Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17]([Cl:20])(=[O:19])[CH3:18]>>[ClH:20].[C:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Product: CC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Product: Cl
Yield: 60 %

Procedure:
3-Acetyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline hydrochloride was prepared from 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and acetyl chloride analogous to Example 63.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[O:21][CH2:22][CH2:23][CH2:24][OH:25])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[CH2:31]([O:33][C:34](=[O:44])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39](O)[CH:38]=1)[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:31]([O:33][C:34](=[O:44])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:20]2[CH:26]=[CH:27][CH:28]=[C:18]([C:3]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)([C:4]([F:6])([F:5])[F:7])[C:2]([F:29])([F:30])[F:1])[CH:19]=2)[CH:38]=1)[CH3:32]
Reactant: COc1ccc(COC(c2cccc(OCCCO)c2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CCOC(=O)CCc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccc(OCCCOc2cccc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
150 mg (0.3 mmol) of 3-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-propan-1-ol and 73 mg (0.38 mmol) of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (CAS 34708-60-6) in 4 mL of THF were treated with 117 mg (0.44 mmol) of triphenylphosphine. The solution was cooled to 0° C. and treated with 88 μL (0.44 mmol) of DIAD. The mixture was stirred at room temperature overnight, the solvent was evaporated and the crude mixture was purified by column chromatography on silica gel with a gradient of EtOAc/n-heptane 1:5 to 1:3 to yield 110 mg (52%) of 3-[3-(3-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-propoxy)-phenyl]-propionic acid ethyl ester as a colorless liquid, MS: 614 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18](=[O:23])(=[O:22])[NH:19][CH2:20][CH3:21])=[C:13]3[N:12]=[CH:11][C:10]=2[C:24](OCC)=[O:25])=[C:4]([CH3:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[CH2:20]([NH:19][S:18]([C:17]1[CH:16]=[N:15][N:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:29])=[C:10]([C:24]([N:40]3[CH2:41][CH2:42][CH:37]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=4)[CH2:38][CH2:39]3)=[O:25])[CH:11]=[N:12][C:13]=12)(=[O:22])=[O:23])[CH3:21]
Reactant: CCNS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3C)c(C(=O)OCC)cnc12
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CCNS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 6.6 %

Procedure:
Using ethyl 7-(4-chloro-2-methylphenylamino)-3-(N-ethylsulfamoyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.33 g, 0.77 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.26 g, 1.44 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.029 g, 6%) was obtained.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=2[OH:19])=[O:18])=[CH:16][CH:15]=1
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)cc1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(Cl)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 69 %

Procedure:
3-[(4-Chlorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 51-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (69% yield); mp 165° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.10 (3H, s, NCH3), 3.72 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.84 (2H, s, NCH2), 7.25–7.34 (4H, m, aromatics). Anal. calcd for C14H15ClN2O4: C, 54.11; H, 4.87; N, 9.02. Found: C, 53.88; H, 4.71; N, 8.78.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:45]>C1COCC1.C1OCCOCCOCCOCCOC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)([O:14][CH3:45])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Reactant: CI
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Reaction time: 20 h
Yield: 68.7 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.31 mmol) in THF (50 mL) was added NaH (112 mg, 2.80 mmol, 60% dispersion in mineral oil) and the resulting mixture allowed to stir for 5 min before the addition of iodomethane (175 μL, 2.80 mmol) and 15-Crown-5 (5 drops). The resulting mixture was stirred for 20 h quenched with H2O and extracted with 2-methyl THF. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 40-80%) affording 4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (915 mg, 69%). LCMS (method H): RT 3.40 min [M+H]+ 577.5
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[N:12]1[CH:11]=[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]2=[N:1]1
Reactant: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1-n1cc2cncc(F)c2n1
Yield: 62.5 %

Procedure:
A solution of [1-(4-azido-5-fluoropyridin-3-yl)meth-(E)-ylidene]-(2-chloro-6-fluorophenyl)amine (˜60 mmol) in toluene (250 mL) was heated under reflux for 3 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was collected by filtration and dried to afford the title compound as an off-white solid (9.96 g, 63% yield over two steps). 1H NMR (400 MHz, DMSO-d6): δ 9.32 (d, J=2.7 Hz, 1H), 9.20 (d, J=2.6 Hz, 1H), 8.29 (d, J=3.8 Hz, 1H), 7.81-7.74 (m, 1H), 7.72-7.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Product: COCCCNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
4-Chloro-2-fluoro-1-nitrobenzene (2.85 mmol, 0.500 g) was added to an oven dried 25 mL round-bottomed flask equipped for stirring under nitrogen. DMF (5 mL) was added and the resultant solution was cooled to 0° C. with an ice-bath. 3-Methoxypropan-1-amine (2.99 mmol, 0.306 mL) was then added drop-wise via syringe and the resultant solution was stirred at 0° C. for 1 hr. The ice-bath was removed and the reaction was allowed to warm to room temperature and stir for 16 hr. The reaction solution was then poured into water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered; filtrate was collected, concentrated, and dried in-vacuo affording 5-chloro-N-(3-methoxypropyl)-2-nitroaniline (32A) as an orange oil. This material was used directly in the next step without further purification. ESI-MS: m/z 245.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[CH:22]=[CH2:23].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:18])[C:15]([O:17][CH2:23][CH:22]=[CH2:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCBr
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(I)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A solution of N-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, 0.075 mmol) in dichloromethane (2 mL) was treated with allyl bromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 23 mg of a clear oil. MS calculated for C16H17F3INO2+H: 440, observed: 440.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10]([CH3:12])=[CH2:11])[CH2:6][CH:5]=1.O>CN(C)C.C(Cl)Cl>[C:10]([CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)([CH3:12])=[CH2:11]
Reactant: C=C(C)C1CC=C(O[Si](C)(C)C)CC1
Agent: CN(C)C
Solvent: O
Solvent: ClCCl
Product: C=C(C)C1CCC(=O)CC1
Reaction time: 2 h

Procedure:
4.1 g of a 37% strength solution of HF in trimethylamine were added dropwise with stirring at room temperature to 8.0 g (0.038 mol) of 1-trimethylsilyloxy-4-isopropenyl-1-cyclohexene in 100 ml of CH2Cl2, and the mixture was subsequently stirred for 2 hours. Water was added, extraction was carried out with CH2Cl21 and the combined organic phases were dried and concentrated. 4.7 g (90% of theory) were obtained of a colorless oil which was reacted without further purification.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH2:38])[C:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH:38][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:11])=[O:12])[C:28]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)([CH3:30])[CH3:29]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)C(C)(C)c1ccc(Cl)cc1
Product: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(C)(C)c1ccc(Cl)cc1
Yield: 90 %

Procedure:
The title compound (61 mg, 90%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (EXAMPLE 101, Part D) and (S)-2-amino-3-(4-chloro-phenyl)-3-methyl-butyric acid methyl ester (EXAMPLE 107, Part F) as in Example 94, Part A. 1H NMR (500 MHz, CDCl3): 11.26 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.21 (dd, J=8.8, 1.0, 1H), 8.07 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.35-7.25 (m, 5H), 6.89 (d, J=8.3, 1H), 6.32 (br d, J=9.2, 1H), 4.97 (d, J=9.0, 1H), 3.64 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][S:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([C:28](OC)=[O:29])=[C:25]([N:32]=[CH:33]N(C)C)[CH:24]=2)=[CH:19][CH:18]=1.C1(O)C=CC=CC=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:27][C:26]3[C:28](=[O:29])[N:11]([C:10]4[CH:9]=[CH:8][C:7]([S:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])=[CH:13][CH:12]=4)[CH:33]=[N:32][C:25]=3[CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CCN(CC)CCSc1ccc(N)cc1
Solvent: Oc1ccccc1
Product: CCN(CC)CCSc1ccc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 190 °C
Reaction time: 8 h

Procedure:
The mixture of 4-{[2-(diethylamino)ethyl]sulfanyl}aniline (1.0 mmol, 271 mg), amidine (methyl 5-(4-chlorophenyl)-3-{[(dimethylamino)methylidene]amino]2-thiophenecarboxylate, 1.0 mmol, 322 mg, the preparation of which may be found in the Example J13) and phenol (350 mg) was heated to 190° C. for 20 minutes. The mixture was cooled to room temperature and then washed with methanol. The crude solid product was collected by filtration and then was dissolved in minimum amount of dichlomethane. Adding methanol slowly and let sitting overnight, the title compound was precipitated out as white solid (180 mg, 39%). 1H NMR (CDCl3): δ 1.05 (6H, t, J=7.2 Hz), 2.61 (4H, q, J=7.1 Hz), 2.78 (2H, t, J=7.6 Hz), 3.10 (2H, t, J=7.6 Hz), 7.34 (2H, d, J=8.6 Hz), 7.45 (4H, m, overlapping), 7.53 (1H, s), 7.65 (2H, d, J=8.5 Hz), 8.12 (1H, s). LCMS m/z=470 (m+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:27])[CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([N:15]([CH3:27])[CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a suspension 5-chloro-N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro [5.5]undecan-9-yl)pyrimidine-2,4-diamine (165 mg, 0.42 mmol) and 2-cyanoacetic acid (107.18 mg, 1.26 mmol) in a mixture of DCM and N,N-dimethylformamide (8 mL/2 mL) were added O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85.75 mg, 0.63 mmol) and N,N-diethylethanamine (127.50 mg, 1.26 mmol). The mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a yellow solid (30 mg, 15.54%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[C:13](OC)[CH:12]=2)[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:24][CH3:23])=[CH:15][C:16]=2[O:31][CH3:30])[CH:3]=1
Reactant: COc1cc(Oc2cc(Cl)ccc2C#N)ccc1C=O
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNCc1ccc(Oc2cc(Cl)ccc2C#N)c(OC)c1
Yield: 109.8 %

Procedure:
4-Chloro-2-(4-formyl-3-methoxy-phenoxy)-benzonitrile (0.93 g, 3.2 mmol), methylamine (2M in methanol, 4.8 ml, 9.6 mmol) and sodium cyanoborohydride (0.22 g, 3.6 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (125 ml) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. Fumaric acid (0.40 g, 3.4 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(2-methoxy-4-methylaminomethyl-phenoxy)-benzonitrile fumarate (782 mg, 58%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>[Ni](Br)Br>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: CCOP(OCC)OCC
Agent: Br[Ni]Br
Product: CCOP(=O)(OCC)c1ccc(C(=O)c2ccc(F)cc2)cc1

Procedure:
(4-Bromophenyl)(4′-fluorophenyl)methanone (formula 28) (400 g, 1.43 mol) from Example 4A and anhydrous nickel bromide (35 g, 0.16 mol) are heated to 160° C. under an atmosphere of nitrogen. A green-blue colored melt is obtained. Then triethyl phosphite (304 g, 1.83 mol) is added over a period of 1 hour while maintaining the temperature between 160 and 165° C. The mixture is stirred at this temperature for an additional hour. Distillation of the mixture gave a pale yellow oil, b.p. 187-188° C./10-2 mbar. The yield is 304-326 g (63-68%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:52][C:53](=[NH:73])[C:54]1[CH:63]=[CH:62][CH:61]=[C:60]2[C:55]=1[CH:56]=[CH:57][N:58]=[C:59]2[CH2:64][CH2:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67]>CN(C=O)C.CO>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:52]=[C:53]([C:54]3[CH:63]=[CH:62][CH:61]=[C:60]4[C:55]=3[CH:56]=[CH:57][N:58]=[C:59]4[CH2:64][CH2:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[N:73]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: N#Cc1cc(C(=O)O)ccc1OCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC(F)(F)F)c(C#N)c4)n3)cccc12
Temperature: 120 °C
Yield: 44.8 %

Procedure:
3-Cyano-4-[(2,2,2-trifluoroethyl)oxy]benzoic acid (D29; 0.171 g, 0.698 mmol) was stirred in DMF (4.5 ml) with HATU (0.318 g, 0.837 mmol) and DIPEA (0.366 ml, 2.093 mmol) at room temperature for 20 mins. 1,1-Dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36, 0.22 g, 0.698 mmol) was added and the resulting mixture was heated to 120° C. for 30 mins in a Biotage Initiator microwave. The solvent was removed under vacuum and diethyl ether was added to the residue to give a colourless solid. Methanol was added to dissolve the brown oil remaining and the mixture filtered. A white solid was collected, which was dried in a vacuum oven to give the title compound as a white solid (164 mg).
Reaction SMILES: [ClH:1].[Cl:2]C1C=CC(OC2C=CC(NC3SC=C([C:20]4([C:27]([NH2:29])=[NH:28])[CH2:24][CH:23]=[C:22]([S:25][CH3:26])[S:21]4)N=3)=CC=2)=CC=1.Br.Cl[C:34]1[CH:62]=[CH:61][C:37]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46]3[S:47][CH:48]=[C:49](C4C=C(C(OC)=S)SC=4C)[N:50]=3)=[CH:41][CH:40]=2)=[CH:36][CH:35]=1>>[ClH:2].[Cl:1][C:34]1[CH:62]=[CH:61][C:37]([O:38][C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]3[S:47][CH:48]=[C:49]([C:23]4[CH:24]=[C:20]([C:27]([NH2:29])=[NH:28])[S:21][C:22]=4[S:25][CH3:26])[N:50]=3)=[CH:43][CH:44]=2)=[CH:36][CH:35]=1
Reactant: CSC1=CCC(C(=N)N)(c2csc(Nc3ccc(Oc4ccc(Cl)cc4)cc3)n2)S1
Reactant: COC(=S)c1cc(-c2csc(Nc3ccc(Oc4ccc(Cl)cc4)cc3)n2)c(C)s1
Agent: Br
Agent: Cl
Product: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(Oc3ccc(Cl)cc3)cc2)n1
Yield: 49 %

Procedure:
4-(2-{[4-(4-Chlorophenoxy)phenyl]amino(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide (300 mg, 0.52 mmol) was treated as described in Example 154, step (b) to give 129.9 mg (49% yield) of 4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) δ 2.72 (s, 3H), 6.97 (m, 2H), 7.07 (m, 2H), 7.15 (s, 1H), 7.40 (m, 2H), 7.85 (m, 2H), 8.46 (s, 1H), 8.82 (bs, 2H), 9.27 (bs, 2H), 10.43 (bss, 1H); Mass Spectrum (ESI) m/z calcd. for C21H17ClN4OS3, 473.1 (M+H), found 473.2, 475.1.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:3][C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: OC1(c2ccccn2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: ClC1(c2ccccn2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Thionyl chloride (0.74 ml, 10.2 mmol) was added dropwise to a solution of 3-hydroxy-3-(2-pyridinyl)-1-azabicyclo[2.2.2]octane (1.04 g, 5.09 mmol, prepared as in Description 1) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 1 h, poured into saturated aqueous potassium carbonate (30 ml) and extracted with dichloromethane. The organic extract was dried over magnesium sulphate and then concentrated to a brown oil. The crude product was chromatographed through silica-gel using dichloromethane/methanol/ammonia (94.5:5:0.5) as eluent to give first 0.28 g of 3-chloro-3-(2-pyridinyl)-1-azabicyclo[2.2.2]octane followed by 0.39 g of 3-(2-pyridinyl)-1-azabicyclo[2.2.2]oct-2-ene.
Reaction SMILES: [C:1]([N:5]1[CH:9]2[CH2:10][CH2:11][CH:6]1[CH:7]([C:12]1[CH:13]=[CH:14][C:15](Cl)=[N:16][CH:17]=1)[CH2:8]2)([O:3][CH3:4])=[O:2].[H][H]>CO>[C:1]([N:5]1[CH:6]2[CH2:11][CH2:10][CH:9]1[CH2:8][CH:7]2[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][CH:13]=1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)N1C2CCC1C(c1ccc(Cl)nc1)C2
Solvent: CO
Product: COC(=O)N1C2CCC1C(c1cccnc1)C2
Yield: 71.8 %

Procedure:
N-carbomethoxy-5-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]hept-2-ene 25 (16 mg) was dissolved in 3 ml methanol containing 7 mg 10% palladium on carbon. The mixture was hydrogenated under a slightly elevated pressure of hydrogen for one hour. After removal of catalyst and solvent, the residue was partitioned between ether and aqueous sodium bicarbonate. The aqueous layer was extracted with ether and the combined organic layer was dried over magnesium sulfate. Removal of solvent gave 10 mg of 7-carbomethoxy-2-(3-pyridyl)-7-azanorbornane (12). MS (CI) m/z 233 (M+1), H1 -NMR 3.72, 3.66 (2s, N--COOCH3).