Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[NH:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.IC.N1[CH2:29]CCN2CCCCCC=12>CN(C=O)C>[CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[N:15]2[CH3:29])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)NC3CCCc4ccccc43)c(=O)c12
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)NC1CCCc3ccccc31)n2C

Procedure:
In analogy to example 2, 50 mg (0.14 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridine-2-carboxylic acid (1,2,3,4-tetrahydronaphthalen-1-yl)amide were reacted with 23.85 mg (0.168 mmol) of iodomethane in DMF with 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) at RT. Yield: 12 mg (23%), M+H+: 371.42.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Product: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1Cl
Temperature: 85 °C
Yield: 89 %

Procedure:
To 5-chloro-6-nitro-1,3-dihydro-benzoimidazol-2-one (5.63 g, 26.35 mmol) was added phosphorus oxychloride (35 mL) and the reaction mixture was heated to 85° C. for 36 h. The reaction mixture was concentrated and the residue triturated with cold saturated aqueous sodium bicarbonate (to pH 8, 0.8 L). The resulting precipitate was collected and dried to yield the titled compound (5.43 g, 89% yield). MS (ESI/CI): mass calcd. for C7H3Cl2N3O2, 231.0; m/z found, 232.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=1
Reactant: CCB(CC)c1cccnc1
Reactant: O=Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccnc2)cc1
Yield: 72.3 %

Procedure:
A mixture of 4-bromobenzaldehyde (2 g, 10.8 mmol), diethyl(3-pyridyl)borane (1.75 g, 11.9 mmol), tetrakis(triphenylphosphine)palladium (375 mg, 0.32 mmol), and 2N sodium carbonate aqueous solution(10.8 ml, 21.6 mmol) in toluene (40 ml) was heated under reflux under a nitrogen atmosphere overnight. The reaction mixture was allowed to return to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford 4-(pyridin-3-yl)benzaldehyde (1.43 g, yield 72%) as a pale yellow crystalline powder.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][C:3]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14].[H-].[Na+].[CH3:23]I.[Na]>CN(C)C=O>[OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH3:23])[C:3]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14]
Reactant: CI
Reactant: O=C(Nc1nccs1)C1=C(O)c2sccc2S(=O)(=O)N1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.329 g (1 mmol) of 4-hydroxy-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide are dissolved in 2 ml. of absolute dimethylformamide and added at 0° C. to a stirred suspension of 0.026 g (1.1 mmol) of sodium hydride in 1 ml. of absolute dimethylformamide. The mixture is stirred at room temperature for a further 1 hour. 0.1 ml. (0.226 g; 1.6 mmol) of methyl iodide are then added to the sodium salt solution and allowed to react for a further 1 hour. After distillation of the solvent, the residue is taken up in 200 ml of methylene chloride and 10 ml. of 0.5-N hydrochloric acid. The organic phase is separated and shaken out with a total of 50 ml. of a 0.5% sodium bicarbonate solution. The aqueous layer, which now contains the desired product, is back-extracted several times with methylene chloride and acidified with hydrochloric acid. The acidic aqueous phase is extracted with methylene chloride and the combined organic extracts dried over sodium sulphate and evaporated. The crystalline residue is digested with a small amount of cold ethanol for purification. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 217° C. (decomposition).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.Br[C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:23]([CH3:36])[CH:22]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][N:15]([C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[C:23]([CH3:36])[CH:22]=1)[CH2:14][CH2:13]2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: COc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCN(c1cc(C)c(NC(=O)CC(C)(C)C)c(C)c1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (134 mg, 0.67 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) were then. added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, filtered through a pad of silica gel, and recrystallized from toluene to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of 4-(3,5-difluorophenoxy)phenol (11.1 g, 50.0 mmol), ethyl 2-bromopropionate (9.96 g, 55.0 mmol), potassium carbonate (7.25 g, 52.5 mmol) and N,N-dimethylformamide (50 ml) was stirred at an inner temperature of 70° to 80° C. for 3 hours. After allowed to cool, the reaction mixture was poured into ice-water and extracted with toluene. The toluene layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]propionate (15.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17].[B][B][B][B][B][B][B][B][B][B]>CO>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=2)[CH2:9][CH3:10])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: CCC(=O)c1ccc(Cl)c(C)c1
Reactant: Cc1ccc(N)cc1Br
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCC(Nc1ccc(C)c(Br)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INT 5 (3.00 g, 16.4 mmol) and 3-bromo-4-methylaniline (3.06 g, 16.4 mmol) in MeOH (164 mL) was added decaborane (1.00 g, 8.2 mmol). The reaction mixture was stirred at room temperature overnight. More decaborane (0.50 g, 4.1 mmol) was added. The mixture was stirred at 60° C. for 2 hours. The mixture was concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 8.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+].ClC/C=C\CCl>C(Cl)Cl>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH:10]=[CH:9][CH2:8]1
Reactant: C1CCOC1
Reactant: CSCS(C)=O
Agent: ClC/C=C\CCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CSC1(S(C)=O)CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.27g) was dissolved in 15 ml. of tetrahydrofuran, and 246 mg of sodium hydride was added. The mixture was stirred for 30 minutes at room temperature, and then for 2 hours at 50° C. With ice cooling, 442 mg of cis-1,4-dichloro-2-butene was added. The mixture was stirred for 1 hour with ice cooling, and then for 6.5 hours at room temperature. Methylene chloride (100 ml) was added, and the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (Florisil, eluted with methylene chloride) to afford 382 mg of 3-cyclopentenone dimethyl mercaptal S-oxide in a yield of 61%.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C@@H:21]3[CH2:23][O:22]3)=[C:14](C(=O)C)[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:29].[OH-].[K+]>C(Cl)(Cl)Cl.CO>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:20][C@@H:21]([CH2:23][OH:22])[O:29][C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OC[C@@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@H](CO)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-benzenesulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone (2.04 g; 0.059 mol) and meta-chloroperoxybenzoic acid (4.13 g; 0.018 mol, max. 77%) in chloroform (20 mL) was heated under reflux for 18 hours. After cooling to ambient temperature the mixture was diluted with chloroform, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. This crude residue (0.85 g; 0.0024 mol) dissolved in methanol (5 mL) was added to a solution of 10% aqueous potassium hydroxide (4 mL) at 0° C. The mixture was stirred for 30 minutes at room temperature. Solvent was removed in vacuo, and the residue was dissolve in ethyl acetate, washed with 10% aqueous hydrochloric acid followed by saturated brine, dried (Na2SO4) and concentrated in vacuo to give (7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-yl)-methanol as an oil (1.44 g; 77%): MS (M+H)+ 307.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[C:26]4[CH:27]=[CH:28][C:29]([Br:31])=[CH:30][C:25]=4[S:24][N:23]=3)[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22]3[C:26]4[CH:27]=[CH:28][C:29]([Br:31])=[CH:30][C:25]=4[S:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(Nc3nsc4cc(Br)ccc34)c2)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cccc(Nc3nsc4cc(Br)ccc34)c2)COCC(N)=N1

Procedure:
To a solution of {5-[3-(6-Bromo-benzo[d]isothiazol-3-ylamino)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl}-carbamic acid tert-butyl ester (36 mg, 0.07 mmol) in DCM (1 ml) was added at +5° C. 1 ml TFA. After 20 minutes the mixture was quenched with water and EtOH and evaporated. The residue was taken up in EtOAc/THF and washed with soda, dried with K2CO3 and purified by chromatography on silica gel (DCM/5% MeOH, then DCM/5-10% MeOH containing aq NH3) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:5]=2[N:6]=1.[CH2:14]([O:16][P:17]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O:19][CH2:20][CH3:21])=[O:18])[CH3:15]>>[S:3]1[C:4]2[C:13]3[C:8]([CH2:7][C:5]=2[N:6]=[C:2]1[NH:1][C:27]([C:26]1[CH:30]=[CH:31][C:23]([CH2:22][P:17](=[O:18])([O:16][CH2:14][CH3:15])[O:19][CH2:20][CH3:21])=[CH:24][CH:25]=1)=[O:28])=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: Nc1nc2c(s1)-c1ccccc1C2
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3c(s2)-c2ccccc2C3)cc1)OCC

Procedure:
Using 2-amino-4H-indeno[2,1-d]thiazol and 4[(diethoxyphosphoryl)methyl]benzoyl chloride, the procedure of Example 1 was otherwise repeated to provide the objective compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:33])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:33][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccc(CCN2CCCC2)c(Cl)c1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Product: O=C(C#Cc1ccc(-c2ccccc2)cc1Br)Nc1ccc(CCN2CCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-pyrrolidin-1-ylethyl)phenylamine. Yield: 140 mg (27.2% of theory); C27H24BrClN201 (M=507.84); calc.: molecular ion peak (M+H)+: 507/09/11; found: molecular ion peak (M+H)+: 507/09/11.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=O.C1N(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.[OH:35][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)=[O:37]>CN(C=O)C.C(N(CC)CC)C>[CH3:1][NH:2][CH2:3][C:4]([CH:38]([CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)[C:36](=[O:35])[OH:37])=[O:6]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CNCC(=O)O
Agent: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
The N-methyl glycine-linked DOTA-biotin conjugate was prepared by an analogous method to that used to prepare D-analine-linked DOTA-biotin conjugates. N-methyl-glycine (trivial name carcosine, available from Sigma Chemical Co.) was condensed with biotin-NHS ester in DMF and triethylamine to obtain N-methyl glycyl-biotin. N-methyl-glycyl biotin was then activated with EDCI and NHS. The resultant NHS ester was not isolated and was condensed in situ with DOTA-aniline and excess pyridine. The reaction solution was heated at 60° C. for 10 minutes and then evaporated. The residue was purified by preparative HPLC to give [N-methyl-N-biotinyl)-N-glycyl]-aminobenzyl-DOTA.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH:15]([O:19][CH3:20])[CH2:16][CH2:17]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:17][CH2:16][CH:15]([O:19][CH3:20])[CH2:14][CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: COC(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reaction time: 3 h
Yield: 3.9 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1.037 g, 4.94 mmol) and 1,5-dibromo-3-methoxypentane (1.2 g, 4.94 mmol) in THF (16 mL) was added NaH (237.12 mg, 60%, 9.88 mmol) at room temperature. The mixture was refluxes for 3 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give the residue, which was purified by column chromatography to give 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (60 mg, 4%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[CH:3][C:1]#[N:2])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add diethyl cyanomethylphosphonate (5.33 g, 4.88 mL, 30.11 mmol) to potassium carbonate (3.47 g, 25.09 mmol) in dry THF (10 mL) and stir at room temperature for 15 min., then heat under reflux for 15 min. To this mixture add 4-oxopiperidine-1-carboxylic acid t-butyl ester (5.00, 25.09 mmol) and heat under reflux under nitrogen for 24 hr., allow to cool to room temperature and stand overnight. Pour the reaction mixture into aqueous potassium carbonate solution (10%, 80 mL) and extract the resultant mixture with ethyl acetate (2×50 mL). Combine the organics, dry (MgSO4) and evaporate in vacuo to give 4-cyanomethylenepiperidine-1-carboxylic acid t-butyl ester as a liquid which solidifies on standing (5.39 g, 96.6%). NMR (δ-CDCl3) 1.5 (s, 9H), 2.4 (m, 2H), 2.6 (m, 2H), 3.5 (m, 4H), 5.2 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[C:60](O)=[O:61])[CH3:54].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[C:60]([CH:2]([NH2:1])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:12])=[O:61])[CH3:54]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN)ccc2c1OCC1CC21
Reactant: CCN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC[C@H]1C(=O)C(N)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 102, 0.515 g), HATU (0.483 g), (S)—N-ethylpyrrolidine-2-carboxylic acid (Intermediate 106, 0.182 g) and N,N-di-isopropyl-N-ethylamine (0.328 g) in dry DMF (25 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum and the residue was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 1-2% to give methyl (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)cabonyl-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.505 g) as a glassy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10](O)[CH3:11])([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.CS([Cl:26])(=O)=O>CN(C)C=O>[Cl:26][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:11]
Reactant: CC(O)c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
311 g 1-(2-nitrophenyl)ethanol (XI-1) (95.8% purity, 1.78 mol) are dissolved in 3000 ml dimethyl formamide in a 6 liter three-necked flask equipped with a stirrer, dropping funnel and thermometer. 921.4 g (7.13 mol) diisopropylethylamine are added in a single portion, stirred for 5 minutes, then 612.5 g (5.35 mol) methanesulfonyl chloride are added dropwise between 20 to 35° C. with good cooling. After the reaction has subsided, it is stirred for another 90 hours at room temperature, and the solvent is removed under vacuum. Then the residue dissolved in ethyl acetate, washed 3 times with water, dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified by column chromatography (silica gel, 9:1 hexane/acetone). 219 g of 1-(1-chloroethyl)-2-nitrobenzene (100% purity by HPLC, 66.2% theoretical yield) are obtained as a brown oil [logP (pH 2.3)=2.87].
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][N:33]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]1)[C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1ccccc1Cl)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.1 g of 2-chlorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexyl amine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.94 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-2-chlorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: Cl.Cl.[CH:3]1([C@@H:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[NH2:7])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Br[C:28]1[C:29]2[CH2:37][N:36]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)[CH2:35][CH2:34][C:30]=2[N:31]=[CH:32][N:33]=1>C(#N)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([N:36]2[CH2:35][CH2:34][C:30]3[N:31]=[CH:32][N:33]=[C:28]([NH:7][C@@H:6]([CH:3]4[CH2:5][CH2:4]4)[C:8]4[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=4)[C:29]=3[CH2:37]2)=[N:39][CH:40]=1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Reactant: N[C@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc([C@@H](Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)C2CC2)cn1
Temperature: 180 °C
Yield: 12.1 %

Procedure:
To a stirred solution of (S)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methanamine dihydrochloride (0.048 g, 0.17 mmol) and N,N-diisopropylethylamine (96 uL, 0.55 mmol) in acetonitrile (1.8 mL) was added 4-bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.045 g, 0.14 mmol). The reaction was heated in microwave for 7 hours at 180° C. The mixture was concentrated and the residue was purified by silica gel column followed by semi-prep HPLC to obtain 7.8 mg of white solid.