Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][O:24]CC4C=CC=CC=4)[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][OH:24])[O:17]3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=C(COCc1ccccc1)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Solvent: CO
Product: O=C(CO)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Yield: 23518.9 %

Procedure:
(R)—N-(7-Benzenesulfonyl-chroman-2-ylmethyl)-2-benzyloxy-acetamide (100 mg, 0.22 mmol) and Perlman's catalyst (12 mg) were added to 15 mL MeOH and hydrogenated for 18 hours at 1.5 atmospheres of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to give 18.7 g of (R)—N-(7-Benzenesulfonyl-chroman-2-ylmethyl)-2-hydroxy-acetamide, MS (M+H)=362.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([OH:16])[CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:15][CH2:14][CH2:13][CH2:12][O:16][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
To a solution of 116.36 g (610.37 mmol) of tosyl chloride in 200 mL of anhydrous pyridine add 19.26 g (253.09 mmol) of 1,3-propanediol in 50 mL of anhydrous pyridine dropwise over the period of two hours at 0-10° C. Stir the reaction mixture for an additional four hours, then pour it into 500 mL of ice cold water. Collect the white precipitate that forms by filtration, wash filter cake with water, dilute aqueous sulfuric acid (10 wt. %), dilute aqueous sodium carbonate (1M), and again with water. Crystallize the wet product from acetone to afford 80.68 g (83%) of 1,3-propanediol bis(4-methylbenzenesulfonate) as off white powder. 1H NMR (400 MHz, CDCl3) δ 7.77-7.69 (m, 4H), 7.37-7.30 (m, 4H), 4.05 (t, J=6.0 Hz, 4H), 2.44 (s, 6H), 1.99 (p, J=6.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 145.01, 132.65, 129.92, 127.84, 65.83, 28.67, 21.61. MS (m/e): 408 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), tert-butyl piperazine-1-carboxylate (218 mg, 1.17 mmol), and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition, the mixture was stirred at room temperature for 5 h. Dichloromethane was removed under reduced pressure. The crude product was purified by flash chromatography to give the title compound (70 mg, yield 32%). LC-MS (ESI) m/z: 556 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br.C(O)(=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCCCCCc1ccc(-c2ccc(OC)c(F)c2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCc1ccc(-c2ccc(O)c(F)c2)nc1

Procedure:
2-(m-Fluoro-p-methoxyphenyl)-5-heptylpyridine (X) (13 g, 0.043 mol) obtained at the step (III) hydrobromic acid (47%) (50 ml) and acetic acid (140 ml) were heated under reflux for 30 hours, followed by cooling the reaction fluid, pouring it in water, filtering off the resulting crystals, dissolving the crystals in 2N-NaOH aqueous solution (about 100 ml), further adding acetic acid (30 ml) to obtain an acidic solution filtering off deposited crystals and recrystallizing them from ethyl alcohol to obtain 2-(m-fluoro-p-hydroxyphenyl)-5-heptylpyridine (a compound of the formula (XI) wherein X=f and R1 =C7H15) (7.2 g) having a m.p. of 83.7°-86.1° C.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>ClCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][NH:13][C:11](=[O:12])[CH2:10][CH:8]2[CH2:7][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:9]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NNC(=O)CC1CN(C(=O)C2CC2)C1
Solvent: ClCCl
Product: O=C(CC1CN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
In a round bottom flask, a solution of 2-[1-(cyclopropylcarbonyl)-3-azetidinyl]acetohydrazide (0.316 g, 1.602 mmol) in dichloromethane (10 mL) was treated with 4-bromophenylisocyanate (0.317 g, 1.602 mmol) and the reaction mixture was stirred at room temperature for 1 h (white precipitate formed). The white solid was filtered, rinsing with cold dichloromethane (4×), and dried under air suction to give the title compound (0.455 g, 87% pure, 62% yield). MS(ES)+ m/e 394.9, 396.6 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Br[CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:33][CH2:32][CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone (500 mg), 1-bromo-2-chloroethane (245 mg), and potassium carbonate (897 mg) were suspended in N,N-dimethylformamide (20 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (465 mg, yield 80%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.[I-].[K+]>[CH2:29]([O:28][C:26]([CH2:25][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:5][CH2:6]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)CN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1
Yield: 89.5 %

Procedure:
To a solution of 1.5 g (4.88 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 30 mL of isopropanol were added 896 mg (5.37 mmol) of ethyl bromoacetate, 853 mg (96.18 mmol) of potassium carbonate and 20 mg of potassium iodide, and the mixture was heated under reflux for 3 hours. The hot solution was subjected to filtration, and the solid matter was washed with 200 mL of hot isopropanol. The filtrate was concentrated in vacuo, and the residue was purified by means of column chromatography (silica gel, 1:9 :90 aqueous ammonia:methanol:chloroform) to give 1.88 g (4.37 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]O.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCCN(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.2 mg, 0.164 mmol) and N,N′-carbonyldiimidazole (68.8 mg, 0.424 mmol, Aldrich) in tetrahydrofuran (5 mL) was stirred at room temperature overnight. N,N-dimethylethanolamine (44.3 mg, 0.495 mmol, Aldrich) was added to a suspension of sodium hydride (12 mg, 0.475 mmol) in tetrahydrofuran (4 mL) and stirred at room temperature for 1 h. It was then added to the above mixture and stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate and concentrated. the crude product was purified by flash chromatography to give chiral 2-(dimethylamino)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (97.2 mg, 86% yield). MS (ES+) m/z calcd. for C35H39Cl2F2N4O4 [(M+H)+]: 687. found: 687.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:35].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32][Br:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)n1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccn([C@@H]2O[C@H](CBr)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
To a solution of compound 3 (0.12 g, 0.27 mmol) and CBr4 (0.11 g, 0.33 mmol) in 5.0 mL of anhydrous CH2Cl2 was added PPh3 (0.12 g, 0.41 mmol) at 0° C. under N2 atmosphere. The resulting solution was stirred for 48 h at room temperature. The solvent was removed under reduced pressure and the residue was purified on silica gel column chromatography (Hexane:EtOAc=1:2 to 1:4 v/v) to give compound 4 (0.08 g, 0.16 mmol) in 60% yield. 1H NMR (CDCl3, 400 MHz) δ 8.95 (br, 1H), 8.14 (d, J=7.6, 1H), 8.05 (d, J=7.2, 2H), 7.92 (d, J=7.2, 2H), 7.62 (m, 3H), 7.52 (d, J=7.6, 1H), 7.48 (m, 3H), 6.06 (dd, J=15.2, 1.2, 1H), 5.63 (dd, J=4.8, 1.2, 0.5H), 5.50 (dd, J=4.8, 1.2, 0.5H), 5.44 (m, 1H), 4.68 (m, 1H), 3.92 (dd, J=12.0, 4.0, 1H), 3.77 (dd, J=12.0, 4.8, 1H); MS calcd for C23H19BrFN3O5 m/z 516.1 (M+H)+, found 518.3.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CS(C)=O>[OH:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24]1
Reactant: O[C@@H]1CCNC1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@@H](O)C3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into an 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), (R)-pyrrolidin-3-ol hydrochloride (212 mg, 1.72 mmol, 4.00 equiv), potassium carbonate (200 mg, 1.55 mmol, 3.00 equiv), toluene (5 mL), DMSO (1.7 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 ml of water. The resulting solution was extracted with 5×10 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (70:1). This resulted in 147.4 mg (95%) of (R)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[N+:13]([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[NH:13][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a suspension of (4-methoxy-2-nitro-phenyl)-acetic acid methyl ester (154 mg, 0.68 mmol) in 3 mL of acetic acid was added acetic anhydride (3.0 mL, 30.0 mmol) and zinc (nanopowder, 220 mg, 3.36 mmol) in portions over 5 min at 0° C. The reaction mixture was maintained for 30 minutes at 0° C. and 1.5 h at room temperature. Additional zinc powder (110 mg, 1.68 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After filtration, the mixture was partitioned between 50 mL of ethyl acetate and 10 mL of saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified on a Biotage (Biotage Inc.) 10 g silica column, eluted with 0-40% EtOAc in heptane to provide 49 mg (68%) of (2-acetylamino-4-methoxy-phenyl)-acetic acid methyl ester. 1H NMR (CDCl3) δ 2.23 (s, 3H), 3.57 (s, 2H), 3.73 (s, 3H), 3.81 (s, 3H), 6.66 (dd, 1H), 7.09 (d, 1H), 7.57 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:36]([O:35][C:34]([NH:33][CH2:32][CH2:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=2)([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C(C)C)cc1
Yield: 90.6 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)-2-methylpropionate (4.85 g), which is the product of Reference example 9(b), t-butyl 2-methanesulfonyloxy-ethylcarbamate (8.47 g) and potassium carbonate (9.78 g) and the reaction mixture was treated to afford the title compound (6.23 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.C([Li])CCC.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[C:33]=2[CH:38]=[O:39])=[CH:28][CH:27]=1>C1COCC1>[CH2:1]([C:8]1[CH:13]=[C:12]([CH:38]([C:33]2[C:34]([CH3:37])=[N:35][O:36][C:32]=2[C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=2)[OH:39])[CH:11]=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: Brc1cncc(Cc2ccccc2)c1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cncc(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Benzyl-5-bromo-pyridine (0.474 g, 1.91 mmol) was dissolved in THF (10 mL) and cooled to 0° C. Isopropylmagnesium chloride (2 M in THF, 0.96 mL, 1.91 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 1 hour. Analytical LCMS indicated no reaction so an additional portion of isopropylmagnesium chloride (1.91 mmol) was added and the reaction stirred for 1 hour at room temperature. Analytical LCMS still indicated no progress so the reaction was cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 0.764 mL, 1.91 mL) was added. The reaction was allowed to slowly warm to 0° C. then 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.610 g, 2.29 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was quenched with H2O, submitted to standard aqueous workup and then purified via silica gel chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:13]([C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:13]([C:14]2[S:33][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)=[N:17][N:16]=2)=[CH:12][CH:11]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Yield: 165.2 %

Procedure:
A mixture of N-[4-(6-methoxy-n-hexyloxy)benzoyl]-N′-(4-methoxycarbonylbenzoyl)hydrazine (193.4 g) and phosphorus pentasulfide (113.34 g) in tetrahydrofuran (2.5 L) was heated to reflux for 1 hour then cooled to room temperature and poured into water (7 L). The resulting precipitate was collected by filtration, washed thoroughly with water then partially dried. The solid was added to 1:1 CH3CN—H2O (200 ml), sitrred then filtered. This procedure was repeated a further 2 times, and the resulting yellow powder washed thoroughly with acetonitrile (500 ml×5) then dried under hi-vacuum at 50° C. to give methyl 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoate (179.6 g) as a yellow powder.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11])=O)(C)(C)C.Cl>ClCCl.CCOCC>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)CNC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)CN)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (4) (0.36 g; 0.61 mmol) in dichloromethane (5 ml) was treated with a 4.8M solution of hydrogen chloride in ether (1 ml). The mixture was stirred at ambient temperature for 1 hour. After dilution with ether, the resulting precipitate was filtered, washed with ether and dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-[(2-aminoacetyl)amino]propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1.N>>[F:32][C:29]1[CH:30]=[C:31]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)[CH:26]=[CH:27][C:28]=1[F:33]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Fc1ccc(Br)cc1F
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole (yield: 310 mg, 65.7%). mp 187-188° C. 1H NMR (300 MHz, CDCl3) δ 3.09 (s, 3H), 7.18 (d, J=9, Hz, 2H), 7.29 (m, 3H), 7.41 (d, J=9 Hz, 2H), 7.52 (m, 1H), 7.65 (m, 1H), 7.92 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 473(M+H)+, 490 (M+NH4)+. Anal. calc. for C23H15ClF2N2O3S.0.5H2O: C, 57.38; H, 3.33; N, 5.82. Found: C, 57.44; H, 3.38; N, 5.52.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[N+:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])([O-:23])=[O:22]>ClCCl.N1C=CC=CC=1>[N+:21]([C:24]1[CH:25]=[C:26]([NH:27][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)=[O:13])[CH:28]=[CH:29][CH:30]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 24.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-nitroaniline (1.60 g, 11.6 mmol) in 13 mL of pyridine. The crude product was recrystallized once from ethanol-ether, then twice from acetonitrile-DMF-water to yield 0.79 g of the title compound, mp >270° C.