Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([CH3:39])[C:19]([C:21]3[C:29]4[C:24](=[C:25]([O:30][CH2:31][C:32](=[O:38])[N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[BH4-].[Na+].CO>C(#N)C.CC(O)C>[NH2:17][C@H:18]([CH3:39])[CH2:19][C:21]1[C:29]2[C:24](=[C:25]([O:30][CH2:31][C:32]([N:33]([CH2:34][CH3:35])[CH2:36][CH3:37])=[O:38])[CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: CCN(CC)C(=O)COc1cccc2c(C(=O)[C@@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)O
Solvent: CO
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Temperature: 25 °C
Yield: 25 %

Procedure:
To a suspension of N-(9-fluorenylmethoxycarbonyl)-D-alanine (8.17 g, 26.3 mmol), methylene chloride (88 ml) and N,N-dimethylformamide (0.14 ml) is added dropwise oxalyl chloride (2.44 ml, 28 mmol) at room temperature with stirring, and the mixture is further stirred for one hour. The reaction solution is concentrated to dryness under reduced pressure to give an oil containing 9-fluorenylmethoxycarbonyl-D-Ala-Cl. A solution of N,N-diethyl-2-(1H-indol-7-yloxy)acetamide (4.31 g, 17.5 mmol) in methylene chloride (44 ml) is cooled to −20° C., and thereto is added dropwise a 3M solution of methyl magnesium bromide in diethyl ether (20.5 ml, 61.4 mmol). After the addition, the mixture is further stirred at −15° C. for one hour. This reaction solution is cooled to −20 to −15° C., and thereto is added dropwise a solution of N-(9-fluorenylmethoxycarbonyl)-D-alanyl chloride in methylene chloride (53 ml) obtained above, and the mixture is further stirred at −20° C. for 5.5 hours. The mixture is warmed to about −5° C., and poured into 2N hydrochloric acid. The organic layer is collected, washed with water (25 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to give an oil (13.3 g) containing (R)-[2-(7-diethylcarbamoylmethoxy-1H-indol-3-yl)-1-methyl-2-oxoethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester. To a solution of the obtained oil in a mixture of acetonitrile (70 mL) and 2-propanol (4.0 ml) is added sodium borohydride (1.98 g, 52 mmol) in portions at room temperature with stirring, and the mixture is refluxed for 5 hours. The reaction solution is cooled to room temperature, and thereto is added dropwise methanol (120 ml). The reaction mixture is concentrated to dryness under reduced pressure. To the residue are added ethyl acetate and water, and the mixture is stirred. The organic layer is separated, washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (methanol/a saturated ammonia solution in chloroform=1/20) to give the desired (R)-2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-N,N-diethyl-acetamide (1.33 g, yield: 25%).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:14]2[O:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:11][C:10]=2[C:9]([O:21]C)=[CH:8][CH:7]=1>ClCCl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:21])=[C:10]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[N:11]2
Reactant: COc1ccc(Br)c2oc(N3CCOCC3)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Br)c2oc(N3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
A solution of boron tribromide (25.6 ml of a 1.0M in dichloromethane) was added slowly to a stirred solution of 7-bromo-4-methoxy-2-(morpholin-4-yl)-benzooxazole (4.0 g) in dry dichloromethane (100 ml) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 90 mins. The mixture was partitioned between sodium hydrogencarbonate solution (50 ml) and dichloromethane (100 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 30-50% ethyl acetate in heptane afforded the title compound as an off-white solid (1.64 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C=O)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(CO)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 4-(3-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 5.98 mmol) in THF (14 mL) at 0° C. was added LAH (6.0 mL, 1M solution in THF). The reaction mixture stirred at 0° C. for 30 min. followed by a quench of H2O (239 μL), 15% NaOH (aq., 239 μL), and H2O (718 μL). After completion of the additions the mixture stirred for 20 min. and was then filtered over a pad of celite. The solvent of the filtrate was removed en vacuo to obtain 4-(3-hydroxymethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a brown solid (1.47 g, 84% yield), which was taken on to the next reaction without further purification. 1H NMR (300 MHz, DMSO-d6): δ 7.17 (t, 1H, J=8.0 Hz), 6.91 (br s, 1H), 6.82-6.76 (m, 2H), 5.06 (t, 1H, J=5.80 Hz), 4.44 (d, 2H, J=5.6 Hz), 3.45 (dd, 4H, J=5.5, 4.9 Hz), 3.08 (dd, 4H, J=5.3, 5.1 Hz), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([C:18]([NH2:20])=[O:19])=[N:11][CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])=O)[CH3:2].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na].[Na].C(=O)([O-])[O-].[Na+].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[NH:20][C:18](=[O:19])[C:10]2[N:11]=[CH:12][CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCCc1ccnc(C(N)=O)c1NC(=O)c1ccccc1OCC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: CCCc1ccnc2c(=O)[nH]c(-c3ccccc3OCC)nc12
Temperature: 210 °C
Yield: 64.6 %

Procedure:
A mixture of 3-(2-ethoxybenzoylamino)-4-n-propylpridine-2-carboxamide (Preparation 7; 1.52 g, 0.0046 mol) and anhydrous zinc chloride (1.88 g, 0.014 mol) was heated at 210° C. for 0.25 hour. The cool mixture was dissolved in methanol (20 ml) and this solution poured into an aqueous solution of disodium ethylenediamine tetraacetic acid (10.3 g in 200 ml water). The resulting mixture was basified with saturated aqueous sodium carbonate solution (20 ml), then extracted with dichloromethane (4×60 ml). The combined organic extracts were dried (MgSO4) and evaporated under vacuum, then the residue crystallised from ethyl acetate to give the title compound as a white solid (0.92 g, 65%), m.p. 134°-137° C. Found: C,69.69; H,6.27; N,13.54. C18H19N3O2 requires C,69.88; H,6.19; N,13.58%.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:17]=1)([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:5][C:6](OC)=[O:7])#[N:2].[H-].[Na+]>COCCOC>[C:12]([CH:11]1[CH2:10][C:3]([C:1]#[N:2])([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:17]=2)[CH2:4][CH2:5][C:6]1=[O:7])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OCC2CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CCC1=O
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of dimethyl 4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)pimelate (10.4 g, 26.7 mmol) in dry 1,2-dimethoxyethane (500 mL) under an argon atmosphere was added sodium hydride (80% dispersion in mineral oil, 2.5 g, 31.2 mmol). The resulting mixture was refluxed for 4 h, cooled to room temperature and quenched with water. The mixture was partitioned between ethyl acetate and acidic water, extracted three times, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide an oil (9 g, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10]([C@H:14]1[C:41](=[O:42])[N:40]2[CH2:43][C@@H:37]([CH2:38][C@H:39]2[C:44]([NH:46][C@:47]2([C:52](=[O:63])[NH:53][S:54]([C:57]3([CH2:60][O:61][CH3:62])[CH2:59][CH2:58]3)(=[O:56])=[O:55])[CH2:49][C@H:48]2[CH:50]=[CH2:51])=[O:45])[O:36][C:26]2=[N:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[C:34]([OH:35])=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:64][CH2:65][CH2:66][C@H:18]2[O:17][C:16](=[O:67])[NH:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C@H:14]1[C:41](=[O:42])[N:40]2[CH2:43][C@@H:37]([CH2:38][C@H:39]2[C:44]([NH:46][C@:47]2([C:52](=[O:63])[NH:53][S:54]([C:57]3([CH2:60][O:61][CH3:62])[CH2:59][CH2:58]3)(=[O:55])=[O:56])[CH2:49][C@H:48]2[CH:50]=[CH2:51])=[O:45])[O:36][C:26]2=[N:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[C:34]([O:35][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:64][CH2:65][CH2:66][C@H:18]2[O:17][C:16](=[O:67])[NH:15]1)([CH3:11])([CH3:12])[CH3:13]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1(COC)CC1
Reactant: BrCCN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1OCCN1CCOCC1)O2)C(=O)NS(=O)(=O)C1(COC)CC1

Procedure:
The title compound was prepared using the same method as described for Example 42 using 4-(2-bromoethyl)morpholine and (3aR,7S,10S,12R,24aR)-7-tert-butyl-N-[(1R,2S)-2-ethenyl-1-({[1-(methoxymethyl)cyclopropyl]sulfonyl}carbamoyl)cyclopropyl]-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 35). Purification by flash chromatography (ISCO) afforded the desired product (21.5 mg). LRMS (ES+) m/z 937.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[OH:11].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]#[N:20])[CH:13]=1.[OH-].[Na+]>CO>[C:19](/[C:18](/[C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([OH:11])[CH:5]=1)#[N:20]
Reactant: N#CCc1cccnc1
Reactant: COc1ccc(C=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C(\C#N)c2cccnc2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A mixture of 4-methoxy-3-hydroxybenzaldehyde (0.5 g, 3.3 mmoles), 3-pyridylacetonitrile (0.35 ml, 3.3 mmoles) and 50% w/v of aqueous NaOH (3 ml) in methanol (10 ml) was stirred at room temperature for 30 minutes. The yellow solid that precipitated was filtered, washed with cooled methanol (1 ml), cooled CH2Cl2 (5 ml) and dried under vacuum over P2O5 to yield 0.5 g (60%) of the title compound as a yellow solid. 1H-NMR (CD3OD) 8.8 (m, 1H), 8.5 (m, 1H), 8.1 (m, 1H), 7.7 (s, 1H), 7.5 (m, 1H), 7.3 (d, 1H), 7.2 (d, 1H), 6.8 (d, 1H). Mass Spectrum m/e (M+1) 253.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.Cl>C1C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH:9]([Cl:15])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)C1CCC(=O)C(Cl)C1

Procedure:
The compound 4-t-butylcyclohexanone, 154.3 grams, is dissolved in 1 liter of benzene to which a trace of ferric chloride is added. The mixture is heated and 148.5 grams of sulfuryl chloride is added dropwise in periodic increments. The reaction mixture is slowly heated to its reflux temperature and maintained at that temperature until no further evolution of hydrochloric acid is observed. The solvent is removed in vacuo and the residue dissolved in a small amount of heptane. The solution is passed through an alumina column and the eluate removed by evaporation under reduced pressure to yield 167.6 grams of crude 4-t-butyl-2-chlorocyclohexanone.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:13])=[C:2]=[S:3].[CH2:14]([NH2:17])[CH2:15][NH2:16]>C1(C)C=CC=CC=1>[NH2:16][CH2:15][CH2:14][NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:13]
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2c1OCO2
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)ccc2c1OCO2
Reaction time: 0.08 h

Procedure:
To a stirred solution of 0.78 g of 5-isothiocyanato-4-methyl-1,3-benzodioxole in 50 mL of toluene at 25° C. is added 0.80 mL of ethylenediamine. After five minutes, the mixture is concentrated under reduced pressure to yield 1.0 g of 5-[N'-(2-aminoethyl)thioureido]-4-methyl-1,3-benzodioxole as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[F:12][C:13]([F:27])([F:26])[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:27][C:13]([F:12])([F:26])[C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH2:10][CH2:9][CH2:8][C:7]3=[O:11])[CH2:24][CH2:25]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCN1CCCCBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C1CCCN1CCCCN1CCN(c2cccc(C(F)(F)F)n2)CC1
Yield: 102.7 %

Procedure:
9 g of 1-(4-bromobutyl)-2-pyrrolidinone and 7.6 g of 1-[6-(trifluoromethyl)-2-pyridinyl]-piperazine were mixed with 100 ml of butanol. 4.3 g of sodium carbonate were added, and the mixture is refluxed for 3 hours. The precipitate is filtered and washed with butanol, and the filtrate is then evaporated. The residue was dissolved in dichloromethane, washed with water, dried over anhydrous magnesium sulfate, after which the solvent was evaporated to obtain 12.5 g of 1-[4-[4-[6-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]-butyl]-2-pyrrolidinone. To make the monofumarate, the free base was mixed with 3.9 g of fumaric acid in absolute ethanol. The resulting substance was recrystallized twice from absolute ethanol, after which 7.8 g (43.6% yield) of 1-[4-[4-[6-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]butyl]-2pyrrolidinone. (E)-2-butenedioate (1:1) salt were obtained. M.p. 173° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([C:36]3([C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)O1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3([C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)OC(C)(C)C

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:33])([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=2)[CH3:16])=[C:6]([CH:13]=1)[C:7]([NH:9][NH:10][CH:11]=O)=[O:8].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:16])([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:32])[F:31])=[N:19][N:18]=2)[CH3:33])=[C:6]([C:7]2[O:8][CH:11]=[N:10][N:9]=2)[CH:13]=1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NNC=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nnco1
Temperature: -10 °C
Reaction time: 20 h
Yield: 13 %

Procedure:
5-chloro-N′-formyl-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl}-4H-1,2,4-triazol-3-yl)ethoxy)benzohydrazide (200 mg) was dissolved in dichloromethane (3 ml), pyridine (80 μl) was added thereto, followed by cooling to −10° C. Trifluoromethanesulfonic anhydride (140 μl) was added to the reaction solution, followed by stirring at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=98:2 to 90:10), the resulting light yellow solid was dissolved in ethyl acetate (3 ml), and 4M hydrogen chloride-ethyl acetate (100 μl) was added thereto. The precipitated solid was collected by filtration, followed by drying and then drying under reduced pressure. The resulting hydrochloride was suspended in chloroform and the suspension was neutralized with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate) and the resulting oily product was powdered with diisopropylether to obtain, as a colorless solid, 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3,4-oxadiazole (25 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](I)[CH:14]=[C:15]([F:21])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH2:29])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[CH:29]/[C:13]2[CH:14]=[C:15]([F:21])[CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])=[CH:26][CH:25]=1
Reactant: Oc1nc(Nc2ccc(Cl)c(Cl)c2)nc2c(I)cc(F)cc12
Reactant: C=Cc1ccc(C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(/C=C/c2cc(F)cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1
Temperature: 120 °C

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-6-fluoro-8-iodoquinazolin-4-ol (45 mg) and palladium acetate (13.5 mg) in dimethylformamide (1.3 mL) was added 4-methylstyrene (26 μL), diisopropylethylamine (200 μL) and tri-o-tolylphosphine (12 mg). The resulting mixture was heated at 120° C. for 3 h. The mixture was then cooled to room temperature and the supernatant was removed by pipette from the settled black solids. The solvent and the excess volatile reagents were removed in vacuo, providing the crude product as a brown solid. This residue was triturated with 50% (v/v) methanol/dichloromethane (3 mL) and the resulting yellow solid was dried in vacuo to afford the title compound (25.1 mg). 1H NMR (300 MHz, DMSO-d6): δ11.24 (brs, 1H), 9.12 (brs, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.04 (dd, J=3 & 10.2 Hz, 1H), 7.91 (d, J=16.8 Hz, 1H), 7.62-7.56 (m, 4H), 7.47 (d, J=16.8 Hz, 1H), 7.36 (dd, J=2.4 & 9 Hz, 1H), 7.31 (d, J=6 Hz, 2H), 2.34 (s, 3H). MS (APCI+): m/z 440.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:5]([O:15][CH3:16])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=[C:8]([Cl:11])[C:9]=1[CH3:10]>CO>[Br:3][C:4]1[C:5]([O:15][CH3:16])=[C:6]([CH:12]([OH:14])[CH3:13])[CH:7]=[C:8]([Cl:11])[C:9]=1[CH3:10]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (from Example 11, Step 1) (1.5 g, 5.4 mmol) in methanol (25 mL) at 0° C. and the resultant reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the resulting residue was diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 40% EtOAc in hexanes (0.30 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Product: CS(=O)(=O)N1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(1-methanesulfonyl-piperidin-4-yl)-urea was prepared starting from intermediate N and methanesulfonyl chloride. MS calcd. for C23H26ClN4O4S [(M+H)+] 489.1, obsd. 489.1.
Reaction SMILES: [Li].[C:2]1([Si:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:10]([CH3:12])[CH3:11])Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH:10]([Si:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[Si:8]([CH:10]([CH3:12])[CH3:11])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)[Si](c1ccccc1)(c1ccccc1)[Si](c1ccccc1)(c1ccccc1)C(C)C
Reaction time: 72 h
Yield: 101.4 %

Procedure:
A 1 liter three necked flask was charged with 200 ml of dry THF and then 5.04 g (0.73 mole) of small pieces of lithium metal was quickly added. To this was added dropwise 155 g of diphenylisopropylchlorosilane (purity: 94% by weight, 0.56 mole) at a room temperature over 2 hours. A mildly exothermic reaction was observed. After the dropwise addition, the reaction mixture was agitated for 3 days. The reaction mixture turned red purple. The formed salt and the solvent were removed from tho reaction mixture. To the residue was added about 300 ml of benzene, whereby the residue was dissolved therein. The benzene solution was washed with a saturated aqueous solution of ammonium chloride (300 ml×3 times) and then with water (300 ml×1 time) and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated to give 128 g of a crude product in a pale yellow solid.
Reaction SMILES: C(CC([N:6]([C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[NH:7][C:8]([NH2:10])=[O:9])=O)#N.[OH2:19].[OH-].[Na+]>C(O)C>[NH2:6][C:11]1[N:7]([NH:6][C:11]2[C:12]([CH3:18])=[CH:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:8](=[O:9])[NH:10][C:13](=[O:19])[CH:12]=1
Reactant: O
Reactant: Cc1cccc(C)c1N(NC(N)=O)C(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Nn1c(N)cc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One mole of the above phenylsemicarbazide is added to 400 ml of water, followed by the addition of 200 ml of ethanol. This mixture is heated to 85° and 165 ml of 10% sodium hydroxide is added. After 30 minutes the mixture is acidified to pH 5, cooled to RT, filtered and recrystallized in acetone/water, yielding 6-amino-1-(2,6-dimethylanilino)-2,4-pyrimidinedione.