Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20].Cl>C(Cl)Cl.C(O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([C:19]([C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)=[O:20])[CH:22]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Reaction time: 0.33 h
Yield: 71 %

Procedure:
Anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in methylene chloride (2050 mL) under a nitrogen protection. To the resulting mixture was added anisole (125 mL, 1.15 mol) in one batch at −5° C. After stirring for 20 mins, to the mixture was added dropwise a solution of 5-bromo-2-chlorobenzoyl chloride in methylene chloride (300 mL). The resulting mixture was reacted at −5° C. for 3 h. TLC indicated the completion of reaction. To the reaction mixture was poured 2N hydrochloric acid. The resulting mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce a solid. To the solid was added ethanol (150 mL), and the resulting mixture was washed and starched for 30 mins and filtered. The filter cake was oven dried to produce 265 g of a product in a yield of 71%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:24]COC)=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:24])=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(N2CCN(Cc3ccccc3)CC2)ccc1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 400 mg of methyl 5-(4-benzylpiperazin-1-yl)-2-methoxymethoxybenzoate (1.1 mmol) in 1,4-dioxane (20 mL) was added a solution of 4 N hydrogen chloride in 1,4-dioxane (4 mL, 16 mmol), and the resulting solution was stirred for 2 hours at 100° C. The resulting reaction solution was subjected to distillation under reduced pressure to obtain a residue. This residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 353 mg of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:15])[S:9][C:10]=1[NH:11][C:12]([NH2:14])=[O:13])=O)C.[OH-].[Na+]>CC(O)C.O>[CH3:15][C:8]1[S:9][C:10]2[NH:11][C:12](=[O:13])[NH:14][C:4](=[O:3])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1nc(C)sc1NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2c(=O)[nH]c(=O)[nH]c2s1
Temperature: 80 °C
Yield: 85 %

Procedure:
To a suspension of 2-methyl-5-ureido-thiazole-4-carboxylic acid ethyl ester (21.0 g, 0.079 mol) in iPrOH (300 mL) was added an aqueous solution of NaOH (3 M, 26 mL, 0.078 mol) at 80° C. The thick white suspension was heated at 80° C. for 45 min, then diluted with H2O and cooled to 0° C. The reaction mixture was acidified to pH 3 and the precipitate collected by filtration. The white solid was washed with H2O and dried in vacuo at 60° C. for 17 h to give the title compound as a white solid (12.3 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][NH:40][CH3:41])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][N:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=1)[CH3:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)cc1
Reactant: CNCCCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Yield: 64.2 %

Procedure:
A solution of toluene-4-sulfonic acid (1R,2R)-2-benzyloxycarbonylamino-cyclohexylmethyl ester (632 mg, 1.51 mmol) in acetone (8 mL) was treated with N-[3-(4-fluorophenyl)-propyl]-methylamine (253 mg, 1.51 mmol) and potassium carbonate (209 mg, 1.51 mmol) and heated at reflux for 23.5 hours. The mixture was cooled and filtered, the solid was rinsed with acetone, and the filtrate was concentrated to provide a yellow-orange oil. Flash chromatography on silica gel, eluting with 50% ethyl acetate in hexane, followed by 50% ethyl acetate in hexane containing 5% ethanol, provided a light yellow viscous oil (400 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:21])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:28][O:29][CH3:30])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:21])=[CH:4][N:3]=1
Reactant: CCc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1cc(S(=O)(=O)N(COC)c2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 2.35 g (5.73 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-ethyl-benzenesulfonamide, 2.76 g of potassium carbonate and 1.3 mL of methoxymethyl chloride in 10 mL THF using procedure x. Yield: 980 mg of a white solid. LC-MSD, m/z for C15H15BrCl2N2O3S [M+H]+=452.9, 454.9, 456.9
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: c1cc(NC2CCOCC2)ccc1CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCOCC1)C(=O)OCC
Temperature: 140 °C

Procedure:
A flask containing N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-pyran-4-amine (0.34 g) is treated with diethyl ethoxymethylenemalonate (0.30 mL) and pyridine (0.20 mL). The flask is tightly capped and heated to 140° C. for 2 hours. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3×). The residue is dissolved in dichloromethane and washed with water, brine, dried and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.41 g of diethyl 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-pyran-4-yl)anilino]methylene}malonate as a tan oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.CO.[BH4-].[Na+]>O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CO)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL) was added sodium borohydride (55.0 mg), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was m washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (166 mg, yield 83%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 467 (MH+).
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([C:9]([NH:11][C@@H:12]([CH2:46][OH:47])[C@@H:13]([OH:45])[C@@H:14]([OH:44])[C@H:15]([OH:43])[C:16]([NH:18][C@H:19]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:20][C:21]([O:23]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22])=[O:17])=[O:10])[NH2:8])(C)(C)C.Cl>C(OCC)(=O)C>[OH:43][C@@H:15]([C@H:14]([OH:44])[C@H:13]([OH:45])[C@@H:12]([NH:11][C:9](=[O:10])[C@H:7]([CH2:6][OH:5])[NH2:8])[CH2:46][OH:47])[C:16]([NH:18][C@H:19]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:17]
Reactant: CC(C)(C)OC[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CO)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.2 %

Procedure:
To diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-(O-tert-butyl-L-seryl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (300 mg) was added 4N hydrogen chloride solution in ethyl acetate (10 ml) and the mixture was stirred at room temperature for 1.5 hours. Removal of the organic solvent gave a residue, which was extracted with water. The aqueous layer was washed with diethylether and concentrated under reduced pressure. The residue was recrystallized from methanol-diethylether to afford the title compound (208 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15]C.BrC1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:28])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH3:15]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C)nc1Br
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(5-bromo-3,6-dimethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.51, 7.36–7.28, 5.66, 4.98, 4.82, 3.25, 3.11, 2.75, 2.42, 2.26; HRMS (FAB) calcd for C21H19C2N3O+H 400.0983, found 400.0995.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([CH3:37])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C:31]3=[O:36])=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].CC(C)=O>CO.O1CCCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH:31]3[OH:36])=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH3:37])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCOCC2O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 17.6 %

Procedure:
To an ice-cooled solution of 494 mg (0.852 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(3-oxo-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide in 5 ml methanol and 5 ml tetrahydrofuran were added 635 mg (1.70 mmol) cerium(III)chloride heptahydrate. After stirring for 5 min, 64 mg (1.70 mmol) sodium borohydride were added in two portions within 2 min. After stirring for 3 h at 0° C., 1 ml acetone was added and stirring was continued for 10 min. The solvent was removed, the residue was re-dissolved in ethyl acetate and the organic phase was washed with saturated sodium carbonate solution, dried (magnesium sulfate) and evaporated. The crude material was purified by flash-chromatography to give 87 mg (16%) ofthe title compound as white crystals. MS m/e (%): 582 (M+H+, 100).
Reaction SMILES: [OH:1][CH:2]([CH:41]1[CH2:45][O:44]C(C)(C)[O:42]1)[CH2:3][NH:4][C:5](=[O:40])[C:6]1[CH:24]=[C:23]([S:25](=[O:39])(=[O:38])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])[CH:22]=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:21])[CH:14]2[CH2:18][O:17]C(C)(C)[O:15]2)=[O:10])[CH:7]=1.Cl>C(O)C.O>[OH:1][CH:2]([CH:41]([OH:42])[CH2:45][OH:44])[CH2:3][NH:4][C:5](=[O:40])[C:6]1[CH:24]=[C:23]([S:25](=[O:38])(=[O:39])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:35])[F:36])[CH:22]=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:21])[CH:14]([OH:15])[CH2:18][OH:17])=[O:10])[CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cc(C(=O)NCC(O)C3COC(C)(C)O3)cc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)c2)O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(NCC(O)C(O)CO)c1cc(C(=O)NCC(O)C(O)CO)cc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3.79 g (5.46 mmol) of 5-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-isophthalic acid-bis[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in a mixture of 40 ml of ethanol and 10 ml of water and the solution is acidified with dilute hydrochloric acid to pH 1. It is stirred at this pH for 4 hours at 60° C. The solution is then adjusted to pH 6.1 with the anion exchanger Amberlite IRA 67, filtered and evaporated to dryness in a vacuum. The solid amorphous residue is dried in a vacuum at 50° C. 2.55 g (4.16 mmol) =76.12% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: N1C=CN=C1C(O)=O.[NH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Br:19])[C:17]=1[Cl:18])[C:13]#[N:14].[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:19][C:16]1[C:17]([Cl:18])=[C:10]([NH:9][C:21](=[O:20])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(N)c(Cl)c(Br)c1
Agent: CN(C)c1ccncc1
Agent: O=C(O)c1ncc[nH]1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
(I1D): A mixture of 3-bromo-4-chloro-5-nitrobenzonitrile (0.99 g, 3.79 mmol), iron (1.057 g, 18.93 mmol) and ammonium chloride (2.025 g, 37.9 mmol) in THF, MeOH and water (60 ml, 1:1:1) was heated to reflux for 1 h. More iron (0.5 g) and NH4Cl (2 g) added, heated for another 2 h and then cooled to room temperature. Filtered off solid, the filtrate was concentrated to remove the organic solvent. The residue was diluted with water, extracted with EtOAc twice, dried and concentrated to dryness. The resulting solid was trituard with EtOAc, solid was filtered off through celite pad and the filtrate was concentrated to give 0.88 g of 3-amino-5-bromo-4-chlorobenzonitrile as yellow solid which was used as such in the next reaction. Intermediate 1: To a solution of 3-amino-5-bromo-4-chlorobenzonitrile (0.88 g, 3.80 mmol) in DCM (25 mL) was added TEA (1.590 mL, 11.41 mmol), BOC2O (1.059 mL, 4.56 mmol) and DMAP (0.464 g, 3.80 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, the crude product was purified using ISCO silica gel column (24 g, EtOAc/hexane=0-30%) to give 0.667 g of tert-butyl 3-bromo-2-chloro-5-cyanophenylcarbamate as white solid
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([C:25]#[N:26])=[C:6]([CH:24]=1)[O:7][C@@H:8]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C>Cl.O1CCOCC1>[ClH:1].[NH2:11][CH2:10][CH2:9][C@@H:8]([O:7][C:6]1[CH:24]=[C:2]([Cl:1])[C:3]([F:27])=[CH:4][C:5]=1[C:25]#[N:26])[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1nccs1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN)c1nccs1
Temperature: 25 °C
Yield: 155.1 %

Procedure:
The product from step (c) (370 mg, 0.9 mmol) was dissolved in 4M hydrochloric acid in dioxan and stirred at room temperature for a half hour. The solvent was removed in vacuo and the residue triturated with a mixture of ethyl acetate and methanol (14:1). The white solid was filtered and dried to afford the title compound (243 mg, 70%).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.[CH3:21][O:22][C:23](=[O:39])[C@@H:24]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:25][CH2:26][NH2:27].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:21][O:22][C:23](=[O:39])[CH:24]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[CH2:25][CH2:26][NH:27][C:11](=[O:13])[CH2:10][N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)Cn1ccc2cnccc21
Reactant: COC(=O)[C@H](CCN)NC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CCNC(=O)Cn1ccc2cnccc21)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
Pyrrolo[3,2-c]pyridin-1-yl-acetic acid (0.50 g, 1.89 mmol), 2-(S)-benzyloxycarbonylamino-4-amino-butyric acid methyl ester trifluoroacetate (0.93 g, 2.45 mmol), 4-methylmorpholine (0.75 g, 7.41 mmol), and 1-hydroxybenzotriazole hydrate (0.36 g, 2.65 mmol) are dissolved in DMF (11 mL) and the resulting mixture is cooled to 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiiimide hydrochloride (0.80 g, 4.17 mmol) is added to the solution. The ice bath is removed and the reaction mixture is stirred at room temperature. After 18 hours, the solution is diluted with a saturated solution of NH4Cl and extracted twice with EtOAc. The combined organic layers are washed with H2O, saturated NaHCO3 and saturated NaCl. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by column chromatography in a gradient of 3% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to afford the title compound (0.33 g, 0.78 mmol) as a solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12])=[O:6])[CH:2]=[CH2:3].Cl.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:14][C:13](=[O:15])[C@H:8]([CH2:9][CH2:10][S:11][CH3:12])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: O=C([O-])O
Reactant: C=CCOC(=O)N[C@@H](CCSC)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](CCSC)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)methionine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)methionine methyl ester.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].Cl.[Cl:20]C1C=CC=C(C(OO)=O)C=1.O>CC(N(C)C)=O>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Cl:20])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cc(Cl)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3'-Azido-2',3'-dideoxyuridine (0.25 g; 1 mMol) was dissolved in 2 mL dry dimethylacetamide (DMAC), cooled to 0° C. and 2 mL of 0.5M HCl in DMAC was added. m-Chloroperbenzoic acid (0.277 g; 1.6 mMol) was added in two portions over ten minutes and the mixture was allowed to come to ambient temperature. After two hours, 4 mL H2O was added and the solution filtered. The aqueous DMAC solution was extracted with Et2O (3×3 mL) and the Et2O was evaporated in vacuo to an oil which was applied to a silica gel column. Elution with CHCl3MeOH (15:1 v/v), combination of the appropriate fractions and evaporation in vacuo yielded an oil which was crystallized from Et2O to give 58.5 mg (0.2 mMol, 20%): mp=169°-170° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:28][C:29]1[N:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1
Reactant: CC(C)(O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2oc(CN3CCC(C(C)(C)O)CC3)cc2n1
Yield: 40 %

Procedure:
A mixture of 2-[1-(2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]propan-2-ol (110 mg, 0.28 mmol), 2-methyl-1H-benzoimidazole (42 mg, 0.32 mmol), Pd2dba3 (14 mg, 0.015 mmol), Xphos (15 mg, 0.031 mmol) and cesium carbonate (203 mg, 0.62 mmol) in DMF (2.5 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 97:3 to 95:5 to 90:10) to afford 241 as a tan solid (55 mg, 40%). LCMS (Method G): RT=5.19 min, M+H+=491. 1H NMR (CDCl3, 400 MHz) δ 7.99 (m, 1 H); 7.71 (m, 1 H); 7.25 (m, 2 H); 6.77 (s, 1 H); 4.09 (t, J=4.7 Hz, 4 H); 3.89 (t, J=4.7 Hz, 4 H); 3.77 (s, 2H); 3.11 (m, 2 H); 2.90 (s, 3 H); 2.16 (m, 2 H); 1.80 (m, 2 H); 1.49 (m, 2 H); 1.33-1.22 (m, 2 H) and 1.20 (s, 6 H)
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.O1CCOCC1>[ClH:27].[ClH:27].[N:11]1([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cc(N2CCCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(6-Ethylquinolin-8-yl)-[1,4]-diazepan-1-carboxylic acid tert-butyl ester (1.0 g, 1.0 equiv) was dissolved in MeOH (5 mL) and 1.0 M HCl in 1,4-dioxane (10 mL) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was concentrated to dryness to afford the title compound (1.0 g). MS (ES) m/z 256.1 (M+H+).