Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]3[N:19]([C:33]4[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=4)[C:36]#[N:37])[C:20](=[O:32])[N:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH:22]([CH3:23])[C:16]3=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:2].[OH-:43].[Na+].C(#N)C1C=CC=CC=1.OO>CS(C)=O.O>[CH2:41]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]3[N:19]([C:33]4[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=4)[C:36]([NH2:37])=[O:43])[C:20](=[O:32])[N:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH:22]([CH3:23])[C:16]3=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:42]
Reactant: CCN(CC)CCc1cccc(Nc2ncc3c(n2)N(c2cccc(C#N)c2)C(=O)N(c2ccc(OC)cc2)C3C)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: N#Cc1ccccc1
Product: CCN(CC)CCc1cccc(Nc2ncc3c(n2)N(c2cccc(C(N)=O)c2)C(=O)N(c2ccc(OC)cc2)C3C)c1
Reaction time: 3 h

Procedure:
(±)-3-[7-[3-(2-Diethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.35 g; 0.60 mmol) (from Example 5b supra) was dissolved in dimethyl sulfoxide (3.5 mL) and the resulting solution was cooled in an ice-water bath. Aqueous sodium hydroxide (1 M; 1.15 mL; 1.15 mmol) was added, resulting in the precipitation of the benzonitrile. Aqueous hydrogen peroxide (30%; 195 μL; 1.91 mmol) was then added. The benzonitrile slowly went back into solution. After 3 hours, water was added to the reaction mixture. The product initially separated out as a gum which then solidified. The solid was collected, washed with water and dried. Recrystallization from dichloromethane-ether gave (±)-3-[7-[3-(2-diethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide. (Yield 0.30 g; 84.8%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)[C:21](OC)=[O:22])=[O:18].Cl>CN(C)C=O.ClCCl>[CH2:1]([N:8]1[CH2:16][C:17](=[O:18])[NH:19][C@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=2)[C:21]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(C)c1)NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1C
Temperature: 35 °C
Reaction time: 3 h

Procedure:
Benzylamine (5.4 ml) and potassium carbonate (4.08 g) were added successively to a solution of methyl (2R)-2-(2-chloroacetylamino)-3-(3,4-dimethylphenyl)propionate (5.33 g) in N,N-dimethylformamide (25 ml) at 20° C. After 3 hours of stirring at 35° C., the mixture was poured into a mixture of ice-water (40 ml) and dichloromethane (40 ml). After the mixture was adjusted to pH 6 with concentrated hydrochloric acid (ca. 1.4 ml), the organic layer was separated, washed with brine (20 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with n-hexane and filtered to give colorless powders of (3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.51 g). The filtrate was evaporated under reduced pressure to give an oil of methyl (2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate (5.67 g).
Reaction SMILES: Cl.C[O:3][CH:4]1[CH:15]2[CH:11]([CH2:12][N:13]([CH2:16][CH2:17][CH3:18])[CH2:14]2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.B(Br)(Br)[Br:20]>C(Cl)Cl>[BrH:20].[OH:3][CH:4]1[CH:15]2[CH:11]([CH2:12][N:13]([CH2:16][CH2:17][CH3:18])[CH2:14]2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: CCCN1CC2c3ccccc3C(OC)C2C1
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Br
Product: CCCN1CC2c3ccccc3C(O)C2C1
Temperature: -78 °C

Procedure:
The product from Example 9 (0.490 g) was dissolved in 25 ml methylene chloride and cooled to -78° C. To the reaction was added 0.69 ml BBr3. The reaction was warmed to 0° C. for 4 h and then cooled to -78° C. The reaction was quenched by the addition of 5 ml methanol and the solvent was evaporated. The resulting solid was recrystallized from ethanol and ether to yield 0.470 g white solid, mp: 187°-9° C. NMR (d6DMSO) δ0.88 (t, 3H), 1.65 (m, 2H), 2.60-4.10 (m, 10H), 6.65 (d, 1H), 6.70 (d, 1H), 7.05 (t, 1H).
Reaction SMILES: [Cl:1][CH2:2][Si:3]([Cl:6])(Cl)[Cl:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>C1COCC1>[Cl:1][CH2:2][Si:3]([Cl:6])([Cl:4])[C:11]1[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=1
Reactant: ClC[Si](Cl)(Cl)Cl
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Fc1ccc([Si](Cl)(Cl)CCl)cc1

Procedure:
In the same apparatus as Example 1, was added 5.6 g of chloromethyltrichlorosilane (0.03 mol) and 50 ml of THF. Through the dropping funnel was firstly added 22 ml of 4-fluorophenylmagnesiumbromide (2.0 M in diethylether) to give chloromethyldichloro(4-fluorophenyl)silane.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]([Br:34])[CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2)=[O:24].[SiH](CC)(CC)CC>C(Cl)Cl>[Br:34][C:27]1[CH:28]=[C:29]2[C:33](=[C:25]([C:23]([O:22][CH3:21])=[O:24])[CH:26]=1)[NH:32][CH:31]=[C:30]2[CH2:7][CH:4]1[CH2:3][CH2:2][S:1][CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=CC1CCSCC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(CC3CCSCC3)c[nH]c12
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of tetrahydro-thiopyran-4-carbaldehyde (1.3 g, 9.84 mmol) in DCM (20 mL) was added TMSOTf (3.5 mL, 19.7 mmol) at 0° C. To this mixture 5-Bromo-1H-indole-7-carboxylic acid methyl ester (2.5 g, 9.84 mmol) was added. After 2 hours, Et3SiH (6.2 mL, 39.4 mmol) was added at 0° C., and stirring continued for 18 hours. The reaction mixture was quenched with sodium bicarbone solution and extracted with DCM. The combined organic layers were dried (MgSO4), concentrated, and purified by column chromatography on silica gel, giving 1.6 g (44%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:21]=[C:20]([OH:22])[C:19]4[C:14](=[C:15]([CH3:25])[C:16]([O:23][CH3:24])=[CH:17][CH:18]=4)[N:13]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C1CC(O)CC1C(=O)NC1(C(OCC)=O)CC1C=C)=O)(C)(C)C.[CH2:52]([O:54][C:55]([C:57]12[CH2:74][CH:73]1[CH:72]=[CH:71][CH2:70][CH2:69][CH2:68][CH2:67][N:66]([CH3:75])[C:65](=[O:76])[CH:64]1[CH:60]([CH2:61][CH:62](OC3C4C(=C(C)C(OC)=CC=4)N=C(C4C=CC=C(C)N=4)C=3)[CH2:63]1)[C:59](=[O:98])[NH:58]2)=[O:56])[CH3:53]>>[CH2:52]([O:54][C:55]([C:57]12[CH2:74][CH:73]1[CH:72]=[CH:71][CH2:70][CH2:69][CH2:68][CH2:67][N:66]([CH3:75])[C:65](=[O:76])[CH:64]1[CH:60]([CH2:61][CH:62]([O:22][C:20]3[C:19]4[C:14](=[C:15]([CH3:25])[C:16]([O:23][CH3:24])=[CH:17][CH:18]=4)[N:13]=[C:12]([C:10]4[N:11]=[C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[S:8][CH:9]=4)[CH:21]=3)[CH2:63]1)[C:59](=[O:98])[NH:58]2)=[O:56])[CH3:53]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4cccc(C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Reactant: COc1ccc2c(O)cc(-c3csc(C4CCCCC4)n3)nc2c1C
Agent: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)OC(C)(C)C)C(=O)OCC
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(C5CCCCC5)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Yield: 50 %

Procedure:
The title compound 121 was prepared in 50% yield from 2-(2-cyclohexylthiazol-4-yl)-4-hydroxy-7-methoxy-8-methylquinoline (119) and 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid tert-butyl ester following the procedure reported for the preparation of 17-[2-(6-methylpyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]-octadec-7-ene-4-carboxylic acid ethyl ester (101): m/z=715 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[CH2:9][CH2:8]2)[C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=2[NH:3]1.CO.[H][H]>[Ni].O1CCCC1>[OH2:1].[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5]3[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=3[NH:3][C:2]2=[O:1])[CH2:8][CH2:9]1)=[O:26].[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5]3[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=3[NH:3][C:2]2=[O:1])[CH2:8][CH2:9]1)=[O:26]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Product: O

Procedure:
A mixture of 4.5 parts of N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-nitrobenzamide, 80 parts of methanol and 45 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized twice from 2-propanol. The product is filtered off and dried, yielding 2 parts of 2-amino-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}benzamide hemihydrate; mp. 219.2° C.
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8].[C:33](=[O:36])([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:30][C:27]([F:29])([F:28])[C:25]1[CH:24]=[C:6]([CH:5]=[C:4]([C:3]([F:2])([F:31])[F:32])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:4][C:5]#[C:6][CH2:7][N:9]2[CH2:14][CH2:33][O:36][CH2:11][CH2:10]2)[CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCN2CCOCC2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Reaction time: 17 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (150 mg) and 1-(4-chloro-2-butynyl)morpholine hydrochloride (63 mg) in N,N-dimethylformamide (0.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (160 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine dihydrochloride (155 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:17][CH2:18][N:19]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:21]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(Cc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (40 mg, 0.14 mmol)) in CH2Cl2 (1.6 mL) and THF (1.6 mL) at 25° C. is added benzaldehyde (23 mg, 0.21 mmol), acetic acid (2 drops) and sodium triacetoxyborohydride (90 mg, 0.43 mmol). After being stirred at 25° C. for 2 h, the mixture is diluted with CH2Cl2 (10 mL) and washed with saturated sodium bicarbonate (2 mL) and water (5 mL). The organic layer is concentrated and purified by HPLC (CH3CN/H2O: 22% 45% with 0.1% TFA) to give 3-benzyl-6-(4-benzyl-piperazin-1-yl)-4,5-dimethyl-pyridazine (20 mg, 37%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12]([NH:14][C@H:15](C(=O)NC)C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1[C@@H](NC(=O)[C@H:53]([N:58]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:69]4[CH:74]=CC=CN=4)=[CH:65][CH:64]=3)=[CH:59]2)CC(O)=O)CC2=CN(C3C2=CC=CC=3)CCOCCN1.CN.[CH3:79]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:74][C:69]([C:66]2[CH:65]=[CH:64][C:63]([C:60]3[CH:59]=[CH:53][N:58]=[CH:62][CH:61]=3)=[CH:68][CH:67]=2)=[CH:79]1)[C:12]([NH:14][CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccc(-c3ccccn3)cc2)c1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Product: CNC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 51 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinic 4-benzyl ester hydrochloride (prepared as described in Example 7(a)) and excess 40% aqueousueous methylamine were coupled with TBTU. The solid that precipitated from the reaction mixture was washed with water and, after drying, with ethyl acetate to give 51% of N-methyl-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a yellow solid: 1HNMR (DMSO-d6): δ—8.58 (d, 2H, J=4.4 Hz), 7.84 (br s, 1H), 7.76-7.70 (m, 4H), 7.60 (d, 2H, J=8.5 Hz), 7.29-7.25 (m, 6H), 6.76 (s, 1H), 6.40 (s, 1H), 5.03 (s, 2H), 4.67 (t, 1H, J=6.2 Hz), 3.20 (dd, 1H, J=15.8, 6.2 Hz), 2.86 (dd, 1H, J=16.0, 8.6 Hz), 2.32 (s, 3H); Anal. Calculated for C27H25N3O3.1.3H2O: C, 70.05; H, 6.01; N, 9.08. Found: C, 69.98, 69.97; H, 5.98, 6.00; N, 9.01, 9.00.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[O:36]1[CH2:39][CH:38]([CH:40]=O)[CH2:37]1.N1CCCC[CH2:43]1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:43][C:38]3([CH3:40])[CH2:39][O:36][CH2:37]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: O=CC1COC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: C1CCNCC1
Solvent: CCO
Product: CC1(C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)COC1
Reaction time: 3 h

Procedure:
To a slurry of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (74.mg, 0.16 mmol) in ethanol (3 mL) was added 3-methy)oxetane-3-carbaldehyde (78.54 mg, 0.78 mmol) and then piperidine (0.02 mL, 0.16 mmol) and the mixture heated to 80° C. with stirring. After 3 h, the mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and the filtered. Solvents were removed to afford an oil which was purified by column chromatography (gradient from neat methylene chloride to 95-5 methylene chloride:MeOH). The pure fractions were concentrated, then taken up in acetonitrile/water, frozen and lyophilized to afford 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-3-(3-methyloxetan-3-yl)prop-2-enenitrile as a colorless solid weighing 14 mg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][N:15]([C:17]([NH2:19])=[S:18])[NH2:16].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:5]1([N:19]=[C:17]2[N:15]([CH3:14])[N:16]=[C:9]([C:8]3[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[S:18]2)[CH2:13][CH2:12][CH2:8][CH2:7][CH2:6]1
Reactant: CN(N)C(N)=S
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(S(C)(=O)=O)cc2)sc1=NC1CCCCC1
Temperature: 95 °C
Yield: 52.3 %

Procedure:
To a mixture of 4-methylsulfonyl-benzoic acid (2.5 mmol, 500 mg), 2-methylthiosemicarbazide (5a) (2.5 mmol, 468 mg) in anhydrous dioxane (5 mL) at 65° C., POCl3 (3 mmol, 280 μL) was added, and the mixture was warmed at 95° C. for 5 hours. The solvent was removed by distillation under reduced pressure to give a crude material which was basified at pH 8-7 with a saturated solution of NaHCO3. The aqueous phase was extracted with dichloromethane. The organic layer was washed with saturated solution of NaCl, dried over magnesium sulfate, filtered, and distilled to give a residue which was purified by silica gel chromatography (eluted with a gradient of cyclohexane/ethyl acetate finishing with the ratio 80:20) to afford 230 mg of the title compound. Yield: 26%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1C(OC)=O.[CH3:12][Mg]I.C([O:17][CH2:18][CH3:19])C>[Cl-].[NH4+]>[CH3:12][C:18]([OH:17])([CH3:19])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccccc1N
Reactant: CCOCC
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)c1ccccc1N

Procedure:
A 30.2-g (0.2 mol) sample of methyl 2-aminobenzoate in 150 ml diethyl ether was added dropwise to a solution of methyl magnesium iodide (prepared from 19.4 g of Mg and 127.8 g of methyl iodide) in 150 ml diethyl ether. The reaction mixture was then heated under reflux for 1 hour, cooled, and diluted with 200 ml of saturated aqueous ammonium chloride solution. The resulting aqueous mixture was extracted with ether. The ether extracts were dried over magnesium sulfate and evaporated to give 19.1 g of α,α-dimethyl-2-aminobenzyl alcohol.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(Cl)c(OCCc2ccc(OC)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCOc2cc(C(=O)O)ccc2Cl)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
1.27 g (3.96 mmol) of 4-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 2 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH2:3]1.Cl[CH2:34][C:35]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][N:36]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:34][C:35]1[N:39]=[C:38]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:37][N:36]=1
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: ClCc1noc(-c2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2noc(-c3ccccc3)n2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.08 h
Yield: 42.1 %

Procedure:
To a stirring solution of 200 mg (0.47 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide in 4 mL DMF at 0° C. is added dropwise 0.98 mL (0.49 mmol, 1.05 equiv) of a 0.5N solution of KN(TMS)2 in toluene. The resulting solution is stirred 5 min, then 100 mg (0.51 mmol, 1.1 equiv) of 3-chloromethyl-5-phenyl-[1,2,4]oxadiazole is added. The reaction mixture is stirred 30 min at 0° C. then 14 h at RT. The reaction mixture is quenched with 1 mL of H2O and the solvent removed in vacuo. The residue is dissolved in 40 mL EtOAc, washed with 40 mL H2O, and the organic layer is dried (MgSO4) and the solvent removed in vacuo. The resulting oil is purified by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O with 0.1% TFA as eluent followed by lyophilization to afford 116 mg of 2-[2,4-Dioxo-5-phenyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylmethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.07 (d, 2H, J=6.9), 7.59-7.13 (m, 16H), 7.00 (dd, 1H, J=1.3, 8.1), 5.01 (m, 1H), 4.27 (s, br, 2H), 4.1 (t, 1H, J=6.1), 3.66 (dd, 1H, J=7.8, 17.1), 3.50 (dd, 1H, J=6.1, 17.1) 1.08 (t, 6H, J=6.9); low resolution MS (FAB) m/e 586 (MH+), 451, 277, 227, 195.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:10]([CH3:12])[CH3:11])[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].CN1CCOCC1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:20][CH2:21][C:22]([NH:2][CH:3]([CH:10]([CH3:12])[CH3:11])[CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CC(C)C(N)C(O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)CCl)C(O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 3-amino-1,1,1-trifluoro-4-methyl-2-pentanol hydrochloride (20 g) in distilled tetrahydrofuran (480 mL) under nitrogen was added 4-methylmorpholine (21.8 mL) resulting in a white precipitate. A solution of chloroacetyl chloride (7.7 mL) in distilled tetrahydrofuran (40 mL) was added dropwise over 1 hour, and the mixture was stirred overnight. The mixture was diluted with ethyl acetate and filtered to remove undissolved solids. The filtrate was washed with 10% hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. The solid that had been filtered was dissolved in water, the aqueous phase was extracted with ethyl acetate (twice), and the extracts were washed as the first extract had been. The organic phases were combined, dried, and evaporated to give 2-chloro-N-(3,3,3-trifluoro-2-hydroxy-1-isopropyl-propyl)acetamide as an oil (23.8 g); TLC: Rf =0.70, dichloromethane:methanol (95:5); MS: m/z=248(M+1 for 35Cl).