Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br-].[CH:24]1([Zn+])[CH2:26][CH2:25]1>O1CCCC1.O.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>[CH:24]1([C:2]2[N:3]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:4]3[C:9]([C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25]1
Reactant: [Zn+]C1CC1
Reactant: COC(=O)c1c(Br)n(C(C)c2ccccc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C2CC2)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of methyl 2-bromo-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.30 g, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) in tetrahydrofuran (20 mL) was added cyclopropylzinc(II) bromide (6.0 mL, 0.5 mol/L in tetrahydrofuran). The reaction mixture was stirred at reflux for 12 hours. After the reaction, it was cooled to room temperature and diluted with water (100 mL). The product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel: ethyl acetate:petroleum ether=1:10) to give the crude product methyl 2-cyclopropyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.22 g, 82%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: CC(=O)N(C)C
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.13 g (0.0005 mole) of 2-chloro-9-cyclopentyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-10), 1 mL of N,N-dimethylacetamide and 0.047 mL (0.00075 mole) of iodomethane at 0 degrees was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.135 g of 2-chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-10) as an yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:13]([CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:15]2)[CH:13]([CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
An optically-active compound of 3-methyl-1,6-diazaspiro[3,5]nonane-1-carboxylic acid 1-benzyl ester (2.20 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.17 g), potassium carbonate (3.17 g) and water (12 ml), and the mixture was stirred for 4 hours with refluxing. The mixture was cooled to room temperature, and extracted with chloroform twice. The combined organic layer was washed with water, 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/0 to 1/3, followed by chloroform/methanol=95/5) to give the titled compound (2.84 g).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1Br)(C)(C)C.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH:26]=1)#[CH:24]>>[CH2:34]([S:31]([C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:22])[CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:32])[CH2:35][CH3:36]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2)cc1Br
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3ccccc3)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl[(3-bromobiphenyl-4-yl)oxy]acetate (Intermediate 188) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.Cl.[CH3:21][CH2:22][O:23]CC>CN(C)C(=O)C>[Br:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:22](=[O:23])[CH3:21])[N:14]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCOCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: CC(=O)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
12.5 mL of a solution of n-BuLi 1.6 M in hexane (20 mmol) are added at −78° C. to a solution of 4.70 g 2,6-dibromopyridine 20 (20 mmol) in 100 mL anhydrous ether. The reaction medium is left in the cold for 30 min. 2 mL N,N-dimethylacetamide are added cold (−78° C.) for 1 h, then allowed to reach the ambient temperature. The reaction medium is neutralized with 25 mL of an aqueous HCl 1M solution. The aqueous phase is extracted with Et2O (3×20 mL). The combined organic phases are washed with brine (3×20 mL), dried on MgSO4, filtered, then evaporated under vacuum. The raw product is recrystallized in an Et2O/n-C5H12 (1/2) mixture. 1.18 g of an orange solid is obtained, i.e. a 28% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)([OH:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: COc1cc(OC)cc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2(O)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-dimethoxyphenyl magnesium bromide in tetrahydrofuran (1.0 M, 6.9 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.5 g, 2.76 mmol) in tetrahydrofuran (14 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 2 hours, 15% aqueous ammonium chloride solution and water were added and mixture extracted with ethyl acetate. Ethyl acetate layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(3,5-dimethoxy-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:21])[C@@H:6]([OH:20])[CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]>C1COCC1.O>[OH:20][CH:6]([CH2:7][CH2:8][N:9]1[C@@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[C:5]([O:4][CH3:3])=[O:21]
Reactant: COC(=O)[C@@H](O)CCN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(O)CCN1C(=O)c2ccccc2[C@@H]1O
Temperature: 25 °C
Yield: 31.7 %

Procedure:
Sodium borohydride (0.474 g, 12.54 mmol) was added portionwise to a -20° C., stirred solution of (s)-(+)-α-hydroxy-1,3-dioxo-2-isoindolinebutyric acid methyl ester (3.0 g, 11.4 mmol) in THF/water (30/1.38 mL) for 6 hours. Upon cooling to room temperature, the reaction mixture was carefully quenched and acidified with 10% aqueous HCl. Aqueous mixture was extracted with ethyl acetate (300 mL). The ethyl acetate extract was washed with water and brine. Silica gel (15 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 95: 5 petroleum ether: dichloromethane) to provide the title compound as an oil (0.96 g, 32%): MS (EI): [M+], 265.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([NH:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[CH3:37].P(Cl)(Cl)Cl>ClC(Cl)C>[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([N:45]([CH:46]([CH3:47])[CH3:48])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:41][CH:40]=1)[CH3:37]
Reactant: CCOc1ccc(NC(C)C)cn1
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: ClP(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOc1ccc(N(C(=O)CN2C(=O)C(Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 20.9 %

Procedure:
Following the procedure described for Example 2(A), [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (300 mg, 0.65 mmol) was reacted with (6-ethoxy-pyridin-3-yl)-isopropyl-amine (Preparation 2(B)) (117 mg, 0.65 mmol) and PCl3 in dichloroethane at 100° C. Purification by medium pressure chromatography eluting with a solvent gradient (5% of 0.5% NH4OH/MeOH in CH2Cl2 to 10% of 0.5% NH4OH/MeOH in CH2Cl2) provided 85.1 mg of N-(6-ethoxy-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CD3OD) δ 8.05 (d, 1H), 7.62 (m, 3H), 7.38-7.52 (m, 6H), 7.24 (d, 1H), 7.11 (m, 2H), 6.99 (t, 1H), 6.89 (m, 3H), 4.78 (m, 1H), 4.53 (m, 1H), 4.35 (q, 2H), 4.12 (m, 1H), 3.88 (t, 1H), 3.78 (dd, 1H), 3.69 (dd, 1H), 1.38 (t, 3H), 0.99 (m, 6H); MS 626.7 (M+1), 624.6 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)c([N+](=O)[O-])c3)n2)c1

Procedure:
Intermediate 4 was coupled to 4-(2-Amino-ethyl)-2-nitro-phenol by procedure F and the resulting product deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 501. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.4 (s, 1H) 8.3 (d, 1H) 8.2 (d, 1H) 8.0 (s, 1H) 7.8 (d, 1H) 7.6 (m, 3H) 7.0 (m, 1H) 4.5 (s, 2H) 4.0 (m, 2H) 3.4 (m, 2H) 3.0 (m, 5H) 2.8 (m, 2H) 1.8 (m, 2H).
Reaction SMILES: N#N.[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11](O)[CH:12]=C>>[C:3]([O:9][CH2:10][CH:11]=[CH2:12])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: C=CCO
Agent: N#N
Product: C=CCOC(=O)CC(C)=O
Yield: 72.8 %

Procedure:
In a 2 l flask equipped with a magnetic stirrer, equipped for a Vigreaux column for distillation, a heating mantle and N2, there was added 4.0 mole (432 ml) of methyl acetoacetate and 8.0 mole (464.6 g) of allyl alcohol. The reaction mixture was distilled for 12 hours at 92° C. There was added 136 ml (2.0 mole) of allyl alcohol and the mixture was distilled 23 hours. There was then added 136 ml (2.0 mole) of allyl alcohol and the mixture was distilled 16 hours. The reaction mixture was then distilled under vacuum and product was collected at 105°-110° C./35 mm Hg. There was obtained 414 g of allyl acetoacetate (73% yield). ##STR230##
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([C@@H:58]3[CH2:62][CH2:61][CH2:60][C@H:59]3[C:63]([OH:65])=[O:64])=[O:57])=[CH:52][CH:51]=2)=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([NH:43][C:44]3[CH:45]=[CH:46][C:47]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([C@@H:58]5[CH2:62][CH2:61][CH2:60][C@H:59]5[C:63]([OH:65])=[O:64])=[O:57])=[CH:52][CH:51]=4)=[CH:48][CH:49]=3)=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.25 g, 1 mmol) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.47 g, 1 mmol) in methylene chloride was added racemic trans-2-(4′-amino-biphenyl-4-carbonyl)-cyclopentanecarboxylic acid (0.20 g, 0.78 mmol) and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated and the residue was re-dissolved in DMSO and acetonitrile. HPLC reverse phase purification with acetonitrile and water afforded 44 mg of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid as a white solid. LCMS calcd for C30H23F3N2O5 (m/e) 548, obsd 549 (M+H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][O:30][CH3:31]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][O:30][CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: COCC(=N)NO
Product: COCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2-methoxy-acetamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.61 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
N-(2-Morpholin-4-yl-ethyl)-4-nitro-benzenesulfonamide (0.14 g, 0.45 mmol) was suspended in a 5:1 mixture of ethanol and water (3 ml). To this solution was added iron powder (0.13 g, 2.25 mmol) followed by saturated ammonium chloride solution (0.1 ml) and the mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.1 g, 78% yield) as a brown solid. Tr=0.35 min, m/z (ES+) (M+H)+ 285.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5]
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1

Procedure:
In analogy to example 1E 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (example 1D) was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 742073-22-9) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid [2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide. Light yellow solid. MS 480.0 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)[N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:8][C:7]1[C:2]([NH:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)=[N:3][C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)=[N:5][CH:6]=1
Reactant: Clc1cnc(-c2cnn3ccncc23)nc1Cl
Reactant: NCc1ccc(F)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CNc2nc(-c3cnn4ccncc34)ncc2Cl)nc1
Yield: 40 %

Procedure:
A mixture of 3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 32, 75 mg, 0.26 mmol), (5-fluoropyridin-2-yl)methanamine (33 mg, 0.26 mmol) and diisopropylethylamine (52 μL, 30 mmol) in tetrahydrofuran (3 mL) was heated to reflux for 72 h. The solvent was then evaporated under reduced pressure and the crude product was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (37 mg, 39%).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O>N1C=CC=CC=1>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: OCCOC1C=CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOC2C=CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-(cyclohex-2-enyloxy)ethanol (intermediate BU) (0.3 g) in anhydrous pyridine was added TsCl (1.3 eq). The mixture was stirred at room temperature for 16 h, after which TLC showed the reaction was complete. The mixture was poured into water, extracted with EA, washed with water and brine, and dried with anhydrous Na2SO4. Solvent was removed and the residue purified by column chromatography to obtain intermediate BV (0.3 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>C1COCC1.C(OCC)(=O)C>[CH2:1]([NH:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Reaction time: 8 h

Procedure:
Benzylamine, (3.1 ml, 28 mmol) was added to 2-fluoronitrobenzene (3 ml, 28.5 mmol) in 20 ml dry THF and the reaction stirred overnight. The crude was diluted with ethyl acetate and washed with said. Bicarbonate and then purified by silica gel chromotography eluting with 10-50% Ethyl acetate in hexanes.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)[CH2:17][CH2:16]1.C=O.C(O)(=O)C>CO>[CH3:1][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1cnc(C2CCNCC2)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnc(C2CCN(C)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
Sodium triacetoxyborohydride (530 mg, 2.50 mmol) was added to methyl 5-(piperidin-4-yl)pyrazine-2-carboxylate (221 mg, 1.00 mmol), formaldehyde (37% aqueous solution, 1.50 ml, 20.00 mmol) and acetic acid (0.11 ml, 2.00 mmol) in methanol (5.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was quenched with water (5 mL) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 5-(1-methylpiperidin-4-yl)pyrazine-2-carboxylate (239 mg, 100%) as a yellow waxy solid. This was used directly with no further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][C:44]([F:48])=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[C:44]([F:48])[CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1cc(F)cc(F)c1F
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)cc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,5-trifluorophenyl)boronic acid gave 261. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J=9.5 Hz, 3H), 5.05-4.71 (m, 2H), 4.20-3.90 (m, 2H), 3.77 (s, 3H), 3.31-3.26 (m, 1H), 2.19-2.09 (m, 1H), 1.91-1.78 (m, 2H), 1.69-1.64 (m, 1H). LCMS (ES+) m/z 485 (M+1).