Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[NH3:31]>O1CCCC1>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:31])=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoyl chloride hydrochloride (100 mg; 0.23 mmol) was suspended in tetrahydrofuran (5 ml) and treated with 0.88 aq. ammonia solution (1 ml) and the resulting mixture stirred at ambient temperature. The title compound (42 mg; 48%) was obtained as a brown powder and collected by filtration, washed with water and dried at 40° C. under reduced pressure. 1H NMR (250 MHz, CDCl3) δ: 5.50-6.40 (2H, br, exchangeable), 6.03 (2H, s), 6.90 (1H, d, J=8 Hz), 7.15 (3H, m), 7.55 (2H, brm), 7.89 (2H, d, J=8 Hz), 8.06 (2H, d, J=8 Hz), 8.54 (1H, brd); (ESMS) (M+H)+=385.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:6](=[S:19])[NH:5][C:4](=[O:20])[CH:3]=1.[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:21][C:3]1[C:4](=[O:20])[NH:5][C:6](=[S:19])[N:7]([CH2:8][CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:2]=1[NH2:1]
Reactant: Nc1cc(=O)[nH]c(=S)n1CCc1nc2ccccc2[nH]1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N)n(CCc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Reaction time: 0.83 h
Yield: 50.5 %

Procedure:
To 6-amino-1-[2-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.55 g, 1.9 mmol, obtained from Example 12(b)) in acetic acid (5 mL) was added, dropwise, a solution of sodium nitrite (0.15 g, 2.1 mmol) in water (1.3 mL). After 50 min, sodium dithionite (0.67 g, 3.8 mmol) was added and the reaction stirred for 20 min, followed by evaporation of acetic acid in vacuo and addition of water (50 mL). The precipitated solid was collected by filtration, washed with water and dried in vacuo, providing the title compound (0.29 g, 50% yield). This material was used in the next step without further purification. MS (ESI)-m/z 303 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][CH:8]([OH:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:10][CH:8]([CH3:9])[CH3:7])[O:4][CH2:5][Cl:6]
Reactant: CC(C)O
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 26 step 1 using a solution of chloromethyl chloroformate (10 g, 78.2 mmol) in DCM (200 mL), a mixture of i-PrOH (6.6 mL, 86.2 mmol) and pyridine (7.5 mL, 93.2 mmol) in DCM (50 mL). The title compound was obtained as colorless oil (9.63 g, 81.0%) and was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: F[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.CS(C)=[O:16].[OH-].[Na+].Cl>O>[F:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([OH:16])[CH:7]=1
Reactant: CS(C)=O
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(F)cc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5-difluoro-2-nitroanisole(4.36 g), dimethylsulphoxide(10 mL) and 10N aqueous sodium hydroxide(6.5 mL) was stirred at ambient temperature for 18 h and then at 60° C. for 3 h. The mixture was diluted with water and acidified with concentrated hydrochloric acid, extracted with ethyl acetate and the extract was washed with water dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (3.0 g),(m/e 186, MH−).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:26][CH:27]=2)=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOc1ccc(O)cc1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCOc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
4-(benzyloxy)benzoic acid (20.0 g, 87.6 mmol), 4-(hexyloxy)phenol (17.0 g, 87.6 mmol), N,N′-dicyclohexylcarbodiimide (21.7 g, 105 mmol) and 4-dimethylaminopyridine (535 mg, 4.38 mmol) were dissolved in 300 mL of methylene chloride. The resulting solution was stirred for 3 hours at room temperature. Then, 300 mL of pure water was added thereto, and then the resulting liquid was filtered to remove insoluble matters. Thereafter, the obtained solution was subjected to separation operation, and the resulting methylene chloride solution was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After methylene chloride was distilled off, the resulting solid matter was washed with methanol. Thereby, a white solid compound, 4-(hexyloxy)phenyl 4-(benzyloxy)benzoate (24.9 g) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[SH:11].B(O)(O)O.[CH:16](O)=O>O>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]2[S:11][CH:16]=[N:2][C:3]=2[CH:8]=1
Reactant: COc1ccc(S)c(N)c1
Reactant: O=CO
Agent: Cl
Agent: OB(O)O
Solvent: O
Product: COc1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A mixture of intermediate 23 (1.33 g, 6.9 mmol), boric acid (2.3 g, 37.2 mmol) and formic acid (17 mL) was heated to reflux and stirred for 6 h. The reaction mixture was cooled to rt and diluted with water. The solution was made alkaline and extracted with ethyl acetate. Further purification by column chromatography (elution with PE/EtOAc=3:1) gave 5-methoxybenzo[d]thiazole (intermediate 24) (290 mg, 15%). HPLC: 99%, RI 2.646 min. MS (ESI) m/z 166.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:14]2)[CH:4]=1
Reactant: Clc1ccnc(N2CCNCC2)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCN(c2cc(Cl)ccn2)CC1

Procedure:
Stir 1-(4-chloro-pyridin-2-yl)-piperazine hydrochloride (2.2 mmol, 0.4 g), triethylamine (7.6 mmol, 1.1 mL) in 13 mL of CH2Cl2 and pivaloyl chloride (2.2 mmol, 0.3 mL) overnight at room temperature. Add CH2Cl2 and wash with saturated aq. sodium chloride and water. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 1-[4-(4-chloro-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one. MS(ES): m/z=282 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N:11]1([C:9]2[N:10]=[C:5]3[N:4]=[CH:3][C:2]([C:24]#[C:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:7][N:6]3[N:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C#Cc1ccccc1
Reactant: Brc1cnc2nc(N3CCOCC3)nn2c1
Product: C(#Cc1cnc2nc(N3CCOCC3)nn2c1)c1ccccc1

Procedure:
The title compound, a light brown solid, MS: m/e=306.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and phenylacetylene.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=4)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:35][CH3:36])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:36][O:35][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[C:21]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine (compound 452) (500 mg) was dissolved in trifluoroacetic acid (5 ml) to prepare a solution. Methanesulfonic acid (0.5 ml) was added to the solution, and the mixture was stirred at 70° C. for 1.5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (358 mg, yield 88%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH:11]=[CH2:12])(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH:11]1[CH2:12][O:21]1)(=[O:4])=[O:3]
Reactant: C=CC1CCCCN1S(C)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCCC1C1CO1
Temperature: 25 °C
Reaction time: 65 h
Yield: 31.2 %

Procedure:
To a solution of 1-(methylsulfonyl)-2-vinylpiperidine (0.369 g, 2.0 mmol) in anhydrous methylene chloride (10 mL) was added purified 3-chloroperbenzoic acid (100%, 1.0 g, 6 mmol). The reaction was stirred at room temperature for 65 hours. The reaction mixture was filtered, saturated aqueous sodium sulfite added, and the biphasic solution was stirred for 5 mins. The mixture was diluted with ethyl acetate, and the organic layer successively washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (30-60% ethyl acetate in hexanes) to give a white semi-solid (0.128 g, 31%). 1H NMR (CDCl3, 300 MHz) δ 3.78-3.74 (br d, 1H, J=13.2 Hz), 3.66-3.61 (m, 1H), 3.37-3.32 (m, 1H), 3.24-3.15 (m, 1H), 2.98 (s, 3H), 2.88-2.85 (dd, 1H, J=4.8, 4.2 Hz), 2.68-2.66 (dd, 1H, J=4.8, 2.6 Hz), 1.81-1.60 (m, 6H). ESI (m/z): 205.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=O)[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21]>O.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][C:8](=[O:9])[C:7]([C:5]3[S:6][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:20]([OH:21])[C:19]=2[CH:22]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)C(=O)c1ccc(Br)s1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1oc2ccc(Br)cc2c(O)c1-c1ccc(Br)s1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
A solution of titanium trichloride (7.71 g) in water (50 ml) was added to a solution of ethyl (5-bromo-2-thienyl)glyoxylate (5.0 g) and 5-bromo-2-hydroxybenzaldehyde (4.36 g) in dry acetic acid (50 ml) with stirring at 4° C. and the mixture was stirred for 11/2 hours. It was extracted with ethyl acetate and the extract was washed with water, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in toluene and p-toluenesulfonic acid (2.5 g) was added and the mixture heated under reflux for 21/2 hours. It was allowed to stand at room temperature overnight and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-bromo-3-(5-bromo-2-thienyl)-4-hydroxy-2H-1-benzopyran-2-one, m.p. 234-6° C. (compound 27)
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:30]=[CH:29][CH:28]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25](=[O:26])[NH:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:22][CH:23]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)O)cc3)ccc2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)NCCCCNC(=O)OC(C)(C)C)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
120 mg (0.295 mmol) of 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]phenylacetic acid are suspended in 2 ml of DMF, and 68 μl (0.354 mmol) of N-tert-butyloxycarbonyl-1,4-diaminobutane, 66 μl (0.59 mmol) of 4-methylmorpholine, 41 mg (0.3 mmol) of 1-hydroxybenzotriazole and 114 (0.59 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 24 h and purified by means of preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH2:29][CH2:30][NH:31][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: Cn1cc(CCN)c2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(CCNC(=O)c2ccc(Cc3cccc(F)c3)cc2)c2cc(Cl)ccc21
Yield: 23.3 %

Procedure:
N-(2-(5-Chloro-1-methyl-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to method A with 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), 2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine (0.080 g; 0.382 mmol), HATU (0.145 g; 0.382 mmol) and N,N-diisopropylethylamine (0.150 mL; 0.869 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.034 g (23%) of the title compound as a yellow oil.
Reaction SMILES: C(N1C=C(C(=O)C=C(O)C(OC)=O)C(=O)N(CC2C=CC=CC=2)C1=O)C1C=CC=CC=1.[F:32][C:33]1[CH:64]=[CH:63][C:36]([CH2:37][N:38]2[CH:43]=[C:42]([C:44](=[O:52])[CH:45]=[C:46]([OH:51])[C:47]([O:49]C)=[O:48])[C:41](=[O:53])[N:40]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)[C:39]2=[O:62])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH:43]=[C:42]([C:44](=[O:52])[CH:45]=[C:46]([OH:51])[C:47]([OH:49])=[O:48])[C:41](=[O:53])[N:40]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=3)[C:39]2=[O:62])=[CH:63][CH:64]=1
Reactant: COC(=O)C(O)=CC(=O)c1cn(Cc2ccc(F)cc2)c(=O)n(Cc2ccc(F)cc2)c1=O
Agent: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccc(F)cc2)c(=O)n(Cc2ccc(F)cc2)c1=O
Yield: 49.7 %

Procedure:
The title compound was synthesized using a similar procedure to that described in Example 2, except that methyl 4-(1,3-dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[1,3-bis(4-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3c). The title compound was crystalized from hexane and ethyl acetate (3:1). The yield was 49.7%. Mp. 186-188° C. 1HNMR (DMSO-d6): 15.07 (br, s, 1H), 14.02 (br, s, 1H), 8.90 (s, 1H), 7.56 (s, 1H), 7.34-7.46 (m, 4H), 7.10-7.21 (m, 4H), 5.13 (s, 2H), 4.98 (s, 2H). 13CNMR (DMSO-d6): 185.8, 169.2, 163.1, 161.8 (d, J=244.1 Hz), 161.3 (d, J=243.2 Hz), 159.7, 150.8, 150.1, 132.6 (d, J=2.9 Hz), 131.8 (d, J=3.4 Hz), 130.2 (d, J=8.2 Hz), 129.9 (d, J=8.2 Hz), 115.4 (d, J=21.6 Hz), 115.0 (d, J=21.0 Hz), 107.7, 100.7, 52.1, 43.5. FAB-HRMS: [M+H]+ calcd. for C22H17F2N2O6 443.1055, found 443.1044.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH:19]C(=O)C)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].Cl>CCO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH2:19])[CH:12]=[CH:13][C:14]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2C)c1
Agent: Cl
Solvent: CCO
Product: CN1CCC[C@@H]1COc1cc(N)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of (R)-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-acetamide (0.49 g, 1.56 mmol) in 18 mL EtOH was added 11 mL concentrated HCl. The reaction was heated, in a sealed tube, at 70° C. for 6 h, then at 100° C. for 2 h. The reaction was cooled, concentrated to aqueous, basified with 6 N NaOH, and extracted 4 times with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][C@H:15]([F:14])[CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: F[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC[C@H](F)C2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.8 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), (S)-3-fluoropyrrolidine hydrochloride (0.35 g, 2.8 mmol) and 4 Å molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 2.5 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc: cyclohexane, gradient 30:70 to 100:0) to give 3-((S)-3-Fluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.342 g, 60%). 1H NMR (300 MHz, CDCl3): δ 5.34-5.10 (m, 1 H), 4.01-3.93 (m, 2 H), 3.91-3.81 (m, 2 H), 3.41-3.31 (m, 1 H), 2.94-2.67 (m, 3 H), 2.56-2.46 (m, 1 H), 2.24-2.06 (m, 2 H), 1.43 (s, 9 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[F:16][C:17]1([C@H:20]([NH2:22])[CH3:21])[CH2:19][CH2:18]1.FC1([C@H](NC2C3N(C=CC=3)N=CC=2C(N)=O)C)CC1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:22][C@@H:20]([C:17]3([F:16])[CH2:19][CH2:18]3)[CH3:21])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C1(F)CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C1(F)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1(F)CC1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 200 mg, 0.73 mmol), (R)-1-(1-fluorocyclopropyl)ethanamine hydrochloride (153 mg, 1.1 mmol, from step 4 of Intermediate 5), and diisopropylethylamine (0.38 mL, 2.2 mmol) in NMP (0.7 mL) was heated to 150° C. for 1 hour in the CEM microwave. The mixture was cooled to rt, diluted with MeOH and purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded 40 mg (16%) of a pale yellow solid as the title compound. HPLC (condition B): retention time=3.75 min. LCMS (condition B): MH+ m/z 342.7.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2cccc(Cl)c2C#N)cn1
Yield: 73 %

Procedure:
As described for example 84a, 2-chloro-6-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and crystallization from ethyl acetate/diisopropylether the title compound was obtained as an off-white solid (yield: 73%). MS: m/e=218.2 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9]Br.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>CC(C)=O>[S:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:9][CH2:8]1
Reactant: BrCCBr
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2c(c1)NCCS2
Reaction time: 8 h
Yield: 66.1 %

Procedure:
K2CO3 (4.4 g, 31.9 mmol) and 1,2-dibromoethane (690 μL, 8.0 mmol) were added to a solution of 2-aminothiophenol (1.0 g, 8.0 mmol) in 20 mL of acetone at rt. The reaction mixture was stirred overnight. The insoluble material was filtered off and the solvent was removed in vacuum. The residue was purified on silica gel column to provide 3,4-dihydro-2H-1,4-benzothiazine (0.8 g, 66%). MS (ES+): 152 (M+1).
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:38])[CH2:32]OS(C)(=O)=O)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:39])[CH2:7]1)=[O:5])=[CH2:2].[I-].[Na+]>CC(C)=O>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:38])[CH3:32])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:39])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)COS(C)(=O)=O)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(C)=O)C1
Temperature: 110 °C
Yield: 100.2 %

Procedure:
In a closed vessel, a mixture of compound 165 (592 mg, 1.039 mmol) and sodium iodide (2181 mg, 14.55 mmol) in acetone (25 ml) is heated under microwave irradiation for 3 hours at 110° C. The reaction mixture is partitioned between AcOEt and a 5% solution of Na2S2O5. The organic phase is washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give the title compound (495 mg, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>>[C:4]([CH2:3][CH2:2][NH:1][C:7](=[O:13])/[CH:8]=[CH:9]\[C:10]([OH:12])=[O:11])([OH:6])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCC(=O)O
Product: O=C(O)/C=C\C(=O)NCCC(=O)O
Yield: 68 %

Procedure:
In the same manner, equimolar amounts of 3-aminopropionic acid and maleic anhydride are reacted to produce N-carboxyethylmaleamic acid (M.P. 150°-152° C.) in 68% yield.