Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][S:26][C:25]1=[S:30]>C(O)(=O)C.C(O)C.O>[CH3:13][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[N:6]=[C:7]([CH:16]=[C:27]2[S:26][C:25](=[S:30])[N:24]([CH3:23])[C:28]2=[O:29])[N:8]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Reactant: CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C(=Cc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)SC1=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A mixture of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (0.50 g, 2.1 mmol), sodium acetate (0.60 g, 7.3 mmol), and 3-methylrhodanine (0.31 g, 2.1 mmol) in glacial acetic acid (10 mL) is placed under nitrogen atmosphere and warmed to reflux. After refluxing 21 hours, the mixture is cooled to room temperature and diluted with a 1:1 mixture of ethanol and water. The resulting slurry is stirred 0.5 hours and filtered. The precipitate is recrystallized from methanol and water to give 0.36 g (47%) of the title compound, mp 226°-228° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][N:29]=1)[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[CH2:26]([C:28]1[N:29]=[CH:30][C:31]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[CH:32][CH:33]=1)[CH3:27]
Reactant: CCc1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 85 mg (0.25 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2.5 mL THF and 129 mg (0.56 mmol) of 2-ethyl-5-iodo-pyridine in 1 mL THF with 0.29 mL 2M isopropylmagnesium chloride. Yield: 41 mg of a white powder. LC-MSD, m/z for C24H21N3O2 [M+H]+=384.1; HPLC retention time: 0.7 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10](=O)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: O
Solvent: CCO
Product: CC(CN(CC(=O)O)C(=O)OC(C)(C)C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of [tert-Butoxycarbonyl-(2-oxo-propyl)-amino]-acetic acid (1 eq), aniline (1.2 eq) and Ti(OiPr)4(1.25 eq) was stirred at RT for 30 min under N2 flow. The mixture was diluted with dry EtOH (0.8 M) and NaBH3(CN) (0.67 eq) was added. The reaction mixture was stirred for 24 h, after which water was added and the resulting white, inorganic precipitate was filtered, and washed with EtOH. The filtrate was concentrated under reduced pressure and the resulting crude was diluted with EtOAc. The solution was extracted with 1N NaOH and the aqueous phase was washed with EtOAc twice. The aqueous phase was acidified to pH 1 by addition of conc. HCl at 0° C. and washed with EtOAc. The pH of the collected aqueous phase was adjusted to pH 3-4 and product extracted with EtOAc (5×). The collected organic phases were dried (Na2SO4), filtered and evaporated to provide LL1 as a transparent oil. MS (ES) C16H24N2O4 requires: 308 found: 309 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[O-]CC.[Na+].[Na].Br[CH2:12][CH2:13][CH2:14][OH:15]>C(O)C>[N:1]1([CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCCBr
Reactant: c1nc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: OCCCn1cncn1
Yield: 89.7 %

Procedure:
Under argon, 1,2,4-triazole (13.8 g, 200 mmol) was added to a solution of sodium ethoxide (freshly prepared from sodium (4.6 g) and ethanol (250 ml)). After complete dissolution, 3-bromopropan-1-ol (18 ml, 200 mmol) was added dropwise. The mixture was refluxed for 18 hours and the solid was filtered and washed with ethanol. The filtrate was evaporated and the residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 3-(1,2,4-triazol-1-yl)propan-1-ol (22.8 g, 90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][C:11]2[C:12]3[C:19]4[CH2:20][CH2:21][NH:22][CH2:23][C:18]=4[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][C:4]=1[OH:24].Cl.[CH3:26][N:27]([CH:34]([CH3:36])[CH3:35])[CH2:28]/[CH:29]=[CH:30]/[C:31](O)=[O:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][C:11]2[C:12]3[C:19]4[CH2:20][CH2:21][N:22]([C:31](=[O:32])/[CH:30]=[CH:29]/[CH2:28][N:27]([CH3:26])[CH:34]([CH3:36])[CH3:35])[CH2:23][C:18]=4[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][C:4]=1[OH:24]
Reactant: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)cc(Cl)c1Cl
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)c(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
2,3-Dichloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 69A (51 mg, 0.13 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (34 mg, 0.18 mmol) were dissolved in DMF (1.5 mL), and DIPEA (82 mg, 0.63 mmol) and TBTU (61 mg, 0.19 mmol) were added. The mixture was stirred at rt overnight. The product was then directly isolated by preparative HPLC to yield 33 mg (52%) of the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]C)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11](C2N=C(C3C=CC=CC=3)NC=2)=[CH:10][C:9]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][C:3]([C:11]1[CH:12]=[CH:13][C:8]([F:7])=[C:9]([CH3:25])[CH:10]=1)=[O:5]
Reactant: COC(=O)CBr
Reactant: Cc1cc(-c2c[nH]c(-c3ccccc3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.41 mL methyl bromoacetate was added to 1 g 4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole and 1.66 g potassium carbonate in 10 mL DMF. The reaction was stirred 3 h at RT. Then 0.41 mL methyl bromoacetate was added and the reaction was stirred overnight at RT. The reaction mixture was added to ice water and extracted with DCM. The organic layer was dried and evaporated to give 1 g desired product. Rt: 0.94 min (method A), (M+H)+: 325
Reaction SMILES: [NH2:1][C:2]([CH2:9][OH:10])([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].[BH4-].[Na+].II.CO>C1COCC1.[Cl-].[Na+].O>[NH2:1][C:2]([CH:6]([CH3:8])[CH3:7])([CH2:9][OH:10])[CH2:3][OH:4]
Reactant: CC(C)C(N)(CO)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)C(N)(CO)CO
Temperature: 66 °C
Yield: 11.3 %

Procedure:
To a solution of 2-amino-2-(hydroxymethyl)-3-methylbutanoic acid (2943 mg, 20 mmol) in THF (60 mL) was added sodium borohydride (2270 mg, 60.0 mmol). The reaction was cooled in an ice bath, and a THF (10 mL) solution of iodine (7614 mg, 30.0 mmol) was added dropwise. The mixture was refluxed (66° C.) for 16 h. The reaction was cooled in an ice bath, and methanol (10 mL) was added (dropwise at first) followed by brine (75 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), then filtered. 4 M HCl in dioxane (6 mL) was added. The mixture was then concentrated. Ether was added, and the precipitate was collected to give the title compound (300 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)(=[O:22])=[O:21])[CH2:14][C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)(=[O:22])=[O:21])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CN(c1c(Cc2c(F)cccc2F)cccc1OC)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)c2c(Cc3c(F)cccc3F)cccc2OC)cc1OC
Reaction time: 18 h
Yield: 105.5 %

Procedure:
To 1.8 g of ethyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]-glycinate dissolved in 50 ml of ethanol are added 10 ml of 2M sodium hydroxide solution. After 18 hours at room temperature, the medium is extracted with diethyl ether and the aqueous phase is acidified and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then concentrated to give 1.8 g of the expected product.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:10]=[CH:11][C:12]=2[C:13]2[CH:14]=[C:15]([C:19](O)=[O:20])[S:16][C:17]=2[CH3:18])[CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:50][C@H:51]1[C:56]([F:58])([F:57])[CH2:55][CH2:54][CH2:53][C@H:52]1[NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63].C(N(C(C)C)CC)(C)C>CN(C=O)C.ClCCl>[C:62]([O:61][C:60](=[O:66])[NH:59][C@@H:52]1[CH2:53][CH2:54][CH2:55][C:56]([F:58])([F:57])[C@@H:51]1[NH:50][C:19]([C:15]1[S:16][C:17]([CH3:18])=[C:13]([C:12]2[CH:11]=[N:10][N:8]3[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:22])[CH:5]=[N:6][C:7]=23)[CH:14]=1)=[O:20])([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: Cc1sc(C(=O)O)cc1-c1cnn2cc(OC(F)F)cnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
4-[6-(Difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophene-2-carboxylic acid (0.768 g, 2.36 mmol) and BOP (3.13 g, 7.08 mmol) were dissolved in DMF (15.7 mL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (0.650 g, 2.60 mmol) and diisopropylethyl amine (619, 3.54 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate twice and brine once. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc/Hex) to give the title compound (0.900 g, 1.61 mmol). LRMS (APCI) calc'd for (C24H27F4N5O4S) [M+H]+, 558.2; found 558.0.
Reaction SMILES: [CH2:1]([C:3](O)([CH:6]([CH3:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:4]=[CH2:5])[CH3:2].P(Br)(Br)[Br:15]>>[Br:15][CH2:2][CH:1]=[C:3]([CH2:4][CH3:5])[CH:6]([CH3:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: C=CC(O)(CC)C(C)CC=C(C)C
Reactant: BrP(Br)Br
Product: CCC(=CCBr)C(C)CC=C(C)C

Procedure:
Following the procedure of Example 9, 3-ethyl-4,7-dimethyl-1,6-octadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3-ethyl-4,7-dimethyl-2,6-octadiene.
Reaction SMILES: [F:1][C:2]1[C:3]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]2=[O:32])=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.O>C(O)(=O)C.[Fe]>[F:1][C:2]1[C:3]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[N:22]([CH3:31])[C:21]2=[O:32])=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2N)c1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 4.17 g of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 10 ml of acetic acid was added dropwise over 20 minutes to a mixture of 4.5 g of iron powder, 10 ml of acetic acid and 1 ml of water. After the addition, the mixture was stirred for 2 hours, filtered through celite and diluted with ethyl acetate. The resultant was washed with water 2 times, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 3.67 g of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21])=[CH:9][CH:8]=1
Reactant: COc1ccc(CCCCCCCCBr)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CCCCCCCCBr)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 1M solution of boron tribromide in dichloromethane (5 ml, 5 mmol) was added to an ice water cooled solution of 8-(4-methoxyphenyl)octylbromide (1.5 g, 5 mmol) in dichloromethane (10 ml). After 4 hours at room temperature, water was added and the dichloromethane separated, washed with water, dried over anhydrous magnesium sulphate, and evaporated to give an oil, which was chromatographed over flash silica, eluting with chloroform, followed by 2% methanol in chloroform to give 8-(4-hydroxyphenyl)octylbromide as an oil (MS: M+ =284).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:12][C:13](=[O:28])[NH:14][C:15]1[C:16]([CH3:27])=[N:17][O:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[CH3:11].[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[O:18][N:17]=[C:16]([CH3:27])[C:15]=3[NH:14][C:13]([O:12][CH:10]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[F:1])[CH3:11])=[O:28])=[CH:21][CH:22]=2)=[CH:36][CH:35]=1)[CH3:30]
Reactant: COc1ccc(C(C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)c(F)c1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccc(OC)cc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-fluoro-4-methoxy-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2-fluoro-4-methoxy-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:11](Br)[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[CH3:12]
Reactant: Oc1cccc2cc[nH]c12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1cccc2cc[nH]c12
Reaction time: 18 h

Procedure:
7-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: O=c1ccc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 86 from 6-(4-phenylsulfonyl-butoxy)-3,4-dihydro-carbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone. Purification was carried out by column chromatography on silica gel (particle size: 0.2-0.5 mm) with chloroform/methanol/ethyl acetate=4/1/1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][C:13]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=1>>[C:1]([NH:10][C:11]1[S:12][C:13]([C:23]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[C:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1)c1ccccc1
Yield: 54 %

Procedure:
Following the procedure as described in Example 16, making variations only as required to use benzoyl chloride in place of hydrocinnamoyl chloride to react with 2-amino-N,4-dibenzylthiazole-5-carboxamide, the title compound was obtained in 54% yield; 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J=7.1 Hz, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.52 (t, J=8.1 Hz, 2H), 7.40-7.15 (m, 10H), 4.58 (d, J=5.6 Hz, 2H), 4.41 (s, 2H); MS (ES+) m/z 428 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:15])[C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[C:23]1([N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCCl>[C:23]1([N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:30][C:12]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:15])[N:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:2]=2[CH3:1])=[O:13])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1c(C(=O)Cl)c2ccccc2c(=O)n1-c1ccccc1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Product: Cc1c(C(=O)NN(c2ccccc2)c2ccccc2)c2ccccc2c(=O)n1-c1ccccc1
Temperature: 140 °C

Procedure:
A mixture of 3-methyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carbonyl chloride (the synthesis is described above in example 1a) (25 mg, 0.08 mmol) and 1,1-diphenylhydrazine hydrochloride (56 mg, 0.25 mmol) in 1,2-dichloroethane (1 ml) was heated under microwave irradiation for 20 min at 140° C. Volatiles were removed in vacuo and the product was purified by preparative LC-MS to give 14 mg of colorless solid. LC-MS (m/z) 446.7 (MH+); tR=1.58.
Reaction SMILES: [C:1]([C:3]1[N:11]2[C:6]([C:7]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:8][C:9]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=32)=[CH:5][CH:4]=1)#[N:2].[Br:29]N1C(=O)CCC1=O.C(C(N=NC(C)(C)C#N)(C)C)#N>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]3[C:3]([C:1]#[N:2])=[CH:4][CH:5]=[C:6]3[C:7]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:8][C:9]=2[CH:15]=1
Reactant: Cc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1ccc(C#N)n1-2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(CBr)ccc1-n1c(C#N)ccc12
Temperature: 80 °C
Yield: 47.6 %

Procedure:
tert-Butyl 1′-cyano-7′-methyl-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (200 mg, 0.527 mmol), 1-bromopyrrolidine-2,5-dione (93.8 mg, 0.527 mmol), and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propanenitrile (8.66 mg, 0.0527 mmol) were combined in carbon tetrachloride (10 mL) and the mixture was heated at 80° C. for 4 hours. The mixture was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (50-100% CH2Cl2/hexanes) to yield tert-butyl 7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (115 mg, 47%). ESI-MS m/z calc. 457.1. found 458.5 (M+1)+; Retention time 2.43 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.N.[CH3:22][N:23](C)C=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:22]#[N:23])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 0 °C

Procedure:
Ten grams of 2-benzyloxy-6-bromonaphthalene was dissolved in 65 ml of dimethyl formamide, 2.83 grams of cuprous cyanide and 5 to 6 drops of pyridine were added thereto, and the mixture was heated to reflux with stirring for twelve hours. After the reaction was completed, the reaction solution was poured into a mixture of 150 ml of concentrated ammonia water and 150 grams of ice, the mixture was extracted with chloroform, the chloroform extract was washed with diluted hydrochloric acid and then with water, dried with anhydrous sodium sulfate, and the solvent was evaporated therefrom. The resulting residue was subjected to a column chromatography using 200 grams of silica gel and eluted with n-hexane and chloroform mixture (1:1) to afford 2-benzyloxy-6-naphthonitrile, colourless crystals, yield 6.8 grams.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na]>COCCO>[CH2:1]([N:19]1[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:16][N:17]=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: [Na]
Solvent: COCCO
Product: c1ccc(Cn2nnnc2-c2ccccc2)cc1
Yield: 92.5 %

Procedure:
Benzyl chloride (0.15 mole; 19.0 g), sodium 5-phenyltetrazole (0.165 mole; 27.4 g) and 2-methoxyethanol (100 ml) were heated at 100° C. for 3.5 hours). The mixture was cooled to precipitate NaCl. Water (250 ml) was added to the filtrate to precipitate a product which was filtered, washed with H2O (50 ml) and dried in-vacuo at 60° C. for four hours. The product weight was 32.8 g. (92.5 percent yield), m.p. 54°-67° C. Reported; 2-benzyl-5-phenyltetrazole, m.p. 65.5°-66° C. 1-benzyl-5-phenyltetrazole, m.p. 92.5°-93° C. Elemental analysis found: C, 71.57; H, 5.30; N, 21.39. Calculation for C14H 12N4 : C, 71.17; H, 5.12; N, 23.71. 13C NMR established a 3/1 isomer ratio for the 2-benzyl/1 -benzyl substitution products, respectively. The isomers are represented by the following structures; ##STR6##
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-cyano-2-fluoro benzoic acid (650 mg, 3.9 mmol) in CH2Cl2 (20 mL) were added 2 drops of DMF and oxalyl chloride (0.7 mL, 7.8 mmol). The mixture was stirred at rt overnight and became a clear solution. The volatile was evaporated to dryness to give 4-cyano-2-fluoro-bezoyl chloride. To a solution of compound 6 (900 mg, 2.62 mmol) in THF (10 mL) was added a THF solution of 4-cyano-2-fluoro-bezoyl chloride. The mixture was stirred for 1 h, and concentrated. The residue was dissolved in EtOAc, washed with sat NaHCO3 and water. The organic layer was dried and evaporated to give compound 7 (1.2 g, 94% yield). MS found for C25H20ClFN4O2Si as (M+H)+: 491.1.