Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[OH:8][C@@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:11](=[O:32])[CH2:10]1.O>ClCCl>[CH3:22][O:21][C:18]1[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)=[CH:16][C:15]([CH2:14][N:12]2[C:11](=[O:32])[CH2:10][C@H:9]([O:8][C:6](=[O:7])[NH2:5])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc(CN2C[C@@H](O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN2C[C@@H](OC(N)=O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 20 mL vial with a stir bar was added chlorosulfonyl isocyanate (42 mg, 0.30 mmol), 1 mL dichloromethane, then P-248 (51.3 mg, 0.15 mmol) in 2 mL of dichloromethane. The reaction was stirred at room temperature for 18 hours after which 2 mL of water was added and the mixture was stirred at room temperature for 30 minutes. The layers were separated and the aqueous was extracted with dichloromethane. The combined organics were concentrated and then purified by preparative layer TLC using 50% acetone/dichloromethane to obtain P-253 (12.4 mg, 21%) as an off-white semi-solid. 1H NMR (400 MHz, DMSO-d6) 8.30 (s, 1H), 8.20 (dd, J=2.1, 8.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.16 (d, J=9.0 Hz, 1H), 6.59 (br. s., 2H), 5.04 (t, J=5.8 Hz, 1H), 4.49-4.30 (m, 2H), 3.80 (s, 3H), 3.46-3.38 (m, 1H), 3.21 (d, J=11.4 Hz, 1H), 2.78 (dd, J=6.9, 17.5 Hz, 1H), 2.23 (d, J=18.1 Hz, 1H) ppm. LC/MS=100.0%, 386.1 (APCI+).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1>CO.[Pd].C(Cl)(Cl)Cl.CO>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)[C@@H](C)OC(C)(C)C

Procedure:
2.36 g of Z-Tyr(tBu)-Thr(tBu)-Gln-Asp(OtBu)-Phe-OCH3 in 450 ml of methanol are hydrogenated with 500 mg of 10 % strength palladium on charcoal in the usual manner at room temperature. A colourless foam is obtained which is homogeneous according to a thin layer chromatogram and is further employed as such. The following Rf-values are obtained in a thin layer chromatogram on silica gel: in chloroform-methanol (95:5) Rf = 0.22; Rf89 = 0.42.
Reaction SMILES: [CH3:1][C:2]([NH2:15])([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:16](OC1C=CC=CC=1)=[O:17]>>[CH3:1][C:2]([NH:15][CH:16]=[O:17])([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=COc1ccccc1
Reactant: CCC(C)(N)Cc1c[nH]c2ccccc12
Product: CCC(C)(Cc1c[nH]c2ccccc12)NC=O

Procedure:
The 3-(2'-methyl-2'-aminobutyl)-indole obtained as reduction product in accordance with Example 1 or 3 was reacted with phenyl formate to yield 3-(2'-methyl-2'-formylaminobutyl)-indole; melting point 121.5°-124.5°C. (from ether). Reduction thereof with LiAlH4 yielded 3-(2'-methyl-2'-methylaminobutyl)-indole having a melting point of 100°-103°C. (from cyclohexane).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][C:18]1[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:24](=[NH:25])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)[N:23]=1
Reactant: Cc1cccc(C#N)n1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (4.2 g, 20.3 mmol) in toluene (100 ml) at 0° C., was added trimethylaluminum (2M solution in toluene, 12 ml, 24 mmol) over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 6-methyl-2-cyanopyridine (3.6 g, 30.5 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85°-90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with hexane and ethyl acetate (1000 ml) and filtered. The white solid (5.1 g, 87%) was used in the next reaction without further purification. Anal. Calc'd. for C14H16N3SClO2H2O: C, 51.05, H, 5.02, N, 12.76. Found C, 50.97, H, 4.78, N, 12.80.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][N:7]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+]>CC(C)=O>[C:2]([C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][N:7]=1)([OH:20])=[O:1]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=CN1CCC(CCCn2ccnc2CO)CC1
Agent: [K+]
Solvent: CC(C)=O
Product: O=CN1CCC(CCCn2ccnc2C(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
The solution of 4-[3-(2-hydroxymethyl-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde in acetone (63 ml) was cooled to 0° C. and potassium permanganate (5.5 g, 0.035 M) was added portionwise. After complete addition, the reaction was stirred at 0° C. for 2 hrs. The acetone solution was separated by filtration, and the residue was stirred twice with water (50 ml). The aqueous solution was freeze dried to yield 4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde (5.5 g, 83% yield). This product (7.1 g, 0.027 M) in water (26 ml) and 1 N NaOH (26 ml) was heated at 100° C. for 5 hrs. The reaction was adjusted pH 6 and purified on ion-exchange column (Bio-Rex 70) eluted with 0.01 N, 0.02 N, 0.04 N, 0.08 N and 0.1 N HCl solution successively to give 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molar hydrochloride 0.65 molar hydrate (4.6 g, 73% yield).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([N:13]2[C:17]3[N:18]=[CH:19][NH:20][C:21](=O)[C:16]=3[CH:15]=[N:14]2)[CH:12]=1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:11]3[CH:12]=[C:7]([F:6])[CH:8]=[CH:9][C:10]=3[CH3:23])[N:14]=[CH:15][C:16]=12
Reactant: Cc1ccc(F)cc1-n1ncc2c(=O)[nH]cnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(F)cc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
Phosphorus oxychloride (5442 μl, 58.39 mmol) was added to 1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (Intermediate AK2) (713 mg, 2.92 mmol), at ambient temperature. The resulting mixture was heated to 100° C. and stirred for 4 hours. The mixture was allowed to cool to ambient temperature. The reaction mixture was evaporated to near dryness. Dissolved into toluene, evaporated, dissolved, in toluene and evaporated to dryness again. The solid was dried under vacuum to give crude product. This was partitioned between EtOAc (70 mL), and water (25 mL). The organic phase was dried (MgSO4), evaporated, then dried under vacuum to afford the product (732 mg, 95%). 1H NMR (400 MHz, DMSO) δ 2.13 (3H, s), 7.52-7.42 (2H, m), 7.64-7.58 (1H, m), 8.83 (1H, s), 8.96 (1H, s); m/z (ES+) (M+H)+=263; HPLC tR=2.39 min.
Reaction SMILES: [S:1]([N:11]=[N+:12]=[N-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[CH:22].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl.[Cu]I>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:13]=[N:12][N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C#Cc1ccccc1Cl
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)nn2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of tosyl azide (16) (1.0 equiv) in CHCl3 (0.5M) cooled to 0° C. was treated with 2-chlorophenyl acetylene (15) (1.2 equiv), 2,6-lutidine (1.2 equiv) and CuI (0.1 equiv). The resulting mixture was stirred at 0° C. for 24 h, quenched with 10% HCl, the layers separated and the aqueous one washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Hexane/AcOEt 5:1, 3:1 and 1:1) to provide 4-(2-chlorophenyl)-1-tosyl-1H-1,2,3-triazole (17) as a pale yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1 mmol) was dissolved in dichloromethane (3 mL) at -78° C. and treated with 4-methylmorpholine (0.25 mL, 2.27 mmol, 2.eq.) and 2,4-dimethoxy-benzoyl chloride (220 mg, 1.1 mmol, 1 eq.) dissolved in 3 mL of dichloromethane. The solution was allowed to warm to 0° C. and stirred for 1 hour. The solution was washed with 1N HCl, and 5% sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 324 mg (69%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCC2)CC1(F)F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reaction time: 3 h

Procedure:
To a mixture of 5.5 g (0.0191 mole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1), 25 mL of dimethylformamide and 9.4 g (0.0287 mole) of cesium carbonate was added 10.9 g (0.0764 mole) of iodomethane. The mixture was stirred for 3 hours, then 80 mL of water was added and the solid collected by suction filtration to give 4.8 g of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1).
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:16][C@@H:15]3[C@@H:11]([CH2:12][O:13][C:14]3=[O:17])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C(O)C>[CH:18]1([NH:21][C:14]([C@@H:15]2[C@H:11]([CH2:12][OH:13])[CH2:10][N:9]([C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH2:16]2)=[O:17])[CH2:20][CH2:19]1
Reactant: C[C@H](c1ccccc1)N1C[C@@H]2COC(=O)[C@@H]2C1
Reactant: NC1CC1
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1C[C@@H](CO)[C@@H](C(=O)NC2CC2)C1
Temperature: 80 °C
Reaction time: 44 h

Procedure:
(1S,5R)-7-[(1R)-1-Phenylethyl]-3-oxa-7-azabicyclo[3.3.0]octane-2-one (7.73 g, 33.4 mmol) was dissolved in ethanol (92 mL). To this solution, cyclopropylamine (46.3 ml) was added and the mixture was stirred at 80° C. for 44 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diisopropylether (300 mL) was added to the residue and the solution was heated to form crystals. The solution was concentrated to approximately half the original volume and the crystals formed were filtered. The collected crystals were washed with diisopropyl ether and were dried under reduced pressure to give (3R,4S)-N-cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide as white crystals (4.41 g). The filtrate and the washings were then combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=1:1->ethyl acetate) to give additional (3R,4S)-N-cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide (1.50 g).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[F:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17]C(O)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:1]([O:5][CH2:4][CH2:3][OH:2])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: OCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
6.8 g of ethylene carbonate and 2.3 g of tetrabutylammonium bromide are added to a solution of 13.8 g of p-(p-fluorophenoxy)phenol in 35 ml of dimethylformamide. After 4 hours at reflux there are added an additional 1.2 g of ethylene carbonate, and the mixture is heated at reflux for an additional 2 hours. The cooled mixture is poured into 150 ml of ice/water and extracted three times with 100 ml of ethyl acetate each time. The extracts are washed twice with 100 ml of saturated sodium chloride solution each time, dried and evaporated. The residue is purified by recrystallization from n-hexane/ethyl acetate to yield pure 2-[p-(p-fluorophenoxy)-phenoxy]-ethanol, m.p. 74°-76° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH2:14][C:15](=[O:18])[CH2:16][CH3:17].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]([OH:33])[CH:14]([CH3:13])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCC(=O)CC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(=O)C(C)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A solution of diisopropylamine (0.63 mL, 4.5 mmol) in THF (16 mL) at 0° C. was treated with 1.6 M n-butyllithium in sol'n in hexanes (2.8 mL). The resulting solution was stirred at 0° C. for 10 min, then cooled to −78° C. 3-Pentanone (0.41 mL, 4.1 mmol) was added and the resulting mixture was stirred cold for 1 h. A solution of 1-(t-butoxycarbonyl)-4-formylpiperidine (435 mg, 2.05 mmol) (from Step B) in THF (3 mL) was then added. After 15 min, the reaction was quenched with sat'd ammonium chloride (25 mL) and extracted with ether (100 mL). The extract was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 4:1 v/v, then 3:2 v/v hexanes/ethyl acetate as the eluent afforded 517 mg (85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10](N)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](O)=[O:13]>Cl>[O:13]1[C:10]2=[CH:9][CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]2[N:1]=[CH:12]1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=CO
Agent: Cl
Product: O=C(O)c1cccc2ocnc12
Yield: 76 %

Procedure:
A mixture of 2,3-diaminobenzoic acid (0.5 g, 3.29 mmol) and formic acid (405 μl, 9.87 mmol) in hydrochloric acid (4M, 10 ml) was heated under reflux for one hour. The precipitate which formed on cooling was collected, redissolved in boiling methanol, and decolorised with activated charcoal. Evaporation of the solvent gave benzoxazole-4-carboxylic acid as a white powder (407.9 mg, 77%) Found: C, 46.11; H, 3.63; N, 13.27. C8H6N2O2.HCl.0.5 H2O requires C, 46.28; H, 3.88; N, 13.49%; δH (d6-DMSO, 200 MHz) 7.7-7.8; (1H, t, Ar-5H), 8.2-8.3 (2H, dd, Ar-4/6H), 9.65 (1H, s, imidazole-2H).
Reaction SMILES: CCOCC.Br[CH2:7][C:8](=O)[CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].[CH:22]([NH2:24])=[S:23]>CCO>[S:23]1[CH:7]=[C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[N:24]=[CH:22]1
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Reactant: NC=S
Solvent: CCO
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1Cc1cscn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ether (7.5 mL) was added to the above solution of 2-(3-bromo-2-oxopropyl)-1H-isoindole-1,3(2H)-dione and cooled to 0° C. in an ice/NaCl salt bath. Then thioformamide (European Journal of Medicinal Chemistry, 2004, 39, 867-872.) (1.20 g) in EtOH (8 mL) was added, and the reaction was stirred overnight. The solvents were evaporated and the reaction mixture was purified by RP-HPLC to provide 2-(1,3-thiazol-4-ylmethyl)-1H-isoindole-1,3(2H)-dione as a white solid. LCMS: (M+H)+=245.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Cu](C#N)[C:14]#[N:15]>CN(C)C=O.O>[O:12]=[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:11]=2)[CH:6]=[CH:7][NH:8]1
Reactant: N#C[Cu]C#N
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2cc[nH]c(=O)c2c1
Temperature: 180 °C
Yield: 70.1 %

Procedure:
To a suspension of 7-bromoisoquinolin-1(2H)-one (70 g, 0.31 mol) in N,N-dimethylformamide (1 L) was added copper cyanide (56 g, 0.63 mol). The reaction was heated to 180° C. for 2 hours. The reaction was cooled to room temperature and was diluted with water (1 L). The solution was extracted with ethyl acetate (3×). The organics were dried over sodium sulfate, filtered, and concentrated to give crude 1-oxo-1,2-dihydroisoquinoline-7-carbonitrile (37 g). This crude material was taken up in ethanol (500 mL) and 1 N aqueous sodium hydroxide (400 mL) was added. The mixture was heated to reflux and stirred for 2 hours. The reaction was cooled to room temperature and the pH was adjusted to ˜2 with 1 N aqueous hydrochloric acid. The solids were collected by filtration, rinsed with water, and dried under vacuum to give the title compound (35 g, 85%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.15 (br. s., 1H), 11.49 (s, 1H), 8.75 (s, 1H), 8.17-8.14 (m, 1H), 7.75 (d, 1H), 7.34-7.29 (m, 1H), 6.62 (d, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:11]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:12])[NH:9][CH:10]=1)=[O:5])C.[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]C(O)=O>C1COCC1>[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26][C:4]([C:6]1[N:7]=[C:8]([C:11]([N:13]2[CH2:14][CH:15]=[CH:16][CH2:17]2)=[O:12])[NH:9][CH:10]=1)=[O:5]
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: CCOC(=O)c1c[nH]c(C(=O)N2CC=CC2)n1
Solvent: C1CCOC1
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c(C(=O)N2CC=CC2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 2-(2,5-dihydro-pyrrole-1-carbonyl)-1H-imidazole-4-carboxylic acid ethyl ester (100 mg, 0.43 mmol) and (2,3-difluoro-phenyl)acetic acid (75 mg, 0.44 mmol) in anhydrous THF (5 mL) was added LDMS (1.0M in THF, 1.5 mL, 1.5 mmol) at −78° C. After addition of LDMS, the dry-ice bath was removed and the reaction was stirred at ambient temperature for 6 hours. To this reaction mixture was added 1 mL of sat. NH4Cl solution and EtOAc then the organic layer was separated and dried over MgSO4. After removal of solvent, the residue was washed with water to afford the title compound as a yellow solid. This crude product was used directly for the next step without further purification. MS (ES+): m/e=318.2 (M+H); Rt=3.21 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:35])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: OCc1ccc(Br)cc1OC(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1cc(Br)ccc1CBr
Temperature: 0 °C
Yield: 87.3 %

Procedure:
Add (4-bromo-2-(trifluoromethoxy)phenyl)methanol (9.757 g, 36 mmol) and dichloromethane (180 mL) to a 500 mL flask equipped with a magnetic stir bar and N2 inlet. Cool the solution to 0° C. and then treat with triphenylphosphine (11.33 g, 43 mmol) and carbon tetrabromide (14.26 g, 43 mmol). Stir the reaction at 0° C. for 45 minutes, warm to room temperature and stir an additional 1 hour. Wash the reaction with water (2×180 mL) and saturated sodium chloride solution (1×180 mL), then dry over anhydrous magnesium sulfate. Filter through Celite® and concentrate under vacuum to dryness. Dissolve the residue in hexanes, filter to remove the triphenyl phosphine oxide, and concentrate to a colorless oil. Purify the crude product via silica gel chromatography eluting with hexanes to afford 10.5 g (88%) of the product as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.38-7.33 (m, 1H), 4.46 (s, 3H).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Ca+2].[Cl-].O>C(O)C.[Fe]>[NH2:19][C:15]1[CH:14]=[C:13]([C:10]2([CH3:22])[CH:9]3[CH:11]2[CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]3=[O:23])[CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(N)c1
Temperature: 25 °C

Procedure:
3-Hexyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Preparation 11, 6.3 g, 19.9 mmol) was dissolved in ethanol (250 ml), and iron powder (8.5 g, 0.15 mol), calcium chloride (0.95 g, 8.6 mmol) and water (50 ml) was added. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature and calcium chloride (0.95 g, 8.6 mmol) was added, the reaction mixture was refluxed for a further 16 h. The reaction mixture was cooled and filtered and then concentrated in vacuo, the residue was partitioned between dichloromethane and water and the organic layer separated, the aqueous layer was extracted with dichloromethane (3×) and the combined extracts were dried (Na2SO4) and concentrated in vacuo. The title compound was obtained as an orange solid (5.72 g, 100%).