Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=O)(C)(C)C.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][C@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][NH:67][CH2:66][C@H:65]1[CH3:77])=[O:57]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CNCCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A solution of PyBOP (313 mg, 0.60 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (153 mg, 0.43 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. A solution of (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (133 mg, 0.45 mmol) and DIPEA (0.12 mL, 0.68 mmol) in DCM (10 mL) were added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The isolated intermediate was re-dissolved in DCM (6 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure and the residue re-dissolved in DCM (50 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by preparative HPLC gave 112 as a white solid (41 mg, 22% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.92 (s, 1H), 7.38-7.25 (m, 1H), 7.03 (t, J=9.0 Hz, 2H), 6.20 (s, 2H), 3.77 (s, 3H), 3.27-3.15 (m, 2H), 3.10-2.93 (m, 4H), 2.59 (dd, J=12.5, 9.5 Hz, 1H), 0.88 (d, J=6.3 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.Cl.[CH3:29][NH:30][CH3:31]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([N:30]([CH3:31])[CH3:29])=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[N:3]=1
Reactant: CNC
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N(C)C)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and dimethylamine hydrochloride (Aldrich Cat. No. 391956).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1ccc(C(=C(c2ccccc2)c2ccc(OC)cc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A suspension of p-methoxybenzophenone (1.06 g, 5.0 mmol), 1.34 equiv of TiCl3/AlCl3 (5.81 g, 6.7 mmol), and 25 equiv of Zn dust (8.01 g, 122.0 mmol) in 100 ml of dry THF was refluxed for 20 h. The reaction mixture was cooled to room temperature and filtered. The filtrates were evaporated and the crude product was purified by a silica gel column using hexane as eluent. 1,2-Bis(4-methoxyphenyl)-1,2-diphenylethene (TPE-OMe) was isolated in 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14](O)[CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)O)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]2[CH2:15][CH2:16][CH:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:33]2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc(OC)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1cc(C2CCC(c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Temperature: 90 °C

Procedure:
1-(3,4-Dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol (4.61 g, 10.55 mmole) and 6.57 g of P4S10 were suspended in 60 mL of pyridine and heated at 90° C. for 16 hours. The solvent was removed by distillation in vacuo. The residue was acidified with 10% HCl and extracted with dichloromethane. The organic layer was washed with 10% HCl, water and saturated aqueous sodium chloride, dried over MgSO4, filtered and evaporated to give a gummy residue that was purified by flash column chromatography using 3:1 hexane/ethyl acetate as the solvent (335.6 mg, 7.3%).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[C@@H:24]([O:25]C([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:23][C@:19]2([OH:46])[C:20]([CH3:22])([CH3:21])[C:8]=1[C@@H:9]([O:64][C:65]([CH3:67])=[O:66])[C:10]([C@@:12]1([CH3:63])[C@H:17]([C@@H:18]2[O:47][C:48]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:49])[C@:16]2([O:58][C:59]([CH3:61])=[O:60])[CH2:56][O:57][C@@H:15]2[CH2:14][C@@H:13]1[OH:62])=[O:11].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH3:6][C:7]1[C@@H:24]([OH:25])[CH2:23][C@:19]2([OH:46])[C:20]([CH3:21])([CH3:22])[C:8]=1[C@@H:9]([O:64][C:65]([CH3:67])=[O:66])[C:10]([C@@:12]1([CH3:63])[C@H:17]([C@@H:18]2[O:47][C:48]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:49])[C@:16]2([O:58][C:59]([CH3:61])=[O:60])[CH2:56][O:57][C@@H:15]2[CH2:14][C@@H:13]1[OH:62])=[O:11]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [BH4-]
Solvent: ClCCl
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Yield: 121.7 %

Procedure:
In the third embodiment, the addition of 10% tin chloride (based on the taxol in the starting material) to tetrabutylammonium borohydride in dichloromethane at 0° C. for one hour resulted in a 121.7% yield of Baccatin III. It would appear material other then just the cephalomannine and taxol in the starting material was cleaved to produce Baccatin III. It is hypothesized that certain taxol compounds may be bound to sugars and other biological material and that these may have been converted to Baccatin III in this process.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[F:10]
Reactant: OCc1ccc(Br)c(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (4-bromo-3-fluoro-phenyl)-methanol (4.3 g, 21 mmol) in CHCl3 (50 mL) was added manganese dioxide (18.7 g, 210 mmol), and the resulting mixture was stirred overnight at room temperature until the starting material had been consumed. After filtration, the filtrate was concentrated in vacuo to give product (2.3 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.C([O-])(=O)C.[NH4+:20]>C(O)C>[NH2:20][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccccc2Cl)C1
Yield: 88.4 %

Procedure:
A solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.5 g) and ammonium acetate (2.6 g) in ethanol (50 ml) was heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, and aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant crystal was recrystallized from ethyl acetate-hexane to obtain 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.2 g) as a pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Na+].Cl[Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOCC>[Cl:1][C:2]([F:7])([F:6])[C:3]([O:5][Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[O:4]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)OC(=O)C(F)(F)Cl
Temperature: -70 °C

Procedure:
15.246 g (0.10 mol) sodium chlorodifluoroacetate, is dissolved to 100 mL Et2O and cooled to −70° C. 19.7 mL (0.10 mol, 19.872 g) chlorotriethoxysilane in Et2O (50 mL) was added dropwise to reaction solution. The solution was stirred for over night allowing it to warm up to room temperature. NaCl is removed by filtration and solution evaporated to dryness to result clear colourless liquid, chlorodifluoroacetic acid, triethoxysilyl ester.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=1.C(N(CC)CC)C>C(O)C>[CH3:38][S:37][C:33]1[N:34]=[C:35]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:31][N:32]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: CSc1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1nccc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)n1
Yield: 26.8 %

Procedure:
A mixture of 1.50 g (0.0037 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine [U.S. Pat. No. 4,025,629], 0.44 ml (0.00375 mol) of 4-chloro-2-methylthiopyrimidine, 0.52 ml (0.00375 mol) of triethylamine, and 125 ml of ethanol is stirred at reflux for 3 hours. After cooling, the ethanol is removed in vacuo and the residue is stirred with methylene chloride and aqueous sodium bicarbonate. The resultant solid is collected and washed with water and ether. Crystallization from methanol-chloroform gives 0.52 g (26%) of 1-[2-(methylthio)-4-pyrimidinyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, of melting point 166°-267° C.
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:11]=2[O:15][CH2:16][CH2:17][CH3:18])[N:6]1[C:25](=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:2]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:11]([O:15][CH2:16][CH2:17][CH3:18])=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]([C:25](=[O:27])[CH3:26])[C@@H:5]([CH3:4])[CH2:14][CH2:13]3)[CH2:20][CH2:21]1)[CH3:3]
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(C2CCN(CC)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
Iodoethane (5 μl, 0.06 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (20 mg, 0.06 mmol) and potassium carbonate (38 mg, 0.27 mmol) in DMF (1.0 mL), and the reaction was stirred at room temperature overnight. The reaction was quenched via the addition of water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was collected and further washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-80% methanol in ethyl acetate) to afford (S)-1-(6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (10 mg, 51%) as a light yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.06 (m, 6H), 1.15 (t, J=7.04 Hz, 3H), 1.15-1.26 (m, 1H), 1.38-1.61 (m, 4H), 1.66-1.89 (m, 2H), 2.20 (s, 3H), 2.16-2.28 (m, 2H), 2.52 (m, 2H), 2.67-2.80 (m, 2H), 2.83-2.94 (m, 1H), 2.92-3.07 (m, 3H), 3.58-3.72 (m, 2H), 4.40-4.63 (br d, J=6.75 Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos. ion) m/z 359 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH2:42][C:43]([CH3:53])([CH3:52])[CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH:35]=[C:34]2[CH2:54][N:55]1[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C@H:56]1[CH3:68]>C(#N)C.O.[Cl-].[Na+].O>[CH:1]1([NH:4][C:5]([C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:41])[N:36]([CH2:42][C:43]([CH3:52])([CH3:53])[CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([CH3:50])[CH3:48])[CH:35]=[C:34]4[CH2:54][N:55]3[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C@H:56]3[CH3:68])[CH:11]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cn(CC(C)(C)COC(=O)C(C)(C)C)c(=O)c2ccc(Br)cc12
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)COC(=O)C(C)(C)C)cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
Pd-118 (0.688 g) was stirred in acetonitrile (80 mL) under nitrogen and after 5 min, N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9.26 g) was added. After 5 min, a solution of potassium carbonate (7.29 g) in water (80 mL) was added and after 10 min, a solution of (3R)-tert-butyl 4-((6-bromo-2-(2,2-dimethyl-3-(pivaloyloxy)propyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylate (16 g) in acetonitrile (80 mL) was added and the reaction heated at 70° C. for 1.5 h. After cooling to room temperature, brine (200 mL) was added and the mixture extracted with ethyl acetate (2×125 mL). The combined organics were dried (Na2SO4), filtered and the solvents evaporated. The residue was purified (SiO2 chromatography, eluting with 20%-35% ethyl acetate/2% triethylamine in isohexane) to give the subtitle compound (14.20 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:16][N:17](C=O)C.CN>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:17][CH3:16])=[O:11])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CNC(=O)Cc1ccc(Br)cc1
Reaction time: 1 h
Yield: 910.6 %

Procedure:
To a solution of 4-bromophenyl acetic acid (50 g, 233 mmol) in SOCl2 (170 mL, 2.32 mol) was added DMF (2 mL, 26 mmol). After stirred at this temperature for 1 h, the excess SOCl2 was removed under reduced pressure. The residue was dissolved in CH2Cl2 (300 mL), and the resulting solution was added to a cooled (0° C.) solution of CH3NH2 (90 mL, 40 wt % in H2O, 1.03 mol) in THF (200 mL) dropwise. After the addition was complete, the solution was further stirred at 0° C. for 15 min. Water (400 mL) was added to the reaction solution, and organic layer separated. The aqueous layer was extracted with CH2Cl2 (200 mL). The organic layers were combined, washed with brine (500 mL), dried and concentrated to give 4-bromophenyl-N-methyl acetamide (54 g, quant.) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J=8.9 Hz, 2H), 7.15 (d, J=8.9 Hz, 2H), 3.51 (s, 2H), 2.77 (s, 3H); ESI-MS m/z 228 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[O:55])[CH:47]=[CH:46]3)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:43]4[CH:44]=[C:45]5[C:50](=[CH:51][CH:52]=4)[N:49]=[C:48]([NH:53][C:54]([CH:56]4[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]4)=[O:55])[CH:47]=[CH:46]5)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2ccc3nc(NC(=O)C4CCCCC4)ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(NC(=O)C6CCCCC6)ccc5c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (20.0 mg, 0.038 mmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-yl)cyclohexanecarboxamide (17.2 mg, 0.045 mmol) in dioxane (0.4 mL) was added Pd(PPh3)4 (2.2 mg, 0.002 mmol) and 2N K2CO3 (79 μL, 0.158 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 90° C. for 10 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes) to give the product. LCMS-ESI+: calc'd for C41H41ClN5O4S: 734.3 (M+H+); found: 734.3 (M+H+).
Reaction SMILES: CC(O[CH2:5][C:6]1[C:11]2=[CH:12][CH:13]=[C:14](C=O)[C:10]2=[CH:9]OC=1)=O.C([NH2:21])(CC)C>>[CH:9]1[NH:21][CH:5]=[CH:6][C:11]2[C:10]=1[CH:14]=[CH:13][CH:12]=2
Reactant: CC(=O)OCc1cocc2c(C=O)ccc1-2
Reactant: CCC(C)N
Product: c1cc2cc[nH]cc-2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Baldrinal (2) (1.1 g) was reacted with 2.5 g of sec-butylamine. After stirring for 10 minutes at room temperature, color changes from yellow to orange. When all the baldrinal was reacted, the excess amine was removed by rotary evaporation. After column chromatography with 8:3 hexanes:ethyl acetate as solvent, 15.7 mg of cyclopenta[c]pyridine (3) was collected.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[N:22][N:23]3[CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[N:22][N:23]3[CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1cccc2c1cnn2CCN1CCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Cc1ccc(O)cc1)Nc1cccc2c1cnn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-(4-Benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-yl]-acetamide (Example 3, 500 mg, 1.10 mmol) and Pd (50 mg, 10% on carbon) were suspended in ethanol (40 mL) and stirred under a hydrogen atmosphere at room temperature for 6 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.45 (m, 4H), 2.87 (t, 2H, J=6.78), 3.65 (s, 2H), 4.47 (t, 2H, J=6.78), 6.72 (m, 2H), 7.16 (m, 2H), 7.25–7.65 (m, 3H), 8.26 (s, 1H), 9.26 (s, 1H), 10.09 (s, 1H); MS (DCI/NH3) m/z 365 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][OH:15])=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:15][CH2:14][CH:13]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Methanesulfonyl chloride (1.451 mL, 18.74 mmol) was added to tert-butyl 1-(4-chlorophenyl)-2-hydroxyethylcarbamate (4.63 g, 17.04 mmol) and N,N-diisopropylethylamine (6.23 mL, 35.78 mmol) in DCM (40 mL) cooled to 0° C. over a period of 5 minutes under nitrogen. The resulting solution was stirred at 20° C. for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed sequentially with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl methanesulfonate (3.12 g, 52.3%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.39 (9H, s), 3.17 (3H, s), 4.22-4.28 (2H, m), 4.90 (1H, d), 7.40-7.46 (4H, m), 7.68 (1H, d). m/z (ESI+) (M−H)−=348; HPLC tR=2.32 min.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1.[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]([CH2:19][CH:16]2[CH2:18][CH2:17]2)[C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1cc(Cl)n(CC2CC2)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
6-Chlorouracil I (49.64 g, 0.34 mol; Lancaster) was dissolved in anhydrous DMSO (375 mL) and treated with solid K2CO3 (23.46 g, 0.17 mol) under nitrogen. The resulting white suspension was heated to ca. 80-90° C. and kept at this temperature for 2¼ h. Foaming was observed as the temperature increased, then the reaction mixture became mostly clear. Cyclopropylmethyl bromide (65 g, 0.48 mol) was added neat via syringe, resulting in a white fluffy precipitate. This was followed by a catalytic amount of KI (2.88 g, 0.017 mol). The reaction mixture was heated for 19 hr, becoming mostly homogenous, then turbid with white granular precipitate, and eventually orange as the reaction progressed, remaining heterogeneous. 375 mL 1 N NaOH (aq) was added to the hot reaction mixture, causing it to darken and clear. The heat was removed and the reaction mixture allowed to cool to room temperature while stirring. It was washed with 4×125 mL toluene and the organic washings discarded. The aqueous phase was brought to pH 2-3 by the addition of ca. 100 mL conc. HCl (aq.). 50 mL water was added, and precipitation began after about one hour at room temperature; cooling in ice completed the crystallization. The yellow-green solid was collected by filtration and washed with very cold ether to remove most of the color, then dried under vacuum. Yield: 29.37 g (43%) of a light yellow solid.