Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[CH3:13].COB(OC)OC.[C:21]([O:25][C:26](=[O:47])[NH:27][C:28]([C:30]1[S:31][C:32]([S:45][CH3:46])=[C:33]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40](Br)[CH:39]=2)(=[O:37])=[O:36])[CH:34]=1)=[NH:29])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:21]([O:25][C:26](=[O:47])[NH:27][C:28](=[NH:29])[C:30]1[S:31][C:32]([S:45][CH3:46])=[C:33]([S:35]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][C:12]=3[CH3:13])[CH:43]=2)(=[O:37])=[O:36])[CH:34]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1ccncc1Br
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cnccc2C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Butyllithium (2.5 M, 1.88 mL, 4.5 mmol) was added dropwise to a −78° C. solution of 3-bromo-4-methylpyridine (645 mg, 3.75 mmol) in Et2O (15 mL). The solution was stirred at −78° C. for 1 h and trimethylborate (5 mL, 44 mmol) was added in one portion. The solution was warmed to rt over 15 min and stirred for 2 h at rt. The volatile components were removed in vacuo and the solid residue was dried under high vacuum for 2 h. A portion of the crude solid (81 mg, 0.4 mmol) was reacted with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL) according to the procedure used in Example 1: step c. Analogous aqueous workup and purification of the crude material by preparative TLC (50% EtOAc in hexanes) yielded the title compound (36 mg, 71%) as a light-yellow glass. 1H-NMR (CDCl3): δ 8.50 (d 1H, J=5.1 Hz), 8.42 (s, 1H), 8.07 (s, 1H), 7.99 (m, 2H), 7.45–7.70 (m, 5H), 7.24 (d, 1H, J=5.1 Hz), 2.59 (s, 3H), 2.27 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C23H25N3O4S3: 503.7; found: 503.8.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:4]1>CO.[Pd]>[CH3:1][O:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:4]1
Reactant: CO[C@H]1CCN(Cc2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1CCN(Cc2ccc(N)cn2)C1
Yield: 91.9 %

Procedure:
A solution of 32 (0.25 g, 1.05 mmol) in MeOH (6 mL) was hydrogenated using 10% Pd/C (50 mg) under a hydrogen atmosphere (balloon pressure) at rt for 1 h. The reaction mixture was filtered through a Celite bed and the filtrate was evaporated to give the desired amine (0.2 g, 82%) as brown liquid. Rf: 0.1 (10% MeOH/DCM); m/z): 208 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 7.82 (1H, d, J=2.4 Hz), 7.01-6.99 (1H, m), 6.88-6.86 (1H, m), 5.16 (2H, br s), 3.93-3.80 (3H, m), 3.21-3.13 (5H, m), 2.65-2.61 (1H, m), 2.42-2.34 (2H, m), 1.99-1.92 (1H, m).
Reaction SMILES: C[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=S)[CH:6]3[CH2:16][CH2:17][CH2:18][CH:5]3[C:4]=2[CH:3]=1.[NH3:19]>>[NH2:19][C:7]1[CH:6]2[CH2:16][CH2:17][CH2:18][CH:5]2[C:4]2[CH:3]=[CH:2][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]=2[N:8]=1
Reactant: N
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=S)C1CCCC21
Product: NC1=Nc2cc([N+](=O)[O-])ccc2C2CCCC12
Yield: 77 %

Procedure:
As described for Example 4, 8-methyl-7-nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (42 mg, 0.16 mmol) is reacted with 7N methanolic ammonia solution (10 ml) to form 30 mg (77%) of product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12]C)=[CH:7]2.B(Br)(Br)Br.ClCCl>ClCCCl>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2
Reactant: COc1cnc2c(Cl)nccc2c1
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: ClCCl
Product: Oc1cnc2c(Cl)nccc2c1
Temperature: 25 °C

Procedure:
To a 75 mL pressure vessel were charged with 8-chloro-3-methoxy-1,7-naphthyridine (0.8 g, 4.11 mmol) and DCE (10 ml). To this was added boron tribromide, 1.0M in dichloromethane (20.55 ml, 20.55 mmol) slowly. The brown heterogeneous mixture was stirred at RT and then was heated to 60° C. in oil bath and stirred for 3 h. It was cooled to 0° C. by ice bath and quenched with sat. Na2CO3 very slowly. Organic solvents were reduced, and 100 ml EtOH was added to the resulting residue. The white precipitate was filtered out. The filtrate was concentrated to yield 8-chloro-1,7-naphthyridin-3-ol as crude product which was used for next step directly. MS m/z: 181.2 [M+H].
Reaction SMILES: [CH2:1]([N:8]([CH2:17]C1C=CC=CC=1)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14](C)C)C1C=CC=CC=1>CO.[Pd]>[NH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:8]([CH3:17])[CH3:1]
Reactant: CN(C)CCOCCN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOCCN
Yield: 55 %

Procedure:
[2-(2-Amino-ethoxy)-ethyl]-dimethyl-amine (100 mg) was prepared following General Procedure T starting from [2-(2-dibenzylamino-ethoxy)-ethyl]dimethyl-amine (430 mg) and Pd—C (86 mg) in methanol (1 mL).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5](OCCC)=[CH:4][CH:3]=1.[CH:21](C1C2SC3C(=CC=CC=3)C(=O)C=2C=CC=1)([CH3:23])[CH3:22]>>[CH:21]([C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=1)([CH3:23])[CH3:22]
Reactant: CCCOc1ccc(Cl)c2c(=O)c3ccccc3sc12
Reactant: CC(C)c1cccc2c(=O)c3ccccc3sc12
Product: CC(C)c1ccc2sc3ccccc3c(=O)c2c1

Procedure:
1-chloro-4-propoxythioxanthone; 4-isopropylthioxanthone; and the mixture thereof.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][O:10][CH2:11][C:12]3=[O:16])[CH2:7]2)[CH2:3]1.Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1)[C:23]([N:25]([CH2:27][C@H:28]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)[CH2:29][CH2:30]N1CC(N2CCN3C(=O)CCCC3C2)C1)[CH3:26])=[O:24]>CO.O.C(O)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:53]=[C:54]([C:56]([F:59])([F:57])[F:58])[CH:55]=1)[C:23]([N:25]([CH2:27][C@H:28]([C:46]1[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=1)[CH2:29][CH2:30][N:2]1[CH2:5][CH:4]([N:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][O:10][CH2:11][C:12]3=[O:16])[CH2:7]2)[CH2:3]1)[CH3:26])=[O:24]
Reactant: O=C1COCC2CN(C3CNC3)CCN12
Reactant: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCN3C(=O)COCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 45.8 %

Procedure:
8-Azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochloride (see Method 8; 43 mg, 0.17 mmol) was dissolved in methanol (3 mL) together with a few drops of water and acetic acid (0.2 mL). 3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 80 mg, 0.18 mmol) dissolved in methanol (1 mL) was added to the former solution together with (polystyrylmethyl)-trimethylammonium cyanoborohydride (4.2 mmol/g, 47 mg, 0.25 mmol). The reaction mixture was heated to 120° C. for 5 min using microwave single node heating. The resin was filtered off and washed with methanol. The filtrate was concentrated by evaporation. The product was purified by reversed phase chromatography (acetonitrile-aqueous solution of ammonium formate 0.1M and formic acid 0.1M, 10% to 50%). The solvent of the collected fractions was removed by evaporation followed by freeze-drying. The residue was partitioned between methylene chloride and aqueous NaHCO3. The two phases were separated by means of a phase separator column and then the solvent of the organic solution was removed by evaporation. There was obtained 50 mg (44%) of the title compound. 1H NMR (500 MHz, CD3OD): 1.5-1.7 (b, 1H), 1.7-2.0 (cm, 3H), 2.2-4.2 (cm, 21H), 4.5 (d, 1H), 7.0-7.6 (cm, 6H), 7.9 (d, 1H); LCMS: m/z 642 (M+1)+.
Reaction SMILES: O.[NH2:2][NH2:3].C(OCC)C.[CH3:9][C:10](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=O>O>[CH3:9][CH:10]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3][N:2]=[CH:11]1
Reactant: NN
Reactant: CC(C=O)=Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC1C=NNC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.22 ml (1 equiv.) hydrazine hydrate was added to 100 mL diethylether. The emulsion was cooled with an ice bath. 15.0 mL 2-Methyl-3-phenyl-propenal was added dropwise, and the mixture was stirred overnight at room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum destillation yielded 5.9 g of desired product (mixture of diastereomeric pairs) as a clear fluid (76-82° C., 0.2-0.3 mbar). 1H NMR (400 MHz, CDCl3) of first diastereomeric pair: δ 0.71 (d, J=7 Hz), 3H), 3.20-3.31 (m, 1H), 4.77 (d, J=10 Hz, 1H), 6.73 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H). 1H NMR (400 MHz, CDCl3) of second diastereomeric pair: δ 1.24 (d, J=7 Hz), 3H), 2.90-3.11 (m, 1H), 4.22 (d, J=11 Hz, 1H), 6.71 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:13][CH2:12][CH2:11][C:9]3[O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCCc1cc(-c2cccs2)no1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(N2CCN(CCCc3cc(-c4cccs4)no3)CC2)cc1
Yield: 74.7 %

Procedure:
About 2 min after dissolving 3-[3-(2-thienyl)isoxazol-5-yl]propanal (20 mg, 0.1 mmol), 1-phenylpiperazine (14.7, 0.1 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (61.4 mg, 0.3 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 3.5 hr and followed the same processes as in Example 1 to obtain 26.4 mg (77.4%) of the target compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]4[C:18](=[C:19](Br)[CH:20]=[C:21]([O:29][CH3:30])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]4[C:18](=[C:19]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)[CH:20]=[C:21]([O:29][CH3:30])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a suspension of 8-bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide Reference Example 28b) (139.9 mg, 0.288 mmol), N-methylpiperazine (48 μL, 0.43 mmol), and 4 Å sieves in 15 mL anhydrous toluene was added Pd2 (dba)2 (15.3 mg, 16.7 μmol), BINAP (63.0 mg, 0.101 mmol) and cesium carbonate (0.436 g, 1.345 mmol). The resulting wine colored mixture was heated at reflux under nitrogen for 20 hours. The reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol to afford the desired product as a yellow solid (96.9 mg, 67%). 1H NMR (300 MHz, DMSO, d6) δ 10.06 (s, 1 H, C(O)NH), 7.69 (d, 2 H, Jo=9.0 Hz, ArH2′& H6′), 7.58 (s, 1 H, ArH3), 7.58 (d, 2 H, Jo=9.0 Hz, ArH3′& H5′), 6.95 (d, 1 H, Jm=2.7 Hz, ArH5), 6.76 (d, 1 H, Jm=2.7 Hz, ArH7), 3.90 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.37 (bs, 4 H, ArNCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.01 (s, 6 H, N(CH3)2), 2.71 (bs, 4 H, ArNCH2CH2N), 2.35 (s, 3 H, R2NCH3); Mass Spec.: calc. for [C28H36N6O3+H]+ Theor. m/z=505; Obs.=505.5.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:41][CH2:40]2)=[O:38])[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[O:17])=[CH:6][C:5]=1[Cl:57]>O.C1COCC1>[NH2:3][C:4]1[C:9]([C:10]([F:12])([F:11])[F:13])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:40][CH2:41][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:43][CH2:44]2)=[O:38])[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)[CH2:22][CH2:23]2)=[O:17])=[CH:6][C:5]=1[Cl:57]
Reactant: CCOC(=O)C1(C)CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)O)CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2.00 mg (0.08 mmol) LiOH in 1 mL water was added to 40 mg (0.05 m mol) ethyl 1′-{(R)-3-(4-amino-3-chloro-5-trifluoromethyl -phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4-methyl-1,4′-bipiperidinyl-4-carboxylate in 0.8 mL THF and the reaction mixture was stirred for 1 h at RT and for 8 h at 50° C. This was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](OCC)=[O:22])=[CH:15][C:14]=2[O:26][CH3:27])[N:10]=1.[BH4-].[Na+].O1CCCC1.CO>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=2[O:26][CH3:27])[N:10]=1
Reactant: CCOC(=O)CCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CCCO)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 87 %

Procedure:
To a mixture of ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propionate (20 g), sodium borohydride (9.8 g) and tetrahydrofuran (THF) (200 ml) was added dropwise methanol (50 ml) over 2 hours under reflux. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to yield 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propanol (15.5 g, 87%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.99-100° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[N:11](C(OC(C)(C)C)=O)[C:10]=1[C:26]([O:28][CH3:29])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1c(NCCC(=O)c2cccc(F)c2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1cccc(F)c1
Yield: 70 %

Procedure:
Dissolve 3-[(m-fluorophenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoraceticacid (5 mL) and stir for 4 hours at room temperature. Dilute with ethyl acetate (50 mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography (30% ethyl acetate/hexane) and recrystallize from ethyl acetate/hexane to yield the title compound (700 mg, 70%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:6][C@H:5]([O:7][C:8]2[C:9]3[C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:13]=2)[CH2:4]1.O.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(OCC)(=O)C>[CH3:1][N:2]([C@H:3]1[CH2:6][C@H:5]([O:7][C:8]2[C:9]3[C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:13]=2)[CH2:4]1)[C:31](=[O:34])[CH:32]=[CH2:33]
Reactant: CN[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)C1
Reactant: C=CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)N(C)[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude 4-{[trans-3-(methylamino)cyclobutyl]oxy}-N-(1-methyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.4 mmol) was partitioned between water (8 mL) and ethyl acetate (15 mL). Acryloyl chloride (36 μL, 0.44 mmol) was added and the mixture stirred at ambient temperature for 1 hr. The organic layer was separated, dried over Na2SO4 and evaporated to give a residue, which was purified by SFC (Zymor Spher Diol Monol, 150×21.2 mm, 5 μm column at 35° C. eluting with a 20%-50% EtOH gradient at 5%/min in CO2 at 140 bar with a flow rate of 60 mL/min) to give the title compound (7.4 mg, 4% yield). 1H NMR (700 MHz, DMSO-17 mm) δ ppm 11.64 (br. s., 1H) 8.87-9.00 (m, 2H) 8.43 (d, J=3.96 Hz, 1H) 8.12 (d, J=7.26 Hz, 1H) 7.87 (br. s., 1H) 7.52 (s, 1H) 7.42 (br. s., 1H) 7.33 (s, 1H) 6.59-6.80 (m, 1H) 5.95-6.15 (m, 1H) 5.65 (br. s., 2H) 5.47 (br. s., 1H) 3.74-3.88 (m, 3H) 3.07 (br. s., 1H) 2.91-3.00 (m, 1H) 2.72 (br. s., 2H) 2.29-2.46 (m, 2H). m/z (APCI+) for C23H24N8O2 445.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[NH:12][C:11]([CH:13]=[C:14]4[N:36]=[C:17]([C:18]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[C:19]5[NH:29][C:22](=[CH:23][C:24]6[CH:25]=[CH:26][C:27]=2[N:28]=6)[CH:21]=[CH:20]5)[CH:16]=[CH:15]4)=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:50])C=CC=1)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[I:50][C:23]1[C:24]2[CH:25]=[CH:26][C:27]([N:28]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[NH:12][C:11]([CH:13]=[C:14]3[N:36]=[C:17]([C:18]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:19]4[NH:29][C:22]=1[CH:21]=[CH:20]4)[CH:16]=[CH:15]3)=[CH:10][CH:9]=2
Reactant: C1=Cc2nc1cc1ccc([nH]1)c(-c1ccccc1)c1nc(cc3ccc([nH]3)c2-c2ccccc2)C=C1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Ic1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
50 mg (0.11 mmol) of 5,15-diphenylporphyrin was dissolved in 50 ml of dry CHCl3. To the stirred solution was added 3 ml of a solution of iodine in chloroform (0.055M). Finally, a solution of 50 mg (0.12 mmol) bis(trifluoroacetoxy)iodobenzene dissolved in 25 ml of chloroform was added dropwise, followed by 200 μl of pyridine. The mixture was stirred at 25° C., in the dark, for one hour. After evaporation of the solvent in vacuo, the residue was chromatographed on silica gel, eluting with 50% 1,1-dichloromethane in hexane to give 44 mg of 10-iodo-5,15-diphenylporphyrin (70% yield). UV-Vis (CH2Cl2): λmax 422, 520, 560, 600, 660 nm; MS (EI) m/e 588(100). Annotated wavelengths for electronic absorption spectrum shown in FIG. 1:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[O:16][C@@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:12][C@H:11]([CH3:10])[O:16][C@H:15]([CH3:17])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
To a mixture of 4-bromobenzaldehyde (3.70 g, 20 mmol) and cis-2,6-dimethylmorpholine (2.52 g, 22 mmol) in DCE (100 mL) was added NaBH(OAc)3 (5.30 g, 25 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with sat. NaHCO3 (30 mL) and H2O (30 mL), and was extracted with DCM (30 mL×2). Concentration of the solvents afforded the crude title compound as a pale yellow liquid (6.41 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 3.64-3.55 (m, 2H), 3.44 (s, 2H), 2.68 (d, J=11.6 Hz, 2H), 1.75 (t, J=11.0 Hz, 2H), 1.54 (d, J=6.0 Hz, 6H); MS ESI 284.0 [M+H]+, calcd for [C13H18BrNO+H]+ 284.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1CCCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10](=[CH:20][N:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: COC(OC)N(C)C
Solvent: C1CCCCC1
Product: CCOC(=O)C(=CN(C)C)C(=O)Nc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 21.12 grams (0.07 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate, 12.58 grams (0.11 mole) of N,N-dimethylformamide dimethyl acetal and 900 milliliters of cyclohexane was heated under reflux for a period of thirty two minutes at which time TLC indicated the reaction to be incomplete. Another 12.58-gram (0.11 mole) portion of the acetal was then added and the reaction mixture stirred overnight at ambient temperature. Solvent was stripped from the mixture under reduced pressure and the resulting solid then crystallized from hexane-ethyl acetate (10:1) to give 12.6 grams (0.035 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-(dimethylaminomethylene)-3-oxopropanoate having a melting point of 88° C.-90° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:9][CH:24]=[N:23][CH:22]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2cnco2)cc1
Yield: 89 %

Procedure:
A mixture of 4-nitro-benzaldehyde (5.0 g, 33.1 mmol), tosylmethyl isocyanide (6.4 g, 33.1 mmol) and potassium carbonate (7.8 g, 82.7 mmol) in methanol (100 ml) was heated under reflux for 30 minutes. After concentrating under reduced pressure, the residue was stirred with water (50 ml). The solid that was filtered to afford 5-(4-nitro-phenyl)-oxazole (5.6 g, 89% yield). 1H NMR (acetone-d6) δ 7.89 (s, 1H, Ar), 8.05 (d, 2H, J=9.3 Hz, Ar), 8.35-8.38 (m, 3H, Ar).