Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:31][N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1>>[CH3:31][N:32]1[C:40]2[C:35](=[C:36]([C:18]3[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=3)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1
Reactant: Cn1ncc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: Cn1ncc2c(C3=COCCN3C(=O)OC(C)(C)C)cccc21
Yield: 45 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a brown solid (45% yield); 1H-NMR (d6-DMSO) 0.80 (9H, s), 3.81 (2H, m), 4.02 (3H, s), 4.18 (2H, m), 6.50 (1H, s), 6.94 (1H, d), 7.31 (1H, t), 7.47 (1H, m), 7.90 (1H, s); 13C-NMR (CDCl3) 27.4, 35.4, 41.3, 66.8, 107.0, 116.5, 126.2, 131.8; MS ES(+) 316.0 (M++1); HRMS m/z calcd for C17H21N3O3+H+ 316.1661 [M+H+]. Found 316.1664. IR λmax=1692, 1638 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])[CH3:23]>ClCCl>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.3 %

Procedure:
To a solution of 2,6-dichloro-3-(trifluoromethyl)pyridine (2.38 g, 11.0 mmol) in anhydrous dichloromethane (20 ml) was added dropwise N,N-diisopropylethylamine (3.7 ml, 225 mmol). A solution of 1-acetylpiperazine (1.69 g, 13.2 mmol) in anhydrous dichloromethane (10 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 5 hrs. The mixture was warmed, heated under reflux for 2.5 hrs, and stirred at room temperature for 14 hrs. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→ethyl acetate→ethanol:ethyl acetate=1:20) to give 1-acetyl-4-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazine (451 mg, yield 13%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH:9]1[CH2:18][CH2:19]O)=[O:7].S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:19][CH2:18][CH:9]1[N:8]([C:6](=[O:7])[C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:4]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1c2ccccc2OCC1CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1c2ccccc2OCC1CCCl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 21.93 g of (±)-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 280 ml of dichloromethane are added 18 ml (0.248 mol) of thionyl chloride and the mixture is stirred at room temperature for 6 h.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[OH-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>O>[CH3:6][C@H:3]([CH2:2][S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9])[CH2:4][OH:5]
Reactant: C[C@@H](CO)CBr
Reactant: COc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1SC[C@@H](C)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
2.2 ml (0.021 mol) of 3-bromo-2-(S)-methyl-1-propanol are introduced into a round-bottomed flask kept under an inert atmosphere. 20 ml of an aqueous sodium hydroxide solution (1N) are added dropwise, followed by 2.3 ml (0.019 mol) of 2-methoxythiophenol. The mixture is brought to 90° C. for 4 hours and is then cooled to ambient temperature. 50 ml of water are then added and the mixture is extracted with dichloromethane. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol=99:1). 4 g (0.019 mol) of the title compound (XXb-1) are recovered in the form of a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([OH:34])=O)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][C:45]1=[O:49]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([NH:40][CH2:41][CH2:42][CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][C:45]2=[O:49])=[O:34])=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCCC1=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)O)c2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)NCCCN3CCCC3=O)c2)cc1

Procedure:
The product from Example 62C and 1-(3-aminopropyl)-2-pyrolidinone was processed as described in Example 68D to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 8.07 (m, 1 H), 7.23 (m, 8 H), 6.85-7.06 (m, 4 H), 6.45-6.79 (m, 4 H), 4.43 (s, 2 H), 4.08 (s, 2 H), 4.06 (s, 2 H), 2.99-3.39 (m, 6 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.17 (m, 2 H), 1.87 (m, 2 H), 1.56 (m, 2 H); MS (APCI) m/z 671 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][N:14]=[C:15]=[O:16].N12CCN(CC1)CC2.C1C=CC=CC=1>O>[CH3:13][NH:14][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:16]
Reactant: CN=C=O
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: c1ccccc1
Product: CNC(=O)OC1CC(C)(C)N(C)C(C)(C)C1
Reaction time: 24 h

Procedure:
A mixture of 16.4 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol, 6.27 parts of methyl isocyanate and 0.5 parts of 1,4-diazabicyclo[2,2,2]octane was refluxed in 150 parts of dry benzene for 24 hours. Removal of the benzene solvent by distillation under reduced pressure yielded an oily solid which was poured on to 200 parts of water and allowed to stand for 24 hours. The solid formed was collected by filtration, dried and crystallised from n-hexane to give 14.2 parts of 4-methylcarbamoyloxy-1,2,2,6,6-pentamethylpiperidine having a melting point of 96°-7° C. and the following elemental analysis by weight:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[O:10])[CH2:3][CH2:2]1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[CH:25]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]3[CH:15]=[N:14][NH:13][CH:12]=3)=[O:10])[CH2:3][CH2:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(NCC1CCNCC1)c1cn[nH]c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(NCC1CCN(C[C@@H]2C[C@H]2c2ccccc2)CC1)c1cn[nH]c1
Reaction time: 1 h

Procedure:
A solution of 1H-pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide (290 mg, 1.39 mmol), trans-2-phenylcyclopropanecarbaldehyde (224 mg, 1.53 mmol) and sodium triacetoxyborohydride (590 mg, 2.78 mmol) in MeOH (15 mL) was heated to 50° C. and stirred for 1 h. The resulting reaction mixture was concentrated and purified by silica gel chromatography (gradient: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) to give the trans 1H-pyrazole-4-carboxylic acid [1-(2-phenyl-cyclopropylmethyl)-piperidin-4-ylmethyl]-amide product.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[C:27]([I:41])=[C:28]([CH2:34][CH:35]([CH2:39][CH3:40])[C:36]([OH:38])=[O:37])[C:29]([I:33])=[CH:30][C:31]=1[I:32])=[O:24])=[O:16]>CC(N(C)C)=O>[CH2:39]([CH:35]([CH2:34][C:28]1[C:29]([I:33])=[CH:30][C:31]([I:32])=[C:26]([NH:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15](=[O:16])[CH2:14][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:27]=1[I:41])[C:36]([OH:38])=[O:37])[CH3:40]
Reactant: C1CNCCNCCNCCN1
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CCl)c1I)C(=O)O
Solvent: CC(=O)N(C)C
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN2CCNCCNCCNCC2)c1I)C(=O)O
Yield: 58.8 %

Procedure:
According to the procedure described in Example 5, 171.3 g of 1,4,7,10-tetraazacyclododecane (1,00 mol) in 500 ml of DMA are reacted with 190 g of 3-[[6-[(chloroacetyl) amino]-1-oxohexyl]amino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid (prepared according to the procedure described in Example 2) (0,25 mol) in 250 ml of DMA. 155 g of α-ethyl-2,4,6-triiodo-3-[[1-oxo-6-[(1,4,7,10-tetraazacyclododec-1-yl-acetyl)amino]hexyl]amino]benzenepropanoic acid (0.147 mol) are obtained.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]2[S:22][C:23]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@@H:9]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]2[S:22][C:23]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:5]1
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N=[N+]=[N-])C3)sc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Yield: 73.5 %

Procedure:
Ethyl cis(±)-2-(3-azido-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (81d) (84 mg, 0.17 mmol) was dissolved in THF (3 mL). Triphenylphosphine (63 mg, 0.24 mmol) and distilled water (0.2 mL) were added, and the mixture was heated under reflux for 15 hours. The reaction solution was concentrated under reduced pressure and the precipitated solid was collected by filtration, to obtain 59.6 mg of the title compound as a white solid (75%).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH:1]1([S:4]([O:18][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCCCO
Solvent: c1ccncc1
Product: CCCCOS(=O)(=O)C1CC1
Temperature: -10 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Cyclopropanesulfonyl chloride (5 g, 35 mmol, 1 eq) was dissolved in an excess BuOH (20 ml), the reaction mixture was cooled at −10° C. and pyridine (5.8 mL, 70 mmol, 2 eq) was slowly added dropwise. The mixture was slowly warmed at room temperature and stirred overnight. The solvent was removed under reduced pressure and the resulting white solid was dissolved in CHCl3. The organic phase was washed with water, brine and dried (MgSO4) and concentrated to give an oil (4.8 g, 24.9 mmol, 71%). 1H NMR (300 MHz, CDCl3): δ 4.25 (t, 2H), 2.46 (m, 1H), 1.74 (m, 2H), 1.45 (m, 2H), 1.25 (dd, 2H), 1.09 (dd, 2H), 0.93 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH:9]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:8][C:5]2=[CH:6][N:7]=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>>[CH:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH:11]([CH:9]2[O:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH2:10]2)[CH2:12][CH2:13]1)=[O:19])([CH3:23])[CH3:22]
Reactant: Clc1cc2c(cn1)OC(C1CCNCC1)C2
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1

Procedure:
The title compound is prepared from 5-chloro-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and isopropyl chloroformate following a procedure analogous to that described in Example 4. LC (method 7): tR=1.37 min; Mass spectrum (ESI+): m/z=325 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[CH3:20][N:21]1[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[N:22]1>>[CH3:20][N:21]1[CH:25]=[N:24][C:23]([CH2:26][O:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[CH:12][N:13]=[C:14]([C:15]4[CH:19]=[CH:18][O:17][N:16]=4)[N:4]3[N:3]=2)=[N:22]1
Reactant: Clc1nn2c(-c3ccon3)ncc2c2ccccc12
Reactant: Cn1cnc(CO)n1
Product: Cn1cnc(COc2nn3c(-c4ccon4)ncc3c3ccccc23)n1

Procedure:
The title compound was prepared from 6-chloro-3-(isoxazol-3-yl)-imidazo[5,1-a]phthalazine (Part b) and (2-methyl-1,2,4-triazol-5-yl)methanol as described in Example 1, Part c. 1H NMR (360 MHz, CDCl3) δ 3.96 (s, 3H), 5.7 (s, 2H), 7.40 (s, 1H), 7.52 (t, J=8 Hz, 1H), 7.76 (t, J=8 Hz, 1H), 7.89 (s, 1H), 8.0 (d, J=8 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 8.56 (s, 1H). MS (ES+) m/e 348 [MH]+.
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=[C:4]1[CH:1]([CH3:3])[CH3:2])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(C(C)C)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Part A. Sodium hydride (1.62 g of a 50% slurry, 33.8 mmol) was washed with hexane and dried under vacuum. Dimethylformamide (50 mL) was added, followed by a solution of 2-isopropyl-1H-benzimidazole (5.41 g, 33.8 mmol) in dimethylformamide (15 mL). After stirring at ambient temperature for two hours, the mixture was treated with ethyl 5-bromovalerate (5.50 mL, 34.8 mmol) and sodium iodide (1.19 g, 7.94 mmol). The mixture was heated to 80° C. for 18 hours, then cooled and poured into ethyl acetate (200 mL). This was washed with water (4×200 mL), then brine (200 mL), and dried over anhydrous magnesium sulfate, filtered and evaporated. The product, 1-(4-carboethoxybutyl)-2-(1-methylethyl)-1H-benzimidazole, was obtained as an oil after purification by silica gel chromatography (1:2 ethyl acetate-hexane) (9.54 g, 33.1 mmol, 98%). 1H NMR (CDCl3): 7.75 (1H, dd, J= 5.6, 3.1 Hz); 7.34-7.19 (3H, m); 4.12 (2H, q, J=7.1 Hz); 1.92-1.80 (2H, m); 1.78-1.65 (2H, m); 1.45 (6H, d, J=6.6 Hz); 1.24 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH:4]=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OCC)(=O)C>C1C=CC=CC=1>[Br:16][CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([N:3]([CH2:1][CH3:2])[CH:4]=[O:5])[O:7][C:8]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(C=O)c1nc2ccc(C)cc2o1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCN(C=O)c1nc2ccc(CBr)cc2o1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
The mixture of 2-(N-ethylformamido)-6-methylbenzoxazole (7.6 g), N-bromosuccinimide (6.6 g) and benzoyl perioxide (0.2 g) in benzene (150 ml) was refluxed for 70 minutes and the mixture was cooled to ambient temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated in a mixture of diisopropyl ether and n-hexane to give 6-bromomethyl-2-(N-ethylformamido)benzoxazole (6.18 g).
Reaction SMILES: [Cl-].[Li+].CS(C)=O.[CH2:7]([C:10]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH2:9]>O>[CH:21]1([CH:10]([CH2:7][CH:8]=[CH2:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C=CCC(C(=O)OCC)(C(=O)OCC)C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC(C(=O)OCC)C1CCCC1
Temperature: 185 °C
Reaction time: 6 h

Procedure:
Lithium chloride (3.60 g, 84.9 mmol) and water (0.76 mL, 41.9 mmol) were added to a dimethyl sulfoxide (20 mL) solution of diethyl allyl(cyclopentyl)malonate (10.10 g, 37.7 mmol), and the mixture was stirred at 185° C. for 6 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a brown oil substance (6.10 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:36]#[N:37]>CN(C)C=O>[C:36]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[O:1][C:2]1[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)#[N:37]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A resealable tube was charged with 6-hydroxy-1-naphthoic acid (0.596 g, 3.17 mmol), cesium carbonate (3.10 g, 9.51 mmol), and N,N-dimethylformamide (15 mL, Aldrich). The system was flushed with argon, the tube was sealed, and the mixture stirred at RT for 15 min. A solution of 4-chloro-3-cyano-6,7-dimethoxyquinoline (0.788 g, 3.17 mmol) in N,N-dimethylformamide (10 mL) was added (along with a 5 mL DMF rinse), and the system was again flushed with argon. The tube was sealed and the mixture stirred at 60° C. for 2 h. The mixture was diluted with water (30 mL) and 6 N HCl (aq) was added dropwise with stirring until the pH of the solution was 6-7. The resulting precipitate was filtered and washed with water. The filter cake was dried under vacuum to afford 6-(3-cyano-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid as a light brown solid. MS (ESI, pos. ion) m/z: 401.0 (M+H). Mass Calc'd for C23H16N2O5: 400.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.ClCCl.[C:20](#[N:22])C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:20]#[N:22])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1
Reactant: CC#N
Reactant: Fc1cncc(-c2cc3ccccc3[nH]2)c1
Solvent: ClCCl
Product: N#Cc1c(-c2cncc(F)c2)[nH]c2ccccc12

Procedure:
2-(5-Fluoro-pyridin-3-yl)-1H-indole (Example 92) is processed according to the method described in Example 140, using a mixture of dichloromethane and acetonitrile instead of dichloromethane, to give 2-(5-fluoro-pyridin-3-yl)-1H-indole-3-carbonitrile. MS (ESI) m/z 238.0 (M+H)+.
Reaction SMILES: C([C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[NH:24][C:15]3[CH:16]=[N:17][C:18](C(C)(C)C)=[CH:19][C:14]=3[N:13]=2)=[CH:7][N:6]=1)(C)(C)C.N[C:26]1C(C2NC3C=CC=CC=3N=2)=CC=CN=1>>[CH:7]1[C:8]2[C:12]3[N:24]([CH:26]=[N:11][C:9]=2[N:10]=[CH:5][N:6]=1)[C:15]1[C:14](=[CH:19][CH:18]=[N:17][CH:16]=1)[N:13]=3
Reactant: CC(C)(C)c1cc2nc(-c3cnc(C(C)(C)C)nc3N)[nH]c2cn1
Reactant: Nc1ncccc1-c1nc2ccccc2[nH]1
Product: c1cc2nc3c4cncnc4ncn3c2cn1

Procedure:
Preparation analogous to 7), using 32.4 g (100 mmol) of 2-(2-tert-butyl-4-aminopyrimidin-5-yl)-6-tert-butyl-3H-imidazo[4,5-c]pyridine (S56) (employed as equimolar mixture with 2,6-di-tert-butyl-3H-imidazo[4,5-c]-pyridine as obtained from synthesis 27)) instead of 100 mmol of the 2-(2-aminopyridin-3-yl)benzimidazole derivative. After crystallisation from methanol, the crude products are passed through a silica-gel column (heptane:ethyl acetate, 3:1 vv). The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 200-240° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[N+:37](=[C:10]([C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-:38]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 3-(2,6-difluorophenyl)-3-oxopropanoate (12.3 g, 53.8 mmol) and triethylamine (22.5 mL, 0.161 mol, 3.0 equiv) were dissolved in acetonitrile (160 mL) and treated with 4-acetamidobenzenesulfonyl azide. The mixture was stirred for 18 hours at ambient temperature, concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with chloroform), providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N+:8]([O-:14])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[CH2:22](C(CC)(CC)C([O-])([O-])[O-])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH3:23])=[N:13][N:12]=[C:10]3[CH2:9][N+:8]([O-:14])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2

Procedure:
A mixture of 13.5 g. of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4-oxide, 200 ml. of ethanol, 9 ml. of triethylorthoacetate and 0.5 g. of p-toluenesulfonic acid was refluxed for 20 minutes. The ethanol was removed under reduced pressure. The residue was partitioned between methylene chloride and aqueous sodium carbonate solution. The methylene chloride layer was dried and evaporated. The remaining crystals were recrystallized from ethyl acetate to yield 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 5-oxide with a melting point of 280°-282°.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2].[OH-:23].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20](=[O:23])[CH3:21])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2]
Reactant: C#CCn1c(-c2ccccc2)nc(C(F)(F)F)c(CC)c1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1c(C(F)(F)F)nc(-c2ccccc2)n(CC(C)=O)c1=O

Procedure:
To a stirred solution of 4.83 g (15.8 mmol) of 5-ethyl-3-propargyl-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (compound 46) in 50 mL of THF was added 50 mL of 10% aq NaOH. The mixture was heated at reflux for 2 h, cooled and diluted with 150 mL of ethyl acetate. The organic layer was separated, washed with 50 mL of water and 50 mL of brine and dried over MgSO4. Removal of the solvent afforded 4.74 g of 5-ethyl-3-(2-oxopropyl)-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (compound 179) as a white solid. 1H-NMR (CDCl3) 1.2(3H), 2.2(3H,s), 2.7(2H,q), 4.7(2H,s), 7.45(5H,m).