Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]([NH2:7])=[O:6])[C:2]([NH2:4])=[O:3].C1(C)C=CC(S([N:17]=[N+:18]=[N-])(=O)=O)=CC=1>C(O)C>[OH:3][C:2]1[N:4]=[N:17][NH:18][C:1]=1[C:5]([NH2:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: NC(=O)CC(N)=O
Solvent: CCO
Product: NC(=O)c1[nH]nnc1O
Yield: 70.3 %

Procedure:
To a solution of sodium ethoxide obtained from sodium (2.3 g, 0.10 mole) and absolute ethanol (150 ml) was added malondiamide (10.2 g, 0.10 mole). The mixture was stirred until most of the malondiamide dissolved. p-Toluenesulfonyl azide (19.7 g, 0.10 mole) was dissolved in ethanol (20 ml) and added dropwise with stirring. The thick mixture was stirred at room temperature for 30 min and heated under reflux in an oil bath for an additional 30 min. The mixture was cooled and the sodium salt was removed by filtration and washed with ethanol followed by ether. The salt was dissolved in a minimum of hot water and the solution was acidified to pH 2 with dilute hydrochloric acid. Upon cooling, the product crystallized. The compound was recrystallized from water to give 9.0 g of the known compound 4-hydroxy-1,2,3-triazole-5-carboxamide, m.p. 191°-192°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].Cl.[CH3:14][C:15]1[S:16][C:17]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:18]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:21]2[CH2:22][CH2:23][C:17]3[S:16][C:15]([CH3:14])=[N:24][C:18]=3[CH2:19][CH2:20]2)[N:7]=1
Reactant: Cc1nc2c(s1)CCNCC2
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3nc(C)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 60 h
Yield: 78.5 %

Procedure:
A suspension of 0.234 g (1.00 mmol) of the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one, 0.205 g (1.00 mmol) of the 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride and 0.304 g (2.20 mmol) of potassium carbonate in 2.0 ml of N,N-dimethylformamide was stirred at room temperature for 60 hours. The reaction mixture was then poured into 50 ml of an ice/water mixture and the crystals formed collected by filtration. Thus, a first crop of the 2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one was obtained. The mother liquor was then evaporated and the residue chromatographed on silica gel using a 9:1 v/v mixture of dichloromethane and methanol as eluent giving a second crop of the 2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one, in total 0.252 g (0.785 mmol, yield 78.5%) as light yellow solid; m.p. >200° C.; MS: [M+H]+=322.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]CCCCC.[CH3:25][OH:26]>>[CH3:25][O:26][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([C:11]([O:13][CH3:19])=[O:12])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(C(=O)O)c1
Reactant: CCCCCC
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Yield: 90 %

Procedure:
To a solution of 4-bromoisophthalic acid 201 (10 g, 40.8 mmol) in methanol (150 mL) was added concentrated sulfuric acid (3.5 mL). The solution mixture was heated at reflux temperature for 24 hours. After the reaction was complete, the methanol solvent was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate (NaHCO3). The solution was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate (Na2SO4). Removal of solvent gave oil, which solidified at ambient temperature. The solid was titurated twice with 20 mL of methanol and hexane (1:3) to give 8 g (90%) of 4-bromoisophthalic acid dimethyl ester 202: 1H NMR (400 MHz, CDCl3) δ 3.93 (s, 3H), 3.93 (s, 3H), 7.74 (d, J=8 Hz, 1H), 7.95 (dd, J=2 Hz, J=8 Hz, 1H), 8.43 (d, J=2 Hz, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][N:6]=1>O1CCOCC1.O>[Br:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(Br)nc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
To a stirred solution of NaCN (117 g, 2.38 mol) in dioxane (1 L) and water (1 L), was added the above crude 2-bromo-5-bromomethylpyridine (275 g) and the mixture was stirred at rt for 15 h. The reaction mixture was quenched with cold water (15 L) and extracted with EtOAc (3×1 L). The organic layer was washed with water (3×1 L), brine (2×1 L), dried with Na2SO4 and concentrated under reduced pressure to give crude title compound. The crude residue was purified by column chromatography over silica gel (pet. ether/ethylacetate, 7:3) to give 95 g (6-bromopyridin-3-yl)acetonitrile as a pale yellow solid (49%). [TLC, Rf=0.5, pet. ether/ethylacetate 7:3]
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH2:11]1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH2:11]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: NC1CNc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)NC1CNc2ccccc2C1

Procedure:
10 ml of a 10% sodium hydroxide solution and 0.34 ml of ethyl chloroformate are added in succession to a solution of 0.5 g of 3(R,S)-amino-1,2,3,4-tetrahydroquinoline in 6 ml of toluene, while stirring vigorously, and when the addition has ended, the mixture is stirred for a further 5 min. Customary working up and chromatography of the crude product over 25 g of silica gel with methylene chloride as the mobile phase gives the title compound: Rf (P)=0.78; MS: M+ =220.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:20]([F:23])([F:22])[F:21])=[C:12]([N:15]3[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=2)[NH:8][C:7](=[O:24])[C:6]1=[O:25])([OH:3])=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH2:26]([NH:33][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:20]([F:23])([F:22])[F:21])=[C:12]([N:15]3[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=2)[NH:8][C:7](=[O:24])[C:6]1=[O:25])=[O:3])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
2.0 g (6.5 mmol) of 1-carboxymethyl-7-(1-pyrrolyl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione and 0.64 g (5.9 mmol) of benzylamine were dissolved in 50 ml of anhydrous dimethylformamide. At 0° C., 1.6 g (5.9 mmol) of diphenylphosphoryl azide dissolved in a little dimethylformamide, and 1.3 g (12.5 mmol) of triethylamine were successively added dropwise. The mixture was stirred at room temperature for 4 h and then poured into water buffered with sodium bicarbonate. The resulting precipitate was filtered off with suction to yield 1.6 g (62%) of the product. Melting point 241°-242° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=2[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C-:19]#[N:20].[K+].[I-].[K+].C(O)C>O>[Cl:18][C:16]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([CH2:2][C:19]#[N:20])[C:4]=2[CH:17]=1
Reactant: Clc1ccc2sc(-c3ccccc3)c(CBr)c2c1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 52 °C
Reaction time: 0.5 h

Procedure:
13.0 Parts by weight of 3-bromomethyl-5-chloro-2-phenylbenzo[b]thiophene, 5.1 parts by weight of potassium cyanide and 1.5 parts by weight of potassium iodide are suspended in 250 parts by volume of 95% ethanol and heated at 52° C. under a nitrogen atmosphere for 22.5 hours. The reaction mixture is then diluted with 250 parts by volume of water and stirred for an additional 0.5 hour. The resulting precipitate is separated from the reaction mixture by filtration. Crystallization of this precipitate from ethyl acetate affords as a white crystalline solid 5-chloro-2-phenylbenzo[b]thiophene-3-acetonitrile, melting at 158°-160° C. This compound is represented by the following structural formula. ##STR12##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4]/[N:5]=[CH:6]/[CH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([CH:4]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:6]([CH2:7][C:8]([CH3:18])([CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:5]1)=[O:20]
Reactant: COC(=O)C/N=C/CC(C)(C)Cc1ccc(OC)cc1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1NC(CC(C)(C)Cc2ccc(OC)cc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 70.2 %

Procedure:
In a manner similar to the method described in Example 1c, [4-(4-methoxy-phenyl)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester prepared in Example 126a (2.7 g, 9.7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (3.1 g, 10 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (6 g, 60 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester as a yellow solid (4 g, 70%).
Reaction SMILES: [CH:1]1([N:7]([CH3:13])[S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[NH3:16]>>[CH:1]1([N:7]([CH3:13])[S:8]([CH2:11][CH2:12][NH2:16])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N
Reactant: C=CS(=O)(=O)N(C)C1CCCCC1
Solvent: CO
Product: CN(C1CCCCC1)S(=O)(=O)CCN

Procedure:
Ethenesulfonic acid cyclohexyl-methyl-amide (0.0167 mol) was reacted with a mixture of methanol/ammonia (10 mL) in an autoclave for 16 hours at room temperature, and then the solvent was evaporated. The residue was purified by column chromatography (eluent: 90:10 CH2Cl2:(CH3OH:NH3)). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C([O-])(=O)C.[Na+].[BH4-].[Na+]>CO>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[OH:8]
Reactant: O=Cc1ccc[nH]1
Reactant: Cc1ccc(N)cc1O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(NCc2ccc[nH]2)cc1O
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
To a stirred solution of 5-amino-2-methylphenol (9.84 g, 80 mmole) in methanol (100 mL) at 4° C. was added pyrrole-2-carboxaldehyde (11.41 g, 120 mmole) and sodium acetate (13.13 g, 160 mmole). The reaction mixture was stirred for 15 minutes and sodium borohydride (3.78 g, 100 mmole) was added portionwise over 1 hour at 4° C. After the addition was complete, the reaction was allowed to stir for an additional 3 hours. The reaction mixture was poured onto crushed ice slurry (200 g) and the resulting precipitate was collected and washed with cold water three times and air-dried to afford 2-methyl-5-[(1H-pyrrol-2-yl-methyl)amino]phenol (6.62 g, 41% yield): mp 115.4-116.8° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.94 (s, 3H), 4.03 (d, 2H, J=5.6 Hz), 5.37 (t, 1H, J=5.6 Hz), 5.90 (m, 2H), 6.01 (dd, 1H, J=2.2, 8.0 Hz), 6.12 (d, 1H J=2.1 Hz), 6.61 (m, 1H), 6.70 (d, 1H, J=8.1 Hz), 8.77 (s, 1H), 10.64 (s, 1H); MS m/z 202 (M+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.Cl.[NH2:58][CH:59]([C:65]([F:68])([F:67])[F:66])[CH2:60][C:61]([O:63][CH3:64])=[O:62]>CN(C=O)C.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:58][CH:59]([C:65]([F:66])([F:67])[F:68])[CH2:60][C:61]([O:63][CH3:64])=[O:62])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CC(N)C(F)(F)F
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
750 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 3A (2.36 mmol, 1 equivalent) were initially charged in 15 ml of DMF, and 2.24 g of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU, 5.89 mmol, 2.5 equivalents) and 1.03 ml of N,N-diisopropylethylamine (0.76 g, 5.89 mmol, 2.5 equivalents) were added. The mixture was stirred at 60° C. for 20 min, 0.98 g of methyl 3-amino-4,4,4-trifluorobutanoate hydrochloride (Example 22A, 4.71 mmol, 2 equivalents) was added and the mixture was stirred at 60° C. overnight. The mixture was then added to 120 ml of water and stirred at RT for 30 min. The precipitated solid was filtered off, washed with 6 ml of diethyl ether and dried under reduced pressure. The residue was then concentrated on a silica gel column (mobile phases: dichloromethane/ethyl acetate 10:1). This gave 0.32 g (29% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:16](Cl)(Cl)=[S:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:9]=[C:16]=[S:17])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1nc(Cl)ccc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1nc(Cl)ccc1Cl
Temperature: 55 °C

Procedure:
A mixture of 3,6-dichloropyridin-2-amine (0.772 g, 4.74 mmol), sodium carbonate (2.01 g, 18.9 mmol), and thiophosgene (0.726 mL, 9.47 mmol) in 6 mL DCM was heated to 55° C. in a sealed tube for 36 h. The reaction was filtered through a frit, rinsing with DCM, and the material was adsorbed onto 6 g silica gel and dried. The material was purified by silica gel chromatography, 40 g, 0-100% EA/hexanes to give 3,6-dichloro-2-isothiocyanatopyridine. 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.19 (d, J=8.5 Hz, 1 H), 7.59 (d, J=9.5 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Br:16][C:17]1C=CC(OC(F)(F)F)=CC=1>>[Br:16][CH2:17][C:7]([C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OC(F)(F)F
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Product: O=C(CBr)c1cc(Br)ccc1OC(F)(F)F

Procedure:
The title compound was synthesized from 5-bromo-2-trifluoromethoxy-benzoic acid (prepared from 1-bromo-4-trifluoromethoxy-benzene by the orth-lithiation method according to Schlosser et al. Eur. J. Org. Chem.2001, 21, 3991-3997) according to the general scheme 12.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[S:3][C:4]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:41][CH2:40]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[F:45])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1nc(Cl)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 77.4 %

Procedure:
In the same manner as in Example 259 and using 2-chloro-4-methyl-1,3-thiazole-5-carboxylic acid (140 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (140 μL, 1.6 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (230 mg, 78%) was obtained as a pale-green solid.
Reaction SMILES: C([SiH](CC)CC)C.O[C:9]1([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.[C:25](=[O:28])([O-:27])O.[Na+].FC(F)(F)[C:32]([OH:34])=[O:33]>>[C:32]([OH:34])(=[O:33])[C:25]([OH:27])=[O:28].[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH:9]2[CH:14]3[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]3)[CH2:10]2)=[CH:18][CH:19]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C2(O)CN3CCC2CC3)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Product: COc1ccc(C2CN3CCC2CC3)cc1
Product: O=C(O)C(=O)O

Procedure:
Triethylsilane (3.8 mL, 0.024 mol) was added to a stirred solution of 3-hydroxy-3-(4-methoxyphenyl)quinuclidine (1.0 g, 0.0048 mol, prepared as in Example 2) in trifluoroacetic acid (10 mL). After 20 hours at 50° C. the solution was cooled to 5° C. and basified to pH9 with saturated sodium hydrogen carbonate solution. The mixture was extracted with dichloromethane (3× 100 mL), then the combined organics were dried (sodium sulphate) then evaporated to dryness. The crude product was purified by flash chromatography on silica using dichloromethane/methanol (20:1) to afford the title compound free base (0.86 g, 83%). The hydrogen oxalate salt had mp 104° C.-106° C. (acetone). Rf =0.77 in dichlormethane/methanol (20:1) on alumina plates; 1H NMR (360 MHz, D2O) δ 1.75-1.87 (1H, m), 1.88-1.92 (1H, m) and 2.03-2.17 (2H, m, 5-CH2 and 8-CH2); 2.22-2.24 (1H, m, 4-CH); 3.29-3.63 (6H, m, 2-CH2, 6-CH2 and 7-CH2); 3.70-3.79 (1H, m, 3-CH); 3.83 (3H, s, OCH3); 7.03 (2H, d, J=9 Hz, 2×Ar-H); 7.34 (2 H, d, J=9 Hz, 2×Ar-H); MS, m/z 217 for M+ of free base. (Found: C, 61.86; H, 61.86; H, 6.81; N, 4.50.C14H19NO.C2H2O4.0.25 H2O requires C, 61.62; H, 6.95; N, 4.49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14]1([CH3:25])[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:25])=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: Cc1ccc(NCC(=O)O)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)CNc2ccc(C)cc2)cc1OC
Yield: 71.4 %

Procedure:
3,4-Dimethoxyphenethylamine (14.4 g) and p-toluidinoacetic acid (13.1 g) were heated for 1.5 hours at 190° C. in a stream of nitrogen. After cooling, the reaction mixture was dissolved in ethyl acetate and the solution was washed with a cooled 1 N sodium hydroxide solution and water and then dried. The solvent was distilled off and the oily residue was crystallized by adding ether to give N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(p-toluidino)acetamide (18.6 g), mp 87° to 88.5° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:9])[CH:6](Cl)[Cl:7])[CH:2]=[CH2:3].COCCOCCOC.N1CCCC1=O.C(Cl)[Cl:33]>>[CH2:10]([N:4]1[CH2:1][CH:2]([CH2:3][Cl:33])[CH:6]([Cl:7])[C:5]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCl
Reactant: C=CCN(Cc1ccccc1)C(=O)C(Cl)Cl
Agent: O=C1CCCN1
Solvent: COCCOCCOC
Product: O=C1C(Cl)C(CCl)CN1Cc1ccccc1

Procedure:
Eleven and one-tenth grams of N-allyl-N-benzyl dichloroacetamide was dissolved in 12 ml. of diglyme and 1 g. of anhydrous ferrous chloride added. The mixture was heated at reflux under nitrogen until conversion to the pyrrolidinone was complete as indicated by GLPC. The mixture was diluted with methylene chloride, washed with 5 percent hydrochloric acid, separated, dried over anhydrous magnesium sulfate, treated with activated carbon and Florisil and stripped under vacuum. Yield was 6 g. of the title compound, nD30 1.5387.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 57 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 57% of theory, C36H45N7O5 (655.8) Rf value: 0.46 (silica gel; dichloromethane/methanol =9:1 ##EQU83##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH:9]([N-]C(C)C)([CH3:11])[CH3:10].[Li+].C(=[O:20])CC>O1CCCC1>[F:1][C:2]1[C:7]([CH2:10][CH:9]([OH:20])[CH3:11])=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1
Reactant: Fc1cccc(F)n1
Reactant: CCC=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)Cc1ccc(F)nc1F
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2,6-difluoropyridine (5.0 mL, 0.0551 mol) in tetrahydrofuran (55 mL) was slowly added to a 1-necked flask containing lithium diisopropylamide (31 mL, 1.8 M in tetrahydrofuran) at −78° C. The reaction was stirred at this temperature for 30 minutes and then propionaldehyde (3.96 mL, 0.0551 mol) was added. After stirring at this temperature for an additional 30 minutes, the reaction was quenched by the addition of a saturated solution of ammonium chloride (20 mL). The product was extracted with diethylether, and purified by column chromatography using as eluent 10% ethyl acetate in hexanes to provide 6.7 g (70%) of 1-(2,6-difluoropyridin-3-yl)propan-2-ol.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([CH2:15]O)([CH2:13][OH:14])[CH3:12]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:14][CH2:13][C:11]([CH3:15])([CH3:12])[CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Temperature: 25 °C
Yield: 64 %

Procedure:
The following describes an improved procedure at three times larger scale in much shorter time compared with the literature (Hewlins et al. (1986) J. Chem. Res. (M), 8: 2645-2696). 4-Bromobenzaldehyde (3.00 g, 16.2 mmol), neopentylglycol (1.86 g, 17.9 mmol) and p-toluenesulfonic acid (50 mg, 0.3 mmol) were dissolved in toluene (30 mL) and the solution was refluxed for 3 h. Then the solution was cooled to rt, washed twice with aq NaHCO3 (10%), twice with water and dried (Na2SO4). The solvent was evaporated and the oily residue was crystallized from hexanes, affording colorless needles (2.81 g, 64%). 13C NMR (APT) δ 21.7 (−), 22.9 (−), 30.1 (+), 77.5 (+), 100.8 (−), 122.7 (+), 127.8 (−), 131.3 (−), 137.5 (+).