Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:13]2=[N:14][C:15](S(C)=O)=[N:16][CH:17]=[C:12]2[CH2:11][NH:10][C:9]1=[O:21].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:13]2=[N:14][C:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[CH:27][CH:28]=3)=[N:16][CH:17]=[C:12]2[CH2:11][NH:10][C:9]1=[O:21]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2c(n1)N(C1CC3CCC1C3)C(=O)NC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C3CC5CCC3C5)C(=O)NC4)cc2)CC1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
To a suspension of 300 mg (0.98 mmol) of 1-bicyclo[2.2.1]hept-2-yl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 374 mg (1.96 mmol) of 1-(4-aminophenyl)-4-methylpiperazine in 4.0 mL of acetonitrile is added 377 μL (4.90 mmol) of trifluoroacetic acid. The mixture is heated at 85° C. overnight. The cooled reaction mixture is diluted with ethyl acetate and washed two times with saturated aqueous sodium bicarbonate solution and once with brine. The organic phase is dried over magnesium sulfate and concentrated. The dark solid residue is triturated in 4 mL of 1:1 dichloromethane/ethyl acetate, filtered, washed with ethyl acetate, and dried to give 266 mg (63%) of the title compound: mp 251-254° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:31])[CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:18])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[BH4-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([OH:31])[CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[OH:18])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.1 %

Procedure:
1-(3,4-Dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione (4.65 g, 10.74 mmole) was dissolved in 40 mL THF and the solution was diluted with 75 mL of methanol. To this solution sodium borohydride (0.73 g, 19.33 mmole) in 20 mL of water was added dropwise. The solution was stirred at room temperature for 2.5 hours, and the reaction mixture cooled, quenched with water, and the aqueous layer extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to provide 4.61 g of product (98.3%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[F:31][C:32]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:33]=1[C:34](O)=[O:35].CCN=C=NCCCN(C)C>ClC(Cl)C.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:34](=[O:35])[C:33]2[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:32]=2[F:31])[CH:25]=1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cc(C)ccc3F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To the mixture of methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate, (85.6 mg, 0.2 mmol, 1 eq) and 2-fluoro-5-methylbenzoic acid (32.7 mg, 1.05 eq) in dichloroethane (2 mL) at 60° C. was added catalytic amount of DMAP (5 mg, 0.2 eq) and EDCI (46.1 mg, 1.2 eq). The reaction was stirred at that temperature for 4 h and then cooled to room temperature. It was then partitioned between EtOAc and saturated aq NaHCO3. The organic layer was further washed with aq NH4Cl, brine and then dried with anhydrous sodium sulfate. The organic layer was decanted, concentrated, and the residue was subject to a gradient column chromatography (EtOAc-Hex 1:4 to neat EtOAc). The product containing fractions were concentrated to give the title compound as a white foam (92 mg).
Reaction SMILES: Cl[C:2]1C=CC(S(N2[C@@H](C)CC(=O)C[C@@H]2C)(=O)=O)=CC=1.CN(C(OC)OC)C.O.NN.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]2[CH2:46][CH2:45]C(=O)[CH2:43][CH:42]2[C:48]2[CH:49]=[N:50]C=[N:52][CH:53]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([N:41]2[C@@H:46]([CH3:45])[CH2:2][C:53]3[NH:52][N:50]=[CH:49][C:48]=3[C@@H:42]2[CH3:43])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: C[C@H]1CC(=O)C[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(Cl)cc2)C(c2cncnc2)C1
Agent: COC(OC)N(C)C
Agent: NN
Solvent: O
Product: C[C@H]1Cc2[nH]ncc2[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
trans-1-(4-Chlorophenylsulfonyl)-2,6-dimethylpiperidin-4-one (94) was treated with DMF-DMA followed by hydrazine hydrate as described for compound 71 in Example 4. 1H-NMR (CD3OD) δ 7.81-7.79 (m, 2H), 7.62 (m, 3H), 5.38 (q, J=7.1 Hz, 1H), 4.20-4.13, (m, 1H), 2.78 (dd, J=16.2, 4.4 Hz, 1H), 2.56-2.48 (m, 1H), 1.54-1.47 (m, 6H); MS (m/z) 326.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[C:26]([O:32][CH3:33])=[N:27][CH:28]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ncc(Cl)cc1Br
Product: COc1ncc(Cl)cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 25 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromo-5-chloro-2-methoxypyridine, the title compound was formed in 25% yield as a white solid, mp 195-200 C, (dec). free base: 1H NMR (CDCl3, 250 MHz) 7.99 (d, J=2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.20 (m, 4H), 6.93 (m, 4H), 4.27 (s, 1H), 3.99 (s, 3H), 3.58 (s, 1H), 3.47 (s, 2H), 2.82 (m, 4H), 2.60 (d, J=0.8 Hz, 2H), 2.00 (m, 4H) MS (CI, CH4) m/z 447 (M+1,100), 475 (M+29,18), 429 (34), 449 (36) hydrochloride salt:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([CH:11]=O)=[N:2]1.OS([O-])=O.[Na+].[CH3:18][C:19]1[C:20]([NH2:36])=[C:21]([NH2:35])[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[CH:24]=1>CCO>[CH3:18][C:19]1[C:20]2[NH:36][C:11]([C:3]3[CH2:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1][N:2]=3)=[N:35][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:33])[F:34])[CH:24]=1
Reactant: O=CC1=NOC2(CCCCC2)C1
Reactant: Cc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(-c2ccccc2C(F)(F)F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (135 mg, 0.807 mmol, as prepared in Example 19, step B) was placed in a 4 mL vial equipped with a magnetic stir bar. 40% Aqueous NaHSO3 (0.8 mL) was added via syringe, and the mixture stirred at rt for 2 h. 5-Methyl-2′-trifluoromethyl-biphenyl-3,4-diamine (246 mg, 0.923 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar. EtOH (2 mL) was added. The 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde solution was added to the 5-methyl-2′-trifluoromethyl-biphenyl-3,4-diamine solution. The flask which had contained the 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde solution was rinsed with EtOH (0.5 mL) and water (0.25 mL), and this was also added to the 5-methyl-2′-trifluoromethyl-biphenyl-3,4-diamine solution. The mixture was heated to 90° C. for 2 h. The mixture was poured into water, and the precipitate was isolated by filtration. The solid was washed with water, dissolved in EtOAc, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/heptane, 0:1 to 3:7, v/v over 30 min, yielding 136 mg (41%) of the title compound. 1H-NMR (400 MHz, d4-MeOH) δ: 7.76 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.26-7.49 (m, 2H), 7.03 (br. s., 1H), 2.63 (br. s., 3H), 1.69-1.88 (m, 6H), 1.45-1.63 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]>O1CCOCC1.O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Yield: 73 %

Procedure:
A solution of 25.5 g of (2-chloro-4,5-difluorobenzoyl)propanedioic acid, diethyl ester in 500 ml of p-dioxane and 2.74 ml of water was refluxed for 3 hours, then evaporated to dryness and distilled on a Kugelrohr, giving 14.6 g of the desired compound as a bright yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)[O:31][C:32](Cl)(Cl)Cl.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([C:30]([O:31][CH3:32])=[O:29])[N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Clc1ccc(-c2c(-c3ccccc3)cn3c2CCC3)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2n1CCC2
Reaction time: 12 h
Yield: 178.1 %

Procedure:
7-(4-Chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (Example 21 b, 4.0 g, 13.6 mmol), dissolved in THF (25 ml) is treated with triethylamine (2.0 ml, 1.5 g, 15 mmol). A solution of diphosgene (1.5 g, 7.5 mmol), dissolved in THF (15 ml), is added dropwise to this solution at RT, and it is stirred for 12 h. Methanol (abs., 8.0 ml, 6.3 g, 200 mmol) and triethylamine (2.0 ml, 1.5 g, 15 mmol) are then added, and the mixture is stirred at RT for a further 48 h. The reaction mixture is concentrated in vacuo, ammonium salts are taken up in water (10 ml), and the residue which remains is filtered off with suction and dried. 4.7 g (98.3%) of crude product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][CH2:12][CH2:13][O:14][CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: Cc1ccc(Br)c(O)c1
Reactant: COCCCCl
Product: COCCCOc1cc(C)ccc1Br

Procedure:
Analogously to Method F, 10.0 g of 2-bromo-5-methylphenol and 11.6 g of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly orange oil. Rf=0.31 (1:4 EtOAc-heptane); Rt=5.01.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH2:9][NH:10][C:11]([C:13]2[NH:22][C:16]3=[CH:17][N:18]=[C:19]([Cl:21])[CH:20]=[C:15]3[CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[BH4-]>C(O)C>[CH3:2][CH2:3][CH2:4][CH:5]([CH3:8])[CH3:6].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][NH:10][C:11]([C:13]2[NH:22][C:16]3=[CH:17][N:18]=[C:19]([Cl:21])[CH:20]=[C:15]3[CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1ccc(F)cc1
Agent: [BH4-]
Solvent: CCO
Product: CCCC(C)C
Product: O=C(NCC(O)c1ccc(F)cc1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred suspension of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(4-fluorophenyl)-2-oxoethyl]amide EXAMPLE 48 (0.05 g, 151 mmol) in ethanol (5 mL, absolute) was added polymer-supported borohydride (2.5 mmol/g, 0.09 g, 226 mmol) and the mixture sonicated with gentle warming until the ketone had dissolved. The reaction mixture was stirred for 2 days at rt then filtered, washing with methanol. The filtrate was evaporated to dryness in vacuo to give a colourless oil. Purification via flash column chromatography (SiO2, ethyl acetate:isohexane, 1:1, v/v) gave the title compound as a white solid. m/z (ES+)=334 [M+H]+; RT=2.93 min.
Reaction SMILES: [Br-].[CH:2]([C:5]1[C:18]2[NH2+:17][C:16]3[C:11](=[CH:12][C:13]([Br:19])=[CH:14][CH:15]=3)[S:10][C:9]=2[CH:8]=[C:7](Br)[CH:6]=1)([CH3:4])[CH3:3].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(Cl)(Cl)Cl>[Br-:19].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:7]2[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[C:18]3[C:9]([CH:8]=2)=[S+:10][C:11]2[C:16](=[CH:15][CH:14]=[C:13]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[CH:12]=2)[N:17]=3)[CH2:24][CH2:23]1
Reactant: CC(C)c1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Reactant: CN1CCNCC1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(N2CCN(C)CC2)cc2[s+]c3cc(N4CCN(C)CC4)ccc3nc12
Reaction time: 3 h

Procedure:
To a solution of 1-i-propyl-3,7-dibromophenothiazinium bromide (200 mg, 0.42 mmol) in chloroform (10 mL) kept under argon, 1-methylpiperazine (290 mg, 2.9 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (10 mL, 1% v/v) and twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum. Compound was purified by flash chromatography (solvent system: dichloromethane-methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.O>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[CH:10]1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C)cn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
6-(Methoxycarbonyl)-3-methylindole (0.57 g) is dissolved in N,N-dimethylformamide (10 ml), to which is added sodium hydride (60% oily, 0.145 g) with cooling with ice. Then, 2,4-dichlorobenzyl chloride (0.707 g) is added thereto, and stirred at room temperature for 1.5 hours. Water is added to the reaction mixture, which is then extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous magnesium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-3-methylindole (72) (0.83 g).
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[OH:39].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:39][C:33]5[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Cc1cccc(N)c1O
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cccc2nc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)oc12

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-methyl-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-6-methylphenol (0.030 g, 0.245 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4052419F). The compound was formed as an off-white solid (0.018 g, 14%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=7.37 min., 85%; m/z 539 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[O:22])=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](O)=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.[NH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH3:51])=[O:49].C(N(CC)CC)C>O>[CH:24]1([NH:23][C:21](=[O:22])/[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([NH:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[O:19])=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: O=C(O)C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1
Reactant: COC(=O)CCCCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C=CCCCNC(=O)C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 52 %

Procedure:
To a suspension of 3-(1E)-(4-(2-(4-fluorophenyl)-3-(cyclopropylamino)-3-oxoprop-1-en-1-yl)phenyl)acrylic acid (prepared according to the procedure described in Example 59, step-I) (0.35 g, 1 mmol) in DMF (15 mL) EDCI (0.83 g, 2 mmol), HOBt (0.13 g, 1 mmol), methyl 6-aminocaproate (0.16 g, 0.9 mmol), were added, followed by triethylamine (0.4 mL, 3 mmol). The reaction mixture was stirred for 2 hours after which the mixture was added to cold water (50 mL). The aqueous layer was extracted with ethyl organic layer was dried over anhydrous Na2SO4 and concentrated to get the crude compound. The crude yellow colored compound was washed with ethyl acetate/hexane (0.5/9.5, 2×20 mL) to afford the title compound as a yellow solid (0.25 g, 52% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][N:19]([CH3:23])[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CN(C)C(=O)Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)N(C)C)cc23)CC1
Yield: 78.5 %

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.4 mg (0.059 mMol) dimethyl carbamoyl chloride, 13.2 mg (79%) of the title compound were recovered.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21](=[O:23])[NH2:22])=[CH:16][C:15]=1[CH3:24])[C:10]([OH:12])=O)=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.[C:35]1([C:41]2[N:42]=[C:43]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][NH:47]3)[NH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)CCCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[NH2:8][CH:9]([C:10](=[O:12])[N:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH:46]1[C:43]1[NH:44][CH:45]=[C:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:42]=1)[CH2:13][C:14]1[C:15]([CH3:24])=[CH:16][C:17]([C:21]([NH2:22])=[O:23])=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Agent: CCN=C=NCCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)cc(C)c1CC(N)C(=O)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 107.7 %

Procedure:
2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid (0.42 g, 1.25 mmol) was dissolved in DMF (5 mL) followed by 1-hydroxybenzotriazole (0.34 g, 1.75 mmol), and the resulting solution was cooled to 0° C. To this reaction mixture was added 2-(4-phenyl-1H-imidazol-2-yl)-piperidine (0.31 g, 1.75 mmol) followed by (4-dimethylamino-butyl)-ethyl-carbodiimide (0.34 g, 1.75 mmol). The reaction was then warmed to room temperature and stirred for 16 hours. The reaction mixture was then combined with 2N citric acid and washed multiple times with ethyl acetate. The combined organics were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 600 mg of desired product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester as a glass which was used as is without further purification. (TLC: 5:1 CHCl3:MeOH Rf=0.6)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C@H:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[NH2:42])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[NH:42][C:24]([C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:10]4[O:9][C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=4[CH:17]=3)[CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:35][CH:36]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: N[C@@H]1CCC[C@@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N[C@@H]4CCC[C@@H]4c4ccc(Cl)cc4)c3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
In a 1 dram vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol), cis-2-(4-chlorophenyl)cyclopentanamine (14 mg, 0.072 mmol), and HATU (31 mg, 0.082 mmol). DMF (0.4 mL) and DIPEA (50 μL, 0.29 mmol) were added, and the vial was capped and stirred at r.t. for 2 h, then diluted with MeOH, filtered, and purify directly by prep HPLC. Concentration afforded the title compound (15 mg, 52% yield) as a fluffy white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.47-8.59 (m, 1H) 8.06 (d, J=8.85 Hz, 1H) 7.97-8.03 (m, 2H) 7.86 (d, J=1.83 Hz, 1H) 7.75-7.82 (m, 2H) 7.68 (s, 1H) 7.65 (dd, J=8.55, 1.83 Hz, 1H) 7.45-7.53 (m, 2H) 7.40 (t, J=8.85 Hz, 2H) 7.27 (s, 4H) 4.60-4.71 (m, J=7.67, 7.67, 7.55, 7.32 Hz, 1H) 3.33-3.41 (m, 1H) 2.87 (d, J=4.58 Hz, 3H) 1.99-2.15 (m, 3H) 1.89-1.98 (m, 1H) 1.72-1.82 (m, 1H) 1.57-1.71 (m, 1H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=2.02 min, (ES+) m/z (MH+)=567. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=15.42 min, purity=98%; column: Waters XBridge phenyl 3.5 μm 4.6×150 mm, Rt=13.74 min, purity=97%.