Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([S:35][CH2:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])=[CH:22][C:21]=2[O:38][CH3:39])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:36]([S:35][C:31]1[CH:30]=[C:29]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH:17]3[CH2:18][CH2:19][NH:15][CH2:16]3)=[C:21]([O:38][CH3:39])[CH:22]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1)[CH3:37]
Reactant: CCSc1cccc(S(=O)(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)C3)c(OC)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCSc1cccc(S(=O)(=O)c2ccc(C3CCNC3)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 3-[4-(3-ethylsulfanyl-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.1256 mmol) in DCM (3 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between NaOH (2 M) and DCM. The organic layer was separated and washed with water, dried over Na2SO4, and evaporated under reduced pressure, affording 3-[4-(3-ethylsulfanyl-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine, which was transformed in the corresponding hydrochloride (white foam, 53 mg) by addition of a small excess of HCl in 1,4-dioxane. MS (M+H)=378.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:21]2[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:14](=[O:24])[C:13]=1C.Cl[CH2:27][C@H:28]1[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]1>CN(C=O)C>[CH3:33][C:30]1([CH3:34])[O:29][C@@H:28]([CH2:27][N:19]2[C:20](=[O:22])[C:21]3[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=4[F:3])=[CH:13][C:14](=[O:24])[N:15]([CH3:23])[C:16]=3[N:17]=[CH:18]2)[CH2:32][O:31]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H]3COC(C)(C)O3)cnc21
Reaction time: 0.17 h

Procedure:
Sodium hydride (89 mg, 4.7 mmol, 5 eq) was stirred in anhydrous DMF (1 mL) for 10 minutes. 5-(2-Fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (400 mg, 0.94 mmol, 1 eq) in anhydrous DMF (400 μL) was added and the mixture stirred for 10 minutes. (R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (260 μl, 1.88 mmol, 2 eq) was added and the mixture subjected to microwave irradiation at 150° C. for 35 minutes. The solvent was removed in vacuo and the residue purified by HPLC. 1H NMR (400 MHz, MeOD) δ ppm 1.37 (s, 3 H) 1.47 (s, 3 H) 3.70 (s, 3 H) 3.85 (dd, J=8.97, 5.68 Hz, 1 H) 4.13 (dd, J=13.89, 7.07 Hz, 1 H) 4.20 (dd, J=8.72, 6.69 Hz, 1 H) 4.38 (dd, J=13.89, 3.03 Hz, 1 H) 4.50-4.59 (m, 1 H) 5.81 (s, 1 H) 7.36 (t, J=8.21 Hz, 1 H) 7.62-7.74 (m, 2 H) 8.49 (s, 1 H). [M+H] calc'd for C20H20FIN4O4, 527; found, 527.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:19][C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[N:17][CH:16]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)c(F)c1

Procedure:
3,4-Difluoronitrobenzene (5.0 g, 32 mmol) and 5-chloro-3-pyridinol were combined using the procedure described in Example 1, to produce 8.2 g of the title compound.
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:11]=1[CH:12]=[O:13].Cl>C(COC)OC.[F-].[Cs+]>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:11]=1[CH:12]([OH:13])[C:3]([F:6])([F:5])[F:4]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC(c1c(Cl)cccc1Cl)C(F)(F)F
Temperature: 15 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Add 1.75 g of trimethyl(trifluoromethyl)silane to a solution of 2.1 g of 2,6-dichlorobenzaldehyde in 60 cm3 of dimethoxyethane. The reaction mixture becomes clear with a yellow sheen; it is then cooled on a water/ice bath to about 15° C. Add 0.055 g of caesium fluoride in one go. Stir for 4 hours at a temperature close to 20° C. The reaction mixture is then poured into 7.2 cm3 of a 4N aqueous solution of hydrochloric acid. The aqueous phase is decanted then extracted three times with 40 cm3 of diethyl oxide. The organic phases are combined and then dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). We obtain 2.9 g of 1-(2,6-dichlorophenyl)-2,2,2-trifluoroethanol in the form of an oil with a yellow sheen, which has the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][C@H:20]([NH:25][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:19]2.CN(C)CC(O)=O>CS(C)=O.C(OCC)(=O)C.[Cu-]=O>[CH3:1][C:2]1[C:7]([O:8][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][C@H:20]([NH:25][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[CH2:19]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Br)cc2C1
Reactant: Cc1ncccc1O
Agent: O=[Cu-]
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ncccc1Oc1ccc2c(c1)C[C@@H](NS(=O)(=O)C(C)C)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.6 %

Procedure:
A mixture of 2-methyl-3-pyridinol (8.57 g, 79 mmol), cesium carbonate (51.2 g, 157 mmol) and copper (I) oxide (11.24 g, 79 mmol) in dimethyl sulfoxide (250 mL) was stirred for 5 minutes at room temperature. N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (25 g, 79 mmol, Description 1) was added followed by N,N-dimethylglycine (8.10 g, 79 mmol). The reaction was heated at 130° C. overnight. The reaction was allowed to reach room temperature and diluted with ethyl acetate (500 ml) then filtered through celite washing with ethyl acetate. The organic phase was washed with water (2×500 ml), dried over Na2SO4 and concentrated in vacuo. This material was purified using Biotage 75 L eluting with cyclohexane/ethyl acetate 2/8 to give N-{(2S)-5-[(2-methyl-3-pyridinyl)oxy]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide (free base, 18.5 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:16]=[C:17](/[C:21](/[CH3:25])=[CH:22]/[CH2:23]O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>ClCCl>[Cl:1][CH2:23]/[CH:22]=[C:21](/[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)\[CH3:25]
Reactant: C/C(=C\CO)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: C/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) in dichloromethane (800 ml) at 0° C. was added dropwise over 1 h dimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwise over 30 min at 0° C. a solution of (E)-3-(3-nitrophenyl)-2-buten-1-ol (Preparation 2, 72 g, 0.373 mol) in dichloromethane (200 ml). The mixture was warmed to room temperature over 1 h, then poured onto brine (500 ml). The layers were separated, and the aqueous layer extracted with ether (500 ml). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with 10:1 hexane/ethyl acetate, then as a gradient up to 4:1 hexane/ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow solid (69 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])[C:14]3[N:26](COCC[Si](C)(C)C)[CH:27]=[N:28][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])[C:14]3[NH:26][CH:27]=[N:28][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc3ncn(COCC[Si](C)(C)C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3nc[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC

Procedure:
Into the solution of (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.08 (200 mg, 0.39 mmol) in THF (5 mL), was added 1 M solution of TBAF in THF (3.9 mL, 3.9 mmol). After reflux for 12 h, the reaction mixture was taken up with ethyl acetate (150 mL) and washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to yield residues which were purified by silica gel column chromatography to isolate (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.09.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([O:22]CC)=O)[N:17]=[CH:16]1)[C@@H:12]([OH:14])[CH3:13].[OH-].[NH4+:26]>COCCOC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:26])=[O:22])[N:17]=[CH:16]1)[C@@H:12]([OH:14])[CH3:13]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cn([C@@H](CSc2cccc(Cl)c2Cl)[C@H](C)O)cn1
Agent: [OH-]
Solvent: COCCOC
Product: C[C@H](O)[C@H](CSc1cccc(Cl)c1Cl)n1cnc(C(N)=O)c1

Procedure:
A mixture of ethyl 1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxylate (0.17 g), 28% ammonium hydroxide (10 mL) and 1,2-dimethoxyethane (20 mL) was heated at 100° C. in the stainless steel bottle for 24 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution; 10:1 chloroform-1% ammonium hydroxide/methanol) to give the product, which was recrystallized from 1:1 n-hexane-ethyl acetate (10 mL) to give 1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxamide (104) (0.10 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[F:15])#[N:8].C([O-])([O-])=O.[K+].[K+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[F:15][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:10][C:9]=1[C:7]#[N:8]
Reactant: Brc1nccs1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2nccs2)ccc1F
Temperature: 85 °C
Yield: 70.3 %

Procedure:
A solution of 2-bromothiazole (25 g, 153.4 mmol), (3-cyano-4-fluorophenyl)boronic acid (25.3 g, 153.3 mmol), K2CO3 (63.6 g, 460 mmol) and 3:1 DME/H2O (205 mL) was purged with N2 for 1 h before the addition of Pd(PPh3)4 (9.2 g, 7.9 mmol). The mixture was further degassed with N2 for 5 min and then heated to 85° C. for 7 h under N2. Upon cooling, the reaction mixture was diluted with EA (250 mL), washed with water (200 mL) and brine (200 mL), and dried over MgSO4. The reaction mixture was filtered and concentrated to give beige solid. The crude product was purified by recrystallization from 20% EA/hexanes to afford 22 g (71%) of 2-fluoro-5-(thiazol-2-yl)benzonitrile THZ INT-1 as a pale yellow solid. LCMS-ESI (m/z) calculated for C10H5FN2S: 204.2; found 205.0 [M+H]+, tR=3.26 min. 1H NMR (400 MHz, CDCl3) δ 8.21-8.16 (m, 1H), 8.15-8.08 (m, 1H), 7.86-7.81 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.21 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 164.31, 162.22, 143.73, 132.68, 131.28, 128.34, 119.94, 116.98, 113.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17]
Reactant: COc1cccc(OC)c1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)c(OC)c1
Yield: 68 %

Procedure:
1,3-Dimethoxybenzene 10 h (99%, 6 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 19 h according to the general procedure. Recrystallization in EtOH gave white crystals of 11 h in 68% yield. 1H-NMR: 7.89 (d, 1H, J=8.7 Hz, Ar--H; 6.55 (dd, 1H, J=8.7 and 2.3 Hz, Ar--H); 6.46 (d, 1H, J=2.3 Hz, Ar--H); 3.91 (s, 3H, OCH3); 3.86 (s, 3H, OCH3); 3.30 (t, 2H, J=6.6 Hz, CH2CH2COOH); 2.73(t, 2H, J=6.6 Hz, CH2CH2COOH). 13C-NMR: 197.62; 164.79; 161.23; 132.96; 105.29; 98.31; 55.54; 55.47; 38.42; 28.67.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][NH:13][CH2:14][C:15]1[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[CH:18][N:19]=1.[CH:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)=[O:31]>>[CH:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:13]([CH2:14][C:15]2[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[CH:18][N:19]=2)[CH2:12][C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:28])[CH3:1])[CH:11]=[CH:10][N:9]=2)=[O:37])=[CH:34][CH:33]=1)=[O:31]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1CNCc1nccn1COCC[Si](C)(C)C
Product: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc(C=O)cc1

Procedure:
The same procedure as a series of reactions of Example 17 was carried out, except that the compound 2 was used in place of the compound 16 and 4-formylbenzoic acid was used in place of 1H-imidazole-2-carboxylic acid, to obtain the title compound having the following physical properties.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10](=[O:12])[CH3:11].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)NCc1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCc1nccn1COCC[Si](C)(C)C
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 0.08 g of sodium hydride (60% oily) was added to a solution of 0.31 g of N-(imidazol-2-ylmethyl)acetamide in N,N-dimethylformamide (10 ml). After stirring for 15 minutes, a solution of 0.35 ml of 2-(trimethylsilyl)ethoxymethyl chloride in N,N-dimethylformamide (1 ml) was dropped thereinto and the resulting mixture was stirred at room temperature for additional 16 hours. Then the reaction mixture was distributed into water and ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.16 g of the title compound as a colorless oily substance.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:11].C(=O)([O-])O.[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH3:11][C:4]1([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]#[N:19])[CH:5]2[CH:3]1[CH2:2][N:34]([CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]2=[O:8]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cccc(C#N)c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 100 °C
Yield: 39.1 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropanecarboxylate (Preparation 35, 170 mg, 0.62 mmol) in N,N-dimethylformamide (6.0 ml) at room temperature was added sodium hydrogen carbonate (52 mg, 0.62 mmol) followed by 3-phenylpropylamine (0.35 ml, 2.47 mmol). The mixture was heated at 100° C. for 6 h and under reflux for 5 h. After the mixture had cooled to room temperature, water (4 ml) was added and the aqueous layer was extracted with diethyl ether (3×4 ml). The combined ethereal extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by silica column chromatography eluting with a gradient of hexane:ethyl acetate (50:50 to 0:100) to afford the title compound (80 mg, 40%) as a colourless oil.
Reaction SMILES: B.C(N)(C)(C)C.[Cl-].[Cl-].[Cl-].[Al+3].O=[C:12]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C:14]2[S:24][CH:25]=[CH:26][C:13]1=2>C(Cl)Cl>[S:24]1[C:14]2[CH2:15][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18][CH2:12][C:13]=2[CH:26]=[CH:25]1
Reactant: CCOC(=O)N1CCC(=O)c2ccsc2C1
Agent: B
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)(C)N
Solvent: ClCCl
Product: CCOC(=O)N1CCCc2ccsc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Solid borane-t-butylamine pellets (2.77 g, 31.84 mmol) were crushed and suspended in methylene chloride (300 mL) at 0° C. Solid aluminum trichloride (2.12 g, 15.92 mmol) was added and the mixture was stirred for 1 hour. Compound 1043 (1.27 g, 5.31 mmol) was added slowly and the reaction mixture allowed to warm to room temperature overnight. The reaction was quenched by addition of ethanol (50 mL) then saturated ammonium chloride (100 mL). The mixture was brought to a neutral pH with saturated sodium bicarbonate, extracted with ethyl acetate (3×100 mL), and concentrated to give ethyl 5,6-dihydro-4H-thieno[2,3-c]azepine-7(8H)-carboxylate (Compound 1044) as a tan oil; 1H NMR (300 MHz, CDCl3): δ 6.95-6.85 (m, 1H), 6.70 (d, J=4.7 Hz, 1H), 4.49 (s, 2H), 4.18-4.00 (m, 2H), 3.66-3.58 (m, 2H), 2.77 (t, J=5.7 Hz, 2H), 1.62 (qn, J=6.0 Hz, 2H) and 1.24-1.08 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH3:28][CH2:29]O>O>[CH2:28]([O:15][C:14](=[O:16])[CH:13]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:29]
Reactant: O=C(O)C(c1ccccc1)c1c(O)c2ccccc2oc1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid in EtOH with a catalytic amount of conc. sulfuric acid was heated to reflux for 5 hours, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4 and conc. in vacuo to give (4-Hydroxy-2-oxo-2H-chromen-3-yl) -phenyl-acetic acid ethyl ester as colorless oil, which crystallize upon standing (910 mg). MS: 323[M−H].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:8](=[O:27])[C:7]3=[CH:28][N:29]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:5]([C:6]=23)=[N:4][CH:3]=1.[OH-:40].[Na+]>CO.C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[C@H:12]([NH:9][CH2:10][C:11]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[N:29]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:32])=[O:31])[CH:28]=[C:7]([C:8]([OH:40])=[O:27])[C:6]=12)[C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OCc2ccccc2)C(C)(C)C)C3=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OCc4ccccc4)C(C)(C)C)c(Cl)cnc32)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
Crude (R)-benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate was dissolved in MeOH/THF (50%, 5 mL). Aqueous NaOH (1N, 2 mL) was added. The reaction mixture was stirred at 50° C. for 16 h and was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (34 mg, 38.9% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 1.22-1.32 (m, 9 H) 4.92 (br. s., 1 H) 5.18 (d, J=18.95 Hz, 1 H) 5.33 (d, J=18.95 Hz, 1 H) 7.88 (s, 1 H) 8.29 (s, 1 H). [M+H] calc'd for C15H16ClN3O3, 322; found, 322.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])=[CH:28][CH:27]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Yield: 96.9 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.385 g (96% yield) of the title amide as white crystals; mp 166-167° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.14 (2H, t, J=9 Hz, CH2), 4.42 (1H, m, CH), 4.50 (2H, d, J=6.0 Hz, NCH2), 5.09 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.3-7.37 (3H, m, aromatics), 7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). Anal. Calcd for C24H25FN4O3: C, 66.04; H, 5.77, N 12.83. Found: C, 65.84; H, 5.85; N, 12.58.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:11][SiH:12]([CH3:17])[O:13][SiH:14]([CH3:16])[CH3:15]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:5]1([NH:4][CH2:1][CH2:2][CH2:3][Si:12]([CH3:17])([CH3:11])[O:13][Si:14]([CH2:3][CH2:2][CH2:1][NH:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)([CH3:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C[SiH](C)O[SiH](C)C
Reactant: C=CCNC1CCCCC1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: C[Si](C)(CCCNC1CCCCC1)O[Si](C)(C)CCCNC1CCCCC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Following the technique described in Example 1, N-allylcyclohexylamine (0.173 mole), 1,1,3,3-tetramethyldisiloxane (0.0783 mole), and 0.05 g hexachloroplatinic acid are stirred at 70° C. for eight hours at 110° C. under nitrogen. The product, in nearly quantitative yield, is purified by vacuum distillation at <1 torr at a temperature of 207°-210° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:14](=O)[CH2:15][CH3:16].[BH3-]C#N.[Na+]>>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CCC=O
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 69.8 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (530 mg, 2.9 mmol), propionaldehyde (1.61 g, 28 mmol) and NaBH3CN (872 mg, 14 mmol) to afford 450 mg (69%) of 3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine, an orange oil. Data for 3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine: Rf 0.57 (2:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, 1H, J=9.1, 2.6), 7.66 (d, 1H, J=2.6), 6.56 (d, 1H, J=9.0), 4.22 (t, 2H, J=4.5), 3.49 (t, 2H, J=4.5), 3.33 (t, 2H, J=7.5), 1.67 (sext, 2H, J=7.4), 0.98 (t, 3H, J=7.4).