Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1.[NH3:21]>S(Cl)(Cl)=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:21])=[O:18])=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A stirred suspension of 1-(4-fluoro-phenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carboxylic acid (1 g, 3.7 mmol) in thionyl chloride (25 mL) was heated at reflux for 25 min, during which time the solid dissolved. The thionyl chloride was then evaporated, and the residue was dissolved in toluene, and again evaporated. The residue was dissolved in toluene (15 mL) and was treated with a solution of ammonia in ether and a heavy precipitate formed. The mixture was stirred overnight, diluted with toluene and aqueous ammonia solution, and filtered. The residue was dried to give the title compound as a white solid (0.80 g, 80%). 1H NMR (d6-DMSO): δ 6.81 (s, 1H), 7.25 (t, 2H), 7.40 (dd, 2H), 7.54 (d, 1H), 7.59 (bs, 1H), 8.24 (bs, 1H), 8.24 (dd, 1H), 8.42 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[O:9][C:10]([CH3:21])([CH3:20])[C@@H:11]([OH:19])[C@H:12]([N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[C:7]=2[CH:6]=1)(=O)C.Cl.C(O)C>O.[OH-].[Na+]>[NH2:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[O:9][C:10]([CH3:20])([CH3:21])[C@@H:11]([OH:19])[C@H:12]([N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H](O)[C@@H]2N1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Yield: 113.1 %

Procedure:
The compound of Example 1 (130 mg), 5N HCl (5 ml) and ethanol (9 ml) were heated under reflux for 3 h. After cooling, the reaction mixture was diluted with water and basified with dilute sodium hydroxide solution, extracted with ethyl acetate, and dried with anhydrous magnesium sulphate. Removal of drying agent and evaporation gave a red solid (130 mg). Recrystallisation from ethyl acetate-pentane gave the nitroamine (40 mg) as brick red crystals of m.p. 244°-245° C.
Reaction SMILES: [CH:1](O)=[O:2].CC(OC(C)=O)=O.[NH2:11][CH:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[C:18]([CH:12]([NH:11][CH:1]=[O:2])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:19]
Reactant: O=CO
Reactant: CCOC(=O)C(N)C#N
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)NC=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
Under N2, HCOOH (2.44 g, 53 mmol) was added to Ac2O (6.48 g, 63.6 mmol) at 0° C. After it was allowed to warm to ambient temperature the reaction was heated at 50° C. for 15 hr. It was allowed to cool to ambient temperature. This mixed acid anhydride was then added dropwise to a solution of ethyl 2-amino-2-cyanoacetate (128 mg, 1 mmol) in dry THF (5 mL) at 0° C. After the cooling bath was removed, the reaction was maintained at ambient temperature for additional 1 hr. The reaction mixture was concentrated and purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-cyano-2-formamidoacetate (110 mg, 70%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]1[C:18](N)=[CH:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16][CH3:15])(=[O:9])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccccc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccccc1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 95.5 %

Procedure:
4-Chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol) was dissolved in CH2Cl2 (7.0 mL). o-Anisidine (1.00 g, 8.13 mmol) was added dropwise at room temperature, followed by a slow addition of pyridine (2.0 mL). After 16 h of continued stirring, the reaction mixture was diluted with EtOAc (50 mL) and washed with 1 M HCl (3×50 mL). The organic phase was dried (MgSO4) filtered and evaporated to a brown solid, upon which re-crystallization from ethanol/water gave 2.22 g (95%) of the product as white crystals. 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.80 (dd, 1H), 7.56 (d, 1H), 7.53 (d, 1H), 7.13 (t, 1H), 6.96 (t, 1H), 6.76 (d, 1H), 3.66 (s, 3H). The sulfonamide proton was not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C@H:13]3[C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:12]3[O:11][C:10]([NH2:19])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:19][C:10]1[O:11][C@@H:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Reactant: N#Cc1cnc(C(=O)O)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(C#N)cn3)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Yield: 28 %

Procedure:
The coupling of (4S,4aR,7aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-2-ylamine (intermediate XIIIa-1) and 5-cyano-pyrazine-2-carboxylic acid (CAS 1211533-09-3) following procedure Q yielded the title compound as a light yellow solid (28% yield). MS: m/z=431.3 [M+H]+.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=O)[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[Br:6][C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[CH2:2])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1
Reactant: [Li]CCCC
Reactant: O=c1c2ccccc2cc(Br)c2ccccc12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1c2ccccc2C=C(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a glove box, methyltriphenylphosphonium bromide (8.22 g, 23 mmol, 357.23 g/mol) was dissolved in 150 mL of THF in a flame-dried flask, and n-BuLi (9.21 mL, 23 mmol, 2.5 M in hexane) was added drop wise. The yellow mixture was stirred at ambient temperature for 30 min. and 10-bromo-5H-dibenzo[a,d]cyclohepten-5-one (6.55 g, 23 mmol, 285.14 g/mol) was added as a THF solution. The mixture was stirred and heated at reflux for two days. The cooled solution was taken out of glove box and diluted with 100 mL of hexane. A small amount of water was added to quench the excess reagent, and the mixture was filtered through a plug of silica gel. The silica was rinsed with additional hexane, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel and eluted with ether/hexane (1:1) mixture by volume. Solvent was removed to yield 5.53 g (85 percent, 283.17 g/mol) of the title compound as a pale yellow oil that crystallized upon standing.
Reaction SMILES: [NH:1]([C:3]([C@H:5]1[N:15]2[C@@H:9]([S:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]2=[O:16])[CH2:8][CH2:7][CH2:6]1)=[O:4])[NH2:2].[CH3:25]OC(OC)OC>>[O:4]1[CH:25]=[N:2][N:1]=[C:3]1[C@H:5]1[N:15]2[C@@H:9]([S:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:14]2=[O:16])[CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)NN)N2C1=O
Reactant: COC(OC)OC
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a round bottom flask was added tert-butyl (4S,7S,10aS)-7-(hydrazinecarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (0.13 g, 0.35 mmol) and trimethoxymethane (2.50 mL, 22.9 mmol). The reaction was heated at 70° C. for 5 hr. and then at 95° C. for 18 hr. The reaction was concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-(1,3,4-oxadiazol-2-yl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (94 mg, 0.26 mmol, 73% yield) as a white solid. Anal. Calcd. for C16H24N4O4S m/z 368.4. found: 369.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[C:10]([I:15])[C:9]=1[OH:16].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[I:7][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[C:10]([I:15])[C:9]=1[O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1c(I)cc(I)cc1I
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cc(I)c(OC2CCCC2)c(I)c1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 107.9 %

Procedure:
Milled, anhydrous potassium carbonate (14.2 g, 103 mmol, 1.2 eq) was added in portions to a stirred solution of 2,4,6-triiodophenol (40.5 g, 85.8 mmol) in 50 ml of dry (4A sieves) dimethylformamide at room temperature. After stirring for 20 minutes, cyclopentyl bromide (12 ml, 112 mmol, 1.3 eq) in dimethylformamide (20 ml) was added and the viscous mixture was gradually heated to 130° C. under argon for approximately 45 minutes. After cooling, the mixture was filtered and the collected solid was washed with chloroform. The filtrate was concentrated in vacuo to give 50 g of an amber oil. The crude oily product was partitioned between ethyl acetate (300 ml) and water (500 ml); the organic layer was dried over magnesium sulfate and passed through a short pad of silica gel. The filtrate was treated with decolorizing carbon, filtered, and stripped to give an amber oil. The oil was dried at 60° C. under high vacuum to give 40.4 g (87%) of product.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1.[C:22](=[O:25])([O-])[O-].[Na+].[Na+].C(O[CH2:32][CH3:33])(=O)C>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][O:25][N:8]=[C:7]1[C:32]2[C:33](=[CH:2][C:3]([C:2]3[CH:6]=[C:5]([CH2:7][N:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[O:4][C:3]=3[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=3)=[CH:14][CH:19]=2)[CH2:6][CH2:5]1
Reactant: CCOC(C)=O
Reactant: CSc1nccc(-c2oc(CN3CCCCC3)cc2Br)n1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CON=C1CCc2cc(-c3cc(CN4CCCCC4)oc3-c3ccnc(SC)n3)ccc21
Temperature: 25 °C

Procedure:
A mixture of the products from Step 2 (0.6 g, 1.62 mmol) and Description 1 Step 2 (0.367 g, 1.8 mmol) in toluene (10 ml) was treated with bis(triphenylphosphine) palladium (II) chloride (0.113 g, 0.162 mmol) and 2M aqueous sodium carbonate (0.2 ml, 3.93 mmol) and heated under reflux for 18 hours. After cooling to room temperature, the mixture was poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried and reduced in vacuo. The crude title compound (0.310 g) was used in the next step without further purification; MS(ES+) m/e 449 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][O:27]C)[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)[Br:30].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][OH:27])[N:9]=2)=[CH:6][CH:7]=1.[Br:30][CH2:26][C@H:24]1[C@@:10]2([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH2:25]1
Reactant: BrB(Br)Br
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CBr)c1nnc(C)n1-2
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CO)c1nnc(C)n1-2

Procedure:
To a solution of (1S,2R)-4′-(4-chlorophenyl)-2-(methoxymethyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine] (2.35 g, 5.69 mmol) in DCM (70 mL) at −78° C. was added a solution of boron tribromide (1M in DCM) (Compound 202; 17.07 mmol). The reaction was warmed to rt for 30 min before MeOH was added followed by sat. aq. NaHCO3. The product was extracted with DCM (repeated 4 times), dried over a cotton plug and concentrated to dryness under vacuum. The residue was purified by flash chromatography (MeOH/DCM 0.5:99.5 to 5:95) to give ((1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin]-2-yl)methanol (Compound 203) (1.9 g) as a white solid and (1S,2R)-2-(bromomethyl)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine] (Compound 237) (449 mg) as a side product. LRMS (M+H)+: 399 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 7.41-7.53 (m, 4H), 4.64 (t, J=5.72 Hz, 0.5H), 4.51 (t, J=5.38 Hz, 0.5H), 3.95 (quin, J=6.20 Hz, 0.5H), 3.69 (quin, J=6.20 Hz, 0.5H), 3.10-3.18 (m, 0.5H), 3.01-3.09 (m, 0.5H), 2.60 (s, 3H), 2.39 (s, 1.5H), 2.38 (s, 1.5H), 2.14-2.23 (m, 0.5H), 1.96-2.04 (m, 0.5H), 1.57 (s, 1.5H), 1.55 (s, 1.5H), 1.32-1.37 (m, 0.5H), 1.25-1.32 (m, 0.5H), 0.96 (dd, J=5.26, 9.16 Hz, 0.5H), 0.58 (t, J=6.20 Hz, 0.5H).
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Reactant: COc1ccccc1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1NC1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Yield: 75 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and (2-methoxyphenyl)amine, the title compound was synthesized in the same manner as in Example 297. Yield: 75%. Melting point: 184-185° C. (ethyl acetate-hexane).
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[C:26]2[C:21](=[C:22]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:28](=[O:29])[CH:27]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[CH:20]=[CH:19][N:18]=[CH:17]4)[CH3:31])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(N2CCCCCC2)c(F)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(N2CCCCCC2)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(1-azepanyl)-3-fluorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 406 (M+H)+; MS (ESI−) m/z 404 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (m, 7H), 1.72 (m, 4H), 3.32 (m, 4H), 3.65 (s, 2H), 4.18 (q, J 7.1, 1H), 6.86 (m, 3H), 7.58 (m, 2H), 7.74 (m, 1H), 8.13 (m, 2H), 8.52 (d, J 7.8, 1H), 9.30 (s, 1H); Anal. Calcd for C25H28FN3O+3.25 HCl: C, 57.30; H, 6.01. Found: C, 57.26; H, 5.98.
Reaction SMILES: C([O:4][C:5]1[C:12]([Br:13])=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][C:6]=1[Br:14])(=O)C.O.NN.O>C1COCC1.CO>[Br:13][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([Br:14])[C:5]=1[OH:4])[CH:9]=[CH2:10]
Reactant: C=Cc1cc(Br)c(OC(C)=O)c(Br)c1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(Br)c(O)c(Br)c1
Reaction time: 0.67 h

Procedure:
10 g of 4-acetoxy-3,5-dibromostyrene are dissolved in 50 ml THF and 25 ml methanol, 12 g hydrazine hydrate (80% aqueous solution) is added, and the cloudy mixture is then converted into a clear solution by adding 3 ml of water. After 40 minutes it is acidified with a:semi-concentrated HCl to pH2 and extracted twice with ether the ether phase is washed twice with waterand dried over sodium sulfate and the ether is removed with a rotary evaporator at room temperature under aspirator vacuum. 8.5 g of crude product remain, from which 6.45 g of white crystals (mp 74° C.) areobtained by recrystallization from petroleum ether.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]1[CH2:18][O:17][C:16]2[CH:19]=[CH:20][C:21]3[C:22]4[C:27]([C:28](=O)[C:29]=3[C:15]1=2)=[CH:26][CH:25]=[CH:24][CH:23]=4.CCOCC>C1COCC1.[Cl-].[Na+].O>[CH2:14]1[CH2:18][O:17][C:16]2[CH:19]=[CH:20][C:21]3[C:22]4[C:27]([C:28](=[CH:3][C:1]#[N:2])[C:29]=3[C:15]1=2)=[CH:26][CH:25]=[CH:24][CH:23]=4
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1c2ccccc2-c2ccc3c(c21)CCO3
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC=C1c2ccccc2-c2ccc3c(c21)CCO3
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A magnetically stirred solution of diethyl cyanomethylphosphonate (0.502 g, 2.83 mmol) in anhydrous THF (150 mL) was treated with sodium hydride (60% in mineral oil, 0.113 g, 2.82 mmol) in portions. The resultant suspension was treated dropwise with 2,10-dihydro-1H-fluoreno[2,1-b]furan-10-one (0.525 g, 2.36 mmol) in THF (100 mL), stirred 12 h, poured over ice (100 g), and treated with brine (100 mL), and Et2O (150 mL). The layers were separated and the aqueous layer further extracted with fresh Et2O (2×150 mL). The combined organic extracts were washed with brine (200 mL), dried (K2CO3), filtered, and concentrated in vacuo.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[C:66]([CH:71]=[CH:72][CH:73]=1)[C:67]([O:69][CH3:70])=[O:68]>>[CH3:70][O:69][C:67](=[O:68])[C:66]1[CH:71]=[CH:72][CH:73]=[C:64]([NH:63][C:30]([C@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[CH:65]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.53 mmol), was reacted with diisopropylethylamine (0.28 g, 2.1 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with methyl 3-aminobenzoate (Aldrich) (0.12 g, 0.8 mmol) to give rac-3-{[(2′S,3′R,4′S,5′S)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester as a off white solid (Yield, 0.07 g, 22%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:20][CH2:21][N:22]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:23][CH2:24]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCN(CC(F)(F)F)CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.7 %

Procedure:
2-(4-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (Example 28, Step A; 0.050 g, 0.11 mmol) was dissolved in DIEA (0.12 mL, 0.70 mmol) and DMF (0.2 mL) with sonication. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.025 g, 0.11 mmol) was added and the reaction was stirred at ambient temperature. After four hours the reaction was applied to a silica caplet and pumped to dryness. The caplet was applied to a silica column and eluted with 0.5-2% MeOH/DCM. The purified product was isolated to provide 2-(4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetonitrile (5.0 mg, 10% yield) as a solid. MS (apci) m/z=470.2 (M+H).
Reaction SMILES: CN1CCCC1.C=C(OC(=O)[N:12]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[C:29]([NH:31][C:32](OC(C)=C)=[O:33])[C:28]([F:38])=[CH:27][C:26]=3[CH3:39])[C:20]([CH3:24])=[N:21]2)=[CH:16][N:15]=1)[CH3:13])C.[CH2:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCOCC1>[F:38][C:28]1[CH:27]=[C:26]([CH3:39])[C:25]([C:19]2[C:20]([CH3:24])=[N:21][C:22]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:12][CH3:13])[CH:23]=3)=[CH:30][C:29]=1[NH:31][C:32]([NH:49][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:33]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)C(=O)OC(=C)C)cc3nc2C)c(C)cc1F
Reactant: NCCc1ccccc1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCc4ccccc4)c(F)cc3C)cc2cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Add 1-methylpyrrolidine (0.075 mL, 0.717 mmol) to a solution of prop-1-en-2-yl(3-(4-fluoro-2-methyl-5-(((prop-1-en-2-yloxy)carbonyl)amino)phenyl)-2-methyl-1,6-naphthyridin-7-yl)(methyl)carbamate (0.333 g, 0.717 mmol) and phenethylamine (0.091 g, 0.753 mmol) in dioxane (6 mL) and heat at 50° C. overnight. Cool to RT, add satd. NaHCO3, extract with EtOAc (3×), dry the combined organics over MgSO4 and concentrate to dryness. Dissolve the residue in dioxane (10 mL), add NaOH (1.0M, 2 mL), stir at RT for 2 h, then heat to 50° C. overnight. Add NaOH (3M, 0.5 mL), heat the mixture at 55° C. for 24 h, then add additional NaOH (3M, 0.25 mL) and heat at 60° C. for 24 h. Cool the mixture to RT, add brine, extract with EtOAc (3×), dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford 1-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)-3-phenethylurea (245 mg, 77%). MS(ESI) m/z: 444.2 (M+H+). Add 0.1N HCl (6.08 mL, 0.608 mmol) to a suspension of 1-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)-3-phenethylurea (0.245 g, 0.552 mmol) in MeCN (2 mL), sonicate for 5 min, freeze, lyophilize and dry to afford the title compound (244 mg, 92%) as an orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.32-7.17 (m, 6H), 6.66 (m, 2H), 3.29 (m, 2H), 2.91 (s, 3H), 2.71 (t, J=7.1 Hz, 2H), 2.51 (s, 3H), 2.01 (s, 3H).