Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Br:18]P(Br)Br>C(Cl)Cl.C1COCC1>[Br:18][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cccc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(Br)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl 3-(1-hydroxyethyl)phenylcarbamate (5.8 g, 24.44 mmol) in CH2Cl2 (30 mL) and THF (20 mL) at 0° C. was added tribromophosphine (1 M solution in CH2Cl2, 24.44 mL, 24.44 mmol). The reaction was stirred at 0-10° C. for 1.5 h and then quenched with water. The mixture was extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to afford the title compound (5.7 g, 78% yield) as a colorless oil. LCMS, [M+Na]+=322.1.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:9]=[CH:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:1][CH2:8][CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C1=CCCC=CCC1
Reactant: C=CCCCC
Product: C=CCCC=CCCC=CCCCC

Procedure:
disproportionating 1,5-cyclooctadiene and 1-hexene in the presence of a disproportionation catalyst under disproportionation conditions suitable to give 1,5,9-tetradecatriene,
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCC=CC/C=C/CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCC=CC/C=C/C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.3 %

Procedure:
To a solution of trans, trans-2,5-nonadien-1-ol (15 g) in chloroform (1500 ml) was added manganese dioxide (150 g). The reaction mixture was stirred for 20 hours at ambient temperature and then filtered. The filtrate was concentrated under reduced pressure to give a yellowish oily residue, which was subjected to a column chromatography on silicagel (developing solvent: chloroform). The fraction containing object compound was concentrated under reduced pressure to give colorless oily trans, trans-2,5-nonadienal (7 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].Cl>CS(C)=O.CCOC(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])[C:3]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a mixture of NaH (60%, 7 g, 0.16 mol) in dimethyl sulfoxide (150 mL) was added dropwise dimethyl malonate (20 mL, 0.16 mol). The mixture was heated to 100° C. for 10 min then cooled to room temperature, followed by the addition of 2,5-difluoronitrobenzene (14 g, 0.08 mol). After stirred at 90° C. for 2 h, the mixture was cooled and poured into 5% aq.HCl with ice cooling. EtOAc (50 mL) was added and the organic phase was separated, washed by water and dried with Na2SO4. The solvent was removed in vacuo to give 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (19.4 g). 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (6 g, 22 mmol) was dissolved in glacial acetic acid (30 mL), the aqueous HCl (6N, 30 mL) was added and the reaction mixture were heated ar refluxing for 4 h, Iron power (5 g, 88 mmol) was added portionwise to the mixture and the refluxing was allowed to continue for another 2 h. The solvent was removed in vacuo and the remaining residue was extracted by EtOAc. The organic phase washed with aqueous HCl (1N), brine and dried over Na2SO4. concentrated to give the titled compound as a yellow solid (3 g, 89%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)=[C:15]([F:26])[CH:14]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:25][C:22]1[N:23]=[CH:24][C:19]([C:16]2[C:15]([F:26])=[CH:14][C:13]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][OH:1])=[CH:18][CH:17]=2)=[N:20][CH:21]=1
Reactant: OCc1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(-c3ccccc3CO)cc2F)cn1
Yield: 61.6 %

Procedure:
A mixture of 2-(hydroxymethyl)phenylboronic acid (1 g, 7 mmol), 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (1.76 g, 6.6 mmol), Pd(dppf)Cl2.CH2Cl2 (483 mg, 0.66 mmol) and Na2CO3 (2.1 g, 20 mmol) in DMF (50 mL) was stirred at 110° Celsius overnight under N2. The solution was concentrated to dryness and the residue purified by FCC to give (4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methanol (1.2 g, 62%). 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.02 (d, J=1.4, 1H), 7.90 (m, 1H), 7.57 (d, J=7.4, 1H), 7.49-7.26 (m, 5H), 6.69 (s, 2H), 5.20 (t, J=5.3, 1H), 4.44 (d, J=5.3, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:13]([NH2:15])=[O:14].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:13]([NH2:15])=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@H](Cc2c[nH]c3ccccc23)C(N)=O)cc1Br
Yield: 31.3 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (160 mg, 0.800 mmol), (R)-2-amino-3-(1H-indol-3-yl)propanamide (164 mg, 0.807 mmol) and DIEA (0.300 mL, 1.72 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, which was eluted with 0-80% EtOAc in hexane to give (R)-2-(3-bromo-4-cyanophenylamino)-3-(1H-indol-3-yl)propanamide (96 mg)
Reaction SMILES: N#N.C([NH:6][C:7]1[NH:8][C:9](=[O:35])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:14]=2[N:15]=1)(=O)C>[OH-].[NH4+].CO>[CH3:31][C:30]([CH3:33])([CH3:32])[C:29]([O:28][CH2:27][CH:18]([O:17][CH2:16][N:13]1[CH:12]=[N:11][C:10]2[C:9](=[O:35])[NH:8][C:7]([NH2:6])=[N:15][C:14]1=2)[CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[O:34]
Reactant: CC(=O)Nc1nc2c(ncn2COC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C)c(=O)[nH]1
Agent: N#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)OCC(COC(=O)C(C)(C)C)OCn1cnc2c(=O)[nH]c(N)nc21

Procedure:
A solution of N2 -acetyl-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine in 10% ammonium hydroxide in methanol was kept at room temperature for 7 hours and then evaporated. The residue was recrystallized from methanol to give 9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine, m.p. 230°-232° C.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C(OC(=O)C)(=O)C.[ClH:19].[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.C(N(CC)CC)C>O.C1(C)C(C)=CC=CC=1>[ClH:19].[ClH:19].[CH2:31]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:20]=[C:6]([CH:3]2[CH2:4][CH2:5][CH:1]([C:9]([OH:11])=[O:10])[CH2:2]2)[OH:8])[CH2:30][CH2:29]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NCCCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)C1CCC(C(=O)O)C1
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=C(O)C1CCC(C(O)=NCCCCN2CCN(Cc3ccccc3)CC2)C1
Reaction time: 18 h

Procedure:
1,3-Cyclopentane dicarboxylic acid (8.0 g., 51 mmole) was converted to the anhydride by refluxing for 3 hours in 100 ml. of acetic anhydride. The excess solvent was removed under vacuum and the residue was stored in vacuum for 18 hours. The crude anhydride thus obtained was combined with 14 g. (50 mmole) of 1-(4-aminobutyl)-4-benzylpiperazine hydrochloride and 5.0 g. (50 mmole) of triethylamine in 500 ml. of xylene. The mixture was refluxed for 48 hours with water separation via a Dean-Stark trap. The product was concentrated under vacuum and chromatographed on 200 g. of silica gel with 2% ethanol/chloroform. The product was crystallized from ethanol by addition of 4N HCl/isopropyl alcohol to obtain cyclopentane-1,3-dicarboxylic-N-[4-(4-benzyl-1-piperazinyl)butyl]imide dihydrochloride; m.p. 273°-275° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[Cl:19][C:18]1[C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccnc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2ncccc2Cl)c1
Temperature: 120 °C

Procedure:
20 7.68 g of sodium hydride dispersion (ca. 50 percent in mineral oil) was washed with pentane under nitrogen and 100 ml of N,N-dimethylformamide was then added. 21.92 g (135 mmol) of 3-(trifluoromethyl)phenol was added dropwise over 30 minutes at room temperature. The resultant phenate solution was added dropwise over 2 hours, under nitrogen, to a solution of 20.1 g (136 mmol) of 2,3-dichloropyridine in 80 ml of N,N-dimethylformamide, heated to 120° C. After a reaction time of 3 hours, the mixture was cooled to room temperature, the precipitate of sodium chloride was filtered off and the filtrate was concentrated. The residue was extracted with toluene and 0.1 N hydrochloric acid, and the organic was washed with saturated sodium chloride solution and concentrated. The oily residue was distilled under vacuum. The yield of the title compound was 24.75 g (67 percent) of a colorless oil, content (GC) 99.7 percent. Other data concerning the title compound was:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 135 °C
Reaction time: 36 h
Yield: 36.7 %

Procedure:
A suspension of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (178 mg, 0.740 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (255 mg, 0.673 mmol), CuI (154 mg, 0.808 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol) and Cs2CO3 (241 mg, 0.740 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135° C. for 36 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH was added and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (133 mg, 33%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.00 (br s, 1H), 8.07 (br d, J=8.3 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.60-7.52 (m, 2H), 7.32 (s, 1H), 7.28-7.20 (overlapping with solvent peak, 1H), 7.11-7.02 (m, 2H), 3.84-3.60 (m, 7H), 3.12-2.95 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:12]([N:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c[nH]c2ccc(Cl)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.O.[NH2:10][NH2:11].C(O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][NH2:11])=[N:6][CH:7]=1
Reactant: NN
Reactant: Fc1ccc(Br)cn1
Solvent: O
Solvent: CCO
Product: NNc1ccc(Br)cn1
Yield: 94.3 %

Procedure:
5-Bromo-2-fluoropyridine (25.12 g) and hydrazine monohydrate (100%) (91 g) were added to ethanol (75 ml), stirred under reflux for four hours, and then water was added thereto and the precipitated solid was washed with water to give 5-bromopyridin-2-ylhydrazine (25.3 g) as a white solid.
Reaction SMILES: CS([O:5][C@@H:6]([CH3:16])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.CC(C)([O-])C.[K+].CS(C)=O.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[N:32][C:33]=1[O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:45][C:46]1[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=1>O>[Si:9]([O:8][CH2:7][C@@H:6]([CH3:16])[O:5][C:30]1[CH:29]=[C:28]([Cl:27])[C:33]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][N:39]=[C:38]3[NH:45][C:46]2[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=2)=[N:32][CH:31]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 33.1 %

Procedure:
(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl methanesulfonate (79 mg, 0.29 mmol) and potassium tert-butoxide (55 mg, 0.49 mmol) were added to a dimethyl sulfoxide solution (3 ml) of 5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (90 mg, 0.24 mmol) obtained in Example 22, then stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to 0:1) to obtain 6-{[5-((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (43 mg, yield: 33%) as a white solid.
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1.[C:12]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]#[N:18])(=O)[CH2:13][CH3:14]>O.CC1C=CC=CC=1C>[CH2:13]([C:12]1[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:17]([NH2:18])[N:8]2[N:9]=[CH:10][N:11]=[C:7]2[N:6]=1)[CH3:14]
Reactant: Nc1nc[nH]n1
Reactant: CCCCCCCCC(C#N)C(=O)CC
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCc1c(CC)nc2ncnn2c1N
Temperature: 140 °C
Yield: 83 %

Procedure:
In a 2.5 l jacketed vessel fitted with condenser and water separator, 737 g of o-xylene was initially charged, and 39.5 g of chlorosulfonic acid was added. 191.2 g of 3-amino-1,2,4-triazole and 1254 g of a solution of 2-propionyldecanonitrile (37.7% by weight in o-xylene) were added, and the mixture was heated to reflux. The mixture was stirred under reflux for 12 hours, and the water of reaction formed was removed via a phase separator. Once no more water was separated off, the mixture was cooled to 140° C. and 59.4 g of triethylamine were added. On further cooling, the product precipitated in the form of colorless crystals. At a temperature 105° C., 152.8 g of methanol were added. The mixture was cooled further to 20° C., and the solid formed was separated off. The filtercake was washed with a mixture of 850 g of methanol and 119 g of water and then dried under reduced pressure. This gave 525.5 g of colorless crystals having a content of 98.3% a/a (HPLC). The title compound was obtained as a mixture of two modifications having melting points of 199° C. and 201° C., respectively. Yield: 83.0%.
Reaction SMILES: [CH2:1]([CH2:4][C:5](Cl)=[S:6])[CH:2]=[CH2:3].[CH3:8][CH:9]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[N:12]2[C:23](=[O:26])[CH:24]([NH2:25])[C@H:11]2[S:10]1>ClCCl>[CH3:8][CH:9]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:20])[Cl:21])=[O:16])[N:12]2[C:23](=[O:26])[CH:24]([NH:25][C:5](=[S:6])[CH2:4][CH2:1][CH:2]=[CH2:3])[C@H:11]2[S:10]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: C=CCCC(=S)Cl
Solvent: ClCCl
Product: C=CCCC(=S)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (0.764 g) in dried dichloromethane (8 ml) were added at -30° C. a solution of triethylamine (0.18 g) in dichloromethane (2 ml) and then a solution of dimethylaniline (0.27 g) in dichloromethane (2 ml). While, allylthioacetate acid (0.528 g) was added to thionyl chloride (5 ml) and the mixture was allowed to stand for 20 minutes at room temperature and 5 minutes at 50° C., after which thionyl chloride was removed under reduced pressure, and the residue was added a small amount of benzene, and then removed under reduced pressure to give allylthioacetyl chloride (0.527 g). A solution of this obtained allylthioacetyl chloride (0.452 g) in dichloromethane (3 ml) was dropwise added at -30° C. over 5 minutes to the above-mentioned solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate, and the mixture was stirred for 1 hour at -20° C. After the reaction, the reaction mixture was in turn washed twice with 5% hydrochloric acid, once with water, twice with a saturated sodium bicarbonate aqueous solution and once with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After the solvent was distilled off, the residue (0.82 g) was recrystallized from a mixture of ether and isopropyl ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate (0.71 g), mp 96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:23][N:22]([CH3:33])[CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)CCC(N)c1ccccc1
Product: CN(C)CCC(NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)c1ccccc1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and N1,N1-dimethyl-3-phenylpropane-1,3-diamine (17.8 mg, 0.1 mmol). The title compound was obtained as a solid (15.8 mg, 31% yield). MS m/z: 510.89, 513.89 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:18]3[C:17](=[O:19])O[C:15](=[O:20])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][CH2:28][NH2:29]>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[C:17](=[O:19])[N:29]([CH2:28][CH2:27][CH:23]2[CH2:24][CH2:25][CH2:26][N:22]2[CH3:21])[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: CN1CCCC1CCN
Reactant: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Solvent: C1COCCO1
Product: CN1CCCC1CCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O

Procedure:
50 mg (0.16 mmol) of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thiophenecarboxamide and 20.8 mg of (0.16 mmol) 2-(1-methyl-2-pyrrolidinyl)ethylamine are dissolved in 2 ml of dioxane and heated at reflux for 24 h. Removal of the solvent under reduced pressure gives 65 mg (97% of theory) of the desired product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[NH:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][Mg]Br>C1(C)C=CC=CC=1.C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([NH2:12])[CH3:13])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N=Cc1cccc2c1OCCO2
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(N)c1cccc2c1OCCO2
Temperature: 60 °C
Reaction time: 24 h

Procedure:
The dried resin to which the C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine (1 eq) was bound was suspended in dry toluene. Under a nitrogen atmosphere methyl magnesium bromide (150 eq) in a 3 M solution in ethyl ether was added. This mixture was shaken for 24 hours at 60° C. then filtered and washed with toluene, water, then methanol and dichloromethane alternately three times. The final wash was with methanol. The solid was dried under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][C@H:6]([NH:20]C(C1C=C(C)N=C(N(CCC)CCC)N=1)=O)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.[CH2:41]([N:45]([CH3:56])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([Cl:55])[N:54]=1)[C:49]([OH:51])=O)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([N:45]([CH3:56])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([Cl:55])[N:54]=1)[C:49]([NH:20][C@@H:6]([CH2:5][C:4]1[CH:37]=[C:38]([F:40])[CH:39]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1)=[O:51])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCN(C)c1cc(C(=O)O)cc(Cl)n1
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Product: CCCCN(C)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(Cl)n1

Procedure:
In the same manner as for N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(dipropylamino)-6-methylpyrimidine-4-carboxamide {Example S-2435}, Step 3, 2-[butyl(methyl)amino]-6-chloroisonicotinic acid (0.15 g) was converted to 0.13 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1S(NC1C=C(C=CC=1)C(O)=O)(=O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:9])=[O:8]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Product: O=C(O)c1ccc(NS(=O)(=O)c2ccccn2)cc1
Yield: 50 %

Procedure:
Intermediate 5c (solid) is prepared using intermediate 4b and ethyl 4-aminobenzoate using the procedure described for 5a.