Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[CH2:19][CH3:20])C.[CH3:21][C@@H:22]([NH2:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[O:8]=[C:7]1[C:6](=[O:9])[C:5]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[CH2:19][CH3:20])=[C:4]1[NH:27][C@H:22]([CH3:21])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@@H](N)C(C)(C)C
Reactant: CCOc1c(Nc2ccc(C#N)cc2CC)c(=O)c1=O
Solvent: CCO
Product: CCc1cc(C#N)ccc1Nc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Yield: 52.1 %

Procedure:
4-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-3-ethylbenzonitrile (1.26 g, 4.66 mmol) and a solution of (R)-1,2,2-trimethylpropylamine (9.3 mmol) in ethanol (58 mL) were stirred at room temperature for 24 hours. The resulting yellow solution was concentrated to a yellow oil, which was dissolved in acetonitrile (20 mL) and stirred at room temperature. The yellow solid which precipitated was filtered off and rinsed with ethyl acetate to yield 0.79 g (52%) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethylbenzonitrile as an off-white solid: mp 235°-237° C.; [α]D25 =+68.20° (DMSO, c 0.0072); 1H NMR (DMSO-d6): δ 8.04 (br s, 1H), 8.04 (d, 1H), 7.69-7.57 (m, 3H), 4.05 (m, 1H), 2.71 (q, 2H), 1.27-1.16 (overlapping doublet and triplet, 6H), 0.91 (s, 9H). IR (KBr): 3278, 2959, 2222, 1793, 1674, 1598, 1576, 1522 cm-1 ; MS (m/z) 325 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=[O:37])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[NH:20]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccncc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccncc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butyl ester (Example G28) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a red-brown solid (25 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].C(N(C(C)C)CC)(C)C.ClCCl.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([N:5]([CH3:6])[C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: CNc1cccc(Br)c1C
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1N(C)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-N,2-dimethylaniline (150 mg) and diisopropylethylamine (291 mg) were added to dichloromethane (5 mL). Cyclohexanecarbonyl chloride (115 mg) was added and the solution was stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed two times with 1M aqueous HCl and once with brine. The solution was dried on anhydrous sodium sulfate, filtered, and the solvent was removed to provide the title compound which was used without further purification.
Reaction SMILES: CO[C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CO>[N:10]1([C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CCC(=O)CC(=O)OC
Reactant: C1COCCN1
Solvent: CO
Product: CCC(=O)CC(=O)N1CCOCC1

Procedure:
50.0 g (384 mmol) of 3-oxovaleric acid methyl ester and 35.1 g (403 mmol) of morpholine were heated for 9 h at 110° C., whereby the methanol formed was removed via a distillation bridge. The reaction mixture was then freed of volatile constituents on a rotary evaporator and purified by column chromatography (silica gel, eluent: gradient of ethyl acetate to ethanol). The pure product fractions were freed from solvent on a rotary evaporator and yielded 39.7 g (60%) of a viscous, colorless, clear oil.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:21]=[C:22]([CH3:24])[CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([F:17])[CH:19]=3)=[O:32])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1cc(F)cc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: Cc1cc(F)cc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([CH3:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:14](OC(=O)C)(=[O:16])[CH3:15].O.O.O.C([O-])(=O)C.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:12])[CH3:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(C)=O)cc1Br
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(C(C)=O)C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A mixture of 1-(3-bromo-4-methoxyphenyl)acetone (410 mg, 1.69 mmol), acetic anhydride (0.318 mL, 344 mg, 3.37 mmol), and p-toluenesulfonic acid (12.7 mg, 0.067 mmol) was stirred for 30 min. at RT. Boron trifluoride-acetic acid complex (0.275 mL, 372 mg, 2.92 mmol) was added and stirring was continued for 20 h. Sodium acetate trihydrate (919 mg, 6.76 mmol) in 1.7 mL of water was added and the mixture was refluxed for 3 h. Upon cooling, the reaction was partitioned between 50 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with 30 mL of brine. Drying over sodium sulfate and evaporation provided 450 mg of crude product. Purification by flash column chromatography, eluting with 10% ethyl ether in hexane, gave the 234 mg of the title compound as pale crystals. Mass spectrum (NH3/CI): m/z=285.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][Br:14])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 25 °C
Yield: 307.7 %

Procedure:
3-Methylpyrazole-1-carboxylic acid tert-butyl ester (6.0 g, 33 mmol), N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg) were dissolved in 20 mL of carbon tetrachloride. The reaction was heated at reflux for 16 h. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) gave a light yellow oil (4.5 g, 53%): 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=2.6 Hz, 1H), 6.47 (d, J=2.6 Hz, 1H), 4.48 (s, 2H), 1.64 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+:30]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:30]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
7-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 5 g.) was gradually added to an aqueous solution (30 ml.) of sodium bicarbonate (1.04 g.) at 35° to 40° C., and stirred at 50° to 53° C. for 30 minutes. After removing the insoluble substance from the resultant solution, the filtrate was treated with activated charcoal (0.3 g.), and filtered. The filtrate was lyophilized to give sodium 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 4.2 g.)
Reaction SMILES: [Br:1][C:2]1[C:10]([NH:11]C(=O)OC(C)(C)C)=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[ClH:19]>O1CCOCC1>[ClH:19].[Br:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cc1Br)OCC2
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc2c(cc1Br)OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl (6-bromo-2,3-dihydro-1-benzofuran-5-yl)carbamate (2.75 g) and dioxane (15.0 mL) was added hydrogen chloride (4 M dioxane solution, 15.0 mL), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure to obtain 6-bromo-2,3-dihydro-1-benzofuran-5-amine hydrochloride (2.23 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:11][OH:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H](C)NC(=O)OC(C)(C)C
Yield: 70 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alaninol (438 mg, 2.5 mmol) was dissolved in 5 mL of methylene chloride in an ice bath and acetyl chloride (0.294 mL, 3.75 mmol), followed by triethylamine (0.7 mL, 5 mmol) were added. It was then reacted at 0° C. for 1 hour and at room temperature for 2 days. The mixture was diluted with 25 mL of ethyl acetate and the organic layer was washed with 10%-sodium hydrogen carbonate (3x), brine (2x), dried over magnesium sulfate anhydrous, and then evaporated to dryness to yield 380 mg of N-(tert-butoxycarbonyl)-O-acetyl-L-alaninol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([NH:14][NH:15][C:16](=O)[CH3:17])=[S:13])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[S:13][C:16]([CH3:17])=[N:15][N:14]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(C(=S)NNC(C)=O)cc12
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc2oc(-c3nnc(C)s3)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution (50 ml) of N′-(4-methoxybenzo(b)furan-2-ylthiocarbonyl)acetohydrazide (1.1 g) in toluene was added methanesulfonic acid (1.0 ml) and the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and aqueous potassium carbonate solution, followed by partitioning. After washing with water, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (0.82 g) as yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:35](C(OCC)=O)=NC(OCC)=O.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[NH2:35][C@H:10]1[C@@H:11]([O:13][CH3:14])[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: CO[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO[C@H]1CN(Cc2ccccc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.6 g (25 mmol) of trans-1-benzyl-3-hydroxy-4-methoxypyrrolidine and 8.6 g (33 mmol) of triphenylphosphine are initially introduced into 40 ml of absolute tetrahydrofuran and a solution of 6 g (34 mmol) of diethyl azodicarboxylate in 40 ml of absolute tetrahydrofuran is added dropwise at 0° C. 3.9 g (27 mmol) of phthalimide are then added in small portions at 0° C. in the course of one hour. The mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in 80 ml of ethyl acetate and 80 ml of petroleum ether are added. The mixture is left to crystallize out overnight and the crystals (triphenylphosphine oxide and diethyl hydrazinedicarboxylate) are filtered off. The filtrate is concentrated and the residue is heated under reflux with 60 ml of concentrated hydrochloric acid overnight. The undissolved residues are decanted and the solution is concentrated. The residue is taken up in a little water and the solution is rendered alkaline with solid potassium carbonate and extracted five times with 50 ml of chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:37])[C@@H:6]([NH:25][C:26](=[O:36])[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([OH:34])=[CH:29][C:28]=1[Cl:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[C:38]([O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48]Br)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:4][C:5](=[O:37])[C@@H:6]([NH:25][C:26](=[O:36])[C:27]1[C:28]([Cl:35])=[CH:29][C:30]([O:34][CH2:48][CH2:47][CH2:46][NH:45][C:43]([O:42][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:44])=[CH:31][C:32]=1[Cl:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cc(OCCCNC(=O)OC(C)(C)C)cc1Cl

Procedure:
The title compound was prepared using a similar procedure as described in Example 5, Step 5, starting from (S)-2-(2,6-dichloro-4-hydroxy-benzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (558 mg, 1.07 mmol), 3-tert-butoxycarbonylaminopropyl bromide (306 mg, 1.28 mmol), and potassium carbonate (445 mg, 3.22 mmol), and after ISCO column chromatography purification, resulted in a white solid (654 mg, 87%). ES(+)-HRMS m/e calcd. for C34H42Cl2N4O8 (M+H)+ 705.2453, obsd. 705.2451.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:21])[CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:21])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Agent: NN
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](CN)c1ccc(F)cc1
Temperature: 80 °C
Yield: 100.2 %

Procedure:
To a room-temperature solution of (S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3-dione (900 mg, 3.2 mmol, 1.0 equiv) in toluene (14 mL) was added hydrazine hydrate (1.4 mL, 45 mmol, 14 equiv) by syringe. The resulting mixture was heated to 80° C. for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with additional toluene. The combined organic layers were combined and concentrated in vacuo to provide the title compound (491 mg, 99%), which was used without further purification.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[O:32])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=442.99.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]=O)=[CH:2]1.[CH2:10]([NH2:13])[CH:11]=[CH2:12].C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:10]([NH:13][CH2:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: O=CCCc1ccoc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCNCCCc1ccoc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the above crude 3-(3-furyl)propanal, 7.94 ml (106 mmol) of allylamine and 2.54 ml (42.3 mmol) of acetic acid in 100 ml of methanol, 1.33 g (21.2 mmol) of sodium cyanoborohydride was added at room temperature, followed by stirring at room temperature for 1 day. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].C(NC(C)C)(C)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45](I)=[CH:44][CH:43]=2)=[CH:26]/[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:18][C:19]1[CH:20]=[CH:21][C:22](/[C:25](/[C:42]2[CH:43]=[CH:44][C:45]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=3)=[CH:46][CH:47]=2)=[CH:26]/[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(I)cc2)cc1C
Reactant: C#Cc1ccc(CO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(C#Cc3ccc(CO)cc3)cc2)cc1C
Temperature: 25 °C

Procedure:
(4-Ethynylphenyl)methanol (200 mg, 1.51 mmol) and diisopropylamine (360 mg, 3.56 mmol) were added to a solution of methyl (Z)-[4-[3-(4-bromophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (445 mg, 0.75 mmol) in anhydrous tetrahydrofuran (15 mL). The solution was degassed and bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) and copper(I) iodide (15 mg, 0.078 mmol) were added. The reaction solution was degassed again and then stirred under inert atmosphere at ambient temperature over night. The reaction mixture was filtered through a paddle of silica gel; the paddle was thoroughly washed with ethyl acetate (4×20 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (E)-[4-[3-(4-bromophenyl)-3-[4-[4-(hydroxymethyl)-phenylethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:3]=1.O1CC[N:31]([C:34]2[N:39]=[C:38](C3C=NC(N)=NC=3)[CH:37]=[C:36]([O:47][C:48]3C=NC=CC=3)[N:35]=2)CC1>C(COC)OC.C([O-])([O-])=O.[Na+].[Na+].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.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:48][O:47][CH:36]1[NH:35][C:34]([NH2:31])=[N:39][CH:38]=[C:37]1[C:2]1[CH:3]=[C:4]([O:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[N:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:7]=1
Reactant: Nc1ncc(-c2cc(Oc3cccnc3)nc(N3CCOCC3)n2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(N3CCOCC3)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COC1NC(N)=NC=C1c1cc(OC2CCNCC2)nc(N2CCOCC2)n1
Temperature: 120 °C
Reaction time: 12 h
Yield: 94.6 %

Procedure:
A mixture of tert-butyl 4-(6-chloro-2-morpholinopyrimidin-4-yloxy)piperidine-1-carboxylate (500 mg, 1.26 mmol), 4-methoxy-2-aminopyrimidyl boronate ester (prepared as in Method 8, 630 mg, 2.51 mmol) and Pd(dppf)Cl2—CH2Cl2 (51 mg, 0.063 mmol) in dimethoxyethane and 2 M Na2CO3 (3:1, 12 mL) was heated under microwave irradiation for 15 minutes at 120° C. The reaction mixture was partitioned between EtOAc (200 mL) and Na2CO3(sat.) (50 mL), the organic layer was separated and washed with brine (50 mL). The combined aqueous layers were extracted further with EtOAc (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated. To this material was added 4 M HCl/dioxane (20 mL) to remove the Boc group. After standing for 12 hours, the volatiles were removed in vacuo, and the residue was partitioned between CH2Cl2 (200 mL) and 1N NaOH (50 mL). Upon separating, the aqueous layer was extracted further with CH2Cl2 (200 mL) and then CHCl3 (2×150 mL). The combined organic layers were concentrated yielding 1,6-dihydro-6-methoxy-5-(2-morpholino-6-(piperidin-4-yloxy)pyrimidin-4-yl)pyrimidin-2-amine (464 mg). The crude compound and morpholine (0.9 mL, 10.45 mmol) in NMP (10 mL) were heated under microwave irradiation for 15 minutes at 200° C. to convert the methoxy pyrimidine to the pyrimidone. Additional morpholine (0.9 mL, 10.45 mmol) was added and the solution was heated under microwave irradiation for 15 minutes and than 10 minutes at 200° C. Upon cooling the material was directly purified by reverse-phase HPLC. After lyophilization, the bis TFA salt of the 2-amino-5-(2-morpholino-6-(piperidin-4-yloxy)pyrimidin-4-yl)pyrimidin-4(3H)-one was isolated as an off-white solid (325 mg, 45%). LCMS (m/z): 374.1 (MH+). The title compound was prepared by acylation of the secondary amino group as shown in Example 19, step 4. LCMS (m/z): 416.0 (MH+), Rt 1.67.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:19]=[C:20](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:20](=[O:19])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12][CH2:13]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCN(c2ccc(N)c(C(=O)O)c2)CC1
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC1

Procedure:
To the mixture of 5.3 g of 2-amino-5-(4-methylpiperazino)benzoic acid in 30 mL of dioxane, under stirring and external cold water cooling 6 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 mL of ether. The product is stirred for 5 minutes in the mixture of 50 mL of methanol and 5 mL of triethylamine, filtered off, washed with 30 mL of methanol. After drying 5.4 g of the title product is obtained, m.p.: 285° C.