Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:49])[CH:15]([C:20]1[CH:21]=[C:22]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].O.OO.[O-:55]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][C:24]2[CH:25]=[C:20]([C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:55])=[O:49])[CH:21]=[C:22]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=3)[CH:23]=2)=[C:29]([C:35]([F:37])([F:38])[F:36])[CH:30]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(4-fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (0.535 g, 0.78 mmol) in THF (9 mL) was added water (3 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (33 mg, 0.78 mmol) and 30% H2O2 (0.354 mL, 3.12 mmol,) and stirred at 0° C. for 20 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (2.08 mL, 3.12 mmol) and stirred at room temperature for 5 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×50 mL) and dried (MgSO4). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield (R)-2-[5-(4-Fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (310 mg).
Reaction SMILES: [CH2:1]([OH:20])[CH:2]([OH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>ClCCl>[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:20][CH2:1][CH:2]([OH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCCCCCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC(O)COC1CCCCO1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A 1-liter flask equipped with a stirrer and dropping funnel was charged with 20 g (70 mmol) of octadecane-1,2-diol, 0.7 g (3.5 mmol) of p-toluenesulfonic acid and 350 ml of dichloromethane. While stirring the contents at room temperature, 5.9 g (70 mmol) of dihydropyran were added dropwise. After stirring the mixture at room temperature for 30 minutes, it was neutralized with NaHCO3 and concentrated under reduced pressure, and the resultant residue was then purified by column chromatography on silica gel, thereby obtaining 7.5 g (yield[: 29%) of 1-(2-tetrahydropyranyloxy)-2-octadecanol. This compound was charged into a 200-ml flask equipped with a stirrer, to which 5.1 g (50 mmol) of triethylamine and 50 ml of dichloromethane were added. Further, 3.8 g (33 mmol) of methanesulfonyl chloride were added at room temperature with stirring. After the resultant mixture was stirred at room temperature for 14 hours, the reaction mixture was added with water and subjected to extraction with dichloromethane, and the solvent was distilled off under reduced pressure. The resultant residue and 15 ml of dimethylformamide was charged into a 100-ml flask equipped with a stirrer, to which 5.5 g (83 mmol) of NaN3 were added. The contents were stirred at 90° C. for 1.5 hours. After cooling the reaction mixture to room temperature, it was added with water and subjected to extraction with chloroform, followed by concentration under reduced pressure. Thereafter, the resultant residue was purified by column chromatography on silica gel, thereby obtaining 7.1 g (yield: 90%) of an azide intermediate.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH:7](/Br)=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(NCC)C>[C:9]1(/[CH:8]=[CH:7]/[C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCCCO
Reactant: Br/C=C/c1ccccc1
Solvent: CCNCC
Product: OCCCC#C/C=C/c1ccccc1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
Cuprous iodide (0.4 g, 2.1 mmol) and bis-triphenylphosphine palladium (II) chloride (0.8 g, 1.14 mmol) were added to a solution of pent-4-yn-1-ol (16 g, 193 mmol) (Jones, Eglinton, and Whiting, Org. Syn. Coll., 4, 755, (1963)) and E-styryl bromide (34.34 g, 188 mmol) (Feurerstein and Heimann, Ber., 34, 1468 (1901)) in anhydrous diethylamine (250 m). The whole was stirred under an atmosphere of dry nitrogen with the exclusion of moisture and light for 16 hours. The diethylamine was removed at reduced pressure and the residue diluted with water (500 ml). The aqueous mixture was extracted with ether. The ethereal extracts were passed down a column composed of silica (100 g), Celite (trade name, from Koch-light Ltd) (100 g) and activated charcoal (20 g) at 3 psi (21 KPa) pressure. The column was washed with ether (200 ml) and the combined organic extracts dried over anhydrous magensium sulphate. Removal of solvents gave 30.5 g of 7-phenyl-hept-4-yn-6E-en-1-ol as a pale brown oil. The material was not purified further.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O1CCCC1.B.ClCCCl>O1CCCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[CH:7]=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1I
Agent: O=[Mn]=O
Agent: B
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=Cc1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 121.4 %

Procedure:
To a solution of 5-chloro-2-iodo benzoic acid (4.92 g, 17 mmol) (TRANS) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added borane tetrahydrofuran (1 M, 34 mL, 34 mmol) dropwise. The reaction mixture was then stirred at room temperature for 18 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give a colorless oil. The oil was dissolved into 1,2-dichloroethane (50 mL), and activated MnO2 (15 g) was added. The mixture was then heated at reflux for 2 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated and purified by chromatography (EtOAc:hexanes=1;8) to give 5-chloro-2-Iodo-benzaldehyde as a white solid (Yield 5.5 g, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(C)cc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-p-tolyl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 4-methyl-phenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.23 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 7.64-7.51 (m, 4H), 7.38-7.26 (m, 2H), 4.02 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 68.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol), 3-(trifluoromethyl)benzoic acid (54 mg, 0.29 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol), 1-hydroxybenzotriazole (39 mg, 0.29 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (86 mg, 69%) was obtained as a white powder.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:38]([F:41])([F:40])[F:39])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]([NH:30]C(=O)OC(C)(C)C)([CH3:29])[CH2:23][O:24][P:25]([OH:28])([OH:27])=[O:26])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[P:25]([OH:27])([OH:28])([O:24][CH2:23][C@:22]([NH2:30])([C@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]3)[C:13]=2[C:38]([F:39])([F:41])[F:40])[CH2:18]1)[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)[C@H]1CCc2c(ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)c2C(F)(F)F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2C(F)(F)F)CC[C@H]([C@@](C)(N)COP(=O)(O)O)C3)CC1
Reaction time: 1 h

Procedure:
tert-Butyl (R)-2-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-1-(phosphonooxy)propan-2-ylcarbamate (22.0 mg, 0.0000362 mol) was dissolved in trifluoroacetic Acid (1.0 mL, 0.013 mol) and methylene chloride (1.0 mL, 0.016 mol) was added and the mixture was stirred for 1 h. Concentration and lypholyzing gave pure (R)-2-amino-2-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)propyl dihydrogen phosphate as a white solid (18.0 mg, 98%). LCMS: Rf=1.74min 508.41 [M+1]. 1H NMR (400 MHz, MeOD) δ=7.25 (d, J=9.0 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 4.23 (dd, J=4.9, 11.2 Hz, 1H), 4.18 (m, 1H), 4.03 (dd, J=4.1, 11.3 Hz, 1H), 3.22-2.82 (m, 3H), 2.77-2.64 (m, 1H), 2.15 (d, J=12.6 Hz, 2H), 2.02 (d, J=10.6 Hz, 1H), 1.87 (d, J=13.2 Hz, 2H), 1.56-1.35 (m, 2H), 1.33 (s, 3H), 1.24-1.01 (m, 2H), is 0.89 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[NH:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24](=[O:26])[CH3:25]>>[CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[N:13]([CH2:23][C:24](=[O:26])[CH3:25])[CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2[nH]cnc2n(CC2CCC2)c(=O)n1CC1CCC1
Reactant: CC(=O)CCl
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CCC1)c(=O)n2CC1CCC1

Procedure:
1,3-Di-cyclobutylmethyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclobutylmethyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 155° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=O)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C1C(=O)N(O)C(=O)C1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:44][N:45]1[CH2:49][C@@H:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:47][C:46]1=[O:57]>>[CH3:44][N:45]1[CH2:49][C@@H:48]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[N:47]([C:17](=[O:19])[C@@H:16]([NH:15][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:20])[C:46]1=[O:57]
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 70.5 %

Procedure:
560 mg of (2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionic acid, 230 mg of 1-hydroxysuccinimide, 413 mg of dicyclohexylcarbodiimide and 400 mg of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are treated in the same manner as described in Example 1-(1), whereby 650 mg of tert.-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate are obtained as colorless viscous oil. Yield: 70.4%
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9](=[O:12])[C:8]([NH:13][C:14](=[O:16])[CH3:15])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>>[N:1]1([C:2]2[C:11]3[O:10][C:9](=[O:12])[C:8]([NH:13][C:14](=[O:16])[CH3:15])=[CH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: ClCCNCCCl
Reactant: CC(=O)Nc1cc2cccc(N)c2oc1=O
Product: CC(=O)Nc1cc2cccc(N3CCNCC3)c2oc1=O

Procedure:
Step 4 was the alkylation of N-(8-amino-2-oxo-2H-1-benzopyran-3-yl)-acetamide (4*) with bis-chloroethylamine yielding N-(8-(1-piperazinyl)-2-oxo-2H-1-benzopyran-3-yl-)acetamide (5*).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.[Li]CCCC.[CH3:21][O:22][CH2:23]Cl.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH2:23][NH:15][S:12]([CH:9]1[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: COCCl
Reactant: NS(=O)(=O)C1CC1
Agent: CC(C)(C)NC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCNS(=O)(=O)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Step 15IId) To a solution of cyclopropylsulfonylamine tert-butyl carbamate (1.0 g, 4.5 mmol) dissolved in THF (30 mL) cooled to −78° C., was added n-BuLi (6.4 mL, 10.2 mmol, 1.6 M in hexane) and the reaction mixture was stirred for 1 h. To this solution was added a neat solution of chloromethyl methyl ether (0.40 mL, 5.24 mmol), and the mixture was slowly allowed to warm to room temperature overnite. The solution pH was adjusted to 3 using 1N aqueous HCl and was then extracted with EtOAc (4×50 mL portions). The combined extracts were dried (MgSO4) and concentrated to afford Example 18, 1-methoxy-methylcyclopropylsulfonylamine tert-butylcarbamate, as a waxy solid (1.20 g, 100%) which was taken directly into the next reaction without further purification: 1H NMR (CDCl3) δ 1.03 (m, 2H), 1.52 (s, 9H), 1.66 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H), 7.54 (s, 1H); 13C NMR (CDCl3) δ 11.37, 28.29, 40.38, 58.94, 73.43, 83.61, 149.57.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])=[CH:6][CH:5]=1.[OH-:18].[NH4+].[OH-].[K+]>O.C(Cl)Cl>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:16]([NH2:17])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: NCc1ccc(-c2ccccc2C(N)=O)cc1
Temperature: 72.5 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
4-Aminomethyl-2′-cyanobiphenyl hydrochloride (XVII) (100 g, 0.408 mole) was suspended in a mixture of water (500 ml) and methylene chloride (200 ml) at 25-30° C. and adjusted the pH to 9.0-9.5 with ammonium hydroxide (65 ml, 20% w/w) at 25-30° C. to get a clear solution. Organic layer was separated, washed with water (100 ml) and dried over sodium sulfate. Thereafter, organic layer was concentrated at below 60° C. and tert.butanol (300 ml) was added to the residue. The reaction mass was heated to 70-75° C. Thereafter, powdered potassium hydroxide (32.35 g, 0.491 mole) was added and heated to reflux for completion of the reaction. Water (400 ml) was added and aqueous layer was separated and extracted with methylene chloride (500 ml). The combined organic layer was washed with water (200 ml) and dried over sodium sulfate. Methylene chloride solution was cooled to 2-5° C. and the pH adjusted to 1.2-1.4 with hydrochloric acid. The precipitated product was stirred for one hour and filtered, washed with methylene chloride to afford the title compound as white powder (90 g, 84.1% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][N:5]=[N:4][CH2:3]1.[CH2:8]([N:10]=[C:11]=[S:12])[CH3:9]>C(O)C>[CH2:8]([NH:10][C:11]([N:4]1[CH2:3][C:2]([CH3:7])([CH3:1])[CH:6]=[N:5]1)=[S:12])[CH3:9]
Reactant: CCN=C=S
Reactant: CC1(C)CN=NC1
Solvent: CCO
Product: CCNC(=S)N1CC(C)(C)C=N1
Yield: 8.2 %

Procedure:
10 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-3H-pyrazole (synthesized as described in WO 2008/034863) and 11.6 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 100 mL ethanol. The reaction mixture was refluxed for 1 hour. Silica gel was added and volatiles were removed in vacuo. Purification by flash chromatography on silica gel (Et2O:PA=1:2) afforded 15.2 g (80%) of 4,4-dimethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 1.19-1.30 (m, 9H), 3.63-3.72 (m, 2H), 3.93 (s, 2H), 6.74 (s, 1H), 7.14 (br.s., 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][O:36][C:34](=[O:35])[CH2:33][N:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:2]1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)CC1CNC1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CC(CN(Cc2ncccc2C)Cc2ncccc2C)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 23.9 %

Procedure:
To a solution of azetidin-3-ylmethyl-bis-(3-methyl-pyridin-2-ylmethyl)-amine (0.4739 g, 1.6 mmol) in CH2Cl2 (16 mL) were added DIPEA (0.56 mL, 3.2 mmol), and methyl bromoacetate (0.18 mL, 1.9 mmol). The mixture was stirred at room temperature for 19 hours, and then saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1411 g (24%) of (3-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidin-1-yl)-acetic acid methyl ester as a yellow sticky oil. 1H NMR (CDCl3) δ 2.09 (s, 6H), 2.53-2.58 (m, 2H), 2.65-2.78 (m, 3H), 3.10 (s, 2H), 3.51 (t, 2H, J=6.0 Hz), 3.65 (s, 3H), 3.68 (s, 4H), 7.06-7.10 (m, 2H), 7.38 (d, 2H, J=9.0 Hz), 8.35 (d, 2H, J=6.0 Hz).
Reaction SMILES: C(S[C:6](=[O:24])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:25][C:26]1[CH:27]=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32]>>[CH3:22][C:19]([CH3:20])([CH3:21])[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:25][C:26]2[CH:27]=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=2[F:32])=[O:24])=[CH:17][CH:16]=1)=[O:23]
Reactant: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-[4-(2,2-dimethylpropionyl)benzyl]-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-fluorophenol.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C(=O)Nc2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methoxy-benzoyl chloride (34.1 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (12.5 mg, 0.0323 mmol, 16.2%). ESI-MS m/z calc. 386.1. found 387.2 (M+1)+ Retention time 3.95 minutes.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH3:30])=[C:18]([C:27]([NH2:29])=[O:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:31][C:16]1[C:17]([CH3:30])=[C:18]([C:27]([NH2:29])=[O:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C(N)=O
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1C(N)=O
Temperature: 90 °C
Yield: 41.2 %

Procedure:
A mixture of 6-bromo-9H-purine (110 mg, 0.56 mmol), 6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide (0.086 g, 0.28 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in isopropyl alcohol (2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (49 mg, 41%). LCMS calculated for C21H19ClFN6O (M+H)+: m/z=425.1. found: 425.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:34][CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].[H-].[Na+]>CN(C)C=O>[O:38]=[S:37]1(=[O:39])[CH2:36][CH2:35][CH2:34][N:1]1[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N)c3)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
A mixture of N-[5-(3-aminophenyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.30 mmol), and diisopropylethylamine (79 mg, 0.61 mmol), in dry dimethylformamide (2 ml) was treated with 3-chloropropanesulfonyl chloride (54 mg, 0.30 mmol) and stirred at room temperature for 1 h. Sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) was added and the mixture stirred at 60° C. for 0.5 h. The reaction mix was cooled then partitioned between dichloromethane and 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 5 g isolute silica sep-pak column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a yellow oil (12 mg, 9%).