Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Nc1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
Into a flame dried flask, N-(1-benzyl-piperidin-4-yl)-2-(2-nitro-phenyl)-acetamide (3.2 g, 9.06 mmol) and lithium aluminium hydride (1.0 g, 18.12 mmol) were combined. 1,4-Dioxane (15 mL) was added and the mixture slowly brought to reflux over 1 h and stirred at reflux for 16 h. The reaction mixture was cooled to 0° C. and excess lithium aluminium hydride destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate concentrated and used as is for the next reaction.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: COC(=O)c1nc2nc(C(C)C)cc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1nc2nc(C(C)C)cc(Cl)n2n1
Yield: 91.3 %

Procedure:
To a suspension of the product obtained in Step 1 (50 g) in 700 ml of phosphorus oxychloride 31 g of N,N-dimethylaniline was dropwise added at room temperature over a period of 20 minutes. The mixture was refluxed for one hour, excess phosphorus oxychloride was removed by distillation under normal pressure, and the reddish brown residue was dissolved in 2 liters of chloroform. This solution was slowly poured into 1.5 liters of ice-cooled saturated sodium bicarbonate solution, the chloroform layer was collected after shaking, and the aqueous layer was again extracted with fresh chloroform. The organic layers were joined together, washed with 800 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to about 100 ml, and 200 ml n-hexane was added to this concentrate, giving 47 g of the objective compound as colorless crystals.
Reaction SMILES: [Na+].[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=[O:4])[CH3:3].Cl>O>[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9])(=[O:4])[CH3:3]
Reactant: COc1ccc(CC(CSC(C)=O)C(=O)Nc2cccc(C(=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC(CSC(C)=O)C(=O)Nc2cccc(C(=O)O)c2)cc1
Yield: 70.4 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4 methoxyphenyl)-propionyl]amino]benzoic acid sodium salt (compound of Example 36) (1.5 g) is dissolved in water (30 ml), and the mixture is adjusted to pH 3.0 with 1 N hydrochloric acid with stirring under ice cooling, and the mixture is extracted with ethyl acetate (50 ml). The extract is washed with water and dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to give the title compound (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=2)=[CH:7][C:3]=1[C:4]([O:6][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=1)=[O:5]
Reactant: Clc1cccc(CBr)c1
Reactant: O=C(O)c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1cccc(Cl)c1)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Temperature: 60 °C
Yield: 94.9 %

Procedure:
To a mixture of 2-chloro-5-hydroxybenzoic acid (500 mg, 2.9 mmol) in DMF (20 ml) were added potassium carbonate (1.0 g, 7.3 mmol, 2.5 eq) and 3-chlorobenzyl bromide (0.8 ml, 6.1 mmol, 2.1 eq). The mixture was heated at 60° C. for 2.5 hours. On cooling the mixture was diluted with ethyl acetate (300 ml) and washed with water (2×100 ml) then brine (70 ml). Organic layer dried and evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 100 g silica column) eluting with 0-30% ethyl acetate in hexanes to afford the title compound as a clear oil (1.16 g). MS (ES+) m/z 421 [M+H]+ (C21H1535Cl3O3). 1H-NMR (400 MHz, d6-DMSO) δ 5.19 (2H, s), 5.35 (2H, s), 7.26 (1H, dd, J 8.8, J 3.2), 7.40-7.56 (10H, m).
Reaction SMILES: CN(C)/C=[CH:4]/[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CCOC(C)=O>[N+:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:6]2[C:5]=1[CH:4]=[CH:10][O:9][C:7]2=[O:8])([O-:17])=[O:16]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1/C=C/N(C)C
Solvent: CCOC(C)=O
Product: O=c1occc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
(E)-Methyl 2-(2-(dimethylamino)vinyl)-3-nitrobenzoate was re-dissolved in EtOAc (200 mL), and silica gel (200 g) was added. The resulting suspension was stirred at room temperature for 1 h. The EtOAc solution was filtered off. Silica gel was washed with EtOAc (2×150 mL) and the combined organics were evaporated and dried under reduced pressure to yield 5-nitro-1H-isochromen-1-one (4.0 g, 21.0 mmol, 82% after two steps) of as a brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=[O:18])[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.Br>C(O)(=O)C.O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=[O:18])[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2cccc(O)c2)nc2ccsc12
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a suspension of 2-(3-methoxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one (30.31 g, 0.12 mol) in acetic acid (170 mL) was added 48% aqueous hydrogen bromide (170 mL) and the mixture heated under reflux for 48 hours. The mixture was then cooled in ice-water and diluted with water (200 mL). The grey solid was collected by filtration, washed with water and dried to give compound 3 (28.58 g, 100%).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]([CH3:10])[C:6]=1[CH:7]1[CH2:9][CH2:8]1.[CH:18]1(B(O)O)[CH2:20][CH2:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:18]1([C:2]2[C:3](=[O:17])[N:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:5]([CH3:10])[C:6]=2[CH:7]2[CH2:9][CH2:8]2)[CH2:20][CH2:19]1
Reactant: OB(O)C1CC1
Reactant: Cn1c(C2CC2)c(Br)c(=O)n1-c1ccccc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(C2CC2)c(C2CC2)c(=O)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
Into a sealable tube under argon was added 4-bromo-5-cyclopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (2.59 g), cyclopropylboronic acid (1.23 g), potassium phosphate (8.18 g), tricyclohexyl phosphine (0.30 g), toluene (50 mL) and water (3.2 mL). To this was added palladium acetate (0.11 g) and the tube was sealed and stirred at 100° C. for 4 days. The reaction vessel was then cooled and then diluted with water/EtOAc. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo to afford a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 4,5-dicyclopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one which was further purified by crystallization from EtOAc/pentante to give 1.12 g of the desired title compound as a white crystalline solid. MS (ESI+): 255.3 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[Cl:24])=[C:7]([F:15])[C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O.O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:9]3[C:10]([CH3:13])=[N:11][O:12][C:8]=3[C:7]=2[F:15])=[C:18]([Cl:24])[CH:19]=1
Reactant: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid methyl ester (8a) (200 mg, 0.48 mmol) in THF-water (3 mL/1.5 mL) was added aqueous LiOH (1 M, 1.00 mL) at room temperature. After 15 hours, the reaction mixture was acidified to pH 1 with aqueous HCl (1 M), diluted with water, and extracted with EtOAc/THF. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 191.5 mg (99%) of the crude acid (9a) which was used without further purification. MS APCI (−) m/z 397, 399 (M+, Br, Cl pattern) detected: 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.37 (s, 1H), 7.75 (s, 1H), 7.42 (d, 1H), 6.97 (t, 1H), 2.60 (s, 3H): 19F NMR (376 MHz, DMSO-d6) −140.15 (s, 1F).
Reaction SMILES: [C:1]([CH:3]([CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)#[N:2].CC(OC(C)=O)=O.[N+:22]([O-])([OH:24])=[O:23]>O>[C:1]([CH:3]([CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1)#[N:2]
Reactant: CC(=O)Nc1ccc(C(C)C#N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(C(C)C#N)cc1[N+](=O)[O-]

Procedure:
To the flask of N-[4-(Cyano-methyl-methyl)-phenyl]-acetamide (12.9 g, 68.5 mmol) was added Ac2O (35 mL) at 5° C. The mixture was stirred and added HNO3 (7.45 g, 70.9 mmol) at 0° C. This reaction was very exothermic. The mixture was stirred for 1 hr at 0° C. and additionally stirred for 3 hrs at room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[N:11]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=O)=[C:19]([O:27][CH3:28])[CH:18]=2)[N:10]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[N:11]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([C:30]([F:29])([F:38])[F:39])[CH:32]=3)=[O:23])=[C:19]([O:27][CH3:28])[CH:18]=2)[N:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCn1c(-c2c(Cl)cccc2Cl)nn(-c2ccc(C(=O)OC)c(OC)c2)c1=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCn1c(-c2c(Cl)cccc2Cl)nn(-c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)c(OC)c2)c1=O

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-41, 0.040 g, 0.09 mmol), 3-(trifluoromethyl)aniline (0.010 g, 0.6 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.015 g of crude product which was purified by column chromatography in basic alumina eluting with 0.2% methanol:DCM to afford 0.015 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.14 (t, 3H), 3.55-3.57 (m, 2H), 3.95 (s, 3H), 7.46 (m, 1H), 7.59 (t, 1H), 7.69-7.81 (m, 6H), 7.94 (m, 1H), 8.25 (s, 1H), 10.38 (s, 1H); MS (m/z): 551.11 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].CCOC(C)=O.[CH3:16][N:17](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9])#[N:17]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(F)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a degassed solution of 4-bromo-3-fluorotoluene (50.0 g, 264 mmol) in 500 mL of DMF was added Zn(CN)2 (18.6 g, 159 mmol) and Pd(PPh3)4 (6.1 g, 5.3 mmol). The reaction was stirred at 80° C. for 6 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (0-5% EtOAc/hexane) provided the titled product.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:19]I>C(Cl)Cl.C(OCC)C.N([O-])=O.[Ag+]>[F:1][C:2]1[C:3]([C:9]2[C:13]([I:19])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: II
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Agent: [Ag+]
Agent: O=N[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nc(-c2ncc(Cl)cc2F)c(I)c1OC(F)F
Temperature: 22 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
3.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H15) are dissolved in 30 ml of methylene chloride, and 1.83 g of silver(I) nitrite and 3.02 g of iodine are then added. The mixture is stirred overnight at 22° C. It is then diluted with diethyl ether and extracted successively with aqueous sodium metabisulfite solution and brine. After drying of the organic phase over sodium sulfate and filtration, the filtrate is concentrated in vacuo together with twice the amount of silica gel. After application of this silica gel to a flash column, the column is eluted with n-hexane/ethyl acetate (3/1). 3.97 g of the desired title compound are obtained as a beige solid of melting point 77-78° C. in this manner.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12](=[O:20])[NH:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(OC(=O)C)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12](=[O:20])[NH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Cc2ccccc2C(c2cccc([N+](=O)[O-])c2)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(C2NC(=O)Cc3ccccc32)c1
Yield: 83.1 %

Procedure:
A mixture of 1-(3-nitrophenyl)-1,4-dihydroisoquinol-3-one (12.2 g) and 5% palladium-carbon (3 g) in ethylacetate (400 ml) was hydrogenated at room temperature and pressure until uptake of hydrogen ceased. The mixture was filtered (celite), and the filtrate evaporated to dryness to give 1-(3-aminophenyl)-1,4-dihydroisoquinol-3-one (9.0 g), m.p. 179°-180° C. which was used without purification.
Reaction SMILES: [NH3:1].[C:2]1([C:9]([O:11][CH3:12])=[O:10])([C:5](OC)=[O:6])[CH2:4][CH2:3]1>CO>[NH2:1][C:5]([C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1)=[O:6]
Reactant: N
Reactant: COC(=O)C1(C(=O)OC)CC1
Solvent: CO
Product: COC(=O)C1(C(N)=O)CC1
Temperature: 8 °C
Reaction time: 10 h

Procedure:
Ammonia (20 l/h) is passed at 20° C. into a solution of 1,106 g (7 mol) of dimethyl cyclopropanedicarboxylate in 700 ml of methanol, with stirring. After approximately 10 hours, addition of NH3 is stopped, and the reaction mixture is cooled to 8° C. The solid formed is filtered off with suction, then washed using 200 g of cold methanol. After drying the product, 926.2 g (92.5%) of methyl 1-aminocarbonylcyclopropanecarboxylate are obtained (m.p.: 157° C.).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(Cl)CCl>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C@@H:28]([NH:37][C:13]([C:9]2[CH:10]=[C:11]([OH:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:15])[CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.6 g 1-phenyl-3-carboxy-5-pyrazolone and 10.6 g 4-((S)-2-Amino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 30 ml DMF 4.9 g HOBT, 10.6 ml DIPEA and 6.2 g EDC were added and the reaction mixture was stirred for 16 h at RT. Then the reaction mixture was evaporated, diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].[OH-].[K+]>O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([N:8]([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CN(C)c1ncc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ncc(Br)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
5-Bromo-N2,N2-dimethylpyridine-2,3-diamine (53 mg, 0.25 mmol) was taken into THF (2 mL) followed by addition of diisopropylethylamine (213 uL, 1.25 mmol) and methanesulfonyl chloride (95 ul, 1.25 mmol). The mixture was allowed to stir for 48 h at room temperature then partitioned with ethyl acetate and water. The organic phase was washed with brine then dried over sodium sulfate, filtered and concentrated. The residue was taken into methanol (3 mL) followed by addition of potassium hydroxide (108 mg, 10 eq) in a minimum of water. The mixture was stirred for 15 minutes at room temperature then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give N-(5-bromo-2-(dimethylamino)pyridin-3-yl)methanesulfonamide (27.9 mg, 39%). MS (EI) for C8H12N3SO2Br: 294, 296 (MH+, Br pattern).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2[C:19](=[O:26])[C@@H:20]([NH2:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:11].[CH3:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[C:33]([C:37](O)=[O:38])[NH:34]2)=[CH:30][CH:29]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2[C:19]([C@@H:20]([NH:25][C:37]([C:33]1[NH:34][C:35]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH3:27])[CH:36]=2)=[O:38])[C:21]([CH3:22])([CH3:23])[CH3:24])=[O:26])=[O:11]
Reactant: Cc1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)(C)[C@H](N)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1ccc2cc(C(=O)N[C@H](C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)c3nc4ccccc4[nH]3)C(C)(C)C)[nH]c2c1
Yield: 60.2 %

Procedure:
A solution of (2S)-1-[(1S,4S)-5-(1H-benzimidazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3,3-dimethyl-1-oxo-2-butanamine (120 mg, 0.34 mmol), 6-methyl-1H-indole-2-carboxylic acid (60 mg, 0.34 mmol), EDC (78 mg, 0.41 mmol), HOBt (9 mg, 0.068 mmol), NMM (103 mg, 1.02 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and CH2Cl2 then washed with sat. NaHCO3 (20 mL) and brine (20 mL). The solution was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by reverse phase HPLC: 50-80% ACN/Water (0.1% TFA). Concentration of the fractions containing product afforded the title compound (105 mg) as a white solid. LCMS (m/z): 513.1 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm: 0.90-1.10 (m, 9H), 1.75-2.20 (m, 2H), 2.30-2.40 (m, 3H), 3.45-3.95 (m, 3H), 4.00-5.25 m, 4H), 6.20-6.75 (m, 1H), 6.80-7.70 (m, 9H), 9.30-9.70 (m, 1H)
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([NH2:28])[CH:27]=1.C(=O)([O-])O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:28][C:26]1[CH:27]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC1(C)OB(c2ccc(Cl)cc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(Cl)cc3N)[nH]c2c1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.20 g, 15.4 mmol) obtained in the same manner as in the method described in WO03/010140 and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (4.11 g, 16.2 mmol) in 1,2-dimethoxyethane (20 ml) and water (10 ml) were added sodium hydrogen carbonate (4.10 g, 48.6 μmmol) and tetrakis(triphenylphosphine)palladium (1.87 g, 1.62 mmol) and the mixture was heated under reflux for 12 hr. The mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give methyl 2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.17 g, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=O)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].P(Cl)(Cl)([Cl:30])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2[Cl:30])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-5-fluoro-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 1 hour at room temperature and thereafter for 1 hour at 60° C. there is obtained isopropyl 2-chloro-5-[2-chloro-5-fluoro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]4-fluorobenzoate, 1H-NMR (CDCl3, 60 MHz): 7.88 ppm (d,1H), 7.47 ppm (d,1H), 5.30 ppm (m,1H), 1.41 ppm (d,6H);