Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][S:37]([CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:39])=[O:38])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NS(=O)(=O)Cc3ccccc3)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 39 mg (0.2 mmol) alpha-toluenesulphonylchloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 40 mg (38%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-C-phenyl-methanesulfonamide as a light yellow solid. MS ISP (m/e): 525.9 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.48 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.60 (d, 1H), 7.26-7.21 (m, 6H), 7.06 (d, 1H), 7.03 (s, 1H), 4.39 (q, 1H), 4.13 (d, 1H), 4.03 (d, 1H), 3.83 (s, 3H), 2.14 (s, 3H), 1.69 (m, 2H), 1.56 (m, 1H), 0.86 (d, 6H).
Reaction SMILES: CO[C:3]([O:20]C)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:38])[CH3:37]>CN(C=O)C.O>[CH3:37][C:36]1[N:38]=[C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:20])=[CH:13][CH:12]=2)[O:11][N:35]=1
Reactant: COC(Cc1ccc(C(=O)O)cc1)(OC)c1ccccc1
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(CC(=O)c3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
To 4-(2,2-dimethoxy-2-phenylethyl)benzoic acid (1.1 g, 3.84 mmole) in DMF (15 mL) was added carbonyldiimidazole (0.68 g, 4.2 mmole). After 20 min, N-hydroxy ethanimidamide (0.33 g, 4.5 mmole) was added and the mixture stirred for 45 min. at r.t. followed by 100° C. overnight. The reaction was cooled, poured in H2O (30 mL) and extracted with hexane/ethylacetate 1:1. The organic phase was dried over Na2SO4 and concentrated. The residue was dissolved in 100 mL acetone and treated with p-toluene sulfonic acid (100 mg) for 2 h. Et3N (0.5 mL) was added, and the mixture was concentrated to dryness. The residue was dissolved in 2:1 hexane/ethyl acetate (10 mL) and passed through a pad of silica gel, eluting with 1: 1 hexane:EtOAc. The fractions were concentrated, and the residue was stirred with 4:1 hexane:EtOAc 10 mL to give 0.49 g of the desired compound.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].N([O-])=O.[Na+].[ClH:16]>O1CCOCC1.O>[Cl:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(O)c1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in concentrated HCl (75 mL) and 1,4-dioxane (14.7 mL). The mixture was heated to 70° C. until most of the solids were in solution. The reaction mixture was cooled to 0° C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained below 10° C. during the addition and the stirring was continued for an additional 15 min. at 0° C. This diazonium intermediate was poured into a solution of Cu(I)Cl (3.8 g; 38.9 mmol) in H2O (18.5 mL) and conc. HCl (18.5 mL) at 0° C. The reaction was stirred for 15 min. at 0° C., warmed to 60° C., and stirred for an additional 15 min. The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3×150 mL). The organic layers were combined, washed with brine (1×), dried (Na2SO4), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure 2-chloro-3-nitrophenol 1c1 (48%; 2.7 g) as an orange solid. MS 171.8 (MH)−: Homogeneity by HPLC (TFA) @220 nm: 96%.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31]Br)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]([N:37]([CH:40]([CH3:42])C)CC)([CH3:36])C.N1CCCC1.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31][N:37]2[CH2:34][CH2:36][CH2:42][CH2:40]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)CBr)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCCC1)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 60 °C

Procedure:
To a solution of Example 305A (44 mg, 0.086 mmol) and diisopropylethylamine (0.015 mL, 0.086 mmol) in acetonitrile (1 mL) was added pyrrolidine (0.021 mL, 0.25 mmol) and the reaction mixture was heated at about 60° C. for about 15 minutes. The reaction mixture was cooled to ambient temperature and trifluoroacetic acid (1 mL) was added. The reaction mixture was heated at about 60° C. for about 48 hours. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (20 mL) and washed with 15% aqueous sodium hydroxide solution (20 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (s, 1H), 8.24 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.27-7.45 (m, 5H), 5.64 (s, 2H), 3.35 (s, 2H), 2.65 (s, 4H), 1.76 (s, 4H). MS (ESI+) m/z 402 (M+H)+.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>C(O)(=O)C>[BrH:1].[NH2:3][C:4]1[N:12]=[CH:11][C:10]([Br:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ncccc1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Nc1ncc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 183.9 %

Procedure:
Bromine (7.5 mL, 146 mmol) was added dropwise over 10 min to a suspension of 2-amino-nicotinic acid (20.0 g, 145 mmol) in glacial acetic acid (250 mL) cooled in an ice bath. After the bromine addition was complete, the mixture was stirred at ambient temperature for 2 d. The resulting light yellow solid was isolated by filtration, washed with Et2O, and dried under high vacuum (40° C.) for several hours to give the title compound (40.0 g, 93%): 1H NMR (300 MHz, DMSO-d6) δ 8.33 (d, J=2.5 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 8.02 (bs, 3H); ESI MS m/e 217 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]C1C=C2C(=CC=1)N(CC)C(=O)C2=O>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CCN1C(=O)C(=O)c2cc(Cl)ccc21
Product: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-chloro-1-ethylindoline-2,3-dione. 1H-NMR δ 8.11 (dd, 2H), 7.60 (dt, 1H), 7.47 (m, 2H) 7.45 (m, 1H), 7.33 (dd, 1H), 6.80 (d, 1H), 6.10 (d, 1H), 3.85 (m, 2H), 1.33 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:44]CCCl>>[ClH:44].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:14]2[CH2:15][CH2:16][N:17]([CH2:28][C:26]3[CH:25]=[N:24][N:23]([CH2:22][CH2:21][OH:20])[CH:27]=3)[CH2:18][CH2:19]2)=[N:10][CH:11]=[CH:12][N:13]=1
Reactant: ClCCCl
Reactant: O=Cc1cnn(CCO)c1
Reactant: Fc1ccccc1-c1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: OCCn1cc(CN2CCN(c3nccnc3-c3ccccc3F)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
Dissolve 3′-(2-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.213 g, 0.825 mmol) in DCE (5 mL). Add 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.137 g, 0.990 mmol) followed by sodium triacetoxyborohydride (0.262 g, 1.24 mmol) and stir at ambient temperature for 18 hr. Add additional 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.093 g, 0.663 mmol) and stir at ambient temperature for 18 hr. Purify via SCX chromatography followed by silica gel chromatography, (eluting with 100:0 to 0:100 hexanes:ethyl acetate, then 10:90 methanol:ethyl acetate), to give the free base of the title compound (116 mg, 37%). Dissolve the free base (0.114 g, 0.298 mmol) in methanol and add a solution of ammonium chloride (0.016 g, 0.298 mmol) in a minimal volume of methanol. Shake for 18 hr. at ambient temperature and concentrate to give the title compound (125 mg, 100%). MS (ES): m/z=383[M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](OCCOC)[C:8]([C:12]3[NH:13][CH2:14][CH2:15][N:16]=3)=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[O:38]1[CH2:43]C[O:41][CH2:40][CH2:39]1>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>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:12]4[NH:13][CH2:14][CH2:15][N:16]=4)([O:41][CH2:40][CH2:39][O:38][CH3:43])[CH2:9]3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: C1COCCO1
Reactant: COCCOc1cc2ccc(Br)cc2cc1C1=NCCN1
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+]
Product: COCCOC1(C2=NCCN2)C=Cc2ccc(-c3ccc(C)cc3)cc2C1
Temperature: 80 °C
Yield: 32 %

Procedure:
To a solution of 1.4 g (4 mmol) of 2-(7-Bromo-3-[2-methoxyethoxy]-naphthalen-2-yl)-4,5-dihydro-1H-imidazole in 80 ml 1,4-dioxane was added under argon 0.46 g (0.4 mmol) of Pd(PPh3)4 and 8 ml of 2M Na2CO3. After stirring at room temperature for 20 minutes 0.816 g 4-methylbenzeneboronic acid was added and the mixture was heated for 20 hours at 80° C. The mixture was cooled to room temperature and filtered to remove the solid. The solution was acidified with 2N HCl and chromatographed on silica gel with dichloromethane/methanole 90/10 and gave 0.52 g (32%) of an amorphus product.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[CH2:31]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:32]>>[CH2:31]([C:33]1[CH:39]=[CH:38][C:36]([N:37]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=4[C:27]([F:30])([F:29])[F:28])(=[O:25])=[O:24])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:35][CH:34]=1)[CH3:32]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccc(F)cc4C(F)(F)F)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 485.15 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 4-fluoro-2-trifluoromethyl-benzenesulfonyl chloride and 4-ethyl-aniline.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(O[CH:23](OCC)[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29](F)=[N:30][CH:31]=1)C.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:36]([NH:39][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([O:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[N:30][CH:31]=1)([CH3:38])[CH3:37]
Reactant: CC(C)N
Reactant: CCOC(COc1ccc(F)nc1)OCC
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ccc(OCCNC(C)C)cn4)cc23)cn1

Procedure:
Using 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol, 5-(2,2-diethoxyethoxy)-2-fluoropyridine and isopropylamine, and in the same manner as in Example 31 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (62 mg) was obtained as a pale yellow solid.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.Cl.[N:29]1([C:34](N)=[NH:35])C=CC=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[ClH:27].[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:34]([NH2:35])=[NH:29])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N=C(N)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 500 mg (1.303 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5), 229 mg (1.562 mmol) of 1H-pyrazole-1-carbamidine monohydrochloride (Fluka), 202 mg (1.563 mmol) of N-ethyldiisopropylamine and 5 ml of DMF is stirred at RT for 7 hours and then concentrated by evaporation under a high vacuum. Crystallization of the residue from methanol, filtration and washing the filter residue with methanol yield 4-(3-chloro-phenyl-amino)-3-(4-{guanidino-methyl}-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine hydrochloride having a water content of 2.86%; m.p. 254-256° C.
Reaction SMILES: Br.[CH2:2]([N:4]1[CH2:10][CH2:9][CH:8](Br)[C:7](=O)[CH2:6][CH2:5]1)[CH3:3].[NH2:13]O.Cl.[NH2:16][CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[CH:17]=[N:16][C:8]2[CH2:9][CH2:10][N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][C:7]=2[N:13]=1
Reactant: CCN1CCC(=O)C(Br)CC1
Reactant: NO
Reactant: N#CCN
Agent: Br
Agent: Cl
Product: CCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 40 from 1-ethyl-5-bromo-hexahydro-azepin-4-one hydrobromide, hydroxylamine and α-amino-acetonitrile hydrochloride.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:38]=[CH:37][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:38][CH:37]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](c2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)Cn1nccn1
Yield: 62 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4S)—N-(4-(4-fluorophenoxy)phenyl)-4-phenylpyrrolidine-2-carboxamide, gave Compound 77, (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenylpyrrolidine-2-carboxamide (170 mg, 62%). 1H-NMR (400 MHz, CDCl3): σ 9.21 (s, 1H), 7.74 (s, 2H), 7.48 (d, 2H), 7.40-7.36 (m, 2H), 7.32-7.29 (m, 3H), 7.04-6.99 (m, 2H), 6.96-6.92 (m, 4H), 5.35 (s, 2H), 5.00 (d, 1H), 3.93 (t, 1H), 3.89-3.80 (m, 1H), 3.54 (t, 1H), 2.91 (dd, 1H), 2.18-2.09 (m, 1H). MS (EI) for C27H24FN5O3. found 486.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])#[N:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccccc1N
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 2-aminobenzonitrile (2.36 g (20.0 mmol in pyridine (10.0 ml), p-toluenesulfonyl chloride (4.20 g (22.0 mmol) was added with stirring at room temperature. After 15 hours' stirring at room temperature, water (100 ml) was added to the reaction mixture and stirring was continued for another 30 minutes. The crystals separated were filtered, washed with water and re-dissolved in chloroform. The soluble part in 1% aqueous sodium hydroxide solution was extracted from the chloroform solution. The extract was made acidic with hydrochloric acid and re-extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a product which then crystallized. The crystals were washed with diisopropyl ether and filtered to give 4.83 g (89%) of 2′-cyano-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[NH:18][C:17]2=[O:29])[C:5]2[C:6](=[N:8][N:9]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:10]=2)[N:7]=1.C([NH:37][CH2:38][CH2:39][NH2:40])(OC(C)(C)C)=O>C(O)C>[ClH:1].[NH2:37][CH2:38][CH2:39][NH:40][C:2]1[N:3]=[C:4]([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=3)[NH:18][C:17]2=[O:29])[C:5]2[C:6](=[N:8][N:9]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:10]=2)[N:7]=1
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C1c1nc(Cl)nc2nn(C3CCCC3)cc12
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Product: Cl
Product: NCCNc1nc(C2C(=O)Nc3ccc(C(F)(F)F)cc32)c2cn(C3CCCC3)nc2n1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A mixture of Example 153 (63 mg, 0.15 mmol), N-BOC-ethylenediamine (0.24 gm, 1.5 mmol), and ethanol (1 mL) were heated in a microwave at 130° C. for 10 minutes. The reaction was cooled to room temperature and a precipitate formed. The solid was filtered, washed with ethanol and ethyl ether to give 56 mg (68%) of the intermediate. Next, the material was stirred in 4N HCl in 1,4-dioxane (2 mL). After 1 hour the reaction was concentrated. The solid was treated with ether and filtered to give 35 mg (70%) of Example 252. Example 252: 1HNMR (400 MHz, DMSO-d6) δ 12.0 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.6 (s, 1H), 8.0 (m, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 4.8 (m, 1H), 3.7 (m, 2H), 3.2 (m, 2H), 1.6-2.2 (m, 8H); MS (m/e) 446 (M+1); HPLC (99%) purity, retention time 3.917 minutes—Method C; mp 290-293° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:4][CH:3]=1.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[C:21]([S:24]([N:26]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[O:25])([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)S(N)=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(F)cc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=NS(=O)C(C)(C)C)c1ccc(F)cc1

Procedure:
The intermediate in Reference Example 5, t-butyl N-[(1S)-2-(4-fluorophenyl)-1-methyl-2-oxoethyl]carbamate and 2-methyl-2-propanesulfinamide were condensed in the presence of a dehydrating agent to give t-butyl N-[(1S)-2-[(t-butylsulfinyl)imino]-2-(4-fluorophenyl)-1-methylethyl]carbamate. 1.0M trimethylaluminum-hexane solution (0.43 mL) was added to the solution of said sulfinylimine compound (80 mg) in toluene (2 mL) at −78° C., and the mixture was stirred for 5 minutes. The obtained solution was dropwise added slowly to 2-fluoro-4-pyridyllithium solution (prepared by the reaction of 4-fluoro-2-bromopyridine (114 mg) and 1.56M butyllithium-hexane solution (0.46 mL) in diethyl ether solvent (3 mL) at −78° C.) at −78° C. Thereafter tetrahydrofuran (3 mL) was added to the reaction mixture, and then the reaction mixture was stirred at −78° C. for 2.5 hours. Saturated sodium chloride aqueous solution was added to the reaction mixture, and temperature of the reaction mixture was raised to room temperature. The obtained reaction mixture was filtered through celite, and then the organic layer of filtrate was dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and then the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=2:1) to give the optical active t-butyl N-[(1S)-2-[(t-butylsulfinyl)amino]-2-(4-fluorophenyl)-2-(2-fluoro-4-pyridyl)-1-methylethyl]carbamate (49 mg). The product was treated with 4N hydrogen chloride-dioxane solution to give the optical active title diamine (31 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:8][CH2:7][CH2:6]1.C([N-]C(C)C)(C)C.[Li+].[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1([C:9]2[S:10][C:11]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][N:13]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: COCOC1(c2nccs2)CCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(OCOC)CCC2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of the 2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1B) (5.67 g, 28.5 mmol) in tetrahydrofuran (95 mL) was added a solution of lithium diisopropylamide (34.1 mmol) in tetrahydrofuran (30 mL) dropwise. The solution was stirred at −78° C. for 45 minutes, and tributyltin chloride (9.26 mL, 34.1 mmol) was added dropwise. The cold bath was removed, and the reaction warmed to room temperature. The ambient reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and ether. The layers were separated, and the aqueous layer was extracted with additional ether. The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 490 [M+H]+.