Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[NH:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:33][CH2:32]1>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([N:26]5[CH2:30][CH2:29][CH2:28][CH:27]5[CH:31]5[CH2:36][CH2:35][N:34]([CH:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)[CH2:33][CH2:32]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: C1CNC(C2CCN(C3CCOCC3)CC2)C1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CCCC4C4CCN(C5CCOCC5)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (200 mg, 0.516 mmol), 4-(pyrrolidin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine hydrochloride (354 mg, 1.29 mmol), Pd(PtBu3)2 (20 mg, 0.04 mmol), Na2OtBu (148 mg, 1.55 mmol) in toluene (5.0 ml) in a seal tube was degassed with N2 for three times. The mixture was stirred at 110° C. for 120 min. The solid was filtered through Celite. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min) to give racemic 254 (13 mg, 4.6% yield). LCMS (ESI): RT=2.00 min, m/z: 546.4 [M+H+]. 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 6.47 (dd, J=9.5 Hz, 2.5 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 5.95-5.92 (m, 1H), 4.48-4.36 (m, 4H), 4.05 (d, J=8.5 Hz, 1H), 3.85-3.75 (m, 1H), 3.41-3.24 (m, 6H), 2.41 (s, 4H), 2.02-1.74 (m, 14H), 1.56 (d, J=6.5 Hz, 7H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[CH:13]=[N:14][NH:15][C:7]=12.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].CO.CCOCC>N1C=CC=CC=1.O1CCOCC1>[C:16]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[CH:13]=[N:14][NH:15][C:7]=12)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1cc(NCCCO)c2[nH]ncc2n1
Reactant: CCCCC(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC(=O)OCCCNc1cc(C)nc2cn[nH]c12
Reaction time: 8 h

Procedure:
7-[3-Hydroxypropylamino]-5-methyl-1H-pyrazolo[4,3-b]-pyridine,* (0.15 g, 0.73 mmol) was suspended in dry pyridine (2 ml) and 1,4-dioxan (2 ml) and cooled in an ice-bath. A solution of valeryl chloride (0.18 ml, 2.1 equiv.) in dioxan (1.5 ml) was added dropwise with stirring and then left at room temperature overnight. Methanol (10 ml) was added and the resulting solution stirred for 1 h and then solvents removed under reduced pressure. The residue was chromatographed on basic alumina eluting initially with ethyl acetate rising to 30% methanol/ethyl acetate. After removal of solvent a colourless oil was obtained, which on trituration with ether gave the title compound as a white solid, m.p. 92°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([CH2:20][CH2:21][NH:22][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCN1CCOCC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-morpholin-4-ylethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. δH (CD3OD): 2.54-2.60 (4H, m), 2.64 (2H, t), 3.58 (2H, t), 3.69-3.73 (4H, m), 7.05 (1H, s), 7.66 (1H, s), 8.58 (1H, s); m/z (ES+)=309 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[O:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([S:21]([N:24](CC3C=CC(OC)=CC=3OC)[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[C:16]([F:42])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[O:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([S:21]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)(=[O:22])=[O:23])=[C:16]([F:42])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnc(N)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc([C@H]2CCC[C@@H]2Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)ccn1
Yield: 88 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (185 mg, 0.310 mmol) prepared in Example 36c, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (122 mg, 88%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[CH:15][CH2:16][OH:17])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[H-].[Na+].S(OC)(O[CH3:26])(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[CH:15][CH2:16][O:17][CH3:26])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: OCC=C1c2ccccc2CCc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Product: COCC=C1c2ccccc2CCc2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Treat 2-(2-chloro-10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-ethanol (1 equivalent) with sodium hydride (2 equivalents) in a suitable dry solvent at 0° C. and stir for 15 minutes. Add dimethyl sulfate dropwise (2 equivalents) and stir at 0° C. for one hour. Quench with aqueous citric acid solution and partition between water and ethyl acetate. Dry and evaporate the organic layer. Purify the residue by silica gel chromatography to give the title compound in 82% yield
Reaction SMILES: P(=O)(O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]([C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)=[C:21]([CH3:34])[CH:20]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[CH3:34][C:21]1[CH:20]=[C:19]([CH2:17][N:14]2[CH2:15][CH2:16][CH:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:13]2)[CH:33]=[CH:32][C:22]=1[O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Yield: 71 %

Procedure:
Using a method similar to Example 362, using 3-phenyl-pyrrolidine phosphoric acid salt (1.543 g, 6.29 mmol), 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (compound of example 365, step 1) (1.499 g, 6.30 mmol), sodium triacetoxyborohydride (2.00 g, 9.44 mmol) and acetic acid (0.58 mL, 10.1 mmol) in 1,2-dichloroethane (50 mL), after silica gel chromatography (19:1→1:3 hexanes:ethyl acetate) provides 1.65 g (71%) of the title compound as a clear syrup: Mass spectrum (electrospray): m/z=370 (M+1); 1H NMR (CDCl3): 8.47 (d, 1H, J=2.4 Hz), 7.91 (dd, 1H, J=2.0, 8.3 Hz), 7.32-7.28 (m, 5H), 7.26-7.17 (m, 2H), 3.67 (s, 2H), 3.45-3.35 (m, 1H), 3.08 (t, 1H, J=9.3 Hz), 2.93-2.85 (m, 1H), 2.72 (dt, 1H, J=5.9, 8.8 Hz), 2.53 (dd, 1H, J=8.3, 9.3 Hz), 2.43-2.32 (m, 1H), 2.14 (s, 3H), 1.99-1.88 (m, 1H).
Reaction SMILES: [N+](C1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.C([O-])(=O)C([O-])=[O:20].[K+].[K+].[OH-].[Na+].O>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:17](=[O:20])[C:5]3[C:10](=[N:9][CH:8]=[CH:7][CH:6]=3)[C:11]=12
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Reactant: O=C([O-])C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2cccnc2-c2ncccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a 1 L one-necked flask was added a mixture of 30 g (0.13 mol, 68%) 5-nitro-1,10-phenanthroline, 51 g (0.61 mol) potassium oxalate, 12.5% NaOH(aq) 150 ml and 450 ml water. The mixture was then heated to reflux (100° C.) and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was added with 1 L ethyl acetate, stirred for 30 minutes, and filtered to collect the filtrate. The residual solids were added into 300 ml ethyl acetate, stirred for 30 minutes and filtered to collect the filtrate. The combined filtrates were extracted to separate the organic layer, dehydrated by MgSO4, concentrated, and recrystallized from 200 ml methanol, so as to obtain light yellow solids cyclopenta[2,1-b;3,4-b′]dipyridin-5-one 13.3 g (0.07 mol, yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][CH2:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[O:24][CH2:25][CH2:26][CH2:27][CH:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCCCO3)c2s1

Procedure:
From (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester with tributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane, bis(dibenzylideneacetone)palladium, trifurylphosphine and triethylamine in dioxane. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:8]=2)[N:3]=1.C(OC([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([NH2:43])[CH:41]=2)[C:36](=[O:44])[NH:35]1)=O)(C)(C)C.C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.C(Cl)Cl>[CH:18]1([C:16]2[CH:17]=[C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:8]=4)[N:3]=[C:2]([NH:43][C:40]4[CH:41]=[C:42]5[C:37]([C:36](=[O:44])[NH:35][NH:34]5)=[CH:38][CH:39]=4)[N:11]=3)[NH:14][N:15]=2)[CH2:20][CH2:19]1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(N3CCCCC3)ccc2n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(N5CCCCC5)ccc4n3)ccc12
Temperature: 90 °C

Procedure:
To (2-Chloro-6-piperidin-1-yl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (80 mg, 0.217 mmol) in NMP (1 mL) was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (65 mg, 0.26 mmol) and heated to 90° C. for 12 hr in a sealed tube. Solution was poured into sat. NaHCO3, resulting in a brown solid. The dried solid was taken up in 5 ml of methylene chloride and treated with 5 mL of TFA for 6 hr. The reaction was evaporated and the title compound was isolated by preparative HPLC to give a yellow solid (47,5 mg). HNMR (500 MHz, dmso); δ11.45 (1H, bs), 10.45 (1H, bs), 8.0 (1H, s), 7.70 (1h, m), 7.6 (1H, m), 7.5 (1H, m), 7.4 (1H, s), 7.1 (1H, m), 6.25 (1H, bs), 3.3 (4H, bs), 2.80–2.55 (7H, m), 0.80 (2H, m), 0.40 (2H, m); HPLC tr=3.51 min (10% to 90% MeCN over 8 min, total time 12 min, 3×150 mm C18 column) FIA m/e 482.5 (M+H), 480.2 (M−H).
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([NH:8][C:9]1[CH:10]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:13][C:14]=1[NH2:15])[CH:5]([CH3:7])[CH3:6]>C(O)(C)C.C(OCC)(=O)C>[CH2:4]([N:8]1[C:9]2[CH:10]=[C:11]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:13][C:14]=2[N:15]=[C:2]1[NH2:1])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CNc1cc(-n2ccnc2-c2ccccc2)ccc1N
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)Cn1c(N)nc2ccc(-n3ccnc3-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Add cyanogen bromide (177 mg, 1.67 mmol) to a solution of 1-(3-(isobutylamino)-4-aminophenyl)-2-phenyl-1H-imidazole (410 mg, 1.34 mmol) in 10 mL isopropanol cooled to 0° C. Stir for one hour at this temperature and then stir at room temperature over night. Dilute with ethyl acetate and wash with 1N sodium hydroxide. Dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to radial silica gel chromatography, eluting with methanol containing 4% methanol to provide the title compound as a tan solid (220 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)=[N:12][N:13]=1.[CH2:29]([N:31](CC)CC)[CH3:30].CN(C1C=CC=CN=1)C.C1(S(Cl)(=O)=O)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:30][C:29]#[N:31])[C:9]1[O:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: Cn1cc(-c2cnc3[nH]cc(-c4nnc(Nc5ccccc5Cl)o4)c3c2)cn1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccccn1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3[nH]cc(-c4nnc(N(CC#N)c5ccccc5Cl)o4)c3c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.3 g of (2-chlorophenyl)-{5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-pyridin-3-yl]-1,3,4-oxadiazol-2-yl}amine are dissolved in 15 ml of DMF at 60° C. When the solution has re-cooled to RT, 1.4 ml of triethylamine and 40 mg of dimethylaminopyridine are added. This solution is then cooled to 0° C., before 0.5 ml of benzenesulfonyl chloride is added dropwise. When the addition is complete, the batch is stirred at RT for a further 4 h. After undissolved constituents have been filtered off, the solution which remains is evaporated completely to dryness, and the residue is partitioned between ethyl acetate and water, with crystals precipitating out after a short time. The product is filtered off with suction and combined with the second crystal batch, giving 1.3 g of the title compound. HPLC-MS: Rt=2.567 min; [M+H+]: 532.1
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[C:11]([OH:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[P:16]([O:23]CC)([O:20]CC)[O:17]CC.C[Si](Br)(C)C>ClCCl>[OH:14][C:11]([CH3:13])([CH3:12])[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][P:16](=[O:17])([OH:23])[OH:20])=[CH:5][CH:6]=1)=[O:15]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(O)C(=O)c1ccc(CCBr)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)(O)C(=O)c1ccc(CCP(=O)(O)O)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A mixture of 10 g of 1-[4-(2-bromoethyl)phenyl]-2-hydroxy-2-methylpropan-1-one (0.037 moles) and 6.7 g (0.041 mol) of triethyl phosphite is heated externally at 140° C. for 24 hours. The reaction mixture is distilled to give 12.1 g of 2-[4-(2-hydroxy-2-methylpropionyl)phenyl]ethyl}phosphonic acid dimethyl ester. The ester is dissolved in 50 ml of dichloromethane, and a solution of 6.2 g (0.0405 mol) of trimethylsilyl bromide in 10 ml of dichloromethane is added drop wise at room temperature. The reaction mixture is stirred overnight. The reaction mixture is concentrated, and methanol (200 ml) is added. The mixture is stirred at temperature for 24 hours, and then concentrated to give 5.0 g of the title compound, a yellow oil.
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[Mg].[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]=[O:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C.C1COCC1>[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]([OH:18])[CH:2]([CH3:4])[CH3:3])[N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)Cl
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1C(O)C(C)C
Yield: 57.9 %

Procedure:
35 Grams (0.45 mol) of 2-chloropropane was added to 10.8 g (0.45 mol) of magnesium in 100 ml of diethyl ether. Then 55.8 g (0.3 mol) of 2-phenyl-4-formyl-5-methyl-1H-imidazole in 100 ml of THF were added. At the end of the addition, the mixture was refluxed for 30 minutes and then cooled and poured on ice water. The aqueous layer was extracted twice with 100 ml of diethyl ether. Evaporation of the solvent gave a residue which was recrystallized in ethanol to yield 40 grams of 2-phenyl-4-(1-hydroxy-2-methylpropyl)-5-methyl-1H-imidazole, which melted at 214° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([SiH2:11][O:12][C:13]([CH3:32])([CH3:31])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:30])[C:21]2[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=2)[C:26]#[N:27])=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[NH+]1C=CC=CC=1.C1(C)C(S([O-])(=O)=O)=CC=CC=1>ClCCl>[C:7]([SiH2:11][O:12][C:13]([CH3:32])([CH3:31])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:30][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:21]2[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=2)[C:26]#[N:27])=[CH:18][CH:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(O)c2ccc(F)c(C#N)c2)cc1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(OC2CCCCO2)c2ccc(F)c(C#N)c2)cc1
Yield: 97.8 %

Procedure:
Add 3,4-dihydro-2H-pyran (0.340 g, 4.04 mmol) to a solution of 5-{[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-hydroxy-methyl}-2-fluoro-benzonitrile (1.00 g, 2.69 mmol) and pyridinium-toluenesulfonate (0.068 g, 0.269 mmol) in dichloromethane (0.2M). Stir the reaction for 3 h at room temperature. Evaporate solvent and filter through a short pad of silica gel. The title compound (1.20 g, 2.63 mmol, 98%) is taken directly onto the next step (Preparation 58). MS (m/z): 456 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:19])=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[NH2:14].[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.CCOC(C)=O>[Br:1][C:2]1[C:3]([Cl:19])=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]2[N:14]=[N:20][NH:13][C:8]=2[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Clc1cc(Br)c(Cl)c(Oc2c(Cl)ccc3[nH]nnc23)c1
Reaction time: 1.5 h

Procedure:
3-(3-bromo-2,5-dichlorophenoxy)-4-chlorobenzene-1,2-diamine (2.48 g, 6.47 mmol) in acetic acid (20 mL) was cooled to 15° C., after which sodium nitrite (0.446 g, 6.47 mmol) in water (6.47 mL) was added dropwise under N2. After 1.5 hours, the reaction mixture was diluted with EtOAc (200 mL), and the organic phase was separated and washed with water (3×75 mL). The organic phase was dried (MgSO4), filtered, concentrated and placed under vacuum to yield the title compound. LRMS (M+1)=393.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A 100-mL, round-bottomed flask, fitted with a reflux condenser was charged with 2,5-dichloropyridine (1.00 g, 6.76 mmol), phenylboronic acid (1.07 g, 8.78 mmol), [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.204 g, 0.338 mmol), argon-degassed toluene/ethanol (4:1, 17 mL) and argon-degassed aqueous 1 N sodium carbonate (6.6 mL). The mixture was heated to reflux for 3 h, cooled to room temperature and diluted with water (15 mL) and EtOAc (100 mL). The layers separated and the aqueous phase was extracted with EtOAc (100 mL). The combine organic extracts were dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 50:50 hexanes/CH2Cl2) provided 5-chloro-2-phenylpyridine (0.959 g, 75%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:10][CH2:9][CH:8]2[C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+:17]>>[CH:1]1([N:7]2[CH2:10][CH2:9][CH:8]2[C:11]([O-:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+:17]
Reactant: COC(=O)C1CCN1C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C1CCN1C1CCCCC1

Procedure:
The reaction of methyl 1-(cyclohexyl)azetidine-2-carboxylate 19A and lithium hydroxide monohydrate yielded lithium 1-(cyclohexyl)azetidine-2-carboxylate as a brown oil (quant). MS ISP (m/e): 184.2 (100) [(M+H)]+.
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:32]([CH:34]([C:40](OCC)=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:33])[CH2:31][CH2:30][O:29][CH2:28]2)=[CH:23][CH:22]=1>CCOC(C)=O>[Cl:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][CH:22]=1)[C:27]1([CH2:31][CH2:30][O:29][CH2:28]1)[C:32](=[O:33])[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:40]2[OH:41]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(Cl)cc2)CCOC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOC2)C1=O
Reaction time: 1 h

Procedure:
Concentrated H2SO4 (66483 mg, 677858 μmol) was cooled to 0° C. and treated with P2O5 (11546 mg, 81343 μmol). The reaction was stirred for 60 minutes and treated with diethyl 2-(3-(4-chlorophenyl)-tetrahydrofuran-3-carbonyl)malonate (5 g, 13557 μmol). After 60 minutes, the reaction was diluted with EtOAc and poured onto ice. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with brine and dried over MgSO4. Purification by silica flash chromatography (2-5% MeOH/DCM) gave the title compound as a white solid. MS m/e=323.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[CH:19]=[CH:18][C:12]3[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[CH:19]=[CH:18][C:12]3[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CSc2ccc3c(c2)OCC(=O)N3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1COc2cc(SCc3ccc(O)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
A solution of 7-(4-methoxy-benzylsulfanyl)-2H-1,4-benzoxazin-3(4H)-one(150 mg; 0.5 mmol) in CH2Cl2 (2 ml) was treated with BBr3 (350 mg; 1.5 mmol). The mixture was stirred at room temperature overnight. After evaporation to dryness the residue was taken up in EtOAc and water. The organic phase was washed with water, brine and dried over MgSO4. The residue was triturated with EtOAc, filtered and dried to give 7-(4-hydroxybenzylsulfanyl)-2-H-1,4-benzoxazin-3(4H)-one as a beige solid (149 mg), Melting point 207-209° C. Yield: 100% 1H NMR spectrum (DMSO d6): 4.07(s, 2H); 4.56 (s, 2H); 6.68 (m, 2H); 6.81 (d, 1H); 6.91 (m, 2H); 7.11 (d, 2H); 9.35 (s, 1H); 10.72 (s, 1H). LCMS-ESI: 288 [MH]+