Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]1[N:34]=[C:35]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)[S:36][CH:37]=1.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][C:33]3[N:34]=[C:35]([C:38]4[S:39][CH:40]=[CH:41][CH:42]=4)[S:36][CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: ClCc1csc(-c2cccs2)n1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(OCc4csc(-c5cccs5)n4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (100 mg, 0.3 mmol), cesium carbonate (195 mg, 0.6 mmol), 4-(chloromethyl)-2-(2-thienyl)-1,3-thiazole (71 mg, 0.33 mmol), tetrabutylammonium bromide (10 mg, 0.03 mmol), triethylamine (0.5 ml), and acetonitrile (10 mL) were combined and stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and dichloromethane was added to the residue. Undissolved solids were removed by filtration. The filtrate was concentrated under reduced pressure and subsequently purified by flash column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane. The clean fractions were combined and concentrated under reduced pressure. The solid was recrystallized from acetonitrile to yield 82 mg of 1-[4-amino-2-ethoxymethyl-7-[2-(thiophen-2-yl)thiazol-4-ylmethoxy]-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off white powder, mp 192.0-194.0° C.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C[O-].[Na+].CO.[CH3:10][C:11]([CH3:20])([CH3:19])[C:12](=O)[CH2:13][C:14](OC)=[O:15]>C(O)(=O)C.O>[C:11]([C:12]1[CH:13]=[C:14]([OH:15])[N:4]=[CH:2][N:3]=1)([CH3:20])([CH3:19])[CH3:10]
Reactant: N=CN
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
First, 7.2 g of formamidine hydrochloride, 7.5 g of sodium methoxide, and 70 mL of methanol were put into a 100 mL three-neck flask. Then, 10 g of methyl 4,4-dimethyl-3-oxovalerate was added to this mixed solution. The mixture was stirred at room temperature for 24 hours. After that, a mixed solution of 17 mL of water and 7.2 mL of acetic acid was added to the reacted solution, and the mixture was stirred at room temperature. This mixture was concentrated, and the resulting residue was dissolved in water. The solution was subjected to extraction with ethyl acetate. The obtained solution of the extract was washed with saturated brine, and magnesium sulfate was added for drying. After the drying, the solution was filtered. After the solvent of this solution was distilled off, the obtained solid was washed with ethyl acetate, so that the pyrimidine derivative to be produced was obtained as a white solid in a yield of 49%. A synthesis scheme of Step 1 is shown in (k-1).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)=O)(C)(C)C.C(OCC)C>Cl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Solvent: CCOCC
Product: CN1CCN(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.7 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(1-methylpiperazin-4-yl)benzamide (Method 16, 196 mg, 0.48 mmol) was dissolved in a 1M solution of hydrogen chloride in diethyl ether (7.2 ml, 7.2 mmol) and stirred at ambient temperature for 24 hours. The resultant precipitate was collected by filtration and washed with diethyl ether. To the solid was added a 2M solution of aqueous sodium hydroxide (5 ml) and the mixture extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered and evaporated to afford the title compound as a colourless solid (16 mg, 11%); NMR Spectrum: (CDCl3) 2.36 (s, 3H), 2.57 (t, 4H), 3.33 (t, 4H), 3.88 (br, 2H), 6.81 (m, 2H), 6.91 (d, 2H) 7.06 (t, 1H), 7.27 (d, 1H), 7.79 (s, 1H), 7.80 (m, 2H); Mass Spectrum: M+H+ 311.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)(=[O:10])=[O:9])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCNCc1cccnc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C)cn2)cc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cn1

Procedure:
prepared by reaction of [(5-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>O1CCCC1>[CH3:23][N:24](/[CH:26]=[C:11]1\[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[C:10]\1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:25]
Reactant: COC(OC)N(C)C
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Solvent: C1CCOC1
Product: CN(C)/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one [(Example 107, Step 1), 0.20 g, 0.73 mmol] and N,N-dimethylformamide dimethylacetal (0.12 mL, 0.88 mmol, 1.2 equiv) were combined in tetrahydrofuran (5 mL) and placed into a preheated oil bath at 65° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH:12](=[N:19][N+:20]1[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]=1SC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS.C(OCC)C>CN(C)C=O>[F:7][B-:8]([F:11])([F:10])[F:9].[CH:12](=[N:19][N+:20]1[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Reactant: C1COCCN1
Agent: CS
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C(=Nn1cc[n+](N=Cc2ccccc2)c1N1CCOCC1)c1ccccc1

Procedure:
1.45 g of absolute morpholine are added under an argon atmosphere to 4.1 g of 1,3-bis-(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate in 15 ml of absolute dimethylformamide, whereby the evolution of methyl mercaptan occurs immediately and a yellow-orange solution results. The solution is stirred at room temperature until the cleavage of methyl mercaptan is complete (about 12 hours). Then the solution is treated with 120 ml of diethyl ether and the resulting, slightly yellowish precipitate is removed by filtration under suction. The precipitate is washed five times with diethyl ether, and twice with a small amount of cold ethanol and re-precipitated from acetonitrile/diethyl ether. There is obtained colorless 1,3-bis(benzylideneamino)-2-morpholinoimidazolium tetrafluoroborate of melting point 242°-245° (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[Br-].[CH2:19]1COC[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH2:6][C:5]2([CH:19]=[CH2:20])[OH:17]
Reactant: C1CCOC1
Reactant: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Agent: [Br-]
Product: C=CC1(O)CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (383 mg, 1.30 mmol) in anhydrous THF (10 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 1.95 mL, 1.95 mmol) dropwise within 10 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH4Cl, and extracted with ethyl acetate (2×30 mL). The combined organic phases are washed with H2O, brine, dried over Na2SO4, and filtered. The filtrate is concentrated to give crude 6-bromo-4-vinylspiro[chroman-2,1′-cyclohexan]-4-ol as an oil, which is used for the next step without further purification. MS ESI+ve m/z 305 (M+H—H2O)+.
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:8](OC)=[O:9].Cl.[CH:23]([NH2:25])=[NH:24]>CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:7]1[C:8]([OH:9])=[N:24][CH:23]=[N:25][C:6]=1[OH:5]
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)ncnc1O
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
At 5° C. 12.7 g of sodium methylate was added portionwise to a solution of 18.9 g of dimethyl-2-(o-methoxyphenoxy)malonate in 450 ml of methanol. Upon completion of the addition stirring was continued at room temperature for 30 min followed by the addition of 6 g of formamidine hydrochloride. The mixture was stirred at room temperature for 72 h. Eventually, the solvent was removed under reduced pressure and the remaining residue was suspended in diethyl ether. The solid material was filtered off and dissolved in 100 ml of water. The solution was acidified with conc. hydrochloric acid. A white precipitate formed. The precipitate was collected, washed with water and dried to give 15.1 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-pyrimidine (or a tautomer) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[CH3:14]C(C)([O-])C.[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH3:14])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)cc(F)c2N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(Br)cc(F)c21
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A solution of 6-bromo-8-fluoro-3,4-dihydro-1H-quinolin-2-one (0.21 g, 0.86 mmol) in DMF (2 mL) was treated with potassium tert-butoxide (0.19 g, 1.72 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes before methyl iodide (0.18 g, 1.29 mmol) was added. After stirring for 2 hours, the reaction mixture was treated with water, extracted with EtOAc, washed with water and brine in sequence, and dried over anhydrous Na2SO4. After removal of solvent under reduced pressure, the crude product (0.18 g, 80%) was obtained as a white solid. MS: 258.0 (M+H+)+.
Reaction SMILES: [Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Br:55][C:56]1[CH:65]=[C:64]2[C:59]([CH2:60][CH2:61][CH2:62][C:63]2=[O:66])=[CH:58][CH:57]=1.C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+]>ClCCl.CO>[Br:55][C:56]1[CH:65]=[C:64]2[C:59]([CH:60]=[CH:61][CH:62]=[C:63]2[OH:66])=[CH:58][CH:57]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Product: Oc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.5 %

Procedure:
A solution of tetrabutylammonium tribromide (11.8 g, 24.4 mmol) in dichloromethane (80 ml) was added dropwise to a solution of the product from Step C (5.0 g, 22.2 mmol) in dichloromethane (20 ml) and methanol (20 ml) at room temperature over 1 hour. At completion of the addition, the mixture was stirred at room temperature for 15 hours and was then concentrated. The residue was taken into dichloromethane and was washed with saturated sodium bicarbonate three times. The organic layer was concentrated and the residue was dissolved in dimethylformamide (100 ml). Lithium carbonate (5.3 g, 71.1 mmol) and lithium bromide (4.1 g, 46.6 mmol) were added and the resulting mixture was stirred at 140° C. for 1.5 hours. After cooling to room temperature, the solids were filtered and rinsed with ethyl acetate. The filtrate was washed with water four times and dried over sodium sulfate to give 7-bromonaphthalen-1-ol (2.7 g, 56%): 1H NMR (300 MHz, CDCl3) δ 8.41 (d, J=1.8 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.7, 1.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.28-7.35 (m, 1H), 6.62 (d, J=7.2 Hz, 1H), 5.80 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([Cl:28])[CH:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[C:19]([Cl:28])[CH:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)c(Cl)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 50 h

Procedure:
Tert-butyl 5-chloro-4-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluorobenzoate (Preparation 161, 41.88 g, 0.0868 mol) was dissolved in dichloromethane (75 mL), then trifluoroacetic acid (21.2 mL, 0.285 mol) was added and the mixture was stirred at room temperature for 50 hours. Trifluoroacetic acid was added again (1.2 mL, 0.017 mol) and the reaction left to stir for 4 hours. A solid was observed in the flask, so it was collected by filtration. The filtrate was concentrated in vacuo and dichloromethane (5 mL) was added to the crude, which was stirred for 5 minutes at room temperature. The resulting solid was collected by filtration and set aside. The crops were combined and title compound was isolated as a white solid (29.6 g, 81%).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:28]1[CH2:42][O:41][C:36]23[O:37][CH2:38][CH2:39][O:40][C:30]2([C@:31]2([CH2:55][CH2:54][C@H:53]4[C@@H:43]([CH2:44][CH:45]=[C:46]5[C@:51]4([CH3:52])[CH2:50][CH2:49][CH2:48][CH2:47]5)[C@@H:34]2[CH2:35]3)[CH:32]=O)[O:29]1.C(OCC)(=O)C>CCCCCC.O1CCCC1.N1CCCCC1>[CH2:39]1[CH2:38][O:37][C:55]23[O:41][CH2:42][CH2:28][O:29][C:30]4([C@:31]2(/[CH:32]=[CH:8]\[Cl:7])[C@H:34]([C@@H:43]2[CH2:44][CH:45]=[C:46]5[C@:51]([CH3:52])([CH2:50][CH2:49][CH2:48][CH2:47]5)[C@H:53]2[CH2:54]3)[CH2:35][CH2:36]4)[O:40]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@@]2(C=O)[C@H]1CC13OCCOC12OCCO3
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: C[C@]12CCCCC1=CC[C@H]1[C@@H]3CCC45OCCOC(C[C@@H]12)(OCCO4)[C@@]35/C=C\Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.4 ml of a 1.56 molar solution of butyl-lithium in hexane is added to a suspension of 5.82 g of chloromethyltriphenyl-phosphonium chloride in 107 ml of absolute tetrahydrofurane and 1.67 ml of piperidine at 0° C, under argon and with complete exclusion of moisture. After 30 minutes, 1.3 g of 3,3:17,17-bis-(ethylenedioxy)-androst-5-en-18-al in 22.5 ml of tetrahydrofurane are added dropwise at room temperature. Thereafter, the mixture is stirred for 1 hour at room temperature and then poured into ice water. Ethyl acetate is added to the mixture and the organic phase is separated off and washed with cold 1 N hydrochloric acid, with water, with sodium bicarbonate solution and with saturated sodium chloride solution. After drying over sodium sulphate and evaporating the solvent, the residue is chromatographed on silica gel using a mixture of hexane/ethyl acetate (9:1). 3,3;17,17-Bis-(ethylenedioxy)-13-(cis-2-chlorovinyl)-10-methyl-gon-5-ene is isolated from the first fractions and is recrystallised from methylene chloride/hexane; melting point 172°-174° C, [α]D 25 = -81°. The corresponding trans isomer is obtained from the later fractions and after recrystallisation from petroleum ether melts at 108°-110° C, and has an [α]D25 = -52°.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:18][CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:19]/[C:18](=[CH:11]\[CH2:10][CH2:9][C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=CCCC#Cc1ccccc1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C(C)=C/CCC#Cc1ccccc1
Yield: 98 %

Procedure:
5-phenyl-pent-4-yn-1-al (1 g, 6.33 mmol) (Example 1) and carboethoxymethylmethylene triphenylphosphorane were used with the same method as in Example 1 to give 1.5 g (98% of theory) of ethyl 2-methyl-7-phenyl-(2E)-hepten-6-ynoate as a pale yellow oil.
Reaction SMILES: C(O)C.Cl.Cl.[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:38](=[O:37])[CH2:39][OH:40])[CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: CC(=O)OCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CO)CC1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)-quinazoline dihydrochloride ethanol solvate (91.8 g), 4-(dimethylamino)pyridine (73.3 g) and acetonitrile (330 ml) were stirred at 20° C. to 25° C., under nitrogen. Acetoxyacetyl chloride (28 ml) was added maintaining the temperature at less than 30° C., followed by an acetonitrile line wash (37 ml). The reaction mixture was stirred at ambient for 60 minutes before water (250 ml) and 47% w/w sodium hydroxide solution (77.2 ml) were added followed by a water line wash (25 ml), keeping the temperature at less than 30° C. The reaction mixture was stirred at ambient for 120 minutes before the lower aqueous layer was separated. Water (735 ml) was added to the organic layer and mixture stirred at ambient until a solid crystallised. The solid was filtered, washed with a 50% aqueous acetonitrile (2×90 ml), and then dried in a vacuum oven between 50° C. and 55° C. to give the title product (65.8 g; 83.9% yield); melting point 195.5–196.5° C.; NMR Spectrum: (DMSO d6) 1.64–1.83 (m, 2H); 1.98–2.14 (m 2H); 3.28–3.48 (m, 1H); (m, 2H); 3.57–3.67 (m, 1H); 3.81–3.92 (m, 1H); 4.00 (s 3H); 4.14 (s, 2H); 4.81 (m 1H); 7.27 (s 1H); 7.36 (t 1H); 7.54–7.64 (m 2H); 8.00 (s 1H); 8.66 (s 1H); Mass Spectrum: (M+H)30 460.9.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:34])[CH2:32][NH2:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:33][CH2:32][CH:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)[CH3:34])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(CN)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)O)c(NS(=O)(=O)c2cccc3nsnc23)c1
Product: Cc1ccc(C(=O)NCC(C)c2ccc(Cl)cc2)c(NS(=O)(=O)c2cccc3nsnc23)c1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methyl-benzoic acid was coupled with (±)-2-(4-chloro-phenyl)-propylamine as in EXAMPLE 1, Part C. HPLC: RT=10.22 min. MS (ESI−): mass calcd. for C23H21ClN4O3S2, 500.07; m/z found, 499 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.48 (s, 1H), 8.31 (dd, J=7.0, 1.0, 1H), 8.18 (dd, J=8.8, 1.0, 1H), 7.67 (dd, J=8.8, 7.0, 1H), 7.47 (s, 1H), 7.33-7.27 (m, 2H), 7.16-7.10 (m, 2H), 6.90 (d, J=8.0, 1H), 6.71 (d, J=8.0, 1H), 5.75-5.70 (m, 1H), 3.73-3.64 (m, 1H), 3.30-3.21 (m, 1H), 3.05-2.94 (m, 1H), 2.26 (s, 3H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:9][CH2:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[C:12](O)=[O:13])[CH2:8][CH2:7]1)[CH3:2].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:9][CH2:10][CH:11]([CH2:12][OH:13])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1(CCC(Cc2ccc(C(=O)OC)cc2)C(=O)O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(CCC(CO)Cc2ccc(C(=O)OC)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At −10° C., 12.31 ml of a 1 M borane/THF complex solution (12.31 mmol) are added dropwise to a solution of 2.23 g (6.15 mmol) of 4-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-2-[4-(methoxy-carbonyl)benzyl]butanoic acid in 50 ml of THF. After warming to 0° C., the mixture is stirred at this temperature for another 2 hours and then at room temperature for 1 hour. After complete conversion, saturated ammonium chloride solution is added, and the reaction mixture is extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are then dried over sodium sulfate, and the solvent is evaporated to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). This gives 1680 mg (78% of theory) of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCO)=C(C)C1=O
Yield: 83.5 %

Procedure:
Oxidation as described in protocol B, using 56.7 mg (0.184 mmol) of 6-hydroxy-N-(3-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 222 mg CAN (0.406 mmol) yielded 49.7 mg of 2-hydroxy-N-(3-hydroxypropyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH:13](=[N:5][CH2:4][CH2:3][CH2:2][Br:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: BrCCCN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
The hydrobromide salt of 3-bromopropylamine (5.364 g, 24.50 mmol) was treated with triethylamine (4 mL) in CHCl3 (100 mL) and allowed to stir at room temperature for 5 min. Benzaldehyde (2.000 g, 18.85 mmol) and magnesium sulfate (6.000 g) were added and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was filtered and the filter pad was washed with CHCl3 (50 mL). The filtrate was washed with water (3×50 mL), sat NaCl (50 mL), dried over sodium sulfate, and concentrated to provide a yellow oil (4.262 g, 100%). IR (film) 1645, 754, and 693 cm−1; 1H NMR (CDCl3) δ 8.34 (s, 1 H), 7.76 (m, 2 H), 7.44 (m, 3 H), 3.78 (dt, J=6.3 Hz and 1.3 Hz, 2 H), 3.52 (t, J=6.5 Hz, 2 H), 2.31 (pent, J=6.4 Hz, 2 H); ESIMS m/z (rel intensity) 226/228 (MH+, 100/91). Anal. (C10H12BrN) C, H, N.