Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:9][CH:8]2[CH2:10][CH2:11][CH:5]1[CH:6]=[C:7]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:18][C@@:4]1([CH2:3][CH2:2][O:1][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:9][C@H:8]2[CH2:10][CH2:11][C@@H:5]1[CH:6]=[C:7]2[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CC2CCC1C=C2c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2C=C3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 227 mg of rac-(1R*,2R*,4R*)-2-(2-hydroxy-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol, 195 mg of Ts-Cl, 0.16 mL of NEt3 and 11 mg of DMAP in 3 mL toluene was stirred overnight at rt. The reaction mixture was quenched with water, the organic phase was separated, washed with brine and evaporated. The residue was purified by CC with Hept-EtOAc (6:4) to yield 0.32 g of oily rac-toluene-4-sulfonic acid (1R*,2R*,4R*)-2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl ester as yellowish oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:25]([NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH2:41][CH3:42])([CH3:40])[CH3:39])=[CH:34][C:33]=1[C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[O:26]>C(O)C.[C].[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:25]([NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH2:41][CH3:42])([CH3:39])[CH3:40])=[CH:34][C:33]=1[C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[O:26]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(OCCOc3ccc([N+](=O)[O-])cc3)c3ccccc3c2O)c(C(C)(C)CC)c1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(OCCOc3ccc(N)cc3)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
By dispersing 6.4 g of Intermediate 3 in 64 ml of ethanol and then hydrogenating the intermediate in an autoclave using a palladium-carbon catalyst, the desired product was obtained. The solvent used for the recrystallization was ethanol. The melting point of the product was 147-149° C.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]([NH:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[Cl:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[C:9]([OH:33])=[O:8])=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A suspension of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid benzyl ester (10.0 g, 21.5 mmol) and 5% Pd on carbon (0.914 g) in EtOAc (200 mL) was treated with H2 (balloon) and stirred at 10-15° C. for 1.5 hour and at room temperature for 0.5 hour. The resulted precipitate was dissolved in methanol and filtered through celite pad. The filtrate was concentrated under reduced pressure and the obtained residue was re-crystallized from EtOAc to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (5.6 g). The mother liquor was concentrated under reduced pressure and purified by silica gel column chromatography to give additional amount of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (1.4 g). 1H NMR (400 MHz, DMSO-d6) δ 1.13 (t, 3H, J=7.1 Hz), 1.15 (d, 3H, J=6.8 Hz), 2.85 (dd, 1H, J=7.1, 14.1 Hz), 2.93 (dd, 1H, J=6.3, 13.6 Hz), 3.30-3.37 (m, 1H), 3.48 (dd, 1H, J=6.5, 6.5 Hz), 4.03 (q, 2H, J=7.1 Hz), 7.32 (d, 2H, J=8.3 Hz), 7.38-7.43 (m, 1H), 7.48 (dd, 1H, J=7.8, 7.8 Hz), 7.59-7.65 (m, 3H), 7.70 (dd, 1H, J=2.0, 2.0 Hz); MS: m/z (MH+) 376.
Reaction SMILES: O=O.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1O)([CH3:6])([CH3:5])[CH3:4].[OH-:18].[K+].[OH-:20].[Na+]>>[C:3]([C:7]1[CH:12]=[C:11]([OH:20])[CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[C:8]1[C:7]([C:3]([CH3:5])([CH3:4])[CH3:6])=[CH:12][C:11]([OH:18])=[CH:10][C:9]=1[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=O
Agent: [K+]
Agent: [Na+]
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1-c1c(C(C)(C)C)cc(O)cc1C(C)(C)C

Procedure:
oxidizing the resulting reaction liquid using oxygen without isolating said 2,6-di-t-butyl phenol from the liquid in the presence of KOH or NaOH as an alkaline catalyst to produce 3,3',5,5'-tetra-t-butyl-4,4'-biphenol,
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[C:4]([CH3:8])([C:6]#[CH:7])[CH3:5])[CH3:2].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27](I)[S:28][C:21]=12)[NH2:15]>>[CH2:1]([N:3]([CH2:9][CH3:10])[C:4]([CH3:8])([CH3:5])[C:6]#[C:7][C:27]1[S:28][C:21]2[C:22](=[N:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[F:11])[CH:26]=1)[CH3:2]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CC(C)(C)N(CC)CC
Product: CCN(CC)C(C)(C)C#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 50 °C
Yield: 32.7 %

Procedure:
Prepared from N,N-diethyl-2-methylbut-3-yn-2-amine (21 mg, 0.15 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 39 mg, 0.10 mmol) using the procedure described for Example 6, Step B, except the reaction was heated to 50° C. for 24 hours. The crude was purified by preparative TLC (10% MeOH/CH2Cl2). The product was obtained as a waxy solid (13 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 8.47 (m, 1H), 7.51 (s, 1H), 7.02 (m, 1H), 6.49 (m, 3H), 3.85 (s, 2H), 2.76 (m, 4H), 1.52 (s, 6H), 1.14 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:21]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11][CH:20]=1)[CH3:27]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC1=CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
A solution of 2-amino-5-nitro-benzenethiol (4.1 g, 23.9 mmol) in tetrahydrofuran (60 mL) was treated with triethylamine (4.8 g, 47.8 mmol) and ethyl chloroacetoacetate (4.3 g, 26.3 mmol). The reaction mixture was stirred at 25° C. for 12 h, concentrated in vacuo, taken up in ethyl acetate, and heated at 80° C. for 3 h. The reaction mixture was allowed to cool to 25° C., washed with saturated aqueous brine solution, dried over sodium sulfate, and concentrated in vacuo. The resulting brown solid was triturated with diethyl ether to afford the desired product, (7-nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (5.8 g, 20.7 mmol, 87%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=7.1 Hz), 3.49 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 4.89 (s, 1H), 6.91 (d, 1H, J=8.7 Hz), 8.00 (dd, 1H, J1=9.5 Hz, J2=2.3 Hz), 8.12 (d, 1H, J=3.1 Hz), 10.95 (bs, 1H). LC-MS (ESI) calcd for C12H12N2O4S [M+H+] 281.05, found 281.23 [M+H+].
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:34])(=[O:33])[N:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH3:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([N:23]([CH3:24])[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][N:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)(=[O:33])=[O:34])[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3ccc(S(=O)(=O)N(C)c4cccc(OC)c4)cc3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(-c3ccc(CN4CC(C(=O)O)C4)cc3)cc2)c1
Reaction time: 0.5 h
Yield: 4.3 %

Procedure:
To a stirred solution of the product of Step D (0.06 g, 0.13 mmol) in THF (3 ml) a solution of LiOH (0.006 g, 0.25 mmol) in H2O (1 ml) was added at 80° C. The mixture was stirred for 0.5 h and solvents were evaporated to dryness. The residue was purified by FCC(SiO2) to give the title compound (0.0026 g, 43%) as creamy solid. 1H-NMR (CDCl3:CD3OD) 7.58 (s, 4H); 7.58 (d, 2H, J=8 Hz); 7.56 (d, 2H, J=7.23 Hz); 7.49 (d, 2H, J=8.25 Hz); 7.13 (t, 1H, J=8.14 Hz); 6.76 (dd, 1H, J=8.33, 2.05 Hz); 6.68 (t, 1H, J=2.15 Hz); 6.58 (dd, 1H, J=7.94, 1.32 Hz); 4.25 (s, 2H); 4.21-4.02 (m, 4H); 3.70 (s, 3H); 3.38-3.32 (m, 3H); 3.13 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.NC(N)=O>C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O>[C:14]1([NH:20][C:21]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: NC(N)=O
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 82 %

Procedure:
0,5 mole of diphenylamine was taken together with 0.53 mole of phenyl isocyanate and 0.6 g of di-n-butl phosphate in 150 ml of toluene. The mixture was heated at 100° C. for 24 hours, with stirring, and then cooled to room temperature. At about 30° C., the urea started to crystallize out. After filtering off, washing with 150 ml of cold toluene and drying, 0.41 mole of N-phenyl-N',N'-diphenylurea was obtained. Melting point: 131° C./yield: 82% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([C:16]([C:19](OCC)=[O:20])([CH3:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[NH3:25]>C(O)C>[C:19]([C:16]([CH3:18])([CH3:17])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([OH:24])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:20])[NH2:25]
Reactant: N
Reactant: CCOC(=O)C(C)(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Solvent: CCO
Product: CC(C)(C(N)=O)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 192 h

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-3-ethoxycarbonyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (75 mg) in ethanol (5 ml), aqueous ammonia (sp. gr. 0.88, 12 ml.) was added and the solution was left at room temperature (20° C.) for eight days. The solvent was then evaporated in vacuo, the residue was partitioned between methylene chloride and water, and the organic extracts were washed with brine and dried (MgSO4). Removal of solvent followed by flash chromatography on silica (30 g) and elution with a mixture of methylene chloride/methanol/ammonia (93:7:1) gave the title compound, m.p. 162°-163° C. (34.5 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N+:19]([O-:21])=[O:20])=[C:7]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH:24]=2)[N:6]=1)(=O)=O.[OH:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:38]#[N:39].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:44]([O:43][C:42]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[O:34][C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N+:19]([O-:21])=[O:20])=[C:7]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH:24]=2)[N:6]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CN(C)C(=O)c1cccc(Oc2nc(S(C)(=O)=O)nc(NCc3ccccc3)c2[N+](=O)[O-])c1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)C(=O)c1cccc(Oc2nc(Oc3cc(C#N)ccc3OCc3ccccc3)nc(NCc3ccccc3)c2[N+](=O)[O-])c1

Procedure:
In a similar manner, 2-methylsulfonyl-4-benzylamino-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine was treated with 3-hydroxy-4-benzyloxybenzonitrile in the presence of cesium carbonate to afford 2-(2-benzyloxy-5-cyanophenoxy)-4-benzylamino-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (P).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=CC)[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:9]=2)[CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([CH2:16][CH2:15][CH2:14][C:12]2[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:9]=[C:8]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[CH:13]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: CC=CCCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Product: Cc1cc(Nc2cc(CCCN3CCCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1

Procedure:
Example 44 was prepared by an analogous method to that described in Example 43 starting from 4-(5-methyl-1H-pyrazol-3-ylamino)-6-(pent-3-en-1-yl)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Example 34) and pyrrolidine.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31]C1C=CC=CC=1C=O>>[F:31][C:29]1[CH:30]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: O=Cc1ccccc1F
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccccc1F)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-fluorobenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 410 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46-11.56 (1H, m) 10.26 (1H, s) 8.03 (1H, t, J=5.56 Hz) 7.99 (1H, d, J=5.47 Hz) 7.75 (1H, d, J=5.47 Hz) 7.44 (1H, d, J=5.47 Hz) 7.37-7.42 (1H, m) 7.26-7.30 (1H, m) 7.19-7.26 (1H, m) 7.05-7.12 (1H, m) 6.78 (1H, d, J=5.47 Hz) 6.40 (1H, dd, J=3.61, 1.66 Hz) 3.70 (2H, s) 3.32-3.37 (2H, m) 2.62 (2H, t, J=6.54 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][C@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH:9]([O:8][C:4]1[CH:3]=[C:2](/[CH:16]=[CH:15]/[CH2:14][C@@H:13]([OH:17])[CH3:12])[CH:7]=[N:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: C=CC[C@H](C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1cncc(/C=C/C[C@H](C)O)c1
Temperature: 135 °C
Yield: 60.7 %

Procedure:
A mixture of 5-bromo-3-isopropoxypyridine (12.56 g, 58.13 mmol), (2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (130 mg, 0.58 mmol), tri-o-tolylphosphine (706 mg, 2.32 mmol), triethylamine (35 mL, 252 mmol) and acetonitrile (35 mL) was heated in a sealed glass tube at 130-140° C. for 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure on a rotary evaporator. Water (50 mL) was added and the mixture was extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (95:5, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing 7.80 g (60.7%) of a pale-yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH3:18][N:19]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:20](Cl)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:20]([N:19]([CH3:18])[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21]
Reactant: CNCCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: CN(C(=O)Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCOc1ccc2[nH]c(=O)ccc2c1)C(=O)N(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
6-(3-Methylaminopropoxy)carbostyril (3 g) is dissolved in dimethylformamide (150 ml), and thereto are added N-methyl-N-cyclohexylaminocarbonyl chloride (2.3 g) and potassium carbonate (2 g). The mixture is stirred at room temperature overnight, and further heated with stirring at 80° C. for 2 hours. The reaction solution is poured into water, and extracted with ethyl acetate. The extract is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=30:1), and recrystallized from ethyl acetate to give 6-[3-(1,3-dimethyl-3-cyclohexylureido)propoxy]carbostyril (2.3 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([CH2:22][CH2:23][C:24](Cl)=[O:25])=[O:21]>>[CH3:18][O:19][C:20]([CH2:22][CH2:23][C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25])=[O:21]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: COC(=O)CCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 66 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.057 mMol) 3-methoxycarbonylpropionyl chloride, 0.01 gm (67%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[C:28]([F:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:28]1[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[CH:32][CH:31]=[C:30]([CH3:33])[N:29]=1
Reactant: Cc1ccc(Br)c(F)n1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c(F)n1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (250 mg, 0.68 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (14 mg, 0.5 mmol/g, 0.007 mmol) was added along with 3-bromo-2-fluoro-6-methylpyridine (194 mg, 1.02 mmol) and 680 μl of a 2M Na2CO3 solution in water. The resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 175 mg of title compound were recovered as white solid (74%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(2-fluoro-6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][NH:26][C:25]2=[O:29])=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:26]1[C:25](=[O:29])[N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:31])[F:30])=[CH:23][CH:22]=2)[CH:28]=[N:27]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(OC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 62.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.33 g of 4-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone (1.45 g) was obtained as colorless prisms.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:13]C2CCCCO2)[CH:5]([C:20]2[NH:21][CH2:22][CH2:23][N:24]=2)[O:4]1)[CH3:2].[ClH:25]>CO.C(OCC)C>[ClH:25].[NH:24]1[CH2:23][CH2:22][N:21]=[C:20]1[CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:13])[C:11]=2[CH2:12][CH:3]([CH2:1][CH3:2])[O:4]1
Reactant: CCC1Cc2c(OC3CCCCO3)cccc2C(C2=NCCN2)O1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCC1Cc2c(O)cccc2C(C2=NCCN2)O1

Procedure:
Methyl 3-ethyl-5-hydroxyisochroman-1-carboxylate (90 mg) was dissolved dichloromethane (1 mL) and 3,4-dihydro-2H-pyran (52 μL) and pyridinium p-toluenesulfonate (9.6 mg) were added. After 28 hours more 3,4-dihydro-2H-pyran (102 μL) and pyridinium p-toluenesulfonate (10 mg) were added and mixture was stirred for another 24 hours. 3,4-Dihydro-2H-pyran (200 μL) was then added and mixture was stirred overnight after which it was diluted with diethyl ether (5 ml) and washed with saturated NaHCO3-solution. Organic phase was dried with Na2SO4 and concentrated. Purification of the evaporation residue by column chromatography (ethyl acetate-heptane) afforded 37 mg of oil that was converted to 2-(3-ethyl-5-((tetrahydro-2H-pyran-2-yl)oxy)isochroman-1-yl)-4,5-dihydro-1H-imidazole (13 mg) using the synthesis method A3. The crude product of this procedure was dissolved in methanol (1 ml) and HCl solution in diethyl ether (2M, 39 μL) was added. After 2.5 hours reaction mixture was concentrated and the residue was taken in water (10 mL). The solution was washed with ethyl acetate and the water layer was concentrated in freeze dryer to afford the title compound. (Yield 6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:3]=1>[OH-].[Na+].O1CCOCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:5]=[C:4]([C:22]([F:24])([F:25])[F:23])[N:3]=[C:2]([Cl:1])[CH:7]=2)(=[O:10])=[O:11])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Yield: 34.1 %

Procedure:
0.20 g (0.0005 mol) of N-[4-(2-chloro-6-trifluoromethyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamide was dissolved in a mixture of 5 ml of 1N NaOH and 5 ml of dioxan and boiled at reflux for 5 hours. After cooling the dioxan was distilled off, the residue was adjusted to pH 6 with 0.1N HCl, the aqueous phase was extracted with ethyl acetate, back-washed with saturated sodium chloride solution and the organic phase was dried over Na2SO4. Subsequently, chromatography was carried out on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.06 g (34%) of 4-amino-N-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-benzene-sulfonamide as pale yellow crystals; m.p.: 179-181° C.