Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:16]([OH:18])=[O:17])=[C:11]3[C:6]([CH:7]=[C:8]4[CH:22]=[CH:21][CH:20]=[CH:19][C:9]4=[CH:10]3)=[N:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.[CH2:30]([N:32]([CH2:35][CH2:36]Br)[CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:35][CH2:36][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:16]([O:18][CH2:31][CH2:30][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:17])=[C:11]3[C:6]([CH:7]=[C:8]4[CH:22]=[CH:21][CH:20]=[CH:19][C:9]4=[CH:10]3)=[N:5][C:4]=2[CH:3]=1)[CH2:33][CH3:34])[CH3:31]
Reactant: O=C(O)c1c2ccc(O)cc2nc2cc3ccccc3cc12
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CC)CCOC(=O)c1c2ccc(OCCN(CC)CC)cc2nc2cc3ccccc3cc12

Procedure:
treating 3-hydroxy-benz[b]acridine-12-carboxylic acid with cesium carbonate and diethylaminoethyl bromide hydrobromide to produce N,N-diethylaminoethyl 3-(N,N-diethylamino)ethoxy-benz[b]acridine-12-carboxylate;
Reaction SMILES: [CH2:1]([O:3]C(C1C(OC)=C2C(NC3C=CC(OC4C=CC=CC=4)=CC=3)=C(C#N)C=NN2C=1)=O)C.[OH:33][C:34]([C:37]1[C:38](C)=[C:39]2[C:44]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:48][CH:47]=3)=[C:43]([C:59]#[N:60])[CH:42]=[N:41][N:40]2[CH:61]=1)([CH3:36])[CH3:35].C(O)(C(F)(F)F)=O.O.C(O)(C(F)(F)F)=O.CC#N>>[OH:33][C:34]([C:37]1[C:38]([O:3][CH3:1])=[C:39]2[C:44]([NH:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:50][CH:51]=3)=[C:43]([C:59]#[N:60])[CH:42]=[N:41][N:40]2[CH:61]=1)([CH3:36])[CH3:35]
Reactant: Cc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1OC
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.13 h
Yield: 98 %

Procedure:
The title compound (170 mg, 98%) was prepared from 393 (180 mg, 0.42 mmol) by a route analogous to that used for the preparation of compound 396. It has a retention time of 6.49 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M−H)+=413.3
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:39]4[CH2:40][CH2:41][N:36]([C:33](=[O:35])[CH3:34])[CH2:37][CH2:38]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:31])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CC(F)(F)C4)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and 1-acetylpiperazine. White solid (12%). MS (EI): 598.2 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([N:13]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([C:22]3[CH:23]=[C:24]([C:29]4[CH:34]=[C:33]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)[N:32]=[CH:31][C:30]=4[NH2:41])[C:25](F)=[N:26][CH:27]=3)=[CH:21][C:15]=2[CH2:14]1)[CH3:12]>C1COCC1>[CH2:11]([N:13]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([C:22]3[CH:27]=[N:26][C:25]4[NH:41][C:30]5[CH:31]=[N:32][C:33]([C:35]6[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=6)=[CH:34][C:29]=5[C:24]=4[CH:23]=3)=[CH:21][C:15]=2[CH2:14]1)[CH3:12]
Reactant: CCN1CCc2sc(-c3cnc(F)c(-c4cc(-c5cnn(C)c5)ncc4N)c3)cc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2sc(-c3cnc4[nH]c5cnc(-c6cnn(C)c6)cc5c4c3)cc2C1
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1N solution in THF, 4.5 mL, 4.5 mmol) was added dropwise over 10 minutes to a solution of 5-(5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4′]bipyridinyl-3′-ylamine (638 mg, 1.50 mmol) in anhydrous THF (26 mL). After 30 minutes, the reaction was quenched by the addition of aqueous saturated aqueous potassium fluoride solution (10 mL). The resultant brown solution was partitioned between DCM (75 mL) and brine (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as a white solid (96 mg, 16%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.82 (s, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 4.00 (s, 3H), 3.64 (s, 2H), 3.02-2.95 (m, 2H), 2.93-2.86 (m, 2H), 2.70 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[C:12]([F:19])[CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Nc1ncc(Br)cn1
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1ncc(-c2ccc(Cl)cc2F)cn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
To a 500 mL round-bottomed flask were added 5-bromo-2-aminopyrimidine (4.0 g, 23 mmol), 4-chloro-2-fluorophenylboronic acid (3.9 g, 23 mmol), palladium(II)trifluoroacetate (240 mg, 0.72 mmol), and triphenylphoshine (373 mg, 1.40 mmol). The reaction vessel was fitted with a rubber septum, sparged with nitrogen and then charged with sparged toluene (75 mL), ethanol (75 mL), and a 2M solution of sodium carbonate (42 mL, 84 mmol) (solvents were sparged individually nitrogen gas for 30 minutes). The resulting mixture was stirred vigorously and heated at 50° Celsius. After 12 hours, the mixture was cooled to rt and treated with 100 mL of water. The precipitate was isolated via vacuum filtration, and the filtrate extracted with EtOAC. The EtOAc solution was dried, filtered and concentrated to dryness. The resultant solids were recrystallized from IPA (80 mL) to afford title compound (3.8 g, 74%). MS (ESI): mass calcd. for C10H7ClFN3, 223.03; m/z found, 224.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J=1.4, 2H), 7.59 (m, 1H), 7.54 (dd, J=10.7, 2.1, 1H), 7.37 (dd, J=8.3, 2.1, 1H), 6.94 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][C@@H:38]([OH:40])[CH3:39]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][C@@H:38]([OH:40])[CH3:39])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: C[C@H](O)CN
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: C[C@H](O)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 291 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.464 mmol) and (S)-(+)-1-amino-2-propanol (348 mg, 4.64 mmol), the title compound was obtained as an off white solid (40 mg, 14%). MS (ESI): 578 [M+H]+.
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:3][CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6]
Reactant: O=CNC(CO)CCOc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(CO)CCOc1cccc2ccccc12
Temperature: 45 °C

Procedure:
A solution of 2-(formylamino)-4-(1-naphthyloxy)butanol (7.1 g), prepared as described in Example 3, in dry THF (150 ml) is added dropwise to a suspension of LiAlH4 (5.0 g) in THF (150 ml). The mixture is heated at 45° C for 3 hours and cooled. Excess LiAlH4 is destroyed by the careful addition of THF/water (9:1). The mixture is filtered through diatomaceous earth (Celite). The filtrate is dried and evaporated. The residue is crystallized from diethyl ether to give the title compound, γmaxCHCl3 3650, 3352, 1595 and 1580 cm-1.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6]N.[OH-:22].[Na+]>O.O1CCOCC1.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[N-]=O.O.O.[Na+].[Na+].[Fe+4]>[C:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:22])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Fe+4]
Agent: [C-]#N
Agent: [N-]=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCO)C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
A vigorously stirred solution of Boc-Lys-OtBu 2 (6.20 g, 20.5 mmol) in water (120 mL) and dioxane (60 mL) was warmed to 65° C. and treated with sodium nitroprusside (SNP, Na2[Fe(CN)5NO].2H2O) (9.8 g, 33 mmol) portionwise over 1 hour. The reaction mixture was stirred at 65° C. for an additional 4 hours while its pH was maintained at 9-10 by addition of 2M NaOH. It was then cooled to room temperature and filtered through a pad of CELITE. The filtrate was extracted with EtOAc (6×100 mL) and the combined extracts were dried (MgSO4), filtered, and evaporated in vacuo to give a purple oil. Its purification by flash chromatography (silica gel; hexanes/EtOAc, 8/1→3/7) gave the title compound 25 (2.28 g, 37%) as a clear oil.
Reaction SMILES: Br[CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:3]=O.[CH3:18][NH:19][C:20]([NH:22][CH3:23])=[S:21]>C(O)C>[CH3:23][N:22]1[CH:3]=[C:2]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[S:21]/[C:20]/1=[N:19]\[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Reactant: CNC(=S)NC
Solvent: CCO
Product: C/N=c1\sc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1C
Yield: 68 %

Procedure:
tert-Butyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (WO 0059502: 21.0 g) and a solution of N,N′-dimethylthiourea (6.0 g) in ethanol (300 mL) were heated under reflux. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate and water. The aqueous layer was collected by separation. The aqueous layer was basified with an aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off to give the title compound (12.2 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[CH2:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[CH3:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: C=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccc2ncccc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Reaction time: 10 h

Procedure:
6-{1-[6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-vinyl}-quinoline (Example 155, 2.2 g, 6.24 mmol) was dissolved in ethanol (300 mL) and hydrogenated under H2 atm. at rt in presence of Pd/5% C. After 10 h, the RM was filtered over Celite and the filtrate evaporated under vacuo. The residue was dried over night under vacuo and eluted on a silica gel column with EtOAc/MeOH=9:1 then 85:15 to afford, after evaporation of the solvent, the title compound as a yellow foam (tR 3.21 min (conditions 3), MH+=355).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9].[N+:10]([O-])([O-:12])=[O:11].[K+].[OH-].[NH4+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Nc1nccc(Cl)c1I
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: Nc1ncc([N+](=O)[O-])c(Cl)c1I
Temperature: 0 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
A solution of 4-chloro-3-iodopyridin-2-amine (0.25 g, 0.982 mmol, Boa Pharma) in concd H2SO4 (1.95 mL) was cooled to about 0° C. before the portion wise addition of potassium nitrate (0.21 g, 2.2 mmol) over 10 min. The reaction was stirred for about 4 h at about 0° C. The reaction mixture was slowly pipetted over a solution of ammonium hydroxide and crushed ice (10 mL) in an ice bath. The pH of the reaction was maintained above 9 by the incremental addition of ammonium hydroxide. The resulting precipitate is filtered and dried to afford 4-chloro-3-iodo-5-nitropyridin-2-amine (0.085 g, 29%) as a green-tinted solid LC/MS (Table 1, Method n) Rt=0.64 min; MS m/z: 298 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].C[O-].[Na+].[Cl-].[NH4+]>CO>[CH3:9][O:10][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1Cl
Reaction time: 7 h

Procedure:
Commercially available 2,3 dichloropyrazine was dissolved in a suitable amount of methanol to which was added a slight excess of an alkali methoxide, preferably 1.05 equiv. of sodium methoxide. The mixture was then stirred for a period of 1-24 hr, preferably 7 hr, after which time the solution was neutralized with solid ammonium chloride, the solvent removed in vacuo, the residue taken up in an organic solvent chosen from a group consisting of diethyl ether, ethyl acetate, and methylene chloride, preferably methylene chloride, and filtered to remove unwanted salts. The filtrate was reduced in vacuo to afford 2-methoxy-3-chloro-pyrazine as white crystals which were used without further purification.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(=CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-N-(2-(3-(2-Methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (2.3 g, 5.6 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (1.4 ml) was added. The reaction mixture was stirred at room temperature for 4 h. A concentrated hydrochloric acid solution was added with cooling of the reaction vessel in an ice-bath until pH 1 and dichloromethane (250 ml) was added. The resulting emulsion was dried (Na2SO4) and the solvent was evaporated in vacuo to give a residue which was crystallised from acetone. This afforded 1.75 g (76%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:10]([N:15]=2)=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:2]=1.CCCCCC.[H-].[Na+].Br[CH2:25][C:26]1[CH:43]=[CH:42][C:29]([C:30]([N:32]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[O:44][CH3:45]>CC(N(C)C)=O>[CH:36]1([N:32]([CH:33]([CH3:35])[CH3:34])[C:30](=[O:31])[C:29]2[CH:42]=[CH:43][C:26]([CH2:25][N:11]3[CH:12]=[CH:13][CH:14]=[C:9]4[N:8]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[N:15]=[C:10]34)=[C:27]([O:44][CH3:45])[CH:28]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: c1cncc(-c2nc3ncccc3[nH]2)c1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Cn1cccc2nc(-c3cccnc3)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
2-(3-Pyridyl)-1H imidazo(4,5-b)pyridine (1.3 g, 6.6 mmol) was added to a hexane-washed suspension of NaH (175 mg, 7.26 mmol) in dimethylacetamide (15 ml) under Ar and stirred under an argon atomsphere for one hour at 25° C. 4-Bromomethyl-3-methoxy-N-cyclohexyl-N-isopropylbenzamide (2.5 g, 6.6 mmol) was added portionwise over 30 minutes and the mixture stirred overnight at 25° C. The solvent was removed via oil pump at <50° C. and the residue was chromatographed using 7/3/0.5 CH2Cl2 /MeOH/NH4OH as the eluent to produce the title compound (1.70 g, 52%). An analytical sample was prepared by recrystallization from ethyl acetate, m.p. 185°-188° C. Anal. Calc. for C29H33N5O2.0.5H2O: C, 70.71; H, 6.96; N, 14.22. Found: C, 70.88; H, 6.80; N, 14.18.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[O:13][NH:12][C:11](=[O:14])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH3:18]>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[O:13][N:12]([CH2:17][CH3:18])[C:11](=[O:14])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CC(=O)NO1
Reactant: CCBr
Product: CCN1OC(CNC(=O)OC(C)(C)C)CC1=O

Procedure:
The product obtained in Step B (0.1 g) was alkylated with bromoethane as described in Example 4, step A to afford the O-alkylated product (18 mg), 1HNMR (CDCl3, 400 MHz): 4.90 (m, 1H), 4.70 (m, 1H), 4.2 (q, 2H), 3.35 (m, 2H), 3.00 (dd, 1H), 2.75 (dd, 1H), 1.50 (s, 9H), 1.35 (t, 3H); and the title N-alkylated product (63 mg). 1HNMR (CDCl3, 400 MHz): 4.85 (m, 1H), 4.55 (m, 1H), 3.60 (m, 2H), 3.40 (m, 2H), 2.80 (dd, 1H), 2.60 (dd, 1H), 1.50 (s, 9H), 1.20 (t, 3H).
Reaction SMILES: [I:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([CH:12]([CH3:14])[CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][C:9]#[N:10].C(O[CH:22]([N:26]([CH3:28])[CH3:27])[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:28][N:26]([CH3:27])[CH:22]([N:23]([CH3:24])[CH3:25])[CH:8]([O:7][C:6]1[CH:11]=[C:2]([I:1])[C:3]([O:15][CH3:16])=[CH:4][C:5]=1[CH:12]([CH3:14])[CH3:13])[C:9]#[N:10]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(C(C)C)c(OCC#N)cc1I
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(OC(C#N)C(N(C)C)N(C)C)cc1I
Temperature: 100 °C

Procedure:
To a solution of (5-iodo-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (250 g, 0.75 mol) in 500 ml of DMF, t-butoxybis(dimethylamino)methane (167 g, 0.96 mol) was added. The mixture was heated to 100° C. for 4 hours, then cooled to 25° C. to provide a DMF solution of 3,3-bis-dimethylamino-2-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-propionitrile (not isolated). To this solution was added aniline hydrochloride (225 g, 1.7 mol), and the resultant mixture was heated to 100° C. for 11 hours. After cooling to 60° C., 100 ml of isopropanol was added, followed by 1 L of water, at a rate to maintain an internal temperature of 50° C. The resulting slurry was cooled to 20° C. and aged. Precipitated 2-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrile was collected by filtration, washed with isopropanol until the filtrate was colorless, and dried in a vacuum oven (50° C., 24 inches Hg) to give 310 g of 2-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrile, 93% yield: Melting Point: 170° C.; 1HNMR (CDCl3) δ=1.3 (d, 6H), 3.3 (m, 1H), 3.85 (s, 3H), 6.6 (d, 2H), 6.75 (s, 1H), 6.9 (d, 2H), 7.05 (t, 1H), 7.15 (d, 1H), 7.3 (t, 3H)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCCl.CS(C)=O.[CH3:14][C:15]1[C:20]2[CH2:21][CH2:22][CH:23]([CH2:25][OH:26])[O:24][C:19]=2[CH:18]=[C:17]([CH3:27])[CH:16]=1>O.C(N(CC)CC)C>[CH3:14][C:15]1[C:20]2[CH2:21][CH2:22][CH:23]([CH:25]=[O:26])[O:24][C:19]=2[CH:18]=[C:17]([CH3:27])[CH:16]=1
Reactant: Cc1cc(C)c2c(c1)OC(CO)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c2c(c1)OC(C=O)CC2
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a stirred solution of 72 parts of ethanedioyl dichloride in 650 parts of dichloromethane were added, during a period of 10 minutes, 83.5 parts of dimethyl sulfoxide at -60° C. and under nitrogen atmosphere. After stirring for 10 minutes, a solution of 97 parts of 3,4-dihydro-5,7-dimethyl-2H-1-benzopyran-2-methanol in 130 parts of dichloromethane was added during a 5 minutes period. The whole was stirred for 15 minutes and 242.9 parts of N,N-diethylethanamine were added. The reaction mixture was allowed to reach room temperature. It was poured into water. The product was extracted with dichloromethane. The extract was washed successively with water, a hydrochloric acid solution 10%, water, a sodium hydrogen carbonate solution 10% and water, dried, filtered and evaporated. The oily residue was crystallized from a small amount of petroleumether. The product was filtered off and dried, yielding 58 parts (72%) of 3,4-dihydro-5,7-dimethyl-2H-1-benzopyran-2-carboxaldehyde (intermediate 34).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][OH:6])=[O:4].[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][C:3]([NH:5][OH:6])=[O:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCC(=O)NO
Reactant: O=S(=O)(Cl)c1ccc(OCCCCF)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNS(=O)(=O)c1ccc(OCCCCF)cc1)NO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the resin from stage 58.1 (350 mg, ˜0.3 mmol) are added successively 4-(4-fluorobutoxy)-benzenesulfonyl chloride (306 mg, 1.15 mmol) in dry dichloromethane (4 ml), and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) in dry dichloromethane (4 ml). After stirring for 15 h at r.t. the suspension is filtered and the resin washed with dichloromethane (2×), DMF (2×), alternating with H2O and DMF (3×), alternating with THF and 2-propanol (3×), dichloromethane (3×). The resin is dried under reduced pressure to provide polymer-bound 2-[4-(4-fluoro-butoxy)-benzenesulfonylamino]-N-hydroxy-acetamide.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[C:7]1=2)C.Cl>C(O)(=O)C>[NH2:20][CH2:19][CH2:18][CH2:17][O:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:35])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:28][C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCCCNC(=O)OC(C)(C)C)c21
Agent: Cl
Solvent: CC(=O)O
Product: NCCCOc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Yield: 53.6 %

Procedure:
A solution of [4-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (81 mg) in acetic acid (4 mL) was treated with 1N HCl (1 mL) at 100° C. for 2 h. The reaction was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (32 mg) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 8.31-8.30 (m, 1H), 8.17-8.15 (m, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 5.66-5.62 (m, 1H), 4.16 (t, 2H), 3.19 (t, 2H), 3.17-3.09 (m, 1H), 2.47-2.39 (m, 1H), 2.23-2.21 (m, 2H). MS calcd for (C16H18BN3O6+H)+:360.2. MS found: (M+H)+=360.2.