Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].CN(C)C=O>C(O)C.[Fe].O.C(OCC)(=O)C>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Temperature: 90 °C
Yield: 87.9 %

Procedure:
To a suspension of morpholine-4-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (941 mg) in ethanol (50 ml) were added water (10 ml), electrolytic iron powder (581 mg), ammonium chloride (1.11 g) and N,N-dimethylformamide (0.75 ml), followed by stirring to heat at 90° C. for 30 min. The reaction mixture was cooled down to room temperature, and filtered to remove an insoluble portion, which was washed with water and N,N-dimethylformamide in this order. The filtrate was concentrated under a reduced pressure to give a residue, to which ethyl acetate (100 ml) and water (100 ml) were added to partition. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated to provide the titled compound (759 mg, 87.8%) as a pale yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:50])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]3[N:36]=[N:37][N:38]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[C:42]([N+:47]([O-])=O)[CH:41]=4)[CH:39]=3)[CH:23]=1)[C@H:7]([OH:51])[C@@H:6]2[OH:52])=[O:4].CNC([C@@]12C[C@@H]1[C@@H](N1C=NC3C1=NC(Cl)=NC=3NCC1C=CC=C(C#CCCCC3N=NN(C4C=CC(F)=C(N)C=4)C=3)C=1)[C@H](O)[C@@H]2O)=O>>[CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:50])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]3[N:36]=[N:37][N:38]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[C:42]([NH2:47])[CH:41]=4)[CH:39]=3)[CH:23]=1)[C@H:7]([OH:51])[C@@H:6]2[OH:52])=[O:4]
Reactant: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCCCc5cn(-c6ccc(F)c([N+](=O)[O-])c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Agent: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCc5cn(-c6ccc(F)c(N)c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Product: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCCCc5cn(-c6ccc(F)c(N)c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Yield: 64 %

Procedure:
Compound 208 (64%) was synthesized from compound 205 following the same procedure as for compound 207. 1H NMR (CD3OD, 400 MHz) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.38 (s, 1H), 7.32-7.21 (m, 4H), 7.06-7.02 (m, 1H), 6.90-6.86 (m, 1H), 5.08 (d, J=7.2 Hz, 1H), 4.80 (s, 1H), 4.70 (br s, 2H), 4.01 (d, J=6.4 Hz, 1H), 2.87 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 2.44 (t, J=6.8 Hz, 2H), 2.02-2.09 (m, 1H), 1.83-1.78 (m, 2H), 1.68-1.54 (m, 5H), 0.89-0.93 (m, 1H). HRMS calculated for C40H37ClFN8O (M+H)+: 699.2763. Found 699.2745.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:5](=O)[C:3]1=[O:4].NN.[Na].O>C(O)C>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)C(=O)c2c(Cl)cc(Cl)cc21
Agent: NN
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CN1C(=O)Cc2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Yield: 87 %

Procedure:
1-Methyl-4,6-dichloroisatin (4.0 g) was suspended in dry ethanol (40 ml), hydrazine (9 ml) was added and the mixture was refluxed in 6 h. The mixture was then added slowly at 70° C. to a solution of sodium (1.74 g) in dry ethanol (80 ml) and refluxed overnight. The reaction mixture was cooled to room temperature, water (50 ml) was added and the volume was reduced to about one third by evaporation. The mixture was then poured onto icewater (1000 ml) and acidified with 6M HCl (pH=1). The precipitate was filtered off washed with water and dried to afford 3.27 g (87%) of (43). M.p. 144°-145° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([C@@H]1CC[C@H](C(O)=O)CC1)CCC>>[CH2:1]([C@@H:7]1[CH2:8][CH2:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:14][CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)O)cc1
Agent: CCCC[C@H]1CC[C@@H](C(=O)O)CC1
Product: CCCCCC[C@H]1CC[C@@H](C(=O)O)CC1
Yield: 80 %

Procedure:
This acid (21) was prepared from 4-n-hexylbenzoic acid (18, 72.34g, 0.28 mol) in a manner similar to the procedure described for cis-4-n-butylcyclohexane-carboxylic acid (9) in Example II, preparation 1, in an overall yield of 80% of (47.6g).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:20])=[C:4]([C:10]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([F:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32]Cl.Cl>ClCCl>[F:1][C:2]1[C:3]([O:20][CH2:30][O:31][CH3:32])=[C:4]([C:10]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([F:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COCCl
Reactant: CCOC(=O)Nc1c(F)cc(F)c(O)c1C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1c(F)cc(F)c(OCOC)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5.72 g of the resulting ethyl 3,5-difluoro-6-(N-ethoxycarbonylamino)-2-hydroxybenzoate was dissolved in 70 ml of dichloromethane under argon atmosphere, 4.13 ml of diisopropylethylamine and 1.80 ml of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at 0 ° C. for 20 minutes. An aqueous dilute solution of hydrochloric acid was added to the reaction solution, the mixture was extracted with ether, the organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 3,5-difluoro-6-(N-ethoxycarbonylamino)-2-methoxymethoxybenzoate.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][CH3:28])[N:21]=2)O)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].O>ClCCCl.[Pd](Cl)Cl>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:20]2[N:21]=[C:22]([O:27][CH3:28])[C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: OCC1CCCC1
Reactant: COc1nc(C(O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: Cl[Pd]Cl
Solvent: ClCCCl
Solvent: O
Product: COc1nc(C(OCC2CCCC2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
Cyclopentylmethanol (0.039 mL) and palladium chloride (6.0 mg) were added to a solution of (4-tert-butylphenyl)(5-chloro-6-methoxypyridin-2-yl)methanol (110 mg) in 1,2-dichloroethane (2 mL) at room temperature, after which the mixture was stirred at 80° C. for six hours and then stirred at room temperature for two days. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 6-[(4-tert-butylphenyl)(cyclopentylmethoxy)methyl]-3-chloro-2-methoxypyridine as a pale red oil (112 mg, 86%).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([C:9]1[C:21]([OH:22])=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12]C(OCC)=O)(=O)[CH3:7].Cl>C(O)C>[CH3:7][C:6]1[C:9]2[C:21]([OH:22])=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:19]=[CH:18][C:10]=2[O:11][CH:12]=1
Reactant: CCOC(=O)COc1ccc(C(C)(C)C)c(O)c1C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1coc2ccc(C(C)(C)C)c(O)c12

Procedure:
To a solution of sodium ethoxide freshly prepared from sodium metal (0.104 g, 4.50 mmol) in ethanol (25 mL) was added ethyl 2-(2-acetyl-3-hydroxy-4-tert-butylphenoxy)acetate 11b (1.26 g, 4.28 mmol) and the mixture heated to reflux for 10 minutes. The reaction mixture was cooled and acidified by pouring into 2N HCl (75 mL). The resulting solution was extracted with ethyl acetate (2×35 mL) and the combined extracts dried (Na2SO4), and concentrated. Flash chromatography afforded, in order of elution 3-methyl-4-hydroxy-5-tert-butylbenzofuran, compound 12b. mp 79°-81° C.; 1H NMR d 1.49 (9H, s), 2.48 (3H, s), 5.27 (1H, s), 7.00 (1H, d, J=8 Hz), 7.24 (1H, d, J=8 Hz), 7.26 (1H, s) and ethyl 3-methyl-4-hydroxy-5-tert-butylbenzofuran-2-carboxylate, compound 12 a, mp. 109-112 (from hexane); 1H NMR d 1.42 (3H, J=6 Hz), 1.46 (9H, s), 2.83 (3H, s), 4.43 (2H, q, J=6 Hz), 5.45 (1H, br s), 7.04 (1H, d, J=8 Hz), 7.37 (1H, d, J=8 Hz).
Reaction SMILES: C([N:3](CC)CC)C.[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].CCOC(C)=O>ClCCCl>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH2:3])=[O:13]
Reactant: CCN(CC)CC
Reactant: O=C1OCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1CO
Temperature: 17.5 °C
Yield: 97.5 %

Procedure:
A solution of triethylamine (TEA, 0.824 g, 1.13 ml, 8.14 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.796 g, 5.97 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.505 g, 5.97 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215, which is incorporated herein by reference in its entirety) and phthalide (17) (0.728 g, 5.43 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for further 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (15-70% EtOAc in hexanes containing 1% of TEA, gradient elution) yielding 0.80 g (27%) of compound (19) as a pale yellow oil. Rf=0.68 (EtOAc containing 1% TEA). 1H NMR (400 MHz, CD3CN) δ 7.61-7.19 (m, 14H), 6.85 (d, J=8.9 Hz, 4H), 5.33 (s, 1H), 4.50 (s, 2H), 3.75 (s, 6H), 3.32 (q, J=6.6 Hz, 2H), 3.01 (t, J=6.6 Hz, 2H), 1.63-1.53 (m, 4H), 1.44-1.28 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: CC(C)OC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)Cc1ccccc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted with benzenemethanesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:36])[C:14](=[CH:32][N:33]([CH3:35])[CH3:34])[C:15]2[O:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.Cl>C1COCC1>[OH:6][C:7]1[CH:8]=[C:9]([C:13](=[O:36])[C:14](=[CH:32][N:33]([CH3:35])[CH3:34])[C:15]2[O:16][C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=C(C(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C=C(C(=O)c1cccc(O)c1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 95.7 %

Procedure:
The 1-[3-[(1,1-dimethylethyl)dimethylsiloxy]phenyl]-2-[(dimethylamino)methylene]-2-(4,5-diphenyl-2-oxazolyl)ethanone (19) (10.3 g, 19.6 mmol) was dissolved in THF (100 mL) and tetra-n-butyl ammonium fluoride (17.5 mL of 1M in THF) was added dropwise. The reaction mixture was stirred for about 1/4 hour and poured onto an ether (180 mL)/1N HCl(20 mL) solution, and the organic phase separated and dried (MgSO4). Chromatography (elution with 75% ethyl acetate/hexanes) gave the phenol 7.7 g (96%). IR (KBr, cm-1) 3170, 3060, 2920, 1735, 1635, 1600, 1447, 1375, 1310, 1210, 1010, 965, 870, 765, 695. 1H NMR (300 MHz, CDCl3) δ 2.6 to 3.1 (6H, Series of Br. s) 6.84 (1H, Br.s), 6.95 (1H, Br. s), 7.04 to 7.24 (10H, m), 7.32 to 7.60 (5H, m). m/e 411 (MH+)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([O:25]C)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Li+].Cl>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([OH:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)OC)cnc12
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Temperature: 95 °C
Yield: 86.3 %

Procedure:
Methyl 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (6.4 g, 17.7 mmol) obtained in step 3 was dissolved in pyridine (90 mL), lithium iodide (23.7 g, 0.18 mol) was added, and the mixture was stirred with heating at 95° C. for 4 hr. The reaction mixture was allowed to cool, added dropwise to 2 mol/L hydrochloric acid containing ice (about 500 mL), and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration, washed with isopropanol (100 mL), and dried under reduced pressure at 50° C. overnight to give the title compound (5.2 g, 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[C:4]([CH3:28])=[CH:3][C:2]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][N:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1
Reactant: CS(=O)[O-]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Br)cc1C
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(S(C)(=O)=O)cc1C
Temperature: 180 °C
Yield: 36.2 %

Procedure:
A mixture of 1-(5-bromo-3-methylpyridin-2-yl)-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (463 mg, 0.216 mmol), sodium methanesulfinate (66 mg, 0.648 mmol) and copper(I) iodide (123 mg, 0.648 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was heated under microwave irradiation at 180° C. for 1 hr. After cooling, the mixture was diluted with ethyl acetate, filtered through a pad of celite, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to afford the title compound (36 mg, 36%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=2)=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[CH:25][CH:26]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: O=C(Nc1ccc(O)cc1)c1cccnc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(NC(=O)c3cccnc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and N-(4-hydroxy-phenyl)-nicotinamide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C24H24N2O6 [M+H]+: 437.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH:35]=[CH2:34])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Reaction time: 18 h

Procedure:
To a mixture of 4-[3-(2-benzyloxy-5-hydroxyphenyl)propyl]- benzoic acid (150 mg) (prepared as described in Example 4) and potassium carbonate (125 mg) in DMF (5 ml) was added allyl bromide (0.076 ml). The mixture was stirred for 18 hours, then potassium carbonate (125 mg) and allyl bromide (0.076 ml) were added and the mixture stirred for a further 18 hours. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2×20 ml). The combined organics solutions were washed with brine (25 ml) and sodium bicarbonate (25 ml), dried (magnesium sulphate) filtered and evaporated. There was thus obtained allyl 4-[3-(2-benzyloxy-5-(allyloxy)phenyl)propyl]benzoate (150 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].CCN(CC)CC.[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:35][N:36]([CH3:40])[C:37](=[O:38])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reaction time: 48 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (75 mg, 0.17 mmol) and dimethylcarbamic chloride (30 μL, 0.33 mmol,) in CH2Cl2 (2 mL) was added Et3N (46 μL, 0.33 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of dimethylcarbamic chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added. Upon the addition of the third addition of the chloride and the Et3N the temperature was raised to 45° C. The reaction mixture was stirred for 48 h. Concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (62 mg, 70%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5]O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.[I-:42].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5][I:42]
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Reactant: [I-]
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: COc1ccc(Oc2c(Cl)cc(CI)cc2Cl)cc1C(C)C
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
3,5-Dichloro-4-(4-methoxy-3-isopropylphenoxy)-benzylalcohol (3.21 g) (Example 6a) was added into a mixture of P2O5 (576 mg) and H3PO4 (5.5 ml) followed by addition of sodium iodide (2.43 g). The mixture was stirred at 120° C. for 15 min and then partitioned between water and ethyl acetate. The organic layer was washed with an aqueous solution of Na2S2O3 and brine, dried, filtered and concentrated. The residue was crystallized from petroleum ether to give 2.9 g (79%) of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzyliodide.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3].[OH-].[Na+].Cl[CH2:21][CH:22]([OH:25])[CH2:23][OH:24].C>O.C(O)(C)C.C(Cl)(Cl)Cl.CO>[OH:25][CH:22]([CH2:23][OH:24])[CH2:21][N:11]1[C:12]2[C:13](=[O:14])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:15][CH2:16][CH3:17])[C:8]=2[N:9]=[CH:10]1
Reactant: CCCn1c(=O)c2[nH]cnc2n(CCC)c1=O
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2c(ncn2CC(O)CO)n(CCC)c1=O

Procedure:
A suspension of 1,3-di-n-propylxanthine (250.1 g., 1.06 mole) in water (300 ml.) was treated with sodium hydroxide solution (50%, 85 ml.). The mixture was filtered, and evaporated to dryness. The residue obtained was treated with a solution of 1-chloro-2,3-dihydroxypropane (170 g., 1.59 mole) in isopropanol (700 ml.). The mixture was stirred at reflux overnight, filtered, and evaporated to dryness to obtain a brown gummy residue. This residue was dissolved in isopropyl alcohol, and stirred overnight with charcoal (20 gm.). The mixture was filtered, concentrated and allowed to crystallize over night at 0° to -5° C. The crystals were filtered, suspended in ether, refiltered and air dried to yield white crystals (224 g., 72.17%), melting point 88° - 91°. Tlc (5μl of a 5% solution) on a silica plate developed in chloroform:methanol (9.5:0.5) showed one spot. IR and NMR spectra were consistent with the proposed structure.