Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].[CH3:22][SH:23]>O>[CH:18]([NH:17][C@@H:16]1[C:15](=[O:20])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][S:23][CH3:22])[CH2:7][S:8][C@H:9]12)=[O:19]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reactant: CS
Agent: [Na+]
Solvent: O
Product: CSCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium 3-acetoxymethyl-7β-formamidoceph-3-em-4-carboxylate (3.22 g., 0.01 mole) in water (50 ml.) was treated with methanethiol (1.44 g., 0.03 mole) in a sealed glass tube at 70° for 2 hr. The contents of the tube were transferred to an open vessel and stirred at room temperature for 15 min. to allow the excess thiol to evaporate off. The solution was covered with ethyl acetate (50 ml.) and the pH of the aqueous layer adjusted to 1. The ethyl acetate layer was collected and combined with further ethyl acetate extracts (2 × 50 ml.) of the aqueous layer. The combined extract was washed successively with water (50 ml.) and brine (50 ml.), dried, and the solution evaporated, leaving impure 7β-formamido-3-methylthiomethylceph-3-em-4-carboxylic acid as a colourless foam (2.22 g.), which was dissolved in acetone (12 ml.) and ether (12 ml.), and a 10% w/v solution of sodium 2 -ethylhexanoate in acetone (12 ml.) was added. After refrigeration for 1 hr. the precipitate was collected by filtration, washed with acetone:ether (1:1, 2 × 10 ml.) and ether (2 × 20 ml.), and dried in vacuo giving sodium 7β-formamido-3-methylthiomethylceph-3-em-4-carboxylate as a colourless solid (1.69 g.), essentially homogeneous by thin-layer chromatography (trace of starting cephalosporanic acid), [α]D20 + 75.5° (c 1.00, water), λmax. (pH 6 buffer) 263 nm. (ε 7,760), νmax. (Nujol) 1760 (β-lactam), 1680, 1540 (amide), 1608 cm.-1 (CO2-), τ(D2O) 1.78 (1-proton singlet, CHO), 4.31 (1-proton doublet, J 4.5 Hz.: C-7H), 4.84 (1-proton doublet, J 4.5 Hz.: C-6 H) 6.20, 6.65 [two 1-proton doublets (branches or a quartet) J 17 Hz.: C-2 H2 ], 6.22, 6.69 [two 1-proton doublets (branches of a quartet), J 14 Hz.: C-3 CH2 ], 7.98 (3-proton singlet; SCH3)
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO>[Cu]I.C(O)CCC>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccccc1Cl
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Product: O=C(O)c1ccccc1NCc1ccccc1
Temperature: 100 °C
Yield: 48 %

Procedure:
Copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-chlorobenzoic acid (157 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 1-butanol (1.0 mL) were used and heated to 100° C. for 72 hours. The above workup procedure was followed and gave 2-(N-benzyl)aminobenzoic acid (109 mg, 48% isolated yield) as a light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]=O)[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>[CH:13]([C:11]1[CH:10]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1)=[CH2:21]
Reactant: O=Cc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Product: C=Cc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.33 g (0.01289 mol) of [1,1′;3′,1″]terphenyl-5′-carbaldehyde are dissolved in 12 ml of THF and added to methyltriphenylphosphonium bromide solution. The yellowish mixture is stirred at 0° C. for 1 h. After cooling to room temperature, the mixture is taken up in dichloromethane. The solution is washed with water, and the combined organic phases are dried over sodium sulfate. The mixture is evaporated to dryness. Column chromatography is carried out with hexane/ethyl acetate. The column chromatography results in a yield of 2.4 g (71%) of clean substance.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([CH:23]=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O:41]C(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([C:23]([OH:41])=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C(=O)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 77.8 %

Procedure:
The procedure of Example 6 was repeated except that 140 mg of 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carbaldehyde was used in lieu of 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 112 mg of 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)O1.N.[C:36]([C:40]([OH:42])=[O:41])([F:39])([F:38])[F:37]>>[F:37][C:36]([F:39])([F:38])[C:40]([OH:42])=[O:41].[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([C:2]3[N:7]=[N:6][C:5]([O:8][C@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: Clc1ccc(O[C@@H]2CN3CCC2CC3)nn1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: c1cc2[nH]ncc2cc1-c1ccc(O[C@@H]2CN3CCC2CC3)nn1

Procedure:
The product of Example 30A (132 mg, 0.549 mmol) was the product of Example 49A (325 mg, 1.33 mmol) according to the procedure of Example 26B. The title product was purified by preparative HPLC (column: Xterra™, RP-18, 5 μm, 30×100 mm; eluting solvent, MeCN/H2O (with 0.1% v. TFA), (v. 90/10 to 10/90 over 20 min.); flow rate, 40 mL/min.; uv, 254 nm) to provide a solid (115.3 mg, yield, 45.8%). 1H NMR (300 MHz, CD3OD) δ 1.92-2.25 (m, 3H) 2.34-2.49 (m, 1H) 2.63-2.72 (m, 1H) 3.34-3.57 (m, 5H) 3.99 (dd, J=13.90, 8.14 Hz, 1H) 5.54-5.61 (m, 1H) 7.36 (d, J=9.49 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 8.08 (dd, J=8.82, 1.70 Hz, 1H) 8.16-8.23 (m, 2H) 8.38 (dd, J=1.53, 0.85 Hz, 1H) ppm. MS (DCI/NH3) m/z 322 (M+H)+. Anal. Calculated for C18H19N5O.1.2 CF3CO2H: C, 53.47; H, 4.44; N, 15.28. Found: C, 53.67; H, 3.99; N, 15.40.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([Cl:20])[CH:19]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:3]([C:2]([F:6])([F:5])[F:1])=[CH2:4])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: C=CC(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F

Procedure:
3,3,3-Trifluoropropene (3.2 g), potassium carbonate (4.6 g) and bis-(triphenylphosphine)-palladium chloride (0.2 g) is added to a solution of 3,5-dichlorophenylboronic acid in THF (20 ml) under nitrogen. After 3 hours at reflux, the reaction is quenched with ethyl acetate (50 ml) and water (50 ml). The organic phase is then extracted with water and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on silica gel (35×45 mm) using heptane (150 ml) as eluant to yield 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.7 g), as a colorless oil. MS (HPLC/MS): no ionisation. Retention time: 5.10 min.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].CN(C=O)C.[F:20][C:21]1[N:26]=[C:25]([F:27])[C:24]([F:28])=[C:23](F)[C:22]=1[F:30]>O>[F:27][C:25]1[C:24]([F:28])=[C:23]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:11]([F:12])([F:13])[F:14])[C:22]([F:30])=[C:21]([F:20])[N:26]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2c(F)c(F)nc(F)c2F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.0 grams of 50% oil dispersion) was washed with pentane, filtered, and cooled to 0° C. A solution of 4-nitro-2-trifluoromethylaniline (6.1 grams; 0.030 mole) in 25 ml. of DMF was added over a five-minute period. The reaction mixture was allowed to stir for one hour, the temperature rising as high as 10° C. The reaction mixture was then cooled back down to 0° C. and pentafluoropyridine (5.0 grams; 0.030 mole) in 25 ml. of DMF was added. The reaction mixture was allowed to stir without further cooling for about sixteen hours, then poured over 1.8 liter of crushed ice and the volume adjusted to 1.8 liter with water. A precipitate formed and was allowed to remain in the reaction mixture for about twenty-four hours. The precipitate was then separated by filtration. It was recrystallized from ethanol, yielding 2.6 grams of a first crop (m.p. 104°-5° C.; U.S. Pat. No. 3,926,611 reports 107.7-108) and 3.0 grams of a second crop. Elemental analysis of the first crop showed
Reaction SMILES: Br[C:2]1C2C(=C([C@H](OCC3(C4C=CC(F)=CC=4)CCN(C)CC3)C)C=C(Br)C=2)NN=1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C@H:40]([O:42][CH2:43][C:44]3([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH3:41])[CH:39]=1)[NH:36][N:35]=[C:34]2[CH3:57]>>[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C@H:40]([O:42][CH2:43][C:44]3([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)[CH2:49][CH2:48][N:47]([CH3:2])[CH2:46][CH2:45]3)[CH3:41])[CH:39]=1)[NH:36][N:35]=[C:34]2[CH3:57]
Reactant: Cc1n[nH]c2c([C@@H](C)OCC3(c4ccc(F)cc4)CCNCC3)cc(Cl)cc12
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Br)cc2c(Br)n[nH]c12
Product: Cc1n[nH]c2c([C@@H](C)OCC3(c4ccc(F)cc4)CCN(C)CC3)cc(Cl)cc12

Procedure:
Prepared according to the procedure used to prepare (R)-3,5-dibromo-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indazole using (R)-5-chloro-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-3-methyl-1H-indazole as starting material. 1H-NMR (CDCl3, 500 MHz) δ 9.82 (bs, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.23 (dd, J=8.9, 5.5 Hz, 2H), 7.00 (dd, J=8.9, 8.5 Hz, 2H), 6.92 (d, J=1.8 Hz, 1H), 4.43 (q, J=6.4 Hz, 1H), 3.33 (d, J=8.9, 8.5 Hz, 2H), 6.92 (d, J=1.8 Hz, 1H), 4.43 (q, J=6.4 Hz, 1H), 3.33 (d, J=8.9 Hz, 1H), 3.24 (d, J =9.2 Hz, 1H), 2.40-2.65 (m, 5H), 1.85-2.30 (m, 9H), 1.38 (d, J=6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 142.3, 136.7, 128.7 (d, J=7.7 Hz), 127.6, 125.3, 124.4, 124.0, 118.5, 115.3 (d, J=21 Hz), 78.7 (br), 78.1, 51.9, 51.8, 46.2, 40.4, 32.6, 32.4, 22.0, 11.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Product: COc1ccc(-c2nc(C)c([N+](=O)[O-])[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
A mixture of 2-(p-methoxyphenyl)-4-methylimidazole (5.2 g, 0.0277 mole) and 3N HNO3 (125 ml) was stirred at room temperature. After 15 minutes, the mixture was placed in a preheated 90° C. bath. Heating was continued for 20 minutes and the hot solution was quenched in ice-water (250 ml). The yellow solid was collected, washed with water, and suspended in cold saturated NaHCO3 solution (25 ml). After a 15 minute period of stirring, the product was collected and recrystallized from 50% EtOH to yield 1.6 g (25%) of 41; m.p. 198°-204° C. A sample recrystallized from 50% EtOH melted at 199°-204° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[OH:13])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc([N+](=O)[O-])ccc1O
Yield: 83.1 %

Procedure:
Using 5-nitrosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: CN1CCNCC1
Product: CN1CCN(c2c[nH]c(=O)[nH]c2=O)CC1
Yield: 91 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 10 (Step1), starting from 5-bromouracil (0.10 g, 0.52 mmol) and 20 equivalents of 1-methyl piperazine. The crude was purified by washing with water (10 dichloromethane (5 mL) and then collected by dispersion in EtOAc. (10 mL). The solvent was removed by evaporation to afford the title compound (0.15 g, 91%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 2.34-2.42 (m, 4H), 2.74-2.84 (m, 4H), 6.72 (s, 1H). 10.41 (br s, 1H), 11.04 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pt]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCCCC#Cc1cccc(Br)c1
Agent: O=[Pt]
Product: OCCCCCc1cccc(Br)c1
Yield: 74 %

Procedure:
A mixture of an ethanolic solution of 5-(3-Bromo-phenyl)-pent-4-yn-1-ol (Example 3, step a) (1 g, 4.2 mmol)and platinum oxide (24 mg, 10% mol) was placed on a parr shaker for 4 hrs under 40 psi of hydrogen. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The resultant residu was purified by flash chromatography on silica gel, 1st 10:1 hexane/ ethyl acetate, 2nd 2:1 hexane/ethyl acetate as eluent, to give 5-(3-bromophenyl)pentan-1-ol as a clear oil, 0.75 g (74% yield); 1H NMR (DMSO-d6) δ 1.2 (m, 2H); 1.3 (m, 2H); 1.5 (m, 2 H); 3.3 (q, 2H); 4.3 (t, 1 H); 7.2 (m, 2 H); 7.4 (m, 2 H) MS [(+)ESI] m/z=243 [M−H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][CH:25]([OH:42])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=1)[CH:19]=[CH:18]2)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25](=[O:42])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=1)[CH:19]=[CH:18]2)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.33 g (52.2 mmol) acetic anhydride are mixed with 30 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.626 g (1.31 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate in 20 ml absolute DMSO. Having stirred for 17 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1>>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=2[NH2:20])=[O:9])=[CH:10][CH:11]=1
Reactant: Nc1ccc(F)cc1N
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: NCc1ccc(C(=O)Nc2ccc(F)cc2N)cc1
Yield: 35.9 %

Procedure:
The title compound (186 mg, 72% yield) was prepared as a brown solid from 4-cyano-benzoic acid (294 mg, 2 mmol) and 4-fluoro-o-phenylenediamine (302 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 260 (M+1).
Reaction SMILES: [Al].ClC(Cl)=[CH:4][C@@H:5]1[C@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].O.[Br:15][CH2:16][Br:17]>>[Br:15][C:16]([Br:17])=[CH:4][C@@H:5]1[C@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11]
Reactant: BrCBr
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Agent: [Al]
Solvent: O
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under a dry nitrogen atmosphere, approximately 3 g of aluminum shot was added to 225 ml of dibromomethane. The temperature was raised to 35°-40° C., and hydrogen bromide gas was bubbled into the mixture. After 1 hour a reaction began to occur, and, with the temperature being maintained at 35°-40° C., a second and third portion of aluminum shot (total of 9.67 g, 0.358 mole) was added to the mixture. After complete addition, the reaction mixture was heated at 55° C. for 1 hour. The hydrogen bromide gas flow was stopped, and the reaction mixture was cooled to approximately 6° C. Cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (50.0 g, 0.239 mole) in 150 ml of dibromomethane was added to the cooled reaction mixture during 1 hour. After complete addition, the reaction mixture was stirred for 30 minutes. A nitrogen inlet was placed in the reaction mixture, and nitrogen was pulled through the mixture for 90 minutes by applying a slight vacuum to the reaction pot. Distilled water was added dropwise, and the resulting mixture was allowed to stand at room temperature for approximately 18 hours. The organic phase was separated, and the aqueous phase was extracted with 600 ml and 200 ml portions of diethyl ether. The ether washes were combined with the organic phase, and the whole was washed once with a 1 N hydrochloric acid solution and once with a saturated aqueous solution of sodium chloride. The organic phase was dried with magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a solid. The solid was dried under a vacuum for 18 hours, then was recrystallized twice from n-heptane and sublimed to give (+)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid, m.p. 109°-111° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: NC1CC1
Product: O=[N+]([O-])c1ccc(NC2CC2)cn1

Procedure:
Using analogous procedures to those described in the portion of Note [9] immediately above that is concerned with the preparation of starting materials, 5-bromo-2-nitropyridine (0.41 g) was reacted with cyclopropylamine (0.21 ml) to give 5-cyclopropylamino-2-nitropyridine (0.322 g); 1H NMR: (CDCl3) 0.62 (m, 2H), 0.91 (m, 2H), 2.57 (m, 1H), 4.96 (br s, 1H), 7.19 (m, 1H), 7.99 (d, 1H), 8.16 (m, 1H); which in turn was converted into 5-(N-tert-butoxycarbonyl-N-cyclopropylamino)-2-nitropyridine (0.48 g); 1H NMR: (CDCl3) 0.59 (m, 2H), 1.05 (m, 2H), 1.53 (s, 9H), 3.02 (m, 1H), 8.05 (m, 1H), 8.22 (d, 1H), 8.64 (m, 1H); which in turn was converted into 2-amino-5-(N-tert-butoxycarbonyl-N-cyclopropylamino) pyridine (0.349 g); 1H NMR: (CDCl3) 0.5 (m, 2H), 0.79 (m, 2H), 1.44 (s, 9H), 2.95 (m, 1H), 4.39 (br s, 2H), 6.46 (d, 1H), 7.24 (m, 1H), 7.87 (m, 1H); Mass Spectrum: M+H+ 250; and which in turn was converted into N-[5-(N-tert-butoxycarbonyl-N-cyclopropylamino) pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetamide; Mass Spectrum: M+H+ 572.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC=C=O)=[C:6]([O:12][CH3:13])[C:5]([O:14][CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([F:24])[C:17]=2[F:25])=[CH:4][C:3]=1[N:26]1[C:34](=[O:35])[NH:33][C:32]2[C:27]1=[N:28][C:29]([CH3:38])=[N:30][C:31]=2[O:36][CH3:37].C[Mg]Br.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH2:13][C:6]([OH:12])([CH3:7])[CH3:5])[C:5]([O:14][CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([F:24])[C:17]=2[F:25])=[CH:4][C:3]=1[N:26]1[C:34](=[O:35])[NH:33][C:32]2[C:27]1=[N:28][C:29]([CH3:38])=[N:30][C:31]=2[O:36][CH3:37]
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)c(OC=C=O)c1OC
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)cc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxy-carbonylmethoxyphenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (34 mg) in tetrahydrofuran (3 mL) was added methylmagnesium bromide (1 mol/L tetrahydrofuran solution, 031 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/4) to give the title compound (4 mg).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C.C(OCC)(=O)C>[NH2:21][C:19]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1(c2ccc(-c3csc(N)n3)cc2)CC1

Procedure:
A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate (0.30 g, 1.2 mmol) and thiourea (0.18 g, 2.4 mmol) in ethanol (5.0 ml) was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 and brine successively; then dried; and then concentrated. The residue was triturated with ether followed by filtration to afford the product. LC-MS: 275.1 (M+H)+.