Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][S:31]([C:34]2[S:35][C:36](Br)=[CH:37][CH:38]=2)(=[O:33])=[O:32])=[CH:24][CH:23]=1>>[N:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][S:31]([C:34]2[S:35][C:36]([C:21]#[C:20][C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]5[CH2:16][CH2:15]5)=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[CH:37][CH:38]=2)(=[O:33])=[O:32])=[CH:26][CH:27]=1
Reactant: O=S(=O)(NCCc1ccncc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: O=S(=O)(NCCc1ccncc1)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (147 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-pyridin-4-yl-ethyl)-amide (example B.60) (174 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (112 mg, 40%). MS (ISP) 560.2 [(M+H)+]; mp 172-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:15][CH3:14])=[O:8]
Reactant: COc1ncc(Br)cc1C(=O)O
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc(Br)cnc1OC
Yield: 43 %

Procedure:
The title compound was synthesized as described for Intermediate example I-36 in 43% yield, starting from 5-bromo-2-methoxynicotinic acid and methylamine hydrochloride (4.3 equiv); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, 1 H), 8.26-8.35 (m, 1 H), 8.20 (d, 1 H), 3.95 (s, 3 H), 2.79 (d, 3 H); MS (APPI/APCI) m/z 245, 247[M+H+].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:6]=1.[OH:14][CH:15]=[C:16]([CH3:22])[C:17](OCC)=O>>[C:8]1([S:7][C:4]2[S:3][C:2]3=[N:1][CH:17]=[C:16]([CH3:22])[C:15](=[O:14])[N:6]3[N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1nnc(Sc2ccccc2)s1
Reactant: CCOC(=O)C(C)=CO
Product: Cc1cnc2sc(Sc3ccccc3)nn2c1=O
Yield: 58 %

Procedure:
Seven point two (7.2) g of the thus obtained 2-amino-5-phenylthio-1,3,4-thiadiazole and 4.9 g of ethyl 3-hydroxy-2-methyl-2-propenoate were mixed with 13 g of polyphosphoric acid. By the same procedure as in Preparation Example 4, 5.9 g of 2-phenylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CN(C=O)C.C1C(=O)N([Br:32])C(=O)C1>O.C(OCC)(=O)C>[Br:32][C:17]1[S:16][C:15]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH2:4][CH2:3]2)=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C1CCC(O)(c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(O)(c2ncc(Br)s2)CC1
Yield: 79.7 %

Procedure:
To a flask containing the product of Step 1 (9.25 g, 33 mmol) was added DMF (36 mL) and then n-bromosuccinimide (6.97 g, 32 mmol). The reaction was allowed to stir until complete by LCMS. The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexane-carboxylate (9.24 g, 25.5 mmol, 78% yield). MS ESI: [M+H]+ m/z 364.0.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[CH3:8][N:9]=[C:10]=[S:11].[CH3:12]I>CN(C)C=O>[C:5]([C:4]([C:3]#[N:7])=[C:10]([S:11][CH3:12])[NH:9][CH3:8])#[N:6]
Reactant: CI
Reactant: N#CCC#N
Reactant: CN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(SC)=C(C#N)C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (50% oil dispersion, 9.6 g) was added portionwise to a solution of malononitrile (13.21 g) in dry dimethylformamide (150 ml). The mixture was stirred at 0° for 10 minutes and then to it was added dropwise a solution of methyl isothiocyanate (14.62 g) in dimethylformamide, maintaining the reaction temperature below 40°. The dark red solution was stirred for 45 minutes and a solution of methyl iodide (28.4 g) in dimethylformamide (25 ml) was then added. The reaction mixture was stirred vigorously for 20 minutes and then poured on to crushed ice (500 ml). The crude product (26 g, m.p. 115°) was filtered off and taken up in hot ethanol ether (3:1, 600 ml). Filtration and cooling furnished 1,1-dicyano-2-methylthio-2-methylamino ethylene m.p. 119°-120°. Further recrystallisation from water gave a sample of m.p. 120°-121°. (Found: C, 46.7; H, 4.6; N, 27.1; S, 20.8; C6H7N3S requires: C, 47.0; H, 4.4; N, 27.4; S, 20.9)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCc1cccc(Cl)c1)c1ccc(Cl)nn1
Product: O=C(NCCc1cccc(Cl)c1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(3-chlorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow powder (59.6% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.94, 7.75, 7.64, 7.57, 7.37, 7.26, 7.24-7.19, 7.12, 7.00, 4.10, 3.95-3.66, 3.38, 2.90.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC1C=CC(C(C)(C)C)=CC=1)(=O)C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(=O)OCc1ccc(C(C)(C)C)cc1
Product: Cc1ccc(C(C)(C)C)cc1
Yield: 9.7 %

Procedure:
If the material discharged from the electrolysis is worked up similarly to Example 1, 284.8 g of p-tert.-butylbenzaldehyde and 295.3 g of p-tert.-butylbenzyl acetate are obtained in addition to 25.2 g of unconverted p-tert.-butyltoluene. This corresponds to a yield of 83.3% and a current efficiency of 58.2%. The p-tert.-butylbenzaldehyde is separated from the p-tert.-butylbenzyl acetate by the method described in Example 1.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:60]=[CH:59][C:28]([CH2:29][N:30]([CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])[C:31](=[O:50])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:49])[CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)=[CH:34][CH:33]=2)=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C:39]([NH:38][C:35]2[CH:34]=[CH:33][C:32]([C:31]([N:30]([CH2:51][C:52]([OH:54])=[O:53])[CH2:29][C:28]3[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])[C:12]4[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:17][CH:16]=4)=[CH:60][CH:59]=3)=[O:50])=[CH:37][CH:36]=2)=[O:49])=[CH:46][CH:45]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-octylbenzoic acid (42 mg, 0.178 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.016 mL, 0.190 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (60 mg, 0.119 mmol) and TEA (0.050 mL, 0.357 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to provide to afford 15.3 mg (19%) of 2-(4-(2-(4-methoxyphenyl)acetamido)-N-(4-((4-octylbenzoyl)oxy)benzyl)benzamido)acetic acid 40. LCMS-ESI (m/z) calculated for C40H44N2O7: 664; found 665 [M+H]+, tR=10.33 min (Method 4). 1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.50-7.21 (m, 10H), 6.89 (d, J=8.4 Hz, 2H), 4.63 (d, J=36.7 Hz, 2H), 3.95 (d, J=33.1 Hz, 2H), 3.73 (s, 3H), 3.58 (s, 2H), 2.76-2.64 (m, 2H), 1.61 (s, 2H), 1.36-1.10 (m, 10H), 0.86 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]12[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.C(N(CC)CC)C>C(O)(C)C>[CH3:11][C:10]1[C:3]2[C:2]([N:14]3[CH2:13][CH:12]4[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CC4CCC(C3)N4C(=O)OC(C)(C)C)c12
Temperature: 180 °C
Yield: 71.4 %

Procedure:
To a solution of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (25 mg, 0.15 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.14 mmol) in isopropanol (2 ml) was added triethylamine (36 μL, 0.26 mmol). The reaction was heated at 180° C. for 30 min in the microwave, then concentrated under vacuum. The residue was purified by prep HPLC (Sunfire C18 30×50 mm, 10-90% H2O/MeOH w/0.01% TFA, 15 min, 35 ml/min, 220 nm) to give tert-butyl 3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.10 mmol, 66%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29].[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][N:31]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[C:40]([O:39][C:37]([N:31]1[CH2:32][C@@H:33]2[CH2:36][C@H:30]1[CH2:35][N:34]2[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7F (500 mg), tert-butyl (1S,4S)-(−)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate (0.259 g), and diisopropylethylamine (0.622 mL) in acetonitrile (11.9 mL) was heated at 50° C. for 18 hours then cooled, diluted with dichloromethane, washed with saturated ammonium chloride and brine, and dried (MgSO4), filtered, and concentrated; and the concentrate was recrystallized from diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][C:28]([NH2:30])=[O:29].C(O)(=O)C.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](\[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)/[CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: NC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 7.9 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (1.00 g), 4-oxo-4-phenylbutanamide (571 mg), acetic acid (0.553 ml), sodium acetate (528 mg) and ethanol (20 ml) was heated to reflux for 10 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography and concentrated a portion from an ethyl acetate-hexane (3:1, v/v)-eluted fraction which eluted following the E-compound, to obtain crystals. The crystals were recrystallized from ethanol to obtain Z-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanamide (120 mg, yield 8%) as colorless crystals. m.p. 110-112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH2:26][S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:26][S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)C1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
A solution of 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester (3.1 g, 5.7 mmol) in ethyl acetate was treated sequentially with ethanol and tin (II) chloride dihydrate (20.2 g, 89.5 mmol), stirred at 75° C., under nitrogen, for 2 hours, 20 minutes, poured into excess water and extracted with ethyl acetate. The combined extracts were washed sequentially with 2.5 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo for 20 minutes at 80° C. to yield 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester as a yellow solid, 2.37 g (82% yield), mp 162-4° C.; Mass spectrum (+EI, [M+H]+) m/z 517. 1HNMR (500 MHz, DMSO-d6): δ8.60-8.63 (m, 1H), 8.26 (dd, 1H, J=12.81 Hz and 8.23 Hz), 8.03-8.08 (m, 2H), 7.58-7.72 (m, 3H), 7.27-7.40 (m, 5H), 6.56-6.61 (m, 2H), 6.06 (s, 1H), 5.03-5.09 (m, 2H), 4.72 (s, 2H), 4.67 (s, 2H), 4.30 (s, 1H), 3.32-3.42 (m, 2H), 3.15-3.21 (m, 2H), 1.74-1.81 (m, 1H), 1.66-1.63 ppm (m, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[C:10]([F:16])[C:8]=1[NH2:9].CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[NH2:9][C:8]1[C:10]([F:16])=[C:11]([Cl:15])[C:12]([F:14])=[CH:13][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Nc1c(Br)cc(F)c(Cl)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1c(C=O)cc(F)c(Cl)c1F
Temperature: -75 °C
Reaction time: 3 h

Procedure:
66 cm3 of a 2 N butyllithium solution (in hexane) was added dropwise over 30 minutes to a stirred solution of 13.4 g of 2-bromo-5-chloro-4,6-difluoroaniline in 150 cm3 of anhydrous tetrahydrofuran (THF) cooled to a temperature in the region of −75° C. After stirring for 1 hour at this temperature, 12.8 cm3 of dimethylformamide was added. After the addition, the mixture was again stirred for 3 hours at a temperature in the region of −70° C. The mixture was brought to a temperature in the region of −5° C., and then an aqueous ammonium chloride solution (18 g dissolved in 180 cm3) was added. The reaction mixture was extracted twice with 200 cm of diethyl ether. The combined ethereal extracts were washed once with 150 cm3 of water and once with 150 cm3 of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the solution was concentrated under reduced pressure (5 kPa), at a temperature in the region of 40° C. After taking up the solid residue obtained in 80 cm3 of hexane and then filtration, 6.2 g of 2-amino-4-chloro-3,5-difluorobenzaldehyde was obtained in the form of a yellow solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1>O.C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[C:15](=[N:1][OH:3])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CCc1cccc(Cl)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (12.6 g) in water (25 ml) was added to a stirred solution of the product from step (i) (42.2 g) in acetic acid (50 ml) at <30° C. The reaction mixture was stirred at room temperature for 30 min. Water (75 ml) was added and the mixture was stirred for 2 hours and extracted with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was collected, dried (MgSO4) and solvent evaporated under reduced pressure to give the subtitle product.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:23]4[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (76 mg, 86%), MS (ISP) m/z=356.5 [(M+H)+], mp 359° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH:24]=[N+:25]([CH3:27])[CH3:26].COC1C=C(C=CC=1OC)C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:24]([N:25]([CH3:27])[CH3:26])[C:23]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1Cl
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2c(-c3ccc(F)c(Cl)c3)[nH]c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(3-chloro-4-fluoro-phenyl)-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[C@H:8]2[S:7]1.Cl.C(OCC)(=O)C>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Nc3ccccc3)[C@H]2S1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Nc3ccccc3)[C@H]2S1
Yield: 34 %

Procedure:
Acetic acid (8 ml) and zinc powder (6 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate (4.1 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1 hour under ice-cooling and then 3.5 hours at room temperature. After the reaction, 10% hydrochloric acid and ethyl acetate were added to the reaction mixture. The insoluble material was filtered off and the ethyl acetate layer was separated, and then extracted with a sodium bicarbonate aqueous solution. The extract was acidified with 10% hydrochloric acid and extracted with ethyl acetate, after which the extract was dried over magnesium sulfate. After the solvent was distilled off, the residue was crystallized by adding ether to give 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid (1.0 g), mp 148° to 151° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[Cl-].[Li+].N12CCCN=C1CCCCC2.[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>C(#N)C.O>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:29]/[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([OH:25])[CH:27]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A solution of trimethyl phosphonoacetate (9.94 mL, 61.4 mmol), lithium chloride (2.60 g, 12.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.92 mL, 106.5 mmol) in acetonitrile (80 mL) at room temperature under a nitrogen atmosphere was stirred at room temperature for 30 minutes. 3-Hydroxybenzaldehyde (5.00 g, 40.9 mmol) was added, and the mixture was stirred at room temperature for an additional 3 hours. Water was added and the aqueous phase was extracted with diethyl ether. The combined organic fractions were washed with water, brine, dried over magnesium sulfate, and evaporated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave trans-3-(3-hydroxyphenyl)acrylic acid methyl ester as a white crystalline solid (6.30 g, 86%).