Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.[CH3:16][C:17]([CH3:20])([O-])[CH3:18].[K+].BrCC(C)=C>C(OCC)C.CCCCCC>[CH3:18][C:17]([CH2:20][CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:16]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc2ccccc2[nH]1
Agent: C=C(C)CBr
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C(C)CCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 47 %

Procedure:
To a stirred solution of 2-methylindole (1 g) in diethylether (76 ml) under nitrogen was added a 1.6M solution of n-butyllithium in hexane (14.3 ml) slowly dropwise via syringe. Potassium tert-butoxide (1.711 g) was then added, producing a bright yellow mixture. After stirring at room temperature under nitrogen for 50 min., the mixture was cooled to -78° C., whereupon 3-bromo-2-methylpropene (1.54 ml) was added dropwise via syringe, giving a red-orange solution. The reaction mixture was stirred at -780° C. for 2 h, then quenched with water (10 ml). After warming to room temperature, water (150 ml) and 1N HCl (1 ml) was added to neutralize the reaction mixture. The mixture was extracted with ethyl acetate (250 ml), and the organic layer was washed with brine (100 ml) and dried with sodium sulfate. The solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography (4-ethyl acetate/hexane) to afford 2-(2-methyl-1-butene-4-yl) indole (664 mg. 47%) as a waxy yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:40])([CH3:39])[O:6][CH2:7][C@H:8]1[O:13][C@:12]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH2:23][C:24]3[S:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:27][CH:28]=3)[CH:17]=2)([O:14][CH3:15])[C@H:11]([OH:36])[C@@H:10]([OH:37])[C@@H:9]1[OH:38])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[CH2:43]([O:38][C@H:9]1[C@H:10]([O:37][CH2:26][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:11]([O:36][CH2:12][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@:12]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH2:23][C:24]3[S:25][C:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[CH:17]=2)([O:14][CH3:15])[O:13][C@@H:8]1[CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:39])[CH3:40])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: BrCc1ccccc1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 198.5 %

Procedure:
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 9e (2.0 g, 3.4 mmol) was dissolved in 20 mL DMF and cooled to 0° C., followed by addition of 60% NaH (680 mg, 17 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes. Thereafter, benzyl bromide (2.0 mL, 17 mmol) was added before the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure after 10 mL methanol were added and was partitioned after 30 mL ethyl acetate and 30 mL water were added. The aqueous phase was extracted with ethyl acetate (20 mL×3) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 9f (2.9 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Se](=O)=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH:13]=[O:15])[CH:7]=[CH:6]2
Reactant: O=[Se]=O
Reactant: COc1ccc2nc(C)ccc2c1
Product: COc1ccc2nc(C=O)ccc2c1
Yield: 68 %

Procedure:
The title compound was prepared from 6-methoxy-2-methylquinoline (6g) and selenium dioxide using methods as described in the literature for similar compounds (Mathes et al., 1957) in 68% yield.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([O:9][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:8]
Reactant: CC(O)c1ccsc1Br
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOC(C)c1ccsc1Br
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 2-bromo-3-(l-hydroxyethyl)thiophene (97.5 g, 0.47 mol) in dry methylene chloride (400 ml) was cooled in ice and N,N-diisopropylethylamine (68.2 g, 0.517 mol) was added followed by methoxyethoxymethYl chloride (64.4 g, 0.517 mol). The solution was stirred at room temperature over night. The dark solution was washed with water, 3N HCl, saturated NaHCO3 and finally with water. The solution was dried over anhydrous Na2SO4 filtered and concentrated in vacuo at room temperature. A dark amber oil was obtained (123.1 g). The impure product was distilled and the product was collected at 108-116° C. at 0.7 mm Hg. to give 91.1 g (66%) of colorless liquid. NMR supported the structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:14])=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:3]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:14])=[C:9]([NH:13][C:31](=[O:32])[C:30]([CH3:34])([CH3:35])[CH2:29][CH2:28][CH2:27][O:26][C:25]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:24]=3[CH3:23])[CH:10]=[CH:11][CH:12]=2)=[N:3]1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Reactant: Cc1c(N)cccc1C1=NC(C)(C)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(C3=NC(C)(C)CO3)c2C)c1
Yield: 59.6 %

Procedure:
To a solution of 10.2 g (0.05 mol) of 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylbenzenamine and 10 ml of triethylamine in dichloromethane is added 13.4 g (0.05 mol) of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride (U.S. Pat. No. 4,285,951). The mixture is worked up, chromatographed over silica gel and eluted with toluene-diethyl ether (2:1) to give 13 g of N-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylphenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide; mp 51°-52° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26](CC4OCCO4)[CH:25]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:36]([F:39])([F:38])[F:37])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C[C:58](C)=[O:59]>>[CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[CH:58]=[O:59])=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:36]([F:37])([F:38])[F:39])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cccc2c(-c3ccc(Oc4cccc(CC5OCCO5)c4)cc3)n(Cc3ccccc3)nc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=Cc1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1

Procedure:
2-benzyl-3-[4-(3-[1,3]dioxolan-2-ylmethyl-phenoxy)-phenyl]-7-trifluoromethyl-2H-indazole (14 mg, 0.0264 mmol) was treated with 6.6 mg PPTS in 1.5 ml acetone under reflux for 2 hrs. The reaction mixture was extracted with NaHCO3 and CH2Cl2. The combined organic phases were dried, evaporated and the crude material was purified on a chromatotron using a gradient changing from 1:99 (EtOAc/heptane) to 3:7 (EtOAc/heptane) to afford 5 mg of analytically pure product.
Reaction SMILES: FC(F)(C(F)(F)C(F)(F)C(F)F)COC(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F.FC(F)(C(F)(F)C(F)(F)C(F)F)C[NH:34][C:35](=[O:62])[O:36][CH2:37][CH:38]1[CH:43]=[CH:42][CH2:41][CH:40]([CH2:44][O:45][C:46](=[O:61])[NH:47]CC(F)(F)C(F)(F)C(F)(F)C(F)F)[CH2:39]1>>[C:46](=[O:61])([O:45][CH2:44][CH:40]1[CH:41]=[CH:42][CH2:43][CH:38]([CH2:37][O:36][C:35](=[O:62])[NH2:34])[CH2:39]1)[NH2:47]
Reactant: O=C(NCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC1C=CCC(COC(=O)NCC(F)(F)C(F)(F)C(F)(F)C(F)F)C1
Agent: O=C(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Product: NC(=O)OCC1C=CCC(COC(N)=O)C1
Yield: 98 %

Procedure:
The reaction was carried out in the same manner as Example 7 except for using 80.5 g (0.1642 mol) of bis(2,2,3,3,4,4,5,5-octafluoropentyl)carbonate (to be referred to as “BOFC” hereinafter) synthesized in the above Synthesis Example 4 in place of BTFC, and it was confirmed that tetrahydro-m-xylylene bis(2,2,3,3,4,4,5,5-octafluoropentyl carbamate) (to be referred to as H-XDC-4 hereinafter) was generated as the main product (H-XDA base yield 98.0%). Structural assignment of the product H-XDC-4 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of H-XDC-4, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1.N([O-])=[O:23].[Na+].NC(N)=O>CC(O)=O.O>[OH:23][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
Concentrated sulfuric acid (17 ml) was added slowly to a solution of 7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (4.6 g, 0.016 mol) in HOAc (50 ml). The reaction mixture was cooled to 0° C. and a solution of NaNO2 (1.52 g, 0.022 mol) in water (10 ml) was added dropwise. The reaction mixture was stirred for a further 20 min at 0° C. prior to the addition of urea (0.55 g, 0.009 mol) and cold water (50 ml). The reaction mixture was then added carefully to a refluxing mixture of sulfuric acid (28 ml) in water (115 ml) and the reaction was stirred for a further 10 min at reflux before being allowed to cool to RT. Upon standing, an orange precipitate was observed, which was collected by filtration and washed with water to give the title compound (4.22 g, 93% yield) as an orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:13])([CH3:12])[CH:8]=[CH:7]2.CO.C(=O)([O-])[O-:23].[K+].[K+]>[Pd](Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]2=[O:23]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)c1cc(Cl)c2c(c1)C=CC(C)(C)N2
Agent: Cl[Pd]Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C)c1cc(Cl)c2c(c1)C(=O)CC(C)(C)N2
Reaction time: 6 h
Yield: 28.4 %

Procedure:
1.0 g of methyl 2-(8-chloro-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate was added to 20 ml of methanol. 2.0 g of palladium chloride was further added to the solution, and the mixture was stirred at 55°-60° C. for 6 hours. After cooling, 2 g of potassium carbonate and benzene were added to the mixture, then the mixture was further stirred. The precipitates were filtered off and washed with benzene. The filtrate and the wash were combined and concentrated, followed by addition of dilute aqueous solution of sodium hydrogencarbonate, and extraction with ether. The ethereal solution was washed with water, saturated aqueous solution of sodium sulfate and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (benzene:ether=9:1) to give 0.3 g of methyl 2-(8-chloro-1,2,3,4-tetrahydro-2,2-dimethyl-4-oxoquinolin-6-yl)propionate (Compound 31).
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([CH2:28][CH2:29][CH2:30][CH:31]2[NH2:34])=[CH:26][CH:25]=1>>[CH2:1]([C:3]1[C:4]([NH:34][CH:31]2[C:32]3[C:27](=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:33]=3)[CH2:28][CH2:29][CH2:30]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: COc1ccc2c(c1)C(N)CCC2
Product: CCc1cnc(CC)c(NC2CCCc3ccc(OC)cc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.67, 7.08, 6.92, 6.81, 5.42, 4.54, 3.75, 2.84–2.77, 2.68, 2.56, 2.10, 1.88, 1.36–1.27; (MS/CI) calcd for C19H25N3O+H 312.4, found 312.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20](OCC)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:11][CH:10]=1.C(O)C>C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([C:20]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)cc2)s1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1
Temperature: 92.5 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Piperidine (1.84 g, 21.63 mmol) was added to a stirred solution of ethyl 5-(4-methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to the procedure reported in WO 2006/089076, 0.6 g, 2.16 mmol) in a ethanol (10 ml) in a tube at 25° C. under nitrogen atmosphere. The tube was agitated for about 15 minutes under nitrogen and was sealed. The reaction mixture was heated at 90-95° C. for 15 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and was concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate (50 ml). The mixture was washed with saturated sodium bicarbonate solution (20 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.50 g, 73.0%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)C#N)=[C:6]2[C:5](=[O:24])[N:4]([CH3:25])[C:3]1=[O:26])[CH2:12][CH2:11][CH2:10][C:9]3=[O:23].BrC1C=CC=C([F:34])C=1>>[F:34][C:17]1[CH:16]=[C:15]([C:14]2[N:13]3[C:8]([C:9](=[O:23])[CH2:10][CH2:11][CH2:12]3)=[C:7]3[N:2]([CH3:1])[C:3](=[O:26])[N:4]([CH3:25])[C:5](=[O:24])[C:6]=23)[CH:22]=[CH:21][CH:20]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Reactant: Fc1cccc(Br)c1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(=O)CCC3

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4,10-trioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (Example 9 steps 1-7) by replacing 3-bromobenzonitrile (step 3) with 1-bromo-3-fluorobenzene (commercially available).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH2:49][O:50][CH3:51])=[CH:47][C:39]([O:40][CH2:41][C:42]2([CH3:46])[CH2:45][O:44][CH2:43]2)=[CH:38][C:37]=1[CH2:52][O:53][CH3:54].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:54][O:53][CH2:52][C:37]1[CH:38]=[C:39]([O:40][CH2:41][C:42]2([CH3:46])[CH2:45][O:44][CH2:43]2)[CH:47]=[C:48]([CH2:49][O:50][CH3:51])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: COCc1cc(OCC2(C)COC2)cc(COC)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COCc1cc(OCC2(C)COC2)cc(COC)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)OC

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 3-((4-bromo-3,5-bis(methoxymethyl)phenoxy)methyl)-3-methyloxetane following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.72 min; Mass spectrum (ESI+): m/z=607 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1CN.Cl[C:11]1[NH:12]C2C=C(OC)C=CC=2[N:15]=1>C(Cl)Cl>[N:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[NH:12][C:11]=1[NH2:15]
Reactant: COc1ccc2nc(Cl)[nH]c2c1
Reactant: NCc1ccccc1N
Solvent: ClCCl
Product: Nc1nc2ccccc2[nH]1
Temperature: 120 °C

Procedure:
A mixture of 2-aminobenzylamine (500 mg, 4.1 mmol) and 2-chloro-5-methoxybenzoimidazole (210 mg, 1.2 mmol) was heated at 120° C. for 18 h. The resulting oily residue was dissolved in CH2Cl2 (30 mL) and washed with H2O (30 mL). The organic layer was separated, dried over Na2SO4, and concentrated to provide crude benzimidazole amine as a solid which was treated with CDI (1.0 g, 6.0 mmol) in anhydrous DMF (15 mL). After stirring at RT for 18 h, the reaction mixture was concentrated. The residue was purified by prep TLC to give an oil which was triturated from CH2Cl2 and hexane to yield a solid. Further purification by prep HPLC provided the title compound as white solid. MS m/z: 295 (M+H+); MALDI FTMS (DHB) m/z: 295.1184 (M+H; Calc'd for C16H15N4O2, 295.1189).
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[C:1]1([S:7][CH2:8][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCSc1ccccc1
Product: CCOP(=O)(CSc1ccccc1)OCC
Yield: 93.9 %

Procedure:
A stirred solution of 40.0 grams (0.25 mole) of phenylthiomethyl chloride and 58.2 grams (0.35 mole) of triethylphosphite was heated at 150°-160° C. for 4 hours, cooled and excess triethylphosphite removed by evaporation under reduced pressure. The residue was purified by distillation to give 61.1 grams (93.1%) of diethyl phenylthiomethylphosphonate; b.p. 155° C./0.6 mm. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].O1CCOCC1.C(=O)([O-])O.[Na+].[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[CH3:32][N:33]([CH3:38])[S:34]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:20])[CH2:4]1)(=[O:36])=[O:35]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: C[C@@H]1CCNC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCN(S(=O)(=O)N(C)C)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a solution of rel-1-[(3R,4R)-4-methylpiperidin-3-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (80 mg), dioxane (1.6 mL) and 4M saturated aqueous sodium hydrogencarbonate (2.4 mL) was added dimethylsulfamoyl chloride (51 mg) at ambient temperature. The mixture was stirred for 2 hours then chloroform (8 mL) was added. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give rel-(3R,4R)—N,N,4-trimethyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidine-1-sulfonamide (41 mg) as a colorless solid.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([SH:15])=[N:12][N:11]=2)=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[C:7]([C:10]2[O:14][C:13]([S:15][CH3:1])=[N:12][N:11]=2)=[CH:8][N:9]=1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(S)o1
Reactant: CI
Solvent: CO
Product: CSc1nnc(-c2cnc(Cl)cc2NC(C)C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (22 mmol, 2 equiv.) was added to a solution of 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-thiol (42) (1.5 g, 5.5 mmol) in MeOH (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by column chromatography through silica gel and MeOH:DCM as eluent to furnish the desired compound, 2-chloro-N-isopropyl-5-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyridin-4-amine (43). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.994 min; LCMS (ES-API), m/z 285.1 (M+H).
Reaction SMILES: CCN(CC)CC.[CH2:8]([O:10][C:11](=[O:36])[CH2:12][CH2:13][NH:14][C:15]([C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])=[CH:19][CH:18]=1)=[O:16])[CH3:9].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:25]([C:24]3[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:35])[F:33])=[CH:31][C:23]=3[C:20]3[CH:19]=[CH:18][C:17]([C:15]([NH:14][CH2:13][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:36])=[O:16])=[N:22][CH:21]=3)=[O:26])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Temperature: 25 °C

Procedure:
Neat Et3N (0.28 mL, 2.0 mmol) was added to a DCM mixture (3 mL) of 2-(6-((3-ethoxy-3-oxopropyl)carbamoyl)pyridin-3-yl)-4-(trifluoromethyl)benzoic acid (˜40% pure) (616 mg, 0.6 mmol), 4′-chloro-2′-methyl-[1,1′-biphenyl]-4-amine (109 mg, 0.5 mmol), and EDCI (383 mg, 2.0 mmol) and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture was directly purified via column chromatography to yield the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[Br:16]Br.Cl>O.C(OCC)C>[Br:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][C:5]2=[O:15]
Reactant: BrBr
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: O=C1CCCc2c(Br)cccc21
Temperature: 80 °C

Procedure:
2.21 g of AlCl3 are placed in a round-bottomed flask, to which 0.91 ml of 3,4-dihydro-2H-naphth-1-one is added over 10 min and 0.41 ml of Br2 is added over 5 min, and the mixture is heated at 80° C. for 10 min. It is allowed to return to ambient temperature and a solution comprising 20 g of ice and 2.7 ml of concentrated hydrochloric acid is added thereto. The mixture is then diluted with water and diethyl ether. The organic phase is subsequently separated, dried and concentrated under reduced pressure. The residue is purified by reverse phase preparative chromatography. 172 mg of compound are obtained.