Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][OH:29])=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][O:29][C:38](=[O:39])[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=1)=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: N=C(NO)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: N=C(NOC(=O)Cc1ccc(F)cc1)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
The product of example 20 (200 mg, 0.51 mmol) and 4-fluorophenylacetyl chloride (0.073 mL, 0.53 mmol) were dissolved in THF (5 ml). To this solution was added TEA (0.14 mL, 1.02 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then poured into water (30 ml). The crude product was obtained by filtration. It was recrystallized from CH2Cl2/PE to give the titled product (261 mg, yield 97.0%)
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([N:14]1[C:18]2[N:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([O:35][CH3:36])=[O:34])[CH:27]=3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:17]=2[C:16]([I:37])=[N:15]1)C1C=CC=CC=1.OS([O-])(=O)=O.[K+].C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:20]2[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:17]3[C:16]([I:37])=[N:15][N:14]([CH:6]4[CH2:5][CH2:4][CH2:3][CH2:2][O:1]4)[C:18]=3[N:19]=2)=[CH:27][C:28]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(Cc4ccccc4)c3n2)ccc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(C4CCCCO4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.9 %

Procedure:
para-Toluenesulphonic acid (38 mg/0.20 mmol) and 3,4-dihydro-2H-pyran (2.75 mL/30.1 mmol) are added successively to a solution of 1-benzyl-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4.43 g/10.0 mmol) in 50 mL of DCM. The solution is stirred at ambient temperature for 12 hours. The reaction medium is run into a solution of KHSO4 (1 M) and extracted with EtOAc. The organic phase is washed with water and with a saturated aqueous solution of NaCl, dried over sodium sulphate, filtered and concentrated to dryness. The brown gum obtained is dissolved in 75 mL of DCM and added to the TEA scavenger resin (FL-TEA, Polymerlab, Variant, 3.53 mmol/g) (3.3 g/11 mmol). After stirring at ambient temperature for 2 h, the resin is filtered and washed with DCM. After drying under vacuum, the resin is then stirred for 20 minutes in a solution of triethylamine (2.6 mL/18 mmol) in 90 mL of DCM and then filtered and rinsed with DCM. The filtrate is acidified with a solution of KHSO4 (1 M). After extraction with EtOAc, the organic phase is washed with water and with a saturated aqueous solution of NaCl, dried over sodium sulphate, filtered and concentrated to dryness to give 4.3 g of an orange powder (yield: 82%).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Sc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Fc1nc(Sc2ccccc2)c2[nH]cnc2n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To a solution of 2-fluoro-6-chloropurine (10.0 g, 57.9 mmol) in methanol (200 mL) is added diisopropylethylamine (25.2 mL, 144.7 mmol). The mixture is cooled to 0° C. and followed by slow addition of thiophenol (11.9 mL, 115.8 mmol) via an addition funnel over one hour. The reaction is stirred at 0° C. for 12 hours. The solvent is then removed under reduced pressure and the solid is collected by filtration and washed twice with hexanes. The collected solid is further purified by re-crystallization from methanol to afford desired product (11.8 g, 83% yield). 1H NMR (400 MHz, (CD3)2SO) δ 7.54 (m, 3H), 7.66(m, 2H), 8.49(s, 1H); MS C11H7FN4S [MH+] 246.04, found: 247.05.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:31][CH3:32])[CH:16]=2)[N:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[OH:8][CH2:9][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:31][CH3:32])[CH:16]=2)[N:11]=1
Reactant: [H][H]
Reactant: COc1ccc2nc(COCc3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2nc(CO)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89.5 %

Procedure:
1.5 g of 10% palladium/carbon powder was added to a solution of 1.26 g (2.93 mmol) of 2-benzyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in an ethyl acetate/ethanol (20 ml--20 ml) mixture. The obtained mixture was stirred at room temperature in a stream of hydrogen for 24 hours and filtered through Celite. The filter cake was washed with hot ethyl acetate/ethanol. The filtrate and the washings were distilled under a reduced pressure to remove the solvent. Thus 0.89 g of the title compound was obtained as a pale-yellow crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:18])C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccccc2)cc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
4-Benzyloxypyridine 1-oxide (24.8 g, 123 mmols) was refluxed in acetic anhydride (150 mL) for 1.5 hours. Cooling the system to room temperature, the system was concentrated under reduced pressure and the resulting residue was dissolved in a mixed solvent of ethyl acetate (150 mL) and methanol (10 mL), followed by stirring at 60° C. for 2 hours. The solid formed upon cooling the system to room temperature was recovered by filtration to provide crude title compound (8.84 g). Concentrating the filtrate, additional crude title compound (4.17 g) was obtained. The combined crude product was recrystallized from a mixed solvent of methanol and ethyl acetate to provide the title compound (12.1 g, 49%).
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=O)[N:14]=2)[CH:11]=1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=3)=[O:17])[N:14]=2)[CH:11]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Me3Al (2.0M solution in toluene) (2.78 ml, 5.57 mmol) was added to a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (500 mg, 1.85 mmol) in methylene chloride (10 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. (4-(trifluoromethoxy)phenyl)methanamine (0.42 ml, 2.78 mmol) was added to the above mixture at room temperature. The reaction mixture was stirred at 50° C. for 20 hours. After cooling to room temperature, the reaction was quenched by 1N HCl solution (2-3 mL). The reaction mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride. The combined organic layer was washed with brine, then dried over anhydrous magnesium sulfate. After concentration, the residue was purified by flash chromatography (ethyl acetate:hexane=1:1) to give the title compound, 6-bromo-N-(4-(trifluoromethoxy)-benzyl)imidazo[1,2-a]pyridine-2-carboxamide, as a solid (440 mg, 57% yield).
Reaction SMILES: [CH:1]1([N:4]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[N:10]=2)[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.[OH-:17].[Na+]>O1CCOCC1.O>[Cl:15][C:13]1[CH:14]=[C:9]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][CH2:7][OH:8])[NH:10][C:11](=[O:17])[N:12]=1
Reactant: [OH-]
Reactant: OCCCN(c1cc(Cl)nc(Cl)n1)C1CC1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1nc(Cl)cc(N(CCCO)C2CC2)[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a solution of 3-(cyclopropyl(2,6-dichloropyrimidin-4-yl)amino)propan-1-ol (5.0 g, 19.07 mmol) in 1,4-dioxane (50 mL) was added a solution of NaOH (7.63 g, 191 mmol) in water (50 mL) at r.t, stirred for 4 h at 100° C. The organic solvent was removed under reduce vacuum and the PH was adjusted to 8 with aq. HCl (12 N). Purification via reverse C-18 column afforded the title compound (2.1 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccccc1
Yield: 62.5 %

Procedure:
Using the procedure of Step A of Example 6, 40.28 g of o-trifluoromethyl aniline and 35.14 g of benzoyl chloride were reacted in the presence of 25.3 g of triethylamine in 400 ml of acetone to obtain 41.45 g of N-(2-trifluoromethylphenyl)-benzamide melting at 146° C which was used as is for the next step.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:11])[NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([SH:23])(Cl)Cl>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:20]([Cl:19])[S:23][N:11]=2)=[CH:5][CH:4]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1nc(-c2ccc(Br)cc2)ns1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
4-Bromobenzenecarboximidamide hydrochloride (1.00 g, 4.25 mmol), prepared in the previous step, was suspended in methylene chloride (25 mL) and triethylamine (6.1 mL, 42.5 mmol) was added and the mixture was cooled to 0° C. Perchloromethyl mercaptan (0.47 g, 4.25 mmol) was added slowly, the mixture was stirred for 30 min, warmed to 25° C. and stirred 4 h. The mixture was diluted with methylene chloride, filtered through the Celite™ reagent, and concentrated. Flash chromatography (2% acetone in hexane) afforded 3-(4-bromophenyl)-5-chloro-1,2,4-thiadiazole (327 mg, 28%). HRMS: calcd for C8H4BrClN2S, 273.89671; found (EI, M+.), 273.8968; Analytical HPLC: purity 100% at 210-370 nm, 11.2 min; 100% at 272 nm, 11.2 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: C=O.C[C:4](C)(O)[C:5]#[N:6].[C:9]([NH:12][C:13]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)(=[O:11])[CH3:10].[OH-].[Na+]>>[C:9]([NH:12][C:13]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH2:4][C:5]#[N:6])[C:15]([CH3:21])([CH3:22])[CH2:14]1)(=[O:11])[CH3:10]
Reactant: CC(C)(O)C#N
Reactant: CCOC(=O)C1(NC(C)=O)CC(C)(C)NC(C)(C)C1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C1(NC(C)=O)CC(C)(C)N(CC#N)C(C)(C)C1
Temperature: 25 °C

Procedure:
0.9 g of 37% formalin solution and 2 ml of acetone cyanohydrin were added to 1 g of 4-acetamido-4-ethoxycarbonyl-2,2,6,6-tetramethylpiperidine obtained by the procedure of Example 2. The resulting mixture was stirred at room temperature, 0.4 ml of 0.1 N-sodium hydroxide solution was added to it, and the mixture was then stirred at room temperature for 3 hours.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:15][NH2:16])=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[C:19](OC(=O)C)(=O)[CH3:20]>>[CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]3[O:14][C:19]([CH3:20])=[N:16][N:15]=3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c(OC)nc2nc(C(=O)NN)cn2c1C
Product: CCc1c(OC)nc2nc(-c3nnc(C)o3)cn2c1C
Yield: 34 %

Procedure:
Using the procedure of Steps B and C of Example 3, 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbohydrazide and acetic anhydride were reacted to obtain a 34% yield of 6-ethyl-7-methoxy-5-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrimidine.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][N:11]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:13]2[C@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=4)[CH2:27][CH2:28]3)=[O:22])[CH2:12]2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 73.2 %

Procedure:
To a solution of [(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (3.20 g, 6.12 mmol) in acetonitrile (30 mL) was added at ambient temperature trifluoroacetic acid (4.7 mL, 61.2 mmol) and the reaction mixture was stirred for 4 h at this temperature. After concentration, the residue was dissolved in ethyl acetate and washed with aqueous sodium carbonate (20%). The organic layer was dried over sodium sulfate and concentrated affording the title compound (1.90 g, 73%) as a light yellow foam. MS m/e: 424.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](=O)([O:18]C)[O:16][CH3:17].[H-].[Na+]>CO>[O:14]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:16][CH3:17])=[O:18]
Reactant: O=C1CCCCC(c2ccccc2)C1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCC(c2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
A mixture of 3-phenylcycloheptanone (1.88 g, 9.99 mmol) and 5 drops of methanol in dimethyl carbonate (1.68 mL, 20.0 mmol) was treated with sodium hydride (60% dispersion, 800 mg, 20.0 mmol). The reaction was then refluxed for 2 hours before being cooled back to room temperature. The reaction was quenched with 2 M hydrochloric acid and extracted with ether, then chromatographed on silica gel (15% ethyl acetate/hexane, eluant) to afford the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.26 (m, 5H), 3.81 (dd, J=11.70, 3.77 Hz, 1H), 3.63 (s, 3H), 3.17 (m, 2H), 1.86 (m, 6H); MS (DCI+) m/z 247 (M+H)+, 264 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([NH:28][C@H:26]([C:24]1[NH:23][C:22]2[CH:29]=[CH:30][C:19]([Cl:18])=[CH:20][C:21]=2[N:25]=1)[CH3:27])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CCCNC2=O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCCNC2=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 0 °C

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then pouring into ice water, adding conc. ammonia solution, filtering, washing with water and purifying by chromatography on silica gel (eluting gradient ethyl acetate/(methanol/conc. ammonia solution 19:1)=98:2→90:10) with subsequent filtration through activated charcoal, trituration with ether and drying in the drying pistol at 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[CH3:14][N:15]([CH3:20])[S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClC(Cl)C>[CH3:14][N:15]([CH3:20])[S:16]([N:9]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=2[N:7]=[CH:8]1)(=[O:18])=[O:17]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc2nc[nH]c2cc1OC
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncn(S(=O)(=O)N(C)C)c2cc1OC
Yield: 86.3 %

Procedure:
A suspension of 5,6-dimethoxybenzimidazole (6.2 g) in dichloroethane (100 ml) was added to N,N-dimethylsulfamoyl chloride (5.3 g) and triethylamine (6 g) was added dropwise while stirring. After the mixture was reacted at room temperature for 24 hours, the reaction solution was washed with an aqueous sodium hydrogen carbonate solution and then with a saturated saline solution and dried over anhydrous Na2SO4. The solvent was distilled off, precipitated crystals were filtered, washed with n-hexane and dried to give the title compound (8.57 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:12]([C:14]([O:16][CH3:17])=[O:15])[NH2:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:11])[NH:13][NH:12][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)NN
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: COC(=O)NNC(=O)Nc1cc(Cl)cc(Cl)c1
Reaction time: 28 h
Yield: 81.9 %

Procedure:
3,5-Dichlorophenyl isocyanate (25 g, 133 mmol) was added dropwise to a cooled solution of methyl hydrazinocarboxylate (12 g, 133 mmol) in dry toluene (250 ml), with the temperature in the reaction flask maintained below 10° C. during the addition. After 28 h at RT, the precipitate was filtered, washed with toluene and isopropyl ether, and dried to yield the above compound as a white solid (30.3 g, mp=246° C.).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[NH:18][C:17](=[O:19])[C:16]2([CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[NH:15]1.[CH:32]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[CH:32]1([N:18]2[C:17](=[O:19])[C:16]3([CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[NH:15][C:14]2=[O:13])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)NC2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)N(C1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (0.315 mL, 0.00200 mol) was added to a mixture of tert-butyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate (269.3 mg, 0.001000 mol), cyclohexanol (0.156 mL, 0.00150 mol), and triphenylphosphine (524 mg, 0.00200 mol) in tetrahydrofuran (6 mL, 0.08 mol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by Combiflash with ethyl acetate/hexane. LC-MS: 296.2 (M−Bu+2H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=2)[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4-c4nccn4C)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine in a analogous manner to example 712. Product was isolated as a pink solid (0.122 g, 22%); Mp 58-62° C.; LCMS (m/e) 503 (M); 1H-NMR (DMSO, 400 MHz) δ 11.09 (s, 1H), 9.26 (s, 1H), 8.6-6.61 (d, 1H), 8.15 (s, 1H), 7.65-7.63 (d, 1H, J=7.83 Hz), 7.43-7.39 (t, 1H, J=7.58 Hz), 7.37 (s, 1H), 7.24-7.20 (t, 1H, J=7.83 Hz), 7.17 (s, 1H), 7.13 (s, 1H), 7.00-6.98 (d, 1H, J=7.83 Hz), 6.87 (s, 1H), 6.64 (s, 1H), 3.77 (s, 3H), 3.58 (s, 2H), 3.31 (s, 3H), 3.10-2.99 (q, 2H, J=7.33 Hz), 2.90 (m, 2H), 2.76 (m, 2H), 2.40-2.33 (q, 2H, J=7.08 Hz), 2.18 (s, 2H), 1.14-1.08 (t, 3H, J=6.79 Hz), 1.09-1.03 (t, 3H, J=7.07 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:19][CH3:20])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4].[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1CCCCC1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:19][CH3:20])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCc1nn(-c2cccc(Br)c2)c(CC)c1C(=O)OC
Reactant: C#CCCCC
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCCCC#Cc1cccc(-n2nc(CC)c(C(=O)OC)c2CC)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.20 g (10.0 mmol) of 1-(3-bromo-phenyl)-3,5-diethyl-1H-pyrazole-4-carboxylic acid methyl ester (intermediate 1C) in 35 ml of piperidine was treated with 0.19 g (1.0 mmol) of copper(I)iodide and 1.16 g (1.0 mmol) of tetrakis-(triphenylphosphine)-palladium. The reaction mixture was warmed up to 60° C. and after 15 min, a solution of 0.82 g=1.00 ml (10.0 mmol) of hex-1-yne in 15 ml of piperidine was added drop by drop during 1 hour. After 30 min, the oil bath temperature was steadily increased to 80° C. The reaction mixture was then stirred at 80° C. for 4 hours, and subsequently cooled down to RT. The solvent was evaporated and the residue poured into crashed ice, acidified with HCl (37%) to pH 1-2 and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane:EtOAc 1:0-9:1) to afford the title compound as light yellow oil. MS: 339.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[S:27][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:10]=2[CH:9]=1>>[CH3:1][C:2]1[N:3]([C:13]2[N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:10]3[CH:9]=[CH:8][S:27][C:11]=3[N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cccc(CNc2ncnc3sc(Cl)cc23)c1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2ccsc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 6-chloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.