043 g, 0.242 mmol) and the mixture heated to 80° C. for 12 h. After completion of reaction, water (10 mL) was added and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford crude compound which was purified by preparative TLC to afford (S)-tert-butyl (1-((9-bromo-5-oxo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.163 mmol, 67% yield) as a pale yellow solid. LCMS (ESI) m/e 491.2 [(M+H)+, calcd for C23H28BrN2O5491.1] LC/MS retention time (method F): tR=1.12 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH3:13])[C:6]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([CH3:13])[C:6]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Temperature: 90 °C
Yield: 46.6 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-methyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (100 mg, 0.37 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (88 mg, 0.37 mmol) and DIPEA (340 μL, 1.85 mmol) in IPA (5 mL) were added and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was loaded onto an SCX column to remove the THP group. The column was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The product fractions were collected, concentrated in vacuo and the resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-5% MeOH in DCM) to give 413 as a white solid (67 mg, 47%). LCMS (Method K): RT 2.53 min [M+H]+ 389. 1H NMR (DMSO-d6, 400 MHz): δ 12.7 (1H, br s), 8.68 (1H, ddd, J=4.8, 1.7, 0.8 Hz), 8.13 (2H, d, J=21.9 Hz), 7.91 (1H, br s), 7.90 (1H, td, J=7.8, 1.8 Hz), 7.65 (1H, dd, J=8.8, 4.8 Hz), 7.60 (1H, tq, J=7.7, 1.1 Hz), 7.44 (1H, ddd, J=7.5, 4.8, 1.1 Hz), 7.10 (1H, dd, J=10.4, 8.8 Hz), 5.82-5.67 (1H, m), 3.15 (3H, s), 1.61 (3H, d, J=6.7 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH2:40][O:41][CH3:42])[CH2:25][CH2:26]3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: COCCl
Reactant: COC(=O)c1nc2n(CCN3CCNCC3)c3ccccc3n2c(=O)c1OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN1CCN(CCn2c3ccccc3n3c(=O)c(OC(C)=O)c(C(=O)OC)nc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.9 %

Procedure:
3-Acetoxy-4-oxo-10-(2-piperazin-1-yl-ethyl)-4,10-dihydro-benzo[4,5]imidazo[1,2-α]pyrimidine-2-carboxylic acid methyl ester (Example 15.3) (97 mg, 0.235 mmol) was dissolved in Dichloromethane (1 mL) and to it was added diisopropylethylamine (95 μL, 0.52 mmol), followed by methoxymethyl chloride (20 μA, 0.258 mmol). The reaction was stirred at room temperature for 24 h before the solvents were evaporated and the residue purified by column chromatography (98:1.5:0.5 dichloromethane: methanol: aqueous ammonia) to afford the desired product (30 mg, 28%).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:5].[C:16](OC(=NC(C)C)NC(C)C)([CH3:19])([CH3:18])[CH3:17]>ClCCl.COC(C)(C)C>[CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a slurry of 4-(3-methylbutanoyl)benzoic acid (499 mg, 2.42 mmol) in dichloromethane (6 mL) was added O-tert-butyl-N,N′-diisopropylisourea (1.82 g, 9.07 mmol). The mixture was stirred at room temperature for 50 hours then diluted with tert-butyl methyl ether (75 mL). The mixture was washed with sat. aq sodium bicarbonate (50 mL), dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave tert-butyl 4-(3-methylbutanoyl)benzoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.09-8.04 (m, 2 H), 8.00-7.94 (m, 2 H), 2.86 (d, J=6.8 Hz, 2 H), 2.37-2.23 (m, 1 H), 1.62 (s, 9 H), 1.01 (d, J=6.7 Hz, 6 H).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[CH3:17][C:18]1[N:22]([CH2:23][C:24](=[O:32])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=[C:20]([C:33](O)=O)[CH:19]=1.CCN=C=NCCCN(C)C.Cl>CO>[O:6]=[C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:11]2[N:12]=[C:33]([C:20]3[CH:19]=[C:18]([CH3:17])[N:22]([CH2:23][C:24]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:32])[N:21]=3)[NH:13][C:10]=2[C:8](=[O:9])[N:7]1[CH2:14][CH2:15][CH3:16]
Reactant: Cc1cc(C(=O)O)nn1CC(=O)Nc1ccccc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(C)n(CC(=O)Nc4ccccc4)n3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1,3-dipropyl-5,6-diaminouracil (2.20 mmol), in MeOH (10 mL), is added an equimolar amount of the title C compound, 5-methyl-1-phenylcarbamoylmethyl-1H-pyrazole-3-carboxylic acid, and EDCl (2.21 mmol). The reaction mixture is stirred at RT for 4-5 h while being monitored by TLC. The solvent is concentrated in vacuo and the amide intermediate is precipitated by the addition of water. After filtration, the solid is dissolved in MeOH (10 mL) and aqueous NaOH (2.5 N, 15 mL) and the mixture is stirred at 50-60° C. for 1 h. The MeOH is distilled off, and the residue is taken up in H2O and acidified with HCl to pH 4-5. The precipitate is collected by filtration, washed with water, and purified by flash chromatography (ethyl acetate-petroleum ether) to afford 2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-phenyl-acetamide: m.p. 255-257° C.; 1H-NMR (DMSO-d6) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.32 (s, 3H), 3.84 (m, 2H), 3.98 (m, 2H), δ0.08 (s, 2H), 6.74 (s, 1H), 7.08 (m, 1H), 7.33 (m, 2H), 7.59 (m, 2H), 10.41 (s, 1H), 13.85 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1.[I-:14].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1
Reactant: ClCCCc1cc2ccccc2s1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCc1cc2ccccc2s1
Temperature: 25 °C

Procedure:
A mixture of 2-(3-Chloro-propyl)-benzo[b]thiophene (902 mg, 4.28 mmol) and sodium iodide (1.29 g, 8.6 mmol) was heated to 50° C. in acetone (5 ml) for 72 h, then cooled to room temperature. Aqueous sodium thiosulphate (1 M, 10 ml) was added and the product was extracted with diethyl ether (2×20 ml). The organic layer was dried (K2CO3), filtered and concentrated in vacuo to give a white solid that was filtered through Celite and eluted with heptanes. The filtrate was concentrated in vacuo to give a white solid. Yield 1.038 g (80%). 1H NMR (CDCl3): δ2.24 (tt, 2H), 3.04 (dt, 2H), 3.27 (t, 2H), 7.07 (q, 1H), 7.28 (m, 2H), 7.68 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.25 g, 5.55 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in dichlormethane (30 mL) and triethylamine (1.20 mL) was added 4-chloro-benzoyl chloride (1.09 g, 6.21 mmol, 1.12 equiv; commercially available) and the reaction stirred at rt overnight. A solution of 1 M NaOH (10 mL) was added and the reaction mixture extracted with ethyl acetate. The combined organic phases were washed with water and a sat. solution of NaCl, dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was crystallized from a mixture of hexane/ethyl acetate yielding 0.71 g (44%) of the title compound as white crystals. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 1.85 (t, J=10.2 Hz, 2H), 2.45 (br s, 2H), 3.24 (t, J=11.8 Hz, 2H), 3.99 (br d, J=13.5 Hz, 2H), 6.87 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H). MS (ISP): 364.4 [M+H]+.
Reaction SMILES: C[C:2]1[N:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([C:12]2[CH:13]=[N:14][N:15]([CH3:27])[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:3]=1.[2H]C([NH2:32])([2H])[2H]>>[CH3:27][N:15]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[C:12]([C:4]2[N:3]=[CH:2][N:10]3[C:5]=2[C:6]([NH2:32])=[N:7][CH:8]=[N:9]3)[CH:13]=[N:14]1
Reactant: [2H]C([2H])([2H])N
Reactant: Cc1nc(-c2cnn(C)c2-c2ccc(C(F)(F)F)cc2)c2c(=O)[nH]cnn12
Product: Cn1ncc(-c2ncn3ncnc(N)c23)c1-c1ccc(C(F)(F)F)cc1

Procedure:
7-Methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4(3H)-one was converted to the product according to the general procedure for the synthesis of 4-(azetidin-1-yl)-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine in Example 2, except that methyl-d3-amine was used in place of azetidine hydrochloride. In this case, the reaction was worked up via removal of solvent in vacuo, followed by addition of water and extraction with ethyl acetate. The combined organic layers were concentrated under reduced pressure and purified using silica gel chromatography (Gradient: 0% to 100% [5% methanol/5% triethylamine/90% ethyl acetate] in heptane) to afford the product as a gummy oil. Yield: 20 mg, 0.051 mmol, 42%. LCMS m/z 391.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.57 (s, 3H), 3.94 (s, 3H), 7.51 (br d, J=8.1 Hz, 2H), 7.70 (br d, J=8.2 Hz, 2H), 7.75 (s, 1H), 7.79 (s, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[N:11]1([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[(4-nitrophenyl)methyl]morpholine (220 mg, 1.0 mmol, Step A), iron powder (279 mg, 5.0 mmol) and NH4Cl (39 mg, 0.7 mmol) in EtOH (3 mL) and H2O (3 mL) was stirred for 4 h at 80° C. Filtration and concentration gave the crude 4-(morpholin-4-ylmethyl)-phenylamine, which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[NH:10][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1cccc(COc2ccc(Nc3ncnc4cc(-c5ccco5)[nH]c34)cc2Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (122 mg).
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:6]([NH:8][C@@H:9]1[CH2:24][N:23]([CH3:25])[C@H:22]2[C@@H:11]([C:12]3[C:17]4[C:18]([CH2:21]2)=[CH:19][NH:20][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10]1)=[O:7])[CH2:4][CH3:5].[I:26]N1C(=O)CCC1=O.C(=O)(O)[O-]>O1CCOCC1>[CH2:4]([N:3]([CH2:2][CH3:1])[C:6]([NH:8][C@H:9]1[CH2:10][C@H:11]2[C@@H:22]([CH2:21][C:18]3[C:17]4[C:16](=[CH:15][CH:14]=[CH:13][C:12]2=4)[NH:20][C:19]=3[I:26])[N:23]([CH3:25])[CH2:24]1)=[O:7])[CH3:5]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(I)c(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution is prepared from 1 mmol of terguride in 20 ml of anhydrous dioxane, combined with about 1.5 ml of N-iodosuccinimide at room temperature and stirred for 30 minutes. The reaction mixture is then poured into a saturated bicarbonate solution, extracted with methylene chloride and the organic phase is dried with magnesium sulfate. After evaporation of the solvent, the residue is chromatographed on silica gel, thus obtaining in a 76% yield 1,1-diethyl-3-(2-iodo-6-methyl-8α-ergolinyl)urea.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:17])[CH:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]=O>CO>[ClH:1].[CH2:19]([C@H:18]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH2:7][C@@H:5]([C:4]([O:3][CH3:2])=[O:17])[NH:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC=O
Reactant: COC(=O)C(N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CO
Product: CCCC[C@@H]1N[C@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Yield: 53 %

Procedure:
A mixture of DL-tryptophan methyl ester hydrochloride (30.49 g), n-valeraldehyde (12.4 g) and methanol (400 ml) is refluxed for 48 hours and then concentrated to about 1/5 volume. After cooling, the precipitates are separated by filtration and recrystallized from methanol to give methyl (1RS,3RS)-cis-1-butyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride (20.5 g, 53%), m.p. 218° C. (decomp.) The hydrochloride thus obtained is treated with aqueous ammonia and recrystallized from diisopropyl ether-isopropanol to give the corresponding free base, m.p. 85°-87° C.
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: BrCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: [K]
Product: N#Cc1ccc(OCCCCCBr)cc1

Procedure:
The intermediate 5-(4-cyanophenoxy)pentyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,5-dibromopentane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:10]1[C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:13][O:12][C:11]1=[O:14]
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)CO1
Reactant: ClCCCCCBr
Product: O=C1OC[C@H](c2ccc(F)c(F)c2)N1CCCCCCl

Procedure:
Prepared by Procedure G and Scheme C1 using (4S)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 1-bromo-5-chloropentane.
Reaction SMILES: B(Br)(Br)[Br:2].[C:5]([NH:8][CH:9](OCC)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:7])[CH3:6].C(Cl)Cl>>[C:5]([NH:8][CH:9]([Br:2])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:7])[CH3:6]
Reactant: BrB(Br)Br
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Solvent: ClCCl
Product: CC(=O)NC(Br)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A BBr3 solution (1M in CH2Cl2, 1.1 equiv) was added to a solution of 2-acetamido-N-benzyl-2-ethoxyacetamide (1 equiv) in CH2Cl2 (10 mmol/125 mL). The mixture was stirred at room temperature (5 h) and then concentrated to dryness in vacuo to give 2-acetamido-N-benzyl-2-bromoacetamide as a pale yellow crystalline material. The bromo adduct was then dissolved in THF (10 mmol/250 mL), cooled (-78° C.), and then added over a 15 min interval to a cooled (-78° C.) solution of the heteroatom nucleophile in THF (1 mmol/1 mL). The reaction mixture was stirred at this temperature (30 min) and then at room temperature (90 min). The insoluble salts were filtered and the filtrate concentrated in vacuo. The residue was then purified by flash column chromatography on SiO2 gel using the indicated solvent as the eluent.
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH2:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[S:14].[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:27]=O)=[C:24]([CH3:26])[N:25]=2)[CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH2:27][NH:1][CH:2]([CH3:15])[CH2:3][N:4]3[C:12]4[N:11]=[CH:10][NH:9][C:8]=4[C:7](=[O:13])[NH:6][C:5]3=[S:14])=[C:24]([CH3:26])[N:25]=2)[CH:22]=1
Reactant: Cc1nc2ccc(Br)cn2c1C=O
Reactant: CC(N)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Product: Cc1nc2ccc(Br)cn2c1CNC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Reaction time: 48 h
Yield: 23.9 %

Procedure:
The title compound was prepared in accordance with the general method described above using 3-(2-aminopropyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (60 mg, 0.18 mmol, obtained from Example 29(c)) and 6-bromo-2-methylimidazo[1,2-a]pyridine-3-carbaldehyde (33.8 mg, 0.14 mmol), with the exception that the imine formation was allowed to run for 48 h, which generated 15 mg (24% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[C:6]([Cl:16])[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>ClCCl>[Cl:16][C:6]1[N:5]=[C:4]([S:17][CH3:18])[N:3]=[C:2]([NH:22][CH:19]([CH3:21])[CH3:20])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15]
Reactant: CC(C)N
Reactant: CSc1nc(Cl)c(-c2c(F)cccc2Cl)c(Cl)n1
Solvent: ClCCl
Product: CSc1nc(Cl)c(-c2c(F)cccc2Cl)c(NC(C)C)n1
Temperature: 22.5 °C
Reaction time: 5 h
Yield: 11.9 %

Procedure:
A solution of 37.5 g (324 mmol) of the product of step b in 150 ml of anhydrous dichloromethane was treated with 24 g (406 mol) of isopropylamine and stirred for five hours at approximately 20 to 25° C. Then, the solvent was distilled off, the residue was taken up in ethyl acetate and washed with dilute HCl, water and dilute NaHCO3 solution, dried and freed from solvent. Following chromatography on silica gel (cyclohexane/methyl tert-butyl ether 100:1 to 19:1), 13.4 g of the title compound were obtained from the residue in the form of colorless crystals of m.p. 94-98° C., which were employed in the next step without further purification.
Reaction SMILES: [CH2:1]([P:3]([Cl:6])([Cl:5])=[S:4])[CH3:2].[CH3:7][CH:8](S)[CH3:9].N1C=CC=CC=1>C(#N)C>[CH2:1]([P:3]([Cl:6])([Cl:5])=[SH:4][CH:8]([CH3:9])[CH3:7])[CH3:2]
Reactant: CC(C)S
Reactant: CCP(=S)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCP(Cl)(Cl)=[SH]C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a mixture of 326 g (2.0 moles) ethylphosphonothioic dichloride in 500 ml acetonitrile, a mixture of 152.3 g (2.0 moles) 2-propanethiol and 158.2 g (2.0 moles) pyridine were added over a period of 20 minutes. The reaction mixture was stirred overnight at room temperature and then heated at reflux for four hours, resulting in the formation of solids. The reaction mixture was cooled to room temperature and then filtered. The filtrate was combined with 500 ml hexane, washed twice with 75 ml water and then stripped to give 373 g of the aboveidentified product as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:3]=1.[CH3:20][O-:21].[Na+]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:4]1[N:3]=[C:2]([O:21][CH3:20])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(-c2c(Cl)cccc2Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2c(Cl)cccc2Cl)cc(N)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h

Procedure:
2-Chloro-6-(2,6-dichlorophenyl)-3-nitropyridin-4-ylamine (28.7 mg, 0.0901 mmol, prepared as described in the previous step) was placed in a 8 mL vial equipped with a stir bar and anhydrous MeOH (1 mL) was added via syringe. NaOMe (0.5 M in MeOH, (0.396 mL, 0.198 mmol) was added to the stirred mixture, which was then stirred at 65° C. for 4 h. The solvent was removed under reduced pressure and the residue was chromatographed on a 12-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/heptane to yield 6-(2,6-dichlorophenyl)-2-methoxy-3-nitropyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 7.37-7.41 (m, 2H), 7.25-7.30 (m, 1H), 6.35 (s, 1H), 6.15 (br. s., 2H), 4.01 (s, 3H).