Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[Li+].CC([N-]C(C)C)C.[I:20]I>C1COCC1.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][CH3:11])=[C:2]([F:1])[C:7]=1[I:20]
Reactant: COc1c(C)cc(F)cc1F
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C)cc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1,5-difluoro-2-methoxy-3-methylbenzene (0.65 g, 4.1 mmol) in THF (1 mL) was added to LDA (4.3 mmol) in THF (10 mL) at −55° C. and the solution stirred for 45 minutes. Solid iodine (1.15 g, 4.5 mmol) was added and the solution allowed to warm to ambient temperature. The solution was diluted with ethyl acetate and washed with sodium bicarbonate (saturated solution 15 mL) and sodium thiosulfate (saturated solution, 15 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 1,3-difluoro-2-iodo-4-methoxy-5-methylbenzene: 1H NMR (300 MHz, CDCl3): δ 6.72 (dd, 1H), 3.84 (d, 3H,), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[S:6]2(=[O:16])=[O:15])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(Cl)cc1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (468 mg) was coupled to p-chloro phenylboronic acid to provide 1-(4-chlorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (50 mg):
Reaction SMILES: COC(/C=C/[C:7]1[CH:12]=[C:11](O)[C:10]2[O:14][CH:15](C3C=CC(O)=C(O)C=3)[CH:16](C(OC)=O)[C:9]=2[CH:8]=1)=O.[Br:29]N1C(=O)CCC1=O>C(#N)C>[Br:29][C:7]1[CH:12]=[CH:11][C:10]2[O:14][CH2:15][CH2:16][C:9]=2[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C=C/c1cc(O)c2c(c1)C(C(=O)OC)C(c1ccc(O)c(O)c1)O2
Solvent: CC#N
Product: Brc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 331.3 %

Procedure:
Dihydrobenzofuran (9.34 g) was dissolved in 130 ml of acetonitrile, 13.9 g of N-bromosuccinimide was added thereto and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, then the residue was dissolved in ethyl acetate and successively washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed, to give 15.94 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][N:17]([CH3:19])[CH3:18]>CO.[Pd]>[CH3:19][N:17]([CH2:16][CH:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=1[F:1])[CH3:18]
Reactant: CN(C)CC1CCCN1c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1CCCN1c1ccc(N)cc1F

Procedure:
[1-(2-Fluoro-4-nitro-phenyl)-pyrrolidin-2-ylmethyl]-dimethyl-amine (77 mg, 0.29 mmol) and Pd/C (16 mg, 10% weight) is shaken under H2 (50 psi) in MeOH overnight. After filtrating the Pd/C, the MeOH is removed and the residue obtained (65 mg, 95%) is directly employed in the next step.
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][NH2:16])=[N:10]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=3)[C:31](O)=[O:32])[C:24]2=[O:37])=[CH:20][CH:19]=1>>[CH3:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][N:36]=[C:28]([N:25]3[CH2:26][CH2:27][N:23]([CH2:22][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:39][CH:38]=4)[C:24]3=[O:37])[CH:29]=2)=[N:10]1
Reactant: Cc1cc(CN)nn1C
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: Cc1cc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)nn1C
Yield: 70 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1,5-dimethyl-1H-pyrazol-3-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 70% yield: mp 150-152° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 7.38-7.36 (m, 1H), 7.28-7.23 (m, 2H), 7.05-6.97 (m, 2H), 6.87 (br s, 1H), 5.98 (s, 1H), 4.53 (d, J=5.1 Hz, 2H), 4.42 (s, 2H), 4.02 (t, J=8.1 Hz, 2H), 3.71 (s, 3H), 3.35 (t, J=8.1 Hz, 2H), 2.21 (s, 3H); MS (ES+) m/z 422.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH2:37]([S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40])[CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([S:39]([CH2:37][CH3:38])(=[O:40])=[O:41])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{3-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-4-ethoxy-phenyl}-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-ethanesulfonyl-piperazine (example 14) in an analogous manner as described in example 25. LR-MS: 682.3 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: c1ccc2nc(CC3CCCCN3)ccc2c1
Product: Cc1nc(C(=O)N2CCCCC2Cc2ccc3ccccc3n2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared, using the method of Example 1, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.09 g, 0.35 mmol) and 2-piperidin-2-ylmethyl-quinoline, D13 (0.053 g, 0.23 mmol) as a colourless solid (0.038 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH2:23][NH2:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[NH:24][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: NN
Reactant: Cc1nnc(Br)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NN2

Procedure:
U.S. patent application Ser. No. 391,647, filed Aug. 27, 1973, now U.S. Pat. No. 3,891,666, describes a process for reacting a mixture of 5-chloro-2-(3-bromo-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone with hydrazine or its mineral acid salt and a base in a lower alkanol, e.g., ethanol at 70°-120° C. to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,3,4]benzotriazepine, indicating that hydrazine reacts with halogen on the triazole ring of triazolylbenzophenone compounds.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[O:28].[BH3-]C#N.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCC(=O)NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)NS(=O)(=O)c4ccccc4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-(Trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(phenylsulfonyl)propanamide (1.19 mmol, 1.5 equiv) were dissolved in anhydrous ethanol. The mixture was stirred at 80° C. for 1 h. Then NaBH3CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80° C. for 16 h. The organic layer was concentrated and purified by preparative thin layer chromatography (mobile phase was methanol:dichloromethane 1:10) to give 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamideas a white solid. 284 mg, white solid, 62%. ESI-MS: 523.0 (M+H)+. HPLC: 99.42%. 1H NMR (400 MHz, DMSO-d6) δ: 7.91 (s, 1H), 7.85˜7.82 (m, 2H), 7.74˜7.72 (m, 2H), 7.53˜7.51 (m, 1H), 7.41˜7.35 (m, 4H), 7.20˜7.15 (m, 1H), 4.45˜4.40 (m, 1H), 4.23 (s, 2H), 2.99 (t, 2H), 2.33 (t, 2H), 2.28˜2.16 (m, 2H), 1.89˜1.78 (m, 2H), 1.41˜1.31 (m, 2H), 1.27˜1.17 (m, 2H), 1.13˜1.06 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: CO[C:3]([CH:5]1[C:9](=O)[CH2:8][O:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15]>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:12]([F:11])=[C:13]([C:14]2[N:16]=[C:3]([OH:4])[C:5]3[CH2:6][O:7][CH2:8][C:9]=3[N:15]=2)[CH:17]=1
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: COC(=O)C1COCC1=O
Solvent: CCO
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 80 °C
Yield: 29.7 %

Procedure:
To a suspension of 4-oxo-tetrahydrofuran-3-carboxylic acid methyl ester (prepared according to Dowd, P.; Choi, S-C. Tetrahedron, 1991, 47, 4847-4860; 800 mg, 5.55 mmol, 1 eq) in ethanol (20 ml) was added a solution of 2-fluoro-5-chlorobenzamidine (961 mg, 5.55 mmol, 1 eq) in EtOH (10 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to rt and the white precipitate was filtered and washed with cold ethyl actetate (2×20 ml). The crude residue was partitioned between chloroform and water. The aqueous layer was acidified to pH 4 and the product was extracted with chloroform (3×50 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude solid which was purified by flash column chromatography (5% MeOH in EtOAc) to give a white solid 2-(5-Chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (440 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:13])[N:9]2[OH:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl-].[NH4+]>CN(C=O)C>[O:13]=[C:8]1[C:7](=[O:14])[NH:6][C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=2)[N:9]1[O:12][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n(O)c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)COn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Reaction time: 0.17 h

Procedure:
In 20 ml of DMF, 500 mg of 7-fluoro-1-hydroxy-6-nitro-2,3(1H,4H)-quinoxalinedione was dissolved. To the aresulting solution, 83 mg of sodium hydride was added, followed by stirring for 10 minutes. To the reaction -z mixture, 218 ml of ethyl bromoacetate was added, followed by reaction for 2 days. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with chloroform three times. The organic layer was concentrated, followed by recrystallization from 2-propanol to give 481 mg of ethyl 2-[(2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalinyl)oxy]acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:3]=1N.B(F)(F)[F:13].F.N([O-])=O.[Na+]>O>[F:13][C:3]1[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc(C(C)C)c1N
Reactant: FB(F)F
Agent: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C(C)C)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
44.7 g (0.3 mole) of 2-methyl-6-isopropylaniline are added dropwise to 200 ml of 40% strength tetrafluoboric acid at 5° C., followed by a solution of 20.7 g of sodium nitrite in 20 ml of water. The mixture is stirred for 1 hour at 10° C. The precipitated diazonium tetrafluoborate is filtered off under suction and suspended in succession in 50 ml of ice water, 50 ml of cold ethanol and 50 ml of diethyl ether. The suspension is added dropwise to a flask preheated at 150° C. When the evolution of gas has ended, the product is obtained by distillation over a Claisen still (bath temperature 100° C., pressure 4 mbar, distillation temperature 41°-42° C.). 28 g (61%) of 2-fluoro-3-isopropyltoluene are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]([C@H:21]([NH:24][C:25]([C:27]1[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=1)=[O:26])CO)[CH2:15][C:16]([O:18][CH2:19]C)=[O:17])=[O:12])=[CH:5]2>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:15][C:16](=[O:17])[O:18][CH2:19][C@H:21]1[NH:24][C:25]([C:27]1[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=1)=[O:26])=[O:12])=[CH:5]2
Reactant: CCOC(=O)C[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)[C@@H](CO)NC(=O)c1nc2c(s1)CN(C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3COC(=O)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Yield: 151.1 %

Procedure:
4N HCl-dioxane (20 mL) was added to the compound (0.31 g) obtained in Example 176, and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated, and the resultant residue was recrystallized from diethyl ether to give the title compound (0.23 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: CC(C)N
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC(C)C)cn1
Yield: 96 %

Procedure:
As described for example 80c, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol), was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (90 mg, 96%) which was obtained as an off white solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:22][CH2:21][CH2:20][NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NCCNCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NCCNCc2ccccc2)nc1

Procedure:
4.6 g of methyl 6-chloronicotinate and 40.5 ml of N-benzylethylenediamine are heated at 135° C. for 6 hours in a round-bottomed flask. The resulting product is poured into water and extraction is carried out with ethyl acetate. The resulting product is dried and evaporated under vacuum; the crude product thus obtained is purified by flash chromatography.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][O:5][CH2:4]1.O.Cl>C1COCC1>[CH3:1][O:2][C@H:3]1[C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@@H]1COCCC1(OC)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1COCCC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A stirred mixture of (R)-3,4,4-trimethoxytetrahydro-2H-pyran (as prepared in the previous step, 141 g, 0.80 mol), in THF (3.6 L) and H2O (1.1 L) in an ice/acetone bath at <0° C., was treated with a solution of HCl (conc., 595 mL, 7.21 mol) added via addition funnel over 45 min while keeping temperature <3° C. After the addition was complete, the reaction was allowed to stir for 1.5 h at 0° C. The reaction was evaporated until ˜1.9 L of concentrate remained. The concentrated was transferred to a separatory funnel and extracted with CH2Cl2 (3×1 L). The combined organic fractions were washed with sat. NaHCO3 (1 L), brine (1 L), dried over MgSO4, filtered and evaporated to afford the title compound (71.4 g, 69%, Chiral GC 92% ee) as an oil which solidified upon standing. Optical Rotation: [α]25(D) −6.97° (c=0.8222, MeOH); Elemental Analysis calc for C6H10O3: C, 53.59; H, 7.58. Found: C, 53.64; H, 7.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH:12]([Mg]Cl)([CH3:14])[CH3:13].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([CH:12]([CH3:14])[CH3:13])=[CH:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1=CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-chloro-1-indanone (3.59 g) in anhydrous tetrahydrofuran (40 ml) was added to a solution of isopropyl magnesium chloride (103 ml, 2M ethereal solution) under nitrogen at a rate to produce gentle refluxing. After the addition, the reaction solution was further stirred at room temperature for 11/4 hr, then poured into water (200 ml) and extracted with diethyl ether (3×150 ml). The combined ether solutions was washed with water, and condensed to an oil. This oil dissolved in benzene (250 ml) with a catalytic amount of p-toluenesulfonic acid was refluxed for 1.5 hr and then poured into water (200 ml). A few drops of diethylamine were added. The aqueous solution was separated and extracted with diethyl ether (3×100 ml). The combined organic phases were washed sequentially with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, then dried (MgSO4) and condensed under reduced pressure. The residue was purified on a flash column (eluted with 5% ether in hexane) to give 6-chloro-3-isopropyl-1H-indene (2.94 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].N.[H][H].[K+].[Br-]>CO.[Ni]>[NH2:12][C:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: [H][H]
Reactant: N#Cc1ccc(CC(N)=O)cc1
Agent: [Ni]
Agent: N
Agent: [Br-]
Solvent: CO
Product: NCc1ccc(CC(N)=O)cc1

Procedure:
0.65 g (4.057 mMol) of 4-cyanophenylacetamide were dissolved in 50 ml of methanol which was saturated with ammonia at+10° C. After the addition of 0.3 g of Raney nickel the mixture was hydrogenated in an autoclave at 40° C. under 5 bar of hydrogen pressure. After the uptake of hydrogen had ended the catalyst was filtered off and excess ammonia was distilled off with the solvent. The residue was acidified with 20 percent hydrochloric acid against Congo red and the non-basic impurities were removed by etherification. The ether extract was discarded, the aqueous solution was made alkaline with sodium hydroxide with external cooling and exhaustively extracted with ether. The ether solution was dried over caustic potash and freed from solvent, the residue was triturated with a few drops of ether and suction filtered. 610 mg (100% of theory) of colourless crystals were obtained, Mp. 138-140° C. IR (KBr): 1660.6, 1637.5 (Amide-C=O) cm-1
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:22]=3[CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]4)=[N:8][C:4]=2[CH:3]=1
Reactant: Nc1cccc2c1CC(O)CC2
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Product: OC1CCc2cccc(Nc3nc4cc(Br)ccc4[nH]3)c2C1

Procedure:
The reaction of 5-bromo-2-chloro-1H-benzo[d]imidazole (345 mg, 1.5 mol, prepared according to the procedure described in WO 2004/035549 A1) with 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (163 mg, 1.0 mmol, prepared according to the procedure described in WO 2003/095420 A1) under the condition of Example 21(b) afforded the title compound. MS (ESI, pos. ion) m/z: 358 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:18])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cccc(Cl)n1

Procedure:
1.5 g 2-benzoyl-pyridine N-oxide (T. Kato et. al., see reference in Ex. 11) and 3.6 ml POCl3 are refluxed for 25 minutes. The cooled mixture is added to slightly alkaline ice:water, extracted with chloroform, the organic extract dried and solvent removed in vacuo. Yield: 1.1 g of title product, which by thin layer and gas chromatography is identical with that described in Ex. 7.
Reaction SMILES: C(O[CH:5]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:7]2([CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[O:6]1)(=O)C.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH2:13]([N:10]1[CH2:11][CH2:12][C:7]2([C:20]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:5][O:6]2)[CH2:8][CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC1OC2(CCN(Cc3ccccc3)CC2)c2cccnc21
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(CN2CCC3(CC2)OCc2ncccc23)cc1
Yield: 87.7 %

Procedure:
To a solution of 0.80 g (2.4 mmol) 1′-benzyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-yl acetate in 47 ml dichloromethane were subsequently added 2.8 ml (18 mmol) triethylsilane and 2.2 ml (18 mmol) boron trifluoride etherate at room temperature. The reaction mixture was heated at reflux over night. The cooling bath was then removed and the reaction mixture was diluted with dichloromethane. The organic layer was washed with aqueous 2 M sodium hydroxide solution. The aqueous layer was extracted with two portions of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash-chromatography (aminopropyl-modified silica gel) gave the title compound (0.59 g, 89%) as a colorless oil.