Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[S:10][C:9]([NH:11]C(=O)C3C=CC=CC=3)=[N:8][C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[S:10][C:9]([NH2:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1nc2ncc(Cl)cc2s1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ncc(Cl)cc2s1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
N-(6-Chlorothiazolo[4,5-b]pyridin-2-yl)benzamide (364 mg, 1.256 mmol) in H2SO4 (4 ml, 75 mmol) was heated to 120° C. for 30 minutes, cooled to ambient temperature, basified with 10N NaOH and the resultant solids were collected by filtration to afford 6-chlorothiazolo[4,5-b]pyridin-2-amine (148 mg, 0.797 mmol, 63.5% yield) 1H NMR (500 MHz, DMSO-d6) δ ppm 8.19-8.24 (m, 2H) 8.09 (br. s., 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCOc2ccc(F)cc21
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2c(c1)C=CCO2
Yield: 58.3 %

Procedure:
6-Fluorochroman-4-ol (8 g, 48 mmol) and toluene-4-sulphonic acidn (1 g) were dissolved in toluene and refluxed over-night with subsequent water removal. The mixture was then cooled and washed with NaHCO3 (aq) and purified by chromatography (silica gel, n-hexane) to give 4.2 g (52%) of pure 6-fluoro-2H-chromene.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.O.[NH2:13][NH2:14]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:13][NH2:14])=[O:2])=[CH:5][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(Br)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(Br)cc1
Yield: 67 %

Procedure:
First, 3.0 g (13.9 mmol) of methyl-4-bromobenzoate was put in a 100-mL three-neck flask, 10 mL of ethanol was added thereto, and the mixture was stirred. Thereafter, 4.0 mL of hydrazine monohydrate was added thereto, and the mixture was heated and stirred at 78° C. for 5 hours. The obtained solid was washed with water and collected by suction filtration; thus, 2.0 g of a white solid of 4-bromobenzohydrazide that was an object was obtained in the yield of 67%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([CH3:31])=[C:16]([O:22][C:23]4[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C1COCC1>[CH3:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:30])[C:23]=1[O:22][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[CH3:31])[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:21]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2cc1Oc1c(C)cccc1C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
A mixture of 1-[6-(2,6-dimethyl-phenoxy)-7-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.25 g, 0.60 mmol), 1M aq. KOH (5.0 mL) and THF (5.0 mL) was stirred for 4 h. The mixture was concentrated to remove the THF and the aqueous residue was acidified to pH 2 with 1M aq. HCl. The resulting precipitate was collected by filtration to provide the titled compound (0.22 g, 93%). MS (ESI): mass calcd. for C21H18N4O4, 390.1; m/z found, 391.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.99 (s, 1H), 12.72 (s, 1H), 8.90 (d, J=13.2 Hz, 1H), 8.22 (s, 1H), 7.68 (s, 1H), 7.25 (d, J=7.4 Hz, 2H), 7.18 (dd, J=8.3, 6.7 Hz, 1H), 6.78 (s, 1H), 2.55 (s, 3H), 2.07 (d, J=8.2 Hz, 6H).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.C([OH:26])(C1C=CC=CC=1)C1C=CC=CC=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C1C=CC=CC=1>[OH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([O:26][C:5]3=[O:12])[CH2:11]1)[CH2:9]2.[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2
Reactant: OC(c1ccccc1)c1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C1C2CC3CC1CC(O)(C3)C2
Solvent: N#Cc1ccccc1
Product: O=C1OC2CC3CC1CC(O)(C3)C2

Procedure:
A mixture of 100 mmol of 5-hydroxy-2-adamantanone, 200 mmol of benzhydrol, 10 mmol of N-hydroxyphthalimide, 0.1 mmol of cobalt(II) acetate, and 200 ml of benzonitrile was stirred at 75° C. in an oxygen atmosphere (1 atm) for 6 hours. A reaction mixture was concentrated and was then subjected to column chromatography on a silica gel to yield 1-hydroxy-4-oxatricyclo[4.3.1.13,8]undecan-5-one of the following formula in a yield of 48% with a conversion rate from 5-hydroxy-2-adamantanone of 67%.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:6]([CH3:8])=[CH2:7].[C:19]([CH2:21][NH:22][C:23](=[O:30])[C@@H:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:20].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CC(C)=O.CCOC(C)=O>C(Cl)Cl.CCOC(C)=O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:29][C@@H:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:23]([NH:22][CH2:21][C:19]#[N:20])=[O:30])[C:6]([CH3:8])=[CH2:7])=[CH:10][CH:11]=1
Reactant: C=C(C)C(OC(=N)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(C)C(O[C@@H](CC(C)C)C(=O)NCC#N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(4-bromophenyl)-2-methylprop-2-enyl 2,2,2-trichloroethanimidoate of step 2 (0.81 mmol, 300 mg) in CH2Cl2 (6 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from Step 1, Example 67 (0.81 mmol, 137 mg) and then PPTS (0.081 mmol, 20 mg). The mixture was stirred at r.t. for 72 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography (10% Acetone/EtOAc) gave 2 diastereomers (20 mg each).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH:18]([CH3:21])[CH:19]=[CH2:20]>CN(C)C=O.O.C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([O:1][CH:19]([CH3:20])[CH:18]=[CH2:21])=[CH:3][CH:4]=1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: C=CC(C)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(C)Oc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 45 °C
Yield: 60.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxybenzoate (5.0 g, 25.7 mmol) in N,N-dimethylformamide (35 ml) was treated with a solution of sodium hydroxide (1.14 g, 35.1 mmol) in water (2 mL). Then 3-chloro-1-butene (3.06 g, 33.8 mmol) was added and the resulting mixture was heated at 45° C. for 5 hours. The cooled mixture was diluted with toluene, washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution toluene-hexane, 1:1) gave 3.84 g (60%) of the title material as a clear oil.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([O:28][CH3:29])=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:35](=O)(O)[O-].[Na+].CI>O.CO>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[C:17]([S:34][CH3:35])=[N:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([O:28][CH3:29])=[O:27])[CH:21]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(SC)nc2=O)c1
Temperature: 40 °C

Procedure:
A mixture of the product from example 2 step (iv) (1 g), sodium bicarbonate (0.22 g) and methyl iodide (0.7 ml) in water (4 ml) and methanol (30 ml) was heated at 40° C. for 4 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Used directly in the next step.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=2)=[O:12])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: N=C(N)Nc1nc(C(=O)O)cs1
Agent: Cl
Product: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=N)N)n2)cc1

Procedure:
In the same manner as described in Example 3, from 2-guanidino-thiazole-4-carboxylic acid and ethyl 4-amino-phenyloxyacetate hydrochloride there is obtained ethyl {4-[(2-guanidino-thiazole-4-carbonyl)-amino]-phenoxy}-acetate, m.p. 206° C., MS: 364 (M+H)+.
Reaction SMILES: Cl.[C:2]1([NH:8][S:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][NH:18][CH2:19]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29]Br)C>>[C:2]1([NH:8][S:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([CH2:29][CH2:28][CH2:27][CH2:26][C:25]([OH:31])=[O:24])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCBr
Reactant: O=S(=O)(Nc1ccccc1)c1ccc2c(c1)CNCC2
Agent: Cl
Product: O=C(O)CCCCN1CCc2ccc(S(=O)(=O)Nc3ccccc3)cc2C1

Procedure:
7-(Phenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride was reacted with ethyl-5-bromovalerate under conditions analogous to those described in Example 5 and the resulting ethyl ester was hydrolysed according to the method described in Example 2(b) to give 5-(7-phenylsulphamoyl-1,2,3,4-tetrahydroisoquinolin-2-yl)valeric acid as a colourless microcrystalline solid. mpt. 176°-176.5° C. (acetonitrile/ethanol).
Reaction SMILES: ClC1N=C2C(N=CN2)=C(N2CCOCC2)N=1.ICC(C)C.Cl[C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][N:29]2[CH2:32][CH:33]([CH3:35])[CH3:34])=[C:25]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:24]=1.C(=O)([O-])[O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[C:45]=1C(C)(C)C>>[CH2:32]([N:29]1[CH:28]=[N:27][C:26]2[C:30]1=[N:31][C:23]([C:46]1[CH:45]=[C:44]([OH:43])[CH:49]=[CH:48][CH:47]=1)=[N:24][C:25]=2[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)c1c(OC(=O)[O-])cccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)CI
Agent: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Product: CC(C)Cn1cnc2c(N3CCOCC3)nc(-c3cccc(O)c3)nc21

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with 1-iodo-2-methylpropane via General Procedure C. 4-(2-Chloro-9-isobutyl-9H-purin-6-yl)morpholine was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 62.6 mg of 145 as a white solid. MS (Q1) 354.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]=O)[CH:3]=1.[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10]2[NH:12][C:13]3[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=3[N:19]=2)[CH:3]=1
Reactant: COc1nnc(Cl)cc1C=O
Reactant: Cc1cccc(N)c1N
Solvent: CN(C)C=O
Product: COc1nnc(Cl)cc1-c1nc2cccc(C)c2[nH]1
Temperature: 120 °C

Procedure:
6-Chloro-3-methoxypyridazine-4-carbaldehyde is dissolved in DMF, und 2,3-diaminotoluene is added. The reaction solution is heated at 120° C. in a microwave for 30 minutes. The crude product is purified on silica gel (eluent ethyl acetate in heptane). MS (ES+) m/z 275 (M+H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]([C:7]1[CH:16]=[C:15]([C:17](=[O:34])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:21]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:6])[CH3:5].C[O-].[Na+].[BH4-].[Na+]>CO>[ClH:1].[ClH:1].[CH3:6][C:4]([C:7]1[CH:16]=[C:15]([CH:17]([OH:34])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:21]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(C(=O)CCC2CCN(CCc3ccccc3)CC2)c2ccccc2n1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1cc(C(O)CCC2CCN(CCc3ccccc3)CC2)c2ccccc2n1
Yield: 167.3 %

Procedure:
The operation was as in Example 5, starting from 10 g of 1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-[1-(2-phenyl-ethyl)-4-piperidyl]-1-propanone dihydrochloride, 2.2 g of sodium methylate and 0.8 g of sodium borohydride in 250 ml of methanol. 8.4 g of 1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-[1-(2-phenyl-ethyl)-4-piperidyl]-1-propanol dihydrochloride (racemic), which melted at 190° C. were obtained.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[F:12].Cl.[OH2:15]>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[F:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH:2]=[O:15])[C:7]([OH:9])=[O:8]
Reactant: O
Reactant: O=C(O)c1ccc(C(Br)Br)c(F)c1
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: O=Cc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
AgNO3 (0.39 mol) in hot H2O (90 mL) is added dropwise to a solution of crude 4-dibromomethyl-3-fluorobenzoic acid (2, 0.19 mol) in ethanol (EtOH) (480 mL) at 50° C. over 10 min and then the mixture is stirred at the same temperature for 45 min. After cooling to room temperature, the mixture is poured into 1 N HCl (200 mL) and filtered off. The residue is washed with EtOH and the filtrate is concentrated to ca. 300 mL. The mixture is extracted twice with ethylacetate (EtOAc) and the combined organic layers are washed with brine, dried over MgSO4 and evaporated in vacuo. The crystals are collected by filtration and washed with ether/hexane (1:1) to give 3-fluoro-4-formyl benzoic acid (3).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[C:35]([O:39][C:40](=[O:45])[C@@H:41](O)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36].CO>C(OCC)(=O)C>[C:35]([O:39][C:40](=[O:45])[C@@H:41]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: CC[C@H](O)C(=O)OC(C)(C)C
Agent: COC(=O)C(O)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C

Procedure:
Following the procedure of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxy-butyric acid tert-butyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (S)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester as a yellow oil contaminated with triphenylphosphine oxide, no further purification was undertaken. LCMS: RT=4.05 min, [M+H]+=494
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)c(OC)c1
Yield: 55 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 55% of theory, C36H45N7O6 (671.8) Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1) ##EQU144##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]([NH:21]C(=O)OC(C)(C)C)([CH3:20])[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[C:16]([CH3:20])([NH2:21])[CH:17]([CH3:18])[CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Yield: 99 %

Procedure:
N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}-2,2-dimethylpropanamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), 2,2-Dimethyl-propionyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-1,2-dimethylpropyl}-2,2-dimethylpropanamide (0.039 g, 67%) as an oil. ES-LCMS m/z 643 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[N:13]=[C:14]([CH:17](O)[C:18]2[NH:19][C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[C:21]3[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:22]=23)[S:15][CH:16]=1.[C:39]([O:46][CH3:47])(=[O:45])[CH2:40][C:41]([O:43][CH3:44])=[O:42]>C1COCC1>[Cl:11][C:12]1[N:13]=[C:14]([CH:17]([C:18]2[NH:19][C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[C:21]3[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:22]=23)[CH:40]([C:39]([O:46][CH3:47])=[O:45])[C:41]([O:43][CH3:44])=[O:42])[S:15][CH:16]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O
Reactant: COC(=O)CC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12

Procedure:
NaHMDS solution (1M in THF, 7.13 mL, 7.13 mmol) was added slowly to a mixture of 7-((4-chlorothiazol-2-yl) (hydroxy)methyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Example 27, step 1) (1 g, 2.376 mmol), dimethyl malonate (0.819 mL, 7.13 mmol) and boron trifluoride THF complex (0.236 mL, 2.139 mmol) in THF (30 mL).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Br:14])=[CH:9][C:8]=1[F:15].CN([CH:19]=[O:20])C.C(OCC)(=O)C>CCOCC.C1COCC1.CCCCCC>[Br:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([CH:19]=[O:20])=[C:8]([F:15])[CH:9]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
n-Butyl lithium (3.6 ml, 7.7 mmol) was added drop wise to a solution of 1,4-dibromo-2,5-difluoro-benzene (2 g, 7.35 mmol) in dry ether at −78° C. under nitrogen atmosphere and the resulting mixture was stirred at −78° C. for 30 minutes. This was followed by the addition of DMF (0.85 ml, 11.03 mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2% ethyl acetate in hexane) to afford 600 mg of the product (37% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:6]1[CH:5]=[CH:4][N+:3]([O-:12])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: C[O-]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g (0.015 mol) of 2,3-dimethyl-4-nitropyridine 1-oxide in 50 ml of abs. methanol is treated with 0.883 g of sodium methylate, whereupon the mixture is stirred at room temperature under argon for 2 days. The reaction mixture is concentrated and the residue is extracted with methylene chloride and saturated sodium chloride solution. The methylene chloride phase is dried and evaporated. The residue, crystallized from methylene chloride/ ether, gives 4-methoxy-2,3-dimethylpyridine 1-oxide of melting point 80°-83°.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:12][S:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][S:13][C:14]1[CH:15]=[C:16]([C:17]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:18]=2)[CH:19]=[CH:20][N:21]=1
Reactant: CSc1cc(C#N)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
Methyl thiosalicylate (0.76 g, 4.5 mmol) and 2-methylthioisonicotinonitrile (0.34 g, 2.3 mmol) were dissolved in toluene (2.0 ml). Triethylamine (0.70 ml, 5.0 mmol) was added thereto and the mixture was refluxed for 6 hrs. The reaction mixture was cooled at room temperature and the precipitated crystals were collected and recrystallized from ethanol to give the titled compound (0.11 g, 17%) as white crystals.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12>C(Cl)(Cl)Cl.[C].[Pd]>[C:4]1(=[O:23])[N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: N#Cc1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Yield: 93.9 %

Procedure:
Catalytic reduction of a solution of 9 g of 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzonitrile in 300 ml of chloroform was carried out with 2 g of a 5% palladium-carbon as catalyst. The reaction mixture was filtered from the spent catalyst and the filtrate was concentrated under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to obtain 8.5 g of 4-[2-(4-phthalimidomethylphenyl)ethyl]benzonitrile; m.p. 194°-197° C.