Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH2:25][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccc(F)cc3C=O)ccc2n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc(F)ccc2-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
114 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-5-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 97 μl of 1-methylpiperazine and 50 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 195 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.[NH2:19][CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[NH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:19][CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=3)[NH:24][CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(O)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 69 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with the 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), 3-(2-aminoethyl)-1H-indol-5-ol hydrochloride (0.081 g; 0.382 mmol), HATU (0.145 g; 0.382 mmol) and N,N-diisopropylethylamine (0.150 mL; 0.869 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.093 g (67%) of the title compound as a white solid.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:22])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:30]1([CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37](O)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH3:22])=[O:19])[NH:17][C:37](=[O:38])[CH:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(O)cc1
Yield: 19.8 %

Procedure:
Prepared according to the method described in Example 3(c) above from (R)-N5 -(Cbz)-(S)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide hydrochloride (3.3 g; 7.8 mmol; from step (b) above), diphenylacetic acid (1.82 g, 8.6 mmol), BOP (3.79 g; 8.58 mmol) and triethylamine (4.0 mL; 1.1 eq.) in 300 mL acetonitrile, yielding 895 mg of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH:55]=[CH:56][C:57]=1[CH3:58])[C:45]([NH:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)=[O:46]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH:55]=[CH:56][C:57]=5[CH3:58])[C:45]([NH:47][CH2:48][C:49]5[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=5)=[O:46])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1ccc(C(=O)NCc2cccnc2)cc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)NCc4cccnc4)ccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and 3-bromo-4-methyl-N-pyridin-3-ylmethyl-benzamide (60 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methyl-N-pyridin-3-ylmethyl-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-303) as a grayish white powder (27 mg, 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:10][S:9][C:8]=2[CH:21]=1)([O-])=O.O.NN>CO.[Ni]>[N:16]1([CH2:15][CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][S:9][C:8]3[CH:21]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)SCCN2CCCN1CCCC1
Yield: 90.7 %

Procedure:
A solution of 7-nitro-4-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.55 g, 1.789 mmol) in dry methanol (10 mL) was treated with hydrazine hydrate (0.652 mL, 17.89 mmol) followed by Raney-Nickel (0.1 g, 1.789 mmol) at room temperature. The resulting mixture was stirred at reflux for 5 minutes using a pre-heated oil bath. The reaction was then brought to room temperature, filtered through a pad of Celite, and washed with methanol (3×10 mL). The combined methanol layers were evaporated, and the crude material was purified by flash column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2) to obtain the title product (0.45 g, 91%) as a syrup. 1H NMR (DMSO-d6) δ 6.51 (d, 1H, J=9.3 Hz), 6.26-6.23 (m, 2H), 4.41 (s, 2H), 3.37-3.30 (m, 2H, merged with water peak), 3.11 (t, 2H, J=6.9 Hz), 2.98-2.95 (m, 2H), 2.42-2.37 (m, 6H), 1.67-1.60 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:44](=[O:45])[C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:43]2[C:44](=[O:45])[N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=[CH:41][CH:42]=2)=[O:47])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:15][C:8]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (144.5 mg, 0.326 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (228.9 mg, 0.977 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (312.3 mg, 1.63 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (220.1 mg, 1.63 mmol), N-ethyl-N-isopropylpropan-2-amine (421.1 mg, 3.26 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (87.3 mg, 40.62%). LRMS (APCI pos): >95% purity, 254 nm, m/e 660 (M+1). 1H NMR (400 MHz, CD3Cl) δ 11.83 (s, 1H), 8.45 (d, 1H), 8.42 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.37-7.68 (m, 5H), 7.21-7.28 (m, 2H), 6.48 (d, 1H), 4.24 (m, 2H), 3.08 (m, 1H), 2.89 (m, 2H), 2.07 (m, 2H), 1.75 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1.Cl.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][O:14][CH2:13]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:19]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1
Reactant: ClCc1cc(Cl)nc(Cl)n1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cc(N2C3CCC2COC3)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A flask was charged with 2,4-dichloro-6-(chloromethyl)pyrimidine (prepared as reported in Bioorg. Med. Chem., 2002, 10, 525), 2.40 g, 12.15 mmol) in dichloromethane (30 mL) to give a yellow solution. 3-Oxa-8-azabicyclo[3.2.1]octane, HCl (33, 1.818 g, 12.15 mmol) and triethylamine (3.56 ml, 25.5 mmol) in dichloromethane (30 mL) were added slowly over 10 minutes, and the resulting solution was allowed to stir at room temperature for 16 hours, then concentrated. The crude product was added to a silica gel column and eluted with 0-40% ethyl acetate in hexanes to provide 8-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.30 g, 69%) as an off-white solid. HRMS; [M+H]+ Obs'd=274.0510, [M+H]+ Calc'd=274.0508
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4]>O1CCOCC1>[CH2:5]([CH:2]1[NH:1][C:3](=[O:4])[CH:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[NH:1][C:3]1=[O:4])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Solvent: C1COCCO1
Product: CC(C)CC1NC(=O)C(CC(C)C)NC1=O

Procedure:
Refluxing a dioxane solution of (S)-2-amino-4-methylpentan-1-ol with complex 1 (1 mol %) led to 64% isolated yield of the cyclic dipeptide, 3,6-diisobutylpiperazine-2,5-dione 7b after workup (Table 31, entry 1). The product structure was confirmed by MS, NMR spectroscopies.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N#N.[CH3:14][N:15](C=O)C>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-]#N.[C-]#N.[Zn+2]>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([C:14]#[N:15])=[CH:2][N:3]=1
Reactant: Brc1cc2ccccc2cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [C-]#N
Product: N#Cc1cncc2ccccc12
Temperature: 120 °C
Yield: 27.4 %

Procedure:
To a stirred solution of 3-bromoisoquinoline (Intermediate-12) (9.2 g, 44.2 mmol) in DMF (15 mL) were added, Pd(PPh3)4 (10.2 g, 8.84 mmol) and Zn(CN)2 (10.34 g, 88.44 mmol, 2.0 eq) and the solution was degassed with N2 for 20 min. It was then heated to 120° C. overnight. After the completion (TLC), reaction mixture was cooled to RT, filtered and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (10% EtOAc:Hexanes) to afford the desired compound (3.4 g, 27.4%) as pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:18][CH3:19])CC)[CH:10]=2)[NH:6][C@@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[O:3]1.[CH3:32][CH2:33]O>Cl[Pd]Cl.C1COCC1>[CH2:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][C@@H:7]([C:2]([OH:3])=[O:1])[NH2:6])[CH2:18][CH2:19][CH2:32][CH3:33]
Reactant: CCO
Reactant: CCC(CC)c1cccc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)c1
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Product: CCCCCc1cccc(C[C@H](N)C(=O)O)c1
Reaction time: 18 h

Procedure:
To a 300 mL Parr bottle were added 0.41 g of PdCl2, 1.36 g of (2R,3S,5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)morpholine, 50 mL of EtOH, and 30 mL of THF. The mixture was deoxygenated by bubbling nitrogen through for 10 min and was hydrogenated at 45 psi for 18 h. The vessel was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated in vacuo to a volume of 15 mL. The solution was chilled in an ice bath and triturated with addition of 50 mL of hexane. A fine precipitate slowly formed. After storing at 5° C. overnight, the solid was collected by filtration and dried in vacuo to afford 0.65 g (72%) of 3-(3-pentyl-L-phenylalanine.HCl as a white powder, m.p. 170° C. (dec).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[C:7](Cl)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])[CH:4]=[CH2:5].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].O>CN(C=O)C>[CH2:3]([C:6]1[C:11]([Cl:12])=[N:10][C:9]([CH3:13])=[N:8][C:7]=1[NH:18][C:17]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=1[Cl:15])[CH:4]=[CH2:5]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: C=CCc1c(Cl)nc(C)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1c(Cl)nc(C)nc1Nc1ccc(Cl)cc1Cl
Reaction time: 0.42 h
Yield: 37 %

Procedure:
Sodium hydride mineral oil dispersion (60%, 1.38 g, 34.5 mmol) was added to a stirred solution of pyrimidine (10) (3.50 g, 17.2 mmol) and 2,4-dichloroaniline (3.07 g, 18.9 mmol) in DMF (40 mL). After 25 min, the mixture was poured into water (100 mL) and extracted with dichloromethane. The combined extracts were dried (MgSO4), concentrated under vacuum, and the residue was chromatographed (elution with dichloromethane) to afford 2.09 g (37%) of pyrimidine (11) as a white powder.
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]([CH:18]([CH3:20])[CH3:19])([CH3:17])[C:14](=[O:16])[N:15]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3].S(=O)(=O)(O)O.[OH-].[NH4+]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]([CH:18]([CH3:20])[CH3:19])([CH3:17])[C:14](=[O:16])[N:15]=2)=[N:9][CH:10]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)C1(C)NC(c2ccc(C(C)(C)O)cn2)=NC1=O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: C=C(C)c1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To 6.4 g of 2-[5-(1-hydroxy-1-methylethyl)-2-pyridyl]-5-isopropyl-5-methyl-2-imidazolin-4-one is added with stirring and cooling (ice) 30 ml concentrated sulfuric acid. The mixture is stirred at room temperature for a further 30 minutes, then poured onto 100 ml ice. The pH of this mixture is adjusted to 4 with concentrated ammonium hydroxide and extracted with 3×200 ml ether. The combined extracts were washed with saturated brine, dried and concentrated to give 5.71 g yellow solid. Recrystallization from ether-hexane gave analytically pure 2-(5-isopropenyl-2-pyridyl)-5-isopropenyl-5-methyl-2-imidazolin-4-one, mp 123°-125° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[K+].O.[Cl:12][CH2:13][C:14]([N:16]([CH2:25]Cl)[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[O:15]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)(Cl)Cl>[Cl:12][CH2:13][C:14]([N:16]([CH2:25][N:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=[N:7]1)[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[O:15]
Reactant: CC(C)c1cn[nH]c1
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cccc(C)c1N(Cn1cc(C(C)C)cn1)C(=O)CCl
Reaction time: 4 h

Procedure:
A solution of 12.1 parts by weight of 4-isopropylpyrazole and 5.6 parts by weight of potassium hydroxide in 30 parts by volume of water was added at 25° C., with vigorous stirring, to a solution of 24.6 parts by weight of 2-chloro-N-chloromethyl-2',6'-dimethylacetanilide and 0.5 part by weight of triethylbenzylammonium chloride in 100 parts by volume of chloroform and stirring was continued for 4 hours at 25° C. The organic phase was washed with three times 50 parts by volume of water, dried over sodium sulfate and evaporated under reduced pressure at 50° C. to give 26.2 parts by weight of 2-chloro-2',6'-dimethyl-N-(4-isopropylpyrazol-1-yl-methyl)-acetanilide of melting point 58° C.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)C>[CH3:17][C:16]1[N:5]2[CH2:6][C:7]3[C:8]4[C:9]([NH:14][CH:15]=3)=[CH:10][CH:11]=[CH:12][C:13]=4[C:4]2=[N:20][N:19]=1
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Reactant: CC(=O)NN
Solvent: CCO
Product: Cc1nnc2n1Cc1c[nH]c3cccc-2c13

Procedure:
Alternatively the title compound is prepared as follows. A suspension of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (9.0 g) in dry ethanol (140 ml) is treated with acetylhydrazine (5.0 g). The mixture is heated at reflux for 2 days. Ethanol is partially removed by distillation and ether-hexane added. The solid is collected from methanol to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][CH:14]=3)[C:9](=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.[W]>[Br:27][C:8]1[C:9](=[O:26])[C:10]2[C:15]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Yield: 59.8 %

Procedure:
3-Phenyl-6-(3-phenyl-propoxy)-indene-1-one (200 mg, 0.586 mmol) obtained in Step 1 was dissolved in carbon tetrachloride, and N-bromosuccinimide (313 mg, 1.75 mmol) and 2,2′-azobisisobutyronitrile (9.7 mg) were added thereto. The mixture was refluxed for 1 hr under the irradiation of a 375 W tungsten lamp. Upon the completion of the reaction, the mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate:hexane=1:5) to obtain 147 mg of the titled compound (yield: 60%) as a red solid.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl.O>CN(C=O)C>[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COCCOCCl
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
3.8 g (0.13 mol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen and a solution of 40 g (0.13 mol) of 2-(1-adamantyl)-4-bromophenol in 100 ml of DMF was added dropwise. The mixture was stirred until the evolution of gas had ceased. A solution of 18 ml (0.15 mol) of 2-methoxyethoxymethyl chloride in 20 ml of DMF was then added dropwise and the mixture was stirred for four hours at room temperature. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (50/50). After evaporation of the solvents, 40.1 g (78%) of the expected compound, having a melting point of 69°-70° C., were recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.[OH-].[K+].C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C.O>[Br:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[CH:10]=2)[NH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(Br)c2c1
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(2,6-difluorophenyl)-1H-indole (2.0 g, 8.7 mmol) in DMF (20 mL) was added KOH (0.98 g, 17.5 mmol) and NBS (1.55 g, 8.7 mmol) at RT and stirred for 1 h. The resulting mixture was diluted with water, extracted with DCM (20 mL), dried over Na2SO4, filtered, concentrated to give crude 3-bromo-5-(2,6-difluorophenyl)-1H-indole.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][NH:8][CH:7]=1)=O)C.[OH-].[Na+].O.C(Cl)Cl>C(O)CO>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:6]=[CH:7][NH:8][CH:9]=2)=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2cc[nH]c2)cc1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
A solution of 55 (2.44 g, 9.92 mmol) in ethylene glycol (25 mL) was flushed with argon for 20 min. The mixture was immersed in an oil bath pre-heated to 160° C., and powdered NaOH (4.22 g, 105 mmol) was added. Stirring was continued for 1.5 h. The reaction mixture was allowed to cool to room temperature, and water and CH2Cl2 were added. The aqueous layer was extracted with CH2Cl2. The organic extract was washed with water and brine. The organic layer was dried (Na2SO4). The solvent was removed at reduced pressure to yield a pale brown oil (502 mg, 25%): 1H NMR δ 6.36-6.48 (m, 1H), 6.69-6.73 (m, 2H), 6.79-6.81 (m, 1H), 6.96-6.98 (m, 1H), 7.33-7.38 (m, 1H), 8.21 (br, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[Cl:23])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([O:18][C:16]([NH:15][CH:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([Cl:23])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc2c(cc1Cl)C(NC(=O)OC(C)(C)C)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NC1CCSc2cc(C(=O)O)c(Cl)cc21
Yield: 63 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using 4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid methyl ester (700 mg) and potassium carbonate (541 mg), the objective 4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid (424 mg) was obtained as colorless crystals.