Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH2:27][CH2:28]O)[CH:17]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.C([N:36]([CH2:39][CH3:40])[CH2:37]C)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].N1CCC1.[NH4+].[Cl-]>C(Cl)Cl.CCOC(C)=O>[N:36]1([CH2:28][CH2:27][S:26][C:18]2[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=2)[C:15]([N:14]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:32][CH3:33])[CH3:31])=[O:30])[CH2:37][CH2:40][CH2:39]1
Reactant: CCN(CC)CC
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCO)cc(C(F)(F)F)c1
Agent: C1CNC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN2CCC2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 3.75 h

Procedure:
To an ice-cold solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-(2-hydroxyethylthio)-N-methyl-5-(trifluoromethyl)benzamide (0.16 g, 333 μmol, example 216) in CH2Cl2 (2 mL) were added triethylamine (50.5 mg, 69.6 μL, 500 μmol) and methanesulfonyl chloride (38.1 mg, 25.8 μL, 333 μmol) and the clear colorless solution was stirred at 0° C. for 3.75 hours. The reaction mixture was poured on saturated aqueous NaHCO3 solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were washed once with brine, dried over MgSO4, filtered, and evaporated. The intermediate mesylate was dissolved in isopropylacetate (2.0 mL), treated with azetidine (41.8 mg, 49.4 μL, 733 μmol) and heated to reflux (oil bath 95° C.) for 16 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.055 g; 31%). MS (ESI): m/z=520.17 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:20]2[N:38](CC(=O)C3C=CC=CC=3)[CH2:39][NH:40][C:19]=2[CH2:18]1)=[O:16].C(#N)C>CCOCC>[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:21][C:20]2[N:38]=[CH:39][N:40]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[C:19]=2[CH2:18]1)=[O:16]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C1Cc2c(ncn2Cc2cccc(C(F)(F)F)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 1.4 g 3-trifluoromethylbenzyl chloride, 3.0 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 20 mL acetonitrile is heated at reflux 16 hr. An additional 1.4 mL 3-trifluoromethylbenzyl chloride is added and refluxing continued 24 hr. The cooled solution is added dropwise to 400 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 60 mL methanol and treated with 10 g zinc dust and 60 mL acetic acid. The resulting suspension is sonicated 2 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 520 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99.5:0.5) as a crisp foam. NMR (CDCl3) 5.05 (s, 2H, NCH2Ar).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[N:13][N:12]([CH3:15])[C:11]=2[CH2:16][O:17][C:18]2[CH:22]=[C:21]([C:23]([O:25]C)=[O:24])[O:20][N:19]=2)=[CH:6][CH:5]=1>O1CCOCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[N:13][N:12]([CH3:15])[C:11]=2[CH2:16][O:17][C:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[O:20][N:19]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)nnn2C)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)on1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
A solution of sodium hydroxide (2 N, 10 mL) was added dropwise to a suspension of methyl 3-[5-(4-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-isoxazole-5-carboxylate (460 mg, 1.38 mmol) in dioxane (20 mL) and the reaction mixture was then heated at 90° C. for 1.5 h. The reaction mixture was then evaporated and acidified with HCl (2N), and the resulting precipitate filtered off to afford the title product (320 mg, 73%) as a white solid and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15].OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:13][C:12](=[O:14])[CH2:11][C:7]1[C:6]2[CH:5]=[CH:4][C:3]([OH:15])=[C:2]([Cl:1])[C:10]=2[O:9][CH:8]=1
Reactant: CO
Reactant: O=C(O)Cc1coc2c(Cl)c(O)ccc12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2c(Cl)c(O)ccc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of (7-chloro-6-hydroxy-1-benzofuran-3-yl)acetic acid (1.65 g) and MeOH (40 mL) was added conc. H2SO4 (0.078 mL). The mixture was stirred at 60° C. for 3 h. The mixture was concentrated in vacuo. The residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in toluene and hexane. The insoluble material was filtered and washed with toluene and hexane. The filtrate was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.49 g).
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])C1C=CC=CC=1.CCN(CC)CC.[N+](C1C=CC([N:39]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:40](=[O:42])[O-])=CC=1)([O-])=O>C(Cl)Cl>[CH2:43]([NH:39][C:40]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])=[O:42])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C([O-])N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)NC1CC(COCc2ccccc2)C1F
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
In a 25 mL flask with benzyl-(3-benzyloxymethyl-2-fluoro-cyclobutyl)-amine (25.8 mg, 0.12 mmol) inside, dry CH2Cl2 2 mL was added under argon at room temperature to give a colorless solution, followed by the addition of Et3N (0.02 mL, 0.14 mmol). After stirring for 5 min, 4-nitrophenyl-N-benzylcarbamate (32.1 mg, 0.12 mmol) was added to give a yellow solution. This was left stirring at room temperature for 10 hr and the reaction was quenched by adding 10 mL CH2Cl2. The organic phase was washed with 1 M NaOH 10 mL, H2O 10 mL and brine 10 mL and was dried over MgSO4. Solvent evaporation gave the crude product 42 mg that is pure enough and crystallization gave the pure product 38 mg (90%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([N:36]2[CH2:41][CH2:40][N:39]3[CH2:42][C@H:43]([OH:45])[CH2:44][C@H:38]3[CH2:37]2)[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:34]1[C:33]([N:36]2[CH2:41][CH2:40][N:39]3[CH2:42][C@H:43]([OH:45])[CH2:44][C@H:38]3[CH2:37]2)=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: N#Cc1cc(N)c(Cl)c(N2CCN3C[C@H](O)C[C@H]3C2)c1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN5C[C@H](O)C[C@H]5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (60.6 mg, 0.171 mmol), (+/−)-3-amino-4-chloro-5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzonitrile (50 mg, 0.171 mmol), palladium(II) acetate (10.16 mg, 0.045 mmol), Xantphos (9.88 mg, 0.017 mmol), DPPF (9.47 mg, 0.017 mmol) and cesium carbonate (145 mg, 0.444 mmol) in dioxane (3 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 5 h. The reaction mixture was filtered through a celite pad, the filtrate was concentrated. And the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 0.5-5% 2 N ammonia in methanol/dichloromethane). It was further purified by prep-HPLC (Pursuit XRs 10 u C18 column, 30×250 mm, room temperature 13.171 min, 30-100% gradient aqueous methanol over 12 minutes containing 0.1% TFA, 40 ml/min at 254 rinm). (+/−)-2-((2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (57 mg) was obtained as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:17][C@@:16]2([O:18][CH3:19])[C@@H:6]([CH2:7][C:8]3[C:20]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]2=4)[NH:10][CH:9]=3)[NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][OH:30]>CN(C)C=O>[OH:30][CH2:29][CH2:28][N:5]1[C@H:6]2[C@@:16]([O:18][CH3:19])([C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:20]=3[C:8]([CH2:7]2)=[CH:9][NH:10]4)[CH2:17][C@@H:3]([CH2:2][OH:1])[CH2:4]1
Reactant: OCCBr
Reactant: CO[C@]12C[C@@H](CO)CN[C@@H]1Cc1c[nH]c3cccc2c13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CO[C@]12C[C@@H](CO)CN(CCO)[C@@H]1Cc1c[nH]c3cccc2c13

Procedure:
To a stirred solution of 3 g of 8β-hydroxymethyl-10α-methoxy-ergoline, 3 g of potassium carbonate in 25 ml of dimethylformamide was added 1.3 g of 2-bromoethanol.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH3:8][C:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>CC(=O)CC>[CH3:8][C:9]1([NH:14][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(N)CCCC1
Reactant: O=S1(=O)CCCO1
Solvent: CCC(C)=O
Product: CC1(NCCCS(=O)(=O)O)CCCC1

Procedure:
A solution of 1,3-propanesultone (9.4 g, 75 mmol) in 2-butanone (35 mL) was added dropwise to a the crude solution of 1-methyl-1-cyclopentylamine (mixture of solvent from previous step).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.CCN(CC)CC>C(O)(C)C>[Cl:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([NH:1][C@H:2]2[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]2)[CH:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a neat mixture of (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (3.00 g, 22.9 mmol) and 4,6-dichloropyrimidine (3.70 g, 24.8 mmol) was added isopropyl alcohol (30.0 mL) and Et3N (8.00 mL, 57.4 mmol) and the resulting mixture was heated to 90° C. for 1 h. The mixture was then cooled to 23° C., filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 5 to 7% MeOH in DCM, and the compound was recrystallized from EtOAc to afford the title compound as a white solid (3.30 g, 59%). LC/MS: Rt=0.84 min, ES+ 244 (AA standard).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Yield: 37 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess N-methylpiperazine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.085 g, 37%) as a white solid. MS (ISP) 552 8 [(M+H)+]; mp 180° C. (dec.).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N)CCCC1.COC(C1CCCC1=O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(=O)C.[Na+]>ClCCl.C(#N)C.C(O)(=O)C>[CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[C:12]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C1=C(NC2CCCC2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: COC(=O)C1CCCC1=O
Solvent: CC(=O)O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C1CCCC1NC1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
To a ice cooled solution of 13.36 g (0.066 mole) of 2-cyclopentylamino-1-cyclopentenecarboxylic acid, methyl ester (prepared from 10.0 g (0.116 mole) of cyclopentylamine and 18.46 g (0.122 mole) of 2-oxocyclopentanecarboxylic acid methyl ester in 200 mL of dichloromethane, in the presence of 38.9 g (0.174 mole) of sodium triacetoxyborohydride and 14.31 g (0.174 mole) of sodium acetate) in 210 mL of acetonitrile and 110 mL of acetic acid was added 44.32 g (0.198 mole) of sodium triacetoxyborohydride. After 10 minutes, the cooling bath was removed and the mixture stirred at room temperature overnight. Solvents were removed under reduced pressure and the residue partitioned between ethyl acetate and water containing sufficient sodium carbonate to make the mixture basic (ca pH 11). The water layer was extracted twice with ethyl acetate and the combined ethyl acetate layers washed successively with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 10.2 g of (rac)-2-cyclopentylamino-cyclopentanecarboxylic acid, methyl ester, which was used without further purification in subsequent steps.
Reaction SMILES: [CH3:1][C@H:2](C(O)=O)[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.C([N:20](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[ClH:42].C(=O)=O>C1C=CC=CC=1.O>[ClH:42].[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([NH2:20])[CH3:1])[CH:4]=[CH:5]2
Reactant: CCN(CC)CC
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Cl
Agent: O=C=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2cc(C(C)N)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A further representative compound of the present invention was prepared according to Scheme 1 in the following manner. To a solution of naproxen (10.0 g, 0.04 mole) in 50 mL benzene at room temperature were added triethylamine (6.1 mL, 0.04 mole) and diphenylphosphoryl azide (9.4 mL, 0.04 mole). The solution was heated to reflux and stirred for two hours before slowly adding concentrated HCl solution (12 M; 7.2 mL, 0.08 mole) via pipet. Evolution of CO2 gas was noted. The mixture was stirred at reflux for thirty minutes, then cooled to room temperature and concentrated in vacuo. Ether was added and the solution was concentrated again. A white solid precipitate was filtered and washed with ether to give 15.4 g of crude salt. Approximately 5.0 g of the salt was then placed in water and an insoluble gum was filtered off. The aqueous layer was basified with 2N NaOH solution and extracted with ethyl acetate (3×50 mL). The organic extract was washed with brine and dried (MgSO4), filtered and concentrated in vacuo to give 2.51 g of the 1-(6-methoxynaphthalen-2-yl)ethyl amine hydrochloride salt 2.1 as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].[I:19][CH2:20]I.O>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH2:20][I:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]
Reactant: ICI
Reactant: COC(=O)C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CI)CCOCC1
Temperature: 25 °C
Yield: 53 %

Procedure:
Lithium diisopropylamide (10.9 ml of 2.0M solution in heptane/tetrahydrofuran/ethylbenzene) was added to a stirred solution of tetrahydropyran-4-carboxylic acid methyl ester (3.00 g) in tetrahydrofuran (50 ml) at 0° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes before dropwise addition of diiodomethane (2.51 ml). Stirring was continued for a further hour during which it warmed to room temperature. The reaction was poured into water (50 ml) and then extracted with diethyl ether (3×40 ml). The combined organics were washed with water (2×20 ml), 2 M hydrochloric acid (20 ml), water (20 ml) and brine (20 ml). After drying (MgSO4), filtering and evaporating under reduced pressure a yellow oil was obtained which was purified by column chromatography eluting with 3:1 hexaneldiethyl ether to give the title compound as a colourless oil (3.11 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:17]=[N:16]2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:9]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:17]=[N:16]2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Temperature: -80 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 3.5 g (8.2 mmoles) of ethyl 3,3-bis(4-fluorophenyl)-2-(5-phenyl-1H-tetrazol-1-yl)-2-propenoate in 75 mL of dry methylene chloride at -80° C. under argon was added dropwise 18 mL (1.0 M, 18 mmoles) of diisobutylaluminum hydride in methylene chloride. The clear solution was stirred at -80° C. for 10 minutes then monitored by TLC. An additional 5 mL of diisobutylaluminum hydride in methylene chloride was added to the mixture and stirring was continued for 30 minutes. The reaction mixture was quenched with 2 M HCl and the product was extracted into ethyl acetate. The organic layers were combined, dried over MgSO4 and evaporated to a semi-solid. Recrystallization from ethyl acetate-hexanes mixture gave 3.2 g (99%) of the title compound; m.p.=196.6°-197.6° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19](OC)=O)[CH:14]=2)[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>CO>[C:19]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][C:16]2=[O:18])#[N:23]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(Cc1ccccc1)O2
Reactant: N
Solvent: CO
Product: N#Cc1ccc2c(c1)C(=O)CC(Cc1ccccc1)O2

Procedure:
Methyl 2-benzylchroman-4-one-6-carboxylate, the product of Preparation A33, is converted to the corresponding amide by the action of a molar excess of ammonia in aqueous methanol, recovered by simple stripping of the solvent and excess ammonia. In turn, the amide is converted to the title nitrile by the action of p-toluenesulfonyl chloride on a pyridine solution of the amide, according to the conditions of Stephens et al., J. Am. Chem. Soc., Vol. 77, pp 1701-1702 (1955). This product is well suited for the preparation of 6-cyano-c-4-hydroxy-r-2-benzylchroman-4-acetic acid by the methods of Examples above.
Reaction SMILES: [N+:1](=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]1=[O:14])=[N-:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>C(O)C>[Cl:15][S:16]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4](=[O:14])[C:3](=[N+:1]=[N-:2])[C:12]2=[O:13])(=[O:18])=[O:17]
Reactant: [N-]=[N+]=C1C(=O)Oc2ccccc2C1=O
Reactant: O=S(=O)(O)Cl
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)Oc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 50 °C
Yield: 81.2 %

Procedure:
A 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, water bath, nitrogen inlet and bubbler, thermometer and temperature controller was charged with 3-diazo-4-oxo-3,4-dihydrocoumarin (10.1 g, 53.7 mmol) prepared in accordance with Example 1 and chlorosulfonic acid (75.1 g). The reaction mixture was then heated to 50° C. and maintained at 50° C. for 42 hours, during which time HPLC analysis showed 99% conversion. The reaction was allowed to cool and was poured slowly, in portions, with stirring, into 420 g ice cold ethanol (the temperature of the ethanol slurry was kept below 10° C. throughout the addition). The ethanolic slurry was filtered, and dried in an oven overnight under vacuum at 58° C. to yield 12.5 g of pure 6-chlorosulfonyl-3-diazo-4-oxo-3,4-dihydrocoumarin (81% yield). The product was characterized by 13C NMR, DSC and UV-Vis. The results are as follows: the vacuum dried sample melted at 184.7° C. 13C-NMR in THF-d8 solvent, showed 9 singlet lines at the following chemical shifts, in ppm: 172.693, 1158.932, 157.050, 141.502, 134.467, 126.202, 121.104, 121.091, 77.983. The UV absorption spectrum of the product in THF solvent was determined at a dilution factor, DF=109,182.05 yielding, λ1 max=232 nm, ε1 max=29,532.1 liters/mole cm; and λ2max=288 nm, ε2 max=9,472.8 liters/mole cm.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(OC)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:28]([CH2:31][CH:32]1[CH2:36][C:35]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:34]=2[O:33]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[CH3:42][O:41][C:40]1[C:34]2[O:33][CH:32]([CH2:31][NH2:28])[CH2:36][C:35]=2[CH:37]=[CH:38][CH:39]=1
Reactant: COc1cccc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Agent: COc1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [N-]=[N+]=[N-]
Product: COc1cccc2c1OC(CN)C2
Yield: 54 %

Procedure:
Treatment of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 2.99 mmol) with sodium azide (0.78 g, 11.96 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.06 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.465 g (54%) (±)-1-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 168-171° C.; Anal. calcd. for C10H13NO2HCl: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.68; H, 6.52; N, 6.5.