Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:32])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-nitrophenyl isocyanate (0.33 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 24 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield an orange oil, which was crystallized from 95% ethanol to yield the title compound as an off-white solid (0.20 g, 30% yield), mp=168–170° C.; MS (−) ESI m/z=343 (M−H)−; [α]D25=+29.4° (c=1, DMSO).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:16])=[CH:3][CH:4]=1)=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C=Cc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(C=Cc2ccccc2)cc1

Procedure:
4-Styrylbenzyl bromide was prepared from 35.4 g. of 4-methylstilbene and 35.6 g. of N-bromosuccinimide in carbon tetrachloride according to the procedure of Example 8(a); yield 35.5 g., m.p. 125°-127° C. after recrystallization from benzene-cyclohexane and acetonitrile.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][N:17]=[C:16]3Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].[O:28]1CCOCC1.Cl>O>[F:1][CH:2]([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][NH:17][C:16]3=[O:28])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(OC(F)F)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(OC(F)F)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-difluoromethoxy-phenyl)-amide (0.26 g, 0.68 mmol), 2N NaOH (3.4 mL, 6.8 mmol) and dioxane (4 mL) was heated to 50° C. for 2 hours. The reaction was diluted with water, acidified with conc. HCl to ˜pH 4 and extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-difluoromethoxy-phenyl)-amide (60 mg), 1H-NMR (DMSO-d6) δ: 13.02 (s, 1H), 10.88 (s, 1H), 8.88 (d, 1H), 8.52 (dd, 1H), 8.14 (d, 1H), 7.75 (m, 1H), 7.69 (m, 1H), 7.43 (m, 1H), 7.23 (t, 1H), 6.96 (dd, 1H). m/z (M+H)=366; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-difluoromethoxy-phenyl)-amide (39 mg), 1H-NMR (DMSO-d6) δ: 12.85 (s, 1H), 10.87 (s, 1H), 8.47 (m, 1H), 8.42 (m, 2H), 7.73 (m, 1H), 7.65 (m, 1H), 7.44 (m, 1H), 7.23 (t, 1H), 6.96 (dd, 1H). m/z (M+H)=366.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-:15].[Na+].CS(C)=O>C(OCC)(=O)C>[F:13][C:4]1[C:3]([CH:2]=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc(CBr)c1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C=O)c1F
Temperature: 115 °C
Yield: 68.2 %

Procedure:
Dimethylsulfoxide was degassed with argon for 1 h. Methyl 3-(bromomethyl)-2-fluorobenzoate (3.6 g, 14.5 mmol) from Step B above and solid sodium bicarbonate (10.5 g, 124.6 mmol) were added to the DMSO and the mixture was heated at 115° C. for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 0% to 2% ethyl acetate in hexanes) to give methyl 2-fluoro-3-formylbenzoate (1.8 g, 67%): 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 8.22-8.19 (m, 1H), 8.09-8.06 (m, 1H), 7.37-7.34 (m, 1H), 3.98 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][C:13]([CH3:16])=[CH:14]2)[C:9](=O)[NH:8][C:7]1=[O:18])([CH3:5])[CH3:4].[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.Cl>O1CCCC1>[CH:3]([N:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][C:13]([CH3:16])=[CH:14]2)[C:9]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[N:8][C:7]1=[O:18])([CH3:5])[CH3:4]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC1=CC2C(CC1)C(=O)NC(=O)N2C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CC2C(CC1)C(c1ccc(F)cc1)=NC(=O)N2C(C)C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 2.37 g sodium hydride in 45 ml tetrahydrofurane are added portionwise at room temperature 13.32 g 1-isopropyl-7-methyl-4a,5,6,8a-tetrahydro-2,4-(1H)-quinazolindione and the mixture stirred for 45 minutes. 39 ml of a 2N solution of 4-fluorophenyl magnesium bromide in tetrahydrufurane are then added dropwise within 2 hours at an internal temperature of 40° and the resulting suspension stirred at 40° for 15 hours. 23 ml 15% hydrochloric acid are then added under ice cooling and the solvent removed in vacuo. The residue is taken up with water and methylene chloride. The methylene chloride phase is evaporated to dryness to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][C@@H:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:51]([NH:53][CH3:54])=[O:52]>CN(C=O)C>[CH3:56][C:55]([CH3:58])([CH3:57])[C@H:50]([NH:49][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:51](=[O:52])[NH:53][CH3:54]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cc(OC2COC2)c(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)c1cc(OC2COC2)c(Cl)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Chloro-4-(oxetan-3-yloxy)-pyridine-2-carboxylic acid (Example 23a, 35 mg, 152 μmol) in DMF (1 mL) was added HATU (58 mg, 152 μmol) and DIEA (66.6 μL, 381 μmol). The reaction mixture was then stirred at room temperature for 30 min, followed by addition of (S)-2-amino-N,3,3-trimethylbutanamide (CAN 89226-12-0, 22 mg, 152 μmol). The reaction mixture was stirred for 3 h. The crude reaction mixture was directly purified by preparative HPLC to deliver the desired compound (17.5 mg, 32%) as a yellow oil. MS (ESI, m/z): 356.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](=O)[NH:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:35]=[C:36]([CH:39]4[CH2:43][CH2:42][CH2:41][N:40]4[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])[NH:37][CH:38]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:60]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]1[NH:60][C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[C:36]([CH:39]5[CH2:43][CH2:42][CH2:41][N:40]5[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:47])[CH3:48])[NH:37][CH:38]=4)=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[CH:19][N:18]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4c5ccccc5CN4C(=O)OC(C)(C)C)cc3)cc2)c[nH]1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(-c3ccc(-c4cnc(C5c6ccccc6CN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
1-[2-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (147.8 mg) was taken into m-xylenes (2.0 mL) and heated at 135° C. Solid ammonium acetate (120 mg, 1.5 mmol) was added and the reaction was stirred at 135° C. After 180 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between EtOAc and water. The organic layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product (142 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:31])=[N:3][CH:4]=[N:5]3)=[CH:14][CH:15]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Solvent: ClCCl
Product: COc1ccc(Oc2cccc3ncnc(NC(=O)Nc4cccc(OC)c4)c23)cc1
Yield: 73.9 %

Procedure:
4-Amino-5-(4-methoxyphenoxy)quinazoline (0.35 g, 1.3 mmol) and 3-methoxyphenyl isocyanate (0.23 g, 1.6 mmol) were reacted in 20 ml of dichloromethane according to procedure E to give 1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea (0.4 g, 74.1%, m. p. 209-210° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.O(C(C)(C)C)[K].C1COCC1.[C:22]1([CH2:28][SH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:28]([S:29][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: SCc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: c1ccc(CSc2ncnc3[nH]ccc23)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
To a round bottomed flask with a stir bar was added 4-chloro-1H-pyrrolo-[2,3-d]pyrimidine (5.07 g, 33.0 mmol), 1.00 M of KO-t-Bu in THF (49.5 mL, 49.5 mmol), and benzenemethanethiol (5.81 mL, 49.5 mmol) in isopropyl alcohol (350 mL). The reaction mixture was heated to reflux at 85° C. under an atmosphere of nitrogen. After 48 h, the reaction mixture was cooled and solvent was removed in vacuo. To the residue was added water (300 mL) and the solution was filtered to collect the resulting white solid. The solid was washed with diethyl ether and MeOH and dried under vacuum to afford the product as a white solid (6.29 g, 79% yield). LC/MS: Rt=1.68 min, ES+ 242 (FA standard). Reference: Pathak, A. K., Pathak, V., Seitz, L. E., Suling, W. J., Reynolds, R. C. J. Med. Chem., 2004, 47, 273-276.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH3:12])[CH:6]=1)=O.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:14]>>[CH3:12][C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:17]3[CH:16]=[C:15]([CH2:13][CH3:14])[CH:20]=[CH:19][N:18]3[CH:2]=2)[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: Cc1ccc(C(=O)CBr)cc1C
Reactant: CCc1ccnc(N)c1
Product: CCc1ccn2cc(-c3ccc(C)c(C)c3)nc2c1

Procedure:
The title compound, MS: m/e=250.8 (M+H+), was prepared in accordance with the general method of example 8 from 2-Bromo-1-(3,4-dimethyl-phenyl)-ethanone and 4-Ethyl-pyridin-2-ylamine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[NH:19]=[C:20]1[NH:24][CH2:23][CH2:22][S:21]1>N1C=CC=CC=1>[S:21]1[CH2:22][CH2:23][N:24]=[C:20]1[NH:19][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: O=C(Cl)c1cnc2c(C(F)(F)F)cccc2c1O
Reactant: N=C1NCCS1
Solvent: c1ccncc1
Product: O=C(NC1=NCCS1)c1cnc2c(C(F)(F)F)cccc2c1O
Reaction time: 18 h
Yield: 24.7 %

Procedure:
6.3 g of 4-hydroxy-8-trifluoromethyl-quinoline-3-carboxylic acid chloride were added with stirring under an inert gas to 90 ml of pyridine and a solution of 2.35 g of 2-imino-2,3,4,5-tetrahydrothiazole in 15 ml of pyridine were added thereto. The mixture was stirred for 18 hours and was evaporated to dryness. The 11.5 g of residue were taken up in 40 ml of a 10% potassium carbonate solution and the solution was extracted with ethyl acetate. The combined organic phases were chromatographed over silica gel and the product was eluted with a 9-1 benzene-ethanol mixture. The elute was dried and the product was crystallized from ethanol to obtain 1.93 g of N-(4,5-dihydro-2-thiazolyl)-4-hydroxy-8-trifluoromethyl-quinoline-3-carboxamide melting at 267°-268° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[N:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cccc(CCOS(C)(=O)=O)c1
Reactant: c1cc(C2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(CCN2CCC(c3ccncc3)CC2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
Ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (170 mg) was mixed with MeCN (3.4 ml), and 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl (122 mg) and potassium carbonate (173 mg) were added thereto, followed by stirring at 60° C. overnight. After cooling to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain ethyl 3-{2-[4-(pyridin-4-yl)piperidin-1-yl]ethyl}benzoate (121 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:41][C:38]2([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2cnccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cnccn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.015 g, 0.011 mmol, 1.2 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.034 g (66%). 1H NMR (400 MHz, CD3OD): δ 8.60 (d, J=1.6 Hz, 1H), 8.52 (m, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.98-7.95 (m, 2H), 7.92 (dd, J=1.6, 7.8 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.73-1.71 (m, 2H), 1.47-1.43 (m, 2H). 19F NMR (376.57 MHz, CD3OD) 6-77.68 (TFA), −112.27, −122.72 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])(C)(C)C.[Br:26]Br>C1COCC1.CCCCC>[Br:26][C:8]1[C:7]([O:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C#Cc2ncc(OC)cc2OC)cc1
Reactant: BrBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(C#Cc2ncc(OC)c(Br)c2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a solution of 3,5-dimethoxy-2-(4-methoxyphenylethynyl)pyridine M (120 mg, 0.446 mmol) in dry THF (2.5 ml) at −78° C. was added t-butyllithium (0.49 mmol, 0.30 ml of a 1.6M solution in pentane) and the reaction stirred for 10 minutes. After this time bromine (25 μL, 0.50 mmol) was added neat and the reaction was allowed to warm to room temperature and quenched by the addition of water (10 ml) and ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica-gel, eluted with hexanes:EtOAc, 3:1) to afford the product as a white solid (45 mg, 29%). 1HNMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[C:12]=1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([SH:34])[CH2:32][CH3:33].CCOC(C)=O>C(#N)CCC>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[C:12]=1[S:34][CH2:31][CH2:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCS
Reactant: COC(=O)c1ccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1ccc(C(=O)OC)cc1
Temperature: 180 °C
Yield: 62.1 %

Procedure:
5-Chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester (Intermediate#48) (397 mg, 1.13 mmol) was dissolved in butyronitrile (8 mL), potassium carbonate (470 mg, 3.40 mmol) and propanethiol (128 ul, 1.41 mmol) were added and the mixture heated to reflux and stirred at this temperature over night. The reaction mixture was transferred to a microwave vial (using ˜5 ml extra Butyronitrile to ensure complete transfer), a further 3 eq of propane thiol was added and the reaction was heated at 180° C. for 4 hours. EtOAc (˜50 mL) was added and the mixture washed with water (3×˜20 mL) and brine (˜20 ml) then dried (MgSO4), filtered and evaporated to give a yellow oil. Oil purified by column chromatography (12 g Si, eluting with 10 to 50% EtOAc in IH) to yield the title compound as a yellow oil (274 mg, 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[C:27]([NH2:45])=[CH:28][C:29]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:32][CH2:31][C:30]=2[CH:44]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:45][C:27]2[C:26]([O:25][CH3:24])=[CH:44][C:30]3[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH2:34][CH2:35][C:29]=3[CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CCN1CCOCC1)CC2
Yield: 22 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product isolated as an off-white foam (23 mg, 22%). MS (ESI+): 624 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.29 (d, J=9 Hz, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 6.57 (s, 1H), 6.53 (d, J=9 Hz, 1H), 3.94 (s, 4H), 3.91 (m, 2H), 3.88 (s, 4H), 3.73 (t, J=5 Hz, 4H), 3.17 (t, J=4 Hz, 4H), 2.88 (m, 4H), 2.70 (m, 6H), 2.56-2.51 (m, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].O.NN>C(O)COCCO>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(CC(=O)O)CC(=O)CCCCCCCCCCC(=O)O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC(CCCCCCCCCCCCC(=O)O)CC(=O)O
Temperature: 220 °C
Yield: 91.7 %

Procedure:
35 g (0.11 mol) of 3-methyl-5-keto-hexadecanedioic acid (obtained as described under (a) above), 30.8 g (0.55 mol) of potassium hydroxide, 150 ml of diethylene glycol and 20.6 g (0.33 mol) of 80% strength hydrazine hydrate are heated to the reflux temperature for 2 hours. Water and excess hydrazine are then distilled off and the residue is heated for one hour at 220° C. When it has cooled to 15° C., the reaction mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The residue which remains after removing the ethyl acetate from the organic phase is recrystallized from petroleum ether. 30.3 g (91% of theory) of 3-methyl-hexadecanedioic acid are obtained. Melting point: 77°-78° C.
Reaction SMILES: C(O[C:5]([CH3:8])([CH3:7])[CH3:6])(=O)C.[NH2:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1)[C:11]([OH:13])=[O:12].FC(F)(F)S(O)(=O)=O.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>[Cl-].[Na+].O.CC(=O)OCC>[NH2:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1)[C:11]([O:13][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:12]
Reactant: CC(=O)OC(C)(C)C
Reactant: COc1cc(CC(N)C(=O)O)ccc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CC(N)C(=O)OC(C)(C)C)ccc1O
Temperature: 0 °C
Yield: 37.2 %

Procedure:
Prepared using General Procedure 1: To tert-butyl acetate (192 ml, 1435 mmol) was added finely ground 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoic acid (10.1 g, 47.8 mmol). The mixture was sonicated for 10 min to give a suspension. Trifluoromethanesulfonic acid (5.50 ml, 62.2 mmol) was added with stirring and the mixture was stirred overnight. The crude reaction was poured into a mixture of 2N NaOH (150 mL), brine (100 mL), ice (200 mL), and EA (100 mL) and basified to pH 9 with solid K2CO3. The mixture was filtered through celite and extracted with EA (2×100 mL). The organics were dried over MgSO4 and concentrated. The product residue was purified by chromatography (MeOH/DCM) to afford 4.75 g (37%) of tert-butyl 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-1. LCMS-ESI (m/z) calculated for C14H21NO4: 267. Found 268 [M+H]+, tR=0.9 min (Method 4). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 6.76-6.71 (d, J=1.9 Hz, 1H), 6.70-6.61 (m, 1H), 6.60-6.53 (m, 1H), 3.75-3.68 (s, 3H), 3.32 (s, 1H), 2.68 (m, 2H), 1.75 (s, 2H), 1.33 (s, 9H).