Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9][C:10](=[O:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH2:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[C:16]([CH2:21]Br)[CH:15]=1.[H-].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[C:16]([CH:15]=1)[CH2:21][N:9]([C:4]1[C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=[CH:6][N:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: C=Cc1cccnc1NC(C)=O
Reactant: BrCc1cc(Br)ccc1I
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cccnc1N(Cc1cc(Br)ccc1I)C(C)=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26.3 %

Procedure:
To a stirred solution of N-(3-Vinyl-pyridin-2-yl)-acetamide 78D (122 mg, 0.75 mmol) and 4-Bromo-2-bromomethyl-1-iodo-benzene (285 mg, 0.75 mmol) in anhydrous DMF (6 mL) under argon was added 95% NaH (21 mg, 0.83 mmol). This mixture was stirred at room temperature for 4.5 h and diluted with saturated NaHCO3 solution. This was extracted with EtOAc (4×60 mL). The combined EtOAc extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 10 g column, eluted with CH2Cl2-EtOAc, detected at 220 nM to give 90 mg of desired N-(5-Bromo-2-iodo-benzyl)-N-(3-vinyl-pyridin-2-yl)-acetamide 78E in 29% yield. HPLC Rt=3.48 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=457.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])(C)(C)C.[CH3:16][N:17]1[CH2:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:25]3([OH:27])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:16])[CH2:26]3)=[CH:7][C:6]=2[CH:10]=1
Reactant: CN1CC(=O)c2ccccc2C1
Reactant: Brc1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Product: CN1Cc2ccccc2C(O)(c2cc3cc(Br)ccc3s2)C1
Temperature: -75 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of 5-bromobenzothiophene (511 mg, 2.4 mmol) at −75° C., was added t-butyllithium (1.7 M in pentane, 1.6 mL, 2.6 mmol) dropwise. The reaction mixture was stirred at −75° C. for 1 hour. To the resulting dark brown mixture was added 2-methyl-2,3-dihydro-1H-isoquinolin-4-one (323 mg, 2.0 mmol), which was prepared using the method described by Hanna et al., J. Med. Chem., 17(9):1020-1023 (1974), which is hereby incorporated by reference in its entirety. The reaction mixture was stirred for 15 hours with gradual warming up. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (10-40% ethyl acetate/hexanes) followed by preparative HPLC afforded 4-(benzo[b]thiophen-5-yl)-2-methyl-1,2,3,4-tetrahdro-isoquinoline-4-ol (65 mg, 11%) and 4-(5-bromobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol (58 mg, 8%). 4-(Benzothiophen-5-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 500 MHz) δ 7.81 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.34-7.23 (m, 4H), 7.20 (s, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 3.91 (s, 1H), 3.84 (d, J=15.0 Hz, 1H), 3.53 (d, J=15.0 Hz, 1H), 3.11 (dd, J=11.6, 1.4 Hz, 1 H), 2.87 (d, J=11.6 Hz, 1H), 2.50 (s, 3H); ESI MS m/z=296 [M+H]+. 4-(5-Bromobenzothiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 300 MHz) δ 7.81 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.69 (d, J=15.0 Hz, 1H), 3.48 (d, J=15.0 Hz, 1H), 3.10 (dd, J=11.6, 1.3 Hz, 1H), 2.83 (d, J=11.6 Hz, 1H), 2.47 (s, 3H); ESI MS m/z=374 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[C:47]1[N:51]=[C:50]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[O:49][N:48]=1>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:55]1[CH2:54][CH2:53][CH:52]([C:50]2[O:49][N:48]=[C:47]([C:43]3[S:42][CH:46]=[CH:45][N:44]=3)[N:51]=2)[CH2:57][CH2:56]1)=[O:8]
Reactant: c1csc(-c2noc(C3CCNCC3)n2)n1
Reactant: O=C(O)CCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCC(F)(F)F)N1CCC(c2nc(-c3nccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and DIEA (4 equiv) were mixed in DMF (40 mL) for 5 minutes. 4-(3-thiazol-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (5c) (8.18 g, 30 mmol, 1 equiv) was added with 20 mL of DMF and the reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt and then washed twice with saturated aqueous NaHCO3, twice with HCl 1N and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (DCM/MeOH 100-0 to 98.5-1.5) and then recrystallized in a mixture of isopropanol and diisopropyl ether. Yield 62%; 1H NMR (CD2Cl2) δ 8.06 (d, J=3.0 Hz, 1H), 7.65 (d, J=3.0 Hz, 1H), 4.51-4.55 (m, 1H), 3.90-3.95 (m, 1H), 3.22-3.39 (m, 2H), 2.91-2.98 (m, 1H), 2.44 (t, J=7.2 Hz, 2H), 2.15-2.27 (m, 4H), 1.83-2.01 (m, 4H); 13C NMR (CDCl3) δ 182.06, 169.56, 163.97, 154.00, 144.95, 127.37 (q, J=275 Hz), 122.66, 44.33, 40.60, 34.43, 32.97 (q, J=29 Hz), 31.34, 29.44, 28.90, 17.52. mp 75.6-76.3° C.; tR LCMS 6.1 min. Purity >99%; MS [M+H]+ m/z 375.
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.CC1C=CC([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=C(C=1)C(O)=O>>[CH3:28][C:25]1[CH:26]=[CH:27][C:3]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:4]([CH:24]=1)[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6]
Reactant: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)O)c1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: Cc1ccc(-n2cccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)c1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-methyl-2-(1H-pyrazol-1-yl)benzoic acid (CAS number 1214622-46-4; 74 mg, 0.37 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([CH2:11][N:12]4[C:20](=[O:21])[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]4=[O:22])([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]#[N:39])=[O:32]>CS(C)=O.CCOC(C)=O>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][C:4]12[CH2:10][CH:8]3[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38]#[N:39])=[O:32])([CH2:3]1)[CH:6]([CH2:7]3)[CH2:5]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.4 g, 0.98 mmol) and K2CO3 (0.54 g, 3.92 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture at r.t for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.18 g) in 43% yield. m/z (M+1) 433; 1H NMR (CDCl3) 300 MHz δ 7.90-7.80 (m, 2H), 7.75-7.65 (m, 2-H), 4.86-4.72 (m, 1H), 3.72-3.38 (m, 2H), 3.60 (s, 2H), 3.40 (s, 2H), 2.40-2.05 (m, 7H), 1.90-1.78 (m, 2H), 1.70-1.40 (m, 3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[O:34]1[CH:38]=[CH:37][C:36]([CH:39]([OH:43])[CH2:40][NH:41][CH3:42])=[CH:35]1.O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:41]([CH2:40][CH:39]([C:36]4[CH:37]=[CH:38][O:34][CH:35]=4)[OH:43])[CH3:42])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1ccoc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccoc1
Temperature: 90 °C
Yield: 52.8 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of rac-1-(3-furyl)-2-(methylamino)ethanol (Preparation 43, 0.116 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into water (25 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol, 98/2) followed by recrystallization from ethyl acetate to yield 0.102 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 93-97° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.54-7.53, 7.41-7.32, 6.87, 6.42, 4.97, 4.694.65, 4.55, 3.91, 3.74, 2.63-2.53, 2.30; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.7, 153.2, 150.6, 143.4, 141.1, 139.4, 137.3, 132.8, 128.9, 126.0, 116.8, 114.7, 108.3, 106.6, 102.1, 63.2, 62.7, 54.1, 42.6, 41.8, 37.8; MS (ESI+) m/z 470 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][C:19]=3[O:27][CH3:28])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([NH:47][C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:10]2[C:11](=[O:16])[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[C:19]([O:27][CH3:28])[CH:20]=1)=[O:26])([CH3:46])([CH3:45])[CH3:43]
Reactant: COc1cc(C(=O)O)ccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(C)N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC(C)(C)C)ccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An amount of 50 mg (0.13 mmol) of the compound from Example 21A was introduced in 1 ml of DMF and admixed with 20 mg (0.15 mmol) of HOBt and with 31 mg (0.16 mmol) of EDC. After 10 minutes of stirring at RT, 14.5 μl (0.14 mmol) of 2-methylpropan-2-amine were added and the mixture was stirred further at room temperature for 16 h. Subsequently the reaction solution was diluted with about 5 ml of water and the precipitate formed was filtered and washed with water. Drying under reduced pressure gave 37 mg (66% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][NH:23][CH3:24]>CO>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:24]
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Reactant: CNC
Solvent: CO
Product: COC(=O)c1cccc2nc(-c3ccc(CN(C)C)cc3)oc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the solution of methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (150 mg, 0.72 mmol) in methanol (2 mL), was added dimethylamine solution (0.5 mL, 2.88 mmol), the resulting mixture was stirred at room temperature for 17 hr, then the solvents were evaporated and methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate. LC-MS (ESI) m/z 311 [M+1]+.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1C(O)=O)=[O:7])(C)(C)C.C([N:45](CC)CC)C>C1C=CC=CC=1.O1CCOCC1>[NH2:45][CH:19]1[CH:18]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH2:8][C:6]([OH:5])=[O:7])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]1[C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reactant: CCN(CC)CC
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(N)C2c1ccc2c(c1)OCO2
Temperature: 75 °C
Yield: 45.2 %

Procedure:
(1RS,2SR,3RS)-3-(2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18 mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in dry benzene (4 ml) and heated at 40° C. for 2 h and at 75° C. for 2 h. The reaction mixture was then partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4 anhyd.), filtered and evaporated to give the corresponding isocianate as a colorless oil. After purification by column chromatography (silica gel, ethyl acetate/hexane 30:70), the isocianate (100 mg) thus obtained was dissolved in 1 M HC1 in dioxane (3 mL) and the mixture was heated at 80° C. overnight. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to give a colorless oil that was purified by HPLC (1:1 CNCH3 :H2O (containig 0.1% TFA)) to produce the desired product (40 mg, 42%) as an off-white solid, m.p. 181-182° C. (dec).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([OH:15])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.Cl.Cl.[C:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.O1CCCC1>[C:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([C:13]([CH:5]2[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2](=[O:1])[CH2:3][CH2:4]2)=[O:15])[CH2:36][CH2:35]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)[C@@H]1CCC(=O)N1c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To an ice-cold stirred solution of 5-oxo-1-phenylproline (Reference Example 12, 0.22 g, 1.08 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (10 mL) was added oxalyl chloride (0.14 g, 1.10 mmol). The mixture was stirred at 0° C. for 30 min, and then allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in pyridine (10 mL). To this mixture was added 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% NaHCO3 solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to give an orange solid. This solid was recrystallized from hexane-ethyl acetate to give the title compound (0.26 g, 59%) as a light yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH2:18][CH:19]=[CH2:20])O)=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[N:66]([CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)[CH2:18][C:19]#[CH:20])=[N+:67]=[N-:68]
Reactant: C=CCC(O)c1ccccc1-c1noc2ccccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C#CCC(N=[N+]=[N-])c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
A mixture containing 4.0 g of 2-(1,2-benzisoxazol-3-yl)-α-2-propenyl-benzenemethanol, 4.32 g of triphenylphosphine, 2.61 g of diethyl azodicarboxylate and 4.12 g of diphenylphosphoryl azide in 50 ml of benzene was stirred at room temperature for 24 h. Evaporation of the solvent under reduced pressure afforded a solid which was purified by chromatography on silica gel, eluting with 5% ethanol in toluene, to afford 1.5 g of 3-[2-(1-azido-3-butynyl)phenyl]-1,2-benzisoxazole as an oil, M.S. (C.I:)-(M/Z): 289 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Br)[S:8][CH:7]=1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC.O>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>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1csc(Br)c1
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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1csc(-c2ccc(F)cc2)c1
Yield: 88.8 %

Procedure:
A mixture of 5-bromo-thiophene-3-carboxylic acid ethyl ester (1.0 g, 4.5 mmol), 4-fluorophenylboronic acid (0.88 g. 6.4 mmol), potassium carbonate (1.75 g, 12 mmol) and tetrakistriphenylphosphinepalladium(0) (0.2 g, 4 mole %) in a 50:50 mixture of DME/H2O (10 mL) was heated at reflux temperature overnight under a nitrogen atmosphere. The resulting reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over sodium sulfate and rotary evaporated. The residue was purified by flash chromatography (silica gel; 2% acetone/hexane) to obtain 5-(4-fluorophenyl)-3-thiophenecarboxylic acid ethyl ester as an oil (1.0 g, 88%). MS: m/z=251 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>CCCCCCCC>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([C:22]3[CH:21]=[CH:20][C:19]4[N:18]([CH3:17])[C:30]5[C:25]([C:24]=4[CH:23]=3)=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c2ccccc2c2ccccc21
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: CCCCCCCC
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc2c(c1)c1ccccc1n2C
Yield: 18.3 %

Procedure:
A mixture of 2.2 g (10.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (202), Example 1a, Table 2), 1.8 g (10.0 mmol) of N-methylcarbazole and 0.2 g of Fulcat 22B and 20 ml of n-octane is refluxed for 5 hours under nitrogen. The Fulcat 22B catalyst is subsequently removed by filtration and excess n-octane is distilled off on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system dichloromethan/hexane=1:2 to 1:1 and subsequent crystallisation of the pure fractions from methanol yields 0.70 g (10%) of 7-tert-butyl-5-methyl-3-(9-methyl-9H-carbazol-3-yl)-3H-benzofuran-2-one, m.p. 84°-90° C. (compound (120), Table 1). The product may additionally contain minor amounts of other structural isomers in accordance with the substitution at the carbazole ring.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9]C1C(C)=CC(C(F)(C(F)(F)F)C(F)(F)F)=CC=1C)=[O:8])([O-])=O.[N+](C1C=C(C=CC=1)C(N)=O)([O-])=O>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH2:9])=[O:8]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1
Agent: NC(=O)c1cccc([N+](=O)[O-])c1
Product: NC(=O)c1cccc(N)c1

Procedure:
3-nitro-benzoyl chloride was reacted with an aniline, that is 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine, to form a 3-nitro-benzamide, that is 3-nitro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide, and c) the 3-nitro-benzamide, that is 3-nitro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide, was reduced to afford the desired 3-amino-benzamide, that is 3-amino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide. Further 3-amino-benzamides were made, for example, by using a substituted 3-nitro-benzoic acid, such as 2-fluoro-3-nitro-benzoic acid, in step a) and/or a different aniline, such as 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoro-methyl-ethyl)-phenylamine, in step b). Whilst this three step synthesis gives satisfactory results in the laboratory a shorter route to 3-amino-benzamides is required if the carbamate insecticides or bisamide insecticides are to be manufactured on a commercial scale.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][C@@:15]1([C:30]([O:32][CH3:33])=[O:31])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C>C(Cl)Cl.O>[O:11]=[CH:12][CH2:13][CH2:14][C@@:15]1([C:30]([O:32][CH3:33])=[O:31])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21]
Reactant: COC(=O)[C@]1(CCCO)CCCN1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)[C@]1(CCC=O)CCCN1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of DMSO (5.11 mL, 72.1 mmol) in CH2Cl2 (25 mL) at −78° C. was added a solution of oxalyl chloride (3.15 mL, 36.0 mmol) in CH2Cl2 (25 mL) dropwise. After 10 min of additional stirring, a solution of 1-benzyl 2-methyl (2R)-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate [Cox and Lectka (1998) J. Am. Chem. Soc. 120, 10660-10668] (7.72 g, 24.0 mmol) in CH2Cl2 (50 mL) at −78° C. was added dropwise. After stirring for an additional 1 h, triethylamine (16.7 mL, 120 mmol) was added slowly. The reaction mixture was stirred for 1 h at −78° C. and 2.5 h at ambient temperature. Water (100 mL) was added slowly and the quenched mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with 10% HCl (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-90:10 to 0:100, to give the title compound. MS: m/z=320 (M+1).