Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]([C:18]([OH:20])=O)=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH3:43][NH:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52]>C(Cl)Cl>[CH3:43][N:44]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52])[C:18]([C:10]1[C:11]([CH:15]([CH3:16])[CH3:17])=[C:12]([CH:13]=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:20]
Reactant: CNCc1ccccc1C
Reactant: CC(C)c1c(C(=O)O)nn(-c2ccc(F)cc2)c1C=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1CN(C)C(=O)c1nn(-c2ccc(F)cc2)c(C=O)c1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.6 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid (1.50 g, 5.43 mmol) in CH2Cl2 (100 mL) at 25° C. was added EDCI (1.56 g, 8.14 mmol) followed by HOBt.H2O (1.25 g, 8.14 mmol) and the reaction was stirred for 10 min at 25° C. Subsequently, methyl-(2-methyl-benzyl)-amine (1.10 g, 8.14 mmol) was added and the reaction was stirred for an additional 6 hrs at 25° C. The organic layer was then washed with HCl, saturated NaHCO3 and brine. After drying over Na2SO4 and concentration, the product was purified by column chromatography (10-25 % EtOAc/Hex) to afford desired 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl-(2-methyl-benzyl)-amide as an oil (1.53 g, 71.6%). MS(APCI+) 394.2 m/z (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.Cl[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14][CH2:15][C:16]([C:31]([O:33][CH3:34])=[O:32])([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a chilled solution of diisopropylamine (3.5 mL, 24.7 mmol) in THF (20 mL) at −78° C. was added n-BuLi (2M in hexane, 14.8 mL, 1.2 equiv.). The reaction mixture was stirred for 1 h. A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (5 g, 20.6 mmol, 1 equiv.) in THF (15 mL) was added dropwise at −78° C. The reaction mixture was stirred for 1 h. Methyl chloroformate (1.7 mL, 22.6 mmol, 1.1 equiv.) was added to the above mixture. The reaction mixture was warmed to rt slowly while stirring. After 3 h, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give 1-tert-butyl 4,4-dimethyl piperidine-1,4,4-tricarboxylate (6.2 g, quant.), which was used without further purification. LRMS (M+H+-Boc) m/z 202.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=O)[CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[N:9][CH:8]=[C:4]2[CH:3]=1
Reactant: O=CNCc1cc(Br)ccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Brc1ccn2cncc2c1
Temperature: 25 °C

Procedure:
A solution of 10.75 g of N-(4-bromopyridin-2-ylmethyl)formamide in 100 ml of benzene is admixed with 8.43 g of phosphorus oxychloride. The reaction mixture is heated to reflux over 4 hours. The reaction mixture is subsequently cooled to room temperature and concentrated by evaporation, and the residue is admixed with 200 ml of water. The aqueous solution is basified with 1M NaOH and extracted with dichloromethane (3×300 ml). The combined organic phases are washed with 300 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Yield: 64.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (99 mg, 0.22 mmol) and N-bromosuccinimide (43 mg, 0.24 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (−) m/z 531.23, 533.18 (M−1, 79/81Br).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][N:36]([CH3:41])[CH3:35])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CN(C)CC(=O)O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 16.2 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 459 mg, 1 mmol), N,N-dimethylglycine (206 mg, 2 mmol), and triethylamine (0.278 mL, 2 mmol) were stirred in dry DMF (5 mL) and then HATU (760 mg, 2 mmol) was added portionwise. The reaction mixture was heated at 70° C. for 40 mins then a further quantity of HATU (760 mg, 2 mmol) was added and the mixture heated at 80° C. for 1 hr. The reaction mixture was allowed to cool and then partitioned between EtOAc and water. The organic layer was washed with water followed by brine, and then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was treated with DCM, the suspension filtered and the filtrate purified by flash chromatography with a gradient of 0-10% MeOH in DCM to afford the title compound as a white solid (88 mg).
Reaction SMILES: [CH3:1][C:2]([Mg]Cl)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[Mg].ClC(C)(C)CCCC.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>CCOCC>[Cl:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:2]([CH3:7])([CH3:1])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)(C)[Mg]Cl
Reactant: O=C(Cl)CCCCl
Agent: CCCCC(C)(C)Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(C)(C)C(=O)CCCCl
Reaction time: 12 h

Procedure:
Four hundred ml. of a solution in ether of 1,1-dimethylpentylmagnesium chloride prepared from magnesium (24.3 g., 1.0 mole) and 1-chloro-1,1-dimethylpentane (134.5 g., 1.0 mole) according to the procedure of Whitmore and Badertscher [J. Am. Chem. Soc., 55, 1559 (1933)] is added dropwise with stirring to 4-chlorobutyryl chloride (197 g., 1.4 moles) in ether (400 ml.) during 6 hours. The reaction mixture is stirred for an additional 12 hours. It is then poured into a mixture of ice and dilute hydrochloric acid. The ether layer is separated, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residue distilled at aspirator vacuum through a Vigreaux column to yield the product as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:20]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCN(c2ccccc2)C(=O)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC1CCN(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2-oxo-1-phenylpiperidin-4yl)methyl methanesulfonate (0.37 g, 1.3 mmol) was dissolved in dimethylsulfoxide (6 mL), treated with sodium azide (0.18 g, 2.8 mmol, 2.1 equiv) and placed into a preheated oil bath at 60° C. for 18 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL) and washed twice with water (50 mL) and brine (50 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:26]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C:25]=3[S:24][C:10]=2[N:11]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:15])[CH2:13][N:14]=1.ClC1C=C(C=CC=1)C(OO)=[O:43].C(OC(C)C)(C)C.CCC(C)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:26]3[CH2:27][CH2:28][NH:29][CH2:30][C:25]=3[S:24][C:10]=2[N:11]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:15])[CH:13]([OH:43])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCC(=O)N3CCc2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)C
Solvent: CC(C)OC(C)C
Product: O=C1C(O)N=C(c2ccccc2Cl)c2c(sc3c2CCNC3)N1CCc1ccccc1
Reaction time: 24 h

Procedure:
t-butyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4′,3′:4.5]thieno[2,3-e]-1,4-diazepine-8-carboxylate (22 g, 41 mmol) is dissolved a 23° C. in 1,2-chloro ethane (320 ml). Meta-chloroperoxybenzoic acid at 85% (21.6 g, 0.1 mol) is added. Agitation is carried out for 24 hours at 23° C. then a solution of 5N sodium hydroxide (400 ml) is added. After decanting, the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated with a rotary evaporator. After purification by chromatography on a silica column (eluent: ethyl acetate-heptane: 50-50 to 80-20), the fractions containing only the product ae evaporated. The solid obtained is agitated in a mixture of solvents: isopropyl ether-isopentane (20-80). After filtration on frit and washing with isopentane, the desired product is obtained in the form of a white powder (5.9 g, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=[C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]1=[O:11]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-methyl-2-oxindole (147 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 3-(1H-indol-2-ylmethylene)-4-methyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [OH:1][CH:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([O:16]C)=O)=[CH:10][CH:9]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CCOCC.[ClH:38]>ClCCl>[ClH:38].[OH:1][C@H:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)COc1ccc(OCCNCC(O)COc2ccccc2)cc1
Reactant: COCCN
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCCNC(=O)COc1ccc(OCCNC[C@H](O)COc2ccccc2)cc1

Procedure:
(-)-Methyl 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenoxyacetate (44.0 g) (the same starting material as in Example 2) and 2-methoxyethylamine (30 ml) were heated together on a steam-bath for 24 hours. The mixture was cooled and evaporated under reduced pressure to give an oily residue. This was dissolved in dichloromethane (200 ml) and treated with a solution of ether saturated with hydrogen chloride. The solvent was evaporated and the residual solid crystallised from a mixture of methanol and ethyl acetate to give (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]-N-(2-methoxyethyl)phenoxyacetamide hydrochloride (39.2 g), m.p. 171°-3° C.; αD =-10.7° (c=1.0; methanol); microanalysis: found C, 58.1; H, 7.0; N, 6.0; Cl, 7.9%; required for C22H31ClN2O6 : C, 58.1; H, 6.9; N, 6.2; Cl 7.8%: NMR (DMSO-d6) 3.1(m,1H, CHCH2NH); 3.24(s, 3H,OCH3); 3.24-3.45(m,7H,CHCH2NHCH2 ; NHCH2CH2OCH3); 4.0(m,2H, ArOCH2CHOH); 4.2-4.35(m,3H,CHOH; CH2CH2OAr); 5.95(d,1H,OH); 6.85-7.05(m,7H,Ar); 7.3(m,2H,Ar); 8.15(t,1H, CONHCH2); 9.16 and 9.35 (broad peaks, 2H, NH2+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([O:18]CC)=O)=[C:7]([C:11](OCC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16](=[O:18])[N:23]=[N:22][C:11](=[O:12])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1[nH]c2cc(Br)ccc2c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of diethyl 6-bromoindole-2,3-dicarboxylate (0.5 g, 1.47 mM) in ethanol (4 mL) was added hydrazine hydrate (2.2 mL, 44 mM). The solution was heated to reflux for 90 minutes and then cooled to room temperature. The resulting solid was filtered and then suspended in glacial acetic acid (5 mL). After heating this mixture to reflux for several minutes and cooling to room temperature, the solid was filtered off and dried under vacuum. This afforded the titled compound as a white solid (0.35 g, 85%), mp 260° C. NMR (d6 -DMSO): 11.81 (br s, 2H), 8.04 (dd, J1 =1.0 Hz, J2 =8 Hz), 7.76 (s, 1H), 7.46 (d, J=8 Hz), 3.36 (br s, 1H). MS(CI): 280 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25]([N:29]1[CH2:33][CH2:32][O:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:30][N:29]([CH2:33][CH2:32][OH:31])[CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: CCCCN1CCOC1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(CN(CCO)CCCC)c(O)c(OC)c1)O2
Yield: 56.6 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane and 15.5 g of 3-butyl-1,3-oxazolidine are held in 180 ml of absolute alcohol for 36 hours at 70° C. and subsequently the solvent and excess 3-butyl-1,3-oxazolidine are removed in vacuum. After purification by means of a chromatographic column there is obtained 15.8 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenyl-methyl)-N-(2-hydroxyethyl)-N-butylamine, a colourless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8](=[O:11])[CH2:9][CH3:10])[N:6]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:8]([NH:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Nc1csc(Br)n1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)Nc1cscn1
Yield: 17.9 %

Procedure:
A solution of 2-bromo-4-propionamidothiazole (4g) and sodium acetate (1.4g) in methanol (100 ml.) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst (1.0g) until the theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the extracts evaporated in vacuo. The residue was recrystallised twice from carbon tetrachloride to give the title compound (1.9g) m.p. 129°-32° C. (Found: C, 46.3; H, 5.2; N, 17.7. C6H8N2OS requires C, 46.1; H, 5.2; N, 17.9%).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=[O:3])=[O:2].FC(F)(F)C(O)=O.CC[N:21](C(C)C)C(C)C>>[CH3:9][C:8]1[CH:7]=[CH:6][C:5]([S:1]([NH2:21])(=[O:3])=[O:2])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(N)(=O)=O)cc1

Procedure:
Referring to reaction Scheme I, trans-1,2-di-carbomethoxy-4-methylene-cyclopentane is reacted with sodium hydroxide followed with acid to produce trans-4-methylene-1,2-cyclopentanedicarboxylic acid. The dicarboxylic acid is reacted with acetic anhydride to produce cis-tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3H)-dione. The ammonium salt 4 is prepared by reacting the anhydride 3 in dry methylene chloride with ammonia gas. The imide 5 is prepared from the ammonium salt by reacting the ammonium salt with acetyl chloride. The imide is reacted with lithium aluminum hydride and ditertiarybutyl dicarbonate to produce cis-1,1-dimethylethylhexahydro-5-methylenecyclopenta[c]pyrrole-2(1H)carboxylate 6. The term BOC is used herein to refer to t-butyloxy carbonyl. The BOC-amine 6 is reacted with bis(p-toluenesufonyl) sulfodiimide to produce the p-toluenesulfonamide 7. The term Tos is used herein to represent p-toluenesulfonyl. The p-toluenesulfonamide is reacted with thexyl borane to produce the endo alcohol 8. The endo alcohol is reacted with p-toluenesulfonyl chloride to produce the tosylate 9. The tosylate 9 is reacted with trifluoroacetic acid and treated with Hunig's base to provide the p-toluenesulfonamide tetracycle 10. The sulfonamide tetracycle 10 was reductively cleaved to produce the aminoazatetracycle 11. Coupling of the aminoazatetracycle 11 with benzoic acid derivative 12 under mixed anhydride conditions gave the protected benzamide tetracycle 13. Basic hydrolysis of the acetamide 13 gives the benzamide tetracycle 14 which upon treatment with HCl produces the hydrochloride salt of the benzamide tetracycle 15.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[CH:10]1[CH2:13][O:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:10]2[CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: IC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cn(C2COC2)cn1
Temperature: 120 °C
Yield: 33.4 %

Procedure:
A sealed tube was charged with 4-nitro-1H-imidazole (500 mg, 4.42 mmol), 3-iodooxetane (920 mg, 5.0 mmol), Cs2CO3 (2.90 g, 8.84 mmol), and dioxane (12 mL). The sealed tube was heated at 120° C. for 16 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 285a as a white solid (250 mg, 33%). MS-ESI: [M+H]+ 170.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-4-piperidone (7.2 g, 39.64 mmol), and pyrrolidine (4.23 g, 59.5 mmol) in toluene (50 mL) is refluxed for 4 hr with a Dean-Stark trap to remove water. The mixture is cooled to rt and removal of solvent in vacuo provides the title compound as a light orange oil, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][N:8]=1)[CH3:2].O=P(Cl)(Cl)[Cl:23]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([Cl:23])=[N:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1n[nH]c(=O)c2cc(OC)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)CCc1nnc(Cl)c2cc(OC)ccc12
Yield: 84.8 %

Procedure:
Operating analogously to example 114 starting from 3-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-propionic acid ethyl ester (552 mg, 2 mmoles), prepared as described in example 119, and POCl3 (1.12 ml, 12 mmoles) in acetonitrile (5 ml), 0.5 g of the title compound were obtained (yield: 84.8%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:43][CH:44]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:43][CH:44]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(NC(=O)c1ccc(Br)s1)c1ccccc1
Reaction time: 16 h
Yield: 299.5 %

Procedure:
To a solution of 5-bromo-2-thiophenecarboxylic acid (3.2 g, 15.2 mmol), PyBrOP (8.5 g, 18.2 mmol) and diisopropylethyl amine (10.6 mL, 60.9 mmol) in DCM (76 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (3.6 g, 3.14 mmol)[prepared in Preparation 1]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fraction were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM) affording the title compound (4 g, 62%) as a white solid: LC-MS (ES) m/z=426 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:19]1([CH2:22][C:23]2[C:28]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)=O)[N:30]=3)=[CH:27][N:26]=[C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:24]=2)[CH2:21][CH2:20]1>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([NH:1][C:31]2[N:30]=[C:29]([C:28]3[C:23]([CH2:22][CH:19]4[CH2:21][CH2:20]4)=[N:24][C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])=[N:26][CH:27]=3)[CH:34]=[CH:33][N:32]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Reactant: Nc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccnc(Cl)c3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 4-amino-2-chloropyridine (53.3 mg, 0.415 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 min. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 h. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 min] followed by Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (29 mg, 49%).