Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH3:11])[C:8](=[O:10])[O:9][C:5]=2[CH:4]=1.[CH3:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:27]=[C:28](O)[CH:29]=[CH:30][CH:31]=3)[CH:24]=2)[N:19]=[C:18]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH3:11][N:7]1[C:6]2[CH:12]=[CH:13][C:3]([CH2:2][O:1][C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:23]4[CH:24]=[C:25]5[C:20](=[CH:21][CH:22]=4)[N:19]=[C:18]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[N:17]=[C:16]5[NH:15][CH3:14])[CH:31]=3)=[CH:4][C:5]=2[O:9][C:8]1=[O:10]
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(O)c3)cc12
Reactant: Cn1c(=O)oc2cc(CO)ccc21
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCc4ccc5c(c4)oc(=O)n5C)c3)cc12
Temperature: 50 °C

Procedure:
To 6-(hydroxymethyl)-3-methylbenzo[d]oxazol-2(3H)-one (45.1 μmol) was added the solution of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (30 μmol) in THF (400 μL). After PS-triphenylphosphine (60 μmol) was added, the solution of DBAD (di-tert-butyl azodicarboxylate, 66 mmol) in THF was dispensed to the vials. The mixture was heated at 50° C. for 8 h. After the solvent was removed, the residue was diluted with methanol and purified by Mass triggered PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(OC)c(F)c1
Temperature: 120 °C
Yield: 87.8 %

Procedure:
The mixture of 3-fluoro-4-methoxybenzaldehyde (5.1 g, 33.0 mmol) and (carbethoxymethylene)triphenylphosphorane (17.2 g, 49.5 mmol) in anhydrous toluene (165 mL) was refluxed at 120° C. under nitrogen for 4 hours. The solvent was removed in vacuo and purified by silica gel chromatography (10-20% EtOAc in hexanes) to provide (E)-ethyl 3-(3-fluoro-4-methoxyphenyl)acrylate (537) (6.5 g, 87.6%) as a white solid.
Reaction SMILES: [N:1]([CH:4]([CH2:9][CH2:10][C:11]#[N:12])[C:5]([O:7]C)=[O:6])=[N+:2]=[N-:3].[OH-].[Na+]>C(O)C.O>[N:1]([CH:4]([CH2:9][CH2:10][C:11]#[N:12])[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(=O)C(CCC#N)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CCCC(N=[N+]=[N-])C(=O)O
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
Methyl 2-azido-4-cyanobutyrate (1.1 g, 6.55 mmol) was dissolved into a solution of sodium hydroxide in 90% ethanol (7 ml of 1N) and the resultant solution let stand at room temperature for 45 min. Thin layer chromatography (silica, 10% ether-benzene) indicated the reaction was completed. The reaction mixture was diluted with water (7 ml) and stirred (5 min) with Dowex 50W-X8 (acidic, H30 form) resin and then filtered.The filtrate was concentrated under reduced pressure to half the volume (to remove EtOH) and the remaining solution extracted with chloroform (5×10 ml). The chloroform solution, after drying, was evaporated to give 0.89 g (89%) of the title acid as a liquid; ir (neat) νmax : 3200, 2250, 2110, 1740 cm-1 ; 1Hmr (CDCL3) δ: 2.23 (m, 2H, CH2), 2.57 (m, 2H, CH2CN) and 4.27 ppm (q, J1 =9, J2 =6 Hz, 1H, CHN3). Anal. calcd for C5H6N4O2 : C 39.62, H 3.92, N 36.36; found: C 39.00, H 3.85, N 36.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[N:11]=1)[C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:13][O:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[N:11]=1)[C:6]([NH:18][C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([O:15][CH3:14])=[O:23])=[O:8]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: COc1cc(C(=O)O)cc(OC)n1
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc(OC)nc(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 2,6-Dimethoxy-isonicotinic acid and D-leucine methyl ester. 1H NMR (500 MHz, CDCl3): δ 0.92 (d, 3H, J=7.27 Hz), 0.93 (d, 3H, J=7.26 Hz), 1.41-1.58 (m, 8H), 3.95 (s, 3H), 4.08 (s, 3H), 4.15 (m, 1H), 6.43 (d, 1H, J=8.32 Hz), 7.47 (m, broad, 1H), 8.41 (d, 1H, J=8.34 Hz). MS (M+H; 311).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.ClC1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:36].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccc(Cl)cc1
Agent: Cl
Agent: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Product: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine (97) (25.6 mmol) using the procedure described for compound (9) (8.2 g, 85%).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([CH:18](O)[CH2:19][C:20]3[S:21][C:22]([C:26]([OH:28])=[O:27])=[C:23]([CH3:25])[N:24]=3)=[CH:16][O:15][N:14]=2)=[N:11][CH:12]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17](/[CH:18]=[CH:19]/[C:20]3[S:21][C:22]([C:26]([OH:28])=[O:27])=[C:23]([CH3:25])[N:24]=3)=[CH:16][O:15][N:14]=2)=[N:11][CH:12]=1
Reactant: Cc1nc(CC(O)c2conc2-c2ccc(F)cn2)sc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Temperature: 90 °C
Yield: 61 %

Procedure:
Concentrated sulfuric acid (27 mL) was added to 2-{2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid (1.6 g, 4.6 mmol) then the mixture was heated at 90° C. for 20 min. After cooling to room temperature the mixture was poured into ice (200 g) and the precipitate was filtered off and dried to give the title product (930 mg, 61%) as a light yellow solid after trituration from ethyl acetate. MS: m/e=330.3 [M−H]−.
Reaction SMILES: C([O-])(=[S:3])C.[K+].[Cl:6][CH:7]1[CH:19]=[C:11]2[CH2:12][O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:9]([C:10]=32)[C:8]1([C:22]1[N:27]=[C:26]([S:28]([CH3:30])=[O:29])[N:25]=[C:24](N)[N:23]=1)[C:20]#[N:21].[OH-].[Na+].Cl>CN(C)C=O.O>[Cl:6][CH:7]1[CH:19]=[C:11]2[CH2:12][O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:9]([C:10]=32)[C:8]1([C:22]1[N:27]=[C:26]([S:28]([CH3:30])=[O:29])[N:25]=[C:24]([SH:3])[N:23]=1)[C:20]#[N:21]
Reactant: CS(=O)c1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Reactant: CC([O-])=S
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)c1nc(S)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium thioacetate (2.54 g, 22.2 mmol) was added to a suspension of 4-(5-chloro-6-cyano-1H,3H benzo[de]isochromen-6-yl)-6-methylsulfinyl-[1,3,5]triazin-2-ylamine (4.00 g, 11.1 mmol) in N,N-dimethylformamide (100 mL) at room temperature. After the mixture was stirred at room temperature for 6 hours, an 2N aqueous sodium hydroxide solution (100 mL) was added thereto. After the reaction solution was stirred at room temperature for 30 minutes, the pH was adjusted to 5 to 6 with 1N hydrochloric acid. Water (200 mL) was further added to the solution, and the precipitate was collected by filtration. The precipitate was washed in succession with water and diethyl ether, and then dried under reduced pressure. The title compound was obtained as brown solid (3.25 g, 88%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][S:2]([CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC(=O)Nc1c(C)cccc1C
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CS(C)=O
Temperature: 5 °C
Reaction time: 1.25 h
Yield: 88 %

Procedure:
To a methylene chloride solution containing 2.09 g (10 mmol) of 2-methylthio-N-(2,6-dimethylphenyl)acetamide was added, in portions over 30 min with stirring at 5° C., 2.16 g (10 mmol) of m-chloroperbenzoic acid (80% solution). The reaction mixture was kept at 5° C. for an additional 1.25 hr. The precipitate formed was filtered and washed twice with methylene chloride. The filtrate and washings were combined, washed once with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to afford white crystalline compound (88% yield), mp 112°-114° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[N:25]=2)=[CH:20][CH:19]=1.C(O)(=O)C>C(O)C.[OH-].[Na+].O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[N:25]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cn1nnc(-c2ccc(CCc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1nnc(-c2ccc(CCc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of ethyl [5-(4-(3-(2-quinolinylmethyloxy)phenethyl)phenyl)tetrazol-3-yl]acetate in 5 ml ethanol and 40 ml of 1N NaOH is stirred at 70° C. for 4 hours.This is cooled, diluted with water, acidified with acetic acid, filtered, washed with water, and then ethyl acetate to give 5-(4-(3-(2-quinolinylmethyloxy)phenethyl)phenyl)tetrazol-3-yl acetic acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:18][CH:19]([OH:30])[CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[CH3:31]I>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][CH:19]([O:30][CH3:31])[CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: CI
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(NCC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)OC)c1
Reaction time: 2.5 h

Procedure:
Sodium hydride (9.0 mg, 0.23 mmol) was added to a stirring solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (99.3 mg, 0.20 mmol) in DMF 0.5 ml, 0.39 M). The solution was stirred at room temperature for about 70 minutes before the dropwise addition of a solution of methyl iodide (14 ml. 0.22 mol) in DMF (1.0 ml). The reaction was monitored by lc/ms for the consumption of SM and the appearance of O and N-methyl products. After 2.5 hours of stirring at r.t, conversion was about 30% and about 5% N-methyl product had formed. The reaction was stopped when an increase of N-Me to O-Me had been observed and conversion was about 50%. The brown solution was diluted with ethyl acetate and washed several times with water and finally brine. The organic layer was dried over Na2SO4, filtered and condensed. The mixture was purified by preparative TLC 30% EtOAc/hexanes.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].Br[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CCCC)CCCC)CCC.C(O)C>C(O)(=O)C>[C:7]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:3][CH:1]=[O:2])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CC=O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: CCCCN(CCCC)CCCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCC=O)C(=O)OCC
Reaction time: 2.5 h

Procedure:
First, 100 ml acrolein was added to a solution of 180 g diethyl bromomalonate, 14 g tributylamine, and 600 ml ethanol while cooling in an ice bath. After 2-3 hours, an additional 1.5 g tributylamine and 20 ml acrolein was added. The stirring was continued for an additional 1 to 2 hours without additional cooling. The reaction mixture was neutralized with 7 ml glacial acetic acid and the ethanol and unreacted acrolein were removed on a rotary evaporator. The residue was diluted with 500 ml benzene and washed with 3× 100 ml H2O and 2× 100 ml saturated NaCl solution. The benzene solution was dired over CaSO4 and rotary evaporated to yield 207 g of yellow oil which was indicated to be 48% product by glc.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[C:9]([CH2:11][S:12][CH2:13][C:14]([O:16]CC)=[O:15])[N:10]=2)[CH:7]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=3)=[C:9]([CH2:11][S:12][CH2:13][C:14]([OH:16])=[O:15])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)CSCc1nc2ccc(Cl)cn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)CSCc1nc2ccc(Cl)cn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
16 g (35.3 mmol) of ethyl 2-((6-chloro-3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methylthio)acetate were added to 75 ml of ethanol and 75 ml of tetrahydrofurane before adding 4.24 ml (42.4 mmol) of a 32% sodium hydroxide aqueous solution. The mixture was stirred at r.t. for 2 h, and then 50 ml of water were added after 30 min for solubilising the precipitated solid. The solvent was evaporated in vacuo, the obtained residue was diluted in 250 ml of water and 50 ml of diisopropyl ether, and then the solution was brought to an acid pH by adding 2.53 ml (44.2 mmol) of acetic acid. The precipitated solid was filtered and then washed with water and diisopropyl ether. 12.45 g (yield=83%) of 2-((6-chloro-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methylthio)acetic acid was obtained as a yellow solid. LC-MS: m/z=425 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), 8.96 (s, 1H), 8.19 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.84-7.63 (m, 3H), 7.50 (dd, J=9.5, 1.8 Hz, 1H), 4.07 (s, 2H), 3.40 (s, 2H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.C([O:34][C:35](=[O:47])[CH2:36][NH:37][CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)(C)(C)C>O1CCCC1.C(Cl)(Cl)Cl.O>[C:1]([NH:11][C@H:12]([C:14]([N:37]([CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)[CH2:36][C:35]([OH:47])=[O:34])=[O:16])[CH3:13])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
N-Carbobenzoxy-L-alanine (21.8 g) and 12.3 ml of triethylamine are dissolved in 200 ml of tetrahydrofuran, and 8.5 g of ethyl chlorocarbonate is added dropwise at -15° C. with stirring. After the dropping, stirring is continued for 15 minutes, and then a solution of 22 g of (indan-2-yl)glycine tert-butyl ester in 200 ml of chloroform is added dropwise at -10° C. or below. After stirring at room temperature for an hour, the reaction mixture is poured into 500 ml of water, and the chloroform layer is separated and the chloroform is distilled off. The residue is dissolved in 300 ml of ethyl acetate, the solution is washed with two 50-ml portions of 1 N aqueous sodium hydroxy, one 50-ml portion of water, two 50-ml portions of 20% aqueous phosphoric acid and one 50-ml portion of water, in that order, and then dried over anhydrous magnesium sulfate, and the solvent is distilled off to give 35 g of N-carbobenzoxy-L-alanyl-N-(indan- 2-yl)glycine terbutyl as an oil. This is dissolved in 300 ml of methanol and, after addition of 7 g of oxalic acid and 3.5 g of 10% palladium-carbon (containing 50% water), is subjected to catalytic reduction at ordinary temperature and ordinary pressure. After the reaction, the catalyst is filtered off, the filtrate is distilled off under reduced pressure, and 500 ml of ethanol is added to the residue. On cooling, a precipitate forms, which is collected by filtration and dried to give 21.8 g of L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate melting at 138°-141° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:15]([C:26]([F:29])([F:28])[F:27])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:54][C:49]2[CH:50]=[CH:51][CH:52]=[N:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:15]([C:26]([F:29])([F:27])[F:28])=[CH:14][C:10]=2[C:11]([NH:54][C:49]2[CH:48]=[N:53][CH:52]=[CH:51][CH:50]=2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Reaction time: 0.08 h

Procedure:
2-[(Phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 58; 69 mg) was dissolved in N,N-dimethylformamide (4 ml). Diisopropylethylamine (0.06 ml, 0.34 mmol) and HATU (130 mg, 0.34 mmol) were added, the solution was stirred for 5 minutes then 3-aminopyridine (32.2 mg, 0.34 mmol) was added. The solution was stirred for 90 minutes, the solvent was removed in vacuo and the residue purified by MDAP to give the title compound as a white solid. 29 mg.
Reaction SMILES: C([S:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N-:22]C(=O)C(F)(F)F)(=O)C.CO.C[O-].[Na+].[ClH:34]>O>[ClH:34].[NH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][SH:4]
Reactant: CC(=O)SCCOCCOCCOCCOCCOCC[N-]C(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCCOCCOCCOCCOCCOCCS
Temperature: 25 °C

Procedure:
A solution of compound 16 in 1 ml of abs. MeOH was cooled to −40° C., and admixed with 1.3 ml of freshly prepared NaOMe solution (cooled to −40° C., 1.3 mM). The solution was warmed to RT over the course of 30 min, admixed with 1 ml of H2O, and adjusted to a pH of 6 after 20 min with 1M HCl, and the solvent was removed. The residue was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[C:8]([Cl:29])=[N:9][NH:10]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Cl)c2c1COC(C)=O)C(=O)OCC
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-7-bromo-1H-indazol-5-yl)methyl)succinate (400 mg, 0.879 mmol) was dissolved in N,N-dimethylformamide (5.0 ml). N-Chlorosuccinimide (130 mg, 0.974 mmol) was added to the solution. Mixture was warmed to 150° C. and held with stirring for 1.5 hours. Mixture was cooled to room temperature and then diluted with ethyl acetate. Material was washed twice with water and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as clear colorless oil in 88% yield. MS (M+H)+=491.0.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[S:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:20]1[S:19][CH:23]=[CH:22][N:21]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: c1cscn1
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with an excess of 2-[2-aminoethyl)thiomethyl]thiazole according to the procedure of Example 3, results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 119°-120° (from acetonitrile). By the same procedure, reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with the following compounds
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:18][CH:17]3[CH2:19][C:13]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)=[CH:22][CH:21]=4)([CH2:14][CH:15]1[CH2:16]3)[CH2:12]2)C1C=CC=CC=1>CO>[N:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:13]34[CH2:19][CH:17]5[CH2:18][C:11]([NH2:10])([CH2:12]3)[CH:15]([CH2:16]5)[CH2:14]4)=[CH:25][CH:24]=2)[CH:30]=[CH:29][CH:28]=[CH:27]1
Reactant: O=C(NC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2)OCc1ccccc1
Solvent: CO
Product: NC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a stirred solution of the compound obtained from step I (0.8 g, 1.94 mmol) in MeOH (20 mL) Pd/C (10%, 0.1 g) was added. The reaction mixture was stirred at r.t. for 2 h under H2 pressure with a balloon. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain 2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-amine (0.45 g) as a viscous liquid (0.45 g) in 83% yield. m/z (M+1) 279; 1H NMR (CD3OD) 300 MHz δ 7.40-7.25 (m, 4H), 7.20-7.05 (m, 2H), 6.30-6.20 (m, 2H), 2.57-2.46 (m, 1H), 2.46-2.38 (m, 1H), 2.30-2.13 (m, 2H), 2.13-1.81 (m, 7H), 1.80-1.70 (m, 1H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][O:6][CH2:5]1)[CH:2]=C.[OH2:10]>C(#N)C>[O:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:1][CH:2]=[O:10])[CH2:5]1
Reactant: C=CC[C@H]1CCCOC1
Reactant: O
Solvent: CC#N
Product: O=CC[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a magnetically stirred solution of (R)-3-allyl-tetrahydro-2H-pyran (18.7 g, 148 mmol) in acetonitrile (740 mL) at room temperature was added RuCl3.2H2O (1.43 g, 5.92 mmol) in one portion. The resulting dark brown solution was stirred at room temperature for 5 min and then NaIO4 (69 g, 326 mmol) was added in one portion. H2O was added in small portions (10×8 mL) at 5 min intervals. The reaction was stirred at room temperature for 30 min, at which time it was judged complete by TLC. The reaction mixture was quenched by addition of saturated aqueous Na2S2O3 (250 mL) and H2O (1000 mL). The phases were separated and the aqueous phase was extracted with Et2O (4×400 mL). The combined with organic layers were washed with H2O, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish the crude product as a yellow oil. The crude material was purified by flash chromatography (ISCO; 120 g column; Hexane to 40% EtOAc/Hexane) to provide (R)-2-(tetrahydro-2H-pyran-3-yl)acetaldehyde as a yellow oil (14.3 g, 111 mmol, 60%); 1H NMR (400 MHz, CDCl3) δ 9.78 (t, J=2, 1H), 3.84-3.88 (m, 2H), 3.40-3.47 (m, 1H), 3.17 (dd, J=11.2, 8.8 Hz, 1H), 2.31-2.41 (m, 2H), 2.21-2.28 (m, 1H), 1.88-1.93 (m, 1H), 1.61-1.72 (m, 2H), 1.29-1.33 (m, 1H).