Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=388.12.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[N:48]1[N:49]=[CH:50][N:51]2[CH2:56][CH2:55][NH:54][CH2:53][C:52]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:48]1[N:49]=[CH:50][N:51]2[CH2:56][CH2:55][N:54]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:5])[CH2:53][C:52]=12
Reactant: c1nnc2n1CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2cnnc2C1
Reaction time: 12 h
Yield: 21.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (170 mg, 0.57 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (323 mg, 0.85 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 17a (100 mg, 0.63 mmol, prepared according to a known method “Journal of Medicinal Chemistry, 2005, 48(1), 141-151”) and N,N-diisopropylethylamine (302 mg, 1.70 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 17 (50 mg, yield 21.7%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[CH3:17][S:18]([N:21]([CH3:45])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:36]2[C:31]([CH:32]=[N:33][C:34](OS(C(F)(F)F)(=O)=O)=[N:35]2)=[CH:30][CH:29]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:34]2[N:33]=[CH:32][C:31]3=[CH:30][CH:29]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH3:45])[S:18]([CH3:17])(=[O:20])=[O:19])[N:36]3[N:35]=2)=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: CN1CCCC1COc1cc(N)ccc1Cl
Product: CN1CCCC1COc1cc(Nc2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)ccc1Cl

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 4-Chloro-3-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine and Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) δ 9.7 (brs, 1H), 9.6 (s, 1H), 9 (s, 1H), 7.8 (m, 1H), 7.7 (m, 1H), 7.5 (m, 3H), 7.3 (d, 1H), 7.2 (d, J=8.7 Hz , 1H), 7.0 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.5 (m, 1H), 3.1 (s, 3H), 3 (s, 3H), 2.8 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H); LC/MS (ESI+): 541 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([CH3:33])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:24]=3)[CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:23]1[N:24]=[C:19]2[CH:18]=[CH:17][C:16]([C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=3)=[CH:21][N:20]2[C:22]=1[CH3:33]
Reactant: Cc1c(-c2ccc(F)cc2F)nc2ccc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(F)cc2F)nc2ccc(-c3cccc(CO)c3)cn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
210 mg of 6-[3-(tert-butyldimethylsilanyloxymethyl)phenyl]-2-(2,4-difluorophenyl)-3-methylimidazo[1,2-α]pyridine in 5 ml of tetrahydrofuran are placed in a round-bottomed flask and 240 mg of tetrabutylammonium fluoride are added thereto. The mixture is stirred at ambient temperature for 48 h. The reaction mixture is then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 130 mg of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11]O)[NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCc1cc2ccc(Cl)cc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65° C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32%). The aqueous layer was extracted with tert-butyl methyl ether (3×200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[F:52][C:53]([F:64])([F:63])[C:54]1[CH:55]=[CH:56][C:57]([CH2:60][CH2:61][NH2:62])=[N:58][CH:59]=1.C(N(CC)CC)C>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:62][CH2:61][CH2:60][C:57]3[CH:56]=[CH:55][C:54]([C:53]([F:64])([F:52])[F:63])=[CH:59][N:58]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: NCCc1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)cn4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (20 mg, 0.0566 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (12.85 mg, 0.0670 mmol), 1-hydroxybenzotriazole monohydrate (10.26 mg, 0.0670 mmol), and 1,2-dichloroethane (1 mL) was stirred at ambient temperature for 20 minutes. 2-(5-(Trifluoromethyl)pyridin-2-yl)ethanamine dihydrochloride (19.23 mg, 0.0731 mmol) and triethylamine (84.91 μl, 0.6092 mmol) were added to the activated acid and the mixture was stirred for 18 hours at ambient temperature. The reaction mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 14.2 mg of the title compound as a thin film (48%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([CH3:34])([CH3:33])[CH2:5][N:6]1[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]1[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=1>CO.O>[F:3][C:4]([CH3:34])([CH3:33])[CH2:5][N:6]1[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]1[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2CC(C)(C)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(F)CN1C(c2ccc(/C=C/C(=O)O)cc2)c2[nH]c3ccccc3c2CC1(C)C
Temperature: 22 °C
Reaction time: 40 h
Yield: 74.3 %

Procedure:
2M Sodium hydroxide solution (0.782 ml, 1.56 mmol) was added to a solution of (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (68 mg, 0.16 mmol) in methanol (5 ml) THF (5.00 ml) and water (5.00 ml) and the mixture stirred for 40 hours at 22° C. The mixture was concentrated to a volume such that all of the organic solvent had been removed and was acidified to pH6 with 2M HCl. Concentrated aqueous ammonia (2 drops) was added, followed by methanol (˜2 ml), giving a pale yellow solution. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title product (isomer 1) (50.0 mg, 76%) as a yellow solid. 1H NMR (500 MHz, DMSO, 30° C.) δ 0.93 (3H, s), 1.19 (3H, d), 1.23 (3H, s), 1.51 (3H, d), 2.56-2.64 (2H, m), 2.75 (1H, d), 3.04 (1H, dd), 5.06 (1H, s), 6.40 (1H d), 7.03 (1H, ddd), 7.09-7.15 (2H, m), 7.35 (1H, dd), 7.44-7.51 (5H, m), 10.87 (1H, s), CO2H not observed. m/z: ES+ [M+H]+ 421. *Stereochemistry inferred to be (R) at the undefined centre by analogy with other examples.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: COC(=O)c1ccccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCOc3ccccc3C(=O)OC)c2n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound obtained in Example 2-1 step (v) was dissolved in dimethylformamide (50 ml), and potassium carbonate (3.52 g) and methyl 2-(2-bromoethoxy)benzoate (2.2 g) were added thereto. The mixture was stirred at room temperature for 96 hours and partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was dried and concentrated under reduced pressure. The residue was dissolved in methanol and purified by RPHPLC to give the titled compound. Yield: 0.768 g (22%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([O:27]C)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 124.6 %

Procedure:
A mixture of methyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (560 mg, 1.48 mmol) and lithium hydroxide monohydrate (125 mg, 2.97 mmol) in methanol (10 ml) and water (3 ml) is stirred for 18 hours at 50° C. The methanol is evaporated and the resulting suspension treated with 2N aqueous hydrochloric acid (1.485 ml, 2.97 mmol) The solvent is evaporated affording 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid containing 2 equivalents lithium chloride (670 mg, 101%). mp.: >250° C. MS: m/z=362.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(F)cc2c1O
Product: O=[N+]([O-])c1cnc2ccc(F)cc2c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.3 g (11 mmol) of 6-fluoro-3-nitro-quinolin-4-ol (Example 19b) in 12 ml POCl3 are heated kept at 130° C. for 4 h. The reaction mixture is cooled to 0° C. and poured into ice-water. A precipitate is formed, which is filtered off and washed with water. The solid material is dissolved in CH2Cl2 and washed with 0.1N NaOH and water. After drying the organic phase over MgSO4, the solvent is evaporated to dryness. The residue is dissolved in a few ml of CH2Cl2 and hexane is added. The title compound precipitates and is filtered off. Drying is done at 60° C. (high-vacuum) overnight. NMR (DMSO-d6): 9.38/s (1H), 8.32/d×d (1H), 8.18/d×d (1H) and 8.02/d×t (1H); HPLC: tret=11.82 min (Grad 1).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.OO.[ClH:13]>>[NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Cl
Agent: OO
Product: Nc1nc2ccc(Cl)cc2[nH]1
Yield: 72 %

Procedure:
Commercial 2-aminobenzimidazole was chlorinated with a mixture of hydrogen peroxide and HCl in aqueous solution at rt for 1.5 h. After removal of all volatiles the residue was dissolved in water and the product precipitated by addition of ammonia solution to give a 72% yield of 2-amino-5-chlorobenzimidazole as beige coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[Cl-].[NH4+]>CCO.O.ClCCl.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[C:4]([CH:3]=1)[NH2:11]
Reactant: COc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1c(N)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
5-Bromo-1-fluoro-2-methoxy-3-nitrobenzene (1.0 g, 4.0 mmol), zinc (2.62 g, 40.0 mmol) and ammonium chloride (2.14 g, 40.0 mmol) in EtOH (20 mL) and water (12 mL) were heated at 80° C. for 10 minutes and then stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (100 mL) and water (60 mL), and filtered through CELITE®. The organic phase was dried over sodium sulfate and filtered and then concentrated to afford Intermediate 25A (723 mg, 82% yield) as a gray solid. HPLC: Rt=1.3 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=222.0 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10]C(C3C4C(=CC=CC=4)NC=3)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[C:32](Cl)=[O:33]>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[C:32]([NH:10][CH2:9][C:4]12[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:33]
Reactant: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: O=C(Cl)c1n[nH]c2ccc(F)cc12
Product: O=C(NCC12CCN(CC1)CC2)c1n[nH]c2ccc(F)cc12

Procedure:
5-Fluoro-N-((quinuclidin-4-yl)methyl)-1H-indazole-3-carboxamide was prepared in a similar manner to N-((quinuclidin-4-yl)methyl)-1H-indole-3-carboxamide, substituting 5-fluoro-1H-indazole-3-carbonyl chloride as the electrophile. 1HNMR: 10.6 (bs, 1H); 8.89 (t, 1H); 8.16 (dd, 1H); 7.9 (dd, 1H); 7.62 (m, 1H); 3.28 (m, 2H); 3.21 (m, 6H); 1.70 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:28]1[CH2:29][CH:30]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26][CH2:27]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CC=C(c2ccccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 49.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (2.21 g, 8.8 mmol) and 1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (7.47 g, 46.6 mmol) were dissolved in acetonitrile (100 ml), and lithium perchlorate trihydrate (7.48 g, 46.6 mmol) was added thereto and refluxed for 48 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 1.90 g of the intended substance (yield 49.6%).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1nccc(-c2ccccc2)n1
Product: Cc1nnc2nc(-c3ccccc3)ccn12

Procedure:
A mixture of 2.0 g. of 2-hydrazino-4-phenylpyrimidine and 25 ml. of triethyl orthoacetate is refluxed for 8 hours. On cooling the desired compound is removed by filtration, m.p. 303°-306° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:16])[C:18]([F:20])([F:19])[F:17])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C=O)c1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(C(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
To a solution of tert-butyl 2-chloro-6-formylisonicotinate (1.5 g, 6.2 mmol) in THF (40 mL) were added (trifluoromethyl)trimethylsilane (1.49 mL, 4.31 mmol) and ground 4 A° molecular sieves. The mixture was cooled to 0° C. and TBAP (1.0 M in THF; 1.86 mL, 1.86 mmol) was added dropwise. The mixture was warmed to ambient temperature. After 30 min, additional (trifluoromethyl)trimethylsilane (0.5 mL, 1.44 mmol), TBAP (1.0 M in THF; 0.62 mL, 0.62 mmol) and ground 4 A° molecular sieves were added. After 30 min, the mixture was filtered with Celite. Aqueous 1 N HCl was added to the filtrate and the filtrate was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→95% hexanes/ethyl acetate) gave the title compound (1.4 g). MS 312.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14])#[N:10].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([NH:12][CH2:11][C:9]#[N:10])=[O:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: N#CCNC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (3.2 g, 0.22 mmol) and 4-(cyanomethylcarbamoyl)phenylboronic acid (3.0 g, 15 mmol) in toluene (146 mL) were added n-propanol (44 mL), aqueous sodium bicarbonate (2M, 22 mL) and tetrakis(triphenylphosphine) palladium[0](850 mg, 0.7 mmol). The reaction was heated at 90° C. for 24 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions washed with brine, dried (Na2SO4) filtered and concentrated. Silica gel chromatography using 30-70% ethyl acetate/petroleum spirit as eluent provided 4-(2-chloropyrimidin-4-yl)-N-(cyanomethyl)benzamide as a pale yellow waxy solid (1.35 g, 33%). 1H NMR (300 MHz, d6-DMSO) δ 9.40 (t, J=5.4 Hz, 1H), 8.88 (d, J=5.2 Hz, 1H), 8.32 (d, J=8.7 Hz, 2H), 8.23 (d, J=5.1 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 4.36 (d, J=5.4 Hz, 2H); LC-ESI-MS (method B): rt 5.3 min.; m/z 273.2/275.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][CH:15]([OH:16])[CH:11]2[O:10][CH2:9]1.[N+:17]([O:20][C@@H:21]([CH2:37][O:38][N+:39]([O-:41])=[O:40])[CH2:22][CH2:23][CH2:24][C:25](O[C@@H]1CO[C@@H]2[C@H](O)CO[C@H]12)=[O:26])([O-:19])=[O:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:17]([O:20][C@@H:21]([CH2:37][O:38][N+:39]([O-:41])=[O:40])[CH2:22][CH2:23][CH2:24][C:25]([O:16][C@H:15]1[CH2:14][O:13][C@@H:12]2[C@@H:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:9][O:10][C@H:11]12)=[O:26])([O-:19])=[O:18]
Reactant: OC1COC2C(OC3CCCCO3)COC12
Reactant: O=C(CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3S,3aR,6S,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol (0.64 g, 2.80 mmol) and (5R)-5,6-bis-nitrooxy-hexanoic acid (1.18 g, 4.95 mmol) (obtained as described in EXAMPLE 5) were dissolved in DCM (30 ml), EDAC (0.81 g, 4.20 mmol) and 4-dimethylaminopyridine (0.068 g, 0.56 mmol) were added. After stirring at room temperature for 12 hrs, the reaction mixture was washed with water. The organic layer was dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 80%), affording the title product as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](OCC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.[BH4-].[Li+].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][CH2:21][OH:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)COC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (277 mg) in tetrahydrofuran (5 mL) was added lithium borohydride (55 mg) at 0° C. After stirring at 0° C. for 1.5 h, lithium borohydride (22 mg) was added to the mixture. The whole was stirred at 0° C. for 2 h, at room temperature for 2.5 h, and then at 50° C. overnight. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give the title compound (37% mg, 15%) as a white amorphous solid. MS 505 (MH+).