Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:33])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1.Cl>C(O)(C)C.O1CCOCC1>[C:35]1([NH:1][C:2]2[C:3]([CH3:33])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Reactant: Clc1nccc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1c(Nc2nccc3ccccc23)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Temperature: 140 °C
Yield: 35.6 %

Procedure:
A suspension of 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-2, 35 mg, 0.079 mmol) and 1-chloroisoquinoline (19.45 mg, 0.119 mmol) in isopropanol (0.5 mL) was treated with 4M hydrogen chloride in 1,4-dioxane (3 drops) and the mixture was heated in a sealed tube by microwave irradiation at 140° C. for 45 min. Additional 4 M hydrogen chloride in 1,4-dioxane (1 drop) was added and the mixture was again heated in a sealed tube by microwave irradiation at 140° C. for 60 min. The mixture was concentrated and the residue was purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(isoquinolin-1-ylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a white solid (16 mg, 32%). 1H NMR (400 MHz, methanol-d4) δ 8.28 (1H, d, J=8.3 Hz), 7.91 (1H, d, J=7.8 Hz), 7.72 (1H, d, J=6.1 Hz), 7.66 (1H, d, J=8.3 Hz), 7.56-7.61 (2H, m), 7.48 (1H, ddd, J=8.0, 7.2, 0.8 Hz), 7.44 (1H, d, J=7.5 Hz), 7.34 (1H, t, J=7.8 Hz), 7.22 (1H, d, J=8.0 Hz), 7.14 (1H, d, J=6.7 Hz), 7.06 (1H, d, J=7.8 Hz), 6.97 (1H, d, J=6.1 Hz), 6.94 (1H, dd, J=8.2, 1.5 Hz), 3.71 (2H, br. s.), 3.42 (2H, br. s.), 2.45 (2H, br. s.), 2.32 (2H, br. s.), 2.23 (3H, s), 1.81 (3H, s). Mass spectrum m/z 569.4 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[CH:11]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a suspension of NaH (74.0 g, 2.16 mol 1.05 equiv, 70%) in tetrahydrofuran (2000 mL) at 0° C., then ethyl 2-(diethoxyphosphoryl)acetate (514 g, 2.06 mol, 1.05 equiv, 98%) was added dropwise with stirring at 0° C. This was followed by the addition of a solution of tert-butyl 4-oxopiperidine-1-carboxylate (400 g, 1.97 mol, 1.00 equiv, 98%) in tetrahydrofuran (1200 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 60 min at room temperature, then quenched by the addition of 2000 mL of water. The resulting solution was extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was washed with 1×1000 mL of hexane and dried to afford tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:27]N1C(=O)CCC1=O.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:27])[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2cc(=O)n3cc(C)sc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (641 mg, 2.841 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.31-0.33 (m, 2H), 0.53-0.56 (m, 2H), 1.22 (br s, 1H), 2.43 (s, 3H), 3.76-3.81 (m, 2H), 3.81 (s, 3H), 7.05-7.11 (m, 2H), 7.25-7.28 (m, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.80 (s, 1H), 8.14 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 495.10 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:20][C:17]2[CH:18]=[CH:19][S:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Using general procedure A, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.800 g, 4.30 mmol), thiophene-3-carbaldehyde (0.480 g, 4.30 mmol), acetic acid (20 drops, cat.) and sodium triacetoxyborohydride (1.27 g, 6.02 mmol) were combined in 1,2-dichloroethane (40 ml) and the resulting mixture was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) gave 4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (0.886 g, 73%). 1H-NMR (CDCl3) δ 1.27 (m, 3H), 1.45 (s+m, 1H), 1.84 (d, 2H, J=12.0 Hz), 2.66 (m, 1H), 2.80 (t, 2H, J=12.0 Hz), 3.85 (s, 2H), 4.01 (br d, 2H), 7.03 (d, 1H, J=6.0 Hz), 7.12 (s, 1H), 7.29 (m, 1H).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][NH:15][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)C2CCC2)cc1OC
Yield: 104.3 %

Procedure:
Cyclobutanecarbonyl chloride (19 g) was added dropwise at ambient temperature to a stirred solution of 3,4-dimethoxyphenethylamine (30.5 g) and triethylamine (23.5 ml) in tetrahydrofuran (11). After 1.5 hours the mixture was poured onto dilute hydrochloric acid (1 l) and the product was extracted into ethyl acetate. The extracts yielded N-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (44 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1[CH:24]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:24][C:23]3[S:22][CH:21]=[N:20][C:19]=3[CH3:18])[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ncsc1C=O
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ncsc1C=Nc1[nH]nc(Nc2cccc(Cl)c2)c1C(N)=O

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 4-methyl-5-thiazolecarboxaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain B62 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:11]O)=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[H][H]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: ON=C1CCc2cc(N3CCOCC3)c(F)cc21
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 27.2 %

Procedure:
A solution of 6-fluoro-5-morpholin-4-ylindan-1-one (200 mg), hydroxylammonium chloride (102 mg) and sodium acetate (241 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 218 mg of 6-fluoro-5-morpholin-4-ylindan-1-one oxime. Next, 10% palladium-carbon (water content: 48%, 200 mg) was added to a solution of the resulting 6-fluoro-5-morpholin-4-ylindan-1-one oxime (218 mg) in ethanol (5.0 mL), and the reaction solution was stirred in a hydrogen atmosphere (0.4 MPa) at room temperature for 9 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 56.0 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([NH:7][N:8]=[CH:9][C:10](Cl)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:16]O>>[C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH:16]=[C:10]([OH:11])[CH:9]=[N:8]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(NN=CC(=O)Cl)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-n2cc(O)cn2)cc1
Reaction time: 2.5 h

Procedure:
(p-Tolyl-hydrazono)-acetyl chloride (4.0 g, 19.04 mmol) was then taken in methanol and sodium hydroxide (1.52 g, 38.0 mmol) was added. And the reaction mixture was stirred for 2.5 hours. Methanol was removed and residue was taken up in water and pH was made 3 by adding dilute HCl. The solid was filtered off through on Buckner funnel, washed with cold water, dried under vacuum, and further washed with petroleum ether and dried under vacuum.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][C:35]1([C:41]([OH:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:39][CH2:40][C:35]([CH3:34])([C:41]([OH:43])=[O:42])[CH2:36][CH2:37]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC1(C(=O)O)CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC1(C(=O)O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-methyl-piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[C:20](=[O:21])[N:12]2[CH:13]([C:18]#[N:19])[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:28]([NH:9][CH:10]2[C:20](=[O:21])[N:12]3[CH:13]([C:18]#[N:19])[C:14]([CH3:16])([CH3:17])[S:15][C@H:11]23)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Reaction time: 0.33 h

Procedure:
Triethylamine (44.5g., 0.44 mole) is added to a slurry of 6-amino-2,2-dimethyl-3-cyanopenam hydrochloride (46.6g., 0.2 mole) in methylene chloride (1500 ml.) at room temperature and the resulting mixture stirred for 20 minutes. Triphenylmethyl chloride (66.9 g., 0.24 mole) is added in one portion to the mixture which is stirred at room temperature for 3.5 hours. The methylene chloride layer is separated and washed with water (5 × 100 ml.). It is then dried (Na3SO4) and concentrated in vacuo to orange-red viscous oil. Methanol (50 ml.) is added and the mixture stirred for a half hour to give a yellow-white solid. The solid is filtered, resuspended in fresh methanol, and the suspension stirred for a half hour. The solid is recovered by filtration and dried in a vacuum oven at room temperature. Yield of crude = 47 gms. M.p. 116-119° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 810.6 %

Procedure:
Prepared from commercially available 2-amino-5-bromopyridine (5.0 g, 29 mmol) and commercially available 4-trifluoromethylphenylboronic acid (6 g, 32 mmol) as described in example C.20 step 2. Obtained the title compound as an off-white solid (56 g, 56%). MS (ISP) 239.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:3][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][N:16]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: O=C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C3CCCCC3)CC2)CC1
Yield: 99 %

Procedure:
Prepared analogously to Example A19a) from 1-(1,1-dimethyl-ethoxycarbonyl)-4-(4-piperidinyl)piperazine and cyclohexanone in a yield of 99% of theory. Colourless, highly viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:19]\[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CCc1ccc(Br)cc1
Reactant: COC(CCCC=O)OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CCCC/C=C(\Cc1ccc(Br)cc1)[N+](=O)[O-]
Yield: 43 %

Procedure:
Prepared according to the general procedure B from 1-bromo-4-(2-nitroethyl)benzene 112h (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (2.15 g, 43% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:20][CH2:19]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].P(C#N)(OCC)(OCC)=O>>[OH:1][C@@H:2]([CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:22][CH2:23]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])=[O:16])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCNCC
Reactant: O=C(O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1
Agent: CCOP(=O)(C#N)OCC
Product: CCN(CC)C(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1

Procedure:
By the reactions in the same manner as in as in Example 3 using (S)-4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)benzo(b)furan-2-carboxylic acid Starting Material Synthesis Example 22, diethylamine (0.24 ml) and diethyl cyanophosphate (0.5 ml), the title compound (0.61 g) was obtained as a brown oil.
Reaction SMILES: C([O:8][NH:9][C:10]([C@@H:12]1[C@@H:17]([C:18](=[O:39])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH:14]([CH2:40][C:41](O)=[O:42])[CH2:13]1)=[O:11])C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1.CN1CCOCC1>CN(C=O)C>[OH:8][NH:9][C:10]([C@H:12]1[CH2:13][CH:14]([CH2:40][C:41](=[O:42])[N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)[CH2:15][CH2:16][C@@H:17]1[C:18]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[C:30]([CH3:38])[CH:29]=2)=[CH:22][CH:21]=1)=[O:39])=[O:11]
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)O)C[C@@H]3C(=O)NOCc3ccccc3)cc2)c2ccccc2n1
Reactant: C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)N4CCCCC4)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 110.6 %

Procedure:
Part 10: 4-(2-Oxo-2-piperidin-1-yl-ethyl)-cyclohexan-1-(S)-,2-(S)-dicarboxylic acid 2-(S)-(benzyloxy-amide) 1-(S)-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide. To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: {3-(S)-benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid (20 mg, 0.034 mmol), anhydrous DMF (1 mL), PyBOP reagent (20 mg, 0.038 mmol), piperidine (0.010 mL, 0.101 mmol), and 4-methyl morpholine (0.01 mL, 0.092 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo. Purification by Combiflash (0 to 10% methanol in methylene chloride over 30 min) to afford 21 mg (95%) of the desired amide. LCMS (ESI): 649 (M+1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:41]=[CH:42][CH:43]=2)[C:22]([C:24]2[C:34](C3C=CC=CC=3)=CC=C[C:25]=2[NH:26]C(=C)C#N)=[O:23])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[NH2:26][C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:34][C:24]=1[C:22](=[O:23])[C:21]1[CH:41]=[CH:42][CH:43]=[C:19]([O:18][CH2:17][CH2:16][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:20]=1
Reactant: C=C(C#N)Nc1cccc(-c2ccccc2)c1C(=O)c1cccc(OCCN2CCOCC2)c1
Reactant: NNc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(OCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and 2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylamlinoacrylonitrile (2.0 g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogen atmosphere. After 6 h, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (elution gradient: CH2Cl2-3%MeOH/CH2Cl2) gave 5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole which was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5° C.).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:11]3=[O:34])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:46][CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:11](=[O:34])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:1]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:46][CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)[CH2:3][CH2:2]4)[CH:9]=3)[N:14]=2)=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reactant: COc1cc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3ccc(N4CCCN(CC5CCOCC5)CC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
2-(6-(1,4-Diazepan-1-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (EXAMPLE 1i) (30 mg, 0.064 mmol), (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (35 mg, 0.128 mmol) and DIPEA (17 mg, 21 μl, 0.128 mmol) were dissolved in DMF (1 mL) and stirred at room temperature overnight. Purification by preparative HPLC afforded 2-{2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-[4-(tetrahydropyran-4-ylmethyl)perhydro-1,4-diazepin-1-yl]-4H-quinazolin-3-yl}-N-isopropylacetamide (EXAMPLE 11a) (5 mg, 0.0088 mmol, 14%).
Reaction SMILES: [NH2:1][CH3:2].[Li]CCCC.C(O[C:11]([C:13]1[N:14]=[N:15][S:16][C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12])C.[NH4+].[Cl-]>C1CCCCC1.CCOC(C)=O>[CH3:2][NH:1][C:11]([C:13]1[N:14]=[N:15][S:16][C:17]=1[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:12]
Reactant: CN
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1nnsc1Nc1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2 M NH2CH3 in cyclohexane (2 mL) at −40° C. was added 0.8 mL of 2 M n-BuLi in cyclohexane under argon. A white precipitate was immediately observed. The mixture was stirred at −30° C. for 0.5 hours, and 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (60 mg, 0.24 mmole) in 1 mL of cyclohexane was slowly added. Greenish solution was immediately obtained. The reaction was slowly warmed up to room temperature and TLC showed a total disappearance of the starting material. A mixture of 7 mL of saturated NH4Cl solution and 7 mL of EtOAc was added to the ice-cooled flask and the solution was stirred for 30 minutes. The aqueous layer was neutralized to pH ˜7 and then extracted with EtOAc. The organic layer was absorbed with silica gel, loaded to a 53 g silica gel column, and eluted with hexane:EtOAc=5:1. A 25 mg white powder was obtained (45%). 1H NMR (ppm, DMSO-d6): 11.00 (br. s, 1H), 8.92 (br. q, 1H), 7.46 (t, 2H), 7.34 (d, 2H), 7.20 (t, 1H), 2.85 (d, 3H).