Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:13]#[N:14])=[CH:4][CH:5]1[CH:7]([C:8]([O-:10])=[O:9])[C:6]1([CH3:12])[CH3:11].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:13]#[N:14])=[CH:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:11])[CH3:12]
Reactant: COC(C#N)=CC1C(C(=O)[O-])C1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(C#N)=CC1C(C(=O)O)C1(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3 g of tert-butyl (1R,trans ΔZ) 3-(2-methoxy-2-cyanoethenyl)-2,2-dimethyl-cyclopropane carboxylate were dissolved in 60 ml of methylene chloride and 14.6 ml of trifluoroacetic acid were introduced slowly at 0° C. with stirring for 3 hours at 0° C. The mixture was evaporated to dryness by distillation under reduced pressure and cyclohexane was added to the residue. The mixture was again evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a mixture of hexane and ethyl acetate (4/6) yielded 2.05 g of (1R,trans,ΔZ) 3-(2-methoxy-2-cyanoethenyl)-2,2-dimethyl-cyclopropane carboxylic acid melting at 110° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(=O)(=O)(O)O.[CH3:20]O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:20])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(O)c1

Procedure:
3-hydroxy-4nitrophenylacetic acid (1.1 g) was refluxed in methanol (20 ml) containing 0.5 ml of conc. sulphuric acid for 4 hrs., diluted with water and extracted with diethyl ether. The organic layer was separated, washed with aqueous sodium bicarbonate, brine, dried and then evaporated to dryness to give methyl 3-hydroxy-4-nitrophenylacetate (1.2 g) as a gum which crystallised on standing.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([O:38]C)=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1.CO>O>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([OH:38])=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)[C@@H]1C[C@@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(CN(C(=O)CC(C)(C)C)[C@@H]2C[C@@H](C(=O)O)N(Cc3ccc4c(c3)OCO4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
Lithium hydroxide monohydrate (17 mg, 0.405 mmol) was added to a solution of methyl (2S,4R)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (10) (100 mg, 0.20 mmol) in 66% v/v methanol in water (1.0 mL). The mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure and the residue partitioned between dichloromethane (1.0 mL) and water (1.0 ml). The aqueous phase was acidified with 1.0 M aqueous citric acid and the two layers were vigorously stirred for 10 min at room temperature. The layers were separated and the aqueous layer was back-extracted with dichloromethane. The combined dichloromethane extracts were dried (MgSO4) and evaporated under reduced pressure to give the title acid (11) (70 mg, 72%) as an off-white solid:
Reaction SMILES: [C:1]1([C@@H:11]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=2)[CH3:12])[C:10]2[C:5](=CC=CC=2)[CH:4]=[CH:3][CH:2]=1.C1([C@@H](N)C)C=CC=CC=1.C1([C@@H](N)C)C2C(=CC=CC=2)C=CC=1>>[C:1]1([C@@H:11]([NH:13][C:14](=[O:25])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:19][CH:20]=2)[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:10]=1
Reactant: C=CCOc1ccc(C(=O)N[C@@H](C)c2cccc3ccccc23)cc1
Agent: C[C@H](N)c1cccc2ccccc12
Agent: C[C@H](N)c1ccccc1
Product: C=CCOc1ccc(C(=O)N[C@@H](C)c2ccccc2)cc1

Procedure:
The compound of this example [(S)-N-1-phenylethyl-4-allyloxybenzamide] was prepared in exactly the same manner as (S)-N-1-(1-naphthyl)ethyl-4-allyloxybenzamide in Example 1 except 2.5 g (0.014 mole) of (S)-1-phenylethylamine was used in Example 2 rather than 2 g (0.012 mole) of (S)-1-(1-naphthyl)ethylamine in Example 1. The (S)-N-1-phenylethyl-4-allyloxybenzamide product was isolated in a 67% yield; mp 147°-148° C.; [α]D25 -12.62° (c=0.745, CHCl3); IR (KBr): 3380 and 1640 cm-1 ; NMR (δ): 1.64 (3H, d, J=7.4 Hz), 4.60 (2H, d, J=4.4 Hz), 5.28-5.52 (3H, m), 5.88-6.60 (2H, m), 6.92 (2H, d, J=8.9 Hz), 7.16-7.44 (5H, m), 7.76 (2H, d, J=8.9 Hz). Anal. for C18H19NO2 ; Calcd: C, 76.87; H, 6.76; Found: C, 77.02; H, 6.82.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[S:13][C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]2[C:14](=[O:23])[C:15]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17].C(N(CC)CC)C.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CO>[CH:31]1([NH:37][C:20]([CH2:19][NH:18][C:16]([C:15]2[C:14](=[O:23])[N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]=4[S:13][C:4]3=[N:3][C:2]=2[OH:1])=[O:17])=[O:22])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)CNC(=O)c1c(O)nc2sc3c(n2c1=O)CCCCC3
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CNC(=O)c1c(O)nc2sc3c(n2c1=O)CCCCC3)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To the stirred suspension of [(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid (0.70 gm, 0.0020 mole) in dichloromethane (20 ml), triethylamine (0.85 ml, 0.0062 mole) and cyclohexylamine (0.29 ml, 0.0025 mole) were added. To the reaction mixture, hydroxybenzotriazole (0.28 gm, 0.0020 mole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.60 gm, 0.0031 mole) were added and stirred at room temperature for 12 hrs. Dichloromethane was distilled off and 1N hydrochloric acid (50 ml) was added to the residue, the separated solid was collected by filtration. The solid thus obtained was stirred in methanol (20 ml) at 60° C. for 0.5 hr, filtered and suck dried to give 0.60 gm title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:11]2=[O:28])[CH:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:35](I)=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:12]2[C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[N:10]([CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][C:35]4[C:30]([Cl:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:8]=3)[C:11]2=[O:28])=[CH:23][CH:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1ncccc1I
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)c3)C(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4Cl)c3)C(C)(C)C2=O)cc1
Temperature: 90 °C

Procedure:
To a solution of 0.8 g of 1-[(2-aminopyridin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione hydrochloride obtained in stage c) of Example 7 in 50 mL of dioxane are successively added under argon 0.628 g of 2-chloro-3-iodopyridine, 2.8 g of caesium carbonate, 150 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (xantphos) and 49 mg of palladium diacetate. The reaction mixture is heated at 90° C. for 3 hours and then filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) to give 0.51 g of 3-(4-tert-butylphenyl)-1-({2-[(2-chloropyridin-3-yl)amino]pyridin-4-yl}methyl)-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: C(OC([NH:11][C:12]1[C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]2[C:15]([C:16]3[CH:32]=[CH:31][O:30][C:17]=3[C:18](=[O:29])[O:19]2)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][C:12]1[C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:20]2[C:15]([C:16]3[CH:32]=[CH:31][O:30][C:17]=3[C:18](=[O:29])[O:19]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc2c1oc(=O)c1occc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(N)ccc2c1oc(=O)c1occc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl 7-benzyloxycarbonylamino-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 58, 0.318 g) in ethyl acetate (10 mL) was added a slurry of 10% palladium on activated carbon (0.032 g) in ethyl acetate (10 mL). The flask was de-gassed and filled with hydrogen and the mixture stirred at room temperature for 90 minutes. The mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give tert-butyl 7-amino-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.214 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(C)(C)C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:23]1[CH2:24][CH2:25][CH:20]([NH2:19])[CH2:21][CH2:22]1
Reactant: Fc1ccc2nccc(Br)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: NC1CCN(c2ccnc3ccc(F)cc23)CC1

Procedure:
Starting from 4-bromo-6-fluoroquinoline (commercial) and piperidin-4-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (223 mg, 40% over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:24])[CH2:20][O:21][CH2:22][CH3:23])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:25])[CH:3]=1.C([O-])(O)=O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](=[O:24])[CH2:20][O:21][CH2:22][CH3:23])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:25])[CH:3]=1
Reactant: CCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CCOCC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
The title compound is prepared from 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanol 10o according to the procedure described in Example 42, Step B except that the reaction mixture is not treated with saturated aqueous NaHCO3 containing sodium thiosulfate pentahydrate. MS APCI (+) m/z 426, 428 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.04 (s, 1H), 7.51 (d, 1H), 7.21 (dd, 1H), 6.51 (dd, 1H), 4.76 (s, 2H), 3.57 (q, 2H), 1.19 (t, 3H); 19F NMR (376 MHz, CD3OD) −133.96 (s).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:25][C@H:26](C)[CH2:27]O)[S:23][CH:24]=2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([N:25]3[C@H:26]([CH3:27])[CH2:2][O:4][C:5]3=[O:11])[S:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Reaction time: 3.5 h
Yield: 113 %

Procedure:
Triphosgene (2.62 g, 8.82 mmol) in 60 mL of methylene chloride was added under nitrogen dropwise over 1.75 h to a solution of (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol (2.30 g, 7.33 mmol), prepared in the previous step, and N,N-diisopropylethylamine in 125 mL of methylene chloride at ice-bath temperature. After the addition, the reaction was stirred at ice-bath temperature for 3.5 h. The ice bath was removed and the stirring continued for 15 h. The reaction was extracted with 2 N HCl, dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give 2.81 g of a yellow solid. Purification of the solid on 500 g of silica gel (230-400 mesh) using 30% methylene chloride-hexane to methylene chloride as the eluents gave the title compound (2.07 g, 83%) as a white solid, mp 197-199° C.; MS (ES) m/z 339.0 [M+H]+; Anal. Calcd for C13H11BrN2O2S: C, 46.03; H, 3.27; N, 8.26. Found: C, 45.80; H, 3.13; N, 8.16.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH2:20][S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:34])C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH2:20][S:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:34])[N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OO
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(CSc2ccccc2)ns1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(CS(=O)c2ccccc2)ns1

Procedure:
A mixture of 2-(2-tert-butylphenoxy)-N-(3-(phenylthiomethyl)-1,2,4-thiadiazol-5-yl)pyridin-3-amine (Example 470) (250 mg, 0.56 mmol), peracetic acid (32% wt/v, 132 μL, 0.56 mmol in DCM (3 mL) was stirred at rt for 2 h. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by preparative HPLC to give Example 471. (M+H)+=465; 1H NMR (400 MHz, DMSO d6) δ ppm 1.29 (s, 9H), 4.33 (d, J=13.13 Hz, 1H), 4.42 (d, J=13.13 Hz, 1H), 6.91 (td, J=7.84, 1.51 Hz, 1H), 7.08 (dd, J=7.84, 4.80, 1H), 7.16 (dt, J=7.58, 1.52, 1H), 7.22 (td, J=7.32, 1.76, 1H), 7.41 (dd, J=7.83, 1.52 Hz, 1H), 7.5-7.7 (m, 5H), 7.75 (dd, J=4.80, 1.51 Hz, 1H), 8.45 (dd, J=7.83, 1.51 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH2:15]O)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH2:15][N:21]2[C:20](=[O:22])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:27])=[CH:13][N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ncc(CO)s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ncc(CN2C(=O)c3ccccc3C2=O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To 20 ml of a THF solution containing 1.06 g of 2-(N-t-butoxycarbonylamino)methyl-5-hydroxymethylthiazole, 959 mg of phthalimide, 1.7 g of triphenylphosphine and 1.03 ml of diethyl azodicarboxylate were added, and the mixture was then stirred at room temperature for 1 hour. Then, the solvent was evaporated under reduced pressure, and the resulting residue was purified by a silica gel column chromatograph and Cephadex LH-20 in succession to obtain 1.02 g of 2-(N-t-butoxycarbonylamino)methyl-5-phthalimidomethylthiazole.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:9][CH3:10])(=O)=O.[F:15][C:16]([F:26])([F:25])[CH2:17][CH2:18][S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:14][C:11]([F:12])([F:13])[CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][CH:22]([S:19]([CH2:18][CH2:17][C:16]([F:26])([F:15])[F:25])(=[O:21])=[O:20])[C:23]#[N:24]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: CCC(CCOS(C)(=O)=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CCC(C#N)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
To a solution of 3.0 g of 3-(trifluoromethyl)pentyl methanesulfonate and 2.6 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 50 ml of dimethyl sulfoxide was added 1.8 g of potassium carbonate at room temperature, heated to 60° C. and then stirred at the same temperature for 3 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 3.00 g of 5-(trifluoromethyl)-2-(3,3,3-trifluoropropylsulfonyl)heptanenitrile (hereinafter referred to as the present compound (14)).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCCl>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([C:8]1[S:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CO
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3OC)sc2c1
Yield: 96.6 %

Procedure:
By the procedure of Example 5, 5.0 g. (0.0208 mole) of 3-phenyl-6-methoxybenzothiophene were treated with 3.60 g. (0.021 mole) of o-methoxybenzoyl chloride and 2.80 g. (0.021 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane as solvent. The crystalline product, 2-(2-methoxybenzoyl)-3-phenyl-6-methoxybenzothiophene (7.52 g.; 97 percent) was obtained from methanol, m.p. 111°-112° C. The product was sufficiently pure to be employed in the next succeeding step; however, a portion of the product was further purified by recrystallization from methanol with the following analytical result.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1)=[O:19]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
A mixture of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (10 g, 38.0 mmol), N,O-dimethylhydroxylamine hydrochloride (5.56 g, 57.0 mmol), and CH2Cl2 (120 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.92 g, 57.0 mmol) and 4-(dimethylamino)pyridine (0.464 g, 3.80 mmol). The mixture was cooled in an ice bath and treated with N,N-diisopropylethylamine (13.23 mL, 76 mmol) over 3 min. After 10 min, the cooling bath was removed and the mixture was stirred at RT overnight (˜14 h). The mixture was diluted with CH2Cl2 (150 mL), washed with saturated NaHCO3 (3×50 mL), 2 M HCl (2×50 mL) and brine, dried over MgSO4, and concentrated to provide a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and 10:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give the title compound (7.8 g, 25.5 mmol, 67% yield) as a pale yellow oil. LC-MS: 307.1, (M+H)+. 1H-NMR (400 MHz, CDCl3) δ ppm 7.25-7.37 (5H, m), 5.11 (2H, s), 4.21 (2H, s), 3.66-3.71 (3H, m), 3.16 (3H, s), 2.83 (3H, d, J=5.93 Hz), 1.64-1.75 (4H, m).
Reaction SMILES: [H-].[Na+].[P:3]([O-:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br)[CH3:22]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][P:3]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:20])[CH3:22]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60%, 2.52 g, 63 mmol) in DMF (60 mL) was added dibenzyl phosphite (12 mL, 48.45 mmol). After 15 minutes of stirring, ethyl-4-bromobutyrate was added and the mixture was stirred for 48 h at room temperature. The DMF was removed by evaporation. The residue was partitioned between brine, ammonium chloride and ether. The water phase was extracted several times with ether. The recombined organic layer was extracted with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed using 50% ethyl acetate in hexanes to afford the product as a colorless oil. 1H-NMR(CDCl3, 400 MHz: 1.23(t, J=7.2 Hz, 3H); 1.77-2.04(m, 4H); 2.37(m, 2H); 4.10(q, J=7.2 Hz, 2H), 5.03(m, 4H); 7.31(m, 10H). 31P-NMR(CDCl3, 400 MHz): 32.78.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29]N.S>C(O)C>[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][NH:25][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[O:24]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=O)cc21
Reactant: CC(C)CCN
Agent: S
Solvent: CCO
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
A solution of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (6 g), and 3-methylbutylamine (18.9 cc) in absolute ethanol (90 cc) is saturated with hydrogen sulphide and brought for 16 hours to a temperature in the region of 105° C. After cooling, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily brown residue is purified by chromatography on a column (height: 40 cm, diameter: 4 cm) of silica gel (0.02-0.063 mm), eluting with methylene chloride (1 liter) and then with a mixture (1.5 liters) of methylene chloride and methanol (95:5 by volume) and collecting 80-cc fractions. Fractions 23 to 36 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-(3-Methylbutyl)-10-[1-(1-pyrrolidinyl) -2-propyl]-2-phenothiazinecarboxamide, L series (6.76 g), is thereby obtained in the form of an orange-colored oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[C:33]([NH2:36])(=S)[CH3:34].O>CN(C=O)C>[NH2:36]/[C:33](/[CH3:34])=[CH:2]\[C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CC(N)=S
Reactant: O=C(O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
To a solution (6 ml) of 4-[[3-(2-bromoacetyl)-6-chloro-1-oxo-4-phenyl-1H-isoquinolin-2-yl]methyl]benzoic acid (570 mg) in DMF was added thioacetamide (170 mg), and the mixture was stirred at 70° C. for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (270 mg).