Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2](=[CH2:5])[CH2:3][OH:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>ClCCl>[C:14]([Si:11]([O:4][CH2:3][C:2]([I:1])=[CH2:5])([CH3:13])[CH3:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=C(I)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C(I)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 2-iodoprop-2-en-1-ol (24 g, 130.4 mmol) in dry dichloromethane (500 mL) was cooled to 0° C. Imidazole (17.75 g, 260.9 mmol) was added in several portions, and the mixture was stirred for 10 minutes. Tert-butyldimethylsilyl chloride (29.49 g, 195.9 mmol) was added in several portions at 0° C., and the reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with water (100 mL), and the organic phase was separated. The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (water bath temperature <25° C.). The residue was purified by column chromatography using 100% petroleum ether as eluent to afford tert-butyl((2-iodoallyl)oxy)dimethylsilane.
Reaction SMILES: [C:1]([Si:5]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:6][CH2:7][CH2:8][C:9]1[C:10](=[O:34])[NH:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][C:27](=[O:29])[CH3:28])=[CH:16][C:15]([C:30]([F:33])([F:32])[F:31])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].CI.[C:49]([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[O:6][CH2:7][CH2:8][C:9]1[C:10](=[O:34])[N:11]([CH3:49])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][C:27](=[O:29])[CH3:28])=[CH:16][C:15]([C:30]([F:31])([F:33])[F:32])=[CH:14][CH:13]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Oc1ccc(Cl)cc1-c1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(Cl)cc1-c1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(=O)n(C)c2ccc(C(F)(F)F)cc12
Reaction time: 18 h

Procedure:
A suspension of the product from step A (6.82 g, 10.3 mmol), methyl iodide (4.37 g, 30.8 mmol) and K2CO3 (3.05 g, 30.8 mmol) in acetone (200 mL) at ambient temperature was stirred for 18 hours. At the end diluted with ethyl acetate (200 mL), washed with water (100 mL), brine (100 mL) and dried. Chromatography with gradient elution (SiO2) using hexanes, ethyl acetate (90:10 to 70:30) afforded the compound of Step B as the major product (5.52 g, 8.1 mmol, 79%, Rt=2.3 minutes C18 LC) as white solid. MS [M+H]=678. 1H NMR (CD3OD) δ 7.82 (d, J=8.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.48 (m, 4H), 7.34 (m, 3H), 7.21 (m, 6H), 3.91 (m, 1H), 3.76 (m, 4H), 2.88 (m, 1H), 2.70 (m, 1H), 1.71 (s, 3H), 0.94 (s, 9H). A minor product characterized as the O-methyl derivative had the following characteristics. MS [M+H]=678. 1H NMR (CD3OD) δ 7.82 (d, J=8.1 Hz, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.48 (m, 4H), 7.34 (m, 3H), 7.21 (m, 6H), 3.91 (m, 1H), 3.76 (m, 4H), 2.88 (m, 1H), 2.70 (m, 1H), 1.71 (s, 3H), 0.94 (s, 9H). The ratio of the N-methyl derivative to the O-methyl derivative was approximately 9:1.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1>CO>[OH:11][C@@H:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3].[OH:11][C@H:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CO
Product: C[N+](C)(C)C[C@@H](O)CC(=O)[O-]
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]

Procedure:
In 700 ml of methanol are dissolved under heat 35.0 g (0.177 mole) of DL-carnitine hydrochloride, and the solution is passed through OH type strongly basic resin (DOWEX-1X8). The methanol solution is concentrated to obtain 28.3 g (0.175 mole) of DL-carnitine. To DL-carnitine are added 62.6 g (0.175 mole) of dibenzoyl-L(+)tartaric acid and 93 ml of methanol, and the mixture is dissolved under heat to form dibenzoyl-L( +)tartarates of D-carnitine and L-carnitine. The tartarates are cooled at a temperature of below -10° C. with stirring to fractionally crystallize L-carnitine dibenzoyl-L(+)tartarate. The tartarare is filtered and washed to give L-carnitine dibenzoyl-L(+)tartarate (yield 30.5 g, purity 93.0%). Recrystallization of the tartarate from 100 ml of methanol gives 23.9 g of L-carnitine dibenzoyl-L(+)tartarate as white crystal. [α]D25 =-96.0° (c=1, MeOH), m.p. 154° C. (dec.), purity 99.5%.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C[CH:12]([SH:16])[C:13]([O-:15])=[O:14].[CH2:17](NCC)C>CS(C)=O.O>[Cl:1][C:2]1[C:3]2[S:16][C:12]([C:13]([O:15][CH3:17])=[O:14])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCNCC
Reactant: CC(S)C(=O)[O-]
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2cccc(Cl)c2s1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
3-Chloro-2-fluorobenzaldehyde(1 g, 6.3 mmol) was dissolved in DMSO (10 mL) and treated with methylthioglycolate, followed by diethylamine (0.58 mL, 6.3 mmol). The reaction was heated to 70° C. and stirred overnight. The reaction was allowed to cool down to room temperature and diluted with water (25 mL). The solid that precipitated out of solution was collected by filtration and washed well with water. The solid was then purified by flash chromatography using a gradient of 2 to 20% ethyl acetate in hexanes to afford a white solid (0.8 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:22]([O:33][C@H:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:35][C:36]([OH:38])=O)(=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(Cl)CCl.CI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([O:33][C@H:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:35][C:36]([NH:1][CH2:2][CH2:3][OH:4])=[O:38])(=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: CC(C)(C)[Si](OCCN)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)NCCO)OC(=O)CCCCCCCCC
Yield: 73.7 %

Procedure:
In the same manner as described in Example 20-(1), 2-amino-1-(t-butyldiphenylsilyloxy)ethane (450 mg, 1.5 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (600 mg, 1.5 mmol) in the presence of EDC·MeI (594 mg, 2.0 mmol) and then deprotected with TBAF (1.0 M in THF, 2.5 mL, 2.5 mmol) in THF (10 mL) to afford 488 mg (81%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethanol as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.CC1C=CC=C(C)C=1CN1C2C(=CC=C(CC(O)=O)C=2)C(C)=N1>>[CH:18]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)=[CH2:19]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1cccc(C)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Product: C=Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The titled compound (207 mg) as a white solid was prepared from tert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate obtained by the method described in the document (WO 1998/43956 A) and tributyl(vinyl)tin according to the method of the process (2) of Example 66.
Reaction SMILES: FC1C=C(NC(=O)CC(NC2C=CC=CC=2)=O)C=CC=1OC1C=CN=C2C=C(C3N=CN(C)C=3)SC=12.[CH3:37][N:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39](=[O:44])[CH2:40][C:41]([OH:43])=O.CCCCCCCCCCCCN.[F:64][C:65]1[CH:66]=[C:67]([CH:69]=[CH:70][C:71]=1[O:72][C:73]1[CH:78]=[CH:77][N:76]=[C:75]2[CH:79]=[C:80]([C:82]3[CH2:83][CH2:84][N:85]([CH3:88])[CH2:86][CH:87]=3)[S:81][C:74]=12)[NH2:68]>>[F:64][C:65]1[CH:66]=[C:67]([NH:68][C:41](=[O:43])[CH2:40][C:39]([N:38]([CH3:37])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[CH:69]=[CH:70][C:71]=1[O:72][C:73]1[CH:78]=[CH:77][N:76]=[C:75]2[CH:79]=[C:80]([C:82]3[CH2:83][CH2:84][N:85]([CH3:88])[CH2:86][CH:87]=3)[S:81][C:74]=12
Reactant: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: CN(C(=O)CC(=O)O)c1ccccc1
Agent: CCCCCCCCCCCCN
Agent: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Product: CN1CC=C(c2cc3nccc(Oc4ccc(NC(=O)CC(=O)N(C)c5ccccc5)cc4F)c3s2)CC1
Yield: 44 %

Procedure:
Following the procedure described above for the compound 5c (scheme 3) but replacing acid 1 with the acid 31 and amine 12 with amine 260; the title compound 256 was obtained in 44% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.31 (s, 1H), 8.44 (d, J=5.48 Hz, 1H), 7.79 (d, 12.72 Hz, 1H), 7.5-7.3 (m, 8H), 6.59 (d, J=5.48 Hz, 1H), 6.38 (t, J=3.52 Hz, 1H), 3.22 (s, 2H), 3.21 (s, 3H), 3.08 (m, 2H), 2.61 (m, 4H), 2.30 (s, 3H). MS (m/z): (M+1) 531.0 (100%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:32][C:31]3[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 1.2 %

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.3 g) using 4-nitrobenzyl bromide (0.3 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClN4O2, 382.12. found, m/z 383.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.23-8.19 (m, 2H), 7.51-7.47 (m, 2H), 7.45-7.47 (m, 2H), 7.32 (d, J=8.6 Hz, 2H), 5.52 (s, 2H), 2.98-2.95 (m, 4H), 2.89-2.85 (m, 2H), 2.83-2.79 (m, 2H).
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH:15]=O)=[CH:14][C:10]=2[CH:9]=1)#[N:7].[Cl-].[CH2:20]([O:22][C:23]1[C:24]([O:56][CH3:57])=[CH:25][C:26]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:27]([CH2:29][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1)[CH3:21].C1CCN2C(=NCCC2)CC1>C(O)C>[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH2:15][CH2:29][C:27]3[CH:28]=[C:23]([O:22][CH2:20][CH3:21])[C:24]([O:56][CH3:57])=[CH:25][C:26]=3[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:14][C:10]=2[CH:9]=1)#[N:7]
Reactant: N#Cc1ccc2sc(C=O)cc2c1
Reactant: CCOC(=O)CCc1cc(OC)c(OCC)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(OC)c(OCC)cc1CCc1cc2cc(C#N)ccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a mixture solution of 50 ml of tetrahydrofuran and 50 ml of ethanol were dissolved 1.5 g of 5-cyanobenzo[b]thiophene-2-carbaldehyde and 6.34 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl]methyltriphenylphosphonium chloride obtained in the above step d). 1.83 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by stirring at room temperature for 18 hours. The resulting reaction solution was concentrated under a reduced pressure, and the residue was dissolved in a mixture solution of 20 ml of tetrahydrofuran and 20 ml of ethanol. The thus prepared solution was mixed with 1.70 g of 10% palladium carbon catalyst (50% wet type) and subjected to catalytic hydrogenation under normal pressure until hydrogen absorption was completed. After removing the catalyst by filtration, the solvent was distilled off. By subjecting the resulting residue to silica gel column chromatography, 1.2 g of oily ethyl 3-[2-[2-(5-cyanobenzo[b]thien-2-yl)ethyl]-4-ethoxy-5-methoxyphenyl]propionate was obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>CN(C)C=O>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:3][CH2:2]2)=[CH:12][CH:11]=1)(=[O:15])[CH3:14]
Reactant: COC(=O)CCCCBr
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCCCN1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
4'-Piperazinoacetophenone (102 mg) is dissolved in 1 mL of N,N-dimethylformamide. After addition of methyl 5-bromovalerate (0.077 mL) and potassium carbonate (69 mg), the mixture is stirred at room temperature for 65 hours. TLC (10% MeOH/CH2Cl2) should show a single product spot without residual starting material. The reaction solution is evaporated under vacuum. The residue is taken up in methylene chloride, washed twice with water and dried over sodium sulfate. Evaporation of the solvent yields 137 mg of 4-(4-acetylphenyl)-1-piperazinevaleric acid, methyl ester as yellow crystals whose 1H-NMR (CDCl3) spectrum is consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#N)=[N:9]2)=[CH:4][CH:3]=1.C(O)=[O:23]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: N#Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Product: O=Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To the cyanide (Step 1, 10 g) in formic acid (200 mL) at 100° was added portionwise Ni-Al alloy (3 g). The reaction mixture was heated at 110° for 6 hrs, filtered and evaporated. The residue was partitioned between NaHCO3 (aq) and ethyl acetate, and the organic layer was dried and evaporated. Flash chromatography using 30% ether in hexane afforded the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH2:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 136.8 g of 3-methoxy-1-tetradecylbenzene in 600 ml of methylene chloride, cooled to -78° C., under inert gas, was added dropwise a solution of 112.8 g of boron tribromide in 100 ml of methylene chloride. The mixture was kept at -78° C. for 1 hour then allowed to warm slowly to room temperature followed by stirring for 16 hours. The mixture was cooled to 0° C. and cold water added dropwise. The organic layer was separated and washed with aqueous sodium bicarbonate, dried and the solvent evaporated. The residue was poured onto crushed ice and 107 g of the desired product collected as a white solid, m.p. 38°-40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C([Mg]Br)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: Brc1cccc2cc[nH]c12
Reactant: N#CCCCCl
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: N#CCCCc1c[nH]c2c(Br)cccc12

Procedure:
To an anhydrous toluene (12 mL) solution of 7-bromoindole (1.0 g) and 4-chlorobutyronitrile (0.26 g), ethylmagnesium bromide (3.0M diethyl ether solution; 1.7 mL) was added dropwise under ice cooling and the mixture was heated to reflux for 4.5 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10→70:30) to obtain the titled compound having the following physical properties (0.40 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]O)[CH:2]=1.S(Cl)(Cl)=O.[C-:17]#[N:18].[K+].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:17]#[N:18])[CH:2]=1
Reactant: OCc1cnc2ccccc2c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: N#CCc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
A solution of quinolin-3-yl-methanol (227, 3.1 g, 19.5 mmol) and thionyl chloride (Aldrich, 16.5 mL, 195 mmol) in 50 mL of benzene was refluxed for 3 h. After cooled to room temperature, the solvent was removed under reduced pressure to dryness. This crude product was used directly in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.82 (s, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.97 (t, J=7.4 Hz, 1H), 7.81 (t, J=7.5 Hz, 1H), 5.09 (s, 2H). MS (EI): m/z 178 (M+H). Quinolin-3-yl-acetonitrile was synthesized from the above crude product, KCN, NaHCO3 and KI in similar manner as described in Example 221. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=2.0 Hz, 1H), 8.36 (s, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.3 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 4.31 (s, 2H). MS (EI): m/z 169 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([NH2:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15](OCC)(OCC)OCC.OS(O)(=O)=O>C1COCC1>[CH3:7][O:6][C:4]([C:3]1[C:2]([NH2:1])=[C:11]([F:12])[C:10]2[N:13]=[CH:15][NH:14][C:9]=2[CH:8]=1)=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cc(N)c(N)c(F)c1N
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]cnc2c(F)c1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a stirred solution of methyl 2,4,5-triamino-3-fluorobenzoate (9) (7.58 g, 38.1 mmol) in THF (152 mL, 20 vol) was added triethyl orthoformate (20.3 g, 22.8 mL, 137.0 mmol), followed by dropwise addition of H2SO4 (9.33 g, 18 M, 94.1 mmol). The mixture was then heated at 60° C. for 6 hours, at which point no starting material was detected by HPLC analysis. The solid product was filtered and rinsed with THF (150 mL, 20 vol), then transferred to a reaction vessel, suspended in water (150 mL) and the resulting mixture was neutralized to about pH 7.5 with 2 N NaOH. After stirring for 30 minutes, the suspension was filtered and the solid product was dried in a vacuum oven at 55° C., overnight to provide 6-amino-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (12) 7.5 g, 94% yield (100% area by HPLC). 1H NMR (400 Hz, d6 DMSO) δ 3.53 (1H, br s, NH), 3.85, (3H, s, OMe), 6.10 (2H, br s, NH2), 7.90 (1H, s, Ar—H), 7.20 (1H, s, Ar—H). MS APCI (+) m/z 210 (M+1) detected with MS APCI (+).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])C[CH2:12][CH3:13].[CH:15]1([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH:28]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.C([Mg]Br)C.[Cl-].[NH4+:40]>O1CCCC1.CC#N.CCCCCC>[CH:15]1([O:24][C:25]2[CH:26]=[C:27]([CH:28]([NH2:40])[CH2:12][CH3:13])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: [Li]CCCC
Reactant: COc1ccc(C=O)cc1OC1CCc2ccccc21
Reactant: [NH4+]
Agent: CC[Mg]Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(N)c1ccc(OC)c(OC2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 9 %

Procedure:
To an ice bath cooled stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (2.7 mL, 13 mmol) in tetrahydrofuran (5 mL) under nitrogen, was added a hexane solution of butyl lithium (2.5M, 4.8 mL, 12 mmol) via syringe. The ice bath was removed and the solution was stirred for 25 minutes at room temperature. This solution then was added dropwise to an ice bath cooled solution of 3-indanyloxy-4-methoxybenzaldehyde (2.68 g, 10.0 mmol) in tetrahydrofuran (4 mL) and the mixture was stirred for one hour. An ethereal solution of ethylmagnesium bromide (3M, 6.7 mL, 20 mmol) then was added dropwise via syringe. The reaction mixture was heated at reflux and was monitored by HPLC (Waters Nova-Pak/EC 18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 40/60, CH3CN/0.1% H3PO4 (aq)). After 48 hours the reaction had reached completion and was allowed to cool to room temperature. The reaction mixture then was slowly poured into a saturated solution of ammonium chloride (80 mL). The resulting mixture was extracted with methylene chloride (3×15 mL) and the combined extracts were dried over magnesium sulfate and concentrated to afford the product which was further purified by flash column chromatography (silica gel, 250/10/1, methylene chloride/methanol/ammonium hydroxide) to afford 0.27 g (9%) of product as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+]([O-])=O)[C:6]=1[CH:17]=[CH:18][N:19](C)C)[CH3:2].Cl[Sn]Cl>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[CH:17]=[CH:18][NH:19][C:7]=2[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C=CN(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc2[nH]ccc12
Yield: 39.7 %

Procedure:
A mixture of 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester (11.3 g, 0.037 mol) and SnCl2 (83 g. 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was concentrated to dryness and the residue was poured into water and basified with sat. Na2CO3 solution to pH 8. The precipitate was filtered off and the filtrate was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (150 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-4-carboxylic acid ethyl ester (B-18) (3 g, 40%). 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 7.11-7.14 (m, 2H), 6.81-6.82 (m, 1H), 6.67-6.68 (m, 1H), 4.94 (br s, 2H), 4.32-4.25 (q, J=7.2 Hz, 2H), 1.35-1.31 (t, J=7.2, 3H). ESI-MS 205.0 m/z (MH+).