Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8]([CH:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC)=[O:9])C.[CH3:22][C:23]([CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:24][CH2:25]O.Cl>CCCCCC.O.O1CCCC1>[CH3:21][C:11]([CH:12]=[CH:25][CH:24]=[C:23]([CH3:22])[CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:10][C:8]([OH:7])=[O:9]
Reactant: CC(C)=CCCC(C)=CC=CC(C)=CCO
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC(=O)O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of 30.3 g. of sodium ethoxide in 300 ml. of tetrahydrofuran was added 118 g. of diethyl 3-ethoxycarbonyl-2-methyl-2-propenylphosphonate. To the mixture was added 67 g. of 3,7,11-trimethyl-2,4,6,10-dodecatetraene-1-ol under stirring, chilling with ice and shielding from the light. After 1 hour, the reaction liquid was poured into 1 liter of water, and 1 liter of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml. portions of a mixture of methanoland water (2:1), and concentrated to give 99 g. ofa concentrate. To a refluxing solution of 8.2 g. of potassium hydroxide and 80 ml. of isopropyl alcohol was added 21 g. of the concentrate under shielding from the light. After 15 minutes, the reaction liquid was poured into 300 ml. of ice-water, made acidic by addition of hydrochloric acid, and extracted with 300 ml. of diethyl ether. The extract was washed with three 100 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was dissolved in 200 ml. of n-hexane and chilled to -20° C. to crystallize it. There was obtained 9.8 g. of the desired product as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31]C(OCC3C=CC=CC=3)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(O)=O>CO.[Pd]>[CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2OC)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(N)C(=O)OC(C)(C)C)cc2OC)cc1
Yield: 92 %

Procedure:
Prepared using General Procedure 4: A solution of 4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-3 (5.46 g, 8.81 mmol) and AcOH (5 mL) in MeOH (150 mL) was passed through the H-cube system with 10% Pd/C as a catalyst at 1 mL/min and 45° C. The reaction mixture was evaporated, dissolved in DCM (50 mL), and washed with saturated aqueous NaHCO3 (200 mL). The organic layer was dried over MgSO4 and concentrated to afford 3.93 g (92%) of 4-(2-amino-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-5. LCMS-ESI (m/z) calculated for C28H39NO6: 485; found 430 [M+H-tBu]+, tR=2.15 min (Method 4). 1H NMR (400 MHz, DMSO) δ 8.06-7.99 (m, 2H), 7.12-7.05 (m, 3H), 7.02-6.98 (d, J=1.9 Hz, 1H), 6.85-6.78 (dd, J=8.1, 1.8 Hz, 1H), 4.11-4.03 (t, J=6.5 Hz, 2H), 3.71 (s, 3H), 3.51-3.45 (t, J=6.9 Hz, 1H), 2.87-2.73 (dt, J=16.9, 6.5 Hz, 2H), 1.91 (s, 2H), 1.79-1.69 (p, J=6.8 Hz, 2H), 1.47-1.23 (m, 17H), 0.90-0.83 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:16])[C@@H:9]([CH2:17][C:18](O)=[O:19])[O:8][C@H:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[Cl-].[NH4+].Cl.C([N:34]=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:16])[C@@H:9]([CH2:17][C:18]([NH2:34])=[O:19])[O:8][C@H:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1
Reactant: CC(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN1C(=O)[C@@H](CC(N)=O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
1.0 g of trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid and 0.5 g of ammonium chloride were dissolved in 8 ml of dimethylformamide, and 0.46 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.7 ml of triethylamine were added, followed by stirring at room temperature for 30 minutes. After water was added, the solution was extracted with ethyl acetate, followed by washing with water, after which the solvent was removed and the residue was recrystallized to yield 0.75 g of a crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:24]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCOCC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and morpholine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.O.S(=O)(=O)(O)[OH:21]>C(OCC)(=O)C>[OH:21][CH:2]([CH2:18][OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:13])=[O:14])[S:11][C:7]=2[CH:6]=1
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1nc2ccc(OCC(O)CO)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2,3-Epoxypropoxy)benzothiazole-2-sulfonamide (1.21 gm, 4.25 mmol) was dissolved in ethyl acetate (35 mL) and added to water (25 mL) containing concentrated sulfuric acid (2.5 mL). This two phase mixture was stirred at room temperature overnight and then was poured into water and repeatedly extracted with 5% methanol/ethyl acetate (V/V). The extracts were dried (Na2SO4) and evaporated. The residue (1.2 gm) was dissolved in methanol and allowed to sit overnight to give 1.0 gm of impure product. This material was purified by chromatography on silica gel, eluting with 1% methanol/ethyl acetate (V/V). The combined fractions containing product were evaporated and the residue was triturated with methanol to give material which was recrystallized from methanol/ethyl acetate (0.3 gm), m.p. 183°-185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)#[N:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])ccc1-c1cccc(C#N)c1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
A solution of 2-bromo-5-nitrotoluene (8.82 gm, 40.83 mmol) in 1,2-dimethoxyethane (150 mL) was added to a solution of tetrakis(triphenylphosphine)palladium(0) (2.35 gm, 2.04 mmol) in 1,2-dimethoxyethane (100 mL) under nitrogen at room temperature. A solution of 3-cyanophenylboronic acid (J. Med.Chem., 1997, 40, 4208)(9.0 gm, 61.25 mmol) in ethanol (45 mL) was added and stirred for 10 mins. Finally, 2M aqueous sodium carbonate (234 mL) was added and the mixture was heated under reflux for 18 h. After being cooled, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with water, dried (Na2SO4), concentrated under reduced pressure and triturated with diethyl ether to give 1-(3-cyanophenyl)-2-methyl-4-nitrobenzene (8.48 gm, 87%) as a brown solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:5]([O:7][CH3:8])=[O:6])#[N:2].C([Sn]([N:33]=[N+:34]=[N-:35])(CCCC)CCCC)CCC>C1COCC1>[NH:33]1[C:1]([CH2:3][CH:4]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:5]([O:7][CH3:8])=[O:6])=[N:2][N:35]=[N:34]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)C(CC#N)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1nnn[nH]1)NC(=O)OCc1ccccc1
Yield: 85.8 %

Procedure:
2.5 g (9.54 mmol, 1 equiv.) of the compound of Example 51 (3-cyano-2-benzyloxymethanamidopropionic acid, methyl ester) was dissolved in 10 mL of dry THF and 3.0 g (9.54 mmol, 1 equiv.) of tri-n-butyltin azide was added. The reaction was refluxed for 72 hours followed by concentration in vacuo. 50 mL of 1M NaOH was added and the aqueous solution was extracted with ethyl acetate (3×50 mL). The aqueous solution was acidified to pH=1 with 4M HCl and extracted with ethyl acetate (4×60 mL). After drying over sodium sulfate, the organics were decanted and concentrated in vacuo to yield 2.5 g of the title compound. 1H-NMR (CDCl3): 7.3 p.p.m. (m, 5H); 6.1 p.p.m. (m, 1H); 5.1 p.p.m. (s, 2H); 4.8 p.p.m. (m, 1H); 3.8 p.p.m. (s, 3H); 3.5 p.p.m. (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[N:8]2[CH2:11][CH2:12][CH2:13][S:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>ClCCl>[CH:15]1([S:14][CH2:13][CH2:12][CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:10]=3)[C:6]([CH3:20])([CH3:19])[C:7]2=[O:18])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(C)C(=O)N(CCCSC2CC2)c2cc(N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C(=O)N(CCCSC2CC2)c2cc(NC(=O)c3ccncc3)ccc21

Procedure:
A solution of 6-amino-1-(3-(cyclopropylthio)propyl)-3,3-dimethylindolin-2-one (160 mg, 496 μmol), isonicotinoyl chloride (84.2 mg, 595 μmol) and DIPEA (192 mg, 260 μl, 1.49 mmol) in dichloromethane (3 ml) was stirred at room temperature for 3 hours. The crude material was purified by flash chromatography on silica gel using EtOAc/heptane as eluent. The title compound was obtained as yellow viscous oil (131 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[S:12]([Cl:15])(Cl)=[O:13].[OH2:16]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][C:7]=1[S:12]([Cl:15])(=[O:13])=[O:16]
Reactant: O
Reactant: COc1ccc(F)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(F)c(S(=O)(=O)Cl)cc1OC
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
To a suspension of sulfur trioxide N,N-dimethylformamide complex (4.108 g, 27 mmol) in 1,2-dichloroethane was added 4-fluoroveratrole (3.49 g, 22 mmol) dropwise. The mixture was slowly heated to 85° C. in an oil bath. After 2.5 h, the solids had dissolved to afford a golden yellow solution. A trace of starting material was still present and heating was continued for a further 4.5 h. The oil bath was removed and thionyl chloride (1.95 mL, 27 mmol) added dropwise. The mixture was heated 4 h at 85° C. and allowed to cool to room temperature. The solution was poured into water and extracted with dichloromethane (3×50 mL), the combined organics washed with water, dried over magnesium sulfate and evaporated. Remaining traces of N,N-dimethylformamide were removed azeotropically with toluene to afford the product as an off-white solid that was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=O)[CH2:27][CH2:26]2)=[CH:19][CH:18]=1>O1CCCC1>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]([C:10]3[S:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:13][C:12]=4[CH:11]=3)([C:5]3[S:1][C:2]4[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=4[CH:4]=3)[OH:33])[CH2:29][CH2:30]2)=[CH:21][CH:22]=1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Reactant: [Li]CCCC
Reactant: c1ccc2sccc2c1
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C(O)(c3cc4ccccc4s3)c3cc4ccccc4s3)CC2)cc1
Temperature: -78 °C

Procedure:
Dissolve benzo[b]thiophene(10.0 g, 74.5 mmol) in anhydrous tetrahydrofuran (100 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, n-butyllithium (32.79 mL, 81.97 mmol) and stir briefly. Add, by dropwise addition, a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (20.67 g, 74.52 mmol) in anhydrous tetrahydrofuran (200 mL) and stir at -78° C. for 1.5 hours. Quench with saturated ammonium chloride, separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl acetate/hexane) and recrystallize (isopropanol) to give the title compound as a white solid; mp 168°-179° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][CH:22]([C:24](O)=[O:25])[CH3:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][CH:22]([C:24]([NH:12][C:10](=[O:11])[C@H:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH2:1])=[O:25])[CH3:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Following General Procedure D and using phenylalanine amide (Bachem) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=177-179° C.). This compound was then purified by trituration with chloroform.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: CCCc1csc2c(NC)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC)c2scc(CCC)c2n1
Yield: 67.2 %

Procedure:
50 mg (0.21 mmol) of 2-chloro-4-methylamino-7-propylthieno[3,2-d]pyrimidine and 189 mg (3.31 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 37 mg (yield: 68.5%) of the title compound.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:15][C:16](=[O:18])[CH3:17]>ClCCl>[C:16]([NH:15][CH:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=2)[CH2:6]1)(=[O:18])[CH3:17]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)NC1Cc2ccccc2C1
Solvent: ClCCl
Product: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.6 ml of chloro sulfonic acid was dropped to the stirred solution of 1.06 g N-Indan-2-yl-acetamide and 50 ml of dichloromethane and the mixture was stirred for 15 hours at room temperature. The reaction was than quenched with cold water and die organic phase separated, dried over sodium sulfate evaporated. The resulting residue was used for further reaction without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([NH2:23])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([NH:23][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Product: CCOC(=O)C(=CNc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1)C(=O)OCC
Temperature: 120 °C

Procedure:
A suspension of 4,5-bis(phenylmethoxy)-2-pyridinamine (8.7 g, 28.4 mmol) in diethyl ethoxymethylenemalonate (61.4 g, 284.0 mmol) was heated to 120° C. (bath temperature) for 2 hours. The major part of the diethyl ethoxymethylenemalonate was distilled off in vacuo and 100 ml of ether was added after cooling. The mixture was stored in the refrigerator overnight. The resulting crystals were filtered off with suction, washed with ether and dried in vacuo. Yield: 10.81 g; melting point 117.3° C.
Reaction SMILES: O.O.O.O.C([O-])(=O)C.[Co+2:9].C([O-])(=O)C.C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:65]3[NH:66][C:62](=[CH:63][CH:64]=3)[C:61]([C:67]3[CH:72]=[CH:71][C:70]([C:73]#[CH:74])=[CH:69][CH:68]=3)=[C:60]3[N:75]=[C:57]([CH:58]=[CH:59]3)[C:56]([C:76]3[CH:81]=[CH:80][C:79]([C:82]#[CH:83])=[CH:78][CH:77]=3)=[C:55]3[NH:84][C:52]([CH:53]=[CH:54]3)=[C:51]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[CH:92])=[CH:87][CH:86]=3)[C:50]3=[N:93][C:47]=2[CH:48]=[CH:49]3)=[CH:42][CH:41]=1)#[CH:39].O>CN(C=O)C>[C:82]([C:79]1[CH:78]=[CH:77][C:76]([C:56]2[C:55]3[NH:84][C:52](=[CH:53][CH:54]=3)[C:51]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[CH:92])=[CH:87][CH:86]=3)=[C:50]3[N:93]=[C:47]([CH:48]=[CH:49]3)[C:46]([C:43]3[CH:44]=[CH:45][C:40]([C:38]#[CH:39])=[CH:41][CH:42]=3)=[C:65]3[NH:66][C:62]([CH:63]=[CH:64]3)=[C:61]([C:67]3[CH:68]=[CH:69][C:70]([C:73]#[CH:74])=[CH:71][CH:72]=3)[C:60]3=[N:75][C:57]=2[CH:58]=[CH:59]3)=[CH:81][CH:80]=1)#[CH:83].[Co:9]
Reactant: [Co+2]
Agent: C#Cc1ccc(-c2c3nc(c(-c4ccc(C#C)cc4)c4ccc([nH]4)c(-c4ccc(C#C)cc4)c4nc(c(-c5ccc(C#C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: [Co]

Procedure:
A solution of 8.71 g (35 mmol) of cobalt acetate tetrahydrate (Co(CH3COO)2.4H2O) in 100 ml of DMF was added portionwise to a solution of 1.7 g (2.39 mmol) of porphyrin TEPP (2) as obtained above in step 2), in 500 ml of DMF. The mixture obtained was refluxed for 20 hours. The heating was stopped and 150 ml of water were added to the reaction medium. The mixture was subsequently extracted with ethanol (4×200 ml) and the organic phase was then evaporated. The residue was dissolved in 300 ml of ethanol, and the organic phase was washed with 3×200 ml of water and dried over sodium sulfate. The solvent was evaporated off and the cobalt tetrakis(4-ethynylphenyl)porphyrin (Co-TEPP) (4) (1.19 g; 1.55 mmol; yield: 65%) was obtained in the form of a powder that was purple/black in color, and red in solution in chloroform.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][C:5](=[O:26])[CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH3:7].OO.CC(C)=[O:31].[OH2:33]>[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[CH3:1][S:2]([CH2:3][O:4][C:5](=[O:26])[CH:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)[CH3:7])(=[O:31])=[O:33]
Reactant: O
Reactant: CC(C)=O
Reactant: CSCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [NH4+]
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 g (0.096 mol) of 2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenoxy]-propionic acid [(methylthio)methyl]ester are dissolved in 120 ml of acetone/water (5:1) and treated slowly with 192 ml of a 30% solution of hydrogen peroxide. 96 ml of ammonium molybdate solution (35.2 g of ammonium molybdate in 96 ml of water) are added dropwise to the mixture which is cooled with an ice-bath. The mixture is stirred at room temperature for 2 hours. It is then extracted several times with ether, the ether extract is washed with sodium dithionite solution and the solution is again washed neutral with eight 100 ml portions of saturated sodium chloride solution and subsequently with five 100 ml portions of water. The mixture is treated with active carbon, filtered and evaporated. The residue is recrystallised from methylene chloride/n-hexane. There is obtained 2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenoxy]-propionic acid [(methylsulphonyl)methyl]ester which melts at 87°-88° C.
Reaction SMILES: Cl.[NH2:2][NH2:3].O.NN.C[O:8][C:9]([C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][C:18]=3[CH3:28])[N:13]([CH3:14])[CH2:12]1)=O>C(O)CC>[CH3:28][C:18]1[NH:19][C:20]2[C:27]3[C:17]=1[CH2:16][C@@H:15]1[C:25]([C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:26][C@H:11]([C:9]([NH:2][NH2:3])=[O:8])[CH2:12][N:13]1[CH3:14]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCCO
Product: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@H](C(=O)NN)CN1C
Reaction time: 15 h

Procedure:
15.9 g hydrazine hydrochloride and 18.4 ml hydrazine hydrate are added under stirring to 22.5 g of the product of step (a) in 20 ml n-propanol and the obtained reaction mixture is heated under reflux for 5 hours. The mixture is concentrated, treated with 500 ml H2O, filtered and washed with H2O (fraction A). The mother liquor is extracted with ethyl acetate and the extract evaporated. To the residue (7.5 g) are added 100 ml n-propanol and 20 ml triethylamine and the mixture is stirred and heated at reflux. The reaction is followed by thin layer chromatography. After approximately 15 hours when all of the β-product is converted into the 8α-product, H2O is added and the mixture is filtered. The filter cake is combined with fraction A and recrystallized twice from hot ethanol to afford the heading compound, m.p. 235°-240°, which is the pure α-isomer by NMR.