Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.P(Cl)(Cl)([Cl:41])=O>C1(C)C=CC=CC=1>[Cl:41][C:17]1[N:16]=[C:15]2[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12][NH:13][C:14]2=[CH:19][CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2nc(-c3ccc4ccccc4c3)c3ncccc32)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2n1

Procedure:
After treating 210 mg of 3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine obtained by Production example 419 in the similar method as described in Production example 4, 2 mL of residue solution in toluene was added at room temperature with 190 μl of phosphorus oxychloride, and treated in the similar method as described in Production example 28, to afford 60 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[K+].O1CCCC1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>O>[O:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:34]1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCOCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 34 ml of a 10% aqueous potassium hydroxide and 2.5 ml of tetrahydrofuran is added 4.5 g of 1-chloro-2-morpholinoethane hydrochloride, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 7.5 g of 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 191°-193° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([O:27]C)=[O:26])([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.[OH-].[K+]>O.CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:16])[F:15])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([OH:27])=[O:26])([CH2:21][CH2:22]1)[CH2:19][CH2:18]2
Reactant: COC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)O)(CC1)CC2

Procedure:
A solution of methyl ester 1-C (1.19 g, 3.0 mmol) in 5% H2O/MeOH (30 ml) was treated with KOH (0.51 g, 9.1 mmol) at 60° C. under a nitrogen atmosphere for 18 h. The resulting mixture was concentrated, diluted with water (150 ml), washed with EtOAc and acidified with aqueous HCl (1 N) to pH=3. The precipitate was filtered, washed with a small amount of water and ether and dried under vacuum to yield 1-D as a pink solid. MS (ESI+)=380.18; 1H NMR (500 MHz, CD3OD): δ 7.95-7.93 (m, 1 H), 7.86-7.82 (m, 2 H), 7.61-7.59 (m, 1 H), 3.53 (s, 3 H), 2.15 (m, 6 H), 2.02-1.96 (m, 6 H) ppm.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[C:18](I)[CH:17]=1)([OH:15])=[O:14]>[Cu]>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[C:18]([S:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH2:8][CH2:7]3)[CH:17]=1)([OH:15])=[O:14]
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1I
Reactant: Sc1ccc2c(c1)CCC2
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(C(=O)O)cc1Sc1ccc2c(c1)CCC2
Temperature: 0 °C

Procedure:
To 50% aqueous potassium hydroxide solution (500 g) under argon was added 5-mercaptoindan (30.0 g, 0.2 mole) and copper powder (16.3 g). Then 4-carboxy-2-iodophenylacetic acid (38.25 g, 0.125 mole) was added with mechanical stirring and the reaction mixture was stirred under reflux (oil-bath 140°-145° C.) for 3 hours. The mixture was diluted with ice-water (800 ml), filtered, and the filtrate was treated with charcoal and refiltered. Acidification of the alkaline solution precipitated a solid which was collected, washed well with water and drained thoroughly on the filter. The solid was stirred with hexane (200 ml) to remove mercaptoindane and was refiltered to yield 33.55 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.BrCC1CCCCO1>>[O:28]1[CH2:29][CH2:30][CH:25]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH2:26][CH2:27]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCC1CCOCC1
Agent: BrCC1CCCCO1
Product: O=C1N(CC2CCOCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 129-131° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.29 (ddd, J=7.9, 7.9, 1.3 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.87 (d, J=8.9 Hz, 1H), 4.62 (d, J=8.9 Hz, 1H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 4.03-3.94 (m, 2H), 3.74 (dd, J=13.8, 7.7 Hz, 1H), 3.55 (dd, J=13.8, 7.1 Hz, 1H), 3.42-3.30 (m, 2H), 2.20-2.03 (m, 1H), 1.66-1.56 (m, 2H), 1.53-1.40 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 144.7, 142.8, 138.4, 132.5, 128.9, 124.2, 123.4, 121.1, 111.5, 108.7, 99.5, 80.4, 67.6, 67.5, 64.6, 64.0, 58.1, 46.2, 34.0, 30.93, 30.86; MS (ES+) m/z 394.2 (M+1); Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.15; H, 5.92; N, 3.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[N:6]2>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C@@H:8]([CH3:13])[CH2:7][NH:6]2
Reactant: COc1ccc2nc(C)cnc2c1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)NC[C@H](C)N2
Temperature: 40 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (5.8 mg, 5.0 μmol) and KO(t-Bu) (15.4 mg, 0.137 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (1.1 mL) solution containing 6-methoxy-2-methylquinoxaline (95.7 mg, 0.549 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 24 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified through a silica gel short path column (hexane:ethyl acetate=1:1, which was subjected to nitrogen bubbling) to obtain (S)-1,2,3,4-tetrahydro-6-methoxy-2-methylquinoxaline (96.9 mg, 99%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=80:20, 1 ml/min) showed that the optical purity of this product was 99% ee or higher.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:18])(=[O:17])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=3[S:6](=[O:18])(=[O:17])[C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[N:3]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2Cl
Reactant: C1COCCN1
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2N1CCOCC1

Procedure:
Reflux a mixture of 5.025 mg (15 mmole) of the 11-chloro ester of Example 14. 3.119 gm of morpholine and 75 ml of acetonitrile for 2 hours. Distill off the acetonitrile under a vacuum and dissolve the residue in 45 ml of methanol at room temperature. Filter, cool and separate the precipitate by filtration. Chromatograph over silica gel eluting with 1:4 ethylacetate in toluene. Recrystallize from ethanol to obtain the title product (m.p. 164°-166° C.).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:10]1[NH:11][C:12](=O)[C:13]2[NH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9].[OH-].[Na+]>>[CH2:6]([C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[NH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc2cc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc(Cl)c2[nH]ccc2n1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Phosphorus oxychloride (20 mL, 21.46 mmol) was added to 2-butyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (1.69 g). The resultant mixture was heated at 100° C. After 4 hours the reaction mixture was cooled to room temperature then poured onto ice. The aqueous phase was treated with aqueous sodium hydroxide solution (5M) until the pH was 7. The resultant mixture was extracted with ethyl acetate (2×150 mL). The combined organic phase were washed with brine, dried (Na2SO4), filtered and evaporated to give the title compound (1.69 g)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[N:22]4)=[CH:17][CH:16]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[CH:29]1([CH2:35][NH2:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:35][NH:36][C:2]2[C:7]([C:8]3[CH:9]=[C:10]([O:14][C:15]4[CH:24]=[C:23]5[C:18]([CH:19]=[CH:20][CH:21]=[N:22]5)=[CH:17][CH:16]=4)[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NCC1CCCCC1
Reactant: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(Cl)n1
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(NCC2CCCCC2)n1

Procedure:
According to the procedure described in Example 188, 7-[6-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yloxy]-quinoline (Example 187) (110 mg, 0.27 mmol) and cyclohexanemethylamine (43 pL, 0.33 mmol, Aldrich), after purification by silica gel chromatography (gradient, 0 to 3% MeOH/CH2Cl2) and then preparative TLC (4% MeOH/CH2Cl2), provided the title compound as a yellow solid. MP: 151-152° C. MS (ESI, pos. ion) m/z: 480 (M+1).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)o1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: CN(CC[C:6]1[C:10]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][CH:7]=1)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:28]([N:32]([CH:37](O)[CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH2:37][CH2:38][C:9]1[C:10]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[CH:6]=[CH:7][CH:8]=1)[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)C1(C(C)C)C=CC=C1CCN(C)C
Reactant: CCCCN(CCCC)C(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCCCN(CCCC)CCC1=CC=CC1(C(C)C)C(C)C
Yield: 53 %

Procedure:
The reaction was carried out in a manner identical to that for (dimethylaminoethyl)di(2-propyl)cyclopentadiene, the tosylate of N,N-di-n-butylaminoethanol being prepared in situ. The conversion was 94%. The non-geminal di-n-butylaminoethyldi(2-propyl)cyclopentadiene was obtained by distillation with a yield of 53%.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]Cl>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:18][C:19]4[C:32]5[C:31]([C:30]6[C:25]([C:24](=[O:34])[C:23]=5[CH:22]=[CH:21][CH:20]=4)=[CH:26][CH:27]=[CH:28][CH:29]=6)=[O:33])[C:15]=3[C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[O:17]
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21
Temperature: 190 °C
Reaction time: 2 h

Procedure:
66 parts of 1-chloroanthraquinone, 60.5 parts of 1-aminoanthraquinone, 26.4 parts of sodium carbonate and 0.75 part of copper(I) chloride are suspended in 550 parts of nitrobenzene. With stirring, the mixture is heated to 190° C. and then a further 0.75 part of copper(I) chloride is added. The reaction mixture is heated to 206° C. and stirred for 3 hours at this temperature while distilling off the water of reaction. The batch is then heated to 214° C. and the pressure rises to about 1 bar. Stirring is continued for another 2 hours under these conditions. The reaction mixture is then cooled slightly and the nitrobenzene is removed by distillation. After drying there are obtained about 115 parts of anthrimide, which is suitable for further processing to give vat dyes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=[O:6].[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>C1COCC1>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]([OH:6])[CH2:18][CH:17]=[CH2:16]
Reactant: C=CC[Mg]Br
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Solvent: C1CCOC1
Product: C=CCC(O)c1c(C)c(OC)c(C)c(C)c1OC
Reaction time: 0.25 h

Procedure:
A stirred solution of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (6.34 g) in 125 mL THF was cooled to 0° C. and treated with 34 mL 1.0 M allyl magnesium bromide (1.0 M in THF, 1.1 equiv.) slowly over 0.25 h via dropping funnel. The solution was stirred for and additional 0.25 h and quenched by the addition of 40 mL 1.0 M aqueous citric acid and stirring until the layers clarified. The layers were separated and the aqueous layer extracted 3×50 mL EtOAc. The combined organics were washed 2×25 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to yield 9.8 g of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol as a brown oil. M+−H2O=233.4 m/z; 1H NMR (400 MHz, CDCl3) δ=5.90 (m, 1H), 5.15 (m, 1H), 5.10 (m, 1H), 4.98 (m, 1H), 3.78 (s, 3H), 3.65 (s, 3H), 2.66 (s, 1H), 2.48 (s, 1H), 2.25 (s, 3H), 2.18 (s, 6H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]([C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:24][C:25]1[C:26]([C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
Using a procedure analogous to Example 1-G, 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the desired product as a solid which was purified by HPLC (2.2 g, 28%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Benzyl chloroformate (91.0 g, 95% purity) was added dropwise over a period of 1 h to a precooled (0° C.) solution of L-valinol (50.0 g) and triethylamine (60.0 g) in chloroform (1500 ml). The reaction mixture was stirred for 1 h at 0° C. and then allowed to warm to,room temperature over 2 h. After the reaction mixture was evaporated, ethyl acetate (1500 ml) was added to the residue and the organic solution was washed (1N NaOH, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, using a stepwise gradient elution of ether:hexane (1:5) followed by ether, to give the alcohol (91.4 g) as a white waxy solid; TLC, Rf =0.23, hexane:ethanol (50:50).
Reaction SMILES: COC1C=CC(C[NH:10][C:11]([C:13]2[C:14]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[C:15]3[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:16]3=[N:17][CH:18]=2)=[O:12])=CC=1.[F:35][C:36]([F:42])([F:41])[S:37]([OH:40])(=[O:39])=[O:38]>ClCCl.C(OCC)C>[F:35][C:36]([F:42])([F:41])[S:37]([OH:40])(=[O:39])=[O:38].[NH2:27][CH2:26][CH2:25][NH:24][C:14]1[C:13]([C:11]([NH2:10])=[O:12])=[CH:18][N:17]=[C:16]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:15]=12
Reactant: COc1ccc(CNC(=O)c2cnc3c(c(C)nn3C)c2NCCNC(=O)OC(C)(C)C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nn(C)c2ncc(C(N)=O)c(NCCN)c12
Temperature: 25 °C
Yield: 117.3 %

Procedure:
To a solution of tert-Butyl N-[2-[[5-[(4-methoxyphenyl)methylcarbamoyl]-1,3-dimethyl-pyrazolo[3,4-b]pyridin-4-yl]amino]ethyl]carbamate (43 mg, 0.092 mmol) in dichloromethane (2.0 ml) was added trifluoromethanesulfonic acid (2.0 mL, 22.60 mmol) and the resulting orange-red mixture was stirred at room temperature over night. The reaction mixture was diluted with dichloromethane (40 ml) and diethylether (100 ml) subsequently upon which a white precipitate was formed. The mixture was stirred for 15 minutes after which the white solids were filtered off, washed with diethylether and dried in a stream of air. 43 mg of an off-white solid was obtained and used directly in the next step. MS (ESI) m/z=249.2.
Reaction SMILES: Br.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11]C)[C:4]=1[F:13]>C(O)(=O)C>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([OH:11])[C:4]=1[F:13]
Reactant: COc1c(C=O)ccc(Br)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc(Br)c(F)c1O
Temperature: 120 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
48% Hydrobromic acid (254 mL) was added to a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (52.3 g) in acetic acid (350 mL) at room temperature. The mixture was stirred at 120° C. under nitrogen atmosphere for 16 hours and concentrated in vacuo. The residue was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether and collected by filtration to give the title compound (34.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].C(Cl)Cl>C1COCC1>[CH3:9][C:5]1[C:3]2[NH:4][C:10](=[O:11])[O:1][C:2]=2[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(O)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc2oc(=O)[nH]c12
Temperature: 70 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
To a solution of 2-hydroxy-6-methylaniline (583 mg) in THF (8 mL) was added 1,1′-carbonyldiimidazole (1.14 g). The reaction mixture was stirred at 70° C. for 20 h. After cooling down, DCM was added and the mixture was washed three times with 2N NaOH. The aq. phases were combined, cooled down to 0° C. and the pH was brought to 6 by addition of 2N HCl. The suspension was filtered, the resulting powder was washed with cold water and dried in high vacuo to afford 587 mg of beige solid. LC-MS (B): tR=0.64 min. 1H-NMR (DMSO-d6): 11.7 (s, NH); 7.09 (m, 1H); 6.97 (m, 2H); 2.29 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: C=Cc1ccc(OC)cc1
Agent: [Li]CCCC
Product: COc1ccc(CCN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.30 g=0.30 ml) of para-methoxystyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate gives the product 1-(4-fluorophenyl)-4-[2-(4-methoxyphenyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15]I.OO.O>CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([I:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: OO
Solvent: CO
Solvent: O
Product: Nc1ccc(Cc2ccccc2)cc1I
Reaction time: 8 h

Procedure:
To a solution of 4-benzylbenzenamine (3.00 g, 16.4 mmol) in 16 mL MeOH was added iodine (2.49 g, 9.82 mmol) followed by hydrogen peroxide, 30% in water (1.67 mL, 16.4 mmol). The dark solution was allowed to stir overnight. The reaction was partitioned between water/brine and EtOAc. The organic layer was washed 1× brine, dried over MgSO4, filtered, and concentrated. The resulting oil was purified by ISCO (120 g, 0-10% EtOAc/hexanes) to give 4-benzyl-2-iodobenzenamine as a red oil which slowly solidified to a red solid. MS (ESI) m/z: Calculated: 309.0; Observed: 310.0 (M++1).