Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([NH2:58])[CH2:53][C:52]2([CH3:60])[CH3:59]>CN(C=O)C.O.CCOC(C)=O>[F:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([NH:58][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[CH2:53][C:52]2([CH3:60])[CH3:59]
Reactant: CC1(C)CN(N)c2ccc(F)cc21
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)NN1CC(C)(C)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (685 mg, 3.18 mmol), HOTT (1.29 g, 3.48 mmol), and DIPEA (1.6 mL, 9.16 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (542 mg, 3.01 mmol) is added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 2% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide (585 mg, 52%) as a solid. MS: 378 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.02 (s, 1H), 8.78 (d, 1H), 8.42 (d, 1H), 8.00 (dt, 1H), 7.56 (dd, 1H), 7.06 (dd, 1H), 6.92 (dt, 1H), 6.76-6.72 (m, 1H), 3.32 (s, 2H), 2.70 (s, 3H), 1.33 (s, 6H).
Reaction SMILES: I[C@@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@:3]12[CH2:11][C@H:7]([C:8](=[O:10])[O:9]1)[C@@H:6]([C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=3)[CH2:16][CH2:15]1)=[O:13])[CH2:5][CH2:4]2.C(=O)([O-])[O-].[Ca+2]>CCOC(C)=O.[Pd]>[CH2:2]([C@:3]12[CH2:11][C@H:7]([C:8](=[O:10])[O:9]1)[C@@H:6]([C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]1)=[O:13])[CH2:5][CH2:4]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1O[C@@]2([C@@H](I)c3ccccc3)CC[C@H](C(=O)N3CCN(c4ccc(I)cc4)CC3)[C@@H]1C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Product: O=C1O[C@@]2(Cc3ccccc3)CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H]1C2
Reaction time: 18 h

Procedure:
To a solution of (1S,2S,5S)-5-[(S)-iodo(phenyl)methyl]-2-[4-(4-iodophenyl)piperazin-1-yl]carbonyl-6-oxabicyclo[3.2.1]octan-7-one (49.0 mg, 0.0000747 mol) in ethyl acetate (5.0 mL, 0.051 mol) in a Parr bottle was added Calcium carbonate (15 mg, 0.00015 mol) and palladium (20 mg, 0.00002 mol) (as 10% Pd/C). The reaction mixture was stirred under hydrogen at 55 psi for 18 h. The reaction mixture was diluted with EtOAc, filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give the crude product. (30 mg, 100% in yield). MS (ESI): (M+H)+=405.1.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:38])[CH2:21][NH:22][C:23](=[O:37])[NH:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[CH:28]([OH:33])[C:29]([O:31]C)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.CO.[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:38])[CH2:21][NH:22][C:23](=[O:37])[NH:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[CH:28]([OH:33])[C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(O)C(=O)O)c1
Yield: 22 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 77, but starting from 0.70 g of methyl (RS)-3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}mandelate in 7 cm3 of a water/methanol (30/70 by volume) mixture and 0.08 g of potassium hydroxide. The crude product (0.45 g) is dissolved in 8.5 cm3 of a 0.1N aqueous sodium hydroxide solution. The solution thus obtained is washed with 2 times 25 cm3 of ethyl acetate, filtered and acidified to a pH of 2 by addition of a 1N aqueous hydrochloric acid solution. The product precipitated is separated by filtration, washed with 2 times 10 cm3 of water and dried in air. 0.15 g of (RS)-3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}mandelic acid is thus obtained in the form of a white product, melting at 135° C. [proton NMR (200 MHz, DMSO D6 plus several drops of CD3COOD, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 110° C.: characteristic chemical shifts at 110° C. 1.55 (s, 9H, --C(CH3)3); 3.32 and 3.53 (2dd, J=12.5 and 6.5, 2H, S--CH2 --); 3.8 (bd, 1H of N--COCH2 --N); 4.08 (d, J=17.5, 1H, the other H of N--COCH2 --N); 5 (m and s, 2H in total respectively N--CH--COO and Ar--CH--); 6.2 (broad, 1H, --NHCO--); 6.54 (s, 1H, S--CH--N); 7.02 (bd, J=7.5, 1H, in position 4 on CO--NH--Ph); 7.1 to 7.5 (m, 6H, aromatic); 7.94 (dd, J=7.5 and 9, 1H, in position 6 on S--CH--Ph--); 8.5 (broad, --CONH--Ar)], [infrared spectrum (KBr), characteristic bands in cm-1 : 3390, 2980, 2930, 2840, 2700 to 2250 (broad band), 1735, 1650, 1610, 1560, 1490, 1455, 1370, 1230, 1150, 1060, 790, 760, 700].
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:21])/[CH:17]=[CH:18]\[O:19][CH3:20])[N:13]([CH:22](O)[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:12]1=[O:37])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)(Cl)=O.[C:50]1([P:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[I-].[Na+]>C1COCC1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:21])/[CH:17]=[CH:18]\[O:19][CH3:20])[N:13]([C:22](=[P:56]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])[C:12]1=[O:37])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CO/C=C\C(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CO/C=C\C(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of 4-nitrobenzyl 2-[(3S ,4R)-3-[(1R)-1(tert-butyldimethylsilyloxy)-ethyl]-4-[(4Z)-methoxy-2-oxobut-3-en-1-yl]-2-azetidinon-1-yl]-2-hydroxyacetate (8.49 g, 15.8 mmol) in THF (300 ml) at -20° C. was added successively 2,6-lutidine (5.5 ml, 47.5 mmol) and thionylchloride (1.7 ml, 24 mmol). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 30 minutes. The mixture was filtered, the solvent evaporated, the residue redissolved in toluene, the solution again filtered and evaporated. The residue was taken up in THF (300 ml) and triphenylphosphine (8.3 g, 32 mmol), 2,6-lutidine (3.7 ml, 32 mmol) and sodium iodide (0.5 g, 32 mmol) were added successively. The reaction mixture was stirred at ambient temperature for 1 hour, filtered and evaporated. The residue was purified by flash chromatography on silica using dichloromethane/ethyl acetate (8:2) as eluant to afford the title compound 4-nitrobenzyl 2-[(3S,4R)-3[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(4Z)-methoxy-2-oxobut-3-en-1-yl]-2-azetidinon-1-yl]-2-(triphenylphosphoranylidene)acetate (7.5 g, 58% ).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[O:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[O:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2c(OCCCCSc3ccccc3)cccc21
Product: CC1(C)OC(=O)Nc2c(OCCCCS(=O)c3ccccc3)cccc21

Procedure:
Prepared analogously to Example 2 from 8-(4-phenylmercapto-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Oc5ccc(Cl)cc5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(4-chlorophenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(4-chlorophenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=O)([C:8](OCC)=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23].Cl>C[O-].[Na+].CO>[OH:15][C:13]1[C:1]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([OH:9])[N:24]=[CH:22][N:23]=1
Reactant: N=CN
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)Cc1c(O)ncnc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
Charge 394.5 L methanol into the reactor at room temperature. Charge 0.3682 Kg of sodium methoxide into the reactor at RT followed by triethyl ethane-1,1,2-tricarboxylate (93.31 Kg). Stir at RT for 3 hours. Heat the reaction to 40-50° C. and distill out methanol completely under vacuum. Charge 263 L of methanol into the reactor at 40-50° C. and distill out methanol completely under vacuum at 40-50° C. Charge 263 L of methanol into the reactor at 40-50° C. cool slowly to 10-15° C. to promote crystallization. Charge 54.54 Kg of sodium methoxide maintaining the temperature at 10-15° C. Heat the reaction slowly to RT and stir for 1 hour. Charge 26.3 Kg of Formamidine acetate into the reactor at RT and slowly raise the temperature of the reaction mass to reflux (65-68° C.). Stir for 2-9 hours by maintaining the temperature at 65-68° C. Slowly decrease the reaction temperature to 10-15° C. and adjust the pH of reaction to 1.5-2.0 by slowly adding the Methanolic HCl (15-18%) maintaining the temperature at 10-15° C. Cool the reaction to 0-5° C. and maintain for 1 hour. Filter the resulting solids via centrifuge at 0-5° C. and spin dry the wet cake for 30 minutes. Wash the wet cake with 26.3 L of chilled methanol (0-5° C.) and spin-dry the wet cake for 30 min. Dry the material under vacuum at 40-45° C. to afford ethyl 2-(4,6-dihydroxypyrimidin-5-yl)acetate (35.65 Kg, 76.6%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C:9]1[C:18](Br)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:50])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:50])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([C:18]2[C:9]([CH2:8][N:7]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1nc2ccccc2cc1Br
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(Cc2ccccc2)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using the following starting materials: benzyl-(3-bromo-quinolin-2-ylmethyl)-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccccc2-c2ccccc2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
2-[(Biphenyl-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (525 mg, 1.36 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.42 g, 24.7 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 30 minutes then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (246) as white solid (453 mg, 93%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1F.[Br:18]C1C=CC=C(Br)C=1>>[Br:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=C(Cc1ccc(F)c(F)c1)c1ccccc1
Product: O=C(Cc1ccccc1)c1cccc(Br)c1
Yield: 47.7 %

Procedure:
Followed the procedure described in Intermediate 12, starting from 1,3-dibromobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to give the desired 1-(3-bromophenyl)-2-phenylethanone (520 mg, yield 47.7%).
Reaction SMILES: [NH3:1].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S(=O)(=O)(O)O>[Ni].C(O)C>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:1])=[CH:5][CH:4]=1
Reactant: N
Reactant: O=Cc1ccc(O)cc1
Agent: [Ni]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: NCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ammonia is passed into 500 ml of ethanol at 10° C. until saturation is reached, 122.1 g=1 mole of p-hydroxybenzaldehyde, 20 g of Raney nickel and 0.1 ml of concentrated sulfuric acid are added and the mixture is stirred in an autoclave for 6 hours at room temperature and under a hydrogen pressure of 100 atmospheres. After releasing the pressure, the catalyst is filtered off and the filtrate is boiled up with active charcoal, filtered and concentrated. The residue is recrystallized from a mixture of ethanol and ether. This gives 104 g (85% of theory), melting point: 104° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](C=O)=[CH:9][N:8]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:31])[CH2:9][N:8]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(Br)cnc32)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC(=O)c3cc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.6 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde obtained by the method described in WO 2004/101565 (4.10 g) was dissolved in THF (100 ml). Triethylamine (3.05 ml) and p-toluenesulfonyl chloride (3.82 g) were added at room temperature and the mixture was stirred overnight. The reaction solvent was distilled off under reduced pressure and then diluted with ethyl acetate. After washing with water and brine in this order, the resulting organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was solidified with (dichloromethane-diethyl ether) and then collected by filtration to give 5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.32 g). Further, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give 5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.55 g). The resulting 5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.83 g) was dissolved in methylene chloride (50 ml). 3-Chloroperbenzoic acid (2.13 g) was added under ice-cooling over 3 hours, and the mixture was stirred at room temperature for 2 hours. Thereafter, a 10% aqueous sodium sulfite solution and a saturated aqueous sodium bicarbonate solution were added to the reaction solution, followed by stirring overnight. The reaction solution was diluted with methylene chloride and the insoluble matter was removed by filtration, followed by extraction with methylene chloride three times. The resulting organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (0.18 g) as a pale red solid.
Reaction SMILES: Br[C:2]1[C:3]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[N:6][CH:7]=1.[C:39]([Zn]C#N)#[N:40].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC(N(C)C)=O.[Zn].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]>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:3]2[C:2]([C:39]#[N:40])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:16][CH2:17][CH:18]([N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)[CH2:19][CH2:20]4)=[CH:11][C:10]=3[O:28][CH3:29])[N:4]=2)=[CH:31]1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Br)c(-c2c[nH]c3ccccc23)n1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(C#N)c(-c2c[nH]c3ccccc23)n1
Yield: 51.7 %

Procedure:
5-Bromo-4-(1H-indol-3-yl)-N-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidin-2-amine (Example 27, 155 mg, 0.27 mmol), zinc powder (0.176 mg, 2.69 μmol), dicyanozinc (47.4 mg, 0.40 mmol), Pd2dba3 (12.31 mg, 0.01 mmol), and xantphos (15.56 mg, 0.03 mmol) in DMA (1.5 mL) were heated at 130° C. for 2 h. The reaction mixture was purified by chromatography on silica gel (10% MeOH/1% NH4OH in DCM) to give the title product (73.0 mg, 52.0%).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH2:20][CH3:21])[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH:2]=[CH:3]C.C(N1C(CC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C=CC1C=CC=CC=1.CC(C)=CCN1C(CC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O.COC(C=CCN1C(CC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)=O.C(N1C(CC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C#C.C(N1C(CC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C#CC.C1(C#CCN2C(CC3C=C(C)C=C(C)C=3)=C(CC)C(=O)NC2=O)C=CC=CC=1>>[CH2:1]([N:5]1[C:10]([CH2:11][C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:9]([CH2:20][CH3:21])[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: CC=CCn1c(Cc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: C#CCn1c(Cc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: CC#CCn1c(Cc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: CCc1c(Cc2cc(C)cc(C)c2)n(CC#Cc2ccccc2)c(=O)[nH]c1=O
Product: C=CCn1c(Cc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O

Procedure:
1-(2-butenyl)-5-ethyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione; 1-cinnamyl-5-ethyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione; 1-(3-methyl-2-butenyl)-5-ethyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione; 1-(methoxycarbonylallyl)-5-ethyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione; 1-propargyl-5-ethyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione; 1-(2-butynyl)-5-ethyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione; 1-(3-phenyl-2-propynyl)-5-ethyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione;
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[CH:17]=3)=[C:13]([F:34])[CH:12]=2)=[O:9])[C:4](=[O:35])[N:3]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH2:42][CH2:43][CH2:44][OH:45]>CN1C(=O)CCC1>[F:34][C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:5]2[C:4](=[O:35])[N:3]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])=[O:9])[CH:33]=[CH:32][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:42][CH2:43][CH2:44][OH:45])=[O:31])[CH:17]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: NCCO
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)NCCO)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 69.4 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-2-yl)carbamate (100 mg, 0.18 mmol), NMP (5 mL) and 2-aminoethanol (3.0 mg, 0.22 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and diluted with EtOAc (20 mL). The precipitate was collected by filtration, and then washed with EtOAc (3 mL) to give the title compound as a white solid (65 mg, 69%).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[C@@H:44]([O:48][C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=1)[C:52]([OH:54])=O)([CH2:46][CH3:47])[CH3:45].[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:52](=[O:54])[C:51]1[CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=[C:49]([O:48][C@H:44]([CH2:46][CH3:47])[CH3:45])[CH:50]=1)[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: CC[C@H](C)Oc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CC[C@H](C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6 from 3-((S)-sec-butyloxy)-5-(2-oxopyrrolidin-1-yl)benzoic acid (D47) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).