Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30]CC)=[O:29].O>C(=O)(OCC)OCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:27][C:28]([OH:30])=[O:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CC(=O)O)N=C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a nitrogen atmosphere, 4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (1 g) was dissolved in diethyl carbonate (35 ml) and 60% sodium hydride was added thereto at room temperature with stirring. After refluxing under heating for 2 hours, the reaction mixture was cooled to room temperature and ethyl bromoacetate (0.32 ml) was added thereto. After stirring at room temperature for 3 hours, the reaction mixture was poured into cold water and extraceted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the objective fraction was concentrated under reduced pressure. The residue concentrated was suspended in a mixture of ethanol (90 ml) and water (30 ml). To the suspension was added barium hydroxide 8 hydrate (0.65 g) at room temperature with stirring and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with 6N hydrochloric acid and allowed to stand at room temperature overnight. The reaction mixture was neutralized with sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and isopropyl ether was added for crystallization. As a result, 0.15 g of (4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (0.15 g) was obtained as pale brown crystals, melting point 198°-202° C.
Reaction SMILES: C1(C)C=CC=CC=1.CN(C)C(=O)C.[CH2:14]([C:18]1[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:40]=[N:41][N:42]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:43]=3)=[CH:29][CH:28]=2)[C:20]([CH2:24][OH:25])=[C:21]([Cl:23])[N:22]=1)[CH2:15][CH2:16][CH3:17].C(OCC)(=O)C>C(O)C>[CH2:14]([C:18]1[N:19]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:40]=[N:41][N:42]([C:44]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:43]=3)=[CH:31][CH:32]=2)[C:20]([CH:24]=[O:25])=[C:21]([Cl:23])[N:22]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1

Procedure:
A mixture of 5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-2triphenylmethyl-2H-tetrazole (0.102 m=63.1 g), 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.113 m=21.1 g) and anhydrous potassium carbonate (0.135 m=18.6 g) in 251 g of N,N-dimethylacetamide was stirred at 0°-5° C. for 8 hours and the temperature of the reaction was raised to 25° C. for an additional 4 hours. Normally the product of this step was not isolated but reduced with sodium borohydride to give 2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-methanol. The title compound can be isolated by extraction into toluene from aqueous N,N-dimethylacetamide, concentration of the toluene solution, and crystallization from ethyl acetate or ethanol, mp 145°-147° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[H-].[Na+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27](=O)[CH3:28]>CN(C=O)C.O>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]=[C:27]([C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])[CH3:28]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: CCOP(=O)(Cc1ccccc1Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccccc1Cl)c1ccc(F)cc1F
Temperature: 3 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
At 3° C., a solution of diethyl 2-chlorobenzylphosphonate (2.00 g, 7.61 mmol) in dry DMF (30 ml) was added to a stirred suspension of sodium hydride (60% by weight suspension in mineral oil, 365 mg, 9.13 mmol; freshly washed with dry heptane) in dry DMF (20 ml). After 1 h of stirring at 3° C., a solution of 2′,4′-difluoroacetophenone (1.31 g, 8.37 mmol) in dry DMF (20 ml) was added dropwise. The resulting mixture was stirred at RT for 68 h and then diluted with water and extracted with diethyl ether. The organic phase was dried and concentrated to dryness under reduced pressure, and the residue was purified by chromatography on silica gel, which gave 1-[1-(2-chlorophenyl)prop-1-en-2-yl]-2,4-difluorobenzene as a 93/7 mixture of diastereoisomers [colourless solid, 560 mg, yield 26%; GC/MS: m/z=264 (M+); HPLC/MS: log P(HCOOH)=5.05 (major diastereoisomer), 5.34 (minor diastereoisomer)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)(=[O:13])=[O:12].[CH2:23](O)[CH2:24][CH2:25][OH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:22][CH2:23][CH2:24][CH2:25][OH:26])(=[O:12])=[O:13]
Reactant: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(O)c2)c1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(OCCCO)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 500 mg (1.54 mmol) of 3-(2,5-dimethoxyphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 1.1 mL (15 mmol) of 1,3-propanediol and 808 mg (3.08 mmol) of triphenylphosphine in 12 mL of anhydrous tetrahydrofuran was added 485 mg (3.08 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 1 h, the reaction mixture was concentrated to a yellow syrup. The resulting mixture was flash chromatographed on 40 g of silica gel with 50-75% ethyl acetate-hexane to afford a mixture of the desired product and triphenylphosphine oxide. Chromatography on 35 g of silica gel with 4% acetone-dichloromethane afforded 483 mg (82% yield) of the title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 7.34 (d, 1 H, J=3.1 Hz), 7.15 (dd, 1 H, J=9.1, 3.1 Hz), 7.03 (d, 1 H, J=9.1 Hz), 6.59 (m, 1 H), 6.53 (m, 1 H), 6.48 (t, 1 H, J=2.1 Hz), 4.01 (t, 2 H, J=6.0 Hz), 3.97 (s, 3 H), 3.81 (dd, 2 H, J=11.2, 5.8 Hz), 3.76 (s, 3 H), 2.25 (s, 3 H) and 1.98 (pentet, 2 H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([OH:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1>CC(C)CO>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:6][CH:7]([CH3:12])[CH3:8])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2O)cc1
Solvent: CC(C)CO
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCC(C)C)cc1

Procedure:
The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted with 2-methyl-1-propanol to provide 2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the method of Example 90D.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([NH2:14])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:14][CH2:12][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a solution of 2.2 g of 1-benzylisonipecotamide in 50 ml of tetrahydrofuran was added 1.58 g of lithium aluminum hydride at 0° C. and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was cooled to 0° C. After adding water and a 10% aqueous solution of sodium hydroxide, the insoluble matters were filtered off. After distilling off the solvent under reduced pressure, 2.0 g of the title compound was obtained as a brown oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[O:26])[NH:13][NH:14][C:15](=[N:18]C(OC(C)(C)C)=O)[S:16][CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[CH2:1]([O:8][C:9]([NH:11][C:12](=[O:26])[NH:13][NH:14][C:15](=[NH:18])[S:16][CH3:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC(=NC(=O)OC(C)(C)C)NNC(=O)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSC(=N)NNC(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.7 %

Procedure:
Compound 35 (401 mg, 1.0 mmol) was treated with TFA (1.0 mL) and was stirred for 30 min at room temperature, evaporated to dryness and dried under reduced pressure for 2 h, triturated with anhydrous Et2O to give 400 mg of 13 as a solid. This crude product was carried on without further purification. 1H NMR (300 MHz, CD3OD): δ2.64 (3H, m); 5.21 (2H, m) 7.31 (5H, m) ppm. IR (NaCl, CH2Cl2): 3252, 2959, 1790, 1682, 1203, 1137, 1025, 778, 722 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1>>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])=[N:25]1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Cn1ccc(N)n1
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccn(C)n1
Yield: 62.5 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmol) and 1-methyl-1H-pyrazol-3-amine (421 mg, 4.33 mmol) following the experimental procedure described in Preparation 27a. 680 mg (36% yield) of the desired compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[NH2:8]>C(OC(=O)CCC)(=O)CCC>[CH3:16][N:4]1[C:3](=[O:17])[C:2]2[NH:1][C:14]([CH2:9][CH2:10][CH3:11])=[N:8][C:7]=2[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:15]
Reactant: Cn1c(=O)c(N)c(N)n(-c2ccccc2)c1=O
Agent: CCCC(=O)OC(=O)CCC
Product: CCCc1nc2c([nH]1)c(=O)n(C)c(=O)n2-c1ccccc1

Procedure:
A solution of 3 g of 5,6-diamino-3-methyl-1-phenyl-2,4-(1H, 3H)-pyrimidinedione XVIII in 25 ml of butyric anhydride was refluxed for 16 hours. After cooling, grey crystals were filtered off and recrystallized from 100 ml of ethanol. Yield 1.1 g NMR.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[CH3:10][C:11]1[C:12]([NH2:18])=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:18][C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: Cc1cccc(N)c1N
Product: Cc1cscc1NC(=S)Nc1cccc(C)c1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3-methyl-1,2-diaminobenzene. Crystalline solid, m.p. 184-186° C.,
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=CN=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[N:24]=C2NC=C(C(=O)C)C2=CC=1>>[C:1]([C:4]1[C:12]2[C:7](=[N:24][C:19]([O:18][CH3:17])=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(C(C)=O)c[nH]c2n1
Reactant: CC(=O)c1cn(CC(=O)O)c2cnccc12
Product: COc1ccc2c(C(C)=O)cn(CC(=O)O)c2n1

Procedure:
was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3-c]pyridin-1-yl)-acetic acid in Scheme A15 from 1-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone. MS (UPLC/MS): 249.2 [M+H]+, 497.3 [2M+H]+, 519.3 [2M+Na]+, 247.1 [M−H]−, 293.2 [M+HCOO]−, 495.3 [2M+HCOO]−; tR (HPLC conditions f): 1.55 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 12.3 (bs, 1H), 8.33 (d, 1H), 8.21 (s, 1H), 6.70 (d, 1H), 3.89 (s, 3H), 3.32 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH2:12]([N:6]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)n1Cc1ccccc1

Procedure:
Ethyl 5-methyl-1H-pyrrole-2-carboxylate (1.1 g) and benzyl bromide (1.35 g) in N,N-dimethylformamide (30 mL) was treated with NaH (95%, 0.5 g) overnight. The reaction was quenched with ice water. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: C(=C(O)[C@@H](O)[C@@H](O)[C@@H](O)C=[O:9])(C)C.N1C=CC=CC=1.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[OH:9])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)=C(O)[C@@H](O)[C@@H](O)[C@@H](O)C=O
Solvent: c1ccncc1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3.0 g (15.8 mmoles) of isopropylidene-ribose in 50 ml of absolute pyridine 4.4 g (15.8 mmoles) of trityl chloride are added and the mixture is stirred in a closed flask for 3 days at room temperature. The yellow-brown solution produced is poured into approximately 1 l of ice water. The brown sirup which separates is decanted off and is thoroughly mixed several times with water. Following this this sirup is dissolved in 50 ml of CHCl3 and washed twice with KHSO4 -solution and 3 times with water. After drying over sodium sulfate the solvent is abstracted. A light brown sirup containing crystals remains. By crystallisation from methanol it is possible to obtain 1 g of triphenylcarbinol.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]([C:33]2[C:37](=[O:38])[N:36]([CH3:39])[C:35](=[O:40])[C:34]=2[C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43](C(OC(C)(C)C)=O)[CH:42]=2)=[CH:25]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)=O>[NH:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41]([C:34]2[C:35](=[O:40])[N:36]([CH3:39])[C:37](=[O:38])[C:33]=2[C:26]2[C:27]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[N:24]([C@@H:6]3[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]3[O:4][C:1](=[O:3])[CH3:2])[CH:25]=2)=[CH:42]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C3=C(c4cn(C(=O)OC(C)(C)C)c5ccccc45)C(=O)N(C)C3=O)c3cccnc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C3=C(c4c[nH]c5ccccc45)C(=O)N(C)C3=O)c3cccnc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound of Example 16a (0.114 mmol) is dissolved in 20 ml of formic acid. After stirring for 24 hours at ambient temperature, the solution is neutralised by adding, dropwise, triethylamine, and then saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and are then dried over magnesium sulphate and filtered; the solvent is evaporated off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 1/1), the expected product is isolated.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([NH:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[N:13]=[CH:12][CH:11]=2)(=O)=O.[CH3:24][O:25][C:26]1[CH:32]=[C:31]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)[CH:30]=[CH:29][C:27]=1[NH2:28]>>[CH:19]1([CH2:18][NH:17][C:14]2[C:15]3[C:10](=[CH:9][N:8]=[C:7]([NH:28][C:27]4[CH:29]=[CH:30][C:31]([C:33]5[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=5)=[CH:32][C:26]=4[O:25][CH3:24])[CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:21][CH2:20]1
Reactant: COc1cc(-c2cnn(C)c2)ccc1N
Reactant: O=S(=O)(Oc1cc2c(NCC3CC3)nccc2cn1)C(F)(F)F
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1cc2c(NCC3CC3)nccc2cn1

Procedure:
The title compound was prepared according to Method 6 (Example 103) using 5-((cyclopropylmethyl)amino)-2,6-naphthyridin-3-yl trifluoromethanesulfonate (Preparation 96) and 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19) for 3 hours. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.96 min; [M+H]+=476.03.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH:37]1[CH2:42][CH2:41][CH:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1>C1COCC1>[CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.[C:49]([N:46]1[CH2:45][CH2:44][CH:43]([CH:40]2[CH2:39][CH2:38][N:37]([C:9]([NH2:11])=[O:8])[CH2:42][CH2:41]2)[CH2:48][CH2:47]1)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(C(N)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 121.1 %

Procedure:
To a solution of CBz-D-phenylglycine (877 mg, 3.1 mmol) in anhydrous THF (40 ml) at −25° C. was added N-methylmorpholine (336 μl, 3.1 mmol) and isobutyl chloroformate (419 μl, 3.1 mmol). The resulting suspension was left to stir for 5 min at this temperature and then the t-Butyl 4-(piperidin-4-yl)piperidine-1-carboxylate (825 mg, 3.1 mmol) in anhydrous THF (5 ml) was added in one portion at −25° C. and the reaction mixture allowed to warm to room temperature over 1 hour. The N-methylmorpholine hydrochloride was filtered off and the THF removed under vacuo. The resulting solid was treated with TFA/DCM (20 ml, 1:1) and the reaction mixture left to stir for 2 hours. The organics were removed under vacuo, the residue dissolved in ethyl acetate (100 ml), washed with aq. sodium bicarbonate solution, brine, dried and concentrated to yield the title compound as a clear oil (1.12 g, 84% over two steps).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]([NH:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:31])[CH3:30].[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[C:29]([NH:32][C:33]1[CH:38]=[C:37]([C:27]2[C:21]3[S:20][C:19]([C:17]([NH:16][C@@H:10]4[CH:11]5[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]5)[CH2:9]4)=[O:18])=[CH:23][C:22]=3[CH:24]=[CH:25][CH:26]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 80 °C

Procedure:
0.75 ml of 2 M aqueous sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 89.1 mg (0.50 mmol) of 3-(acetamido)phenylboronic acid in 2 ml of DMF. The reaction mixture is heated at 80° C. for 17 h. A further 89.1 mg (0.50 mmol) of 3-(acetamido)phenylboronic acid, 1.5 ml of 1N sodium hydroxide solution and 81.3 mg (0.1 mmol) of PdCl2(dppf) are added, and the mixture is heated at 86° C. for a further 18 h. After cooling, it is filtered through kieselguhr and purified by preparative HPLC. The resulting crude product is further purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol/ammonia 100:10:2). The product fractions are concentrated, taken up in a 5:1-mixture of methanol and 1N hydrochloric acid and again concentrated. Drying under high vacuum results in 243.2 mg (86.6% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:28][CH2:29][O:30][CH3:31].[ClH:32]>>[ClH:32].[CH3:31][O:30][CH2:29][CH2:28][N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COCCBr
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2ccncc2)cc1
Agent: Cl
Product: COCCN(c1ccccc1/C=C/c1ccncc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Using 1.00 g of the compound obtained in Example 3A and 1-bromo-2-methoxyethane, the reaction and after-treatment procedure of Example 9 was otherwise carried out and the product was converted to the hydrochloride. By this procedure, 0.45 g of the title compound (amorphous) was obtained.