Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:20][CH:21]=1)([OH:27])=[O:26]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CSc2nc3ccccc3[nH]2)cc1
Reaction time: 4 h

Procedure:
4.6 g (30 mmol) of 2-mercaptobenzimidazole were initially introduced into 60 ml of dry DMF, 8.3 g (60 mmol) of K2CO3 were added, and a solution of 6.7 g (31 mmol) of α-bromo-4-toluic acid in 15 ml of dry DMF was added dropwise at room temperature. After 4 hours, a solid residue was filtered off with suction, the DMF was removed in vacuo, and the residue was taken up in aqueous hydrochloric acid at pH 2. Crystals of the title compound separated out, and these were washed with water, methanol and ether and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][C:3]=1[C:12]([O:14]C)=[O:13].O[Li].O>C1COCC1.CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1ccc(C)c(C(=O)OC)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1C(=O)O
Reaction time: 3 h

Procedure:
A solution of 2-20 (1.5 g, 7.2 mmoles) in THF/MeOH/H2O (1:1:1) (36 ml) at room temperature was treated with LiOH.H2O (1.5 g, 36 mmoles). After stirring for 3 hours, the solvent was removed and the residue acidified with 1N HCl. This was extracted with EtOAc, and the extract was dried (MgSO4) and concentrated to give 2-21.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[C:17]3[C:18]([OH:22])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@@H:28]1OC(=N)C(Cl)(Cl)Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]2[C:17]3[C:18]([O:22][C@@H:28]4[O:36][C@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[C@@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:27]4[O:26][C:23](=[O:25])[CH3:24])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)c23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a mixture of 3-[2-(4-acetylaminophenyl)ethyl]-4-hydroxybenzofuran (30 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (64 mg) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.013 mL), and the mixture was stirred at room temperature for three days. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/3-1/2) to give 3-[2-(4-acetylaminophenyl)ethyl]-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)benzofuran (38 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give the title compound (12 mg).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].[CH:23]1(I)[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.CN(C=O)C>[CH:23]1([O:20][C:4]2[CH:5]=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[B:15]([OH:16])[O:14][CH2:13][C:12]=4[CH:17]=3)[CH:18]=[CH:19][C:3]=2[C:1]#[N:2])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: IC1CCCC1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (200 mg, 0.75 mmol) in THF (50 mL) and DMF (20 mL) was added NaH (47 mg, 95%, 1.87 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of cyclopentyl iodide (0.26 mL, 2.25 mmol). The reaction was stirred at room temperature for 24 hours. After the reaction, all volatile components were evaporated under vacuum. The residue was purified using silica gel column chromatography, eluting with 25% EtOAc/hexane, afforded 36 mg of the title compound in 12.6% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.23 (s, 1H), 7.78 (d, J=7.8 Hz, 1H) 7.69 (d, J=8.6 Hz, 1H), 7.17 (s, 1H), 7.10 (dd, J=2.0, 8.2 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.56 (dd, J=1.9, 8.6 Hz, 1H), 4.96 (s, 2H), 4.95 (t, J=5.8 Hz, 1H), 1.95-1.55 (m, 8H); MS (ES) m/z: 336 (M+H)+; HPLC purity: 99.15% (220 nm), 99.62% (MaxPlot).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[N:7][N:6]([CH3:10])[C:5](=[O:11])[C:4]=1[N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH3:21].S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([C:4]2[C:5](=[O:11])[N:6]([CH3:10])[N:7]=[C:8]([CH3:9])[C:3]=2[O:2][CH3:1])[C:13]=1[CH3:21]
Reactant: COc1c(C)nn(C)c(=O)c1-n1c(C)cc2ccccc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)nn(C)c(=O)c1-n1c(C)c(Cl)c2ccccc21
Yield: 95.6 %

Procedure:
To a stirred solution of 5-methoxy-2,6-dimethyl-4-(2-methylindol-1-yl)pyridazin-3-one (147 mg, 0.52 mmol) in DCM (3 ml) at 0° C., was added dropwise a solution of sulfuryl chloride (70 mg, 0.52 mmol) in DCM (1 ml). Further DCM (1 ml) was added. After a reaction time of 1 h, the mixture was quenched by addition of sat. aqueous NaHCO3 (2 ml). The resulting mixture was filtered through solid MgSO4, washing with DCM. The filtration liquors were concentrated in vacuo to afford the title compound as a pale brown solid (158 mg, 96%). The material was used for subsequent reactions without further purification.
Reaction SMILES: N[C:2]1C=CC2N=CSC=2C=1.[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>O>[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH3:2][NH:36][S:33]([C:27]1[CH:26]=[CH:25][C:30]([NH:31][N:32]=[C:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]4[C:22]=3[S:11][CH:12]=[N:13]4)[NH:18][C:19]2=[O:24])=[CH:29][CH:28]=1)(=[O:34])=[O:35]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Nc1ccc2ncsc2c1
Agent: Cl
Agent: O=C1Nc2ccc3ncsc3c2C1=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
6H-1-Thia-3,6-diaza-as-indacene-7,8-dione was prepared from 6-aminobenzothiazole according to Procedure A: 1H NMR (DMSO-d6): δ7.10 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 9.35 (s, 1H), 11.19 (s, 1H); ESI−MS m/z 204 (M)−. The title compound was prepared from 6H-1-thia-3,6-diaza-as-indacene-7,8-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>260° C.; 1H NMR (DMSO-d6): δ2.39 (d, J=5.1 Hz, 3H), 7.12 (d, J=8.4 Hz, 1H), 7.32 (q, J=5.1 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.6 Hz, 1H), 9.30 (s, 1H), 11.26 (s, 1H), 12.69 (s, 1H); APCI−MS m/z 387 (M)−. Anal. Calcd for C16H13N5O3S2.0.33 H2O: C, 48.85; H, 3.50; N, 17.80; S, 16.30. Found: C, 48.89; H, 3.40; N, 17.67; S, 16.23.
Reaction SMILES: N1CCCC1.ClCC1C=CC([C@H](C2C=CC(Cl)=CC=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16]2)=CC=1.[I-].[Na+]>ClCCl>[F:31][C:26]1[CH:25]=[C:24]([C:19](=[C:17]2[CH2:18][NH:15][CH2:16]2)[S:20]([CH3:23])(=[O:22])=[O:21])[CH:29]=[C:28]([F:30])[CH:27]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: CS(=O)(=O)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
50 mm3 of pyrrolidine are added to a solution of 0.32 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, and 5 mg of sodium iodide in 10 cm3 of dichloromethane. After stirring for 20 hours at 20° C., 50 mm3 of pyrrolidine are added to the mixture, stirred for 8 hours and then 50 mm3 of pyrrolidine are again added and the mixture is stirred for 20 hours at 20° C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol mixture (97.5/2.5 by volume) and collecting 3 cm3 fractions. Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1-{(R*)-(4-chlorophenyl)[4-pyrrolidinylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [a]20365 nm=−22.5°+/−0.7 (c=0.5%; dichloromethane) [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 (s, 3H), 3.58 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[Cl:20][C:17]([F:19])([F:18])[S:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 185 using (R)-5-bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 217.1) and pyrimidin-5-ylboronic acid to afford an off-white foam. HPLC (Condition 4) tR=5.27 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=478.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.78 (m, 1H) 1.80-1.90 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=10.90, 4.30 Hz, 2H) 3.32-3.44 (m, 1H) 4.12-4.26 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.67 (d, J=8.60 Hz, 2H) 7.91 (d, J=8.99 Hz, 2H) 8.09 (d, J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.13-9.33 (m, 1H) 10.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].C(Cl)(=O)C(Cl)=O.[CH2:51]([NH:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])=[CH:58][CH:57]=1)[CH2:52][CH2:53][CH3:54].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[CH2:51]([N:55]([C:56]1[CH:57]=[CH:58][C:59]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])=[CH:60][CH:61]=1)[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:17])=[O:18])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:4]=1)=[O:44])[CH2:52][CH2:53][CH3:54]
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Reactant: CCCCNc1ccc(CCC(=O)OC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(CCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (116 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was added oxalyl chloride (48 μL, 0.55 mmol) followed by 1 drop of DMF. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (1.0 mL), and methyl 3-(4-(butylamino)phenyl)propanoate (Intermediate 122A, 17 mg, 0.074 mmol) and i-Pr2EtN (32 μL, 0.18 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude oil was purified by preparative HPLC to give the title compound (30 mg, 57%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.73 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 8.07-8.06 (m, 1H), 8.04-8.00 (m, 2H), 7.94-7.91 (m, 1H), 7.74-7.66 (m, 2H), 7.48 (br s, 1H), 7.39 (br s, 1H), 7.21-7.19 (m, 3.5H), 7.03 (br s, 1H), 6.98-6.96 (m, 0.5H), 6.90 (br s, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.43 (br s, 1H), 4.73 (br s, 1H), 4.44 (br s, 1H), 4.26 (br s, 1H), 4.10 (br s, 1H), 3.90 (br s, 1H), 3.60-3.56 (m, 3H), 3.48 (br s, 2H), 2.94 (br s, 1H), 2.79-2.71 (m, 2H), 2.54-2.46 (m, 2H), 2.12 (s, 3H), 1.43-1.24 (m, 4H), 0.89-0.83 (m, 3H); MS (ESI+) m/z 847.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([NH2:11])=[C:5]([NH2:12])[C:4]=1[CH3:13].C(N(CC)CC)C.[C:21](Cl)(Cl)=[S:22].O>C(Cl)(Cl)Cl>[CH3:13][C:4]1[C:5]2[N:12]=[C:21]([SH:22])[NH:11][C:6]=2[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1]
Reactant: S=C(Cl)Cl
Reactant: COc1c(C)c(C)c(N)c(N)c1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C)c(C)c2[nH]c(S)nc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 4-methoxy-3,5,6-trimethyl-1,2-phenylenediamine (1.8 g, 0.010 mol) and triethylamine (2.1 g, 0.021 mol) in CHCl3 (15 ml) was added dropwise to a stirred solution of thiophosgene (0.60 g, 0.0052 mol) in CHCl3 (5 ml). The mixture was then stirred at room temperature for 1 hour. Water (15 ml) and triethylamine (0.5 g) was added and the mixture was stirred for 1 hour. The precipitate was filtered off, washed with water and dried in the air giving the desired product (0.96 g, 43%), NMR: δ (CDCl3) 2.5 (s,3H), 2.65(s,6H), 3.65(s,3H), 12.0(br.s.,1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:22][CH:21]([C:23]4[N:27]=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[NH:25][N:24]=4)[CH2:20]3)=[CH:14][CH:13]=2)[C:4]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:9]1[N:8]2[C:3]([NH:2][CH3:1])=[C:4]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:5]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:20][CH:21]([C:23]5[N:27]=[C:26]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[NH:25][N:24]=5)[CH2:22]4)=[CH:16][CH:17]=3)=[N:6][C:7]2=[N:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2nccn12
Solvent: ClC(Cl)Cl
Product: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2ncc(Br)n12
Yield: 26.1 %

Procedure:
50 mg (0.097 mmol) Methyl-(6-phenyl-7-{4-{3-[5-(pyridine-2-yl)-1H-[1,2,4]triazole-3-yl)-azetidine-1-ylmethyl]-phenyl}-imidazo[1,2-a]pyrimidin-5-yl)-amine are dissolved in 3.9 mL chloroform. 19.1 mg (0.11 mmol) N-bromosuccinimide are added and the reaction mixture is heated for one hour at reflux. The solvent is evaporated and the residue purified by chromatography (silicagel, eluents: dichloromethane/methanol). 15 mg (24.7%) of the desired compound are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[O:13])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)c1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(COC(=O)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of 4-isopropylbenzyl alcohol (4.51 g, 30.02 mmol) in 50 mL toluene was added 1,1′-carbonyldiimidazole (4.87 g, 30.02 mmol). This solution was stirred 18 h at ambient temperature. White precipitate was filtered off and the filtrate was concentrated under reduced pressure. The resultant oil was flash chromatographed with 15% ethyl acetate/hexanes to yield 6.41 g (87%) of imidazole-1-carboxylic acid-(4-isopropyl)benzyl ester, a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[NH:6][C:5]2=O.CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Brc1ccc2c(c1)CNC2
Temperature: 0 °C

Procedure:
To a solution of 5-bromo-1H-isoindole-1,3(2H)-dione (4 mmol) in THF (10 mL) was added borane-dimethyl sulfide complex (2M in THF, 14 mL) at 0° C. The reaction mixture was allowed to stir at reflux overnight and was then cooled to 0° C. The reaction mixture was quenched by the slow addition of MeOH (10 mL) and then 2N HCl (10 mL). The reaction mixture was allowed to stir at reflux for 3 hr and then concentrated. Water (10 mL) was added to the residue. Remaining starting material was removed by extraction with DCM. To the aqueous solution was added 4N NaOH until pH>9. The solution was extracted with DCM. The organic solutions from this basic extraction were combined, dried over Na2SO4, filtered and concentrated to give 5-bromoisoindoline, which was dissolved in THF (20 mL). To this solution was added potassium carbonate (8 mmol) in water (1 mL), and BOC2O. The reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (2.5 mmol, 60%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:3]([C:5]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)#[N:4]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To sodium hydride (0.1 g) taken in dry DMF (5 ml), under nitrogen, compound tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate (0.5 g) was added and allowed to stir at room temperature for half an hour. Benzaldehyde (280 mg) was added to the above reaction mixture and allowed to stir for 3 hours at room temperature. The reaction mixture was quenched with ice water (50 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using MeOH: CH2Cl2 (0.5:9.5) as an eluent to afford tert-butyl 4-(1-cyano-2-phenylvinyl)piperazine-1-carboxylate as pure product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[Cl:10].[F:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25]Br)=[CH:19][CH:18]=1.O>CN(C=O)C.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:20]3[CH:30]=[CH:31][C:17]([F:16])=[CH:18][CH:19]=3)[CH:23]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: Fc1ccc(Oc2cccc(CBr)c2)cc1
Reactant: CC(C)(CO)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(COCc1cccc(Oc2ccc(F)cc2)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 20 ml of toluene was added 0.63 g of sodium hydride (60% in oil) and the mixture was refluxed, and a solution of 2.3 g of 2-(3,4-dichlorophenyl)-2-methylpropyl alcohol in 10 ml of 25% DMF/toluene was added dropwise to the mixture over a period of 15 minutes. The mixture was stirred for 15 minutes, and a solution of 3.5 g of 3-(4-fluorophenoxy)benzyl bromide in 10 ml of toluene was added dropwise to the mixture over a period of 20 minutes. Then, the mixture was refluxed for 1 hour and cooled to room temperature, and poured into water.
Reaction SMILES: [CH:1]1([N:4]([CH:12]=[C:13]([C:19](OCC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(=O)(O)[O-]>ClCCl>[CH:1]1([N:4]2[C:5]3[C:6](=[CH:7][C:8]([I:11])=[CH:9][CH:10]=3)[C:19](=[O:20])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CN(c1ccc(I)cc1)C1CC1)C(=O)OCC
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CC2)c2ccc(I)cc2c1=O
Temperature: 120 °C

Procedure:
To a flask containing diethyl 2-[(cyclopropyl-4-iodoanilino)methylene]malonate from Preparation No. 18 (0.22 g) is added polyphosphoric acid (1.4 g). The reaction mixture is capped and heated to 120° C. over 1 hour. After 2 hours at 120° C. the reaction is cooled to room temperature, treated with ice and partioned between dichloromethane and saturated aqueous bicarbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.19 g of the title compound as a tan solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=1.C(OC([N:23]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[N:24]1)=O)(C)(C)C>>[CH2:8]([N:7]1[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=[C:3]1[CH2:2][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[C:25]1[CH:26]=[CH:27][NH:23][N:24]=1)[CH3:9]
Reactant: CCn1c(CCl)nc2cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ncc[nH]2)n1
Product: CCn1c(Cn2ccnc2-c2cc[nH]n2)nc2cc(C#N)ccc21

Procedure:
As described previously, nucleophilic displacement of 2-Chloromethyl-1-ethyl-1H-benzoimidazole-5-carbonitrile with 3-(1H-Imidazol-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester followed by usual work-up provides 1-Ethyl-2-[2-(1H-pyrazol-3-yl)-imidazol-1-ylmethyl]-1H-benzoimidazole-5-carbonitrile; 1H NMR (CD3OD) δ 7.97 (s, 1H), 7.53 (brs, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=6.3 Hz, 2H), 6.79 (br s, 1H), 6.10 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H); m/z 318 [M+l]