Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[O:4]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]4=[O:28])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5]1.CO>CN(C)C=O>[C:1]([CH2:5][C:6]1([OH:4])[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)cc2)C(=O)O1
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by reacting potassium cyanide (20.7 mmol) with (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (13.8 mmol) in 60 ml 5:1 methanol: dimethylformamide mixture under stirring. The reaction was stirred for 12 hours at 25° C. and quenched with saturated ferrous sulfate solution. The reaction mixture was filtered. The filtrate was extracted with ethyl acetate, organic layer was washed with brine and dried over sodium sulfate. Evaporation of organic solvent under vacuum and silica gel chromatographic purification afforded the titled product in 44% yield. M.P. 88-90° C. and MS (M+1)=373 (MH+, 100%) for M.F.=C19H24N4O4.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:21]1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[S:44][C:45]([CH:49]=O)=[C:46]([CH3:48])[N:47]=2)=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[S:44][C:45]([CH2:49][NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31][CH3:32])=[O:30])[CH2:21]3)=[C:46]([CH3:48])[N:47]=2)=[CH:41][CH:42]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=O
Reactant: COC(=O)c1cccc(N2CCCC(N)C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N2CCCC(NCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
Acetic acid (0.0251 mL, 0.438 mmol) and sodium triacetoxyborohydride (97.7 mg, 0.438 mmol) were added to methyl 3-(3-aminopiperidin-1-yl)benzoate (79.0 mg, 0.337 mmol) and 2-(4-chlorophenyl)-4-methylthiazole-5-carboaldehyde (80.1 mg, 0.337 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 16 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was added to make the mixture basic. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane:ethyl acetate=5:1->2:1) gave 59.4 mg (39%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 120 °C
Yield: 53.9 %

Procedure:
To a solution of N-tert-butyloxycarbonylpiperazine (5 g) in anhydrous dimethylformamide (75 ml) containing triethylamine (7.4 ml), was added 1-fluoro-4-nitrobenzene (3.81 g). The solution was heated at 120° C. for 5 h then the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous phase washed with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was triturated with ether and the resultant yellow solid filtered off. The solid was then chromatographed on silica gel, using a gradient elution of 0→1% methanol in dichloromethane to afford the title compound (4.45 g) as a yellow solid. 1H NMR (360 MHz, CDCl3) δ 1.49 (9H, s), 3.40-3.43 (4H, m), 3.59-3.62 (4H, m), 6.82 (2H, dd, J=9 and 1.8 Hz), 8.13 (2H, dd, J=9 and 1.8 Hz). MS (CI, NH3) 307 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.8 g of 6-chloro-1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 28, and 0.5 g of phenyl chloroformate in 20 ml of methylene chloride is stirred at ambient temperature for 16 hours. Thereafter, the mixture is successively washed with 10% sodium hydroxide, washed with water, dried and concentrated under vacuum leaving a brownish oil. The oil is passed through an alumina column, ether eluant, providing a colorless gum of 6-chloro-1-(2-chlorophenyl)-1'-phenoxycarbonylspiro[indoline-3,4'-piperidine]. IR and NMR spectra confirm the assigned structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.BrC1C=C(O)C=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]2[C:23]=1[C:24](=[O:41])[C:25](=[O:40])[N:26]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39].FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:41][C:24]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:23]2[C:27](=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:22]=2[O:21][CH3:20])[N:26]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:25]1=[O:40]
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: COCCOCCN1C(=O)C(=O)c2c(OC)ccc(OC)c21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COCCOCCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c(OC)ccc(OC)c21

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one was obtained (53%): MS (ES+) m/z 443.9 (M−17).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[N:10])[CH2:5][CH2:4]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O.Cl>N1C=CC=CC=1>[S:11]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[N:10])[CH2:5][CH2:4]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1CCC(CO)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.20 g of the 4-(hydroxymethyl)cyclohexanecarbonitrile obtained in 5 ml of pyridine was treated portionwise with 2.46 g of tosyl chloride at room temperature and while gassing with argon. After stirring at room temperature for 3.5 hours (formation of a white precipitate), the mixture, cooled to 0° C., was treated with about 2 ml of water, cautiously made acid with about 7 ml of concentrated hydrochloric acid and extracted three times with 30 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated, there remaining behind 2.31 g of a semi-crystalline oil. Low-pressure chromatography (0.5 bar) on 480 g of silica gel using 30% ethyl acetate/petroleum ether as the eluant gave 1.06 (42%) of trans-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, crystallizing oil (m.p. 84°-85° C.) and 1.03 g (41%) of cis-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, viscous oil. Rf values (30% ethyl acetate/petroleum ether): trans product 0.25, cis product 0.20.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C:13]2[C:20]([CH3:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[CH3:22])[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>O>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([NH:23][C:2]2[N:3]=[C:4]([O:12][C:13]3[C:20]([CH3:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[CH3:22])[C:5]3[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:25][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccn(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 90 °C
Reaction time: 48 h
Yield: 35.9 %

Procedure:
In a sealed tube was added 4-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (294 mg, 0.94 mmol), 4-aminobenzonitrile (455 mg, 3.77 mmol), TFE (3.1 mL) and TFA (0.58 mL, 7.52 mmol). The reaction mixture was stirred at 90° C. for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (4:1-1:2), to give the product as an off-white solid (133 mg, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-3-methylphenol (4.86 g) and imidazole (2.65 g) in DMF (100 mL) was added tert-butyldimethylchlorosilane (4.70 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.97 g) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:28]=[C:29](F)[CH:30]=1)[CH2:5][C@@H:6]([C@@H:10]([C@H:12]1[CH2:16][C@@H:15](OCC=C)[CH2:14]N1C(OC(C)(C)C)=O)O)C(O)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:36][C@H:37]1[C@@H:41]([C@H:42]2[CH2:47][CH2:46][CH2:45][CH2:44][NH:43]2)[O:40]C(=O)[NH:38]1.FC1C=C(C=C(F)C=1)C[C@H](C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C@@H:37]([CH2:36][C:35]1[CH:34]=[C:33]([F:32])[CH:51]=[C:50]([F:52])[CH:49]=1)[C@@H:41]([C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][N:43]1[CH:5]([C:4]1[CH:3]=[CH:2][CH:30]=[CH:29][CH:28]=1)[C:6]1[CH:10]=[CH:12][CH:16]=[CH:15][CH:14]=1)[OH:40]
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CCCCN2)O1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step I (6): Preparation of (4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-piperidin-2-yl)oxazolidin-2-one. A solution of (R)-tert-butyl 2-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)piperidine-1-carboxylate (Step I (5), 200 mg) in CH2Cl2 (4 mL) was treated with TFA (2 mL). This reaction mixture was stirred at rt for 1 h. The mixture was then concentrated in vacuo with addition of toluene. 1N HCl solution (50 mL) was added and the mixture was extracted with diethyl ether, neutralized with 50% aqueous NaOH to pH=12. The mixture was extracted with ethyl acetate (50 mL) twice. The combined organic layers were dried (Na2SO4), and concentrated in vacuo to give 132 mg of the title compound:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].BrCC1C[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]1.[ClH:50]>>[ClH:50].[ClH:50].[CH2:1]([O:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][CH:24]2[CH2:25][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCC3CCNCC3)cc2OCc2ccccc2)n1
Yield: 64.6 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (46.9 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(piperidin-4-ylmethylthio)pyridin-2-amine dihydrochloride (54.4 mg, 64.6% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.20 (bs, 1H), 9.00 (bs, 1H), 7.97 (m, 1H), 7.65 (m, 3H), 7.45-7.30 (m, 3H), 6.90 (s, 1H), 5.41 (s, 2H), 3.75-3.45 (m, 3H), 3.20 (m, 2H), 2.95 (m, 2H), 2.76 (m, 2H), 2.34 (s, 3H), 1.88 (m, 2H), 1.64 (m, 1H), 1.42 (m, 2H); Mass spectrum (apci) m/z=427.1 (M+H-2HCl).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C@@H:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.[OH-].[Li+]>C1COCC1>[CH2:25]([C@H:6]1[CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:9][CH2:10][N:5]1[CH2:4][C:3]([OH:32])=[O:2])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester (Example 57) (342 mg, 0.78 mmol) in THF (5 mL) at room temperature was treated with an aqueous solution (1 mL) containing lithium hydroxide monohydrate (36 mg, 0.858 mmol). The reaction mixture was allowed to stir for 2 h and then evaporated to a small volume. The reaction mixture was then dissolved in water (5 mL) and the pH adjusted to ˜7 with 1 N HCl to precipitate product. The precipitate was then triturated with water (2×5 mL) and dried under a stream of nitrogen to afford product as a colorless solid (318 mg, 96%). 1H NMR (CDCl3) 1.43-1.57 (m, 2H), 1.77-1.79 (m, 6H), 3.02-3.15 (m, 2H), 3.27 (br s, 2H), 3.51 (br s, 1H), 3.74 (s, 3H), 3.77-3.89 (m, 2H), 4.57-4.59 (m, 1H), 6.24-6.31 (m, 2H), 6.55 (br s, OH), 6.67 (d, J=8.6, 1H) 7.18-7.27 (m, 5H). LC/MS 5.34 min, [M+1]+ 425.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:19]([C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=4)=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:41])=[CH:9]1)[CH2:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:55][CH2:56][OH:57]>C(#N)C.O>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:19]([C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[N:34]=4)=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:43][CH2:44][N:45]([CH2:55][CH2:56][OH:57])[CH2:46][CH2:47]2)=[O:41])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCNCC2)cn3C(COC)COC)cn1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(CCO)CC2)cn3C(COC)COC)cn1
Temperature: 55 °C
Yield: 33.9 %

Procedure:
1-{5-[1-(1,3-Dimethoxypropan-2-yl)-4-oxo-3-(piperazin-1-ylcarbonyl)-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea (Example 140, 180 mg, 0.267 mmol) was dissolved in acetonitrile (15 mL). Potassium carbonate (73.7 mg, 0.53 mmol) was added, followed by the addition of 2-bromoethanol (40 mg, 0.32 mmol) and the mixture was heated to 55° C. for 16 h. The reaction mixture was filtered, and the filtrate was concentrated and dried to give the crude compound. The crude was dissolved in water (10 mL) and the pH was adjusted to 2. The aqueous solution was washed with ethyl acetate, then basified to pH˜8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 65 mg (34%) of 1-{5-[1-(1,3-dimethoxypropan-2-yl)-3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-4-oxo-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][O:24][CH3:25])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[C:19]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][O:24][CH3:25])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COCOc1ccc(I)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(-c2ccccn2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide (0.20 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (8 ml). Tri-n-butyl(2-pyridyl)tin (0.13 ml, 0.41 mmol) and dichlorobis(triphenylphosphine)palladium (32.1 mg, 0.05 mmol) were added, and the mixture was stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (37.9 mg, 20.8%) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:28]3[CH2:33][CH2:32][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]3)[CH2:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=3[F:27])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH3:40][C:41]1[C:46]([C:47]([OH:49])=O)=[C:45]([CH3:50])[N:44]=[CH:43][N:42]=1>>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([F:27])=[C:19]([CH:24]=1)[CH2:18][N:17]([CH:28]1[CH2:29][CH2:30][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:47]([C:46]2[C:41]([CH3:40])=[N:42][CH:43]=[N:44][C:45]=2[CH3:50])=[O:49])[CH2:32][CH2:33]1)[C:14]1[CH:13]=[CH:12][C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][CH:8]=2)=[CH:16][CH:15]=1)#[N:26]
Reactant: COC(=O)c1ccc(Oc2ccc(N(Cc3cc(C#N)ccc3F)C3CCN(C(C)CCN)CC3)cc2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
Using general procedure E with the above amine (90 mg, 0.17 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (29 mg, 0.19 mmol) and then using general procedure K with the resulting ester afforded COMPOUND 228 as a white solid (40 mg, 36% over 2 steps). 1H NMR (CDCl3) δ 1.14-1.26 (m, 3H), 1.67-2.19 (m, 4H), 2.40-2.59 (m, 1H), 2.48 (s, 6H), 2.73-2.85 (m, 1H), 3.01-3.17 (m, 3H), 3.32-3.36 (m, 2H), 3.38-3.51 (m, 1H), 3.58-3.75 (m, 2H), 4.20-4.35 (m, 2H), 6.69 (d, 2H, J=8.4 Hz), 6.82-6.92 (m, 4H), 7.10-7.18 (m, 1H), 7.49-7.61 (m, 2H), 7.71 (d, 2H, J=7.8 Hz), 8.41 (br s, 1H), 8.87 (s, 1H). 13C NMR (CDCl3) δ 12.80, 22.42, 27.60, 28.02, 32.11, 38.06, 44.46, 51.32, 53.84, 56.22, 58.67, 108.95, 116.92, 117.30, 118.65, 121.60, 127.77, 129.38 (d, J=15 Hz), 130.85, 131.82, 133.35, 144.82, 148.94, 157.73, 161.83, 163.01 (d, J=256 Hz), 163.50, 167.60, 171.81. ES-MS m/z 651 (M+H). Anal. Calcd. for C37H39N6O4F.1.1CH2Cl2: C, 61.49; H, 5.58; N, 11.29; F, 2.55. Found: C, 61.44; H, 5.70; N, 11.14; F, 2.38.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[Cl:22][C:23]1[N:28]=[C:27](/[CH:29]=[CH:30]/[C:31]#[N:32])[CH:26]=[CH:25][CH:24]=1>>[Cl:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH2:32])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: N#C/C=C/c1cccc(Cl)n1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Product: Nc1cc(-c2cccc(Cl)n2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):323 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and E-3-(6-chloro-pyridin-2-yl )-acrylonitrile.
Reaction SMILES: CO.[NH3:3].[Si:4]([O:21][CH2:22][C@@H:23]1[CH2:27][C@H:26]([N:28]2[C:32]3[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=3[C:30]([I:38])=[CH:29]2)[CH2:25][N:24]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[NH2:3][C:36]1[C:31]2[C:30]([I:38])=[CH:29][N:28]([C@@H:26]3[CH2:25][N:24]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:23]([CH2:22][O:21][Si:4]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:27]3)[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(N)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
THF (10 ml) and an 8N ammonia methanol solution (5 ml) were added to the (2S,4S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (400 mg) obtained in Step 1. The mixture was stirred at 120° C. for 2 hours under microwave irradiation, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/ethanol) to obtain the title compound as a light-yellow solid (293 mg). Physical properties: m/z [M+H]+ 698.5