Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C#N)[C:9](=[O:20])[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1.C([O-])(=O)CCCCC>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9](=[O:20])[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]2=[O:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(C)CC(=O)C(C#N)c1ccc(C)cc1
Agent: CCCCCC(=O)[O-]
Product: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)cc1

Procedure:
This dione was prepared by acid cyclization of ethyl 6-(4'methylphenyl)-6-cyano-5-keto-3,3-dimethylhexanoate. Preparation of the hexanoate is described in Part A and of the dione in Part B.
Reaction SMILES: C1([C:7]2O[N:10]=[C:9]([NH2:12])[N:8]=2)C=CC=CC=1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]1[CH:7]=[N:8][C:9]([NH2:12])=[N:10]1
Reactant: Nc1ccccc1Cl
Reactant: Nc1noc(-c2ccccc2)n1
Product: Nc1ncn(-c2ccccc2Cl)n1

Procedure:
Prepared in analogy to example 18a), starting with 5-phenyl-[1,2,4]oxadiazol-3-ylamine and 2-chloroaniline. The title compound was obtained as brownish solid (Yield=61%). MS ISP (m/e): 195.1 (100) [(M+H)+].
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[B:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([C:39]2[C:57]([CH:58]3[CH2:60][CH2:59]3)=[CH:56][C:42]3[C:43]([C:53]([OH:55])=O)=[C:44]([C:46]4[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=4)[O:45][C:41]=3[CH:40]=2)[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][C:29]=1[Cl:61])([OH:27])[OH:26].CCN(C(C)C)C(C)C.N.CO>CN(C=O)C.CCOC(C)=O.O>[C:53]([C:43]1[C:42]2[CH:56]=[C:57]([CH:58]3[CH2:60][CH2:59]3)[C:39]([N:34]([C:31]3[CH:32]=[CH:33][C:28]([B:25]([OH:27])[OH:26])=[C:29]([Cl:61])[CH:30]=3)[S:35]([CH3:38])(=[O:36])=[O:37])=[CH:40][C:41]=2[O:45][C:44]=1[C:46]1[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=1)(=[O:55])[NH2:2]
Reactant: CS(=O)(=O)N(c1ccc(B(O)O)c(Cl)c1)c1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N(c1ccc(B(O)O)c(Cl)c1)c1cc2oc(-c3ccc(Cl)cc3)c(C(N)=O)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
HATU (27.1 mg, 0.071 mmol) was added to a solution of 6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic acid (20 mg, 0.036 mmol) and Hunig's base (0.031 mL, 0.179 mmol) in DMF (3 mL). After stirring for 1 h at RT, a 2M solution of ammonia in MeOH (0.357 mL, 0.714 mmol) was added and the solution was stirred for 16 h. Water and EtOAc were added. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by Reverse Phase HPLC (water/MeCN+0.1% formic acid) to give (4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-6-yl)methylsulfonamido)-2-chlorophenyl)boronic acid (9 mg, 0.015 mmol, 43% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 2H), 8.12 (s, 1H), 8.05 (s, 1H), 7.94-8.01 (m, 2H), 7.80 (s, 1H), 7.59-7.68 (m, 2H), 7.41-7.46 (m, 1H), 7.39 (d, 1H), 7.30-7.37 (m, 1H), 7.23 (s, 1H), 3.41 (s, 3H), 2.05-2.21 (m, 1H), 1.02 (br. s., 1H), 0.83 (br. s., 2H), 0.53 (br. s., 1H). LCMS (m/z, ES+)=559.2 (M+H+).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][C@H:54]([C:66]([NH:68][C@H:69]([C:73]([O:75]C(C)(C)C)=[O:74])[CH:70]([CH3:72])[CH3:71])=[O:67])[CH2:55][C:56](=[O:65])[O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:33])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:31])[NH:27][N+:28]([O-:30])=[O:29])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>C(Cl)Cl>[NH2:8][C@H:9]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][C@H:54]([C:66]([NH:68][C@H:69]([C:73]([OH:75])=[O:74])[CH:70]([CH3:71])[CH3:72])=[O:67])[CH2:55][C:56](=[O:65])[O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:33])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:31])[NH:27][N+:28]([O-:30])=[O:29])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[F:4][C:3]([C:1]([OH:7])=[O:2])([F:6])[F:5]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
For simultaneous splitting off of the Boc and tert.-butyl ester protective groups, 7.4 ml (96 mmol) of TFA are added to 2.65 g (2.4 mmol) of 9 and the mixture is stirred under an N2 atmosphere at room temperature for 10 minutes. The solution is taken up in 50 ml of CH2Cl2 and the mixture is evaporated. The product is then recrystallized from MeOH/diethyl ether and dried over KOH.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].IC.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([NH:7][C:8]([N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:22])[C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)n1c(=O)[nH]c2ncccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)n1c(=O)n(C)c2ncccc21

Procedure:
In 2.5 ml of DMF, N-hexyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxamide (65 mg, 0.248 mmol), iodomethane (70 mg, 0.5 mmol) and cesium carbonate (80 mg, 0.25 mmol) were stirred at RT for 5 h. After concentration, the mixture was admixed with water and ethyl acetate, and the organic phase was removed, concentrated and purified by means of preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 16 mg (23%), M+H+: 277.17.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:42])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([C:4]([Br:42])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(=O)C(c1ccccc1)C(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC(=O)C(Br)(c1ccccc1)C(C)C

Procedure:
To a magnetically stirred solution of 2-methyl-3-phenyloctan-4-one (Intermediate IIa-1) (4.31 gram, 0.02 mol) in CCl4 (40 ml) was added a catalytic amount of dibenzoyl peroxide and NBS (6.56 gram). The resulting mixture was heated for 6 hours at reflux temperature. The obtained mixture was allowed to attain room temperature. The formed precipitate was removed by filtration. The filtrate was concentrated to give crude 2-methyl-3-bromo-3-phenyloctan-4-one (intermediate IIb-1)—contaminated with some starting material—as a dark-colored oil (6.77 gram). 1H-NMR (400 MHz, CDCl3) Characteristic signals: δ 0.68 (d, J=6, 3H), 0.78 (t, J=7, 3H), 1.08 (d, J=6, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.C[O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[O:32][CH2:33][CH2:34]Cl>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([OH:36])=[O:23])=[C:26]([O:32][CH2:33][CH2:34][N:19]2[CH2:18][CH2:17][CH:16]([C:9]3[C:10]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:7]([CH2:6][C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[CH:8]=3)[CH2:21][CH2:20]2)[CH:27]=1
Reactant: COC(=O)c1ccc(Cl)cc1OCCCl
Reactant: c1cnc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Product: O=C(O)c1ccc(Cl)cc1OCCN1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Yield: 11.8 %

Procedure:
This compound was prepared following the procedure described in example 4, parts E and F, starting with 1.5 g (5.3 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 1.7 g (6.9 mmol) of 2-(2-chloroethoxy)-4-chlorobenzoic acid methyl ester. After standard work-up and purification, 0.3 g (10% yield) of 4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid were obtained.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4](C(C)C(N)=O)[CH2:3]1.CO.Cl.O>O1CCCC1>[CH2:4]([NH:5][C:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=1)[CH2:3][CH3:2]
Reactant: CC(C(N)=O)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 10 °C

Procedure:
4,5-Dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl propionamide (31.93 g, 95.6 mmol) was dissolved in dry tetrahydrofuran (400 ml) with warming and the solution was cooled to 10° C. with stirring. Borane dimethylsulfide complex (10M, 32 ml, 320 mmole) was added dropwise by syringe through a septum cap. The reaction mixture was heated on a steam-bath for 12 hrs then it was cooled in an ice-bath. Methanol (32 ml) was added dropwise and the mixture was stirred for 1 hr until the effervescence had subsided. Concentrated hydrochloric acid (7 ml) was added to give a clear solution. This was poured into water (100 ml) and the mixture was extracted twice with ethyl acetate (100 ml). The extracts were combined, washed with water and dried (MgSO4). Evaporation of the solvent left a yellow oil which was dried under vacuum for 2 hrs. The crude product (37.1 g) was purified by column chromatography on silica gel, eluting with a 2:1 mixture of ethyl acetate and 60-80 petroleum ether to give a pale yellow oil which solidified on standing, 22.0 g, 72%.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:2][O:27][C:26](=[O:28])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:17]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with L-phenylalanine MS (m/z): 180 [M+1]+
Reaction SMILES: C([O:5][C:6](=[O:41])[NH:7]/[C:8](=[N:39]\O)/[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[N:24][C:25]([NH:28][C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)C(C)C>C1(C)C=CC=C(C)C=1.C1COCC1>[F:36][C:35]([F:37])([F:38])[C:32]1[N:31]=[CH:30][C:29]([NH:28][C:25]2[N:24]=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([CH:13]4[CH2:12][CH2:11][CH:10]([CH2:9][C:8]5[NH:7][C:6](=[O:41])[O:5][N:39]=5)[CH2:15][CH2:14]4)=[CH:21][CH:20]=3)=[CH:27][CH:26]=2)=[CH:34][CH:33]=1
Reactant: CC(C)COC(=O)N/C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)=N\O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)c1
Product: O=c1[nH]c(CC2CCC(c3ccc(-c4ccc(Nc5ccc(C(F)(F)F)nc5)nn4)cc3)CC2)no1
Temperature: 180 °C

Procedure:
A solution of [1-[(Z)-hydroxyimino]-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-ethyl]-carbamic acid isobutyl ester (0.13 g, 0.23 mmol; 1.0 equiv) was dissolved in a m-xylene/THF (4:1) mixture and then heated to 180° C. for 20 min. The cooled reaction was partitioned between EtOAc and water, and the organic layers were washed with brine and dried. Purification by silica gel chromatography (10-100% MeOH in DCM) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.10 (m, 2 H) 1.34 (q, J=11.79 Hz, 2 H) 1.59 (ddd, J=11.12, 7.58, 4.04 Hz, 1 H) 1.70 (t, J=14.02 Hz, 4 H) 2.29 (d, J=6.82 Hz, 2 H) 2.38-2.46 (m, 1H) 7.23 (d, J=8.08 Hz, 2 H) 7.18 (d, J=9.35 Hz, 1 H) 7.72 (d, J=8.59 Hz, 1 H) 7.84 (d, J=8.08 Hz, 2 H) 7.94 (d, J=9.35 Hz, 1 H) 8.56 (dd, J=8.59, 1.26 Hz, 1 H) 8.81 (d, J=1.77 Hz, 1 H) 9.90 (s, 1 H) 12.03 (br. S., 1 H); (M+H)+ 497.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:25])[N:10]3[CH2:24][CH2:23][CH2:22][CH:11]3[CH2:12][N:13](C(OCC(Cl)(Cl)Cl)=O)[C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH3:29]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:25])[N:10]3[CH2:24][CH2:23][CH2:22][CH:11]3[CH2:12][NH:13][C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH3:29]
Reactant: COc1cc2c(c(OC)c1OC)C(=O)N1CCCC1CN2C(=O)OCC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1OC)C(=O)N1CCCC1CN2
Reaction time: 4 h
Yield: 63.4 %

Procedure:
10% Cd/Pb couple (2.57 g, 20.6 mmol Cd) was added to a stirred solution of 112 (2.00 g, 4.1 mmol) in THF (20 mL) and 1N NH4OAc buffer (20 mL) and left at room temperature for 4 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (2×100 mL). The organic layer was washed with brine (2×100 mL) and dried (MgSO4). The solvent was removed in vacuo to give 113 (0.76 g, 64%) as a yellow glass: Rf=0.1 (silica, EtOAc); [α]20.7D=+505° (c=0.1, DCM); IR (neat) cm−1 3339, 2976, 2939, 1614, 1455, 1428, 1392, 1359, 1275, 1245, 1203, 1113, 1052, 1035, 1000, 926, 804, 751, 665; 1H NMR (270 MHz, CDCl3) δ (1H, d, J=4.39 Hz), 6.61 (1H, s), 6.14 (1H, d, J=8.24 Hz), 4.36 (1H, d, J=8.79 Hz), 4.01 (3H, s), 3.98 (3H, s), 3.84 (3H, s), 3.48-3.46 (2H, m) 2.26-2.23 (2H, m), 2.16-1.93 (2H, m); HRMS (FAB) calcd for C15H18N2O4 (M+1) 290.1266, found 290.1208.
Reaction SMILES: CC1N=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:12]([OH:14])=[O:13])=[O:9])=[N:6]C=1.[CH3:22][N:23]1[C:27](C)=[CH:26]C(C(O)=O)=N1>>[CH3:22][N:23]1[C:27]([CH3:26])=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:12]([OH:14])=[O:13])=[O:9])=[N:6]1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: C=CCCCCC[C@H](NC(=O)c1cnc(C)cn1)C(=O)O
Product: C=CCCCCC[C@H](NC(=O)c1cc(C)n(C)n1)C(=O)O

Procedure:
Example 50 can be prepared according to the procedure described for the preparation of Example 49, replacing 5-methylpyrazine-2-carboxylic acid from Example 49a with -(1,5-dimethyl-1H-pyrazole-3-carboxylic acid in Example 50a to produce (S)-2-(1,5-dimethyl-1H-pyrazole-3-carboxamido)non-8-enoic acid. All subsequent steps should proceed in a similar fashion to Example 49 to produce Example 50.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][CH:16]=2)=[C:11]([CH3:28])[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:9]1=[O:39])[CH3:7])(=O)C.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[OH:4][CH2:5][C@H:6]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)[N:18]=[CH:17][CH:16]=2)=[C:11]([CH3:28])[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=2)[C:9]1=[O:39])[CH3:7]
Reactant: CC(=O)OC[C@@H](C)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n([C@H](C)CO)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of (R)-2-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (prepared in example 47) (31.9 mg) in ethanol (1.0 ml) was added under ice-cooling 1M aqueous sodium hydroxide solution (65.2 μl) and the resulting mixture was stirred for one hour under ice-cooling. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with 1M hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(1-hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (24.6 mg) as brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([OH:13])[C:6]2[S:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[C-:14]#[N:15].[Na+].O>CS(C)=O>[C:14]([CH2:2][C:3]1[N:4]=[C:5]([OH:13])[C:6]2[S:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1)#[N:15]
Reactant: Oc1nc(CCl)nc2c1SCCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(O)c2c(n1)CCCS2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Product from Example 3, step A, (1.8 g, 0.01 mol) was dissolved in 10 ml of DMSO and sodium cyanide (1.0 g) was added. The reaction mixture was stirred at 25° C. for 3.5 hours and then poured into water (150 ml). The solution was extracted with ethyl acetate, the ethyl acetate was dried and then evaporated to give the title compound as an oil that was used directly in Step B hereof.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[CH:23]=[C:22](Cl)[N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[Cl:38])[NH2:34].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:21]=[C:22]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([Cl:38])=[C:31]([Cl:30])[CH:32]=3)[CH:23]=[C:24]([N:26]([CH3:28])[CH3:27])[N:25]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)c1cc(Cl)nc(N2CCN(Cc3ccccc3)CC2)n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CN(C)c1cc(Nc2ccc(Cl)c(Cl)c2)nc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 110 °C
Reaction time: 7 h
Yield: 65.8 %

Procedure:
Potassium tert-butoxide (1.6 mmol, 1 M in 2-methyl 2-propanol) was added to a solution of N-[2-(4-benzyl-1-piperazinyl)-6-chloro-4-pyrimidinyl]-N,N-dimethylamine (0.331 g, 0.997 mmol) and 3,4 dichloroaniline (0.178 g, 1.10 mmol) in dioxane (2 mL). Subsequently, tris(dibenzylidineacetone)dipalladium (40 mg, 0.04 mmol) and 2,2′-Bis(diphenylphosphino)-1,1′binapthyl (44 mg, 0.070 mmol) were added and the mixture was stirred for 7 h at 110° C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC using hexane/EtOAc to give the desired product (300 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.C1C2C=CC3C(=CC([CH:38]=[O:39])=C4C=3C=CC=C4)C=2C=CC=1.C(Cl)Cl>CCOC(C)=O>[Cl:1][C:2]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH:38]=[O:39])[CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: Clc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
6-Chlorochrysene (Cambridge Chemical, Inc., 70 g, 0.266 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (2.5 L) was used as the reaction solvent. Chromatography on a plug of SiO2 (1 kg) using EtOAc as the eluting solvent afforded after removal of solvent and drying 19.1 g (25%) of 12-chloro-6-chrysenecarbaldehyde mp 255°-257°, (EtOAc).
Reaction SMILES: C1COCC1.O.[N:7]([CH2:10][C:11]1([C:32]([F:35])([F:34])[F:33])[C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=2[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:13](=[O:31])[O:12]1)=[N+]=[N-].P(OC)(OC)OC>C(OCC)(=O)C>[NH2:7][CH2:10][C:11]1([C:32]([F:34])([F:35])[F:33])[C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=2[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:13](=[O:31])[O:12]1
Reactant: COc1ccc(CN2C(=O)OC(CN=[N+]=[N-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: COP(OC)OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2C(=O)OC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixed solution of THF (130 mL) and water (65 mL) containing 4-(azidomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (46 g, 98.0 mmol), trimethyl phosphite (23.1 mL, 195 mmol) was added at room temperature, and the reaction solution was stirred overnight at 60° C. After the reaction solution was left to cool, water was added thereto, and the resulting solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. To the residue, a 4 N hydrochloric acid-dioxane solution (200 mL) was added, and the mixture was stirred at room temperature for 24 hours. After the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, which was washed sequentially with a 2 N aqueous sodium hydroxide solution and saturated brine and the organic layer was dried over magnesium sulfate, whereby the objective compound (30.9 g, 71%) was obtained as a white solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=3)[CH2:16][CH2:15]1)[CH2:9]2>C(O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=3)[CH2:16][CH2:15]1)[CH2:9]2
Reactant: COC(=O)c1ccc2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
KOH (1 mol/l aq) (2 eq) was added to a suspension of (R)-methyl 3-(7-chloro-1-oxoisoindolin-2-yl)-2,3-dihydro-1H-indene-5-carboxylate (D-01) (0.42 mmol, 1 eq) in a mixture of ethanol (4 ml) and water (1.6 ml). The reaction mixture was stirred overnight at RT. Ethanol was removed in vacuo, and the residue was taken up in diethyl ether and water. The phases were separated, and the aqueous phase was adjusted to pH 3 with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried over sodium sulfate. After concentration, the desired product (R)-3-(7-chloro-1-oxoisoindolin-2-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (G-01) was obtained. Yield: 82%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33].[CH:34](=O)[CH2:35][CH3:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][N:28]([CH2:34][CH2:35][CH3:36])[CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33]
Reactant: CCC=O
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCNCC1
Product: CCCN1CCC(N(CC)Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)CC1

Procedure:
Intermediate 85 was coupled with propionaldehyde following procedure E. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 508. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.5-7.4 (m, 3H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 3.6 (s, 2H), 3.5 (d, 2H), 3.1 (d, 2H), 2.7 (q, 2H), 2.6 (m, 3H), 2.3 (m, 4H), 1.7-1.6 (m, 4H), 1.5-1.4 (m, 2H), 0.94 (t, 3H), 0.80 (t, 3H).