Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:23][O-:24].[Na+]>CCOCC.CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:24][CH3:23])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: C[O-]
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.04 g of 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was dissolved in anhydrous ether and the solution cooled with an ice bath, then 3.7 ml of a 25 wt. % sodium methoxide in methanol was added. After addition, the ice bath was removed and the mixture stirred for 30 minutes at room temperature. The solution was then extracted 4 times with water, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed to give 4.63 g of 4-chloro-3-(2-fluoro-5-methoxy-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, mp 115°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].[BH4-].[Na+]>>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: O=C1CCc2cccc(F)c2C1
Reactant: CCCNCCC
Agent: [BH4-]
Agent: [Na+]
Product: CCCN(CCC)C1CCc2cccc(F)c2C1
Yield: 33 %

Procedure:
8-Fluoro-2-tetralone (2.60 gm, 15.8 mMol) was reacted with dipropylamine (3.3 mL, 33 mMol) and sodium borohydride (1.5 gm) as described in Example 1 to give the title compound as a colorless oil (1.3 gm, 33%). The hydrochloride salt was formed and crystallization (ethanol/diethyl ether) gave colorless crystals (m.p.=164° C.).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].Cl>[OH-].[Na+].C1COCC1>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:15]
Reactant: NC(CC(=O)O)C(=O)O
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 3 h
Yield: 75 %

Procedure:
10 g of DL-aspartic acid (Aldrich) are dissolved in 105 ml of a 2.5N aqueous sodium hydroxide solution (60 ml)/THF (45 ml) mixture in a 500 ml, three-necked, round-bottomed flask equipped with a phmeter and with two dropping funnels containing, on the one hand, a 2.5N aqueous sodium hydroxide solution and, on the other hand, 2-methoxybenzoyl chloride. The 2-methoxybenzoyl chloride is added dropwise while maintaining the pH above 9 by simultaneous addition of the 2.5N sodium hydroxide solution. The reaction mixture is kept stirring for 3 h after the end of the addition of the acid chloride before being acidified with a concentrated hydrochloric acid solution. The mixture is exhaustively extracted with ethyl acetate. The organic phase is washed, dried and concentrated to dryness to provide crude N-(2-methoxybenzoyl) aspartic acid. The product can be used as is in the second stage (nonoptimized yield 75%) or purified by washing with a suitable organic solvent. 1H NMR 500 MHz (d6 -DMSO, δppm): 2.83 (m, 2H, H9), 3.92 (s, 3H, H12); 4.80 (m, 1H, H8), 7.07 (d.d.d, 1H, H4), 7.18 (d.d, 1H, H2), 7.52 (d.d.d, 1H, H3), 7.91 (d.d, 1H, H5), 8.85 (d, 1H, NH), 12.68 (s, 2H, OH).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]([O:17][C@@H:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Br:32][CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>C(Cl)Cl>[Br-:32].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]([O:17][C@@H:18]2[CH:23]3[CH2:22][CH2:21][N+:20]([CH2:33][C:34](=[O:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([CH2:25][CH2:24]3)[CH2:19]2)=[O:16])(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
(R)-quinuclidin-3-yl 2-(4-methoxyphenylsulfonamido)-2-phenylacetate hydrochloride (C68) (96 mg, 0.22 mmol) was dissolved in DCM and washed with 1M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated. The resulting solid was dissolved in EtOAc (2 ml) and 2-bromo-1-phenylethanone (49.2 mg, 0.25 mmol) was added. The reaction was stirred at RT for 3 hours, and then it was washed with aq. K2CO3, dried over Na2SO4, filtered and evaporated to obtain (3R)-3-(2-(4-methoxyphenylsulfonamido)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (75 mg; 53% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>O.C(Cl)Cl.CO>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 equiv) is heated to 80° C. for 15 h. After cooling to RT, the reaction mixture is diluted with water and DCM/MeOH, 9:1. The aqueous layer is separated and extracted with DCM/MeOH, 9:1. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) affords the title compound as a yellow solid: ESI-MS: 236.0 [MH]+; tR=2.35 min (purity: 100%, system 1); TLC: Rf=0.50 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cccnc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.3 %

Procedure:
To a solution of 3-pyridinecarboxaldehyde (1.4 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate) to afford a white crystalline solid (1.5 g, 53% yield), m.p. 68°-70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Fc1ccc(Br)cn1
Product: N#Cc1ccc(-c2ccc(F)nc2)cc1

Procedure:
According to the same method as in Example 1-2) but using 2-fluoro-5-bromopyridine and 4-cyanophenylboronic acid, the entitled compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[C:9]([CH2:12][C:13](=O)[CH3:14])O[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[N:20]=1)[NH2:18].[Cl:27]C1C=CC=C(OC)N=1>>[Cl:27][C:1]1[C:2]2[C:11](=[C:6]([CH3:7])[CH:5]=[CH:4][CH:3]=2)[N:10]=[C:9]2[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[N:20]=3)[N:18]=[C:13]([CH3:14])[C:12]=12
Reactant: CC(=O)Cc1nc2c(C)cccc2c(=O)o1
Reactant: COc1cccc(Cl)n1
Reactant: COc1cccc(NN)n1
Product: COc1cccc(-n2nc(C)c3c(Cl)c4cccc(C)c4nc32)n1

Procedure:
Following the procedures described in Reference Example 1-10 and Example 1-34, the title compound was prepared from 8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazino-6-methoxypyridine which was prepared from 2-chloro-6-methoxypyridine following the procedure described in Reference Example 1-9 (75% yield).
Reaction SMILES: [C:1]1([Si:7](C)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][SiH:12]([Cl:14])[Cl:13]>>[C:1]1([Si:12]([Cl:14])([Cl:13])[Cl:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:1][SiH:7]([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)c1ccccc1
Reactant: Cl[SiH](Cl)Cl
Product: C[SiH](C)C
Product: Cl[Si](Cl)(Cl)c1ccccc1

Procedure:
Eaborn et al., J. Organometal. Chem. 4:489 (1965), describes a process where phenyltrimethylsilane and trichlorosilane are reacted at 500° C. in the gas phase to give phenyltrichlorosilane and trimethylsilane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:18][C@@H:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C@H:15]2[C:26]([OH:28])=O)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([N:51](CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]([N:36]1[CH2:37][CH2:38][N:39]([NH:51][C:26]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][N:14]2[S:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:13])=[O:12])=[O:28])[CH2:40][CH2:41]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](Oc3ccccc3)C[C@H]2C(=O)O)cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2C[C@@H](Oc3ccccc3)C[C@H]2C(=O)NN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(3,4-Dimethoxybenzenesulfonyl)-[(2S,4S)-4-phenoxy-2-pyrrolidinecarboxylic acid] (10) (0.64 g; 1.57 mmol) is dissolved in methylene chloride (15 mL) at ambient temperature. 1-(Diphenylmethyl)piperazine (0.48 g; 1.89 mmol), N,N-diisopropylethylamine (0.45 g; 3.46 mmol) and PyBOP (0.98 g; 1.89 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (40%→50% ethyl acetate in hexanes) affording the desired product as a solid foam. CIMS: MH+ 642
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[O:12])[C:6](=O)[O:5][C:4]([CH3:9])([CH3:8])[O:3]1.N12CCCN=C1CCCCC2>C(Cl)(Cl)(Cl)Cl.O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][CH2:6]/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OC/C(=C/C(=O)O[Si](C)(C)C(C)(C)C)O1
Reaction time: 1 h

Procedure:
The solution of crude 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (˜220 ml) was cooled to 0-5° C. and treated dropwise over 10 minutes and under good stirring with a solution of 1,8-diazabicyclo [5,4,0]undec-7-ene (12.1 g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitate was formed which gradually became a granular solid. After 1 h, the solid obtained was filtered and washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure to give a light orange oil which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:7]2[S:6][C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[CH:8]=2)[CH:19]=1
Reactant: Clc1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Chlorobenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Li]CCCC.[CH3:25][N:26]([CH3:44])[S:27]([N:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]=[C:31]1[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=[O:29])=[O:28]>C1COCC1>[CH3:25][N:26]([CH3:44])[S:27]([N:30]1[C:34]([CH:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[S:8][CH2:7][CH2:6][CH:5]3[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[OH:36])=[CH:33][N:32]=[C:31]1[Si:37]([C:40]([CH3:42])([CH3:41])[CH3:43])([CH3:39])[CH3:38])(=[O:28])=[O:29]
Reactant: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCSc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(C(O)c2ccc3c(c2)C(O[Si](C)(C)C(C)(C)C)CCS3)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of (6-bromo-thiochroman-4-yl-oxy)-tert-butyl-dimethyl-silane (Intermediate-K3) (2.74 g, 7.64 mmol) in TH F (30 mL) was treated with nBuLi (3.1 mL of a 2.5 M soln) at −78° C. for 30 m. A solution of 2-(tert-butyl-dimethyl-silanyl)-5-formyl-imidazole-1-sulfonic acid dimethylamide (see the General Method above, Intermediate K1) (2.42 g, 7.63 mmol) in THF (10 mL) was added via cannula. After 15 m, the reaction mixture was allowed to warm to rt for 16 h. The mixture was quenched with water, washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by chromatography on silica gel with 20% EtOAc:hexane to afford 2-(tert-butyl-dimethyl-silanyl)-5-{[4-(tert-butyl-dimethyl-silanyloxy)-thiochroman-6-yl]-hydroxy-methyl}-imidazole-1-sulfonic acid dimethylamide (Intermediate K4) as an oil, 4.12 g.
Reaction SMILES: Cl[C:2]1[C:3]([F:12])=[N:4][CH:5]=[C:6](Cl)[C:7]=1[O:8][CH2:9][CH3:10].C([O-])(=O)C.[Na+].[H][H]>C(O)C.[Pd]>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([F:12])[CH:2]=1)[CH3:10]
Reactant: CCOc1c(Cl)cnc(F)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc(F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 60.5 g (0.31 mol) of 3,5-dichloro-4-ethoxy-2-fluoropyridine and 32.2 g (0.32 mol) of sodium acetate in 400 mL of ethanol in a 1 L stirred steel Parr bomb was added 3 g of 5 percent palladium on carbon catalyst. The reactor was charged with 500 pounds per square inch gauge (3550 kiloPascals) of hydrogen and heated with stirring to 100° C. for 4 hr. The mixture was cooled, filtered, and concentrated by evaporation. The residue was dissolved in ether and the resulting solution was dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by bulb to bulb distillation (60°-80° C. at 0.5 mm Hg (67 Pascals) to obtain 18.5 g (42 percent of theory) of the title compound as a colorless oil which solidified upon standing and melted at 35°-36° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].Cl.Cl[C:13](N)=[NH:14].S1(CCCC1)(=O)=O.CS(C)(=O)=O.[NH3:28]>O>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:13]([NH2:14])[N:5]=[C:4]2[NH2:28]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: N=C(N)Cl
Reactant: N
Agent: CS(C)(=O)=O
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1nc(N)c2cc(Cl)ccc2n1
Temperature: 165 °C
Yield: 99 %

Procedure:
A mixture of 2-amino-5-chlorobenzonitrile (1.07 g, 7.0 mmol), chloro-formamidine hydrochloride (1.6 g, 14 mmol), sulfolane (0.5 ml) and dimethylsulfone (3 g) was heated at 165° C. for 30 minutes. Then, water (30 ml) was added to the reaction mixture. The pH was adjusted to 7-8 by the addition of a 33% aqueous ammonia solution in water. The precipitate was collected by filtration, washed with water and dried over P2O5, yielding the title compound as a yellowish solid (1.35 g, yield: 99%) which was characterized by its mass spectrum as follows: MS (m/z): 195 ([M+H]+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH2:35][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.05 ml, 0.57 mmol) and acetic acid (0.03 ml, 0.57 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared Example 82; 200 mg, 0.57 mmol) in DCE (5 ml) and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (181 mg, 0.86 mmol) was then added and the mixture was warmed to 50° C. overnight. Saturated sodium hydrogencarbonate (10 ml) was added and the mixture was stirred for 10 min before being diluted with dichloromethane (25 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml). The organics were combined and evaporated under reduced pressure. The residue was purified by MDAP to yield the title compound. 150 mg.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16]N[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[C:24]([BH3-])#[N:25].[Na+]>CO>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:25]([CH2:24][CH2:6][CH2:5][C:4]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:3]=4)[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Reactant: [BH3-]C#N
Agent: I
Agent: [Na+]
Solvent: CO
Product: Cc1onc2c1c(=O)n(C1CCCN(CCCc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol) in methanol (3 mL) add approximately 100 mg of finely ground 3 Å sieves and stir the mixture for 30 minutes at room temperature. To the suspension add sodium cyanoborohydride (21 mg, 0.34 mmol) and stir the mixture at room temperature under nitrogen overnight. Concentrate the solution and dissolve in 20% isopropanol/chloroform, wash with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 23.9 mg of the title compound as a yellow foam, 49% yield. 1H NMR: consistent with structure. MS (ion spray) 436 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]3[CH2:12][CH2:13][CH:14]([NH2:16])[CH2:15][C:9]=3[C:8]=2[CH:17]=1)([O-:3])=[O:2].I[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28](C)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]3[CH2:12][CH2:13][CH:14]([N:16]([CH2:19][CH3:20])[CH2:27][CH3:28])[CH2:15][C:9]=3[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: NC1CCc2oc3ccc([N+](=O)[O-])cc3c2C1
Reactant: CCI
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCc2oc3ccc([N+](=O)[O-])cc3c2C1
Yield: 45 %

Procedure:
A mixture of 0.88 gm (3.79 mMol) 8-nitro-1,2,3,4-tetrahydro-2-dibenzofuranamine, 0.89 gm (5.68 mmol) iodoethane and 1.58 gm (11.4 mMol) potassium carbonate in 50 mL acetone was heated at reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water. This mixture was extracted well with chloroform. The organic phases were combined, dried over potassium carbonate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm). Fractions containing product were combined and concentrated under reduced pressure to provide 0.49 gm (45%) 8-nitro-1,2,3,4-tetrahydro-2-diethylaminodibenzofuran as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:17][OH:18])[C@@H:13]([CH3:16])[CH2:14][CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C@H:12]([CH2:17][OH:18])[C@@H:13]([CH3:16])[CH2:14][CH3:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC[C@H](C)[C@@H](CO)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide (0.10 g, 0.343 mmol) dissolved in DMF (2.0 mL) was added potassium carbonate (47 mg, 0.343 mmol). After 30 minutes, the reaction mixture was cooled to 0° C. and iodomethane (50 μL, 0.686 mmol) was added. After 2 hours, the ice bath was removed and the reaction mixture was stirred at 25° C. for 24 hours. The insolubles were then filtered off and the DMF solution was diluted with EtOAc (50 mL) and washed sequentially with 10% citric acid (50 mL) and saturated brine (50 mL), dried over MgSO4 and evaporated to a clear oil which was washed with Et2O and then purified by flash chromatography (eluant: 95-5 CHCl3/iPrOH) to afford the desired product as a clear oil (71 mg, 68%). Mass Spectrum (+APCI): 306 ([M+H]+). Anal: Calc'd for C13H20ClNO3S: C, 51.06; H, 6.59; N, 4.58. Found: C, 51.15; H, 6.73; N, 4.36.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(OCC)=O)C.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:12](#[N:13])[CH:11]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1ccccc1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Four grams of 60% sodium hydride was suspended in 100 ml tetrahydrofuran, and 17.1 g of diethylphosphonoacetonitrile was added with ice cooling. To the resulting solution, was added dropwise a solution of 10.6 g benzaldehyde in 80 ml tetrahydrofuran, and the mixture was stirred for one hour. After admixing 50 ml water, the organic layer was collected, dried over anhydrous sodium sulfate and concentrated. Distillation of the concentrate under reduced pressure (102°-106° C./6 mmHg) gave 8.9 g (yield: 69.0%) of cinnamonitrile.