Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[C:19](=[O:21])=[O:20]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([C:19]([O:21][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:20])[CH:17]=2)([CH3:11])[CH3:10])=[CH:7][CH:8]=1
Reactant: O=C=O
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K]
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)c(C(=O)Oc2ccccc2)c1

Procedure:
Monocarboxylated bisphenol A [i.e., 2-(4-hydroxyphenyl)-2-(3'-carboxy-4'-hydroxyphenyl)propane] was obtained by carboxylating a potassium salt of bisphenol A with CO2 gas and then purifying the product by recrystallizing it from toluene solvent. This monocarboxylated bisphenol A was esterified with an excess of diphenyl carbonate and then refined in a column to obtain 2-(4-hydroxyphenyl)-2-(3'-phenoxycarbonyl-4'-hydroxyphenyl)propane with a purity of at least 99 percent (according to HPLC analysis).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:14][N:15]=[C:16]=[S:17]>>[CH3:13][O:12][C:11]1[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]([NH:15][CH3:14])=[S:17])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccnc1CCCCN
Reactant: CN=C=S
Product: CNC(=S)NCCCCc1ncccc1OC

Procedure:
Reaction of 2-(4-aminobutyl)-3-methoxypyridine with methyl isothiocyanate gives N-[4-(3-methoxy-2-pyridyl)butyl]-N'-methylthiourea.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ccc(Cl)nn2)c(OC)c1
Temperature: 100 °C

Procedure:
To a solution of 3,6-dichloropyridazine (1 g, 6.71 mmol) in nBuOH (25 mL) was added DIPEA (3.31 mL, 18.6 mmol) and 2,4-dimethoxybenzylamine (1.12 g, 6.71 mmol) and the reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was concentrated in vacuo to afford 6-chloro-N-(2,4-dimethoxybenzyl)pyridazin-3-amine.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Cl:18]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:8]([Cl:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(Cl)ccc(C(=O)O)c1N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N)c(C(=O)O)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.6 %

Procedure:
To a mixture of 0.34 g of 2-amino-4-chloro-3-methylbenzoic acid and 10 ml of N,N-dimethylformamide was added 0.26 g of N-chlorosuccinimide at room temperature, and the mixture was stirred at room temperature for 5 hours. After 30 ml of water was poured into the reaction mixture, the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.22 g of 2-amino-4,5-dichloro-3-methylbenzoic acid of the formula:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[S:23][C:22]2[C:21]([NH:24]C3C=C4C(=CC=3)NC=C4)=[N:20][CH:19]=[N:18][C:17]=2[CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:15]2[S:23][C:22]3[C:21]([NH2:24])=[N:20][CH:19]=[N:18][C:17]=3[CH:16]=2)=[CH:7][CH:8]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: Nc1ncnc2cc(-c3ccc(C(F)(F)F)cc3)sc12

Procedure:
The title compound was prepared from 3-trifluoromethylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. M.P. 181-194° C.; LC-MS: 411 (MH+); HPLC RT: 4.88 minutes.
Reaction SMILES: [I:1]I.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:11]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
Iodine (1.58 g; 6.21 mmol) was added to a stirred mixture of silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 1.08 g (61%) of the title compound as a red oil.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([Cl:23])[CH:17]=1.[OH-].[Na+]>CN(C=O)C>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:21]=[C:20]([Cl:22])[N:19]=1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ncnc3[se]c4c(c23)CCCC4)cc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (470 mg, 1.72 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 4-amino-2,6-dichloropyridine (420 mg, 2.58 mmol) and powdered NaOH (210 mg, 5.16 mmol) at rt and the mixture was stirred at rt for 16 h. Work-up of the mixture as described in example 2, gave the product as a pale yellow color solid (500 mg, 73%), mp 238-242° C. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (1H, s, exchangeable with D2O), 8.62 (1H, s), 7.76 (2H, s), 3.07 (2H, br s), 2.94 (2H, br s), 1.84 (4H, br s); 13C NMR (100 MHz, DMSO-d6): δ 172.3, 153.1, 151.3, 151.0, 149.2, 140.5, 128.3, 122.3, 112.1, 27.7, 26.7, 22.6, 21.9; LC-MS (negative ion mode): m/z 395, 397, 399 (M−H)−.
Reaction SMILES: [C:1]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[C:2]([CH2:4][C:5]([O:7]CCCC)=O)=[CH2:3].[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH2:22])[CH3:19]>>[CH2:14]([O:13][C:1]([CH:2]1[CH2:4][C:5](=[O:7])[N:22]([CH2:21][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3]1)=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: C=C(CC(=O)OCCCC)C(=O)OCCCC
Reactant: CCCCC(CC)CN
Product: CCCCOC(=O)C1CC(=O)N(CC(CC)CCCC)C1
Temperature: 75 °C

Procedure:
Bis(butyl) itaconate (400 g; 1.65 Mol) was charged to a 1 L reaction vessel and the material stirred mechanically under nitrogen while heating to 75° C. 2-Ethylhexylamine (1.7 Mol; 219.7 g) was charged to a pressure-equalizing addition funnel and the amine added drop wise to the stirred diester over the course of one hour and stirred at 75° C. for 2 hours after amine addition. The reactor was equipped for distillation and the temperature was increased slowly to 130° C., holding at full vacuum until stripping was complete. Receivers were changed and the pot heated under full vacuum to increase pot temperature to 165 to 185° C. (head temperature 140 to 175° C.). 469.3 g of product 1.58 Mol; 95.6% yield was collected. Sample materials were collected from this preparation and designated 1-(2-ethylhexyl)-5-oxo-3-pyrrolidinecarboxylic acid butyl ester for comparison testing described in the Examples below.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH3:11][C@H:12]([NH2:18])[CH2:13][O:14][N+:15]([O-:17])=[O:16].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:11][C@H:12]([NH:18][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:13][O:14][N+:15]([O-:17])=[O:16]
Reactant: C[C@H](N)CO[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1
Yield: 94.2 %

Procedure:
In 60 ml of dry tetrahydrofuran were suspended 2.06 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 2.00 g of (1S)-1-methyl-2-nitroxyethylamine hydrochloride, 4.5 ml of triethylamine and 3.00 ml of diphenylphosphoryl azide were added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (1:4) as an eluent to obtain 3.00 g of colorless crystals. The crystals were recrystallized from ethyl acetate to obtain 0.964 g of the desired compound as colorless needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Br)nc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(Br)nc1

Procedure:
6-bromo-N-tert-butylnicotinamide was prepared from 6-bromonicotinoyl chloride and tert-butylamine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH2:12])[OH:10])=[CH:4][C:3]=1[Cl:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCCCCC>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: BrCCCCCCOCCSCCc1ccccn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCSCCc2ccccn2)cc1Cl
Yield: 55.4 %

Procedure:
A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (0.56 g,), 2-[2-[[2-[(6-bromohexyl)oxy]ethyl]thio]ethyl]pyridine (0.58 g,) and DEA (0.26 g,) in DMF (10 ml) was stirred under nitrogen for 2 h. The solvent was evaporated in vacuo and the residual oil partitioned between 8% sodium bicarbonate solution (100 ml) and dichloromethane (100 ml). The aqueous phase was re-extracted with dichloromethane (100 ml) and the combined organic phases dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System G (98:2:1) gave an oil. Trituration with hexane afforded the title compound (451 mg,) as a solid m.p. 59.5°-62°. T.l.c. (System E 40:10:1) Rf 0.32.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)(C)(C)C.Cl.O1CCOCC1>CC(O)C>[ClH:15].[NH2:7][C:8]1[CH:9]=[C:10]([Cl:16])[C:11]([Cl:15])=[C:12]([OH:14])[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(O)c(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Nc1cc(O)c(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 189.2 %

Procedure:
tert-Butyl(3,4-dichloro-5-hydroxyphenyl)carbamate from Example 67A (960 mg, 3.45 mmol) was dissolved in 2-propanol (16 mL), and 4 M gaseous hydrogen chloride in dioxane (5.0 mL, 20 mmol) was added. The mixture was heated to 80° C. for 1.5 h. Subsequently, the solvent was removed in vacuo to yield 700 mg (90%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([NH2:65])[C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>CN(C)C=O.ClCCl.CO>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([C:58]3[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=3)[NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC(c1ccc(Cl)cc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NC(c2ccc(Cl)cc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 50 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and C-(5-chloro-1H-benzimidazol-2-yl)-C-(4-chlorophenyl)methylamine in dimethylformamide. Yield: 50%; Rf value: 0.20 (silica gel; dichloromethane/methanol=95:5); C27H24C12N4O2 (507.42); mass spectrum: (M+H)+=507/509/511 (chlorine isotope) and (M−H)−=505/507/509 (chlorine isotope).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:3]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>C(OCC)(=O)C>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)N1CCNCC1
Reactant: Brc1cccc(C2OCCO2)n1
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(c2cccc(C3OCCO3)n2)CC1
Temperature: 120 °C
Yield: 54.1 %

Procedure:
A mixture of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (7, 0.23 g, 1.0 mmol) and 1-isopropylpiperazine (0.38 g, 3.0 mmol) in a sealed tube was heated at 120° C. for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to afford the title compound (0.15 g, 55%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.51-7.48 (m, 1H), 6.83-6.82 (m, 1H), 6.62-6.60 (m, 1H), 5.72 (s, 1H), 4.18-4.14 (m, 2H), 4.08-4.04 (m, 2H), 3.58 (br s, 4H), 2.71 (br s, 1H), 2.62 (br s, 2H), 1.08 (d, J=5.5 Hz, 6H); ESI MS m/z 278 [M+H]+.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Mg].P(=O)(O)(O)O.C1(C)C=CC=CC=1>CN(C)C=O>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: O=P(O)(O)O
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 229 mg (9.42 mmol) of magnesium (turning) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at 100° C. for one hour. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 phosphoric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 710 mg (3.81 mmol) of diphenylphosphine in 81% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[C:13]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:12]=[C:11]([C:24]#[N:25])[N:10]=2)=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[NH2:15][C:14]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:10][C:11]([C:24]#[N:25])=[N:12][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: N#Cc1nc(Nc2ccc(Cl)cc2)c([N+](=O)[O-])c(N2CCOCC2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1nc(Nc2ccc(Cl)cc2)c(N)c(N2CCOCC2)n1

Procedure:
The product from step (ii) (1.7 g) and 10% palladium on charcoal (0.2 g) in ethyl acetate (300 ml) was hydrogenated at 2 Bar for 8 h, filtered through celite and the solvent evaporated under reduced pressure. Yield 1.05 g
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH2:15])=[N:5][C:6]1([CH2:14][NH:13][CH2:12]1)[NH:7]2.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH2:15])=[N:5][C:6]1([CH2:12][N:13]([C:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[O:29])[CH2:14]1)[NH:7]2
Reactant: NC1=NC2(CNC2)Nc2cccc(F)c21
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC1=NC2(CN(C(=O)c3cccs3)C2)Nc2cccc(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
5'-Fluorospiro[azetidine-3,2'(1'H)quinazoline]-4'-amine (Example 250, 206 mg, 1 mmol) and triethylamine (0.28 ml., 2 mmol) in dry dichloromethane (15 ml) was stirred at 20° C. and thiophene-2-carbonyl chloride (0.12 ml, 1.1 mmol) added. The mixture was stirred at ambient temperature for 3 h then concentrated to dryness and separated by flash chromatography on silica using dichloromethane/methanol mixtures as eluant. The more polar fraction eluted afforded the title compound (50 mg) as a solid, m.p. 214°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40](Br)[CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(O)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC#N.CCO>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:39]=[C:40]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:41]=[CH:42][CH:43]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1cccc(Br)c1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)NN(Cc1cccc(-c2ccccc2)c1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B using compound 26 (80.5 mg, 0.118 mmol), phenylboronic acid (72.5 mg, 0.595 mmol), Pd(PPh3)2Cl2 (6.50 mg, 0.00926 mmol), 2 M Na2CO3 (aq., 0.177 mL, 0.354 mmol), DME (1.6 mL) and EtOH (0.4 mL) affording the product (21.2 mg, 26%) after RP-LC-MS (35 min gradient of 40-100% CH3CN in 0.05% aqueous formic acid) as a white solid.
Reaction SMILES: Cl.[NH:2]([C:4]([C:6]1([NH:9][C:10]([C:12]2([NH:15][C:16]([C:18]3[N:22]4[C@@:23]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=5)([CH3:35])[C:24](=[O:34])[N:25]([C:26]5[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=5)[C:21]4=[N:20][CH:19]=3)=[O:17])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7]1)=O)[NH2:3].Cl.C(O[C:49]([CH:51]1[CH2:53][CH2:52]1)=[NH:50])C.CCN(CC)CC>CN(C=O)C>[CH:51]1([C:49]2[NH:50][C:4]([C:6]3([NH:9][C:10]([C:12]4([NH:15][C:16]([C:18]5[N:22]6[C@@:23]([CH2:36][C:37]7[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[CH:41][CH:42]=7)([CH3:35])[C:24](=[O:34])[N:25]([C:26]7[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=7)[C:21]6=[N:20][CH:19]=5)=[O:17])[CH2:13][CH2:14]4)=[O:11])[CH2:7][CH2:8]3)=[N:2][N:3]=2)[CH2:53][CH2:52]1
Reactant: CCOC(=N)C1CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(=O)NN)CC4)CC3)n21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5nnc(C6CC6)[nH]5)CC4)CC3)n21
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [1-(1-hydrazinocarbonyl-cyclopropylcarbamoyl)-cyclopropyl]-amide hydrochloride (0.080 g, 0.12 mmol) and cyclopropanecarboximidic acid ethyl ester hydrochloride (0.018 g, 0.12 mmol) in DMF (1 mL) was added Et3N (0.051 mL, 0.37 mmol). The reaction was heated in a microwave at 140° C. for 45 min and then at 180° C. for 1.5 h. The mixture was cooled to room temperature and purified via reverse-phase HPLC to give (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide (0.022 g, 28%) as a white solid, m/z 670.8 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)([CH3:3])[CH3:2].[I-:15].[Na+].II.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[I:15][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][NH:8][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)c1cc(-c2ccccc2)n[nH]1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1[nH]nc(-c2ccccc2)c1I
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution of 5-isopropyl-3-phenyl-1H-pyrazole (0.64 g, 3.44 mmol) in THF (20 mL) and water (20.00 mL) were added sodium iodide (0.515 g, 3.44 mmol), iodine (1.308 g, 5.15 mmol), and potassium carbonate (0.712 g, 5.15 mmol) at room temperature. The reaction was refluxed for 2 h, cooled to room temperature and quenched with 10% aq. Na2SO3. The organic solvent was removed under reduced pressure and the aqueous residue was extracted with EtOAc. The organic extract was washed with NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a clear liquid (0.42 g). LCMS m/z=313.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (d, J=7.07 Hz, 6H), 3.02 (septet, J=7.07 Hz, 1H), 7.23-7.32 (m, 3H), 7.60-7.67 (m, 2H), 11.81 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.N1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:25]=[CH:24]\[CH2:23]/[CH:22]=[CH:21]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:1][CH2:2][C:8]([O:16][CH2:15][C@H:13]1[O:14][C@@H:10]([N:4]2[C:5](=[O:6])[NH:7][C:8](=[O:9])[C:2]([CH3:1])=[CH:3]2)[CH2:11][C@@H:12]1[N:17]=[N+:18]=[N-:19])=[O:9]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]

Procedure:
The procedure for this preparation is exactly as above. The quantities used were as follows: AZT, 0.723 g, 2.70 mmol. LA acid chloride, 1.3 g, 4.36 mmol. 10 ml of anhydrous pyridine. Yield, 54% (0.770 g, 1.458 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]([C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)=[C:2]2[CH3:1])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(-c2ccncc2)c(C)c2cc(O)ccc21
Product: CCCn1c(-c2ccncc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-methyl-1-propyl-2-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.