Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1ccc(N)cc1
Yield: 76.9 %

Procedure:
To a suspension of Pd/C (0.5 g) in methanol (10 mL), ethyl 2-(4-nitrophenoxy)acetate (1.5 g) was added under nitrogen atmosphere into the 50 mL 3-neck RBF at room temperature. Hydrogen gas was bubbled through the reaction for 2 hr at room temperature. The reaction was monitored on TLC using CHCl3: methanol (9.5:0.5) as mobile phase. After completion of the reaction, the mixture was filtered using Celite and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure at 40° C. to give 1.0 g of ethyl 2-(4-aminophenoxy)acetate as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:14])[CH:13]=1)[C:8](O)=[O:9])=[O:4].C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([I:14])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)cc(CO)c1
Reaction time: 0.75 h

Procedure:
To a solution of 3-methoxycarbonyl-5-iodobenzoic acid (1 g) in tetrahydrofuran (10 ml) was added at -40° C. to -30° C. triethylamine (0.55 ml) followed by slow addition of isobutyl chloroformate (0.51 ml) under nitrogen atmosphere. The reaction mixture was stirred below -20° C. for 45 minutes. Then, triethylamine hydrochloride was filtered off and washed with cold tetrahydrofuran, and the filtrate was added as quickly as possible to a suspension of sodium borohydride (0.37 g) in tetrahydrofuran-water (8:1, 8 ml) at 0° C. with vigorous stirring. The stirring was continued at ambient temperature for 4 hours, followed by acidification of the solution to pH 5. The tetrahydrofuran was removed under reduced pressure, and the product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Ethyl acetate was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-hydroxymethyl-5-iodobenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](Cl)=O>C1(C)C=CC=CC=1>[Cl:15][CH:16]([C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(Cl)C(=O)Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
10.25 g of 2-amino-3-trifluoromethyl benzoic acid in 20 ml of toluene and 18.6 g of 2-chloro-3-methyl butanoyl chloride (prepared by J. Org. Chem., Vol. 40, p. 3420 (1975)) were mixed together, and the procedure of Example 10 of Belgian Patent No. 896,941 was followed for the preparation of 11.9 g of 2-(1-chloro-2-methylpropyl)-8-(trifuoromethy)-4H-3,1-benzoxazin-4-one melting at 78°-80° C.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].O=[C:9]([CH2:15][CH3:16])[CH2:10][C:11](OC)=[O:12].C[O-].[Na+].O>CO.C(O)(=O)C>[CH2:15]([C:9]1[N:7]=[CH:5][N:6]=[C:11]([OH:12])[CH:10]=1)[CH3:16]
Reactant: N=CN
Reactant: CCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(O)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
Formamidine acetate (2.64 g, 25.4 mmol) and methyl 3-oxopentanoate (3.0 g, 23.05 mmol) were added to a mixture of sodium methoxide (2.68 g, 49.6 mmol) in methanol (20 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. Water (6 mL) and acetic acid (3 mL) were added and the solvent was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The resulting solid was triturated with ethyl acetate, filtered and washed with a small volume of ethyl acetate. The solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (932 mg);
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[S:7](=[O:9])(=[O:8])[C:6]2([CH3:22])[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:23])[N:4]=[C:3]1[N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CCOC(C)=O.CCO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][C:6]3([CH3:22])[S:7](=[O:8])(=[O:9])[C:2]([CH3:39])([CH3:1])[C:3]([N:24]([C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[N:4][C@:5]3([CH3:23])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2(C)S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCCC2(C)S(=O)(=O)C1(C)C

Procedure:
A solution of tert-butyl N-[(11bR)-3,3,4a,11b-tetramethyl-10-nitro-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (0.076 g, 0.13 mmol) in EtOAc (0.9 ml) and EtOH (0.5 ml) was stirred under hydrogen balloon in the presence of palladium, 10% wt. on activated carbon (0.036 g, 0.033 mmol) for 15 h. The mixture was filtered through the plug of Celite, filter cake was washed with ethyl acetate. The combined filtrate was concentrated to afford crude tert-butyl N-[(11bR)-10-amino-3,3,4a,11b-tetramethyl-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate as mixture of trans and cis diasteromers (˜1:3 ratio) which was used without further purification. m/z (ESI) 560.0 (M+Na)+.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@:5]2([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]23)[CH2:4]1.[OH-].[NH4+:29]>CN(C=O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]3[C@@:5]3([CH2:4][C@H:3]3[CH2:2][NH2:29])[N:11]=2)=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CBr)c1nnc(C)n1-2
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CN)c1nnc(C)n1-2
Reaction time: 9 h
Yield: 4 %

Procedure:
To a solution of (1S,2R)-2-(bromomethyl)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro-[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine](350 mg, 0.758 mmol) in DMF (4 mL) was added ammonium hydroxide (3 mL, 77 mmol) at rt. After 9 h at rt, silica gel was added, and the solvent was removed under vacuum. The dry silica gel was packed, and the product was purified by chromatography (Hexane/EtOAc 5:5 to 0:10 then DCM/MeOH 10:0 to 9:1). A second (EtOAc/toluene/MeOH 4:4:2) and a third chromatography were performed (2-propanol 100%) to give a tan solid (12 mg). LRMS (M+H)+: 398 m/z.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:17]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@@H:18]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CO>[NH:17]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@@H:18]([C:31]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25]
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Yield: 97.4 %

Procedure:
8.8 Grams (20 mM) of H-Gly-Arg-CHA.2HCl was dissolved in 21.5 ml of DMF, to this solution was added 5.1 ml (40 mM) of NEM. To the mixture was further added with 9.6 g (20 mM) of Z-D-Lys(BOC)-OSu and reacted at room temperature for 18 hours. After the reaction was completed, the DMF was removed by evaporation under a reduced pressure and the residue obtained was dissolved in MeOH and reprecipitated in 1 liter of AcOEt. The crystals precipitated were collected by filtration and dried to obtain 14.9 g (97.4%) of Z-D-Lys(BOC)-Gly-Arg-CHA.HCl. Rf1 =0.50. Melting point: 207.5° C. (decomposed). [α]D20 -8.0 (C=0.5, MeOH)
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCCCC1.NC1SC=NC=1.C([O:53][C:54](=[O:58])C(S)C)C>>[CH:24]1([N:16]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH3:23])[CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:54]([OH:58])=[O:53])=[CH:9][N:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(C)S
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: COC(=O)c1ccc(C)c(-c2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4′-cyano-6-methyl-biphenyl-3-carboxylic acid methyl ester 2 (2.56 g, 10.3 mmol) in 1,4-dioxane-H2O (1:1 mixture, 20 ml) is added NaOH (1.22 g, 30.2 mmol)). The reaction is stirred at ambient temperature for 24 hours. To this mixture is added aqueous HCl (1 N, 36 ml) and it is then extracted with ethyl acetate (40 ml×3). The organic layers are combined, dried over anhydrous Na2SO4. The solver is removed. The solid obtained is washed with small amount of acetonitrile and air dried to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid 3: 1H NMR (DMSO-d6) δ 7.94 (d, 2H, J=8.0 Hz), 7.84 (dd, 1H, J1=8.4 Hz, J2=1.2 Hz), 7.75 (d, 1H, J=1.2 Hz), 7.61 (d, 2H, J=8.0 Hz), 7.48 (d, 1H, J=8.4 Hz), 2.29 (s, 3H); LC-MS m/z 238.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:27][C@H:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:18]1[NH:17][C:12]1[C:11]([CH2:28][CH3:29])=[N:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (214 mg, 0.5 mmol) and pyridine (44 μL, 0.55 mmol) in dichloromethane (5 mL) was purged with nitrogen and cooled to 0° C. The light yellow homogenous solution was treated with acetyl chloride (34 μL, 0.48 mmol) with no visible change. The reaction mixture was gradually warmed to RT. After 16 hrs, the volatiles were removed under reduced pressure and the resulting residue was absorbed on 4 g silica gel and purified by Biotage MPLC (40 g column, 15% ethyl acetate/heptane) to afford the title compound as an off-white solid. IR (diffuse reflectance) 2971, 2934, 1743, 1568, 1550, 1498, 1467, 1393, 1372, 1238, 1207, 1177, 1101, 1036, 751 cm−1; OAMS supporting ions at: ESI+ 470.1; MS (EI) m/z 469 (M+); HRMS (FAB) calcd for C25H25CL2N3O2+H1 470.1402, found 470.1404. [α]25D=73 (c 0.60, methylene chloride); Anal. Calcd for C25H25Cl2N3O2: C, 63.83; H, 5.36; N, 8.93. Found: C, 63.45; H, 5.40; N, 8.79.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[C:12]([CH3:19])[C:11]=1[S:20]([CH2:22][CH3:23])=[O:21].Cl.CN(C)CCCN=C=NCC.Cl.C(N(CC)CC)C.[C-]#N.[K+].C(=O)(O)[O-].[Na+]>ClCCl.CC(C)(O)C#N.C(#N)C.C(OCC)C>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[OH:1])=[O:15])=[C:12]([CH3:19])[C:11]=1[S:20]([CH2:22][CH3:23])=[O:21]
Reactant: Cc1cc(O)n(C)n1
Reactant: CCS(=O)c1c(Cl)ccc(C(=O)O)c1C
Agent: CC(C)(O)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)c1c(Cl)ccc(C(=O)c2c(C)nn(C)c2O)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
128 mg (1.14 mmol) of 5-hydroxy-1,3-dimethylpyrazole were added to 270 mg (purity 95% by weight; 1.04 mmol) of 4-chloro-3-ethylsulfinyl-2-methylbenzoic acid in 20 ml of dichloromethane (CH2Cl2). 239 mg (1.24 mmol) of 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the mixture was stirred at RT for 16 h. For work-up, 3 ml of 1M HCl were added, and the organic phase was freed from the solvent. 210 mg (2.07 mmol) of triethylamine, 10 drops of acetone cyanohydrin and a spatula tip of potassium cyanide were added to the residue in 20 ml of acetonitrile. The reaction mixture was stirred at RT for 16 h and then freed from the solvent. The residue was stirred at RT with 25 ml of a mixture of aqueous saturated sodium bicarbonate solution and diethyl ether for 10 min. The phases were separated, and the aqueous phase was acidified with dilute HCl and then extracted with CH2Cl2. The organic phase was freed from the solvent and the residue was then purified chromatographically. This gave 100 mg of clean product.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[CH2:8][CH2:9][S:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].CCCCCC.CCOC(C)=O>C(O)C.[Pd]>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[CH2:8][CH2:9][S:10][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: C=CCc1ccc2c(c1)SCC2
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1ccc2c(c1)SCC2
Yield: 85.8 %

Procedure:
A solution of 6-allyl-2,3-dihydrobenzothiophene (95 mg, 0.49 mmole) in 10 mL absolute ethanol was hydrogenated at 40 psi over 20 mg 10% Pd/C at room temperature overnight. TLC (90/10, hexane/EtOAc) indicated the reaction to be complete. The catalyst was filtered off through a celite pad and the filtrate concentrated down to afford 96 mg crude product as an oil. Purification by flash chromatography (90/10, hexane/EtOAc) afforded 75 mg white solids mp 58°-60° C. (78%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:21])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
6-Amino-9-benzyl-2-ethylaminopurine (75 mg, 0.28 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (63 mg, yield 65%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCC1CCOCC1

Procedure:
The product of Example 8A (2.9 mmol), triethylamine (1.2 mL, 8.7 mmol) and methanesulfonyl chloride (0.34 mL, 4.4 mmol) in 10 mL tetrahydrofuran (THF) were reacted and the product isolated as in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:16][NH2:17]>CN(C=O)C>[CH3:16][NH:17][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cn1c(=O)c2c(Cl)ccnc2n(C)c1=O
Solvent: CN(C)C=O
Product: CNc1ccnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
0.4 g of Compound 1 and 1.86 g of methylamine (30% methanol solution) were added to 10 ml of DMF. The solution was stirred 2 hr at room temperature and the solvent was distilled off under reduced pressure. After adding water, the resulting crude crystals were separated by filtration and recrystallized from ethyl acetate to give 0.23 g of 5-methylamino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 7)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:13]=[C:14]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH:15]=[CH:16][C:17]=2[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:13]=[C:14]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:15]=[CH:16][C:17]=2[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 193.3 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3,5-dichlorophenyl)ethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50.1 mg, 0.09 mmol) in dichloromethane (2.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 2 hours. The solvent was removed by rotary evaporation to afford the title compound (42.0 mg, 95% yield). 1H NMR (400 MHz, CD3OD): δ 7.67 (d, 1H), 7.37 (s, 2H), 7.35 (s, 1H), 6.41 (d, 1H), 5.84 (s, 1H), 4.79 (m, 1H), 3.57 (m, 4H), 3.25 (m, 4H), 1.61 (d, 3H); MS (ESI) m/z: Calculated for C20H21Cl2F3N3O: 446.1; Observed: 446.5 (M++1) [corresponding to the free base].
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:25])=[C:22]([OH:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:25])=[C:22]([CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Br)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 30.4 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.2 g, 6.7 mmol) in N,N-dimethylformamide (60 mL) were added 5-amino-2-bromophenol (1.9 g, 10 mmol) and potassium carbonate (1.8 g, 13 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0). The solvent was evaporated under reduced pressure and the obtained solid was washed with diisopropyl ether to give the title compound (0.79 g, 31%) as a yellow powder.
Reaction SMILES: Cl[C:2]1[C:3](=[O:29])[O:4][C:5]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([CH3:23])=[N:19][O:20][C:21]=3[CH3:22])=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[N:34]2[N:38]=[C:39]([SH:41])[N:40]=[C:33]2[N:32]=1>>[CH:24]1([C:5]2([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:18]([CH3:23])=[N:19][O:20][C:21]=4[CH3:22])=[CH:13][CH:12]=3)[O:4][C:3](=[O:29])[C:2]([S:41][C:39]3[N:40]=[C:33]4[N:32]=[C:31]([CH3:30])[CH:36]=[C:35]([CH3:37])[N:34]4[N:38]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: Cc1noc(C)c1-c1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1
Product: Cc1cc(C)n2nc(SC3=C(O)CC(CCc4ccc(-c5c(C)noc5C)cc4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared from 3-Chloro-6-cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one from Step 2 and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the coupling method described in Example C(4), 1H NMR (DMSO-d6): δ 1.44-1.75 (br m, 9H), 2.21 (s, 3H), 2.34 (s, 3H), 2.38 (s, 3H), 2.59 (s, 3H), 2.65-2.79 (m, 3H), 2.97 (d, 1H, J=17.0 Hz), 3.17 (s, 2H), 7.02 (s, 1H), 7.29 (d, 2H, J=8.1 Hz), 7.40 (d, 2H, J=8.1 Hz). Anal. Calcd. For C30H33N5O4S.0.75AcOH: C, 62.56; H, 6.00; N, 11.58. Found: C, 62.66; H, 5.98; N, 11.56.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>O1CCOCC1.C(=O)(O)[O-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:32]1([CH2:31][O:30][C:21]2[CH:20]=[CH:25][C:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][C:22]=2[C:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=2)[CH2:33][CH2:34]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1=O
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cc(F)c1=O
Yield: 39.1 %

Procedure:
3-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (40 mg, 0.16 mmol), 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene (49 mg, 0.16 mmol), and Pd(dppf)Cl2 (12 mg, 10%) in 1,4-dioxane (880 μL) and saturated bicarbonate solution (aq) (220 μL) were reacted, worked up, and purified in a manner similar to Example 117. The title compound (22 mg, 46%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.31-0.42 (m, 2H) 0.53-0.63 (m, 2H) 1.17-1.34 (m, 1H) 3.20 (s, 3H) 3.58 (s, 3H) 3.95-4.06 (m, 2H) 7.24-7.33 (m, 1H) 7.72-7.79 (m, 1H) 7.80-7.87 (m, 1H) 7.84 (s, 1H) 7.88-7.93 (m, 1H) LCMS (M+H)+=351.