Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:8][CH2:7]1)C.[ClH:31].O>C(O)C>[ClH:31].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][N:9]3[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:11][CH2:10]3)[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the above ester (0.6 g, 0.0015 mol) in ethanol (5 ml) 4 N sodium hydroxide (0.8 ml) was added and the mixture was stirred at room temperature for 2.5 h and then left in a freezer overnight. The cold reaction mixture was allowed to warm to room temperature during 1 h, and 4 N hydrochloric acid (1.2 ml) and water (10 ml) were added. The mixture was extracted with dichloromethane (2×100 ml). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The residue was reevaporated with a mixture of acetone and isopropyl acetate and then treated with a mixture of acetone and isopropyl acetate to give a solid which was isolated and dried in vacuo. This afforded 0.33 g of the title compound.
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.[CH:20]([C:22]1[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CS(=O)(=O)Nc1cccc(C=O)c1
Product: CS(=O)(=O)Nc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with N-(3-formylphenyl)methanesulfonamide 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 N-[3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]methanesulfonamide.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O[C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:23][C:21]([O:20][C:19]([NH:18][CH2:17][CH2:16][O:15][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])=[O:25])([CH3:22])[CH3:24]
Reactant: COC(=O)c1cccc(OC)c1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OC)c1OCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
DIAD (23.95 ml, 123 mmol) was added dropwise to a stirred solution of 1,1-dimethylethyl (2-hydroxyethyl)carbamate (18.05 g, 112 mmol), methyl 2-hydroxy-3-(methyloxy)benzoate (20.4 g, 112 mmol) and triphenylphosphine (32.3 g, 123 mmol) in THF (400 ml) with cooling in an ice/water bath. Stirred for 30 mins then evaporated and used without any purification. LC/MS showed essentially just product and triphenylphosphine oxide. Yield 98.9 g of crude material. MS (ES): C16H23NO6 requires 325; found 326 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[CH:12]N(C)C)[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].[H-].[Na+].O>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[N:19][C:18]([NH2:20])=[N:17][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ncc(OCc2ccccc2)cn1
Yield: 65.5 %

Procedure:
2-(Benzyloxy)-3-(dimethylamino)acrylaldehyde (10.9 g, 53 mmol) was dissolved in N-methylpyrrolidone (85 mL), the solution was added with guanidine hydrochloride (15.3 g, 160 mmol), and then the mixture was added with sodium hydride (50% in oil, 15.3 g, 320 mmol) with stirring on an ice bath, and stirred on an oil bath at 80° C. for 1 hour. The reaction mixture was added with water on an ice bath to decompose excessive sodium hydride, and then extracted with ether and water, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:acetone=10:1→4:1→2:1→1:1), and the eluate was concentrated under reduced pressure. Then, the resulting residue was washed with ether-hexane, and taken by filtration to obtain 5-(benzyloxy)pyrimidin-2-amine (6.99 g, 65%) as a pale yellow solid.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=2)[CH:13]=1
Reactant: FC(F)(F)c1cncc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]nc(CCc2cncc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.2 %

Procedure:
3,4-bis(Benzyloxy)-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 31; 1.5 g, 3.25 mmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (0.04 g) was added before the mixture was purged and subjected to hydrogen gas. The reaction mixture was stirred for 30 min at room temperature under a hydrogen atmosphere. The reaction mass was then filtered through a celite bed under nitrogen atmosphere and washed with methanol. The filtrate was concentrated in vacuo before the crude was re-dissolved in methanol (10 mL) and 10% palladium on carbon (0.04 g) was added before the mixture was purged and subjected to a pressure of hydrogen gas (200 psi), stirring at room temperature overnight. Upon completion the resulting mixture was filtered through celite under nitrogen and washed with methanol. The filtrate was concentrated under vacuum to afford the crude compound (0.2 g) which was then purified by the preparative HPLC to yield 4-hydroxy-6-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)pyridazin-3(2H)-one (0.03 g, 82% yield).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:20][C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: O=[N+]([O-])c1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 4-nitrobenzaldehyde (85 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (84 mg, 47%). 1H NMR (CDCl3): 9.80 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 7.90 (s, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.47 (d, J=7.2 Hz, 1H), 6.26-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.08 (s, 1H), 2.99 (s, 1H), 1.96-1.89 (m, 1H), 1.70 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.47-1.41 (m, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].C([O:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[N:11]([C:21]2[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)[N:10]=1)=[O:8])C>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]([C:21]3[N:22]=[N:23][C:24]([O:2][CH3:1])=[CH:25][CH:26]=3)[N:10]=[C:9]([C:7]([OH:6])=[O:8])[CH:13]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cn2)n(-c2ccc(Cl)nn2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccc(Cl)cn2)nn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sodium methoxide (150 mg) was added to the above-obtained 1-(6-chloro-3-pyridazinyl)-5-(5-chloro-2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (500 mg) in methanol (10 mL), followed by stirring at room temperature for 15 hours. The reaction mixture was partitioned by use of aqueous 1N hydrochloric acid and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give the title compound as an amorphous product (483 mg, >100%).
Reaction SMILES: [F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3].[CH2:30]1[C:38]2[C:33](=[CH:34][C:35](O)=[CH:36][CH:37]=2)[CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O:27][C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[CH2:30][CH2:31][CH2:32]4)=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Reactant: Oc1ccc2c(c1)CCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)Oc2ccc3c(c2)CCC3)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (4.70 g, 0.01 mol) and 5-indanol (1.34 g, 0.01 mol) in tetrahydrofuran is added dicyclohexylcarbodiimide (2.06 g, 0.01 mol) and the reaction is stirred for 4 hours at room temperature. The solid urea is collected and washed with tetrahydrofuran and the filtrate is evaporated to give 5-indanyl 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][C:23]2[S:24][CH:25]=[N:26][N:27]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[S:24]1[CH:25]=[N:26][N:27]=[C:23]1[NH:22][C:20]([C:19]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])[C:16]([CH3:15])=[CH:29][CH:28]=1)=[O:21]
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: Cc1ccc(C(=O)Nc2nncs2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nncs4)ccc3C)c(C)c2)o1

Procedure:
Example 21 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and 4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-([1,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:22]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:23]
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (3.2 L) and 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (228 g) were combined then stirred at ambient temperature for 15 minutes. Potassium carbonate (228 g) was added to the reaction mixture in a single portion. Idoethane (366.8 g) was added dropwise to the reaction mixture producing a slight exotherm. The reaction mixture was heated at reflux for about 4 hours then stirred overnight while cooling to ambient temperature. The precipitated salts were removed by filtration then rinsed with acetone. The combined filtrates were evaported under vacuum. The residue was dissolved in dichloromethane (1.5 L). The dichloromethane solution was washed with water (1.5 L), dried over magnesium sulfate then concentrated under vacuum to provide 277 g of ethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate as a white solid m.p. 98°-100° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1)[CH3:2].C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH3:40])[CH2:13][CH2:14]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
2-(2-(2-(2-((2-Ethyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (8) (84 mg, 0.16 mmol) was dissolved in methanol (8 mL), 37% formaldehyde solution (53 μL, 0.66 mmol) was added and the mixture stirred for ten minutes at room temperature. Sodium tris(acetoxy)borohydride (174 mg, 0.821 mmol) was added, and after two hours the mixture was concentrated. The residue was diluted with 10% sodium hydroxide (15 mL) and brine (15 mL), and the mixture extracted with ethyl acetate (4×25 mL). The combined ethyl acetate phases were washed with brine, dried over sodium sulfate, evaporated and the residue evaporated from DCM to give the title compound (9) (72 mg, 84% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.46 (s, 1H), 8.49 (s, 1H), 7.36 (s, 1H), 7.21 (t, J=4.6 Hz, 2H), 7.18-7.10 (m, 4H), 7.06 (dd, J=8.2, 1.6 Hz, 1H), 6.88 (s, 1H), 3.44 (s, 2H), 3.07-2.90 (m, 4H), 2.86 (d, J=11.3 Hz, 2H), 2.57 (q, J=7.5 Hz, 2H), 2.48-2.37 (m, 1H), 2.19 (s, 3H), 2.02-1.89 (m, 2H), 1.79-1.59 (m, 4H), 1.09 (t, J=7.5 Hz, 3H). LCMS Method C: rt 5.04 min; m/z 526.2 [M+H]+; m/z 524.2 [M−H]−.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4].[OH-].[Na+].Cl>CO>[NH:1]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@H:2]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 59.2 %

Procedure:
The obtained compound (1) (10.0 g, 33 mmol) was dissolved in methanol (150 mL), and 1 N aqueous sodium hydroxide (33 mL, 33 mmol) was further added thereto, and then the mixture was reacted at room temperature for 3 hours with stirring. After completion of the reaction, the reaction solution was neutralized with 1 N hydrochloric acid, and objective substance was extracted with a mixed solvent of ethyl acetate and n-butanol (mixing ratio=7:3). The extracted objective substance was concentrated under reduced pressure and dried, to obtain Boc-Thr-Gly-OH (2) (5.4 g) (yield; 60.2%).
Reaction SMILES: [Na].[CH:2]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([C:17]#[N:18])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23]>>[CH:2]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([C:17](=[NH:18])[O:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [Na]
Product: COCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
20 ml of 2-methoxyethanol are treated portionwise at 60° C. with 0.23 g of sodium. After 30 minutes, 2.2 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile are added and the mixture is stirred at 80° C. for 1 hour. Subsequently, the 2-methoxyethanol is distilled off at reduced pressure. The residue is poured on to ice-water and the resulting mixture is extracted twice with methylene chloride. The combined extracts are washed twice with water, dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on silica gel with ethyl acetate and increasing amounts of ethanol as the eluent, and there is obtained 2-methoxyethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 296 (6), 237 (45), 194 (100), 178 (74), 165 (49).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O)=[CH:3][CH:2]=1.[NH3:26]>CO.CCOCC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([NH2:26])=[O:17])=[CH:3][CH:2]=1
Reactant: COC(=O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: N
Solvent: CCOCC
Solvent: CO
Product: NC(=O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
A solution of methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyrate (39 g, 120 mmol) in 600 mL of MeOH was saturated with NH3. The solution was periodically treated with additional NH3 over a 24 h period. The solution was degassed with a stream of nitrogen and the solution was concentrated to leave a yellow solid. The solid was, slurried in ether and filtered to leave the title compound: MS (M+H): 325 (base peak).
Reaction SMILES: [NH2:1][CH:2]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])[CH:3]([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[C:30]([CH2:34][CH2:35][C:36](Cl)=[O:37])([O:32][CH3:33])=[O:31]>N1C=CC=CC=1>[C:30]([CH2:34][CH2:35][C:36]([NH:1][CH:2]([P:6](=[O:11])([O:7][CH3:8])[O:9][CH3:10])[CH:3]([CH3:5])[CH3:4])=[O:37])([O:32][CH3:33])=[O:31]
Reactant: COP(=O)(OC)C(N)C(C)C
Reactant: COC(=O)CCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)NC(C(C)C)P(=O)(OC)OC
Temperature: 0 °C

Procedure:
To a solution of a compound of formula 3, preferably dimethyl (1-amino-2-methylpropyl)phosphonate, in an anhydrous polar aprotic solvent, preferably pyridine, is added a tertiary amine, preferably a mixture of tertiary amines, and most preferably, a mixture of diisopropylethylamine and dimethylaminopyridine. The mixture is cooled, preferably to 0° C, and a carboalkoxyalkyl halide, preferably carbomethoxypropionyl chloride is added. The reaction is allowed to stir until the reaction is complete. The product, a compound of Formula 4, preferably dimethyl [1-[N-(3-carbomethoxypropionyl)amino]-2-methylpropyl]phosphonate, may be isolated and purified by conventional means.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:29]2[C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:30]2[C:29]3[O:24][CH2:25][CH2:26][NH:27][C:28]=3[CH:33]=[CH:32][CH:31]=2)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2c1OCCN2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCN3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,4-Dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=488.9.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([CH:23]3[CH2:26][N:25]([C:27](=[O:32])[CH:28]=[CH:29][CH2:30]Br)[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1>C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([CH:23]3[CH2:26][N:25]([C:27](=[O:32])[CH:28]=[CH:29][CH2:30][N:33]4[CH2:36][CH2:35][CH2:34]4)[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(C#Cc2cn(C3CN(C(=O)C=CCBr)C3)c3ncnc(N)c23)cc(OC)c1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: COc1cc(C#Cc2cn(C3CN(C(=O)C=CCN4CCC4)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude product of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-bromobut-2-en-1-one (10 mg) obtained in Step 1 above was suspended in THF (0.5 ml). Azetidine (7 μl) was added thereto, and the resulting mixture was stirred for 1 hour at room temperature. After concentrating under reduced pressure, the resulting residue was purified by reversed-phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (1.6 mg). Table 1 shows the physical properties thereof.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:7]=1[C:8](O)=[O:9].C[N:21](C)C=O>>[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:7]=1[C:8]([NH2:21])=[O:9]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(F)c1F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(C(F)(F)F)cc(F)c1F
Temperature: 75 °C
Yield: 86 %

Procedure:
Thionyl chloride, 6.0 g (50 mmol) was added to a solution of 3.50 g (15 mmol) 2,3-difluoro-5-(trifluoromethyl) benzoic acid in 10 mL dimethylformamide. The reaction mixture was heated to 75° C. for 2 hours, cooled to room temperature and carefully added to 25 mL of ice cold ammonium hydroxide. The mixture was cooled to 0° C. and the solid product filtered, washed with water and dried to yield 3.00 g (86%) of 2,3-difluoro-5-(trifluoromethyl)benzamide m.p. 128°-130° C.
Reaction SMILES: [C:1]([Cl:6])([C:3](Cl)=O)=[O:2].CN(C=O)C.[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[CH:36]=[CH:35]C(C(O)=O)=[CH:30][C:29]=3[CH3:37])=[CH:24][C:19]=2[C:18](=[O:38])[N:17]([CH3:39])[C:16]2[CH:40]=[CH:41][CH:42]=[N:43][C:15]1=2)[CH3:13]>C(Cl)Cl>[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[CH:36]=[CH:35][C:3]([C:1]([Cl:6])=[O:2])=[CH:30][C:29]=3[CH3:37])=[CH:24][C:19]=2[C:18](=[O:38])[N:17]([CH3:39])[C:16]2[CH:40]=[CH:41][CH:42]=[N:43][C:15]1=2)[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN1c2ncc(CCOc3ccc(C(=O)O)cc3C)cc2C(=O)N(C)c2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1c2ncc(CCOc3ccc(C(=O)Cl)cc3C)cc2C(=O)N(C)c2cccnc21
Yield: 101.6 %

Procedure:
(COCl)2 (25 μL, 0.87 mmol) and DMF (10 μL) were added to a solution of 4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylbenzoic acid (52.8 mg, 0.12 mmol) in CH2Cl2 (5 mL). The reaction mixture was heated to reflux for 1 h. The cooled mixture was concentrated under reduced pressure to give the title compound (55 mg, 100% yield), which was used without further purification.