Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH2:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: NCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a suspension of C-[1-(3-thiazol-2-yl-phenyl)-1H-benzoimidazol-5-yl]-methylamine (0.70 g, 2.3 mmol) in dichloromethane (30 ml) was added acetic anhydride (2.4 ml, 2.5 mmol) dropwise with stirring. After the addition, stirring was continued for 30 min and the reaction mixture was washed twice with saturated, aqueous sodium bicarbonate and once with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The concentrate was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (9:1:0.1 v/v/v). This afforded the desired product (0.52 g, 65%). Mp. 156.4° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.C([OH:22])C1C=CC=CC=1.[H-].[Na+]>CN(C=O)C>[CH:8]([C:7]1[C:2]([OH:22])=[N:3][C:4]([O:13][CH3:14])=[N:5][C:6]=1[O:11][CH3:12])([CH3:10])[CH3:9]
Reactant: OCc1ccccc1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(O)c(C(C)C)c(OC)n1
Temperature: 0 °C

Procedure:
To a mixture of 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (1.4 g, 6.51 mmol, 1 eq) and benzyl alcohol (704 mg, 1.0 eq.) in 10 mL DMF, NaH (60% in mineral oil, 273 mg, 1.05 eq.) was added at 0° C. The reaction mixture was stirred at 0° C. then warmed up to room temperature. LC-MS showed that the desired product formed. The reaction mixture was then diluted with ethyl acetate, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give the crude product.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([NH:17][C:18]([CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[C:31]1([CH3:34])[CH:32]=[CH:33][C:28]([S:25]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:18]([NH:17][C@H:4]([C:3]([OH:35])=[O:2])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:8][CH:7]=2)=[O:19])(=[O:26])=[O:27])=[CH:29][CH:30]=1
Reactant: COC(=O)C(Cc1ccc(NS(C)(=O)=O)cc1)NC(=O)C1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(NS(C)(=O)=O)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a solution of 3-(4-methanesulfonylamino-phenyl)-2-{[1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonyl]-amino}-propionic acid methyl ester (0.250 g, 0.477 mmol) in THF (1.0 mL) was added 1H LiOH (955 mL, 0.955 mmol) and the clear solution was stirred at 25° C., under nitrogen, for 16 h. The reaction solution was then diluted with additional water (50 mL) and washed with diethyl ether (25 mL). The aqueous layer was lyophilized to afford a fluffy white solid (0.216 g, 87%). MS (=ESI): 508 [M−1]−
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.O>ClCCl>[OH:6][CH2:7][C:8]1([CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CO)(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
Methanesulfonyl chloride (44 μL, 0.56 mmol) in dichloromethane (10 mL) was added slowly to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4,4-bis(hydroxymethyl)-1-piperidinecarboxylate (Description 67, 140 mg, 0.56 mmol) and triethylamine (95 μL, 0.68 mmol) in dichloromethane (50 mL). The mixture was allowed to warm to room temperature and stirred for 16 hours. Water (10 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×40 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80:20 increasing to 0:100), to give the title compound (98 mg, 54%). m/z (ES+) 324 (M+1).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:9]([CH3:18])=[C:10]([CH:14]=[C:15]([F:17])[CH:16]=1)[C:11]([OH:13])=[O:12].IC>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[C:9]([CH3:18])=[C:10]([CH:14]=[C:15]([F:17])[CH:16]=1)[C:11]([O:13][CH3:1])=[O:12]
Reactant: Cc1c(Br)cc(F)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
K2CO3 (1.2 eq.) was added to a solution of (E3) in DMF (0.26 M) and the resulting suspension was stirred at RT for 30 min. Then, iodomethane (1.2 eq.) was added and the reaction mixture was stirred at RT overnight. The solution was diluted in EtOAc and the organic phase was washed with brine and dried (Na2SO4). Solvent was removed in vacuo giving a residue that was purified by flash chromatography column on silica (EtOAc/Petroleum ether 1:49) yielding (31% over 4 steps) the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 7.74 (1H, dd, J=8.4 and 2.8 Hz), 7.60 (1H, dd, J=7.3 and 2.5 Hz), 3.95 (3H, s), 2.59 (3H, s).
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][N:23]=1.C.IC>O>[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[N:32]([CH3:2])[N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CI
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: -5 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (19.87 mL, 132.90 mmol) was added to a suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (48 g, 102.23 mmol) in 2-methylTHF (300 mL). A dark solution was obtained after 5 minutes which was treated with charcoal and filtered through a celite pad, washing the charcoal and charcoal with additional 2-methylTHF (100 mL). The filtrate was stirred with an air stirrer at −5° C. in a 3 L jacketed fixed vessel under an atmosphere of nitrogen. 2-methylTHF (100 mL) was added to help stir the yellow suspension. Iodomethane (7.96 mL, 127.78 mmol) was added dropwise over 15 minutes. The mixture was stirred for 2 hours and the reaction mixture was warmed to room temperature. After 16 hours, additional iodomethane (6 mL) and DBU (20 mL) was added and stirring was continued for 16 hours. The mixture was poured into water and stirred for 5 minutes. The insoluble material was isolated as a beige solid and dried in vacuo to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (24.77 g, 50.1%). The mother liquors were concentrated under reduced pressure and the residue was purified by flash column chromatography on silica using MTBE as the eluant. A second crop of the desired product (13.04 g, 26%), was thus obtained as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.47 (9H, s), 1.51 (9H, s), 1.57-1.76 (2H, m), 1.94-2.1 (2H, m), 2.87-3.09 (3H, m), 3.9-4.08 (2H, m), 4.26 (3H, s), 7.97 (2H, br, s), 8.92 (1H, s); Mass Spectrum [M+H]+=484
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4](CC2C=CC(OC)=CC=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:53][C:54]1([CH3:61])[O:58][C@H:57]([CH2:59][OH:60])[CH2:56][O:55]1.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:53][C:54]1([CH3:61])[O:58][C@H:57]([CH2:59][O:60][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:9]=3[N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[NH:4][N:3]=2)[CH2:56][O:55]1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(OC[C@@H]4COC(C)(C)O4)c23)CC1
Yield: 114.5 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.15 g, 0.24 mmol, see Example 9), Cu(I)I (0.046 g, 0.24 mmol), 1,10-phenanthroline (0.043 g, 0.24 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.95 g, 7.2 mmol) and KF on Al2O3 (40%; 0.24 g, 1.68 mmol) in toluene (4 mL) was stirred at 110° C. for 60 hours. Ethyl acetate (10 mL) was then added, and the reaction mixture was filtered through a pad of celite. The reaction was then concentrated to dryness, and the residue was purified by column chromatography (hexane:ethyl acetate=1:1) to give (R)-tert-butyl 4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.14 g, 93%) as a solid. MS APCI (+) m/z 630.2 detected.
Reaction SMILES: [NH2:1][C:2](=[C:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[NH:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:21](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH3:15][N:13]1[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[N:9]2[CH:21]=[N:1][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:14]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(N)=C1CN(C)C(=O)c2ccccc2N1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
1.10 g of ethyl α-amino-1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene-acetate are dissolved in 15 ml of toluene and treated with 1.0 ml of triethyl orthoformate. The mixture is heated to reflux for 50 minutes, subsequently cooled and evaporated in vacuo. The crystalline residue is suspended in 25 ml of ethyl acetate, filtered off and dried. There is obtained ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 165° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[Cl:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]([C:21]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (0.24 g, 1.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.21 g, 1.3 mmol) according to the general procedure IVb. Obtained as a light yellow solid (0.23 g, 73%). MS (ISP) 316.1 [(M+H)+]; mp 175° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:20]2[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2ccccc2c1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C
Yield: 84.1 %

Procedure:
To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used without further purification.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[CH2:5]([OH:9])[CH:6]([CH3:8])[CH3:7]>>[C:2]([O:9][CH2:5][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)CO
Reactant: C=C(C)C
Product: CC(C)COC(C)(C)C

Procedure:
In the etherification stage, isobutene is reacted with alcohols, preferably with isobutanol, over an acid catalyst, preferably an acid ion exchanger, to form ethers, preferably isobutyl tert-butyl ether. In one embodiment of the invention, the reaction is carried out in a three-stage reactor cascade in which the reaction mixture flows from the top downward through flooded fixed-bed catalysts. In the first reactor, the inlet temperature is from 0 to 60° C., preferably from 10 to 50° C.; the outlet temperature is from 25 to 85° C., preferably from 35 to 75° C., and the pressure is from 2 to 50 bar, preferably from 3 to 20 bar. At a ratio of isobutanol to isobutene of from 0.8 to 2.0, preferably from 1.0 to 1.5, the conversion is from 70 to 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[N:37]1[CH:42]=[CH:41][C:40](NC)=[CH:39][CH:38]=1.[C:45](P(=O)(OCC)OCC)#[N:46]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:46][CH2:45][C:40]3[CH:39]=[CH:38][N:37]=[CH:42][CH:41]=3)=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CNc1ccncc1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCc4ccncc4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and pyridin-4-yl-methylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 599.15 (M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[C:15]2[C:20]([OH:22])=[O:21])([O-:9])=[O:8].IC.O>CN(C)C=O>[N+:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[C:15]2[C:20]([O:22][CH3:1])=[O:21])([O-:9])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1nccc2c([N+](=O)[O-])cccc12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nccc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.4 %

Procedure:
Potassium carbonate (23 g, 167 mmol) was added to a solution of 5-nitro-isoquinoline-1-carboxylic acid (Description 104, 2.7 g, 12.4 mmol) in N,N-dimethylformamide (50 ml) at room temperature. Iodomethane (1.0 ml, 16.1 mmol) was then added and the reaction stirred at room temperature for 20 h. Water (300 ml) was added and the mixture was extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with water (2×100 ml), brine (100 ml) then dried (Na2SO4) and evaporated. Purification of the residue by column chromatography eluting with ethyl acetate-isohexane (7:13 increasing to 1:1) gave the title compound (558 mg, 19%).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[C:9]([Mg]Br)#[CH:10]>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]#[CH:10])[OH:8])[N:6]=1
Reactant: O=Cc1csc(Br)n1
Reactant: C#C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CC(O)c1csc(Br)n1

Procedure:
Using the procedure of Example 1, 2-bromo-4-thiazole carboxaldehyde and ethynyl magnesium bromide were reacted to obtain the desired product with a Rf=0.17 [hexane-ethyl acetate (7-3)].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:29][OH:30])[N:4]=1.C(N(C(C)C)CC)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[N:4]=1)(=[O:43])=[O:42]
Reactant: COCCOCCOCCN(CCOc1cc(CO)nc(CO)c1)CCC(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCCOCCN(CCOc1cc(COS(C)(=O)=O)nc(COS(C)(=O)=O)c1)CCC(=O)OC
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of 80 mg of methyl 3-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate in 8 ml of DCM, precooled to −25° C., was added 183 μl of diisopropylethylamine and 57 μl of methanesulfonyl chloride. The mixture was stirred for 1 hour at −15° C. and then washed with 5 ml of water. The aqueous phase was extracted with 5 ml of DCM. The organic phases were combined, dried over MgSO4 and concentrated under reduced pressure. 110 mg of methyl 3-([2-(2,6-bis-methanesulfonyloxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate were obtained. LC/MS (B): tr=2.67 min; [M+H]+: m/z 587
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[C:17](=[O:20])([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:4]2[CH2:3][CH2:2][CH2:7][CH2:17][O:20]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCCCCCl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 134.9 %

Procedure:
A mixture consisting of 4-bromophenol (20.75 g), 6-chloro-1-hexanol (20.50 g), potassium carbonate (33.20 g) and potassium iodide (21.9 g) in dimethylsulfoxide was stirred for 6 hours at 80° C. The reaction mixture was cooled and poured into 500 ml of water and extracted with 2×500 ml of ethyl acetate. The combined organic extracts were washed with saturated NaCl solution (3×100 ml) dried over magnesium sulfate and evaporated to dryness. This gave 37.4 g of a slightly beige oil of which 24.9 g were dissolved in 250 ml of dichloromethane containing 8.05 g of 3.4-didydro-2H-pyran. The resulting solution was cooled to 5° C. A solution of bis-trimethylsilyl sulfate (0.38 g) in 10 ml of dichloromethane was then added dropwise to the reaction mixture. The resulting mixture was stirred for two hours at 5° C. Triethylamine (4 ml) was added to the reaction mixture and stirring was continued for one hour at room temperature. The reaction mixture was then poured into 300 ml of water and extracted with dichloromethane (2×300 ml). The combined organic extracts were dried over magnesium sulfate and evaporated to dryness to give 33.95 g of a slightly beige residue, which was then filtered through a silica gel column using a cyclohexane/ethyl acetate (8/2) as eluent to give 28.9 g of 4-bromo-1-[6-(tetrahydropyran-2-yloxy)hexyloxy]benzene as colourless oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1C(O)=O.N[C@H](C(O)=O)C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:1]2[C:2]3=[N:1][CH:2]=[CH:3][CH:4]=[C:3]3[CH2:4][C:5]2=[O:6])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: O=C1Cc2cccnc2N1c1ccccc1
Yield: 55 %

Procedure:
The compound was prepared as described by Ting, Kaminski, et al., in "Substituted 1,3-Dihydro-2H-pyrrolo[2,3-b]pyridin-2-ones as Potential Antiinflammatory Agents", J. Med. Chem., 1990, 33, 2697-2706 in 55% yield; mp 116.0°-117.0° C.; IR(KBr): 1727 cm-1 (CO); 1H NMR(CDCl3TMS): d 3.73 (s, 2H, CH2 --CO), [7.00 (dd, 1H), 7.39 (dd, 1H), 8.18 (d, 1H), 2,3-subs. Pyr], 7.51 (m, 5H, Phe); mass spec m/e 211 (M+1); Anal calcd for C13H10N2O, MW 210.24: C, 74.27; H, 4.79; N, 13.33. Found: C, 74.11; 4.73; N, 12.92.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1Cl.[F:22][C:23]([F:31])([F:30])[CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([C:23]([F:31])([F:30])[F:22])[CH2:25]1
Reactant: FC(F)(F)C1CCCNC1
Reactant: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(3,3,3-trifluoro-propyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (80 mg, 0.246 mmol), 3-trifluormethyl-piperidine (150 mg, 0.98 mmol), DIPEA (0.34 mL, 2.0 mmol) and dioxane (5 mL).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[C:22]([C:23]=2[CH:24]=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:15]2[N:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[C:22]([C:23]=2[CH:24]=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1c(N2CCCNCC2)n(-c2ccccc2)c2ccccc12
Yield: 86 %

Procedure:
4-(3-Formyl-1-phenyl-1H-indole-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.06 g, 2.53 mmol) and trifluoroacetic acid (10 mL) in dichloromethane (4 mL) is stirred overnight at room temperature. The solvent is evaporated off and the residue dissolved in dichloromethane (10 mL), washed with 5% aq sodium carbonate, with water, with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with dichloromethane-5 to 10% methanol. Product containing fraction are combined and concentrated to afford 2-[1,4]diazepan-1-yl-1-phenyl-1H-indole-3-carboxaldehyde (86% yield) as a white solid. LC/MS: MS 320 (M+H); 2.5 min; NMR (CDCl3) 10.30 (1H, s), 8.25 (1H, d), 7.03-7.70 (7H, m), 6.97 (1H, d), 3.20-3.46 (4H, m), 2.84 (4H, m) 1.62(2H, m).