Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][C:16]([CH3:21])([CH2:18][CH2:19][CH3:20])[C:15](=[O:22])[C:14]([CH3:23])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:24]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([C:5]12[CH2:17][C:16]([CH3:21])([CH2:18][CH2:19][CH3:20])[C:15](=[O:22])[C:14]([CH3:23])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:24])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)(CCC)C2
Agent: Cl
Solvent: CO
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(C)(CCC)C2
Temperature: 85 °C

Procedure:
A solution of (2SR,9aRS)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (40 mg, 0.11 mmol) in methanol (approx. 0.5-1 mL) was placed under a nitrogen atmosphere and treated with 2N aqueous HCl (0.165 mL, 0.37 mmol). The resulting yellow solution was stirred and heated in an oil bath at 85° C. for 60 minutes. On cooling, the mixture deposited white crystals. The mixture was cooled in an ice bath and filtered. The crystalline product was washed with ice-cold 5:1 MeOH-2N HCl (2×2 mL) and dried under vacuum to afford (2SR,9aRS)-9a-butyl-2,4-dimethyl-7-hydroxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: COC(=O)c1cccc(S)c1
Product: COC(=O)c1cccc(SC2=C/C(=C3/C(=O)NN=C3C)Nc3ccccc32)c1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and methyl 3-mercaptobenzoate using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 3.90 (s, 3 H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.86-7.96 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H); ESI-MS: m/z calc'd for C21H17N3O3S 391.10. found 392.3 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([OH:11])[CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[CH2:9][CH:8]([OH:11])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: OC(CBr)C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
1,1-Diphenyl-3-bromopropan-2-ol (500mg.) prepared as described in Example 20 was treated with excess dimethylamine in ethanol and the solution allowed to stand overnight. Solvent was removed by evaporation and the residue dissolved in dilute hydrochloric acid and ether. Basification of the acid extract and isolation through ether in the usual manner gave 3-dimethylamino-1,1-diphenyl-propan-2-ol (330mg, 75%) m.p. 72° - 73°
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:25])[C@@H:10]([CH2:22][O:23][CH3:24])[NH:11]C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:26][C:2]1([CH3:1])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:25])[C@@H:10]([CH2:22][O:23][CH3:24])[NH2:11]
Reactant: COC[C@@H](NC(=O)OCc1ccccc1)C(=O)OC1C(C)CCC1(C)C
Agent: [Pd]
Solvent: CO
Product: COC[C@@H](N)C(=O)OC1C(C)CCC1(C)C

Procedure:
To a solution of 5 g N-Cbz-D-serine 2,2,5-trimethylcyclopentyl ester in 50 ml dry CH2Cl2 is added 2 equivalents of Ag2O and 2 equivalents of methyl iodide. After stirring for 2 hours, the mixture is filtered and concentrated to yield the methyl ether of N-Cbz-D-serine 2,2,5-trimethylcyclopentyl ester. 3 g of N-Cbz-D-serine methyl ether 2,2,5-trimethylcyclopentyl ester is hydrogenated over 0.5 g 10% Pd/C in 100 ml CH3OH. Upon completion, the mixture is filtered and concentrated to yield 3-methoxy-D-alanine 2,2,5-trimethylcyclopentyl ester. To a magnetically stirred solution of 2 g of 3-methoxy-D-alanine 2,2,5-trimethylcyclopentyl ester in 100 ml DMF at 0° C. is added 1 equivalent of N-Cbz-L-aspartic acid-β-benzyl ester followed by addition of 1 equivalent each of Cu(II) chloride and dicyclohexylcarbodiimide. After 18 hours the mixture is poured into 200 ml 0.1N HCl and extracted with 300 ml ethyl acetate. The organic phase is washed with saturated NaHCO3, and H2O, dried over MgSO4, filtered and concentrated to an oil that is reconstituted in 50 ml CH3OH and hydrogenated over 0.5 g 5% Pd/C. Filtration following by concentration yields L-aspartyl-D-serine 2,2,5-trimethylcyclopentyl ester methyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.O.[OH-].[Li+].O1CCOCC1.Cl>O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 71.2 %

Procedure:
A mixture of methyl 4-bromo-2-isopropylbenzoate (0.41 g) and lithium hydroxide monohydrate (0.669 g) in water (1 mL)/1,4-dioxane (3 mL) was stirred at room temperature for 5 days. To the reaction mixture was added 2 mol/L hydrochloric acid (10 mL), and the resulting mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/n-hexane to afford the title compound (0.276 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]#[N:11])=[C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[N:5]=[C:4]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:3]=1.[OH-].[K+]>CO.ClCCl>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:4]1[N:5]=[C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[C:7]2[C:2](=[N:1][C:10]([NH2:11])=[CH:9][N:8]=2)[N:3]=1
Reactant: N#CCNc1c(N)nc(SCc2cccc(F)c2F)nc1SCc1cccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Nc1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2n1

Procedure:
A solution of the product from example 1 step b) (1.35 g) and potassium hydroxide (114 mg) in methanol (50 ml) and dichloromethane (20 ml) was stirred at room temperature for 24 hours. After evaporation in vacuo, the residue was purified by silica gel flash column chromatography, eluting with 5:1 dichloromethane:ethyl acetate, to give the subtitled compound as a pale yellow solid (0.37 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>N#N>[CH2:22]([O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[NH2:14])[CH3:23]
Reactant: N[C@@H](Cc1ccc(O)c2ncccc12)C(=O)O
Reactant: CCO
Agent: N#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred slurry of DL-3-(8-hydroxyquinolin-5-yl)alanine (HLM8) (2.19 g, 7.04 mmol) in absolute ethanol (26 ml) at 0° C., with protection from atmospheric moisture by CaCl2 tube in N2, thionyl chloride was added dropwise (1.1 ml, 14.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, and then refluxed overnight. The solution was evaporated to dryness in vacuum. The residue was dissolved in absolute ethanol and reevaporated to dryness. To ensure completeness of the esterification, the whole operation was repeated. The ester HLM9 (yellow solid, 1.67 g, 92% yield), which was shown by HPLC to contain about 1% of free amino acid, was further purified by FC(CH2Cl2:MeOH:AcOH 9:1.5:1.5). 1H NMR (250 MHz, D2O) 0.94 (dd, J=7.2, 7.2 Hz, 3H), 3.63 (m, 2H), 4.01 (m, 2H), 4.34 (dd, J=7.7, 7.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 8.01 (dd,J=8.7, 5.4 Hz, 1H), 8.93 (d, J=5.4 Hz, 1H), 9.08 (d, J=8.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:36]1([C:39]([NH:41][NH2:42])=O)[CH2:38][CH2:37]1>CC1C=CC(C)=CC=1>[CH:36]1([C:39]2[N:26]3[C:21]4[CH:20]=[C:19]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:18]([C:15]5[CH:16]=[CH:17][C:12]([C:8]6([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]6)=[CH:13][CH:14]=5)=[N:28][C:22]=4[O:23][CH2:24][C:25]3=[N:42][N:41]=2)[CH2:38][CH2:37]1
Reactant: NNC(=O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C3CC3)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 21.8 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (150 mg, 0.308 mmol) and cyclopropanecarbohydrazide (41 mg, 0.410 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 20 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (36 mg, 32%). LCMS (Method D): RT=1.457 min, M+1=536.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[N:30](S(C2C=CC(C)=CC=2)(=O)=O)[C:15]2=[N:16][CH:17]=[CH:18][C:19]([C:20]3[S:24][C:23]([C:25]4([OH:29])[CH2:28][CH2:27][CH2:26]4)=[N:22][CH:21]=3)=[C:14]2[CH:13]=1.Cl>CO.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[NH:30][C:15]2=[N:16][CH:17]=[CH:18][C:19]([C:20]3[S:24][C:23]([C:25]4([OH:29])[CH2:28][CH2:27][CH2:26]4)=[N:22][CH:21]=3)=[C:14]2[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(F)cc34)cc3c(-c4cnc(C5(O)CCC5)s4)ccnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)ccnc3[nH]2)c2cc(F)ccc21
Temperature: 25 °C

Procedure:
A solution of 1-(5-(2-(5-fluoro-1-methyl-1H-indol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107D) in methanol (2.0 mL) and 2N sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.14 (s, 1H), 8.54 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.09 (s, 1H), 7.87 (d of d, J=10.08 & 2.4 Hz, 1H), 7.58 (d of d, J=8.95 & 4.5 Hz, 1H), 7.27 (d, J=5.2 Hz, 1H), 7.14 (t, 1H), 6.99 (s, 1H), 3.88 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 419.5 [M+H]+.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH2:26][OH:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:28]([S:38]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)(=[O:40])=[O:39])[S:29]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:18]2)[CH:11]=1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH2:26][OH:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:28]([S:38]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)(=[O:40])=[O:39])[S:29]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:18]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1)C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1
Reaction time: 1 h
Yield: 66 %

Procedure:
1,1-Dimethylethyl[(3-{[3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(hydroxymethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate (for a preparation see Intermediate 71) (93 mg, 0.125 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.125 mL) was added to the solution and stirred for 1 h under nitrogen. The reaction mixture was concentrated under a stream of nitrogen and the residue was dissolved in methanol and loaded onto a methanol pre-conditioned sulphonic acid (SCX-2) cartridge (10 g). The cartridge was washed well with methanol, followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound (53 mg, 66%) as a white solid. LCMS (System A) RT=0.89 min, ES+ve m/z 643/645 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[CH:3]=1.[H-].[Na+].Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl>CN(C)C=O>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][N:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)[C:8](=[O:10])[CH3:9]
Reactant: CN(C)CCCl
Reactant: CC(=O)Nc1cc(C)on1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(CCN(C)C)c1cc(C)on1
Reaction time: 0.25 h

Procedure:
The reaction is run under a nitrogen atmosphere. To a stirred solution of 14.0 g. (0.10 mole) of N-(5-methyl-3-isoxazolyl)acetamide in 100 ml. of dry dimethyl formamide is added 4.3 g. (0.10 ml.) of the 56% sodium hydride suspension. An immediate reaction occurs and solids begin to separate (temperature rises to 55° C.). Then 15.8 g. (0.11 mole) of 2-dimethylaminoethyl chloride hydrochloride is added portionwise along with an additional 4.3 g. (0.11 mole) of sodium hydride (temperature rises to 75°-85° C.). The mixture is stirred for 15 minutes until the temperature begins to fall and is then heated on the steam bath for 28 hours. The dark mixture is filtered to remove precipitated salts, and the dark filtrate is concentrated under reduced pressure at 80°-90° C. This affords 21.7 g. of dark liquid which is dissolved in 150 ml. of ether, filtered through charcoal and concentrated to give 19.0 g. of pale yellow liquid which is used as is in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:19])[CH3:18])=[C:15]3[N:10]([C:11]([S:20][CH3:21])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.C(O[CH:27](OC(C)(C)C)[N:28]([CH3:30])[CH3:29])(C)(C)C>>[CH3:27][N:28]([CH3:30])/[CH:29]=[CH:18]/[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][N:12]=[C:11]2[S:20][CH3:21])=[O:19]
Reactant: CSc1nccc2c(C(C)=O)c(-c3ccc(F)cc3)nn12
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Product: CSc1nccc2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nn12
Temperature: 120 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To 1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone (1.24 g, 4.12 mmol) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (15 mL) and the mixture heated to 120° C. for 1 hour. The reaction was allowed to cool to room temperature and stirred for 16 hours. The mixture was diluted with hexanes. The precipitate was collected by filtration and air dried to yield (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one (880 mg, 60%). 1H NMR (DMSO): δ 8.03 (d, 1H), 7.72–7.82 (m, 3H), 7.57 (d, 1H), 7.37 (t, 2H), 5.08 (d, 1H), 3.04 (bs, 3H), 2.71 (s, 3H), 2.52 (bs, 3H). MS m/z 357 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(#N)C>[N:26]1([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: CC#N
Product: O=C(Cn1ccnc1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 73.5 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and imidazole (96 mg, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (80 mg, 73%), MS (ISP) m/e=388.3 [(M+H)+].
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14](Br)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1cc(Br)c2ncccc2c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CS(=O)(=O)Cc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1

Procedure:
6-(methylsulfonylmethyl)-8-bromoquinoline and 3-nitrobenzene boronic acid can be combined to form 6-(methylsulfonylmethyl)-8-(3-nitrophenyl)quinoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([NH:10]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])O.[Na+]>C(O)C>[NH2:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[F:14]
Reactant: CC(=O)Nc1ccc(C#N)c(Cl)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(N)c(F)c1Cl
Yield: 64 %

Procedure:
A mixture of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (17.0 g) and copper(I) cyanide (5.88 g) in N,N-dimethylformamide was stirred at 150° C. overnight. After warming to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give N-(3-chloro-4-cyano-2-fluorophenyl)acetamide. Ethanol (250 ml)-concentrated hydrogen chloride (26.6 mL) was added to N-(3-chloro-4-cyano-2-fluorophenyl)acetamide, and the mixture was refluxed overnight. The mixture was ice-cooled, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column, and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield: 7.0 g, 64%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1.[Cl-].[Na+].O>[CH:22]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[O:23]
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccncc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of Example 25A (11.4 g, 64 mmol) in 200 mL THF was cooled to −78° C., treated with 1.6 M nBuLi in hexanes (100 mL, 160 mmol), warmed to 0° C., stirred for 1 hour, treated with a solution of DMF (22 g, 215 mmol) in 100 mL THF, warmed to room temperature, stirred for 1 hour, diluted with brine, and extracted three times with ethyl acetate. The combined extracts were washed with water, washed twice with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (9.1 g, 69%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1>>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:19][CH2:20][CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Product: CP(C)(=O)c1ccc(Nc2cc(NCCc3c[nH]c4ccccc34)ncn2)cc1

Procedure:
The compound is prepared as in Example 59 by reacting 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with Tryptamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10](N)=[N:9]2)=[CH:4][CH:3]=1.N(OC(C)(C)C)=O>C(#N)C.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: C1COCCO1
Product: CSc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylthio)-phenyl]pyrazol-3-amine (3 g), cupric chloride (1.6 g) and t-butyl nitrite (1.14 g) in acetonitrile (50 ml) and dioxane (20 ml) was stirred at ambient temperature for 4 hours. The insoluble was filtered, and to the filtrate were added ethyl acetate and water. The organic layer was separated, washed with dilute hydrochloric acid, dried and concentrated. The oily residue (3.8 g) was purified by column chromatography on silica gel (40 g) eluting with a mixture of toluene and ethyl acetate (10:1) to give a brown oil of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-pyrazole (1.4 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([OH:9])=[CH:6][C:7]=1[CH3:8].Cl>[N+](C)([O-])=O>[CH3:8][C:7]1[CH:2]=[CH:3][C:4]([CH3:10])=[C:5]([OH:9])[C:6]=1[C:6]1[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=[CH:2][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)c(C)cc1O
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C)c(-c2c(C)ccc(C)c2O)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a mechanically-stirred mixture of 71.4 g (0.458 mol) of 4-chloro-2,5-xylenol and 120 mL of nitromethane was added 94 g (0.59 mol) of anhydrous ferric chloride in portions over about 20 minutes with cooling to maintain the temperature below 35° C. The mixture was stirred for an additional 3 hours and then 300 mL of ice water containing 50 mL of concentrated HCl was added, followed by 300 mL of hexanes. The mixture was filtered, and the solids were washed with water and hexanes and dried in vacuo to give 51.0 g of product. The organic phase was separated from the filtrate, washed with water, and concentrated; the residue was then slurried in hexanes and filtered to give another 11 g of product. The total yield was thus 62 g (87%) of a tan solid (mp 148-155° C.). Additional purification to remove traces of iron helps facilitate the subsequent reductive dechlorination. Purification could be accomplished by dissolving in ethyl acetate, washing this solution with aqueous ethylenediamine-tetraacetic acid disodium salt (EDTA-2Na, EDTA=ethylenediaminetetraacetic acid), drying (MgSO4), concentration and washing with hexanes to afford off-white material with mp 164° C. 1H-NMR (CDCl3) δ 1.98 (s, 3H), 2.25 (s, 3H), 4.60 (s, 1H), 7.25 (s, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[C@H:7]([O:8][CH3:9])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl.CCO>>[ClH:1].[ClH:1].[CH3:9][O:8][C@@H:7]1[CH2:6][NH:5][CH2:4][C@H:3]1[NH2:2]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N
Agent: Cl
Solvent: CCO
Product: CO[C@@H]1CNC[C@H]1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (trans)-tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate hydrochloride (0.5 g, 1.939 mmol) and HCl in EtOH (15.51 mL, 19.39 mmol) was stirred at RT for 24 h. The solvent was evaporated off under reduced pressure to give the title compound.