Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[CH2:11][CH2:10]1>CC(O)=O>[CH:9]1([CH2:12][NH:13][C:14]2[C:19]([I:1])=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[CH2:10][CH2:11]1
Reactant: Nc1nccc(NCC2CC2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1ncc(I)c(NCC2CC2)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
N-iodosuccinimide (11.5 g, 50.9 mmol) was added to a solution of compound 237 (7.60 g, 46.3 mmol) in AcOH (90 mL). The reaction was warmed to 80° C. and stirred for 1.5 h. Solvent was removed in vacuo. The residue was taken up in dichloromethane (200 mL) and water. The aqueous layer was brought to pH 12 with 5 N NaOH and organics were sequestered. The aqueous was extracted further with dichloromethane (2×100 mL). The combined organics were treated with solid sodium thiosulfate, dried with MgSO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 10 to 75% ethyl acetate in hexanes) afforded compound 238 (8.0 g, 60% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][CH:19]=O)[CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([NH:18][CH3:19])[CH2:16][CH2:17]2)=[CH:7][C:6]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(O[C@H]2CC[C@H](NC=O)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@H]2CC[C@H](NC)CC2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
A solution of trans-N-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-formamide in anhydrous THF at 0° C. may be treated with borane-THF complex in THF (1 M, excess). The reaction may be allowed to come to room temperature and may be monitored by LCMS until the reaction is complete. The reaction may be quenched with MeOH and the solvents may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N NH3 in MeOH) in DCM to give trans-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-methyl-amine. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt may be triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 439 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+]>O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cn1ccc2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O)c1)S(C)(=O)=O
Yield: 90 %

Procedure:
To a solution of methyl 2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetate (520 mg, 1.360 mmol) in a 1:1 mixture of THF and water (20 ml), lithium hydroxide (326 mg, 13.60 mmol) was added, and the mixture was reacted for 2 hours at room temperature. The organic layer was evaporated and 1N HCl was added to the reaction mixture (pH 5); the resulting solid was filtered off affording 2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid that was used in the next step without any additional purification (450 mg, 1.221 mmol, 90% yield). MS/ESI+ 369.2 [MH]+.
Reaction SMILES: [NH:1]1[C:10](=[O:11])C2NC=NC=2N=C1N.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([NH:20][CH:21]=[O:22])=[C:15]([OH:23])[N:14]=1>C(O)=O>[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([NH:20][CH:21]=[O:22])=[C:15]([OH:23])[N:14]=1.[CH:10]([NH2:1])=[O:11]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: Nc1nc(N)c(NC=O)c(O)n1
Solvent: O=CO
Product: NC=O

Procedure:
The objects of the invention, and others, may be accomplished with a process for the preparation of guanine starting from 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP), which comprises reacting isolated DAFHP in the absence of formamide in formic acid, with or without addition of water under reflux conditions, to produce guanine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH2:7][OH:8].[Cl:19][C:20]1[CH:27]=[C:26](O)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.OO>O1CCCC1.C(OCC)C>[Cl:19][C:20]1[CH:27]=[C:26]([O:8][CH2:7][C:6]2[S:5][C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=3)=[N:3][C:2]=2[CH3:1])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1CO
Reactant: N#Cc1ccc(O)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: OO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an ice cooled solution of 2.76 g [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol, 2.06 g 2-chloro-4-hydroxybenzonitrile and 3.03 g triphenylphosphine in 30 ml tetrahydrofuran were added 1.74 ml diethylazodicarboxyate. The reaction mixture was stirred at room temperature overnight. 0.56 ml 30% H2O2 were added and the reaction mixture diluted by addition of 200 ml diethylether. The organic layer was washed with 50 ml 1N NaOH and 50 ml water, dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 2.02 g 2-Chloro-4-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-ylmethoxy]-benzonitrile as a lyophilisate.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[C:7]([NH2:23])[C:8]2[N:9]=[CH:10][N:11]([C:21]=2[N:22]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14]>O>[NH:2]([C:5]1[N:6]=[C:7]([NH2:23])[C:8]2[N:9]=[CH:10][N:11]([C:21]=2[N:22]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14])[NH2:3]
Reactant: NN
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 62 °C

Procedure:
A reaction vessel is charged with hydrazine hydrate (1285 g). The solution is heated to approximately 62° C., and 2-chloroadenosine (500 g) is added while maintaining the temperature of approximately 62° C. The mixture is maintained at a target of 62° C. for at least 2 hours, until the level of residual 2-chloroadenosine in the mixture is not more than 0.10%. The mixture is cooled to approximately 40° C. and the mixture is checked to verify the presence of solids. Water (2275 g) is slowly added while maintaining the temperature at approximately 40° C. The mixture is cooled to approximately 10° C. and held for not less than 1 hour. The product is isolated by filtration, washed with water (1195 g) and then with absolute ethanol (1885 g). The product is dried under vacuum at up to 30° C. for not less than 12 hours, to give 2-hydrazinoadenosine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16].[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:38]2[CH2:39][CH2:40][CH:35]([C:31]3[CH:30]=[C:29]([NH:28][C:26](=[O:27])[CH:25]([CH3:24])[CH3:41])[CH:34]=[CH:33][CH:32]=3)[CH2:36][CH2:37]2)=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCCl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 6-chloro-1-(4-chlorophenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 455.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[Br:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:32][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:18]([Cl:17])[CH:19]=1)=[O:8]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Br
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Br)cc1Cl

Procedure:
The product was prepared according to general working method I from (2-bromo-4-trifluoromethyl-phenoxy)-acetic acid (139b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.N#N.[CH3:17]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1
Agent: N#N
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
2.1 g (15.6 mmol) of 4-aminobenzoic acid was dissolved in anhydrous MeOH, added 14.47 g (123.3 mmol) of thionyl chloride dropwise under N2 while stirring at rt. After dtiring for four hours, solvents were removed and redissolved in 100 mL EtOAc and 40 mL of saturated NaHCO3 aq, stirred 30 min, separated and washed with 3×20 mL water. Organics were dried yielding 2.17 g (yield 92.1%) of methyl 4-aminobenzoate. 1H NMR (300 MHz, CDCl3): 7.88 (2H, d, J=8.6 Hz), 6.66 (2H, d, J=8.6 Hz), 4.19 (2H, broad s), 3.88 (3H, s). 13C NMR (300 MHz, CDCl3): 167.8 (C═O), 151.4 (Cq), 131.9 (2×CH), 120.0 (Cq), 113.8 (2×CH), 50.9 (CH3).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[N:18]3[CH:19]=[CH:20][N:21]=[C:22]([CH3:23])[C:17]3=[N:16][C:15]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:11]=[CH:10][N:9]=1)C.[OH-].[Na+].Cl>CO.C(Cl)Cl.O>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]2[N:16]=[C:17]3[C:22]([CH3:23])=[N:21][CH:20]=[CH:19][N:18]3[C:14]=2[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][CH2:6][C:5]([CH3:32])([CH3:31])[C:4]([OH:33])=[O:3])[N:13]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)CNc1nccc(-c2c(-c3ccc(F)cc3)nc3c(C)nccn23)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1nccn2c(-c3ccnc(NCC(C)(C)C(=O)O)n3)c(-c3ccc(F)cc3)nc12
Reaction time: 96 h
Yield: 45.1 %

Procedure:
3-{4-[2-(4-Fluorophenyl)-8-methylimidazo[1,2-a]pyrazin-3-yl]pyrimidin-2-ylamino}-2,2-dimethyl-propionic acid ethyl ester (Example #A.9.19, 0.085 g, 0.19 mmol) was diluted in MeOH (3 mL) and treated with 2.5 M NaOH (0.36 mL, 0.9 mmol) at ambient temperature. After about 4 days, the mixture was neutralized with 1.0 M HCl (0.90 mL, 0.9 mmol) and diluted with DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, decanted, and concentrated to yield the title compound (0.036 g, 45%): LC/MS (Table 1, Method b) Rt=1.9 min; MS m/z: 421.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1.C(N(CC)CC)C.ClC(Cl)C.C(COC)OC>>[CH2:22]([NH:21][C:19]([C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[N:18][C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][S:32]([CH:29]4[CH2:31][CH2:30]4)(=[O:34])=[O:33])[CH2:7][CH2:6]3)=[N:10]2)=[CH:15][CH:14]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CC(Cl)Cl
Product: O=C(NCc1ccccc1)c1ccc2cnc(N[C@H]3CC[C@H](NS(=O)(=O)C4CC4)CC3)nc2c1

Procedure:
A solution of 2-[(trans-4-aminocyclohexyl)amino]-N-benzylquinazoline-7-carboxamide (200.0 mg, 0.53 mmol), cyclopropanesulfonyl chloride (37.4 mg, 0.53 mmol) and triethylamine (162.0 mg, 1.6 mmol) in 7 ml of a mixed solvents of dichloroethane:dimethoxyethane (1:2) was stirred at room temperature for 16 hours. The crude material was purified by prepHPLC to give 13.0 mg of the product (yield 10.2%). 1H NMR (400 MHz, DMSO-d6) ppm 0.78-1.06 (m, 6H), 1.39 (t, J=9.82 Hz, 4H), 1.99 (d, J=4.28 Hz, 3H), 2.37-2.48 (m, 1H), 2.54-2.64 (m, 1H), 3.13 (s, 1H), 3.78 (s, 1H), 4.18 (d, J=6.55 Hz, 1H), 4.50 (d, J=6.04 Hz, 1H), 7.08 (d, J=7.81 Hz, 1H), 7.22-7.30 (m, 1H), 7.31-7.37 (m, 6H), 7.43-7.50 (m, 1H), 7.64 (d, J=6.80 Hz, 1H), 7.85 (d, J=8.31 Hz, 1H), 8.00 (s, 1H), 9.14 (s, 1H), 9.29 (t, J=5.92 Hz, 1H). HRMS: m/z 480.20484 [M+H]+), calc. 480.20638. MS m/z, (APCI); 480.2 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17]>C(O)C.C(N(CC)CC)C>[C:16]([NH:20][C:21]([NH:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc(C(=O)O)c1
Temperature: 60 °C

Procedure:
The process is performed as in Example 2, starting with 1.82 g of (2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride in 20 cm3 of ethanol, 4.2 cm3 of triethylamine and 1.7 cm3 of tert-butyl isothiocyanate. After heating for 21 hours at a temperature in the region of 60° C. and an identical work-up, 2.31 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea are obtained in the form of a light brown foam. (Rf=0.33 in a 12/6/1 by volume mixture of chloroform/methanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[CH:8]=[O:9].O.O.O.[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(OCC)(=O)C.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>[Pt](=O)=O>[CH:8]([C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:11][C:17](=[O:19])[CH3:18])=[O:9]
Reactant: CC(=O)[O-]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: O=[Pt]=O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(C)=O)c(C=O)c1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
5-Methoxy-2-nitro-benzaldehyde (5.00 g, 0.0276 mol), Platinum dioxide (400 mg, 0.002 mol) and Sodium acetate trihydrate (300 mg, 0.002 mol) were placed in a pressure flask, followed by Ethyl acetate (200 mL, 2 mol). The reaction mixture was then purged under N2 at least 3 times, and H2 was introduced (purged 3 times) and maintained at 52 psi for 3 hours. The reaction mixture was then filtered, and cooled to at −20° C. N,N-Diisopropylethylamine (7.21 mL, 0.0414 mol) was added to the solution followed by Acetyl chloride (2.36 mL, 0.0331 mol). The reaction mixture was allowed to stir for 2 hours, and quenched with KHCO3 (sat). Organic layer was separated, and washed with waster, brine and dried over Na2SO4. Removal of solvent gave a crude product, which was then purified via chromatography (SiO2, 80 g, 0-100% ethyl acetate/hexanes; 4.28 g, 80%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.25 (s, 3H) 3.88 (s, 3H) 7.10-7.26 (m, 2H) 8.69 (d, J=9.06 Hz, 1H) 9.90 (s, 1H) 10.75-11.04 (m, 1H). MS (ESI, M+1): 194.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20]C)=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)(=[O:10])=[O:9])[CH:7]=1.[I-].[Li+].N1C(C)=CC(C)=CC=1C.Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: O=S(=O)(Nc1cc(Cl)cc(Cl)c1)c1cc(Br)ccc1O
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A mixture of the white crystal of 5-Bromo-N-(3,5-dichlorophenyl)-2-methoxybenzenesulfonamide (206 mg, 0.5 mmol), lithium iodide (134 mg, 1 mmol) and 2,4,6-collidine (5 mL) was refluxed for 30 minutes under argon atmosphere. After cooling to room temperature, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from n-hexane-ethyl acetate to give the title compound (90 mg, 45.3%) as a white crystal.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.F[C:19]1[C:20]([CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[C:20]([CH:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:33])[CH3:32])[CH2:29][CH2:30]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of 4-(benzo[d]thiazol-2-ylamino)phenol (91 mg, 0.38 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (56 mg, 0.25 mmol), and cesium carbonate (123 mg, 0.38 mmol) in DMSO (0.85 mL) was heated at 80° C. for 16 h. After cooling to RT, the reaction mixture was partitioned between Teac and brine. The aqueous layer was back extracted with Teac (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% Teac in hexane, then 3% MeOH in Teac, followed by reverse-phase preparative HPLC using a Germini C18 5 uM column, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 15 min, then neutralize with Si carbonate resin, to provide 1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl) as a white solid. MS (ESI, pos. ion) m/z: 445.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Li]CCCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.O=[C:14]1CC[CH2:16][CH:15]1[C:19]([O:21][CH3:22])=[O:20].CI>C1COCC1.COCCOC>[CH3:22][O:21][C:19]([C:15]1[CH2:16][CH2:12][CH:10]([CH3:11])[CH:14]=1)=[O:20]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCCC1=O
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1=CC(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
The intermediate 3-methyl-cyclopent-1-enecarboxylic acid methyl ester was prepared as described below: n-BuLi (40.00 mL, 2.5 M in hexane, 100.00 mmol) was added to diisopropylamine (15.00 mL) in THF at 0° C. After 10 minutes, commercially available methyl 2-oxocyclopentanecarboxylate was added. The reaction mixture was stirred at 0° C. for another 10 minutes, then methyl iodide was added. The resulting reaction mixture was allowed to warm to room temperature over 20 minutes, then quenched with 2N HCl (50 mL). The mixture was extracted with ether, and the combined ether layers were washed with brine, then dried over magnesium sulfate and concentrated. 5.43 g of the methylated ester was dissolved in ethylene glycol dimethyl ether (DME) and cooled to −78° C., then Li(TMS)2N (42.00 mL, 1.0 M in THF, 42.00 mmol) was added. After 60 minutes, the reaction mixture was transferred to Cp2ZrHCl in DME at 0° C. Stirring was continued for another 60 minutes and then the reaction mixture was concentrated. Chromatography (5% EtOAc/hex) gave 1.40 g (29%) of 3-methyl-cyclopent-1-enecarboxylic acid methyl ester. This ester was converted to the final thiourea in accordance with General Procedure G. The intermediates 3-methyl-cyclopent-1-enecarboxylic acid methyl ester and 1-azidomethyl-3-methyl-cyclopentene were isolated and characterized as follows:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl.[OH-].[Na+]>[Sn](F)F>[CH2:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:10]1[O:12][CH2:11]1
Reactant: ClCC1CO1
Reactant: CCCCCCO
Agent: F[Sn]F
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCOCC1CO1
Temperature: 115 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A reactor equipped with stirrer, reflux condenser and thermometer is charged with 102.18 g (1.0 mol) of 1-hexanol and 3.14 g (0.02 mol) of powdered tin difluoride, and the charge is heated to 115° C. Then, with efficient stirring, 86.26 ml (1.1 mol) of epichlorohydrin are added over 1 hour. The reaction is allowed to continue for 8 hours, during which time the temperature slowly rises to about 125° C. The reaction mixture is cooled to 55° C. and then, at this temperature, 88 g (1.1 mol) of a 50% aqueous solution of sodium hydroxide are added dropwise with efficient stirring over 30 minutes. After stirring for 6 hours at 55° C. and cooling to room temperature, the suspension is filtered and the filtrate is washed with ethyl acetate. The phases are separated, and the aqueous phase is extracted with 2×100 ml of ethyl acetate. The combined organic phases are neutralised with CO2, dried over magnesium sulfate and filtered. The filtrate is freed from solvent on a rotary evaporator under vacuum (bath temperature 50° C.). Yield: 142.7 g (90.2% of theory) of colourless 1-hexanol glycidyl ether for which the following analytical values are obtained: epoxy value: 5.5 eq/kg (87% of theory); total chlorine content: 3.2% hydrolysable chlorine content: 0.21%.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:46]=[CH:45][CH:44]=[CH:43][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:42])[CH:19]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])C.[OH-].[Na+]>C1COCC1>[CH2:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][CH2:20][CH:19]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[CH2:12][C:11]1[C:10]2[CH:43]=[CH:44][CH:45]=[CH:46][C:9]=2[O:8][C:7]=1[CH2:6][CH2:5][C:4]([OH:47])=[O:3])=[O:42])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCCNC(=O)OCc1ccccc1)C(=O)N1CCCC1Cc1c(CCC(=O)O)oc2ccccc12

Procedure:
A solution containing the crude 53 (3.0 g, 4.6 mmol) in THF (20 mL) was treated with 3 M NaOH (8 mL) at ambient temperature. The reaction mixture was then warmed to gentle reflux and maintained for 2.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic solution was washed with 1 N HCl then dried over anhydrous Na2SO4, filtered and concentrated to afford ˜3 g (quant.) of 54 as an off-white-colored foam which was used directly without further purification. 1H NMR (CDCl3, 300 MHz) δ7.69-7.67 (m, 1H), 7.39-7.20 (m, 8H), 5.70 (d, J=8.4 Hz, 1H), 5.13-5.09 (m, 2H), 4.50-4.45 (m, 1H), 3.67-3.54 (m, 1H), 3.22-3.18 (m, 2H), 3.13 (t, J=6.9 Hz, 1H), 2.85-2.78 (m, 2H), 2.09-1.97 (m, 3H), 1.76-1.62 (m, 4H), 1.43 (s, 9H) ppm.