Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([N:9]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:5][CH:6]([CH3:8])[CH3:7].O.NN.Cl>CO>[CH3:1][O:2][CH2:3][C@H:4]([NH2:9])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC[C@@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COC[C@H](N)CC(C)C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of (R)-2-(1-methoxy-4-methylpentan-2-yl)isoindoline-1,3-dione (example 9b) (3.87 g, 14.84 mmol) in methanol (30 mL), was added hydrazine hydrate (0.866 ml, 17.81 mmol) and the reaction mixture was warmed up to 45° C. for about 3 hours. The mixture was acidified with 2N HCl and stirred at 45° C. for 30 min. The solution was cooled to room temperature, filtered and evaporated. The residue was taken up with 2N NaOH and extracted with ether, dried over MgSO4, filtered and evaporated to give 1.51 g of (R)-1-methoxy-4-methylpentan-2-amine. Yield 77%. 1H NMR (500 MHz, CDCl3): δ 0.91 (m, 6H); 1.17 (m, 2H); 1.58 (s, 2H); 1.71 (m, 1H); 3.02 (m, 1H); 3.10 (m, 1H); 3.32 (m, 1H); 3.35 (s, 3H).
Reaction SMILES: [N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12](I)[C:11]=2[F:21])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][C:29]1[S:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[S:33][C:32]([C:12]2[C:11]([F:21])=[C:10]([N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH2:3][CH2:2]3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:31][CH:30]=1
Reactant: Fc1c(I)nc2ccccc2c1N1CCc2cnccc21
Reactant: OB(O)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1c(-c2ccc(Cl)s2)nc2ccccc2c1N1CCc2cnccc21
Temperature: 80 °C
Yield: 49.9 %

Procedure:
4-(2,3-Dihydro-pyrrolo[3,2-c]pyridin-1-yl)-3-fluoro-2-iodo-quinoline from step B (0.025 g, 0.063 mmol) was dissolved in tetrahydrofuran (5 ml) in a 25 ml round bottomed flask equipped with a magnetic stirrer. Sodium carbonate (0.06 g, 0.1 mmol) was added followed by 5-chlorothiophene-2-boronic acid (0.019 g, 0.08 mmol) and the mixture was degassed for 5 mins. Tetrakis(triphenylphosphine)-palladium(0) (5 mg, 5 mol %) was added followed by 0.5 ml water and the reaction mixture was heated to 80° C. for 4 hrs. The compound was extracted with ethyl acetate, dried and concentrated in vacuo. The title compound was purified by HPLC over a reverse phase column using a gradient of acetonitrile and water containing 0.1% trifluoroacetic acid to yield desired compound (0.012 g, 52%). MS (ES) 482.4 (M+H)+
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]1([C:10]2[CH:11]=[CH:12][C:13]3[C:11]4[C:10](=[CH:9][C:8]([C:14]5[CH2:5][CH2:6][CH2:1][CH2:2][CH:3]=5)=[CH:13][CH:12]=4)[CH2:14][C:8]=3[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: Cc1ccccc1
Product: C1=C(c2ccc3c(c2)Cc2cc(C4=CCCCC4)ccc2-3)CCCC1

Procedure:
The compound 2,7-di(1-cyclohex-1-enyl)fluorene can be prepared by first forming a Grignard reagent from 2,7-diiodofluorene and magnesium and bromoethane in THF by heating for several days in a Schlenk tube at about 60°-90° C. Then cyclohexanone is added. After acidic workup in hot toluene, the 2,7-dicyclohexenyl fluorene is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([CH2:34][CH3:35])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Br)c23)cc1

Procedure:
The above 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole and 4-ethylbenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound, 4-bromo-3-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)indole as a colorless powder. APCI-Mass m/Z 476/478 (M+H). 1H-NMR (DMSO-d6) δ 1.15 (t, J=7.6 Hz, 3H), 2.56 (q, J=7.5 Hz, 2H), 3.23 (td, J=9.0, 5.5 Hz, 1H), 3.39 (td, J=8.8, 5.1 Hz, 1H), 3.43-3.47 (m, 2H), 3.61-3.69 (m, 2H), 4.26 (s, 2H), 4.53 (t, J=5.3 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.1 Hz, 1H), 5.20 (d, J=5.8 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 7.09-7.14 (m, 4H), 7.21 (d, J=7.5 Hz, 1H), 7.23 (s, 1H), 7.59 (d, J=8.3 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH3:3].O.[NH2:26]N>C(O)C>[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([NH:9][NH2:26])=[NH:8])[CH3:3]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=N)N
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=N)NN
Reaction time: 0.5 h
Yield: 74 %

Procedure:
The 2-ethoxy-5-(4-ethylpiperazin-1-yl-sulfonyl)benzamidine hydrochloride prepared in the above preparation example 1 was dissolved into ethanol (200 ml), and 85% hydrazine hydrate (5.9 g, 0.1 mol) was slowly dropped into the solution under ice bath. The mixture was stirred for 30 minutes and then at room temperature for 1 hour. Then, the solution was concentrated to dryness, and added with ethyl acetate to perform a recrystallization. The separated crystal was dried under vacuum to obtain 28 g of product with a yield of 74%. 1H NMR (CDCl3, 300 MHz) δ: 1.02 (3H, t), 1.49 (3H, t), 2.39 (2H, q), 2.51 (4H, t), 3.05 (4H, t), 4.18 (2H, q), 7.00 (1H, d), 7.69 (1H, dd), 8.13 (1H, d). ESI-MS m/z 356.3 (M++1, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH:6]=1.[Br:16]Br>Br.CC(O)=O>[Br:16][CH2:14][C:13]([C:10]1[CH:11]=[N:12][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:8][CH:9]=1)=[O:15]
Reactant: CC(=O)c1ccc(-n2cnc(C)c2)nc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: Cc1cn(-c2ccc(C(=O)CBr)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.9 %

Procedure:
Compound 19 (6.1 g, 30.30 mmol) was suspended in 30% HBr/AcOH (75 ml). Bromine (4.82 g, 30.30 mmol) was added dropwise over 1 h. The reaction was stirred for 2 h at room temperature. The reaction mixture was poured into 600 mL of ice water and stirred rapidly for 15 min. The resulting precipitate was collected on a filter and washed with water. The compound was air dried to yield 20 as a yellow solid (10.6 g, 80%). LC/MS: [M+1]+=281.1. C11H10BrN3O:2HBr=442.0. 1H NMR (DMSO-d6) 300 MHz δ2.36 and 2.37 (6H, two s), 5.06 (2H, s), 8.16 (1H, d, J=9.0 Hz), 8.29 (1H, s), 8.69 (1H, d, J=9.0 Hz), 9.15 (1H, s), 9.93 (1H, s).
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([NH2:26])=[C:19]2[N:18]=1.CCN(C(C)C)C(C)C.Cl[C:37](=[O:42])[C:38]([O:40][CH3:41])=[O:39]>>[F:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([NH:26][C:37](=[O:42])[C:38]([O:40][CH3:41])=[O:39])=[C:19]2[N:18]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
A DCM (5 mL, 0.7928 mmol) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 250 mg, 0.7928 mmol) and DIEA (0.2071 mL, 1.189 mmol) was first cooled in an ice-water bath, then methyl 2-chloro-2-oxoacetate (0.07657 mL, 0.8325 mmol) was added to reaction drop-wise. Ice bath was removed and the reaction was stirred at ambient temperature for approx. 10 minutes to reach completion. The reaction was washed with 10% citric acid (aqueous). The aqueous layer was back-washed with DCM. The combined organic layer was washed with 1:1 water/brine, dried (Na2SO4) and concentrated. The crude oil residue was directly purified by silica chromatography, eluting with EtOAc/hexanes 1:1 to 2:1, yielding the final product as a pale-yellowish foamy powder (270 mg, 85% yield). MS (apci) m/z=402.2 (M+H).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]1([CH2:1][NH:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[CH2:20][CH2:19]2
Reactant: NCCN1CCCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and N-(2-aminoethyl)piperidine (0.048 ml, 0.334 mmol). The mixture was stirred at rt for 2 h then sodium triacetoxyborohydride (0.177 g, 0.835 mmol) was added. The mixture was stirred at rt for three days then was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step with no additional purification. LCMS: m/e 711.2 (M+H)+, 3.32 min (method 6).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:24])([F:23])[C:15]([F:22])([F:21])[C:16]([F:20])([F:19])[CH2:17][OH:18])=[C:5]([F:27])[C:4]=1[F:28].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[N+:40]([O-:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[CH3:1][N:2]([CH3:29])[C:3]1[C:4]([F:28])=[C:5]([F:27])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:23])([F:24])[C:15]([F:21])([F:22])[C:16]([F:19])([F:20])[CH2:17][O:18][C:35]2[CH:36]=[CH:31][C:32]([N+:40]([O-:42])=[O:41])=[CH:33][C:34]=2[N+:37]([O-:39])=[O:38])=[C:7]([F:10])[C:8]=1[F:9]
Reactant: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(F)c1F
Yield: 73.2 %

Procedure:
N,N-Dimethyl-4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluorobenzeneamine (1.05 g) was treated with 1-chloro-2,4-dinitrobenzene (0.51 g) and potassium carbonate (0.35 g) in NMP (5 mL) at 80° C. for 21.5 hrs. The mixture was diluted with water and extracted with ethyl ether. The extracts were washed with water and brine, dried (K2CO3), and concentrated to an orange oil. The oil was purified by chromatography to give N,N-dimethyl-4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]2,3,5,6-tetrafluorobenzeneamine (1.05 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)C(=O)C.Cl[C:42]([O:44][CH3:45])=[O:43]>>[CH3:45][O:44][C:42](=[O:43])[N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=1)[CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2
Reactant: COC(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21

Procedure:
The titled compound was prepared following the procedures described for the preparation of (+/−) N-(3,5-Bis-trifluoromethyl-benzyl)-N-[1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (example 191, step 3) by replacing acetic anhydride with methyl chloroformate. MS (ES+): 601(M+H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10](Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH:15][NH2:16]>C(O)CCC>[C:1]1([C:7]2[N:12]=[N:11][C:10]([N:15]([CH3:14])[NH2:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CNN
Solvent: CCCCO
Product: CN(N)c1ccc(-c2ccccc2)nn1

Procedure:
A mixture of 10.0 g. of 6-phenyl-3-chloropyridazine 7.8 g. of methylhydrazine and 75 ml. of n-butanol is refluxed 6 hours. The mixture is cooled and filtered to give product and the filtrate is concentrated and filtered to give additional product. The two crops of product are recrystallized from ethanol to give crystals, m.p. 145°-147° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[Li]C(C)(C)C.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[C:18]1=[O:19])[CH3:13].[NH4+].[Cl-]>C1COCC1>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20]([OH:21])([C:2]2[CH:6]=[CH:5][O:4][CH:3]=2)[C:18]1=[O:19])[CH3:30]
Reactant: Brc1ccoc1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccoc2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To 3-bromofuran (95.1 mg, 2.1 eq) in anhydrous THF (2 mL) under a nitrogen atmosphere and with stirring was added t-BuLi (0.38 mL, 2.1 eq, 1.7 M in pentane) at −78° C. (bath temperature). Stirring was continued for 1 hour after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added dropwise. The resulting red coloured solution was stirred at −40° C. for 8 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1% to 2% MeOH in CHCl3) to give the title compound as a yellow solid (103.3 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][C:20]4([CH2:25][CH2:24][CH2:23][N:22]4[CH3:26])[CH2:19]3)=[CH:11][C:10]=2[O:27][CH3:28])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]3[CH2:19][C:20]4([CH2:25][CH2:24][CH2:23][N:22]4[CH3:26])[CH2:21]3)=[CH:11][C:10]=2[O:27][CH3:28])=[N:6][CH:7]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 33.9 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 46, 95 mg, 0.18 mmol), iron (61 mg, 1.09 mmol) and NH4Cl (7.32 mg, 0.14 mmol) was heated at reflux in ethanol (10.5 mL) and water (3.5 mL) for 2 h. The mixture was cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2. This solution was washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2-6% 7N methanolic ammonia in CH2Cl2 gave the title compound (30 mg, 34%) as a brown gum; m/z: ES+ MH+ 491.5.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C@@H:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[C:16]1([CH:6]2[CH2:7][CH2:8][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:5]2[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:31])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2)c1

Procedure:
By proceeding in a fashion similar to that described in Example 2, but starting from 2 g of cis-1-(2-aminoacetyl)-2,5-diphenylpyrrolidine and 0.9 cm3 of 3-methylphenyl isocyanate in solution in 25 cm3 of anhydrous tetrahydrofuran, 1.4 g of (2RS,5SR)-1-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]-3-(3-methylphenyl)urea, melting at 168° C., are obtained after recrystallization in 2-propanol.
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=1[CH:21]=O>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=1[CH:21]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: COc1ccc(OC)c(C=O)c1
Product: COc1ccc(OC)c(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 36 %

Procedure:
Following procedures essentially as described in Preparation 5 and Example 28, above, and using dibenzosuberone (2.00 g, 10.29 mmol) and 2,5-dimethoxybenzaldehyde (1.71 g, 10.29 mmol) affords 1.27 g (36%) of the title compound as a yellow solid. 1H-NMR (CDCl3) δ 2.74-3.67 (br m, 4H), 3.34 (s, 3H), 3.83 (s, 3H), 6.27 (d, 1H), 6.65 (dd, 1H), 6.77 (d, 1H), 6.98-7.28 (m, 8H), 7.56 (dd, 1H); HPLC shows 99% purity.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1)=O.[ClH:20]>C(O)C>[ClH:20].[NH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1
Reactant: O=C(NCCc1ccc2sc(=O)[nH]c2c1)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: NCCc1ccc2sc(=O)[nH]c2c1

Procedure:
5-(2-trifluoroacetylaminoethyl)-1,3-benzothiazol-2(3H)-one (1.7 g) was dissolved in ethanol (17 ml) and HCl 6N (17 ml).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]3[C:14]([C:15]4([CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]([NH:23]C(=O)OC(C)(C)C)=[N:16]4)[C:6]=2[CH:5]=[C:4]([C:38]2[C:39]([F:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[N:3]=1)=[CH:13][C:12]([C:31]1[C:32]([F:37])=[N:33][CH:34]=[CH:35][CH:36]=1)=[CH:11][CH:10]=3.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C:17]1[N:18]([CH3:22])[C:19](=[O:21])[CH2:20][C:15]2([C:6]3[CH:5]=[C:4]([C:38]4[C:39]([F:44])=[N:40][CH:41]=[CH:42][CH:43]=4)[N:3]=[C:2]([F:1])[C:7]=3[O:8][C:9]3[C:14]2=[CH:13][C:12]([C:31]2[C:32]([F:37])=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:11][CH:10]=3)[N:16]=1
Reactant: CN1C(=O)CC2(N=C1NC(=O)OC(C)(C)C)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2cccnc2F)nc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)CC2(N=C1N)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2cccnc2F)nc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Tert-butyl 1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate was obtained as a side product in the synthesis of Example 12. To a solution of tert-butyl 1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate (32 mg, 0.053 mmol) in DCM (2.5 mL) was added TFA (500 μL, 6.49 mmol). The reaction was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The column was washed with MeOH and subsequently eluted with a 2 M solution of ammonia in MeOH to obtain 22.6 mg 2′-amino-1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one as a white solid.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:16][CH2:15][C:5]2([CH2:9][NH:8][C@H:7]([C:10]([O:12]CC)=[O:11])[CH2:6]2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][O:43][C:44]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])=[O:45].C(N(CC)CC)C>C(Cl)Cl>[F:17][C:2]1([F:1])[CH2:3][CH2:4][C:5]2([CH2:9][N:8]([C:51](=[O:52])[C@H:47]([CH:48]([CH3:49])[CH3:50])[NH:46][C:44]([O:43][CH3:42])=[O:45])[C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)[C@@H]1CC2(CCC(F)(F)CC2)CN1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC2(CCC(F)(F)CC2)C[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of ethyl (3S)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxylate (115), (380 mg, 1.54 mmol) in anhydrous CH2Cl2 (10 mL) was added HATU (614 mg, 1.6 mmol), N-[(methyloxy)carbonyl]-L-valine (283 mg, 1.6 mmol) followed by triethylamine (0.43 mL, 3.1 mmol) and the reaction stirred at room temperature under nitrogen for 1 h. The reaction was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 15-80% hexanes/EtOAc. Appropriate fractions were combined and concentrated in vacuo. The residue was dissolved in THF/water/methanol (5 mL/2.5 mL/2.5 mL) and lithium hydroxide monohydrate was added (119 mg, 2.8 mmol) and the solution stirred at room temperature for 30 min. The reaction was treated with 1N HCl (3.5 mL) and partitioned between EtOAc and water (50 mL each). The aqueous layer was extracted with ethyl acetate (50 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo. The residue was triturated in diethyl ether and concentrated in vacuo to afford the title compound as a white solid (542 mg, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s., 1H) 7.41 (d, J=8.0 Hz, 1H) 4.24 (t, J=8.6 Hz, 1H) 3.95-4.14 (m, 2H) 3.52 (s, 3H) 3.25-3.33 (m, 1H) 2.22 (dd, J=12.3, 8.4 Hz, 1H) 1.79-2.11 (m, 5H) 1.58-1.77 (m, 3H) 1.41-1.59 (m, 2H) 0.93 (dd, J=12.7, 6.6 Hz, 6H). LC-MS ESI (M+H)+=377.23.