Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.Cl.COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CNC1)CC2=O>C(Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CNC1)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCNC1)O2
Yield: 94.6 %

Procedure:
(±)-(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (1.90 g, 4.72 mmol) in DCM (33 ml) was treated with 4 M HCl in dioxane (5.90 ml) as described for Intermediate 4, Step C, giving (±)-(E)-3-{3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (1.35 g, hydrochloride salt) as a light brown solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: CSc1nc(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with phenyl chloroformate (324 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[CH:12][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:39]([OH:42])[C:40]#[CH:41]>[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.C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[CH:12][CH:11]=2)[C:2]([C:41]#[C:40][CH2:39][OH:42])=[CH:7][N:6]=1
Reactant: C#CCO
Reactant: CC(C)(C#N)c1ccc(Nc2nc(Cl)ncc2Br)cc1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Nc2nc(Cl)ncc2C#CCO)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2-(4-(5-bromo-2-chloropyrimidin-4-ylamino)phenyl)-2-methylpropanenitrile (1.4 gm, 3.98 mmol), bis(triphenylphosphine) palladium(II) chloride (0.14 gm, 0.2 mmol), tetrabutyl ammonium fluoride (2.6 gm, 9.95 mmol) and propargyl alcohol (0.357 mL, 5.97 mmol) were combined into 12 mL THF in a screw cap high pressure vessel and heated in a 70° C. oil bath. After 2 hr the reaction appeared complete by LC/MS. Volatiles were removed and the residue taken up into EtOAc. Organic layer was filtered to remove insoluble soot. Organic layer was washed with water, brine and then dried over sodium sulfate. Volatiles were removed and the residue purified by NPLC (10-75% EtOAc in Heptane, Analogix). (869 mg, 67%). MS m/z 327.4 (M+H)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:67][N:68]([CH3:73])[CH2:69][CH2:70][CH2:71][NH2:72]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:72][CH2:71][CH2:70][CH2:69][N:68]([CH3:73])[CH3:67])=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCCCN(C)C)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a mixture of (0.05 g, 0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 mL (0.32 mmole) of 3-(dimethylamino)-propylamine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-20:80) to give 0.037 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-2-fluoro-5-methoxy-benzamide (I-172).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(=O)n(CCO)c2ccccc12
Product: O=c1[nH]c(=O)n(CCCl)c2ccccc12
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 3.6 parts of 1-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione and 40 parts of thionyl chloride is stirred and refluxed overnight. The reaction mixture is allowed to cool to room temperature. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 3.4 parts (86%) of 1-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione; mp. 215.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.[Cl-].[NH4+]>[Zn].O>[NH2:12][C:10]1[C:9]([CH3:15])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:1])[CH:11]=1
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C)c(N)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred solution of methyl 2,5-dimethyl-4-nitrobenzoate (523 mg, 2.5 mmol) in a 9:1 mixture of methanol and water (25 mL total) at 0° C. was added ammonium chloride (401 mg, 7.5 mmol). Zinc (1.63 g, 25 mmol) was added portionwise and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide methyl 4-amino-2,5-dimethylbenzoate (450 mg) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.14 (s, 3H), 2.53 (s, 3H), 3.83 (s, 3H), 3.85 (br s, 2H), 6.48 (s, 1H), 7.72 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[C:5]([CH3:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cnc(F)cc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cnc(F)cc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-fluoro-4-iodo-5-methylpyridine (1.9 g), 4-chlorophenylboronic acid (1.504 g), tetrakis(triphenylphosphine)palladium(O) (0.463 g), and sodium carbonate (2.55 g) in ethanol (20 mL), water (10 mL) and toluene (10 mL) was heated under reflux for 6 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layers were extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel using 5% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.IC>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:13])[N:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c([N+](=O)[O-])cnn1C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 110 mg (30%) of the title compound and 195 mg (53%) of the compound of Preparative Example 7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][C@@H:9]1[C@@H:22]([OH:36])[C@@H:23]([N+:33]([O-])=O)[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][C@@H:9]1[C@@H:22]([OH:36])[C@@H:23]([NH2:33])[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(O[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)[N+](=O)[O-])N(C(=O)OC(C)(C)C)C2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(O[C@@H]2C[C@H]([C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)c1
Yield: 94.4 %

Procedure:
Add to a solution of (2R,4R)-2-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-4-(3-methoxy-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (276 mg, 0.54 mmol) in methanol (9 mL) nickel (II) chloride followed by sodium borohydride (0.082 g, 2.17 mmol). Stir reaction for 15 min, add water (1 mL) and concentrate. Partition with ethyl acetate and water and filter through a filtering agent. Rinse cake with ethyl acetate. Separate layers, dry (magnesium sulfate) and concentrate to give the title compound as a white solid (0.244 g, 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[Li]C(C)(C)C.CN([CH:24]=[O:25])C>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:24]=[O:25])=[C:3]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-(2-bromo-5-fluorophenyl)pivalamide(2.4 g, 8.75 mmol)) was dissolved in THF (30 mL) at room temperature, and the colorless solution was cooled to −78° C., followed by fast dropwise addition of t-BuLi (10.3 mL, 1.7M in heptane, 17.4 mmol) under N2 over 10 min. The resulting yellow solution was continued stirring at −78° C. for 1 hr, followed by dropwise addition of DMF (2.7 mL, 35.0 mmol) over 5 min. The light yellow solution was stirred for additional 30 min at −78° C. Thus the mixture was quenched with saturated NH4Cl (30 mL), extracted with Et2O (2×150 mL). The combined organic phase was washed with brine (30 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜50% EtOAc/hexanes (1400 mL) to afford an expected product, as a white solids (1.03 g, 53% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (s, 9 H), 6.80-6.86 (m, 1 H), 7.63 (dd, J=8.56, 6.04 Hz, 1 H), 8.53 (dd, J=12.21, 2.39 Hz, 1 H), 9.83 (s, 1 H), 11.54 (s, 1 H); Mass spec. 224.16(MH+), Calc. for C12H14FNO2 223.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([CH2:27][CH2:28][NH:29]C(=O)OC)[CH:4]=[N:3]1.[ClH:34]>>[ClH:34].[ClH:34].[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[CH2:27][CH2:28][NH2:29]
Reactant: COC(=O)NCCc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: Cn1ncc(CCN)c1N

Procedure:
A mixture of methyl N-[2-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)ethyl]carbamate (15.3 g, 34.7 mmol) and concentrated hydrochloric acid (80 ml) was stirred under reflux for 13 hours. The reaction mixture was washed with ethyl acetate. The organic layer was separated, and the aqueous layer was concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 2-(5-amino-1-methylpyrazol-4-yl)ethylamine dihydrochloride (6.1 g) as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:29][CH3:30])=[CH:20][C:21]([CH:27]=O)=[C:22]([C:23]([F:26])([F:25])[F:24])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:27]([C:21]1[CH:20]=[C:19]([O:29][CH3:30])[C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=3)=[N:11][C:12]=2[C:22]=1[C:23]([F:25])([F:24])[F:26])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(C=O)cc(OC)c21
Reactant: Br[Mg]c1ccccc1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(Cc3ccccc3)cc(OC)c21

Procedure:
The title compound is prepared from 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole-5-carbaldehyde and phenylmagnesiumbromide as described in examples 35 and 51.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:18]=[C:13]3[C:12]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].C(Cl)Cl>CCO>[N:19]1([C:17]2[CH:18]=[C:13]3[C:12]([C:25]4[CH:29]=[N:28][NH:27][CH:26]=4)=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(N3CCOCC3)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: c1n[nH]cc1-c1c[nH]c2ncc(N3CCOCC3)cc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 57 (0.031 g, 0.076 mmol) and 10% aqueous NaOH solution (1 mL) in EtOH (2 mL) was stirred at 90° C. for 1 hour. The mixture was cooled and evaporated to afford a tan syrup. The syrup was dissolved with CH2Cl2 and the solution was washed with brine. The aqueous layer was extracted twice with CH2Cl2. The combined extracts were dried (MgSO4) and concentrated to afford a syrup, which was purified by means of preparative TLC with CH2Cl2:MeOH as eluent to afford 58 (0.016 g, 78%) as a pale brown solid. 1H NMR (400 MHz, CD3OD) δ 3.13-3.17 (m, 4H), 3.85-3.89 (m, 4H), 7.51 (s, 1H), 7.74 (d, J=0.26 Hz, 1H), 7.93 (bs, 2H), 8.06 (d, J=0.26 Hz, 1H).
Reaction SMILES: BrCC(Br)=O.[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[C:8]=1[NH2:9].[Br:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Br:19][CH2:20][CH2:21][C:22]([NH:9][C:8]1[C:10]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:23]
Reactant: O=C(Cl)CCBr
Reactant: CCCC(=O)c1cccc(C)c1N
Agent: O=C(Br)CBr
Product: CCCC(=O)c1cccc(C)c1NC(=O)CCBr

Procedure:
In the same manner as in Example 1 but replacing 2-acetyl-6-methylaniline and bromoacetyl bromide by 2-methyl-6-n-butanoylaniline and 3-bromopropionyl chloride, there was obtained 3-bromo-2'-methyl-6'-n-butanoylpropionanilide. [B] Amination
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=[N:43][CH2:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48].Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C)CCCN>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:43][CH2:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCCN(C)C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added N,N-dimethyl-propane-1,3-diamine (19 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10](N)[CH2:11][NH2:12].[S].[Mn]([O-])(=O)(=O)=O.[K+].[Si](=O)=O>C(O)C.C(#N)C.O.C1(C)C=CC=CC=1>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: Cc1ncccc1C#N
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=[Si]=O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1ncccc1-c1ncc[nH]1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
2-Methyl-3-pyridinecarbonitrile 1.05 g, ethylenediamine 5 mL and sulfur 71 mg were mixed, and stirred at 120° C. for 24 hours. Cooling it off to room temperature, toluene and water were added to effect phase separation. The aqueous layer was dried to solid under reduced pressure. Thus obtained crude product was mixed with potassium permanganate/silicon dioxide (carried at a ratio of 2.81 g:3.57 g) 6.38 g and acetonitrile 10 mL at room temperature, and stirred (inducing a rapid exothermic reaction). After the exotherm subsided and the reaction liquid was restored to room temperature, the liquid was diluted with 20 mL of ethanol and filtered through Celite. The solvent was distilled off and the residue was recrystallized from ethyl acetate/methanol (10:1) to provide 1.03 g of the title compound.
Reaction SMILES: [CH2:1]1[O:20][C:19]2[C:3](=[CH:4][C:5]([NH:21]C(=O)C(F)(F)F)=[C:6]([CH:18]=2)[C:7]([C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)=[O:8])[O:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:21][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:20][C:19]2=[CH:18][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:8]
Reactant: O=C(c1ccc2c(c1)OCO2)c1cc2c(cc1NC(=O)C(F)(F)F)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cc2c(cc1C(=O)c1ccc3c(c1)OCO3)OCO2
Reaction time: 5 h
Yield: 74.8 %

Procedure:
A solution of 4,5-methylenedioxy-2-trifluoroacetamido-(3′,4′-methylenedioxy)benzophenone (5 g, 13.12 mmol) in methanol at 50° C. was treated with a solution of potassium carbonate (3.63 g, in 30 mL water) and stirred for 5 h. The reaction mixture was cooled in an ice bath for 20 min. The resulting solid was filtered and then dissolved in ethyl acetate, dried over anhydrous MgSO4, and concentrated to give a crude yellow product (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[CH3:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[N:36][C:37]=2[NH2:39])[NH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O.CCOCC>[NH2:39][C:37]1[N:36]=[CH:35][N:34]=[C:33]2[N:32]([CH:8]([C:6]3[C:5]([O:11][CH2:12][CH3:13])=[C:4]([CH:14]4[CH2:15][N:16]([C:18]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])[CH2:17]4)[C:3]([CH3:28])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:31]=[C:30]([CH3:29])[C:38]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 140 °C
Yield: 50.5 %

Procedure:
A mixture of benzyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate (0.375 g, 0.888 mmol, from Example 35, Step 3), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.16 g, 1.1 mmol), cesium carbonate (0.43 g, 1.3 mmol) and potassium iodide (15 mg, 0.089 mmol) in N,N-dimethylformamide (2.8 mL) was heated at 140° C. for 1 h. The mixture was diluted with ether, and washed with water. The organic layers were concentrated and purified on silica gel (eluting with 0 to 100% EtOAc in hexanes) to give the desired product (0.24 g, 50%). LCMS calculated for C28H32ClN6O3 (M+H)+: m/z=535.2; Found: 535.0. The enantiomers were separated on a Phenomenex Lux Cellulose C-2 column (5 μM, 21.2×250 mm), eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, and column loading of ˜4.5 mg/injection to separate two enantiomers. First peak retention time: 21.2 min; second peak retention time: 24.6 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH3:2]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCC(CC)Oc1ccccc1Br

Procedure:
Bromo-(4-hexyloxy)-benzene was prepared by alkylation of 4-bromophenol (91.2 g, 527 mmol) with bromohexane (86.0 g, 520 mmol), K2CO3 (80.0 g, 580 mmol) in acetone (200 mL) at reflux for 12 hours. After removal of the salts by filtration, the reaction mixture was concentrated to dryness to give an oil. The oil was dissolved in EtOAc (100 mL) and transferred to a separatory funnel and washed with 5% NaOH (4×200 mL). An additional 200 mL volume of EtOAc was added to the separatory funnel and the contents were washed with NaHCO3 (1×200 mL) and finally dried over MgSO4. Removal of the EtOAc solvents afforded a light yellow oil and was used without further purification. Yield: 119 g, 89%. 1H NMR (500 MHz, CD2Cl2, 25° C.) δ 0.91 (t, 3H), 1.34 (m, 4H), 1.45 (m, 2H), 1.76 (m, 2H), 3.92 (t, 2H), 6.79 (d, 2H), 7.36 (d, 2H).