Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][C:34]1([CH3:40])[O:38][C:37](=[O:39])[N:36]=[CH:35]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:35][C:34]([CH3:40])([CH3:33])[O:38][C:37]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Reactant: CC1(C)C=NC(=O)O1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 50.6 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (779 mg) described in Preparation Example 179 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (420 mg) was obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=O)[C:9](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:10](=[O:12])[CH3:11].[NH2:24][C:25](=[CH:27][C:28](=[O:30])[CH3:29])[CH3:26]>CO>[C:10]([C:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:27]([C:28](=[O:30])[CH3:29])=[C:25]([CH3:26])[NH:24][C:8]=1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:12])[CH3:11]
Reactant: CC(=O)C=C(C)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCBr
Solvent: CO
Product: CC(=O)C1=C(C)NC(CCCCCCBr)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1

Procedure:
45 g (0.14 mol) 1-bromo-8-(3-nitrophenyl-methylene)-7,9-decanedione and 28 g (0.28 mol) 2-amino-2-penten-4-one are boiled under reflux in 300 ml methanol for 24 h. The mixture is concentrated and the residue is prepurified by chromatography with toluene/acetone=99/1. The product thus obtained is chromatographed again over silica gel with toluene/ethyl acetate=8/2The title compound is obtained as a yellow oil. Yield: 10.3 g (16%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=3)=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][N:24]=3)=[O:33])=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:46])[CH3:47])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 227d (366 mg, 0.555 mmol) was dissolved in a 1:1 mixture of TFA in CH2Cl2 and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (47 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.35 (d, J=6.99 Hz, 6 H), 3.29 (dt, J=13.70, 6.94 Hz, 1 H), 6.86-7.00 (m, 5 H), 7.88 (d, J=8.46 Hz, 1 H), 8.11 (dd, J=8.64, 2.39 Hz, 1 H), 8.21-8.30 (m, 2 H), 8.40 (d, J=8.82 Hz, 1 H), 8.79 (s, 1 H), 8.90 (s, 1 H), 9.00 (d, J=8.46 Hz, 1 H), 11.28 (s, 1 H); MS (ESI+) m/z 560 (M+TFA+H)+; (ESI−) m/z 558 (M+TFA−H)−.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([NH2:31])[N:28]=[CH:27][N:26]=2)=[CH:21][N:20]=1>ClCCl.CN(C)C=O>[N:31]([C:29]1[N:28]=[CH:27][N:26]=[C:25]([C:22]2[CH:21]=[N:20][C:19]([O:18][CH3:17])=[N:24][CH:23]=2)[CH:30]=1)=[C:1]=[S:2]
Reactant: COc1ncc(-c2cc(N)ncn2)cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ncc(-c2cc(N=C=S)ncn2)cn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.832 g, 3.58 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 2′-methoxy-4,5′-bipyrimidin-6-amine (0.56 g, 2.76 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.1 g, 0.408 mmol, 15% yield) as an orange solid. LCMS R.T.=2.29; [M+H]+=246.03.
Reaction SMILES: [I-].C([P+](C[CH2:16][CH2:17][CH3:18])(CCCC)CCCC)CCC.C(I)C.[C:22]([OH:26])(=[O:25])[CH2:23][CH3:24].C=C.C(O)C[OH:31].O>CN1C(=O)CCC1>[C:22]([O:26][C:16](=[O:31])[CH2:17][CH3:18])(=[O:25])[CH2:23][CH3:24]
Reactant: OCCO
Reactant: CCCC[P+](CCCC)(CCCC)CCCC
Reactant: CCC(=O)O
Agent: C=C
Agent: [I-]
Solvent: CCI
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(=O)OC(=O)CC
Temperature: 160 °C

Procedure:
To the autoclave was added 5.81 g (0.022 moles) of Mo(CO)6, 15.5 g (0.040 moles) of tetrabutylphosphonium iodide, 109.2 g (0.700 moles) of ethyl iodide, 555 g (7.5 moles) of propionic acid, and 68.6 g of N-methyl pyrrolidinone (NMP) as polar, aprotic solvent. The condenser temperature is set at 5°-10° C. using a cooled ethylene glycol/water mixture. The autoclave was then pressure tested with nitrogen at 68.0 atm and a gas purge of 3 moles/hr of gas was established through the high pressure condenser. (During the reaction this gas purge permitted control of the gas composition over the reaction mixture and is necessary for kinetic measurements.) The nitrogen was vented, the autoclave was then pressurized to 23.8 atm with 5% hydrogen in carbon monoxide, and subsequently heated to 160° C. (The 3 moles/hr of gas purge is maintained throughout heating and the subsequent reaction.) Upon reaching temperature, the pressure is raised to 51.0 atm using a gas mixture consisting of 6% H2, 47% CO, and 47% ethylene while using the 3 mole/hr purge to maintain the gas mixture. Liquid samples are removed every 20 minutes for 5 hours and analyzed for ethyl iodide, ethyl propionate, propionic anhydride, and propionic acid content by GC using a Hewlett Packard 5890 GC containing a 25 m (0.25 mm ID, 0.25 micron film) Quadrex 007 FFAP Capillary Column with p-xylene as an internal standard. (A split injection was used to introduce the sample and sample detection was accomplished with TCD detector.) These components represented the only significant products and all other materials detectable by GC-MS were only present at trace levels. Gas samples were also removed hourly and analyzed by GC to insure that the gas mixture is consistent. The molar quantities of propionic anhydride (npan) formed were determined from the GC data using the following equation: ##EQU1## where, ni =moles of the component
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1>[CH2:36]([O:35][C:29]1[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH:6]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[CH2:5][C:4]([OH:40])=[O:3])=[CH:15][CH:16]=2)=[CH:23][CH:24]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOc1ccc(C)cc1-c1ccc(COc2ccc(C(CC(=O)OCC)c3ccc(F)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOc1ccc(C)cc1-c1ccc(COc2ccc(C(CC(=O)O)c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 45.3 (56 mg, 0.1 mmol) and 2N NaOH(aq) solution (0.31 mL, 0.62 mmol) in THF (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, treated with dilute HCl, and extracted into ethyl acetate. The organic layer washed with water and concentrated to yield product which was purified by flash chromatography to give compound 45 (40 mg). 1H NMR (500 MHz, CDCl3, ppm), δ 0.9 (t, 3H), 1.4 (m, 2H), 1.65 (m, 2H), 2.35 (s, 3H), 3.05 (m, 2H), 3.9 (t, 2H), 4.5 (t, 1H), 5.05 (s, 2H), 6.8-7.5 (m, 15H). MS ESI (neg.) m/e: 511.0 (M−H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([C:21](O)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[NH:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[Li+]>C1COCC1.C(OCC)(=O)C>[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[N:46]1[C:21]([C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:22])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(F)c(F)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic acid (25 g, 78.8 mmol) in THF (350 mL) at -20° C. were added triethylamine (27.45 mL, 197 mmol) and pivaloyl chloride (24.2 mL, 197 mmol) subsequently. Stirring was continued for two hours at the same temperature, and to this mixture were added (S)-4-Benzyl-oxazolidin-2-one (14.7 g, 82.7 mmol) and lithium chloride (3.67 g, 86.7 mmol). The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water two times and saturated sodiumbicarbonate. The separated organic phase was dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 15:85) to yield (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one 18 g (48%) as awhite solid. MS m/e: 477.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[S:34][C:35]([Cl:38])=[CH:36][CH:37]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Cl:38][C:35]1[S:34][C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])=[CH:37][CH:36]=1
Reactant: O=C(CBr)c1ccc(Cl)s1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(Cl)s3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(5-chloro-2-thienyl)ethanone (0.74 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.79 g, 56%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]1[C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10]1)(=O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH2:10][CH:9]([CH2:8][CH2:7][CH2:6][N:29]3[CH2:30][CH2:31][CH:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:27][CH2:28]3)[C:13]=2[CH:14]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCC1COc2ccc(F)cc21
Product: Fc1ccc(C2CCN(CCCC3COc4ccc(F)cc43)CC2)cc1

Procedure:
The title compound, 11a, was prepared from 3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propyl methanesulfonate (4.2 g) and 4-(4-fluorophenyl)piperidine (5.5 g) by the method described in EXAMPLE 2. Yield: 1.8 g, mp: 83-85° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:18][C:19](=[O:21])[CH3:20])[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[F:33][C:34]([F:58])([F:57])[C:35]1[CH:56]=[CH:55][C:38]([CH2:39][CH:40]2[CH2:42][N@@:41]2[S:43]([C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=2)(=[O:45])=[O:44])=[CH:37][CH:36]=1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([N:18]([CH2:42][C@@H:40]([NH:41][S:43]([C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)(=[O:44])=[O:45])[CH2:39][C:38]2[CH:55]=[CH:56][C:35]([C:34]([F:57])([F:33])[F:58])=[CH:36][CH:37]=2)[C:19](=[O:21])[CH3:20])[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[N@]2CC2Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: COCc1nc(NC(C)=O)sc1-c1nc2ccncc2s1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)[N@@]2CC2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(C)=O)sc1-c1nc2ccncc2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a 50 mL round-bottomed flask was added N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.300 g, 0.936 mmol), Cs2CO3 (0.610 g, 1.87 mmol), and DMF (0.0721 mL, 0.936 mmol). The resulting solution was heated to 50° C. A DMF solution of (S)-2-(4-(trifluoromethyl)benzyl)-1-(4-nitrophenylsulfonyl)aziridine (0.724 g, 1.87 mmol) was added to the reaction dropwise, and the reaction mixture was monitored by LCMS. After approximately 30 minutes, the solvent was removed and the residue was taken up in EtOAc and washed with saturated sodium bicarbonate. The solution was dried over sodium sulfate, filtered and loaded onto a plug of silica gel. Chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 1% to 10% 2 M NH3.MeOH in DCM, to provide N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)-N-((S)-2-(4-nitrophenylsulfonamido)-3-(4-(trifluoromethyl)phenyl)propyl)acetamide (0.290 g, 0.410 mmol, 43.8% yield). LCMS (M+H) 707 calc. for C29H26F3N6O6S3 707.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 50 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2,5-dichloro-N-(2-(pyrrolidin-1-ylsulfonyl)phenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 50% yield (yellow solid) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 8.61 (d, 1H, J=8.2 Hz), 8.18 (s, 1H), 7.96 (d, 1H, J=7.9 Hz), 7.58 (t, 1H, J=7.7 Hz), 7.51 (d, 2H, J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.26 (m, 1H), 3.53 (s, 2H), 3.30 (m, 4H), 2.53 (bs, 8H), 2.34 (s, 3H), 1.84 (m, 4H); MS (ESI): 542.20 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH3:29])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CC1C2C(=NC=CC=2C2C=NC3C(C=2)=CC=CC=3)N(C2C=CC=CC=2C(N)=O)C=1>>[O:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:2]2[CH:9]=[C:8]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[C:13]4[C:12]([CH3:29])=[CH:11]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:32][CH2:31]1
Reactant: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: NC1CCOCC1
Agent: Cc1cn(-c2ccccc2C(N)=O)c2nccc(-c3cnc4ccccc4c3)c12
Product: Cc1cn(-c2ccc(C#N)c(NC3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 4 %

Procedure:
According to Example 1(6), a crude product of 2-(tetrahydro-2H-pyran-4-ylamino)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (40f) instead of compound (1e) and using tetrahydro-2H-pyran-4-amine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (53) (the second stage yield: 4%) was prepared as a white solid using 2-(tetrahydro-2H-pyran-4-ylamino)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f). By this reaction, compound (54) (the second stage yield: 21%) was prepared as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][N:30]3[CH2:31][CH2:32][C@@H:28]([F:27])[CH2:29]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: F[C@@H]1CCNC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CC[C@@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and (R)-3-fluoropyrrolidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.682 min, m/z=516.9; 1H NMR (CDCl3) 1.42 (d, 3H), 1.82-2.30 (m, 9H), 2.52-2.64 (m, 1H), 2.67-2.88 (m, 3H), 4.93-5.13 (m, 1H), 5.53 (m, 1H), 6.71 (d, 2H), 6.98 (m, 2H), 7.18 (m, 2H), 7.19 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[OH:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(O)c1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Temperature: 110 °C
Yield: 76.4 %

Procedure:
A mixture of methyl 4-bromo-3-hydroxybenzoate (CombiBlocks, 25 g, 108 mmol), o-tolylboronic acid (22 g, 162 mmol), anhydrous potassium carbonate (44 g, 324 mmol) and Pd(PPh3)4 (6.25 g, 5.4 mmol) was prepared in a mixture of toluene (500 mL) and water (100 mL), and then degassed with N2. The reaction mixture was heated at 110° C. for 12 hours. The reaction mixture was cooled at RT, filtered through a Celite pad and washed with a 10% aqueous solution of NaHCO3, water and brine. The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (silica, pet ether/EtOAc) affording of the title compound as pale yellow solid (20 g, 77%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.85 (s, 1H), 7.52 (s, 1H), 7.45 (d, 1H), 7.20-7.25, (m, 3H), 7.15 (d, 1H), 7.10 (d, 1H), 3.84 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3]CCCC1CCCC1=O.OCCCCCC1CCCC1=O.[C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])(=[O:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>>[C:2]([O:39][C:35]1[CH2:36][CH2:37][CH2:38][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:25](=[O:27])[CH3:26])(=[O:1])[CH3:3]
Reactant: O=C1CCCC1CCCCCO
Reactant: CC(=O)OCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1

Procedure:
A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 1 l. of acetic anhydride is refluxed at a rate to maintain a steady distillation of acetic acid from the reaction through a helix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 452 g. of an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccc(N)nc2)CC1
Yield: 57.8 %

Procedure:
The suspension of 1-methyl-4-(6-nitropyridin-3-yl)piperazine (5 g, 22.5 mmol), NH4Cl (12 g, 225 mmol), and Fe (5 g, 5 mmol) was stirred in EtOH/H2O (1:1) (100 mL) at 80° C. for 3 h. TLC showed starting material 1-methyl-4-(6-nitropyridin-3-yl)piperazine disappeared. After filtration on a pad of Celite, the solvent was removed under vacuum. EA and brine were added into the mixture and the organic layer was separated, dried over Na2SO4 and concentrated at reduced pressure to give 2.5 g of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (yield 60%). LCMS: (M+H)+ 193
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]1([N:24]2[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:26]([CH:34]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:34][C:26]2[CH:27]=[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Product: Cc1cccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)c1C
Yield: 77.9 %

Procedure:
Compound 19 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.