Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:22][CH2:21]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:31][CH:30]=2)[CH2:22][CH2:21]1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCOc2ccc(Nc3ncc4ccc(-c5cccnc5)n4n3)cc2)CC1

Procedure:
Into a microwave vial, 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (0.104 g, 0.000404 mol), 4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenylamine (0.209 g, 0.000888 mol), 1-Methoxy-2-propanol (0.971 mL, 0.00993 mol) and N,N-Diisopropylethylamine (0.155 mL, 0.000888 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 12% methanol). The collected fractions afforded {4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenyl}-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a yellow solid (28 mg, 16%). MP 107-110° C. LCMS (E/I+) 430.8 (M+H). NMR 1H (DSMO-d6)-9.42 (d, 1H, J=2.00), 9.39 (s, 1H), 9.04 (s, 1H), 8.66 (d, 1H, J=7.76 Hz), 8.61 (d, 1H, J=6.56 Hz), 7.60-7.70 (m, 3H), 7.32 (d, 1H, J=4.77 Hz), 6.98 (d, 1H, J=4.76 Hz), 6.95 (d, 2H, J=9.00 Hz), 4.16 (t, 2H, J=5.26 Hz), 2.40-3.50 (m, 13H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1ccnc(Nc2nc3ccc(-c4ccncc4)cc3s2)c1
Product: ClCc1ccnc(Nc2nc3ccc(-c4ccncc4)cc3s2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
(2-((6-(Pyridin-4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)methanol 101 (0.12 g, 0.36 mmol, 1 eq.) was dissolved in POCl3 (3 mL) under N2, and the suspension was stirred at 110° C. for 2 hours. After cooling, POCl3 was evaporated under reduced pressure and the residue was basified with sat. Na2CO3 solution, then extracted with DCM, dried and concentrated in vacuo to afford N-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (80 mg, 63%) which was used directly in the next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH:11][C@@H:12]([CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)[CH2:36][CH2:35]1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][CH2:22][C:21]([C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=O)=[CH:20]2.[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]\[C:53]([OH:55])=[O:54]>C1COCC1.C(O)C>[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]\[C:53]([OH:55])=[O:54].[OH:11][C@@H:12]([CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)[CH2:36][CH2:35]1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][CH2:22][C:21]([CH2:25][N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)=[CH:20]2
Reactant: O=C(C1=Cc2cccc(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)c2OC1)N1CCOCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: O[C@H](COc1cccc2c1OCC(CN1CCOCC1)=C2)CN1CCC(c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (0.55 g) in THF was added aluminum chloride (0.63 g) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was made to become 4° C. and a solution of (S)-4-(8-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-2H-chromen-3-ylcarbonyl)morpholine (2.5 g) in THF (50 ml) was added dropwise. The mixture was stirred for 30 min and hydrous THF was added. The mixture was further stirred for 30 min at room temperature and the precipitated insoluble matter was filtered off through celite. The solvent was evaporated under reduced pressure to give a brown oil. This was dissolved in ethanol and maleic acid was added. The precipitated crystals were collected by filtration and dried to give the title compound (1.3 g) as pale-yellow crystals, melting point 164-166° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:20]2[N:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](OC)=[O:29])=[CH:22][N:21]=2)[CH2:16][C@H:15]1[CH2:47][CH3:48])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C>[C:7]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]2[CH:34]=[C:35]([C:43]([F:46])([F:44])[F:45])[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=2)[C:20]2[N:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:24][N:25]=2)[CH2:16][C@H:15]1[CH2:47][CH3:48])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(CCC(=O)OC)cn2)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(CCCO)cn2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
1.0M solution of LAH (1.7 ml, 1.7 mmol) in diethylether solution is added to (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxycarbonyl-ethyl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 0.58 mmol) in diethylether (8 ml) at 0° C., and this mixture is stirred for 0.5 hour at the same temperature. The reaction mixture is quenched with saturated ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with 1N HCl, sat NaHCO3 aq. and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-hydroxy-propyl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 74%).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]#[CH:29])[CH3:25].ClC1N=C(NCCNC(=O)OC(C)(C)C)C(C#CC(OCC)OCC)=CN=1>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH2:10][C:11]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:2]([C:29]#[C:28][CH:27]([O:30][CH2:31][CH3:32])[O:26][CH2:24][CH3:25])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NC1(CNc2nc(Cl)ncc2Br)CCCC1
Agent: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Product: CCOC(C#Cc1cnc(Cl)nc1NCC1(NC(=O)OC(C)(C)C)CCCC1)OCC

Procedure:
tert-butyl N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]cyclopentyl]carbamate was synthesized by treating tert-butyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamate with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddba using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate LCMS (ESI) 453 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][NH2:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[CH2:19][O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31](O)=[O:32])[CH2:25][CH2:24]1)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:31](=[O:32])[CH2:30][CH2:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][CH2:19][C:18]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:16]([Cl:15])[CH:17]=3)=[O:22])[CH2:28][CH2:27]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cn(Cc2ccccc2)nn1
Reactant: O=C(O)CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCc1cn(Cc2ccccc2)nn1

Procedure:
A reaction mixture comprising of (1-benzyl-1H-1,2,3-triazol-4-yl)methanamine (46.2 mg, 0.245 mmol), 3-(1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidin-4-yl)propanoic acid (88 mg, 0.245 mmol), HATU (187 mg, 0.491 mmol) and TEA (103 μl, 0.736 mmol) in DMF (0.8 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give aqueous solutions which were extracted with ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(O)C.ClCCl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of commercially available (S)-(+)-5-(hydroxymethyl)pyrrolidin-2-one (2 g, 17.36 mmol) in ethanol-free CHCl3 (60 ml), triethylamine (TEA) (2.63 g, 26.04 mmol) and methanesulfonyl chloride (2.38 g, 20.84 mmol) were added dropwise at 0° C. The mixture was left stirring at room temperature for 3 hours, then it was diluted with dichloromethane (DCM) (60 ml) and washed with a saturated aqueous solution of NaHCO3 (3×30 ml). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH 9/1 respectively) to give the title compound as a pale yellow solid (2.2 g, 65% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cccc(CBr)c1
Product: CCOP(=O)(Cc1cccc(F)c1)OCC
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A flask was charged with 1-(bromomethyl)-3-fluorobenzene (7.5 mL, 61.1 mmol) and treated with triethylphosphite (21.39 mL, 122 mmol) dropwise with stirring. Upon completion of the addition, the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen was passed over the reaction mixture. The reaction was slowly warmed to 150° C. and held there for 2 h. The reaction was cooled to room temperature and concentrated under high vacuum to remove most of the excess triethylphosphite. The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.29 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 4.06 (m, 4H), 3.16 (d, J=21.7, 2H), 1.28 (t, J=7.0, 6H). 13C-NMR (CDCl3, 126 MHz) δ 162.85 (dd, J=246, 3.8), 134.2 (t, J=8.6), 130.0 (dd, J=7.7, 2.9), 125.6 (dd, J=6.7, 2.9), 116.9 (dd, J=22, 6.7, 114.0 (dd, J=21, 2.9), 62.3 (d, J=6.7), 33.7 (dd, J=138, 1.9, 16.5 (d, J=5.8).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH2:6][N:5]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:4]1.[C:27]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])#[N:28]>>[C:27]([C:29]1[CH:30]=[C:31]([C:32]([NH:2][CH:3]2[CH2:8][CH:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=3)[CH2:6][N:5]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[CH2:4]2)=[O:33])[CH:35]=[CH:36][CH:37]=1)#[N:28]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: Cl
Product: N#Cc1cccc(C(=O)NC2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)c1

Procedure:
200 mg (0.508 mmol) of the amine from Example 57A [racemic cis isomer] and 112 mg (0.762 mmol) of 3-cyanobenzoic acid were reacted according to General Method 8. Yield: 206 mg (80% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH3:18])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: COc1ccccc1B(O)O
Product: COC(=O)c1c(O)c2cc(-c3ccccc3OC)ccc2sc1=O

Procedure:
4-Hydroxy-6-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 2-methoxy-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.481 (s, 1H), 7.803 (d, 1H), 7.627-7.789 (m, 1H), 7.42-6.92 (m, 4H), 4.022 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH3:20].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)C1Cc2cc(-c3ccccc3)ccc2O1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1Cc2cc(-c3ccccc3)ccc2O1

Procedure:
A mixture of 2.5 g of 1D, 60 ml of ethanol, 20 ml of dry benzene and 2 ml of concentrated sulfuric acid was refluxed for seven hours, with removal of water as it formed. The resulting mixture was concentrated, and the residue dissolved in ether. The solution was washed with saturated sodium bicarbonate solution and water. The aqueous portion was extracted with ether. The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was distilled to give ethyl 2,3-dihydro-5-phenylbenzofuran-2-carboxylate (1E), as a colorless liquid, bp: 180°-181° C., 0.35 Torr.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5].[CH3:20][O:21]C1C=C(OC)C=CC=1C(C1C=CC=CC=1O)=O.COC1C=CC=CC=1C(O)=O.COC1C=C(OC)C=C(OC)C=1.COC1C(OC)=C(OC)C=CC=1C(C1C=CC=CC=1O)=O>>[CH3:20][O:21][C:17]1[C:2]([OH:1])=[C:3]([CH:14]=[CH:15][C:16]=1[O:18][CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5]
Reactant: COc1ccc(C(=O)c2ccccc2O)c(OC)c1
Reactant: COc1ccc(C(=O)c2ccccc2OC)c(O)c1
Agent: COc1cc(OC)cc(OC)c1
Agent: COc1ccc(C(=O)c2ccccc2O)c(OC)c1OC
Agent: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)c1ccc(OC)c(OC)c1O

Procedure:
According to the method of producing 2-hydroxy-4-methoxy-2'-methoxy benzophenone (4a) and 2,4-dimethoxy-2'-hydroxybenzophenone (4b), 2.00g (13.14 mmol) of 2-methoxybenzoic acid was reacted with 2.19g (13.04 mmol) of 1,3,5-trimethoxybenzene to give 2.20g (7.75 mmol) of 3,4-dimethoxy-2-hydroxy-2'-methoxybenzophenone (17a) and 2,3,4-trimethoxy-2'-hydroxy-benzophenone (17b). Then, based on example 3, 1.35 g (5.92 mmol) of 3,4-dihydroxy benzophenone (18H) as pale yellow powder was produced. The physical properties were measured and are listed below.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[Cl:20])=[O:15])=[O:6])[CH3:4].[N:35]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37](O)=[O:38].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[N:35]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[Cl:20])=[O:15])=[O:6])[CH3:4])=[O:38]
Reactant: C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
At 0° C. the solution of 657 mg (1.28 mmol) of HCl.Ala-Lys(ClZ)-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 280 mg (1.3 mmol) of Boc-Pro-OH, 170 mg (1.26 mmol) of 1-hydroxybenzotriazole and 270 mg (1.31 mmol) of dicyclohexylcarbodiimide in 30 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 6 h and TLC (chloroform/methanol, 20:1) indicated complete disappearance of HCl.Ala-Lys(ClZ)-OBzl. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 80 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 134 mg (98%) of the title compound as a colorless powder. Mp86–88° C., FAB-MS (m/e) 674[M+H]+.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1>O.F[B-](F)(F)F.[H+]>[OH:2][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(N)ccc21
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of sodium nitrite (14.8 g, 214 mmol) in 30 mL of water was slowly added to the solution of 6-amino-3,3-dimethyl-indan-1-one (14.0 g, 85.8 mmol) in 30 mL of 48% tetrafluoroboric acid and 30 mL of water at 0°-5° C. After being stirred for 30 min, the mixture was filtered, and the solids were washed with cold 5% tetrafluoroboric acid and dried in vacuum. The solids were then added in several portions into a boiling solution of 50 mL of sulfuric acid in 0.5 liter of water. After refluxing for 1 hour, the solution was cooled to room temperature and extracted with ethyl acetate (100 mL×3). The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc:hexane=1:10 to 1:2) to give 7.60 g (50% yield) of the title compound as a solid; 1H-NMR (CDCl3) δ 1.40 (s, 6H), 2.64 (s, 2H), 7.13 (s, 1H),7.18 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H); MS m/e 177 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.C1C=C(O[C:26](OC2N=CC=CC=2)=[S:27])N=CC=1>C(Cl)Cl>[C:15]([O:14][C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:1]=[C:26]=[S:27])[C:10]=2[CH3:11])[CH2:6][CH2:7]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1c(N)ccc2c1N(C(=O)OC(C)(C)C)CC2
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
6-Amino-1-t-butoxycarbonyl-2,3-dihydro-7-methylindole (0.5 g, 2.13 mmol) is dissolved in methylene chloride (10 mL). To this solution is added N,N-dimethylaminopyridine (0.052 g, 0.42 mmol) and di-2-pyridyl thionocarbonate (0.496 g, 2.13 mmol). The solution is allowed to stir for 20 minutes. The solution is diluted with methylene chloride and washed first with four 75-mL portions of aqueous citric acid solution followed by three 100-mL portions of aqueous potassium carbonate. The organic extracts are dried over anhydrous potassium carbonate, filtered and the solvent is removed by rotary evaporation to yield 0.59 g of crude 1-t-butoxycarbonyl-2,3-dihydro-6-isothiocyanato-7-methylindole as an orange, oily solid. The crude product is taken on to the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:19](=[O:29])[C:20]([CH2:22][C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:21][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:17]C)[CH:10]=3.Br.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:19](=[O:29])[C:20]([CH2:22][C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:21][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:17])[CH:10]=3
Reactant: COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(=O)c(c1)c23
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c(=O)c3cc(O)cc1c32
Yield: 71.2 %

Procedure:
The compound (100 mg) obtained in Example 32 was suspended in acetic acid (3 mL) and to the suspension was added 47% hydrobromic acid (3 mL). The mixture was heated under reflux for 20 hours. After allowing to cool, the mixture was alkalized with 6N-sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (69 mg; 71%).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH:21]=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]>C(Cl)Cl>[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]([I:8])=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)Nc1nccc2cc3cccnc3n12
Solvent: ClCCl
Product: CC(=O)Nc1nccc2c(I)c3cccnc3n12
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
NIS (100 mg, 0.44 mmol) was portionwise added to a cooled (0° C.) solution of 9-Acetylaminopyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine (100 mg, 0.44 mmol) in CH2Cl2 (20 ml). The mixture was stirred for 15 min. The solution was diluted with CH2Cl2 (50 ml) and washed twice with water. The organic layer was dried and evaporated to obtain 20a (142 mg, 93%) as a bright yellow solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:9][C:10]=2I)[CH:7]=1.O.[CH3:22][N:23](C=O)C>[NH4+].[OH-].[C-]#N.[Zn+2].[C-]#N.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:9][C:10]=2[C:22]#[N:23])[CH:7]=1
Reactant: FC(F)(F)C(F)(F)CCc1nc(I)c2ccc(Cl)cn12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1nc(CCC(F)(F)C(F)(F)F)n2cc(Cl)ccc12
Temperature: 120 °C

Procedure:
To a solution of the intermediate from Step H (4.32 g, 10.18 mmol) in DMF (50 mL) was added zinc cyanide (2.39 g, 20.35 mmol), Pd2 dba3 (0.47 g, 0.51 mmol), DPPF (0.564 g, 1.02 mmol), and water (2.5 mL). The resulting solution was heated at 120° C. for 18 hours. The reaction was cooled to room temperature, diluted with 15% NH4OH solution (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. m/z=323.9 (M+H).