Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@@:30]([OH:34])([C:27]2[CH:26]=[C:25]([CH3:24])[O:29][N:28]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
10-Bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 32.6 mg of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 454 (M)+. 1H NMR (400 MHz, DMSO) δ 11.08 (q, J=4.2 Hz, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.05 (d, J=10.5 Hz, 1H), 6.56 (s, 1H), 6.35 (s, 1H), 5.04-4.95 (m, 2H), 4.59-4.51 (m, 2H), 2.80 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH:18]=[C:17]([O:24]CC)[C:16]=3[N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][C:17](=[O:24])[C:16]=3[N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCOC1=CCCc2cnc(-c3ccc(N4CCOCC4)c(Cl)c3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCCc2cnc(-c3ccc(N4CCOCC4)c(Cl)c3)nc21

Procedure:
2-(3-Chloro-4-morpholin-4-yl-phenyl)-8-ethoxy-5,6-dihydro-quinazoline (0.38 g, 1.0 mmol) is refluxed in 20 ml 25% aqueous acetic acid for 1 hour. The reaction mixture is neutralized using solid NaHCO3 and the product is extracted with ethyl acetate. MS (m/z, ES+): 344 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[C:16]([F:25])[CH:15]=2)[CH2:11][CH:10]([C:26](O)=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32]>O1CCOCC1.CN(C=O)C>[CH2:34]([O:33][C:31]1[N:32]=[C:26]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[C:16]([F:25])[CH:15]=3)[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]2)[O:27][N:30]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(OC(F)(F)F)c(F)c2)C1
Reactant: CCOC(N)=NO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)OC(C)(C)C)C2)n1
Reaction time: 3 h

Procedure:
442 mg (1.09 mmol) of 1-(tert-butoxycarbonyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-piperidine-3-carboxylic acid were dissolved in 11.8 ml of dioxane and 5.9 ml of DMF, heated to 60° C. and admixed with 264 mg (1.63 mmol) of 1,1″-carbonyldiimidazole. The reaction mixture was stirred at this temperature for three hours and then admixed with 170 mg (1.63 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390]. The mixture was left to stir at 50° C. for one hour and thereafter at 115° C. for nine hours. The reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 387 mg (75% of theory, purity 61%)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:59][C:60]1[CH:73]=[CH:72][C:63]([CH2:64][C:65]2[CH:66]=[C:67]([NH2:71])[N:68]([CH3:70])[N:69]=2)=[CH:62][CH:61]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:59][C:60]1[CH:73]=[CH:72][C:63]([CH2:64][C:65]2[CH:66]=[C:67]([NH:71][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]4[S:13][CH:14]=[CH:15][N:16]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)[N:68]([CH3:70])[N:69]=2)=[CH:62][CH:61]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Reactant: Cn1nc(Cc2ccc(Cl)cc2)cc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1nc(Cc2ccc(Cl)cc2)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 150 °C
Yield: 6.5 %

Procedure:
To a mixture of 4-iodo-N-thiazol-2-yl-benzenesulfonamide (100 mg, 0.3 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol, 0.04 equiv), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (19 mg, 0.033 mmol, 0.12 equiv) and 5-(4-chloro-benzyl)-2-methyl-2H-pyrazole-3-ylamine (80 mg, 0.36 mmol, 1.2 equiv) in 4.0 mL of anhydrous 1,4-dioxane was added sodium tert-butoxide (100 mg, 0.90 mmol, 3.0 equiv). The vial was capped, and the reaction mixture was heated 30 min at 150° C. in the microwave. The crude reaction mixture was filtered through celite then concentrated in vacuo. The residue was taken up in chloroform-methanol, concentrated onto celite, and purified via automated flash chromatography (12 g SiO2, gradient from hexanes to ethyl acetate). The appropriate fractions were collected, concentrated in vacuo, then purified further via reverse phase HPLC. The appropriate fractions were lyophilized from water-acetonitrile to afford the product as a white solid (9 mg, 6%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:12][NH:11][C:10](=O)[CH2:9][O:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[O:8][CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C1COC(Cc2ccc(F)cc2)CN1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Fc1ccc(CC2CNCCO2)cc1
Yield: 90.6 %

Procedure:
To a tetrahydrofuran solution (4 mL) of 6-(4-fluorobenzyl)morpholin-3-one (100 mg, 0.48 mmol) synthesized in Reference Synthesis Example 43, lithium aluminum hydride (21.8 mg, 0.57 mmol) was added at 0° C. and the resultant solution was stirred for 4 hours. To the reaction solution, lithium aluminum hydride (20.0 mg) was added and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated sodium sulfate aqueous solution was added to the reaction solution at 0° C. and the resultant mixture was stirred at room temperature for 20 minutes. The reaction solution was dried over added anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (84.9 mg) of the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.CO[CH:15](OC)[CH2:16][CH2:17][CH2:18][NH2:19].[OH-].[NH4+]>Cl>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:9][CH:15]=[C:16]2[CH2:17][CH2:18][NH2:19]
Reactant: NNc1ccccc1C(F)(F)F
Reactant: COC(CCCN)OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: NCCc1c[nH]c2c(C(F)(F)F)cccc12
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Combine in a 500 mL round bottom flask equipped with magnetic stirring, (2-trifluoromethyl-phenyl)-hydrazine (5.0 g, 28.4 mmol) and 4-aminobutyraldehyde dimethyl acetal (4.54 g, 34.1 mmol) and stir. After 5 minutes, slowly add 1N HCl (200 mL) and heat the reaction to 85° C. for 2 hours forming an orange-red colored solution. Increase the temperature to 100° C. for 10 minutes and cool to room temperature. Pour the reaction mixture over ice and stir for 10 minutes followed by adjustment to pH ˜10 with ammonium hydroxide. Extract the mixture with methylene chloride, pool the organic phases, dry over sodium sulfate, and concentrate in vacuo to give a dark orange-brown oil. Purification on a pre-packed, HMDS treated silica column using a step gradient of 9% to 17% methanol in methylene chloride gives the pure title compound as an orange oil: 1H NMR (400 MHz, dmso-d6): 11.18 (br s, 1H), 7.82 (d, 1H, J=7.6 Hz), 7.40 (d, 1H, J=7.2 Hz), 7.24 (d, 1H, J=2.0 Hz), 7.13 (t, 1H, J=7.6 Hz) 2.76-2.83 (m, 4H). MS (APCI): m/e 229.0 (M+1), 212.0 (M−NH2).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[C:22]([Cl:34])[CH:21]=3)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)(C)(C)C>O1CCCC1.Cl>[ClH:34].[ClH:34].[ClH:34].[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[C:22]([Cl:34])[CH:21]=3)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Product: NCCn1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 16 h
Yield: 410.5 %

Procedure:
tert-Butyl[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (30 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (826 mg) as a solid powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:18](=[O:30])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]([CH3:23])[C:21]=3[CH3:22])=[O:16])=[CH:10][CH:9]=2)[C:5](/[N:31]=C/N(C)C)=[N:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CS(C)=O.CC#N.C([O-])([O-])=O.[K+].[K+]>[NH2:31][C:5]1[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]3[C:18](=[O:30])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]([CH3:23])[C:21]=3[CH3:22])=[O:16])=[CH:12][CH:13]=2)=[N:7][C:2]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:3][N:4]=1
Reactant: Cc1c(C(=O)Nc2ccc(-c3nc(Br)cnc3/N=C/N(C)C)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1c(C(=O)Nc2ccc(-c3nc(N4CCCCC4)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 120 °C
Yield: 586.9 %

Procedure:
The compound prepared in Example 36 (80 mg) and piperidine (0.300 mg) were mixed in DMSO (0.400 mL) and heated to 120° C. for 18 hours. The reaction mixture was then diluted with MeCN (10 mL) and aqueous 1M K2CO3 (7 mL) and heated to 155° C. for 17 minutes in the microwave. The organic products were extracted with EtOAc/CH2Cl2 (9:1) and washed with brine. The material was purified by HPLC (H2O/MeCN with 0.1% TFA). The solvent was removed and the residue was dissolved in CH2Cl2 and the residual TFA was removed by PL-HCO3 MP SPE ion exchange column to give the title compound (10 mg) having the following physical data.
Reaction SMILES: C12CC(CC1)CC2N[C:9]1[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][CH3:21])[CH2:16]2)[CH:12]=[CH:11][N:10]=1.CCOCC.C(Cl)[Cl:28].Cl>CCOCC>[Cl:28][C:9]1[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][CH3:21])[CH2:16]2)[CH:12]=[CH:11][N:10]=1
Reactant: ClCCl
Reactant: CN[C@@H]1CCN(c2ccnc(NC3CC4CCC3C4)c2)C1
Agent: Cl
Solvent: CCOCC
Product: CN[C@@H]1CCN(c2ccnc(Cl)c2)C1
Yield: 100 %

Procedure:
To a stirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.1 mmol) in toluene (100 mL) was added (R)-methyl-pyrrolidin-3-yl-amine (1.7 g, 17.0 mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). The flask was evacuated and flushed with N2(g) twice. A mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 590 mg, 1.0 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3; 310 mg, 0.34 mmol) was added in one portion and the mixture was heated at 85° C. for 20 h. The mixture was cooled to room temperature (rt), diluted with H2O (75 mL), and extracted with ethyl acetate (EtOAc; 3×). The combined organic layers were dried and concentrated to give a clear brown oil. The oil was purified by FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2) to give the title compound as a brown solid (1.1 g, 30%). MS (ESI): mass calcd. for C10H14ClN3, 211.09 m/z found, 212.1 [M+H]. 1H NMR (DMSO-d6): 7.86 (d, J=5.9, 1H), 6.47-6.38 (m, 2H), 3.45-3.17 (m, 4H), 3.11-3.01 (m, 1H), 2.29 (s, 3H), 2.15-2.00 (m, 1H), 1.82 (br s, 1H), 1.79-1.65 (m, 1H). Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine. To a stirring mixture of [(3R)-1-(2-chloro-pyridin-4-yl)-pyrrolidin-3-yl]-methyl-amine (97 mg, 0.46 mmol), exo-2-aminonorbornane (164 μL, 1.4 mmol) in ethylene glycol dimethyl ether (DME; 4 mL) in a scintillation vial was added sodium tert-butoxide (245 mg, 2.6 mmol). To the stirring mixture was added in one portion Pd(OAc)2 (16 mg, 0.024 mmol) and racemic 2,2′-bis(diphenylphosphino)-1,1′-bihaphthyl (BINAP; 19 mg, 0.031 mmol). The mixture was heated at 65° C. for 20 h, then was cooled to rt and filtered through a plug of diatomaceous earth. The plug was washed with MeOH (2 mL) and the filtrate was purified directly by FCC (5% 2 M NH3 in MeOH/CH2Cl2) to give a clear light golden oil (70 mg, 54%). Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine. To a stirring solution of bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine in 1:1 Et2O/CH2Cl2 (8 mL) was added 1 N HCl in Et2O (1 mL). The organic layers was separated and concentrated to give the desired product (89 mg, 100%) as a beige solid. MS (ESI): mass calcd. for C17H26N4, 286.2; m/z found, 287.3 [M+H]+. 1H NMR (DMSO-d6): 12.07 (s, 1H), 9.57 (br s, 1H), 9.46 (br s, 1H), 7.81 (d, J=5.1, 1H), 7.66 (d, J=4.6, 1H), 6.28 (d, J=7.4, 1H), 5.64 (s, 1H), 3.89 (br s, 1H), 3.85-3.61 (m, 3H), 3.49 (br s, 2H), 2.60 (s, 3H), 2.35-2.20 (m, 3H), 2.18 (s, 1H), 1.95-1.85 (m, 1H), 1.55-1.46 (m, 3H), 1.37-1.25 (m, 2H), 1.21-1.09 (m, 2H). The compounds in Example 2 through Example 15 were prepared using methods analogous to those described for Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][O:21][CH3:20])[CH2:26][CH2:27]3)[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc(Cl)cc2)C1=O
Reactant: COCCCN1CCNCC1
Product: COCCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(3-methoxypropyl)piperazine, in the same manner as in Preparation Example 1(8).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])[CH:9]=2)=[CH:5][C:4]=1[N+:28]([O-])=O>CO.[Pd]>[NH2:28][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:3]=1[NH:2][CH3:1])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:16])[CH:9]=1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)NCCN3CCOCC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(NC(=O)NCCN3CCOCC3)c2)cc1N

Procedure:
To a flask containing N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide in methanol was added a catalytic amount of 10% Pd C and hydrogenated to yield in quantitative amount N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide. MS: MH+=387.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=2[N:32]2[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(N)cncc2F)CC1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
A mixture of (6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (44.02 g, 126.6 mmol) and tert-butyl 1-(3-amino-5-fluoro-4-pyridyl)piperidine-4-carboxylate 27 (prepared according to Preparation N-15) (34 g, 115.1 mmol) in pyridine (510.0 mL) was heated at 95° C. internally overnight (18 h). Mixture was cooled to room temperature (product precipitated) then added ethanol (340.0 mL) and stirred at room temperature for 10 mins. Collected yellow solid by filtration, washed well with ethanol, dried by suction, then on high vac line for 1 h to leave product 28 as a yellow solid, (32.5 g 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15-2.93 (m, 4H), 2.55-2.47 (masked signal, 1H), 2.02-1.91 (m, 4H), 1.47 (s, 9H). MS (ES+) 474.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH3-]C#N.[Na+]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclo-propanecarboxamide (851 mg, 2.26 mmol) in acetic acid (60 mL) was added NaBH3CN (309 mg, 4.91 mmol) at 0° C. The reaction mixture was stirred for 5 min at room temperature after which no starting material could be detected by LCMS. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (5-40% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (760 mg, 89%).
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN(C)C(=O)C=C1C(=O)OC(C)(C)O1.C=O.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:58]=[CH:59][C:60]=1[Cl:61])[CH2:36][N:37]([CH3:57])[C:38]([C:40]1[CH2:44][N:43]([CH2:45][CH2:46][C:47]([NH:49]CCC(O)=O)=O)[C:42](=[O:55])[C:41]=1[OH:56])=[O:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:58]=[CH:59][C:60]=1[Cl:61])[CH2:36][N:37]([CH3:57])[C:38]([C:40]1[CH2:44][N:43]([CH2:45][CH2:46][C:47]#[N:49])[C:42](=[O:55])[C:41]=1[OH:56])=[O:39]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Agent: C=O
Agent: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC#N)C1
Yield: 45 %

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and 3-aminopropionitirile with 1 equivalent of triethyl amine as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a yellow foam (0.0819 g, 45% yield). 1H NMR (300 MHz, CDCl3) δ: 2.73 (t, J=6.3 Hz, 2H), 3.04 (s, 3H), 3.78 (t, J=6.3 Hz, 2H), 4.40 (s, 2H), 4.60 (s, 2H), 7.11 (dd, J=1.8 Hz, J=8.1 Hz, 1H), 7.35 (d, J=1.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H). HRMS (M−H) calcd for C16H15N3Cl2O3: 366.04122. found: 366.0428.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][Li].O>O1CCCC1>[C:14]([C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:15])[CH3:17]
Reactant: [Li]C
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 108 g. of 1-fluorenecarboxylic acid in 2 liters of dry tetrahydrofuran cooled to -78° C. by means of an external dry ice/acetone bath were added 2 moles of methyl lithium (6 molar solution in diethyl ether). The reaction was stirred at room temperature for 3 hours and then poured into 3 liters of water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed over silica gel. The appropriate fractions were combined and evaporated to dryness. Recrystallization of the residue from ethyl acetate/hexane gave 1-acetylfluorene, m.p. 84°-87° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9]C(=O)C(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2]>Cl>[NH2:9][C:4]1[C:3]([CH:1]=[O:2])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: Cl
Product: Nc1ncccc1C=O
Temperature: 25 °C
Yield: 87.8 %

Procedure:
N-(3-Formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (9.68 g) was dissolved in 3 N hydrochloric acid (140 ml) to prepare a solution which was then stirred under reflux overnight. The reaction solution was cooled to room temperature, the reaction solution was washed with diethyl ether, and was neutralized with potassium carbonate powder. Diethyl ether was added thereto for extraction. The diethyl ether layer was dried over potassium carbonate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 2-amino-pyridine-3-carbaldehyde (5.03 g, yield 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8]>[Pd].CO>[F:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the title compound from Example 1 Step A (0.267 g, 1.57 mmol) were added palladium on carbon (0.027 g) and methanol (7.85 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was then filtered through CELITE® using dichloromethane, and the filtrate was concentrated. Purification by flash chromatography (50% ethyl acetate in hexanes, then 100% ethyl acetate) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 6.61 (dd, J=8.2, 5.6 Hz, 1 H), 6.36-6.30 (m, 2 H), 3.22 (br s, 3 H), 2.84 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26]Br)=[O:5])[CH3:2].[CH2:28]([O:30][C:31](=[O:41])[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:7]=1[CH2:26][N:33]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1CBr
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(-c2ccc(F)cc2)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4-bromo-2-bromomethyl-1,5-bis-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 643 (M+Na+).