Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.Cl[C:32]1[N:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=1)[O:1][C:32]1[N:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 75.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (200 mg, 0.464 mmol) synthesized in Example (38d) and methyl 5-chloropyrazine-2-carboxylate (120 mg, 0.695 mmol) synthesized in Example (62b) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (257 mg, 1.86 mmol) was added, followed by stirring at 80° C. for 7 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%). The resulting yellow solid was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (4 mL) was added, followed by stirring at room temperature for 1.5 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%) to afford the desired compound (164 mg, yield 93%) as a yellow solid.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH2:33]Br)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>ClCCl>[C:1]([C:9]1[C:10]([CH2:33][N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)c1ccccc1
Yield: 65.6 %

Procedure:
A mixture of 3-benzoyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (1.5 g), diethylamine (1.05 g) and dichloromethane (40 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-benzoyl-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (0.97 g, 66%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 150°-151° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[O:12]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>COCCOC.O.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.C(O)C>[O:12]([C:19]1[CH:20]=[CH:21][C:22]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:11])=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C1NCc2c(I)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C1NCc2c1cccc2-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Yield: 52.4 %

Procedure:
A suspension of Example 55A (301 mg, 1.16 mmol), 4-phenoxyphenylboronic acid (271 mg, 1.27 mmol) and Na2CO3 (403 mg, 4.75 mmol) in DME (10 mL), water (4.8 mL), and ethanol (2.4 mL) was degassed with N2 for 45 minutes, treated with Pd(PPh3)4 (120 mg), and heated to 80° C. overnight. The suspension was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was triturated with warm ethanol to give 183 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 4.51 (s, 2H); 7.07–7.13 (m, 3H); 7.20 (t, J=7.5 Hz, 1H); 7.33 (t, J=7.1 Hz, 1H); 7.38–7.47 (m, 3H); 7.59 (t, J=7.5 Hz, 1H); 7.62–7.69 (m, 3H); 8.69 (s, 1H); MS (ESI(+)) m/e 302.1 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=1)[CH2:2]2.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:5]12[CH2:6][CH:1]1[CH2:2][N:3]([C:7]1[S:8][C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=1)[CH2:4]2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: Fc1ccc(-c2csc(N3CC4CC4C3)n2)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(-c2sc(N3CC4CC4C3)nc2-c2ccc(F)cc2F)cc1
Temperature: 150 °C
Yield: 24.8 %

Procedure:
To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(2,4-difluorophenyl)thiazole (Step 2 of compound 66, 0.23 g, 0.82 mmol) in dimethyl acetamide (5 ml) were added 4-bromobenzenesulfonamide (0.21 g, 0.90 mmol) and potassium acetate (0.16 g, 1.65 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added palladium (II) acetate (0.019 gm, 0.08 mmol) under nitrogen and the reaction mixture was heated at 150° C. for 15 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml). The reaction mixture was washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.088 g, 24.5%). MS: m/z 434 (M+1).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([NH:31][OH:32])=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:32][N:31]=[C:29]([C:28]([CH3:34])([CH3:33])[CH2:27][OH:26])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CC(C)(CO)C(=N)NO
Product: CC(C)(CO)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 3,N-dihydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.08 min; Mass spectrum (ESI+): m/z=452 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C@@H:19]1[CH2:28][CH2:27][C@H:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)cc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)CC1
Reaction time: 48 h

Procedure:
A mixture of methyl 4-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]benzoate (700 mg, 1.8 mmol) and 5% Rh on alumina (400 mg) in EtOH (10.0 ml) and AcOH (1.0 ml) was hydrogenated at room temperature at 5 atm for 48 hr. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (7:1, v/v) as eluent to give methyl cis-4-[1-tert-butoxycarbonyl-(2S)-octahydro indolylmethoxy]cyclohexanecarboxylate (600 mg, 85%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.10-2.35 (m, 20H), 1.44 (s, 9H), 3.45-3.90 (m, 5H), 3.80 (s, 3H).
Reaction SMILES: C([Li])CCC.N#N.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28](Br)=[CH:29][N:30]=2)[N:27]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[CH:29][N:30]=2)[N:27]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc2nccn2n1
Reaction time: 0.08 h

Procedure:
1.6 M n-butyl lithium in hexanes (5.8 mL, 9.3 mmol) was rapidly syringed into a stirred, colorless, N2 blanketed solution of (S)-2-[(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 4.6 mmol) in anhydrous THF (100 mL) held at −73° C. The reaction solution immediately turned brown in color and was allowed to stir for 5 minutes. The generated aryl lithium was quenched by the careful addition of saturated aqueous NH4Cl (2 mL). The reaction solution was partitioned between brine and ethyl acetate, the extract dried (CaSO4), and the crude product flash chromatographed (silica gel, eluted with 10% (v/v methanol/ethyl acetate) and crystallized from ethyl acetate/heptane to provide S)-2-(imidazo[1,2-b]pyridazin-6-ylaminomethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as 1.5 g of off white powder, mp. 161-162° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H) 1.72-1.95 (m, 4H) 3.10-3.22 (m, 1H) 3.28 (br. s., 2H) 3.41-3.53 (m, 1H) 3.92-4.05 (m, 1H) 6.65 (d, J=9.60 Hz, 1H) 6.96 (br. s., 1H) 7.36 (d, J=0.76 Hz, 1H) 7.66 (d, J=9.60 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 23.15, 28.13, 43.14, 45.96, 46.36, 55.57, 56.15, 78.30, 112.50, 116.01, 125.26, 130.32, 135.78, 153.75. LRMS (ESI) m/z 318.3 [(M+H)]+, calc'd for C16H23N6O2: 317.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:12].[C:13]([CH:18]1[C:23](=O)[CH2:22][CH2:21][NH:20][CH2:19]1)(OCC)=[O:14].OS(O)(=O)=O.C1(O)C=CC=CC=1.[NH4+].[OH-]>C(Cl)(Cl)Cl>[ClH:12].[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:23]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]=3[C:13](=[O:14])[O:11][C:5]=2[CH:4]=1
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: COc1ccc(O)cc1OC
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Temperature: 0 °C

Procedure:
A mixture of 46.0 g (0.3 m) of 3,4-dimethoxyphenol and 41.7 g (0.2 m) of 3-carbethoxy-4-piperidone HCl was cooled in an ice bath and treated with 100 cc of 73% v/v H2SO4 in 1/2 hr with stirring and protection from moisture. After stirring 4 days at room temperature the reaction was chilled and treated with an additional 24 g (0.156 m) of the phenol. After 5 days a second 24 g portion of the phenol was added. After stirring 6 days the reaction was treated with 150 g of ice and conc. NH4OH to pH 8-9. The resultant gum was stirred with 150 cc CHCl3 for 1/2 hr and was filtered. The filtrate was evaporated and the resultant gum was triturated with pet ether followed by ethyl ether. The resultant solid was crystallized from 150 cc 3 N HCl affording 33.4 g of the pyridin-5 -one as the hydrochloride, mp 254°-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=3[C:6]=2[CH:17]=1.[CH3:18][C:19]1(OC)[CH2:23][CH2:22][C:21]([CH3:26])(OC)O1>>[CH3:18][C:19]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]3[CH:14]=[CH:13][C:12]4[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=4[C:6]=3[CH:17]=2)[C:21]([CH3:26])=[CH:22][CH:23]=1
Reactant: Nc1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Reactant: COC1(C)CCC(C)(OC)O1
Product: Cc1ccc(C)n1-c1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1

Procedure:
8.8 mmol of 9-aminobenzo[f]quinoxaline-2,3(1H,4H)-dione were reacted with 8.8 mmol of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C(C3C(C)=NC(C)=CC=3)O)[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([Li])CCC.[CH3:40][C:41]1[S:42][C:43]([C:47]([C:49]2[N:53]([CH3:54])[N:52]=[N:51][CH:50]=2)=[O:48])=[C:44]([CH3:46])[N:45]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:47]([C:43]3[S:42][C:41]([CH3:40])=[N:45][C:44]=3[CH3:46])([C:49]3[N:53]([CH3:54])[N:52]=[N:51][CH:50]=3)[OH:48])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1
Reactant: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3sc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.02 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (500 mg, 116 mmol, Intermediate 12: step d) was added THF (15 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. (the solution remained homogeneous) and then n-butyllithium (2.5 M in hexanes, 0.45 mL, 1.13 mmol) was added dropwise. The color of the solution became a dark brown. After 1 minute, (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (275 mg, 1.24 mmol in 2 mL THF, Intermediate 23: step b) was introduced and the color of the mixture went from dark brown to greenish to light orange color all within 1 minute. The mixture was allowed to warm to 0° C. over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The mixture was diluted further with water and extracted with EtOAc (3×45 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford a light orange foam. The crude was chromatographed on silica gel (initially using 10% CH3CN-toluene then changing to 80% CH3CN-DCM) to provide the title compound as an off white solid.
Reaction SMILES: [NH2:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])[CH3:19]
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CNN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 57.4 %

Procedure:
A mixture of 2-amino-isoindole-1,3-dione (5.0 g, 30.9 mmol), ethyl bromoacetate (10.32 g, 61.8 mmol), K2CO3 (8.5 g, 61.8 mmol) in DMA (38 ml) was heated at 80° C. for 7 h. After cooling to rt, the mixture was filtered, and the filtrate was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was treated with EtOAc and hexanes to give 393A (4.4 g, 57%) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)CO.O>CN1CCCC1=O.[Cu]I>[C:20]1([S:26][C:16]2[CH:17]=[CH:18][C:13]([N:4]3[NH:3][C:2](=[O:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:12])=[CH:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Reactant: Sc1ccccc1
Agent: [Cu]I
Solvent: OCCO
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]n(-c2ccc(Sc3ccccc3)cc2)c(=O)c2ccccc12
Temperature: 90 °C
Reaction time: 26 h

Procedure:
4-Hydroxy-2-(4-iodophenyl)-2H-phthalazin-1-one (see Method Q) (0.20 g, 0.55 mmol), thiophenol (0.061 g, 0.55 mmol), CuI (0.006 g, 0.03 mmol) and ethylene glycol (0.070 g, 1.1 mmol) were dissolved in N-methyl-pyrrolidinone (NMP) (1 ml) under argon and heated to 90° C. Stirring at this temperature was continued for 26 h before the mixture was allowed to warm to room temperature. H2O (50 ml) was added and the resulting solution was extracted with dichloromethane. The title compound was obtained after purification of the raw product by chromatography over silica gel with dichloromethane (0.10 g, 54%). 1H-NMR: (400 MHz, D6-DMSO) 11.91 (1H, s), 8.30 (1H, s), 7.91–8.06 (3H, m), 7.69 (2H, d), 7.34–7.45 (7H, m); MS (ESI+)=347.26 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=1[F:1]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C(=O)OC)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C(=O)OC)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a mixture of dimethyl 2-fluoroterephthalate (42.0 g, 0.198 mol) in concentrated sulfuric acid (200 mL) at 0° C. was added 36 mL of a 1:1 mixture of nitric acid and sulfuric acid dropwise. The mixture was stirred at 0° C. for 15 min., the ice-bath was removed, and the reaction mixture was stirred for an additional 45 min. HPLC indicated that the starting material had been consumed. The reaction mixture was poured over ice and extracted with EtOAc. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by recrystallization from MeOH afforded 48.5 g (95%) of 174A as a white solid. HPLC retention time=2.69 min. (Condition B). 1H-NMR (500 MHz, CDCl3) δ 3.95 (s, 3H), 3.98 (s, 3H), 7.44 (d, 1H), and 8.59 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)(O)[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][N:20]=4)[CH:16]=3)[N:11]([CH3:33])[C:10](=[O:34])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:37])=O>>[Cl:37][C:18]([C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([C:19]1[N:23]([CH3:24])[CH:22]=[N:21][N:20]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:33])[C:10](=[O:34])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Product: Cn1cnnc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone (0.012 mol) (described in Example B13) was added portionwise at 5° C. to thionyl chloride (6 ml). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated till dryness. The product was used without further purification in the next reaction step, yielding 6-[chloro(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.
Reaction SMILES: [C:1]([O-:17])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14].[Na+].[Na+].[C:20]([O-])(=O)[CH2:21]CCCCCCCCCCCCCCCC.[Al+3].C([O-])(=O)CCCCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Na].[Al]>>[C:1]1(=[O:17])[O:16][CH2:21][CH2:20][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])CCCCCCCCCCCC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Al+3]
Agent: [Al]
Agent: [Na+]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Temperature: 200 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Sodium brassylate (0.33 g) and aluminum stearate (1.09 g) were added to 70 g poly(ethylene brassylate) and the mixture heated at 200° C. until a homogeneous viscous mass was obtained. The molar ratio of sodium to aluminum was 2:1. The temperature was then increased to 312° C. and the pressure reduced to 0.3-0.5 mm Hg. The depolymerization reaction was complete in about 3 hours and 88.1% yield ethylene brassylate was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[O:35])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C@@:25]2([CH2:11][CH2:10][CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[O:35])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Product: CC(C)(C)OC(=O)N1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,4-dibromobutyl)benzene (153 mg, 0.4 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-2,4-dioxoimidazolidine-1-carboxylic acid tert-butyl ester (113 mg, 0.33 mmol) (Preparation 11), the above-titled compound was obtained (33 mg) as a white solid. 1H NMR (CDCl3): 7.48 (2H, d, J=8.3 Hz), 7.30 (1H, m), 7.07 (2H, d, J=8.3 Hz), 6.52 (2H, m), 4.06 (1H, dd, J1=13.1 Hz, J2=5.5 Hz), 2.35–2.6 (3H, m), 2–2.35 (3H, m), 1.66 (9H, s).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:11]1[CH:10]=[CH:9][C:7]2[O:8][CH:4]([CH3:3])[CH2:5][C:6]=2[CH:12]=1
Reactant: BrBr
Reactant: CC1Cc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1Cc2cc(Br)ccc2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 215 ml of bromine in 450 ml of methylene chloride is added dropwise over 21/2 hours to an ice-cooled mixture of 562.3 g of 2,3-dihydro-2-methylbenzo[b]furan, 1600 ml of methylene chloride, 1600 ml of water and 352.5 g of sodium bicarbonate. After the mixture has been stirred for another 11/2 hours at the same temperature, the aqueous phase is separated and extracted with two 300 ml portions of methylene chloride. The combined organic phases are washed with 2×250 ml of water, dried over sodium sulfate and concentrated. After removal of all constituents having a boiling point below 99° C. under a pressure of 8 mbar, there are obtained 750.7 g of 5-bromo-2,3-dihydro-2-methylbenzo[b]furan as residue.