Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][C@H:7]([C:9]([OH:11])=O)[CH2:6][N:5]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[C:46]1([CH:52]2[CH2:54][CH:53]2[NH2:55])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH:7]([C:9](=[O:11])[NH:55][CH:53]2[CH2:54][CH:52]2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:6][N:5]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:22]
Reactant: COC(=O)[C@@H]1C[C@H](C(=O)O)CN1C(=O)OCc1ccccc1
Reactant: NC1CC1c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C1CC(C(=O)NC2CC2c2ccccc2)CN1C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a stirred solution of cis-N-(benzyloxycarbonyl)-4-carboxy-proline methyl ester (615 mg, 2 mmol) and HOSu (173 mg, 3 mmol) in 1,4-dioxane (2 mL) was added a solution of DCC (454 mg, 2.2 mmol) in CH2Cl2 (2 mL). After 10 min at room temperature, 2-phenylcyclopropylamine (266 mg, 2 mmol) in CH2Cl2 (1 mL) was added with stirring. After 16 h, the resulting N,N′-dicyclohexylurea was removed by filtration. The filtrate was washed with saturated aqueous NaHCO3 (5 mL), 1 N aqueous citric acid (5 mL), water (5 mL), dried over MgSO4 and concentrated. The residue was purified by a silica gel column using hexane/EtOAc (6:4) as eluant to yield the desired compound as a colorless oil (633 mg, 75%).
Reaction SMILES: [C:1]([O:8]C)(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-])=[O:5].[NH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[NH2:11].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:1]([CH:2]1[CH2:3][C:4](=[O:5])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:14][CH:13]=2)[NH:11]1)([OH:8])=[O:7]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: NNc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)N1
Temperature: 100 °C
Yield: 73 %

Procedure:
5 parts of monomethyl maleate are added with stirring to 25 parts of water containing 7 parts of p-hydrazinobenzene sulphonate and 4 parts of sodium carbonate and the mixture is heated at 100° C for 6 hours. The pH is then adjusted to 3.8 by addition of hydrochloric acid and the 3-carboxy-1-(4'-sulphophenyl)-5-pyrazolidone thus formed is filtered off and dried between 50°-100° C. The actual weight yield is 12 parts of strength 67% (determined by N.M.R.) which represents a yield of 73% theory.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1.C([O-])(O)=O.[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:24]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Temperature: 80 °C
Yield: 19 %

Procedure:
A mixture of 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol), 5-fluoro-2-methoxyphenylboronic acid (10 mg, 0.06 mmol), Pd(PPh3)4 (3 mg, 0.0025 mmol), NaHCO3 (13 mg, 0.15 mmol), EtOH (750 μL) and water (250 μL) was heated in a sealed tube at 80° C. over night. The mixture was concentrated and purified by preparative HPLC (ACE C8 5 μm, 0.1% TFA in water/CH3CN) giving 4.1 mg (19%) of the title compound. MS (ESI+) calcd for C18H14FN5O3S2 431.052209, found 431.051439.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]([OH:11])=O)[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:35][N:36]([C@H:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][CH2:51]1)[C:37]([C:39]1[N:40]=[C:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[S:42][CH:43]=1)=[O:38].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]([N:47]2[CH2:48][CH2:49][CH:44]([C:41]3[S:42][CH:43]=[C:39]([C:37]([N:36]([CH3:35])[C@H:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH2:53][CH2:52][CH2:51]4)=[O:38])[N:40]=3)[CH2:45][CH2:46]2)=[O:11])[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2]
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Reactant: CCc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (170 mg, 0.76 mmol) (i.e. the product of Example 16, Step C) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6 Step C) (219 mg, 0.56 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by silica gel MPLC using ethyl acetate/hexanes as eluant to give 200 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[Br:13]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Br:13])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc(F)cc1N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Br)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of methyl 3-amino-5-fluoropyridine-2-carboxylate (3.6 g, 21 mmol) in MeCN (60 mL), N-bromosuccinimide (4.1 g, 23 mmol) was added portionwise. After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc (200 mL), washed with a saturated aq. NaHCO3 (200 mL) and brine (200 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (4.0 g, 76%) LCMS calc. for C7H7BrFN2O2 (M+H)+: m/z=249.0. found 249.0.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](=S)=[S:20].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH:1]1([N:11]=[C:19]=[S:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: S=C=S
Reactant: NC1CCCc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: S=C=NC1CCCc2ccccc21
Reaction time: 1 h

Procedure:
To a stirred solution of 0.01 mole of 1,2,3,4-tetrahydro-1-naphthylamine in ethyl acetate is added 0.01 mole of triethylamine and 0.011 mole of carbon disulfide. The mixture is stirred about one hour and then 0.01 mole of dicyclohexyl carbodiimide is added. The mixture is stirred overnight, and the mixture filtered to remove solid dicyclohexylthiourea. The filtrate is evaporated, and the residue is purified by dry column chromatography to give 1,2,3,4-tetrahydro-1-naphthyl isothiocyanate.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:31])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[C:22]=3[CH3:30])=[N:17]2)=[O:12])[N:10]=1)(=[O:5])[CH3:4]>O.C(O)C>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[N:10]=[C:6]([CH:3]([OH:5])[CH3:4])[S:7][CH:8]=3)=[O:12])[CH3:31])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(C)O)n3)n2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Sodium borohydride (0.056 g, 1.477 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (0.316 g, 0.738 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., a few drops of water was added, the pH was adjusted below 7 and the mixture was evaporated. 5% of DCM/MeOH was added and the crude product was washed with 1M NaHCO3, water and dried. Yield 68.1%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.40 (dd, 3H), 2.52 (s, 3H), 4.37 (m, 2H), 4.48 (m, 1H), 4.92 (m, 1H), 6.24 (t, 1H), 6.62 (d, 1H), 7.63 (d, 1H), 7.82 (d, 1H), 7.87 (dd, 1H), 8.10 (s, 1H), 8.37 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][Mg]Br.Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1[C:3]([C:9]([OH:11])([CH3:12])[CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(O)c1F
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(O)c1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 1-(2-fluoro-3-hydroxy-phenyl)-ethanone (8.50 g, 55.0 mmol) in tetrahydrofuran (80 mL) was slowly added a methyl magnesium bromide solution in diethyl ether (3.0 M, 46.5 mL, 0.15 mol) at −78° C. The resulting mixture was stirred at −78° C. for 10 min and then allowed to come to room temperature and stirred for an additional 40 min. The reaction mixture was diluted with diethyl ether (100 mL) and cooled in an ice bath before an aqueous hydrochloric acid solution (1N, 200 mL) was added dropwise. The biphasic mixture was separated and the aqueous phase extracted with diethyl ether (2×60 mL). The combined organic phases were washed with water, brine and dried over sodium sulfate. The resulting mixture was filtered and evaporated and the resulting oil was dried under vacuum which afforded 2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenol (9.40 g, 100%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C=O)C.CCN(C(C)C)C(C)C>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([CH2:11][C:12](=[O:14])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:16][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(CC(=O)Nc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56021.9 %

Procedure:
To a solution of 33 (0.206 g, 0.657 mmol, 1.2 eq) and aniline (0.051 g, 0.548 mmol) in dry DMF (5 ml) HATU (0.315 g, 0.9087 mmol, 1.5 eq) and DIPEA (0.340 g, 2.63 mmol, 4 eq) was added at room temperature under Ar. After stirring overnight at room temperature, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×15 ml). The organic extracts were collected, dried over Na2SO4 and the solvent was distilled off under reduced pressure. The crude compound was purified by chromatography on silica gel (3:7 ethyl acetate/hexane, v/v, Rf 0.30) to give 34 as a white solid (0.120 g, 0.307 mol, 47%), mp 165-167° C. 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.55 (1H, dd, J 5.0, 13.8 Hz), 2.75 (1H, dd, J 8.4, 13.6 Hz), 3.16-3.39 (2H, m), 3.52-3.57 (1H, m), 4.60 (1H, bs), 7.07-7.13 (3H, m), 7.29-7.32 (4H, m), 7.54 (2H, d, J 8.4 Hz), 8.61 (1H, bs).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:32])=[C:20]([NH:22][S:23]([C:26]3[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=3)(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][S:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[F:32][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH2:37][CH2:36][CH2:35][S:34][CH3:33])[N:7]=2)=[CH:21][C:20]=1[NH:22][S:23]([C:26]1[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=1)(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CSCCCN
Product: CSCCCNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-methyl-1H-imidazole-4-sulfonamide (75 mg, 0.152 mmol) and [3-(methylthio)propyl]amine (86 mg, 0.817 mmol) the title compound of Step B was obtained as a golden oil (76 mg, 89% yield). MS (ESI): 561.4 [M+H]+.
Reaction SMILES: [CH:1]([N:5]=[C:6]=[O:7])([CH2:3][CH3:4])[CH3:2].[CH3:8][CH:9]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]1[OH:16]>O>[CH3:8][CH:9]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]1[O:16][C:6](=[O:7])[NH:5][CH:1]([CH2:3][CH3:4])[CH3:2]
Reactant: CC1CCCC(O)C1C
Reactant: CCC(C)N=C=O
Solvent: O
Product: CCC(C)NC(=O)OC1CCCC(C)C1C
Yield: 53 %

Procedure:
50.7 g (0.5 mol) sec.-Butyl isocyanate were placed in a 500 ml vessel at ambient temperature and 64.1 g (0.5 mol) 2,3-dimethylcyclohexanol were added. The reaction mixture was heated for 5 h to 150° C., cooled and subsequently 100 ml water were added. After refluxing for one hour the solution was cooled down, the phases separated and extracted once with MTBE (methyl tert.-butyl ether). The raw product was purified by distillation to yield 60.2 g product as a mixture of isomers with a purity of 99.6%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:10][NH:11][C:12]=1C=O.[F:26][C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([NH:31][NH2:32])=[O:30]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12](=[N:32][NH:31][C:29]([C:28]2[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=2[F:26])=[O:30])[N:11]=[N:10][C:9]=1[O:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: NNC(=O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Oc2n[nH]c(C=O)c2-c2ccccc2F)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)OC2=C(c3ccccc3F)C(=NNC(=O)c3ccccc3F)N=N2)cc1

Procedure:
The product from step c) (10 g, 0.028 mol) was suspended in xylene (250 ml) with 2-fluorobenzoic hydrazide (4.7 g, 0.0231 mol) and heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solid produced was washed in the sinter funnel several times with dichloromethane then concentrated under vacuum to leave a solid (10.53 g). The product existed as a 1:1 mixture of 2 tautomers. 1H NMR (400 MHz, CDCl3) δ 2.37 (3H, s), 7.18-7.66 (12H, m), 8.06 (1H, s), 11.90 (0.5H, s), 13.78 (0.5H, s); MS (ES+) m/e 497 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([F:8])[CH:7]=1
Reactant: Fc1ccc(F)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1-Chloro-2,5-difluorobenzene (31.7 g, 0.21 mol) was dissolved in sulfuric acid (110 ml) at −40° C., then a solution of sulfuric acid (20 ml) and nitric acid (30 ml) was added dropwise. The mixture was stirred for 1 hr while temperature slowly raised to 20° C. The product was forced to crystallize by mixing the reaction mixture with ice-water (500 ml), the yellow crystals were filtered, washed with cold water and dried in fume hood overnight. (38.0 g). 1H NMR (CDCl3, 300 MHz) 7.46 (1H, dd, J=9.8, 9.9 Hz), 7.96 (1H, dd, J=7.9, 7.9 Hz) ppm.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1SC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:16].N.C(#[N:20])C>CO>[NH2:20][C:10]1[N:9]([N:8]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][N:11]=1.[ClH:16]
Reactant: CC#N
Reactant: CSC1=NCCN1N=Cc1ccccc1
Agent: Cl
Agent: N
Solvent: CO
Product: NC1=NCCN1N=Cc1ccccc1

Procedure:
1 g of 1-benzylideneamino-2-methylthio-2-imidazoline in the form of a hydrochloride in 10 ml of methanol are treated with 0.33 ml of NH3 (28% in H2O). The mixture obtained is refluxed for ca. 5 hours and a precipitate obtained is filtrated off. From the filtrate obtained the solvent is evaporated off. The residue obtained is treated with acetonitrile. The precipitate obtained is filtrated off and dried. Solid 2-amino-1-benzylideneamino-4,5-dihydro-1H-imidazole in the form of a hydrochloride is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl.N1C=CC=CC=1>[NH2:19][C:17]1[C:18]2[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)=[CH:11][N:12]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A solution of 5-(3-amino-4-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.124 mmol) in dichloromethane (1 ml) and pyridine (1 ml) was cooled to 0° C. and then treated with benzyl chloroformate (32 mg, 0.186 mmol) while maintaining a temperature of less than 5° C. The solution was stirred for another 1 hour at 0° C. then the solvents were removed under reduced pressure. Purification by preparative C-18 RP-HPLC then lyophilization provided benzyl N-[5-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (25 mg) as a white powder: 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.1-7.4 (m, 8H), 6.2 (bs, 2H), 5.15 (s, 2H), 5.07 (m, 1H), 3.8 (s 3H), 1.6-2.2 (m, 8H), RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.63 min.; MS: MH+458.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[CH3:48][S:49]([O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:34]([F:35])[CH:33]=1)(=[O:51])=[O:50]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (3.8 g, 6.75 mmol) and DIPEA (3.52 mL, 20.3 mmol) in DCM (100 mL) at 0° C. was added methanesulfonyl chloride (603 μL, 7.8 mmol). After the reaction was slowly warmed to ambient temperature over 30 min, it was partitioned in DCM (100 mL) and water (100 mL). Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=1:3) to give 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (4.1 g, 95% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.25 Hz, 1H), 7.22 (s, 1H), 6.82-6.72 (m, 2H), 6.58-6.47 (m, 2H), 6.42-6.32 (m, 4H), 4.55 (dd, J=5.27, 3.62 Hz, 2H), 4.18 (dd, J=5.26, 3.64 Hz, 2H), 4.04 (s, 2H), 3.78 (s, 3H), 3.09 (s, 3H), 1.50 (d, J=10.49 Hz, 6H).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH2:18][CH3:19])[S:10]2(=[O:21])=[O:20])C=CC=CC=1.S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH2:18][CH3:19])[S:10]1(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Solvent: ClCCl
Product: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A mixture of 2-phenylthiomethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1, 1-dioxide (3.97 g) and sulfuryl chloride (1.47 ml) in 80 ml of methylene chloride was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in hexane. The solvent was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) to afford 2.4 g (77%) of 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =propyl; R3 =ethyl; X'=Cl) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:24][OH:25])=[NH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2nc(C#N)c(OCc3ccccc3)c(=O)n2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(C(=N)NO)c(OCc3ccccc3)c(=O)n2c1
Temperature: 70 °C
Yield: 80 %

Procedure:
The product from Example 11.2 (530 mg, 1.82 mmol) and hydroxylamine hydrochloride (0.549 g, 7.9 mmol) were mixed with ethanol (50 mL). To this stirred solution was added sodium bicarbonate (663 mg, 7.9 mmol) and the mixture was heated at 70° C. for 3 h. The solvent was removed in vacuo and the residue dissolved in a mixed solvent (dichloromethane/ethanol 200 mL:10 mL), washed with water, dried (Na2SO4) and concentrated in vacuo to give the desired compound (472 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([O:10]C)=[O:9])[CH2:4][O:3]1.[OH-].[Na+].[ClH:15]>CO.O>[ClH:15].[CH3:1][C:2]1([CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][O:3]1
Reactant: COC(=O)[C@@H]1COC(C)(C)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CN[C@H](C(=O)O)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)-methyl 6,6-dimethylmorpholine-3-carboxylate (0.2 g, 1.2 mmol) (The compound was synthesized according to the procedure as described in WO2008024692) in anhydrous methanol (4 mL) was added a solution of sodium hydroxide (0.1 g, 2.4 mmol) in water (1 mL). The reaction mixture was stirred at 25° C. for 2 hours, and cooled to 0° C. The reaction mixture was adjusted to pH 1-2 with con. HCl. The mixture was concentrated in vacuo to give the title compound as a white solid (0.19 g, 100%). The compound was characterized by the following spectroscopic data: