Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]([CH:14]1[C:18]2([CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)[S:17][CH:16]([CH:24]([N:32]2C(=O)C3=CC=CC=C3C2=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:43]>CN(C)C=O>[ClH:43].[NH2:32][CH:24]([CH:16]1[NH:15][CH:14]([C:12]([O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:13])[C:18]2([CH2:19][CH2:20][S:21][CH2:22][CH2:23]2)[S:17]1)[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCSCC2)S1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(N)C1NC(C(=O)OCc2ccccc2)C2(CCSCC2)S1
Reaction time: 1.25 h
Yield: 91.5 %

Procedure:
151.5 ml of a solution of dimethylforamide containing 2 moles per liter of hydrazine hydrate (0.3025 mole) are added, between 0 and 5° C, to a suspension of 156.3 g (0.275 mole) of tert-butyl 4-benzyloxycarbonyl-alpha-phthalimido-1,8-dithia-3-azaspiro[4.5]decane-2-acetate in 170 ml of anhydrous dimethylformamide. The addition is carried out over 75 minutes and is accompanied by a complete dissolution of the product. The reaction mixture is allowed to return to ambient temperature over a period of 1 hour, whereafter 309 ml of 1N hydrochloric acid are added dropwise at 20 to 25° C. The precipitate of phthaloghydrazide formed is filtered off and the mother liquors are evaporated to dryness. The residue is taken up in methanol and is precipitated with diethyl ether. In this way, there are obtained 119.1 g of tert-butyl alpha-amino-4-benzyloxycarbonyl-1,8-dithia-3-azaspiro[4.5]decane-2-acetate hydrochloride (yield 91.5% of theory); M.P. 178-181° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:21](=[O:23])[NH2:22])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:9][CH:8]=1.[CH:24]([O-])([O-])OCC.CN(C)C=O>C(OCC)(=O)C>[OH:23][C:21]1[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][C:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=4)=[CH:9][CH:8]=3)=[C:2]2[N:1]=[CH:24][N:22]=1
Reactant: CCOC([O-])[O-]
Reactant: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Cc2ccc(-c3cnn4c(O)ncnc34)cc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-carbamoyl-4- {4-(3-methylphenylmethyl) phenyl} pyrazole (3.0 g), ethyl orthoformate (2 ml) and N,N-dimethylformamide (4 ml) was heated and stirred at 100° C. to 110° C. After 1 hour, to the mixture was added ethyl acetate (50 ml). The precipitate was separated by filtration, washed with etyl acetate, dried to give the title compound (2.0 g).
Reaction SMILES: [N+](=[CH:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:12])=[O:5])=[N-].[C:28]([OH:31])(=[O:30])[CH3:29].O1CCOCC1>>[C:28]([O:31][CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:12])=[O:5])(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: [N-]=[N+]=CC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 100 °C

Procedure:
(S)-2-[[(S)-2-(Diazoacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (3.63 g) was dissolved in acetic acid-1,4-dioxane (1:1, 36 ml), and the mixture was heated at 100° C. for 10 minutes. The reaction mixture was concentrated, added with methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.47 g) (see Table 1).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+].Cl[CH2:46][C:47]([N:49]([CH3:51])[CH3:50])=[O:48]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH:30]4[CH2:33][N:34]([CH2:46][C:47]([N:49]([CH3:51])[CH3:50])=[O:48])[CH2:35][CH2:36][N:29]4[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), K2CO3 (28 mg, 0.21 mmol), and potassium iodide (19 mg, 0.11 mmol) in DMF (1 mL), 2-chloro-N,N-dimethylacetamide (14 mg, 0.11 mmol) was added at rt. The reaction was heated to 65° C. and allowed to stir for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate (50 mL) and saturated aqueous K2CO3 solution (30 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 5 mg (9%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.36 to 7.30 (m, 5H), 7.12 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.09 (dd, 1H), 3.76 (dd, 1H), 3.36-3.27 (m, 1H), 3.11 (d, 2H), 2.99-2.93 (m, 4H), 2.78-2.63 (m, 6H), 2.48-2.36 (m, 1H), 2.24-2.21 (m, 3H), 1.80 (t, 1H); LC-MS [M+H]+=566, RT=2.07 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:44][C:45]([F:48])([F:47])[F:46])[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:44][C:45]([F:46])([F:47])[F:48])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)c(OC(F)(F)F)c2)CC1
Reactant: C#Cc1ccccc1CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Temperature: 120 °C
Yield: 73 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis (triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH2:1]/[C:2](/[CH3:9])=[C:3](/[C:18](=[O:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(C(=O)Nc1ccc(Cl)cc1)=C(/C)N
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a stirred solution of 12.9 g (0.10 mole) of ethyl 3-aminocrotonate in 50 ml of anhydrous dimethylformamide is added during 10 min. 15.36 g (0.10 mole) of p-chlorophenyl isocyanate in 50 ml of the same solvent. A mild exotherm (5° C.) results. After stirring for 3 hours, the reaction solution is slowly added with stirring to 1.5 l of deionized water. The white solid product is collected by vacuum filtration, washed with water and air dried at 45°-55° to give 23 g of ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate. Recrystallization of a 2.0 g. portion of this material from 15 ml of ethanol gives 1.5 g of pure ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([N:13]1[CH2:24][CH2:23][CH2:22][C@H:14]1[C:15]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[N+](C1C=CC([O:34][C:35](=O)[C@H:36]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=CC=1)([O-])=O.CN(C)C=O>C(OCC)C>[ClH:1].[CH2:41]([O:40][C:38]([NH:37][C@H:36]([C:35]([NH:2][C@H:3]([C:11]([N:13]1[CH2:24][CH2:23][CH2:22][C@H:14]1[C:15]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:34])[CH2:48][CH:49]([CH3:50])[CH3:51])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of L-arginyl-L-prolyl-glycinamide hydrochloride (from de-protection of 21.2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-prolyl-glycinamide hydrochloride), 17 g. of Nα -benzyloxycarbonyl-L-leucine p-nitrophenyl ester and 85 ml. of dimethylformamide is allowed to stand at 25° C. for 48 hours, warmed to 50° C. for 10 minutes and let stand for six hours at 25° C. The solution is poured slowly into 800 ml. of stirred dry diethyl ether. The sticky solid is separated by decanting, dissolved in 50 ml. of methanol with warming and the solution poured into 500 ml. of stirred ether. The solid is separated and dried at 40° C. under reduced pressure. It is dissolved in 50 ml. of methanol and 450 ml. of chloroform and chromatographed over a column of 170 g. of silica gel (prepared in 10% methanol in chloroform) and eluted with 10 to 20% methanol in chloroform. The desired fractions, as shown by thin layer chromatography, are combined and evaporated to dryness at 40° C. under reduced pressure and the residue is dissolved in 50 ml. of methanol and 25 ml. of ethyl acetate and the solution is dropped slowly into 350 ml. of stirred dry ether. The solid is separated and dried at 40° C. under reduced pressure to give Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride; 11.6 g.; [α]D23 -51.6° (c 1.0, methanol); ultraviolet in methanol λmax 257 E11 3.24.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)[N:17]=2)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CS(C)=O>[C:25]1([CH3:29])[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:18]2[N:17]=[C:16]([C:14]3[S:15][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:12][CH:13]=3)[CH:21]=[CH:20][N:19]=2)[CH:24]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)c4ccccc4)s3)n2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
Benzoic acid (5.2 mg, 0.042 mmol), [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (10 mg, 0.035 mmol), DMAP (4.2 mg, 0.035 mmol) and HATU (15.9 mg, 0.042 mmol) were combined in 400 uL DMF and the solution was heated on a hot plate in a capped vial at 70° C. After 16 hours, the mixture was diluted with DMSO and prep purified to afford N-[5-(2-m-tolylamino-pyrimidin-4-yl)-thiophene-2-yl]-benzamide (3.0 mg, 22%). 1H NMR (500 MHz, DMSO-d6) δ 1.29 (s, 3H), 6.70 (d, J=7.5 Hz, 1H), 6.93 (d, J=4 Hz, 1H), 7.10 (t, J=8 Hz, 1H), 7.16 (d, J=5.5 Hz. 1H), 7.47 (d, J=7.5 Hz, 1H), 7.51 (m, 2H), 7.58 (m, 1H), 7.74 (d, J=4 Hz, 1H), 7.78 (s, 1H), 7.95 (m, 2H), 8.31 (d, J=5.5 Hz, 1H), 9.42 (s, 1H). MS: m/z 387 (M+H+).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1.[CH:16]1([CH:19]=[O:20])[CH2:18][CH2:17]1>C1COCC1.CCOC(C)=O.[Cl-].[NH4+]>[CH:16]1([CH:19]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[OH:20])[CH2:18][CH2:17]1
Reactant: Ic1n[nH]c2ncccc12
Reactant: O=CC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1n[nH]c2ncccc12)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
i-PrMgCl (0.32 mL, 0.64 mmol) was added to 3-iodo-1H-pyrazolo[3,4-b]pyridine (3.1 mL, 0.61 mmol) in THF (3 mL) at 0° C. After 10 minutes, another portion of i-PrMgCl (0.32 mL, 0.64 mmol) was added. After 10 minutes, neat cyclopropanecarbaldehyde (0.074 mL, 0.98 mmol) was added dropwise and stirred at 0° C. for 1 hour. The mixture was diluted with EtOAc (5 mL) and aqueous ammonium chloride, and extracted with EtOAc (2×5 mL). The resulting residue was purified via flash chromatography eluting with EtOAc to afford cyclopropyl(1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (0.052 g, 0.28 mmol, 44.9% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(CNC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-(benzyloxycarbonylamino)-2,2-dimethylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.19 (s,6H), 1.90 (m,1H), 2.6-3.0 (m,3H), 3.26 (d,6 Hz,2H), 4.46 (m,1H), 5.07 (s,2H), 5.7 (br t,1H), 6.62 (d,7 Hz,1H), 6.97 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.3 (s,5H), 8.14 (br s,1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C@H:12]([CH2:17][C:18]#[CH:19])[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[C:2]([NH:11][C@H:12]([CH2:17][C:18]#[CH:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: C#CC[C@@H](N)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CC[C@@H](Nc1cccnc1[N+](=O)[O-])C(=O)OC

Procedure:
To a mixture of 3-fluoro-2-nitropyridine (860 mg, 6.05 mmol) and (R)-methyl 2-aminopent-4-ynoate (1.924 g, 15.131 mmol) in DMF was added triethylamine (2.55 ml, 18.16 mmol) and the resulting solution was stirred over the weekend. The reaction mixture was quenched with sat. NaHCO3, extracted with EtOAc/hexane=2:1, washed with brine, dried over Na2SO4 and the solvent was evaporated. Flash chromatography (SiO2, DCM to DCM/EtOAc=3:1 to 2:1) afforded the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH2:28])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH:28][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(Br)cn1
Yield: 87.6 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (1.5 g, 90%) was prepared by following general procedure A from commercially available 5-bromo picolinic acid (0.9 g, 4.7 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 3.9 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:43])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[C:28]([O:27][CH3:26])=[N:29][CH:30]=[C:31]([CH3:43])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 120 °C
Yield: 54 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 120° C. for 20 minutes under microwave irradiation. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (49 mg, 72%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 2.10 minutes.
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[C@@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.O.S(=O)(=O)(O)[OH:33].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:29][C:26]1[O:27][CH2:28][C@:8]2([N:25]=1)[C:9]1[CH:10]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:7]2=[CH:6][C:5]([O:4][CH2:3][C:2]([CH3:1])([OH:33])[CH3:30])=[CH:18][CH:17]=1
Reactant: C=C(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 25 °C

Procedure:
A vial was charged with (S)-2′-(2-methylallyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (41.17 mg, 0.103 mmol) and water (0.5 mL) giving a suspension. Sulfuric acid (110 μL, 2.061 mmol) was added, and the mixture became a cloudy solution. The vial was sealed and placed in a 70° C. oil bath for 8 h. The mixture was cooled to RT, and potassium carbonate was added until bubbling ceased. The resulting suspension was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column eluting with 0-10% MeOH/DCM to give a white solid. The solid was dissolved in methanol and purified further by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-1-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2-methylpropan-2-ol as a white solid. MS m/z=418.2 [M+H]+. Calculated Mass for C24H24N3O4: 418.2.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][N:4]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][N:2]([CH3:16])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH2:10]2)=[CH:5][N:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CN(C)c1ncc(C2CCC(=O)CC2)cn1
Product: CN(C)c1ncc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(2-dimethylamino-pyrimidin-5-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: NCCc1ccccn1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCCc2ccccn2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 2-(2-aminoethyl)pyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.