Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)CCN6CCCCC6)CC5)cc34)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into the suspension of (3-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydro pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (122 mg, 0.190 mmol), 1-piperidinepropanoic acid (48.4 mg, 0.305 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC-HCl) (76.7 mg, 0.400 mmol) and 1-hydroxy benzotriazole (HOBt-H2O) (30.6 mg, 0.200 mmol) in DMF (4.5 mL) was added N,N-diisopropylethylamine (167 μL, 0.952 mmol) under N2 at rt. The reaction mixture, which became a clear wine-red solution, was stirred at rt for 18 h. After that time, the reaction mixture was treated with water/saturated NaHCO3 (5 mL/5 mL) and extracted with EtOAc (4×20 mL). The combined extracts were washed with water (2×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to obtain a light-brown oil that was purified using the mass-directed purification system to yield the title compound as yellow oil. 1H NMR (CD3OD, 400 MHz): δ=1.69 (brs, 2H), 1.88 (brs, 4H), 2.57 (s, 3H), 2.66 (brs, 2 H), 2.95-3.03 (m, 2H), 3.32 (brs, 4H), 3.41 (t, 2H, J=6.0 Hz), 3.76 (t, 1H, J=5.4 Hz), 3.85 (t, 1H, J=5.6 Hz), 4.28 (brs, 2H), 6.30 (d, 1H, J=2.8 Hz), 6.51-6.55 (m, 1H), 7.49 (d, 1H, J=8.4 Hz), 7.55-7.59 (m, 1H), 7.98-8.00 (m, 1H), 8.19 (s, 1H), 8.42 (s I H). MS (ES+): m/z 485.00 (70) [MH+]. HPLC: tR=1.70 min (ZQ2000, polar—5 min).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH2:23][CH:24](OCC)OCC.C(O)C>O>[S:21]1[CH:24]=[CH:23][N:20]=[C:19]1[C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8]
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCOC(CBr)OCC
Solvent: O
Solvent: CCO
Product: O=S(=O)(Nc1cccc2cc(-c3nccs3)[nH]c12)c1cccs1
Yield: 9 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.61 g), 1-bromo-2,2-diethoxyethane (0.32 mL) and ethanol (10 mL) was heated under reflux overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.06 g, yield 9%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 164-165° C.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:5][CH3:6].O>CCOCC>[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][C:2]#[N:1])[CH2:5][CH3:6]
Reactant: CCCc1ccccc1N
Reactant: N#CBr
Solvent: O
Solvent: CCOCC
Product: CCCc1ccccc1NC#N
Reaction time: 2.5 h
Yield: 41.8 %

Procedure:
A mixture of cyanogen bromide (1.89 g, 17.9 mmol), and 2-n-propylaniline (3.87 g, 28.65 mmol) in ether (50 mL) was stirred for 2.5 hours under nitrogen atmosphere. The mixture was poured into water and extracted with diethylether. The solvent was dried over magnesium sulfate and concentrated in vacuo at room temperature to give 2-propylphenylcyanamide (1.2 g, 26%) as an off white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:17]=1)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][S:40][CH3:41])[NH2:37].C1C=C2C(N(O)N=NC2=CC=1)=O.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.O>[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][S:40][CH3:41])[NH:37][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH2:15][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1ccccc1-c1cc(CN(Cc2ccccc2)c2cccnc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN(Cc2ccccc2)c2cccnc2)cc1-c1ccccc1C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a stirred solution of product of Example 407B (12.34 g, 29 mmol) in DMF (80 mL) was added successively methionine methyl ester hydrochloride (7.53 g, 37.7 mmol, 1.3 eq), HOOBt (5.21 g, 31.9 mmol, 1.1 eq), EDCI (6.11 g, 31.9 mmol, 1.1 eq) and 4-methylmorpholine (5.1 mL, 46.4 mmol, 1.6 eq). The mixture was stirred overnight, then poured into water and extracted with ethyl acetate. The organic solution was washed successively with water, sodium carbonate and sodium chloride, dried (Na2SO4), concentrated in vacuo, and the residue purified by flash chromatography on silica gel eluting with 70% ethyl acetate—hexanes changing to 100% ethyl acetate to yield the title compound (15.51 g, 96%).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)=[N:9][CH:10]=[CH:11][CH:12]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ncccc2F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ncccc4F)cc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 62.7 %

Procedure:
To a tetrahydrofuran (2 mL) solution of (4-(3-fluoro-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (33 mg, 0.11 mmol) described in Manufacturing Example 149-1-4 were added 3-ethynyl-pyridin-2,6-diamine (10 mg, 75 mmol) described in Manufacturing Example 13-1-3 and triethylamine (21 μL, 0.15 mmol), which was stirred for 2 hours and 25 minutes at 50° C. and under nitrogen atmosphere. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=20:1) to obtain the title compound (27 mg, 92%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cnccn1)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Yield: 34.1 %

Procedure:
A mixture if 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was wash washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (99.7 mg, 34.0%) as a solid.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=C(OC)C=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1cccc(COC(=O)c2cc(Br)ccc2OCc2cccc(OC)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (395 mg, 9.40 mmol) in water (20 ml) was added dropwise to a stirred solution of [3-(methyloxy)phenyl]methyl 5-bromo-2-({[3-(methyloxy)phenyl]methyl}oxy)benzoate (may be prepared as described in Description 29; 430 mg, 0.94 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a light yellow solid. 275 mg.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH2:16])=[O:15])O1.Br[C:20]1[N:25]2[CH:26]=[CH:27][N:28]=[C:24]2[C:23]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[N:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH3:11].[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:23]3[C:24]4[N:25]([CH:26]=[CH:27][N:28]=4)[C:20]([C:9]4[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=4)[C:14]([NH2:16])=[O:15])=[CH:21][N:22]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2cncc(C(N)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(-c4cncc(C(N)=O)c4)n4ccnc34)cc2)CC1
Product: N
Yield: 10.8 %

Procedure:
In the same way as described for Compound 127, step 4, using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (51.6 mg, 0.207 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (40 mg, 0.103 mol), Pd(PPh3)4 (30 mg, 0.026 mmol) and 1.5M Na2CO3 (0.55 mL), in dioxane (0.46 mL) and DMF (1.01 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH) to afford the title compound (4.8 mg, 11%). LCMS: Rt 1.74 min (97%) m/z (APCI) 429; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.54 (4H, m), 3.12 (4H, m), 6.97 (2H, d), 7.57 (1H, s), 7.73 (1H, s), 7.75 (1H, br s), 7.91 (2H, d), 8.07 (1H, s), 8.29 (1H, br s), 8.54 (1H, s), 9.03 (1H, s), 9.14 (1H, s), 9.58 (1H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Br>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:25][C:24]5[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:23]=5[F:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cc([C@H]2CC[C@H](N3CCNCC3)CC2)cc2c1OCO2
Reactant: Fc1ccc(F)c(CBr)c1
Product: Fc1ccc(F)c(CN2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from trans 1-[4-(1,3-benzodioxol-5-yl) -1-cyclohexyl]piperazine and 2,5-difluorobenzyl bromide by the method described in example 15 to give the product (59%, top: 110°-111° C.). Calc'd for C24H28F2N2O2 : C, 69.55%; H, 6.81%; N, 6.76%. Found: C, 69.55%; H, 6.74%; N, 6.63%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:10](=[O:11])[CH:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:8](=[O:21])[N:7]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][N:7]1[C:8](=[O:21])[C:9]([N+:1]([O-:4])=[O:2])([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[C:10](=[O:11])[N:6]1[CH3:5]
Reactant: Cc1cc(C)c(C2C(=O)N(C)N(C)C2=O)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(C2([N+](=O)[O-])C(=O)N(C)N(C)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A quantity of 0.13 ml (3.1 mmols) of fuming nitric acid was added to a solution of 0.70 g (2.8 mmols) of 1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3,5-dione in 20 ml of chloroform at room temperature. The obtained mixture was stirred at room temperature for 15 minutes. The reaction mixture was washed with water and was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then the residue was purified by column chromatography (benzene:ethyl acetate=3:1) to give 0.53 g (yield 64%) of 1,2-dimethyl-4-nitro-4-(2,4,6-trimethylphenyl)pyrazolidine-3,5-dione in the form of yellowish white crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[NH2-].[Na+].O>C1(C)C=CC=CC=1>[CH:14]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9])([CH3:16])[CH3:15]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Temperature: 80 °C

Procedure:
To a solution of 58 parts of α-phenylacetonitrile in 300 parts by volume of toluene is added 83 parts of 2-chloro-N,N-diisopropylethylamine dissolved in 300 parts by volume of toluene. The mixture is heated with stirring to about 80° C and then 22 parts of sodium amide is added slowly over a period of 30 minutes. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer is separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether and the ether extract is dried over calcium sulfate, concentrated and distilled to afford α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile, as an oil boiling at about 120°-125° C. at 0.3 mm pressure. This compound is represented by the following structural formula ##STR11##
Reaction SMILES: C(OC([CH:6]1[CH2:33][CH2:32][CH2:31][N:9]2[C:10]3[C:15]([C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:8]2[C:7]1=[O:34])=[CH:14][C:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:12][CH:11]=3)=O)C.[Cl-].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[CH2:24]([O:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:31][CH2:32][CH2:33][CH2:6][C:7](=[O:34])[C:8]1=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CCCn2c(c(-c3ccccc3)c3cc(OCc4ccccc4)ccc32)C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCCn2c1c(-c1ccccc1)c1cc(OCc3ccccc3)ccc12

Procedure:
An amount of 2.8 g (6.17 m mole) of 2-benzyloxy-7,8,9,10-tetrahydro-10-oxo-11-phenyl-6H-9-azepino[1,2-a]indole carboxylic acid ethylester and 0.36 g (6.1 m mole) of sodium chloride were refluxed for four hours in 3.5 ml of dimethylsulfoxide and 0.35 ml of water. After cooling, the mixture was taken up in ethyl acetate, dried over sodium sulfate, suction filtered, and evaporated. The residue was triturated with petroleum ether and suction filtered.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([F:19])[C:12]3[O:16][N:15]=[C:14]([CH3:17])[C:13]=3[CH:18]=2)=[O:8])CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH:46]([O:48]CCON)=[CH2:47].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH:46]([O:48][CH2:1][CH2:4][O:5][NH:6][C:7]([C:9]1[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[Cl:28])=[C:11]([F:19])[C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH:18]=1)=[O:8])=[CH2:47]
Reactant: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cc12
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 144 h
Yield: 63.4 %

Procedure:
To a solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (10a) (75.2 mg, 0.188 mmol) in DMF (1.5 mL) was added HOBt (38.2 mg, 0.249 mmol), Et3N (0.080 mL, 0.571 mmol), O-(2-vinyloxyethyl)hydroxylamine (28.5 mg, 0.276 mmol), and EDCI (47.2 mg, 0.246 mmol) at room temperature. After 6 days, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and purified by flash column chromatography using the Biotage system (3% MeOH in CH2Cl2) to give 57.8 mg (63%) of the desired product (11a).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([CH2:32][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:8]=3)[CH2:3][CH2:2]2)=[CH:31][C:26]=1[C:25]([OH:36])=[O:24]
Reactant: c1csc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(Cc4cccs4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 25 (part C) starting with 1.90 g (0.065 mol) of 3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 1.92 (0.071 mol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification and recrystallization with ethanol, 1.2 g (40% of yield) of the expected acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:36][CH2:35][C:34]1=[O:37]>>[O:37]=[C:34]1[CH2:35][CH2:36][N:33]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:23]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccccc1N1CCC1=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1CCC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 1-(2-(aminomethyl)phenyl)azetidin-2-one, derived from reduction of intermediate 115, 2-(2-oxoazetidin-1-yl)benzonitrile. 1H NMR (400 MHz, CDCl3) δ ppm: 8.67 (1H, brt, J=6.3 Hz), 7.60 (1H, dd, J=1.3, 7.6 Hz), 7.53-7.50 (1H, dd, m), 7.34-7.24 (5H, m), 7.18 (1H, ddd(dt), J=1.2, 7.4 Hz), 7.10 (1H, dd, J=1.2, 8.0 Hz), 5.27 (2H, s), 4.60 (2H, d, J=6.3 Hz), 4.01-3.95 (4H, m), 3.71 (2H, t, J=4.5 Hz), 3.10 (2H, t, J=4.5 Hz), 1.60 (6H, s); LCMS (+ESI, M+H+) m/z 489.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[O:29][S:30]([O-:32])=O.[K+].[CH3:34]C(C)=O.O>>[C:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:30]([CH3:34])(=[O:32])=[O:29])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1

Procedure:
(2,6-Diphenyl-pyrimidin-4-yl)-(4-methylsulfanyl-phenyl)-amine (0.17 g, 0.46 mmol) was oxidized with oxone (0.84 g, 1.3 mmol) in acetone-water (2:1, 9 mL) at room temperature for 5 minutes. Solid was filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[Br:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c(=O)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:40])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH2:30])([CH3:26])([CH3:25])[CH3:24].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:40])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:30][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:21][CH:20]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-(benzyloxycarbonylaminomethyl)benzoic acid as obtained in Reference Example 35 (1.0 g), glutamic acid di-t-butyl ester hydrochloride (1.15 g) and DEPC (860 mg) in dimethylformamide (20 ml), triethylamine (1.06 g) was added drop by drop, followed by stirring at room temperature for 1 hour. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to yield the title compound (1.86 g, yield 100%) as a colorless wax-like substance.