Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:31]=[C:32]([CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:38]2[CH:37]=[C:32]([CH:31]=[C:30]([OH:29])[CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: COC(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 120 °C
Yield: 42.8 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.16 mmol) and methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (64 mg, 0.23 mmol) were dissolved in 10 mL dioxane in a microwave vessel. A solution of sodium carbonate (2 M, 365 μl, 0.73 mmol) was added and the mixture was submitted to three vacuum-argon cycles. 2′-(Dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (5 mg, 0.01 mmol) was added and the mixture was submitted to three more vacuum-argon cycles. The reaction mixture was then heated at 120° C. under microwave conditions for 5 h. Further 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (5 mg, 0.01 mmol) and sodium carbonate (2 M, 365 μl, 0.73 mmol) were added and the reaction mixture heated at 120° C. under microwave conditions 2 h more. The reaction mixture was cooled at room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1® Purification System to obtain 35 mg (42% yield) of the title compound. Purity 100%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[C:17]([C:19]([OH:26])([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])#[CH:18]>>[F:10][C:9]([F:12])([F:11])[C:8]([NH:7][CH2:6][CH2:5][C:4]1[CH:14]=[CH:15][CH:16]=[C:2]([C:18]#[C:17][C:19]([OH:26])([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH:3]=1)=[O:13]
Reactant: O=C(NCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(CCNC(=O)C(F)(F)F)c1)CCC
Reaction time: 17 h

Procedure:
N-(3-Bromophenethyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 following the procedure described in Example 18 except that the reaction was run for 17 h to give 2,2,2-trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)phenethyl)-acetamide as a brown oil after purification by flash chromatography (10% to 50% EtOAc in hexanes gradient). Yield (0.975 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dt, J=7.8, 1.2 Hz, 1H), 7.24-7.29 (m, 2H), 7.10-7.15 (m, 1H), 6.27 (br.s, 1H), 3.61 (q, J=6.7 Hz, 2H), 2.86 (t, J=7.0 Hz, 2H), 1.95 (s, 1H), 1.66-1.74 (m, 4H), 1.52-1.64 (m, 4H), 0.99 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:34][NH:35][CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:34][N:35]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:36]
Reactant: CNC
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN(C)C)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (19 mg, 0.043 mmol) and dimethylamine (2 M in THF, 0.026 mL, 0.052 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (16 mg, 0.078 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 2 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified with preparative thin layer chromatography (SiO2, 5% Et3N, 5% MeOH, 90% EtOAc) to furnish methyl 6-(2-(3-(4′-((dimethylamino)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a tan solid (5 mg, 25%): 1H NMR (CDCl3, 600 MHz) δ 8.12 (d, 1H, J=7.7 Hz), 8.03 (d, 2H, J=9.6 Hz), 7.97 (t, 1H, J=7.8 Hz), 7.53 (dd, 4H, J=8.0, 4.9 Hz), 7.38 (d, 2H, J=7.9 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.03 (s, 3H), 3.51 (t, 4H, J=7.6 Hz), 3.15 (t, 2H, J=7.6 Hz), 2.31 (s, 6H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.4, 138.9, 138.3, 129.6, 128.9, 128.0, 127.2, 126.9, 125.2, 123.3, 63.8, 53.1, 45.1, 40.6, 29.3; HR ESI-TOF m/z 470.2071 (M+H+, C28H27N3O4, requires 470.2074).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1>[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:24]
Reactant: CC(C)CCC(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Solvent: C1CCOC1
Product: CC(C)CCC(=O)c1ccco1

Procedure:
A solution of 2-tributylstannylfuran (1 mmol), 4-methylvaleroyl chloride (1.1 mmol), and PdCl2 (PPh3)2 (0.05 mmol) in THF was stirred at 25° C. for 24 h. Extraction and chromatography gave 2-(4-methylvaleryl)furan.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([C:6]([CH3:14])=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:15].[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28](O)=O)=[CH:26][C:25]([C:31]([F:34])([F:33])[F:32])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:3]1[CH:4]=[C:5]2[C:6]([CH3:14])=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:28]([C:27]1[N:23]([C:18]3[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:24]=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=1)[O:12][C:11]2=[O:13]
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1n[nH]c2c(C(=O)O)c(N)c(Cl)cc12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1n[nH]c2c1cc(Cl)c1nc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)oc(=O)c12
Temperature: 0 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
To a suspension of 540 mg (2.39 mmol) of 6-amino-5-chloro-3-methyl-1H-indazole-7-carboxylic acid in 22 mL of anhydrous tetrahydrofuran at 10° C., is added 698 mg (2.39 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 963 μL (11.97 mmol) of pyridine. Then the suspension is cooled to 0° C. and 748 μL (9.57 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is taken-up with acetone. After filtration, the filtrate is evaporated in vacuo. The residue obtained is purified by flash chromatography (SiO2, heptane/ethyl acetate 1:2) and affords 810 mg (1.68 mmol, 70%) of the product as a solid; LC/MS:481/483 (M+H)+.
Reaction SMILES: C([O-])(=[S:3])C.[K+].[CH2:6]([CH:8]1[CH:12]([CH2:13][C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:11]N[C:9]1=[O:20])[CH3:7]>CN(C)C=O>[CH2:6]([CH:8]1[CH:12]([CH2:13][C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][S:3][C:9]1=[O:20])[CH3:7]
Reactant: CCC1C(=O)NCC1Cc1cccnn1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1C(=O)SCC1Cc1cccnn1

Procedure:
Potassium thioacetate (3.3 g, 0.029 mol) and 3.0 g (0.0145 mol) of 3-ethyl-4-(3-pyridazinylmethyl)-2-pyrrolidinone (Example 1) are stirred for 6 hours at 150° C. in 50 mL of dimethylformamide. After cooling and evaporating the solvent, the residue is dissolved in 95% methylene chloride/methanol, washed twice with saturated sodium bicarbonate solution and once with water. After drying the organic phase with sodium sulphate, the mixture is filtered and concentrated by evaporation. The product is purified by chromatography in silica gel to give the title compound.
Reaction SMILES: C(O[C:4]([CH:6]1[C:10]2([CH2:12][CH2:11]2)[CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])C.[CH3:20][Li]>C(OCC)C>[CH2:13]([N:8]1[CH2:7][CH:6]([C:4](=[O:5])[CH3:20])[C:10]2([CH2:11][CH2:12]2)[CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC12CC2
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)C1CN(Cc2ccccc2)CC12CC2
Temperature: -10 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
A solution (−78° C.) of 5-benzyl-5-azaspiro[2.4]heptane-7-carboxylic acid ethyl ester (Example A1a, 8.15 g, 31.4 mmol) in diethyl ether (200 mL) under a nitrogen atmosphere is treated with methyllithium (1.4 M in diethyl ether, 22.4 mL, 31.4 mmol) over a period of 10 minutes. After 1 hour, reaction mixture is warmed to −10° C. and quenched with saturated aqueous ammonium chloride. The mixture is poured into a separatory funnel and the organic layer is washed with saturated aqueous ammonium chloride, water, and brine. The organic layer is then dried with MgSO4, filtered, and the filtrate concentrated. The resulting residue is purified via flash column chromatography (1% triethylamine/7% isopropanol/92% CH2Cl2) to afford the title compound (3.93 g). MS CI: m/z 230 (MH+).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)C1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]>C1C=CC=CC=1>[Cl:19][C:18]([Cl:21])([Cl:20])[CH2:17][O:16][C:14]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:15]
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC=CC1
Reaction time: 1 h

Procedure:
40.0 g (0.25 mol) of N-benzyl-3-pyrroline are dissolved in 400 ml of benzene. 53.0 g (0.25 mol) of 2,2,2-trichloroethyl chloroformate are introduced into this solution in the course of 30 minutes, at 0° and under a nitrogen atmosphere. The reaction mixture is stirred for a further 1 hour at 0°, then washed at room temperature twice with, in each case, 100 ml of a mixture of water and 2 N hydrochloric acid (3:1) and then twice with water, dried over sodium sulphate and evaporated under a water pump vacuum. The oily residue is distilled under a high vacuum and, after 24 g of benzyl chloride has been separated off, N-(β,β,β-trichloroethoxycarbonyl)-3-pyrroline with a boiling point of 84°-85° C./0.12 mm Hg is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C(C2[C:47]([CH2:48][O:49][CH2:50][C:51]3[C:56](C4C(=CC=C(O)C=4)O)=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:46][CH:45]=[CH:44][CH:43]=2)=CC(=CC=1)O)O.N(C(OCC)=O)=NC(OCC)=O.[ClH:77]>C1C=CC=CC=1.CCOCC>[ClH:77].[CH2:50]([O:49][C:48]1[CH:43]=[CH:44][C:45]([O:8][C@@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:46][CH:47]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1CC[C@@H](Oc2ccc(OCc3ccccc3)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 14.2 g of cis-1-methyl-3-phenyl-4-piperidinol, 21.4 g of triphenylphosphine, 16.3 g of hydroquinone monobenzyl ether and 375 ml of anhydrous benzene is added dropwise under nitrogen at 5° C. a solution of 14 g of diethyl azodicarboxylate in 375 ml of benzene. After the addition is complete the mixture is stirred overnight at room temperature and the precipitated solid is filtered and washed with benzene. The filtrate is concentrated in vacuo to a dark brown oil which is triturated overnight with 500 ml of hexane in a stoppered flask. The hexane is decanted and the gummy solid is triturated with a little ether. The resulting solid is filtered and washed well with ether. The combined filtrates are concentrated in vacuo, and the residue is dissolved in 750 ml of ether and extracted with 2 N hydrochloric acid (1×300 ml, 1×150 ml). The acid washings are extracted with dichloromethane (1×300 ml, 1×150 ml). The dichloromethane extracts are washed with 10% sodium hydroxide solution (300 ml), water (300 ml), and sodium chloride solution (300 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a brown gum. The gum is triturated with hexane, then with ether, filtered, washed with ether, and the filtrate concentrated in vacuo to afford a solid. The solid is dissolved in 500 ml of ether and treated dropwise with 20 ml of saturated ethereal hydrogen chloride. The precipitate is filtered, washed with ether, dried and recrystallized from 75 ml of absolute ethanol to afford product as nearly colorless crystals, mp 213.5°-214.5° C.
Reaction SMILES: C[Li].[CH3:3][C:4]12[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:5]1=[N:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:11][C:12]=12.[Cl-].[NH4+].[CH2:25](OCC)C>O1CCCC1>[CH3:25][C@@:5]12[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][C@:4]1([CH3:3])[C:12]1[CH:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:7]=1[NH:6]2
Reactant: CC(C)c1ccc2c(c1)C1(C)Cc3ccccc3C1=N2
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyllithium (1.4M in ether, 14.5 cm3, 12.4 mmol) in dry tetrahydrofuran (20 cm3), at -78° C., under nitrogen, in a flame dried flask, was added dropwise, over 1 hour, a solution of 9b,10-dihydro-9b-methyl-8-isopropylindeno-[1,2-b]indole (1.62 g, 6.20 mmol) in dry tetrahydrofuran (30 cm3). After addition, the mixture was stirred for a further 1/2 hour at -78° C. Saturated ammonium chloride solution (2 cm3) was then added and the mixture allowed to warm to room temperature. The reaction mixture was then portioned between diethyl ether (50 cm3) and saturated ammonium chloride solution (25 cm3), and the layers separated. The aqueous phase was extracted with diethyl ether (2×10 cm3) and the combined organic extracts were washed brine, dried (Na2SO4) and evaporated. The crude material thus obtained was purified by flash chromatography on silica gel eluting with 3-10% ethyl acetate/60°-80° petrol to yield a pale yellow gum. Yield: 0.77 g, 45%. 1H NMR (CDCl3) δ: 7.1-7.3 (4H, m), 6.98 (1H, d, J=1.8 Hz ), 6.82 (1H, dd, J=1.8 Hz and 7.9 Hz ), 6.47 (1H, d, J=7.9 Hz), 3.36 (1H, d, J=15.9 Hz), 3.06 (1H, d, J=15.9 Hz), 2.78 (1H, sept., J=6.8 Hz), 1.45 (3H, s), 1.34 (3H, s), 1.18 (6H, dd, J=1.3 Hz and 6.9 Hz).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17]>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)c2ccccc2)c1
Temperature: 100 °C

Procedure:
Benzoyl chloride (27.09 g., 0.19 mole.) was added, with cooling, during 20 minutes to a stirred solution of 2-(3-amino-4-hydroxyphenyl) propionitrile (28.35 g., 0.175 mole.) in dry pyridine (200 ml.) at 0°-3°C. After addition was complete, the mixture was heated at 100°C. for 1 hour. It was then evaporated under reduced pressure to yield crude 2-(3-benzamido-4-hydroxyphenyl) propionitrile as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH:15]3[CH3:17])[C:7]=12.[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][OH:22]>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:22][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH:15]3[CH3:17])[C:7]=12
Reactant: Cc1c(C)n(CC2CC2C)c2c(Cl)nncc12
Reactant: OCc1ccc(F)cc1F
Product: Cc1c(C)n(CC2CC2C)c2c(OCc3ccc(F)cc3F)nncc12
Yield: 63.8 %

Procedure:
The title compound (trans) was prepared as a white powder in 63.8% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine and 2,4-difluorobenzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[N:38]=[C:37]([C:39](O)=[O:40])[CH:36]=[CH:35][C:34]=1[F:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[N:38]=[C:37]([C:39]([NH:1][C:2]2[C:3]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:12]3)=[C:4]3[CH2:10][CH2:9][CH2:8][C:5]3=[N:6][CH:7]=2)=[O:40])[CH:36]=[CH:35][C:34]=1[F:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
tert-Butyl [(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (5.0 mg, 0.015 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.6 mg, 0.018 mmol), HATU (14 mg, 0.038 mmol), DMF (0.035 mL) and DIPEA (5.8 mg, 0.045 mmol) were mixed together and stirred at room temperature for 1 h. The mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (XBridge™ preparative C18 30×10 mm 5 μm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4.1 mg, 48%). LCMS calc. for C30H33F3N5O3 (M+H)+: m/z=568.3. Found: 568.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][C:21](=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CC(=O)c2ccccc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 82.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (8 g) is alkylated using 3-bromoacetophenone (6.8 g; 33.4 mmol) and K2CO3 (11.3 g; 82 mmol) at RT for 3 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (111 ml) and hydrochloric acid (6 N; 75 ml). Pure 5-amino-3,3-dimethyl-6-nitro-1-(2-oxo-2-phenyl-ethyl)-1,3-dihydro-indol-2-one (8.5 g) is obtained by aqueous work-up and re-crystallization.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.CCN(CC)CC>CCO>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 0 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mol), 4-chloro-6-(trifluoromethyl)quinazoline (48 mg, 0.20 mol) and Et3N (100 mg, 1.0 mol)in EtOH (2 ml) was added to a microwave reaction tube, sealed, and heated in a microwave oven at 100° C. for 60 minutes. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (3%–5% (NH4OH/MeOH)/CH2Cl2) to give 25 mg of the title product, (1R,2S,5R)-methyl 5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=508.24.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:19]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:12]([C:9]4[N:10]=[N:11][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=4)=[O:14])[CH2:25]3)[C:19]=12
Reactant: O=C(O)c1nnn(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1nnn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 2-phenyl-2H-tetrazole-5-carboxylic acid (0.10 g, 0.53 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.15 g, 0.53 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.22 mL, 0.58 mmol, 1.1 eq) and HATU (0.22 g, 0.58 mmol, 3 eq). The mixture was stirred at room temperature for 1 h and was then concentrated and purified by HPLC to afford (S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-2-phenyl-2H-tetrazole-5-carboxamide (0.10 g, 0.26 mmol, 49%). 1H NMR (400 MHz, CD3OD) δ 8.19 (d, J=7.0 Hz, 2 H), 8.06 (s, 1 H), 7.95 (d, J=5.5 Hz, 1H), 7.82 (s, 1H), 7.70-7.58 (m, 3 H), 7.19 (d, J=5.8 Hz, 1 H), 5.00-4.90 (m, 1H), 4.80-3.80 (br, 4 H), 2.62-2.38 (m, 2 H); MS: (ES) m/z calculated for C18H17N9O [M+H]+ 376.2, found 376.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:12]([CH2:41][OH:42])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C([C@@H](NC(N2CCOCC2)=O)CC2C3C(=CC=CC=3)C=CC=2)=O)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:47].[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:57]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:54](O)=[O:55])=[O:51]>>[CH3:48][O:49][C:50](=[O:51])[NH:52][C@H:53]([C:54](=[O:55])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Cl:47])[CH:4]=1)(=[O:10])=[O:9])[CH2:43][CH:44]([CH3:45])[CH3:46])[CH2:41][OH:42])[CH:57]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)c(Cl)c1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from (1S)4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-3-chloro-N-isobutyl-benzenesulfonamide (XII) (example 44, step B) as described in general procedure B using (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (see example 34, step A). The final product was obtained in 43% yield (48 mg).