Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)CCC>[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1ccccc1
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2ccccc2)nn1

Procedure:
A 10.0 g. portion of 5-methyl-6-phenyl-3-chloropyridazine, 10.02 g. of ethyl carbazate and 150 ml. of butyl alcohol are stirred at reflux for 4 hours. The reaction mixture is concentrated free of butyl alcohol and the concentrate is placed in cold water containing a small amount of ethyl and scratched. The resulting solid is filtered, washed with water, recrystallized from a mixture of chloroform and petroleum ether and dried in vacuo giving a white solid, mp 143°-145° C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14][C:13]=1[CH:23](O)[CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14][C:13]=1[CH:23]([Br:2])[CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Cc1ccccc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1Cc1ccccc1
Yield: 2.9 %

Procedure:
1 M PBr3 in DCM (0.105 mL, 1.105 mmol) was added to 4-benzyl-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate B14, 625 mg, 2.230 mmol) in DCM (2 ml) at RT. Reaction mixture was straightforward purified on Biotage SNAP 25 g silica cartridge with a gradient of hexane and EtOAc to give the title compound (22 mg, 2.9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (2 g, 7.8 mmol) in DCM (40 mL) was added pyridine (1.9 mL, 23.5 mmol) followed by isobutylamine (1.56 mL, 15.7 mmol) and the reaction was stirred at room temperature for 16 hours. 1M aqueous HCl was added and the reaction extracted with DCM, filtered through a phase separator and concentrated to give 4-bromo-N-isobutyl-benzenesulfonamide (1.99 g). LCMS (m/z, Method A) ES+ 294[M+1]+
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:33][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:23])=[CH:19][CH:20]=2)[N:4]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccc(F)cc3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1nc(Cc2ccc(NC(=O)OCc3ccc(F)cc3)cc2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
To a mixture of methyl {4-(dimethylamino)-2-[4-({[(4-fluorobenzyl)oxy]carbonyl}amino)benzyl]-pyrimidin-5-yl}acetate (45 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added 1N NaOH aq. (0.2 mL). The reaction mixture was stirred for 20 hours at room temperature and concentrated under reduced pressure. The residue was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. This residue was dissolved with chloroform/methanol (10:1) and the insoluble was removed by filtration. The filtrate was concentrated under reduced pressure to give {4-(dimethylamino)-2-[4-({[(4-fluorobenzyl)oxy]carbonyl}amino)benzyl]pyrimidin-5-yl}acetic acid (35 mg, 80%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)c(OC)c1-c1ccccc1C
Product: COc1ccc(-c2ccccc2)c(OC)c1-c1ccccc1C

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 3 using 1,3-dimethoxy-2-(tol-2-yl)-4-bromobenzene 2 and phenyl boronic acid to yield 34.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[N:15]=[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]4=[C:12]3[CH2:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[N:15]=[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]4=[C:12]3[CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(OCc2ccccc2)C=C2N=C3CCCCC3=C2C1
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1C=C(OCc2ccccc2)C=C2N=C3CCCCC3=C21
Yield: 92.9 %

Procedure:
Using the procedure of Example 9, 6.9 g of 1,2,3,4-tetrahydro-7-phenylmethoxy -9H-dibenzo[b,d]pyrrole from Example 57 was alkylated with 1-bromooctane (5.25 g) giving 9.0 g (92.8%) of 1,2,3,4-tetrahydro-7-phenylmethoxy-9-octyl-9H-dibenzo[b,d]pyrrole as a yellow oil after chromatographic purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Li][CH2:2]CCC.[Si:6]([O:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:9]([Si:6]([O:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)=[CH2:2])([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(Cl)c(F)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(F)c1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
n-BuLi (2.5N, 8.0 mL) was added at −78° C. to a mixture of methyltriphenylphosphonium bromide (5.6 g, 0.15 mol) in THF (50 mL). After being stirred for 0.5 hours, 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (3.9 g, 0.013 mol) was added to the reaction mixture. The mixture was then stirred for 2 hours at 25° C. After quenching with saturated NH4CL (100 mL), the reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether to give tert-butyl (2-(4-chloro-3-fluorophenyl)allyloxy)dimethylsilane (1.6 g, 40% yield).
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:20][C:21]1[CH:22]=[C:23]([CH:51]=[CH:52][CH:53]=1)[CH2:24][CH:25]([C:32]([C:34]1[O:35][C:36]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1)=O)[CH2:26][C:27]([O:29]CC)=[O:28])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.COCCOC>[Si:3]([O:20][C:21]1[CH:22]=[C:23]([CH:51]=[CH:52][CH:53]=1)[CH2:24][CH:25]1[CH2:26][C:27](=[O:28])[O:29][CH:32]1[C:34]1[O:35][C:36]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(Cc1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)C(=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)[Si](Oc1cccc(CC2CC(=O)OC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 181.8 %

Procedure:
NaBH4 (119 mg) was added to a stirred solution of ethyl 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-4- (4,5-diphenyl-2-oxazolyl)-4-oxobutyrate (430 mg) in methanol (2.0 ml) and 1,2-dimethoxyethane (0.5 ml) at room temperature and the resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate -1N hydrochloric acid. The organic layer was washed with 1N hydrochloric acid, aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-2- (4,5-diphenyl-2-oxazolyl)-5-oxotetrahydrofuran (366 mg) as an amorphous powder. NMR (CDCl3, δ): 1.08 and 1.09 (9H, each s), 1.40-1.62 (1H, m), 2.31-2.97 (2H, m), 3.48-3.88 (2H, m), 4.58 and 4.80 (1H, each m), 6.54-7.05 (2H, m), 7.32-7.73 (22H, m)
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].O.[C:18](OCC)(=[O:20])[CH3:19]>>[CH3:14][O:13][C:12]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][C:18](=[O:20])[CH3:19])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc2oc(C(C)=O)cc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2oc(C(=O)CC(C)=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Acetyl-4-methoxybenzo(b)furan (2.4 g) was dissolved in ethyl acetate (50 ml), and sodium hydride (1.5 g) was added under ice-cooling. The mixture was stirred at room temperature for 10 min, and the mixture was refluxed under heating for 1 hr. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.7 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.6 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-chlorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 42 mg (85%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ b2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.38 (d, J=6 Hz, 2H), 7.54 (t, J=6 Hz, 1H), 7.70 (d, J=6 Hz, 2H), 8.12 (d, J=5 Hz, 1H), 9.90 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+.
Reaction SMILES: [O:1]1CCNCC[O:3][B:2]1[C@@H:9]([NH:14][C:15](=[O:33])[C@@H:16]([NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:11]([CH3:13])[CH3:12].Cl>CO>[B:2]([OH:3])([OH:1])[C@@H:9]([NH:14][C:15]([C@@H:16]([NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:33])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OCCNCCO1
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A 100 ml three neck round bottom flask is equipped with a stir bar, thermocouple and nitrogen inlet/outlet then charged with 5.0 g (10.4 mmol) of (2S)—N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide (i.e., diethanolamine ester of bortezomib), 50 ml of methanol and 10.4 ml of 2N aqueous hydrochloric acid. The reaction is stirred at room temperature overnight before removing the solvent in vacuo at 40° C. The resulting residue is dissolved in 50 ml of ethyl acetate and washed with saturated sodium bicarbonate (1×50 mL) before once again concentrating the organic layer to dryness in vacuo. The residue is then triturated overnight at room temperature with 50 mL of pentane under nitrogen. The resulting free flowing solids are collected by vacuum filtration, washed with pentane (1×20 ml) then dried in a vacuum oven at 30° C. overnight to provide 3.29 g (8.56 mmol, 82.3%) of the title compound as a white solid with chemical purity >99.8 A % and a 93.5:6.5 ratio of diastereomers (i.e., 87% de). 1H NMR (d4-MeOH, 400 MHz) δ 9.15 (d, 1H, J=1.36 Hz), 8.77 (d, 1H, J=2.48 Hz), 8.68 (dd, 1H, J=1.52, 2.44 Hz), 7.27 (m, 4H), 7.21 (m, 1H), 5.05 (t, 1H, J=7.68 Hz), 3.2 (m, 2H), 2.66 (t, 1H, J=7.56 Hz), 1.39 (m, 1H), 1.17 (t, 2H, J=7.12 Hz), 0.83 (dd, 6H, J=5.32, 6.40 Hz).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1ccc([C@@H]2C[C@H]2NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and pyridine-2-carbaldehyde (0.17 mL, 1.80 mmol) in CH2Cl2 (12 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.48 g, 2.25 mmol) was slowly added and stirring continued for 2 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel [4% MeOH+1% NH3 (aq)/CH2Cl2] followed by preparative layer chromatography (5% MeOH/CH2Cl2) affording 0.08 g of N-[(trans)-2-phenylcyclopropyl]-N-(pyridin-2-ylmethyl)amine [Rf=0.3 (5% MeOH/CH2Cl2), colorless oil, 24% yield]. 1H-NMR (CDCl3, 250 MHz, δ): 8.60-8.54 (m, 1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H, ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H, CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H, CH2); 1.02-0.94 (m, 1H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.[ClH:14]>C(O)(=O)C.CO.[Pd]>[ClH:14].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=NO)CC2
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc2c1C(N)CC2
Yield: 75 %

Procedure:
7-methoxyindan-1-one oxime (2.92 g, 16 mmol) was dissolved in acetic acid (150 mL) and hydrogenated on the H-Cube: 1 mL/min flow rate, 80° C., 100 bar with 10% Pd/C. The reaction mixture was evaporated, the residue was dissolved in methanol and 1 equivalent of hydrochloric acid in methanol was added. The solvent was evaporated and the residue was triturated with diethyl ether to give 7-methoxy-1-aminoindane hydrochloride (2.38 g, 12 mmol, 75%). ESMS m/z 147 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37](Cl)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32][CH:31]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:27])([F:1])[F:28])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Fc1ccc(N=C(Cl)c2ccccc2)cc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccc(F)cc3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(4-fluorophenyl)-benzimidoyl chloride (2.5 g, 9.15%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:12][S:28]([C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C(N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-3-phenyl-propionic acid methyl ester is dissolved in 25 mL of methylene chloride and the reaction charged with triethylamine (0.97 mL, 7 mmol) and 4-chlorobenzenesulfonylchloride at 0° C. The reaction is allowed to warm to room temperature (rt) and stirred overnight. The reaction is quenched with sodium bicarbonate, extracted with methylene chloride, dried over sodium sulfate, and concentrated in vacuo. The resultant solid is triturated with 20% ethylacetate/hexanes to provide the title compound. 13C NMR (100 MHz, CDCl3) 39.5, 52.8, 57.1, 127.5, 128.8, 128.9, 129.5, 129.6, 135.1, 138.4, 139.4, 171.5. MS 354.1 m/z (M+1).
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2[NH2:42])[NH:35][N:34]=1>CN(C)C=O.C(OCC)(=O)C>[NH2:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]2[N:35]([CH:2]([C:4]3[C:5]([O:24][CH3:25])=[C:6]([CH:13]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]4)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=3)[CH3:3])[N:34]=[C:33]([CH3:32])[C:41]=12
Reactant: COc1c(C(C)Cl)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
The tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate (2.3 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (68 mL) with cesium carbonate (4.1 g, 13 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.4 g, 9.4 mmol) and was heated in an oil bath to 80° C. The reaction was stirred for 18 hrs and allowed to cool to room temperature. The reaction mixture was taken up in ethyl acetate, filtered, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by FCC on silica gel eluting a (hexane: 10% ethanol ethyl acetate) gradient to give tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate as a semisolid (1.5 g, 50%). LCMS calculated for C25H32N7O3(M+H)+: m/z=478.2; found: 478.2. The enantiomers were separated by Chiral column HPLC using: Phenomenex LUX Cellulose Column, 21.1×250 mm, 5 micron, 15% ethanol in hexane, 18 mL/min ˜5 mg/injection to give: First peak retention time: 2.1 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate; Second peak retention time: 3.9 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate.
Reaction SMILES: [CH2:1]([S:8][C:9](SCC1C=CC=CC=1)=[C:10]([C:15]#[N:16])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][NH:26][C:27](=[S:30])[NH:28][NH2:29]>C(O)C>[NH2:16][C:15]1[N:28]([C:27](=[S:30])[NH:26][CH3:25])[N:29]=[C:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CNC(=S)NN
Reactant: COC(=O)C(C#N)=C(SCc1ccccc1)SCc1ccccc1
Solvent: CCO
Product: CNC(=S)n1nc(SCc2ccccc2)c(C(=O)OC)c1N

Procedure:
45.11 g (0.127 mol) Methyl 3,3-dibenzylthio-2-cyanoacrylate and 13.35 g (0.127 mol) 4-methylthiosemicarbazide in 225 ml ethanol were heated under reflux for 10 hours. After cooling, the product was suction filtered, washed with ether and dried.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23][CH:22]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1c(C)nc2cccc(C)c2c1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(C)c2c1NCc1ccc(OC)cc1
Yield: 78.8 %

Procedure:
A solution of ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate (Example 12b, 0.518 g, 1.96 mmol) and (4-methoxyphenyl)methanamine (1.15 mL, 8.86 mmol) in toluene (10 mL) and DMF (5 mL) were stirred at 115° C. under nitrogen for 12 hrs. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel (0% to 50% EtOAc in hexanes) to give the title compound as an oil (563 mg, 79%). 1H NR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.6 Hz, 3H), 2.45 (s, 3H), 2.78 (s, 3H), 3.73 (s, 3H), 4.2-4.3 (m, 4H), 6.27 (t, J=6.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.19 (m, 3H), 7.48 (m, 1H), 7.58 (d, J=8.4 Hz, 1H). MS 365 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]2)[N:3]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(Cl)ccc2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: COc1ccc(Cl)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 90 was used, starting with (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-chloro-2-methoxy-phenyl)-methanone, Example 110, and 1-methanesulfonyl-piperidin-4-ylamine (with trifluoro-acetic acid), Example 162, to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-chloro-2-methoxy-phenyl)-methanone. MS (M+H)+, 404.