Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C@@H:16]1[CH2:23][N:22]2[C:24]3[CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=[CH:28][C:29]=3[C:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:21]2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17]1.[BH3-]C#N.[Na+]>C(OC)(OC)OC>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:15][C@@H:16]1[CH2:23][N:22]2[C:24]3[CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=[CH:28][C:29]=3[C:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:21]2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1ccccc1-3
Reactant: OCCOCCOCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCCOCCOCc1ccccc1)COc1ccccc1-3
Product: O=CCOCCOCc1ccccc1
Reaction time: 4 h
Yield: 35 %

Procedure:
[2-(benzyloxy)ethoxy]acetaldehyde was prepared by Swern oxidation of commercially available 2-[2-(benzyloxy)ethoxy]ethanol. A 0.15M solution of the foregoing aldehyde and methyl (7R)-7-amino-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 1, Step 4) in CH(OMe)3 was stirred overnight at RT; the residue obtained after removing volatiles in vacuo was dissolved in MeOH (0.15M solution), NaCNBH3 (2.3 eq) was added and the mixture was left stirring for 4 h. All volatiles were evaporated and the residual material was dissolved in EtOAc and washed with sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo; FC (Biotage, PE/EtOAc 1:1 to 1:3 with 0.5% NEt3) afforded 35% of methyl (7R)-7-({2-[2-(benzyloxy)ethoxy]ethyl}amino)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:17][CH3:18])(O)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:19]=1)=[O:4].[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=CC=1.B(F)(F)F.[CH3:32][CH2:33]OCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:32][CH3:33])([C:17]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([CH3:27])[CH:18]=3)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:19]=1)=[O:4]
Reactant: CCOCC
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1cc2cc(C(=O)OC)ccc2o1
Agent: FB(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(C(=O)OC)ccc2o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
To a mixture of 2-(1-ethyl-1-hydroxy-propyl)-benzofuran-5-carboxylic acid methyl ester (6.01 g, 22.9 mmol) and o-cresol (3.71 g, 34.4 mmol) in CH2Cl2 (150 mL) at −78° C. is added BF3-Et2O (1.63 ml, 11.5 mol). After stirring for 5 min, the reaction mixture is allowed to warm up to 0° C. over 30 min. The reaction is quenched with water (50 mL) and extracted with CH2Cl2 (50 mL). The organic layer is dried over Na2SO4, concentrated, purified on column chromatography (15-20% EtOAc/Hex) to afford the title compound (7.38 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:18])=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1>CCO.[Pd]>[ClH:18].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 7-methoxy-4-chloro-3-ethoxycarbonylquinoline (Step B, 1.53 g, 5 mmol) in EtOH (15 mL) under inert atmosphere was added Pd/C 10% (153 mg). The mixture was stirred at RT under H2 (atmospheric pressure) for 2 h. The mixture was filtered and solvent removed under vacuum to give crude 7-methoxy-3-ethoxycarbonylquinoline hydrochloride.
Reaction SMILES: [C:1]([C:4]1([NH:37]C(=O)OC(C)(C)C)[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[C:24]4[C:19](=[CH:20][N:21]=[C:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:23]=4)[N:18](C4CCCCO4)[N:17]=3)[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].Cl>CO.O1CCOCC1>[NH2:37][C:4]1([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[C:24]4[C:19](=[CH:20][N:21]=[C:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:23]=4)[NH:18][N:17]=3)[N:11]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)C1(N)CCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A mixture of 45 mg (0.08 mmol) of tert-butyl 4-carbamoyl-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate in 3 ml of methanol and 12 ml of 4 N solution of HCl in dioxane was stirred for 18 hours. The mixture was concentrated in vacuum, the residue purified via reverse phase HPLC using a gradient of MeCN in water with 0.1% HCOOH to afford 20 mg (43%) of 229. ESI MS m/z 415.2 (M+1). 1H NMR (400 MHz, DMSO): 9.22 (d, J=5.7 Hz, 2H), 8.94 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.40-8.32 (m, 4H), 7.67 (t, J=7.9 Hz, 1H), 7.54 (dd, J=8.0, 4.8 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.20 (d, J=13.2 Hz, 1H), 3.50 (t, J=11.4 Hz, 1H), 2.06 (td, J=13.0, 4.2 Hz, 1H), 1.48 (d, J=13.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[O:29][CH:30]=2)[N:3]=1.Cl.N([CH2:41][C:42]([O:44][CH3:45])=[O:43])C.[CH2:46](N(CC)CC)C>C1COCC1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[O:29][CH:30]=[C:26]([CH2:25][S:24][C:4]3[N:3]=[C:2]([N:1]([CH3:46])[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]#[N:9])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:14][CH:15]=4)[C:5]=3[C:22]#[N:23])[N:27]=2)=[CH:36][CH:35]=1
Reactant: CCN(CC)CC
Reactant: CNCC(=O)OC
Reactant: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CN(C)c1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
451 mg (0.51 mmol) of the compound from Example 40A were dissolved in 7.8 ml of dry THF, and 141 mg (1.01 mmol) of methyl sarcosinate hydrochloride and 211 μl (1.52 mmol) of triethylamine were then added in succession. The reaction mixture was stirred at RT for 8 h. After removal of the solvent, the mixture was purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[F:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[O:21][C:20]([CH2:22][C:23](Cl)=[N:24][OH:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[F:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[O:21][C:20]([CH2:22][C:23]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(F)cc2)o1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Cc4ccc(F)cc4)o3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 32.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and (5-(4-fluorobenzyl)-furan-2-yl)acetohydroximoyl chloride (161 mg, 0.602 mmol) described in Manufacturing Example 208-1-5 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 19 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and 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:heptane=1:1, then ethyl acetate) to obtain the title compound (45 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CO.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[OH:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (0.10 g, 0.24 mmol) was dissolved in THF (5 mL). The mixture was cooled on an ice bath and phenylmagnesium bromide (3 M, 0.79 mL, 2.37 mmol) was added over 30 min. MeOH and ammonium chloride (aq, sat) were added. The mixture was extracted with EtOAc (×2). The organic phase was filtered through a pad of silica and sodium sulfate. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film, 50 mg (22%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[CH:15][C:16]([CH2:17][NH2:18])=[C:9]23)C=CC=CC=1.[CH:31](OCC)=[O:32]>>[N:14]1[N:10]2[CH2:11][CH2:12][CH2:13][NH:8][C:9]2=[C:16]([CH2:17][NH:18][CH:31]=[O:32])[CH:15]=1
Reactant: NCc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CCC2
Reactant: CCOC=O
Product: O=CNCc1cnn2c1NCCC2
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of 1-(4-triphenylmethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methylamine (8.4 g) in ethyl formate (30 ml) was stirred at 50° C. for 16 hours. After evaporation of the solvent in vacuo, the residue was triturated with ethyl acetate and dried in vacuo to give N-[(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methyl]formamide (3.0 g) as a solid.
Reaction SMILES: Cl.Cl.[CH:3]([N:16]1[CH2:21][C@@H:20]2[CH2:22][C@H:17]1[CH2:18][NH:19]2)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH:3]([N:16]1[CH2:21][C@@H:20]2[CH2:22][C@H:17]1[CH2:18][N:19]2[C:27]1[N:28]=[CH:29][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:32]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: c1ccc(C(c2ccccc2)N2C[C@@H]3C[C@H]2CN3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3C(c2ccccc2)c2ccccc2)nc1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
Title compound 201 (0.250 g, 0.741 mmol), ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (0.122 g, 0.529 mmol), potassium carbonate (0.280 g, 2.645 mmol) and DME (5 mL) were combined. The reaction mixture was stirred at 50 oC for 2 hours. The mixture was cooled down and quench with water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography eluting with 0% to 30% ethyl acetate in hexanes to afford title compound 202 (0.141 g, 64%). LRMS (ESI): (calc) 414.21 (found) 415.0 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:31][CH2:32]1)[CH3:19]
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: CCOc1ccccc1N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-ethoxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=428.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Fc1ccccn1
Reactant: Oc1cc(F)c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)c(Oc2ccccn2)cc1F
Temperature: 120 °C
Yield: 58.5 %

Procedure:
To a solution of 2-bromo-4,5-difluoro-phenol (1 g, 4.78 mmol) in N,N-dimethylformamide were added K2CO3 and 2-fluoropyridine (0.46 g, 4.78 mmol) and heated at 120° C. for overnight. One more equivalent of 2-fluoropyridine was added and heated at 150° C. for 12 h. The reaction mixture was dissolved in ethyl acetate, washed with 1M NaHCO3, concentrated and purified by flash column chromatography using 0%, 5% and 10% of ethyl acetate in hexanes to yield 0.8 g (59%) of product. MS (ESI+) m/z 286 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.CCOCC.Cl>[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH3:23])[C:4]([OH:32])=[O:3])=[CH:8][CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.08 mL of 4-tert-butylbenzyl bromide is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 45 mg (45%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, 2H, J=8.4 Hz), 7.18, 7.16 (ABq, 4H, J=8.6 Hz), 6.96-6.92 (m, 2H), 6.88-6.85 (m, 2H), 6.77 (d, 2H, J=8.8 Hz), 4.38, 4.29 (ABq, 2H, J=14.8 Hz), 3.98 (t, 2H, J=6.0 Hz), 3.69 (bs, 1H), 3.73-3.66 (m, 1H), 3.44 (t, 1H, J=8.6 Hz), 3.25, 3.11 (ABq, 2H, J=13.8 Hz), 3.06 (t, 1H, J=8.6 Hz), 2.86 (s, 3H), 2.28-2.19 (m, 1H), 1.97-1.89 (m, 1H), 1.38 (s, 3H), 1.30 (s, 9H). HRMS (ES+) m/z exact mass calcd for C33H40N2O5F (m+1) 563.2921, found 563.2917.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[O:32][CH2:31][CH2:30][O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:29]1[CH2:30][CH2:31][O:32][CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([Br:1])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: BrCCCCCCCCC1OCCO1
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a stirred solution of benzyl 3-bromo-5-hydroxybenzoate (2.85 g, 9.22 mmol) in dimethyl formamide (50 mL), was added 2-(8-bromooctyl)-1,3-dioxolane (2.44 g, 9.21 mmol) and potassium carbonate (1.91 g, 13.8 mmol), and the mixture stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulphate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-7% ethyl acetate in iso-hexane to afford the title compound (2.94 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][C:48](Cl)=[O:49].C(N(C(C)C)CC)(C)C>ClCCl>[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][C:48]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2)=[O:49]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)Cc5cccs5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40 mg of product obtained in stage 4 are mixed with 11.4 mg of 2-thiopheneacetyl chloride, 25 μl of diisopropylethylamine and 2 ml of dichloromethane. The mixture is stirred for 1 hour at ambient temperature, and then washing with brine, drying over magnesium sulfate and evaporation to dryness are carried out.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[C:9]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:8][C:7]=2[CH3:18])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CCCCCC>[Br:20][CH2:16][C:15]1([CH3:17])[O:13][C:10]2=[C:11]3[C:6](=[C:7]([CH3:18])[CH:8]=[C:9]2[CH2:14]1)[NH:5][C:4](=[O:19])[C:3]([CH2:1][CH3:2])=[CH:12]3
Reactant: C=C(C)Cc1cc(C)c2[nH]c(=O)c(CC)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Yield: 99.1 %

Procedure:
Using 3-ethyl-6-(2-methyl-2-propenyl)-5-hydroxy-8-methylcarbostyril (710 mg, 2.76 mmol) and N-bromosuccinimide (516 mg, 2.90 mmol), the procedure of Example 227 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane) to obtain 920 mg of the title compound as pale yellow crystals (99.2%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]([CH3:24])[NH:19][C:20](=[O:23])[NH:21][N:22]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:18]([CH3:24])[NH:19][C:20](=[O:23])[NH:21][N:22]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2C(=O)C1CC1
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
Cyclopropanecarbonyl chloride (0.47 g) was added dropwise to a stirred solution of 6-(1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.73 g) and triethylamine (0.6 g) in N,N-dimethylformamide (7.3 ml) under ice cooling and the stirring was continued for 30 minutes. The solution was evaporated in vacuo and the residue was dissolved in chloroform. The solution was washed with diluted hydrochloric acid, dried, and evaporated. The residue was chromatographed on silica gel (5 g) using chloroform and then a mixture of chloroform and methanol (20:1) as an eluents. The eluates were evaporated in vacuo and the oily residue was crystallized from ethanol to give 6-(1-cyclopropanecarbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.26 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>>[Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([S:8](/[N:11]=[C:12]2/[N:13]=[CH:14][N:15]([CH2:23][O:22][CH2:20][CH3:21])[CH:16]=[CH:17]/2)(=[O:9])=[O:10])[CH:7]=1
Reactant: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(F)cc1F
Reactant: CCOCCl
Product: CCOCn1cc/c(=N\S(=O)(=O)c2cc(Cl)c(F)cc2F)nc1

Procedure:
Prepared according to the process of Preparation 716 using 5-chloro-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide, Preparation 723 and chloromethyl ethyl ether. The product was a mixture of three regioisomers that were not separated and used in subsequent reactions as a mixture.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CCO[C:12]([S-:14])=S.[K+].[CH3:16]CO>>[CH3:16][S:14][C:12]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1ncccc1O
Reactant: CCO
Reactant: CCOC(=S)[S-]
Agent: [K+]
Product: CSc1nc2ncccc2o1
Temperature: 78 °C
Reaction time: 18 h

Procedure:
2-(Methylthio)oxazolo[4,5-b]pyridine was prepared according to the procedures of Chu-Moyer and Berger (J. Org. Chem. 1995, 60, 5721-5725) with minor modifications. To a suspension of 2-amino-3-hydroxypyridine (2.8 g, 25 mmol) in EtOH (62 mL, 0.4 M) was added potassium ethyl xanthogenate (8.0 g, 50 mmol, 2 equiv). The reaction mixture was heated to reflux (78° C.) and stirred for a period of 18 hours. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in water (70 mL). Upon acidification to pH 5 with glacial acetic acid, a large quantity of solid precipitated out. The suspension was filtered, washed with water (3×), and dried on the high-vac line overnight to afford 2-thiooxazolo[4,5-b]pyridine as a brown solid (3.3 g, 21.6 mmol, 86%).