Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: NCc1ccccc1
Product: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:26][C:25](=[O:27])[CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[CH3:14][C:4]1[N:5]=[C:6]([CH3:13])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:27][C:25]2[CH:24]=[N:23][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:15])[CH:26]=2)[N:3]=1
Reactant: Cc1ccccc1N1CC(=O)C=N1
Reactant: COC(=O)Cc1c(C)nc(C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(C)nc1Oc1cnn(-c2ccccc2C)c1

Procedure:
A mixture of methyl (4-chloro-2,6-dimethyl-5-pyrimidinyl)-acetate (4.6 g, 21 mmol), 1-(2-methylphenyl)-1H-pyrazol-4-on (4.1 g, 23 mmol) and potassium carbonate (6.4 g, 46 mmol) in dimethylformamide (50 ml) is heated at +120° C. for 2 hours. Addition of water, extraction with ether and drying gives the intermediate methyl 2-[2,4-dimethyl-6-(1-(2-methylphenyl)-1H-pyrazol4-yloxy)-pyrimidin-5-yl]-acetate as an oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([O:10][C:11](=[O:24])[C:12]([O:14][C:15]([CH3:23])([CH2:17][CH2:18][O:19]C(=O)C)[CH3:16])=[O:13])([CH3:9])[CH3:8])(=O)C>C(Cl)Cl.C(NC(C)C)(C)C>[OH:4][CH2:5][CH2:6][C:7]([O:10][C:11](=[O:24])[C:12]([O:14][C:15]([CH3:23])([CH2:17][CH2:18][OH:19])[CH3:16])=[O:13])([CH3:8])[CH3:9]
Reactant: CC(=O)OCCC(C)(C)OC(=O)C(=O)OC(C)(C)CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(C)(CCO)OC(=O)C(=O)OC(C)(C)CCO

Procedure:
The cleavable diol is made in the following manner. To a solution of compound (73) in methylene chloride, diisopropylamine is added and the solution is stirred until reaction is complete. A standard aqueous workup is done and the diol should remain in the organic phase. Evaporate the solvent and collect bis(4-hydroxy-2-methylbutan-2-yl)oxalate (74).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH3:14][C@@H:15]([C@@H:22]1[C@@:26]2([CH3:44])[CH2:27][CH2:28][CH:29]3[C@@:34]4([CH3:43])[CH2:35][CH2:36][CH:37]([O:39][C:40](Cl)=[O:41])[CH2:38][C:33]4=[CH:32][CH2:31][CH:30]3[CH:25]2[CH2:24][CH2:23]1)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>ClCCl.O1CCOCC1>[CH3:14][C@@H:15]([C@@H:22]1[C@@:26]2([CH3:44])[CH2:27][CH2:28][C@@H:29]3[C@@:34]4([CH3:43])[CH2:35][CH2:36][C@H:37]([O:39][C:40]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:41])[CH2:38][C:33]4=[CH:32][CH2:31][C@H:30]3[C@@H:25]2[CH2:24][CH2:23]1)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a stirred solution of 2-dimethylaminoethylamine (19.40 mg, 24:1, 0.22 mmol) and triethylamine (310 μl, 2.23 mmol) in dichloromethane (3 ml) at room temperature was slowly added a solution of cholesteryl chloroformate (100 mg, 0.22 mmol) in 1,4-dioxane. When the reaction was completed, the mixture was evaporated to dryness and the residue was purified by flash chromatography (CHCl3/MeOH, 4:1). A white solid was obtained, yield 105 mg (95%). The structure was verified by NMR and MALDI.
Reaction SMILES: CO.[Na].[CH3:4][SH:5].Br[C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]>O>[CH3:4][S:5][C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]
Reactant: CC(C)C(=O)C(C)(C)Br
Reactant: CS
Agent: [Na]
Solvent: CO
Solvent: O
Product: CSC(C)(C)C(=O)C(C)C

Procedure:
A solution of 200 ml. of methanol containing 9.2 g. (0.40 mole) sodium metal was cooled in an ice-bath and saturated with gaseous methyl mercaptan. To this was added 77.2 g. (0.40 mole) of 2-bromo-2,4-dimethylpentan-3-one at room temperature and the resulting mixture stirred for two hours. The reaction mixture was diluted with water, extracted with ethyl ether, the extracts washed with water, brine and dried over anhdyrous sodium sulfate. The ether was evaporated and the residue distilled in vacuo to afford 50.4 g. of product, B.P. 76° (20 mm.).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:9].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:12]>[OH-].[Na+]>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:11]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:9])=[O:12]
Reactant: O=C1CCCCCN1
Reactant: O
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1Cl
Temperature: 25 °C

Procedure:
1 g (8.8 mmol) of ε-caprolactam was dissolved in 3.88 g of 20 wt % NaOH solution and heated to reflux for 3-5 hours. After ε-caprolactam was hydrolyzed completely, the mixture was cooled down to 5˜10° C. and 5 g of water was added. 1.8 g (8.8 mmol) of 2-chlorobenzyl chloroformate was added dropwise. The mixture was stirred at room temperature for an hour and washed with 15 g of ethyl acetate twice. The pH of the aqueous layer was adjusted to 1-2 by adding 16% HCl and extracted with ethyl acetate twice. Combined ethyl acetate layer was washed with brine. The organic layer was dried by sodium sulfate and concentrated to obtain 6-(2-Chloro-benzyloxycarbonylamino)-hexanoic acid. Purity was 98.9%.
Reaction SMILES: CC1C=C(C=CC=1)C(C1C=CC=CC=1)=[O:6].C(N1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:33]=2)=N1)C1C=CC=CC=1>>[C:25]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:38]([OH:40])=[O:39])(=[O:6])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:25]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])(=[O:6])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1
Reactant: CCOC(=O)c1cccc(-c2nn(Cc3ccccc3)c3ccccc23)c1
Product: CCOC(=O)c1cccc(C(=O)c2ccccc2)c1
Product: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Yield: 72 %
Yield: 86.3 %

Procedure:
3-Methylbenzophenone was treated sequentially with the procedures (a), (b), (c), and (d) in Example 18 to obtain, in the corresponding order, 3-benzoylbenzoic acid (yield: 72%), ethyl 3-benzoylbenzoate (yield: 86.3%), and 1-benzyl-3-(3′-ethoxycarbonylphenyl)indazole in a yield of 25.5%.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH:15]([NH2:17])[CH3:16].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH:15]([NH:17][C:3](=[O:4])[CH:2]([F:6])[F:1])[CH3:16]
Reactant: CC(N)c1ccc(F)cc1Br
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C(F)F)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
Add difluoroacetic acid (777 mg, 8.1 mmol) to a mixture of 1-(2-bromo-4-fluorophenyl)ethanamine (1.18 g, 5.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.55 g, 8.1 mmol), 1-hydroxybenzotriazole hydrate (1.24 g, 8.1 mmol), and triethylamine (2.26 mL, 16.2 mmol) in DCM (20 mL) at 0° C. Stir the mixture at RT overnight. Dilute the mixture with DCM, wash with water and aqueous saturated sodium chloride. Separate the organic layer and dry over sodium sulfate. Filter and concentrate in vacuo. Purify the residue by column chromatography [5% to 50% ethyl acetate in hexanes] to give the title compound (1.06 g, 44%). MS (ES) m/z 296 [M+1]+.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@:43]([CH2:52][CH2:53]OS(C)(=O)=O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:40].C(N(CC)CC)C>C(#N)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@@:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([CH2:52][CH2:53][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]4[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:42]1)=[O:40]
Reactant: FC(F)(F)CCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CCCC(F)(F)F)CC2)(c2ccccc2)C1
Yield: 106.2 %

Procedure:
Reflux a solution of 2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole dihydroiodide (0.65 g, 1.12 immol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.50 g, 1.06 mmol, example 47.2), triethylamine (3.58 mmol) and acetonitrile (15 mL) for 20 hours. Cool and concentrate in vacuo. Dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 solution (3×30 mL), dry (Na2SO4) the organic phase, filter and evaporate. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane and concentrate the appropriate fractions to afford 0.79 g of the title compound as a cream colored foam, Rf=0.46 (silica gel, 1.0% methanol/0.1% ammonium hydroxide solution in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]3)=[CH:19][CH:18]=1
Reactant: CN1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCc2c(-c3ccc(Cl)cc3)ccc([N+](=O)[O-])c2C1

Procedure:
A mixture of 5-bromo-N-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline (4.07 g, 15 mmol), 4-chlorophenylboronic acid (3.5 g, 22.5 mmol), sodium carbonate (8.0 g, 75.5 mmol), 1,2-dimethoxyethane (60 ml), water (30 ml) and tetrakis(triphenyl-phosphine)palladium(0) (0.20 g, 0.17 mmol) was stirred at reflux for 3.5 h. Water (50 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The crude mixture was recrystallized from ethanol (96%). Yield 3.62 g (80%). Mp 162-163° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH2:56]([O:58][C:59](=[O:71])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[NH2:61])[CH3:57]>CS(C)=O>[CH2:56]([O:58][C:59](=[O:71])[C@@H:60]([NH:61][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[N:9][C:10]=2[CH:15]=1)=[O:17])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[CH3:57]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
The carboxylic acid of example 2 (0.060 g, 0.20 mmol) and TBTU (1.3 equiv., 0.26 mmol, 0.084 g) were dissolved in DMSO (0.6 mL) and DIEA (5 equiv., 1.0 mmol, 0.18 mL) was added followed by (S)-4-cyanophenylalanine ethyl ester hydrochloride (1.3 equiv., 0.26 mmol, 0.065 g). The mixture was stirred at room temperature for 1 h and quenched with water. The precipitated solid was collected by filtration, washed with water and dried. The title amide (0.081 g) was obtained as a beige solid.
Reaction SMILES: [F:1][C:2]1([C:15]([O:17]CC)=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:20](=[N:23]O)([NH2:22])[CH3:21].C[O-].[Na+]>O1CCCC1>[F:1][C:2]1([C:15]2[O:17][N:23]=[C:20]([CH3:21])[N:22]=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]1
Reactant: CCOC(=O)C1(F)CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(N)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2(F)CCCN(C(=O)OC(C)(C)C)C2)n1

Procedure:
The mixture of 1-tert-butyl 3-ethyl 3-fluoropiperidine-1,3-dicarboxylate 33 and 1a,b (0.8 g, 0.0029 mol) and acetamide oxime (0.54 g, 0.0073 mol) were dissolved in 30 mL tetrahydrofuran. Sodium methoxide (0.79 g, 0.0146 mol) was added and the mixture was heated at reflux for 1.75 hours. The mixture was concentrated and partitioned between water (25 mL) and ethyl acetate (1×100 mL). The aqueous layer was extracted with an additional 50 mL ethyl acetate. The combined organics were washed with 1×25 mL water, 1×40 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to an oil. The residue was chromatographed to remove 1a,b with 15 g silica gel, 100% dichloromethane to 5% ethyl acetate/dichloromethane, to obtain 0.18 g of clear colorless oil. MS (ESI) m/z 324 [M+K]+. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.55-62 (m, 1H), 1.70-1.74 (d, 1H), 1.92-1.95 (m, 1H), 2.17 (m. 1H), 2.29-2.32 (m, 1H), 2.43 (s, 3H), 3.06-3.12 (m, 1H), 3.89-3.92 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]=1.[Br:18]Br.C(N(CC)CC)C>C(OCC)(=O)C>[NH2:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]1[Br:18]
Reactant: COc1ccc2c(c1)C(CCCN)=CCO2
Reactant: BrBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=CCCN)C(Br)CO2

Procedure:
To a suspension of 20 g of 4-(3-aminopropyl)-6-methoxy-2H-[1]-benzopyran hydrochloride in 200 ml of ethyl acetate is added 12.5 g of bromine at room temperature. After 15 minutes at room temperature 24 g of triethylamine is added to yield 4-(3-aminopropylidene)-3-bromo-6-methoxy-2H-[1]-benzopyran and the reaction mixture is refluxed for 2 hours. After washing with water and drying the solvent is removed in vacuo. The residue is dissolved in ethanol and acidified with ethanolic hydrogen chloride to afford 9-methoxy-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 285°-286°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccnc2)cc1
Temperature: 135 °C
Yield: 32.3 %

Procedure:
3-hydroxypyridine (6.17 g, 64.87 mmol) was dissolved in 100 mL of anhydrous DMF under argon atmosphere. Solid K2CO3 (8.96 g, 64.87 mmol) was added, followed by neat methyl 4-fluorobenzoate (10.0 g, 64.87 mmol). The reaction mixture was heated at 135° C. for 10 hrs. The absence of the starting material was confirmed by LC/MS. The reaction mixture was cooled down to ambient temperature and poured into ca. 500 mL of H2O. The resulting solution was extracted 3 times with ca. 150 mL of EtOAc (during the extraction small volumes of MeOH, Et2O and brine were added to facilitate the separation). Combined EtOAc layers were washed twice with sat. NaHCO3, twice with brine and dried over anhydrous Na2SO4. Solvent was removed in vacuo to give dark-red oil, which was purified by silica gel chromatography using 1:1 mixture of EtOAc/Hexane as eluent to give the title product (4.8 g, 32.3% yield) as yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.C(OC(N[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=O)(C)(C)C.[C:33](=O)([O-])[O-:34].[K+].[K+]>O1CCOCC1.O.[Pd]>[CH3:33][O:34][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)nc(SC)nc1-c1ccc(OC)cc1

Procedure:
A 20 mL reaction vessel was charged with ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.00 g, 4.06 mmol), 4-(tert-butoxycarbonylamino)phenylboronic acid (1.00 g, 4.22 mmol), and tetrakis(triphenyl)phosphine)palladium(0) (0.17 g, 0.15 mmol) in 10 mL dioxane. The reaction mixture was purged with N2 for 25 minutes with stirring. To the mixture was added potassium carbonate (1.17 g, 8.44 mmol) in 4 mL H2O. The biphasic mixture was purged with N2 for 10 minutes. The mixture was stirred at 90° C. for 14 hours. The mixture was diluted with EtOAc, and washed with H2O. The separated organic layer was dried over Na2SO4. The solvents were removed by a rotavapor yielding brown oily residue. The residue was purified by silica gel chromatography using a gradient 0-5% MeOH in dichloromethane providing white solid (1.12 g, 68%). MS m/z: 319 (M+1)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].C1(C)C=CC=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)C)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Yield: 44 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (500 mg, 1.57 mmol) in 4 mL of CH2Cl2 was added at 0° C. 4-dimethylaminopyridine (250 mg, 2.04 mmol), followed by isopropyl chloroformate (1.7 mL of a 1M toluene solution). After 16 hr the reaction was diluted with CH2Cl2 and washed with 1M H3PO4. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (2:1, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(methylethoxycarbonyl)pyrrolidine as a white solid (280 mg, 44%). Anal. Calcd for C22H29NO6 : C, 65.17; H, 7.71; N, 3.45. Found: C, 65.16; H, 7.69; N, 3.43.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].O=[CH:30][CH2:31][NH:32]C(=O)OC(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl.Cl.O1CCOCC1.CCOCC>>[NH2:32][CH2:31][CH2:30][N:26]1[CH2:25][CH:24]=[C:23]([C:20]2[C:15]3[CH:16]=[N:17][C:18]([NH2:19])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[C:14]=3[O:22][CH:21]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(CCN)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (35.0 mg, 0.0829 mmol), tert-butyl N-(2-oxoethyl)carbamate (26.4 mg, 0.166 mmol), sodium triacetoxyborohydride (19.3 mg, 0.0912 mmol) and DCM (3 mL, 50 mmol) was stirred at rt for 30 min. The solution was transferred to a separatory funnel and extracted with DCM and sat. NaHCO3. The organic layer was concentrated in vacuo, redissolved in 1,4-dioxane and transferred to a sealed tube. 4 M of HCl in 1,4-Dioxane (0.5 mL, 2 mmol) was added, and the mixture was heated to 50° C. for 2 h. The solution was concentrated in vacuo, redissolved in DCM and transferred to a separatory funnel. The organic layer was washed with sat. NaHCO3, concentrated in vacuo, and loaded onto a prep TLC plate, eluting with 7% (7N NH3 in MeOH)/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM. To the filtrate was added 2.0 M of HCl in Et2O (0.207 mL, 0.414 mmol) to form the HCl salt, and the mixture was stirred for 30 min at rt. The material was concentrated in vacuo to afford the title compound as bis-HCl salt. 1H NMR (CD3OD, 400 MHz): δ=1.88 (d, J=6.8 Hz, 3H), 2.56 (d, J=1.5 Hz, 2H), 2.79 (ddd, J=19.3, 5.8, 5.7 Hz, 4H), 3.12 (t, J=5.9 Hz, 2H), 3.28 (d, J=2.5 Hz, 2H), 6.27 (br, s, 1H), 6.50 (q, J=6.8 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H), 8.17 (s, 1H). MS (ES+): m/z 465.04 [MH+]. HPLC: tR=2.43 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]=O)=[CH:11][CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:37])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:37])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[CH:10][CH:11]=3)[NH:6][C:5]=2[C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:28][CH:27]=1
Reactant: CC(C)(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1CC=O
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc([N+](=O)[O-])ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a solution of (2-tert-butyl-6-nitro-1H-indol-3-yl)-acetaldehyde (0.74 g, 2.8 mmol) in tetrahydrofuran (20 mL) was added (E)-3-(4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester hydrochloride (0.91 g, 3.4 mmol) and triethylamine (871 μL, 6.26 mmol). The resulting mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (0.88 g, 4.0 mmol) was added. The mixture was stirred at room temperature for 16 h, diluted with ethyl acetate, and washed with a saturated sodium bicarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography to give the title compound (0.77 g, 57%). LCMS (m/z): 476.2539 (M+1).