Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[C:29]3[N:30]=[C:14]([CH:15]=[CH:16][N:17]3[N:18]=[CH:19]1)[N:13]1[C@@H:9]2[CH2:10][CH2:11][CH2:12]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][CH2:23][N:22]([C:1](=[O:3])[CH3:2])[CH2:21][C:20]1=[C:29]3[N:30]=[C:14]([CH:15]=[CH:16][N:17]3[N:18]=[CH:19]1)[N:13]1[C@@H:9]2[CH2:10][CH2:11][CH2:12]1
Reactant: CC(=O)Cl
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Acetyl chloride (1.7 mg, 0.021 mmol) was added to a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5.0 mg, 0.014 mmol), followed by DIEA (7.4 μL, 0.042 mmol). After stirring at ambient temperature overnight, the reaction was concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H2O to provide the title product (3.9 mg, 70% yield). MS (apci) m/z=396.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)C(C)C)(C)C.Cl[C:30]1[C:35]([CH3:36])=[C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[N:33]=[CH:32][N:31]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([C:30]2[C:35]([CH3:36])=[C:34]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=3)[N:33]=[CH:32][N:31]=2)[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Reactant: CCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 100 °C
Yield: 45.3 %

Procedure:
A mixture of ethyl {2-methyl-4-[(propylamino)methyl]phenoxy}acetate (0.279 g, 1.05 mmol), N,N-diisopropylethylamine (0.24 mL, 1.4 mmol) and 4-chloro-5-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (0.191 g, 0.7 mmol) were heated at 100° C. in a sealed reactivial for 18 h. After this time the reactivial was allowed to cool to room temperature and the residue dissolved in CH2Cl2 (50 mL) and washed with water (20 mL). The organic extract was separated by hydrophobic frit and evaporated. Purification by Biotage™ chromatography (Si, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (159 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:35]1([CH:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1C=CCCC1>[C:35]1([CH:41]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCCCC1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: OCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
20 g (111 mmol) 3-piperidin-4-yl-propan-1-ol hydrochloride are suspended in 70 ml 3,4-dihydro-2H-pyrane and added to 0.5 g pyridinium tosylate. The mixture is stirred for two days at RT. After addition of 1 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[3-tetrahydropyran-2-yloxy)-propyl]-piperidine is dissolved in 90 ml acetonitrile without further purification and added to 35 g (135 mmol) diphenyl bromomethane (95%) and 29 g (210 mmol) potassium carbonate and stirred for four days at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-diphenylmethyl-4-[3-(tetrahydropyran-2-yloxy)-propyl]-piperidine is dissolved without further purification in 130 ml methanol and added to 25 ml conc. hydrochloric acid, and the mixture is stirred at RT overnight. Subsequently, the solvent is removed under vacuum and the residue is taken up with 300 ml water and extracted with 300 ml acetic acid ethyl ester. The organic phase is discarded and the aqueous phase is made alkaline with 17 g sodium hydroxide and extracted with 300 g acetic acid ethyl ester. After washing the organic phase with 40 ml water, this is dried over sodium sulfate and the solvent is removed under vacuum: The oil is dried under high-vacuum and processed further without purification. Yield: 22.4 g (65%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.O(C)[Li].CON(C)[C:32]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:33]>>[CH:34]1([C:32]([C:2]2[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]3[O:9][C:8]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:7][C:6]=3[CH:22]=2)=[O:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Reactant: CON(C)C(=O)C1CCCCC1
Agent: [Li]OC
Product: O=C(O)c1cc(C(=O)C2CCCCC2)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1.26 g, 3.16 mmol, 1 eq.), LiOMe (240 mg, 6.32 mmol, 2 eq.) and cyclohexanecarboxylic acid methoxy-methyl-amide (650 mg, 3.8 mmol, 1.2 eq.) as the electrophile were reacted according to GP4, Method A. The crude product was purified using flash chromatography (silica gel, hexane/Et2O/AcOH 5:1:0.1) and subsequent recrystallization from CH2Cl2/hexane to give the title compound as a yellowish solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1.C([O-])(=O)C.[K+]>[Pd].C(O)(=O)C>[C:17]1([C:5]2[C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]([NH2:16])=[O:15])[CH2:12][CH2:13]3)=[N:7][CH:2]=[N:3][CH:4]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)C1CCN(c2nc(Cl)ncc2-c2ccccc2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: NC(=O)C1CCN(c2ncncc2-c2ccccc2)CC1
Yield: 29 %

Procedure:
A mixture of 1-(2-chloro-5-phenylpyrimidin-4-yl)piperidine-4-carboxamide E32 (35 mg, 0.11 mmol), potassium acetate (22 mg, 0.22 mmol) and 10% wt palladium on carbon (3.5 mg) in acetic acid (2 mL) was stirred under an atmosphere of hydrogen (1 atm) for 18 h. The mixture was filtered through celite, washed with AcOH (2×10 mL) and concentrated under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2/MeOH, 10:1) to furnish the title compound as a white solid (9 mg, 29%) m/z 283 (100%, [M+H]+); m/z (ESI) C16H19N4O requires 283.1553 found [M+H]+ 283.1549.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:24]=3[N:25]2[S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:21][CH:20]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[O:15]=[C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[CH:14]=[CH:13][N:12]1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:24]=3[N:25]2[S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:30])=[O:29])=[CH:21][CH:20]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cc6)cc5=O)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 135 °C
Reaction time: 2.5 h
Yield: 50.8 %

Procedure:
A suspension of 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (121 mg, 0.504 mmol), tert-butyl 7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (305 mg, 0.605 mmol), CuI (115 mg, 0.605 mmol), 8-hydroxyquinoline (88 mg, 0.605 mmol) and Cs2CO3 (181 mg, 0.605 mmol) in DMSO (5 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135° C. with stirring for 2.5 h. The suspension was cooled, 4:1 CH2Cl2/(9:1 MeOH/NH4OH) (25 mL) was added and the resulting suspension was stirred at 25° C. for 10 min. The suspension was passed through a plug of silica gel and the filtrate was washed with brine. The solution was dried over Na2SO4 and concentrated under reduced pressure to afford an amorphous solid. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH) 100:0 to 0:100) gave the title compound (170 mg, 51%) as a pink foam: 1H NMR (300 MHz, CDCl3) δ 8.26 (br s, 1H), 7.83-7.74 (m, 6H), 7.53 (d, J=7.2 Hz, 1H), 7.51-7.45 (m, 1H), 7.35-7.23 (m, 3H), 6.93 (d, J=1.8 Hz, 1H), 6.54 (dd, J=7.2, 1.8 Hz, 1H), 4.91 (br s, 2H), 3.75-3.65 (m, 2H), 2.73-2.68 (m, 2H), 2.36 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a room temperature solution of 4-(3,4-dichlorobenzoyl)piperidine-1-carboxylic acid tert-butyl ester (3.8 g, 10.6 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (25 mL) and the solution was stirred for 1 h. After removing the organics, ethyl acetate (200 mL) was added and the resulting solution was basified with 1N aqueous sodium hydroxide solution. The ethyl acetate layer was separated, dried with magnesium sulfate and concentrated to give 4-(3,4-dichlorobenzoyl)piperidine (2.73 g) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:37]([C:39]1[CH:55]=[CH:54][C:42]([CH2:43][C@@H:44]([C:46]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:47])[NH2:45])=[CH:41][CH:40]=1)#[N:38]>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:19]([NH:45][C@H:44]([C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:47])[CH2:43][C:42]1[CH:41]=[CH:40][C:39]([C:37]#[N:38])=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Reactant: N#Cc1ccc(C[C@H](N)C(=O)N2CCCCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N1CCCCC1
Reaction time: 1 h

Procedure:
To a suspension of 7 g (0.023 mole) of N-betanaphthylsulphonylvaline (III: R1 =CH(CH3)2 ; Ar=betanaphthyl) racemic (RS) in 10 ml of dichloromethane, kept at between 0° and +5° C., 2.6 g (0.023 mole) triethylamine is added, then 3.4 g (0.025 mole) of isobutyl chloroformate is added drop by drop, and the whole is left for one hour at this temperature. Then 6.2 g (0.024 mole) of 1-(p-cyanophenylalanyl)piperidine (II: NR2R3 =piperidino) dissolved in 50 ml of dichloromethane is added, and the reactional medium is left for 20 hours at ambient temperature. After evaporating to dryness, the residue is taken up with water. The aqueous phase is extracted with dichloromethane. The organic extracts are dried on anhydrous sodium sulphate and evaporated to dryness. The oily residue is purified by chromatography on a silica column (elution: toluene-ethyl acetate, 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1ccc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(Br)ccc1=O
Temperature: 80 °C
Yield: 60.2 %

Procedure:
To an ice-cold solution of 5-bromo-2(1H)-pyridone (1.0 g, 5.75 mmol) in DMF (5.0 mL) was added NaH (60% suspension in mineral oil, 0.25 g, 10.30 mmol) portion wise and the resulting solution was heated to 80° C. for 90 min. The reaction mixture was then again cooled to 0° C. followed by addition ethyl bromoacetate (1.92 g, 11.50 mmol). The reaction mixture was then heated to 80° C. for 16 h. After the completion of reaction (TLC monitoring), DMF was distilled off, added water and extracted with EtOAc (3×100 mL). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 20% EtOAc-hexane) to obtain the desired product (0.90 g, 60%). MS: 260.10 (M+H)+.
Reaction SMILES: C(O)(=O)CCCCCCCCC(O)=O.NCCNCCNCCNCCNCCN.O[CH:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:33](O)=[O:34].NCCNCCNCCN.C(C1OC1)Cl>O.C(O)(=O)C>[CH2:36]([CH:32]=[C:33]=[O:34])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCCCCCC(O)C(=O)O
Agent: NCCNCCNCCN
Agent: NCCNCCNCCNCCNCCN
Agent: O=C(O)CCCCCCCCC(=O)O
Solvent: O
Solvent: ClCC1CO1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCC=C=O

Procedure:
Except that 60.5 g of castor oil fatty acid, 20.2 g of sebacic acid and 48.7 g of pentaethylenehexamine were used instead of hydroxystearic acid and triethylenetetramine, the same procedures and conditions as those used in the foregoing Example 1 were repeated to subject the input materials to a reaction. At the end of the reaction, 54 g of glacial acetic acid was added thereto, followed by dilution with warm water. Then, after adding 7.4 g of epichlorohydrin thereto, the resultant system was subjected to a reaction at 80°-85° C. for 2 hours to produce a dispersion having a solid content of 20% by weight. Hereinafter, this dispersion shall be referred to as the dispersing agent Hs according to the present invention. Thereafter, by using 10 parts by weight, as solid content, of the dispersing agent Hs, a dispersion of hexadecyl ketene dimer was prepared in the same manner as in the preceding Example 7. Hereinafter, this dispersion shall be referred to as the cellulose treating agent H according to the present invention.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH2:41][CH2:42][CH2:43]O)[N:36]=[CH:35]3)=[O:22])[N:17]([CH3:19])[N:18]=1)([CH3:13])([CH3:12])[CH3:11].[CH:45]([N:48](C(C)C)[CH2:49]C)(C)C.CNC>C1COCC1>[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32]2[CH:40]=[C:39]3[C:38](=[CH:34][CH:33]=2)[N:37]([CH2:41][CH2:42][CH2:43][N:48]([CH3:49])[CH3:45])[N:36]=[CH:35]3)=[O:22])[N:17]([CH3:19])[N:18]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1ccccc1Nc1ccc2c(cnn2CCCO)c1
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CN(C)CCCn1ncc2cc(Nc3ccccc3CNC(=O)Nc3cc(C(C)(C)C)nn3C)ccc21
Reaction time: 1 h
Yield: 43.8 %

Procedure:
Methanesulfonic anhydride (12 mg, 0.070 mmol) was added to a solution of alcohol (7s) (24 mg, 0.050 mmol) and diisopropylethylamine (20 mg, 0.15 mmol) at room temperature. The solution was stirred for 1 hour. Dimethylamine (2.0 M in THF, 0.25 mL, 0.50 mmol) was added and the reaction was stirred overnight. Additional dimethylamine was added (2.0 M in THF, 0.25 mL, 0.50 mmol) and the reaction was stirred an additional 2 days. The mixture was then partitioned between CHCl3 and water. The aqueous phase was extracted once with CHCl3. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel with 5% MeOH/CH2Cl2 containing 1% Et3N to provide the desired compound (8s-1) (11 mg, 43% yield) as a dark foam. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.42 (s, 1H), 7.35-7.33 (m, 2H), 7.19-7.11 (m, 4H), 6.80-6.75 (m, 2H), 5.94 (s, 1H), 5.55 (m, 1H), 4.43 (d, J=6.6 Hz, 2H), 4.38 (t, J=10.5 Hz, 2H), 3.57 (s, 3H), 2.24 (t, J=10.5 Hz, 2H), 2.19 (s, 6H), 2.08-2.01 (m, 2H), 1.24 (s, 9H); MS (ESI+) m/z 503 (M+H)+; HPLC (5 to 95%) 2.59 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].Cl.[CH2:13]([NH2:15])[CH3:14]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][NH:15][CH2:13][CH3:14])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCN
Agent: Cl
Product: CCNCc1cccc([N+](=O)[O-])c1
Yield: 47 %

Procedure:
Using m-nitrobenzaldehyde as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 42 gave 2.8 g of the titled compound (yield, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH2:13])=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].BrBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl.O>[N+:1]([C:4]1[C:5]2[S:12][C:11]([NH2:13])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=S)Nc1cccc([N+](=O)[O-])c1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1nc2cccc([N+](=O)[O-])c2s1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To 0.60 g (3.0 mmol) of (3-nitrophenyl)thiourea in 25 mL of carbon tetrachloride was added 0.17 mL (3.4 mmol) of bromine in 10 mL of carbon tetrachloride dropwise over 1 h. The mixture was heated to reflux for 18 h, cooled to room temperature and the precipitate that formed was collected by filtration. The precipitate was slurried in glacial acetic acid and the solids were collected by filtration. The solids thus obtained were slurried in water and saturated potassium carbonate was added until the pH was about 9. The free base was collected by filtration to give 0.30 g (51%) of the title compound as a light orange solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[O:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: c1ccc(CN2CCN(c3ccccc3-c3ncco3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: c1ccc(N2CCNCC2)c(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A mixture of the 4-benzyl-1-(2-oxazol-2-ylphenyl)piperazine (0.906 g, 2.84 mmol), obtained as in the proceeding paragraph, 10% palladium on carbon (1 g) and methanol (20 mL) was stirred 4 hours at 25° C. under a hydrogen atmosphere (15 psi). The reaction mixture then was filtered and concentrated by rotary evaporation to give 1-(2-oxazol-2-ylphenyl)piperazine (0.480 g, 2.1 mmol).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.[N:35]1([C:41]2[CH:51]=[CH:50][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC.CCO.O>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:37][CH2:36][N:35]([C:41]4[CH:42]=[CH:43][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:50][CH:51]=4)[CH2:40][CH2:39]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][S:15][CH2:16][C@@H:8]12
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (333 mg, 1.325 mmol) in propiononitrile (3313 μl) was added (cyanomethyl)trimethylphosphonium iodide (386 mg, 1.590 mmol) and DIPEA (694 μl, 3.98 mmol) and finally ethyl 4-(piperazin-1-yl)benzoate (310 mg, 1.325 mmol). The vial was heated to 90° C. for 12 hours. The reaction was then cooled to room temperature, diluted with EtOH (8 ml) and water (1 mL), then filtered. The precipitate was filtered off and dried in vacuum to afford the title compound 508 mg, 82%) as a white solid. [M+H] calc'd for C24H29N5O3S, 468. found, 468.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=C[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[C:14]1([S:13][C:10]2[N:11]=[CH:12][C:4]([CH:5]=[O:1])=[CH:3][CH:2]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc(Sc2ccccc2)nc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To a tetrahydrofuran (40 mL) solution of 5-bromo-2-phenylsulfanyl-pyridine (2.24 g, 8.42 mmol) described in Manufacturing Example 97-1-1 was added n-butyl lithium (6.35 mL, 1.6 M hexane solution, 10.1 mmol) under nitrogen atmosphere at −78° C., which was stirred for 45 minutes at −78°. Next, N,N-dimethylformamide (848 μL, 10.9 mmol) was added to this reaction mixture, and stirred for 35 minutes as the temperature was gradually raised to room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (583 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:7])=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccc(Cl)nc1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 79 %

Procedure:
A solution of 6-chloro-2-cyclopropylnicotinoyl chloride (PATENT WO2005/080342) (0.216 g, 1 mmol) in DCM (2.5 mL) was added drop wise to a stirred solution of cyclohexylamine (0.171 mL, 1.50 mmol) and N-ethyldiisopropylamine (0.606 mL, 3.50 mmol) in THF (5 mL) at 20° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (10 mL) and washed sequentially with 2M HCl (10 mL), saturated NaHCO3 (10 mL), and saturated brine (10 mL). The organic layer was collected from a phase separation cartridge (15 ml) and evaporated to afford crude product. This was triturated with Et2O to give a solid that was collected by filtration and dried under vacuum to give 6-chloro-N-cyclohexyl-2-cyclopropylnicotinamide (79%) as a white solid.