Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19](=[O:21])[CH3:20])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BrH:23].BrBr>C(O)(=O)C>[Br:23][CH2:20][C:19]([C:18]1[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:22])=[CH:6][CH:5]=3)(=[O:9])=[O:8])[C:14]=2[N:15]=[CH:16][N:17]=1)=[O:21]
Reactant: Br
Reactant: CC(=O)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)CBr)ncnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
[5.95 g, 18.88 mmol] of 1-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethanone was dissolved/suspended in 90 mL of glacial acetic acid and [7.53 mL, 10.197 g, 37.76 mmol] of 30% hydrogen bromide in acetic acid. Added dropwise to this stirring mixture at ambient temperature, was [0.970 mL, 3.02 g, 18.88 mmol] of bromine in 10 mL of glacial acetic acid over 1.0 hour. The reaction was stirred an additional 4.0 hours at ambient temperature during which time a yellow precipitate forms. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase was washed with water, brine, and dried with anhydrous sodium sulphate and the solvent was removed under reduce pressure. The crude solid was triturated/stirred with MTBE overnight and the solid isolated via suction filtration and airdried to yield 4.2 g of pale yellow solid, a 56.6% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3=[C:20]4[C:14](=[C:15]5[N:24]([CH3:25])[CH:23]=[CH:22][C:21]([C:26](O)=[O:27])=[C:16]5[CH:17]=[CH:18]3)[C:13](=[O:29])[NH:12][C:11]4=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH2:46][NH2:47])[CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH:45]=1)[CH2:46][NH:47][C:26]([C:21]1[CH:22]=[CH:23][N:24]([CH3:25])[C:15]2[C:16]=1[CH:17]=[CH:18][C:19]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH:10]=[C:11]3[NH:12][C:13](=[O:29])[C:14]=2[C:20]=13)=[O:27]
Reactant: COc1ccc(F)cc1CN
Reactant: CN1C=CC(C(=O)O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1CNC(=O)C1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(F)cc1
Yield: 8 %

Procedure:
A stock solution of Example 56d and N,N-diisopropylethylamine (0.15 M and 0.42 M in N,N-dimethylacetamide, respectively, 254 μL) and (5-fluoro-2-methoxyphenyl)-methanamine (0.4 M in N,N-dimethylacetamide, 115 μL), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.22 M in N,N-dimethylacetamide, 254 μL) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0016 g (8%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.39 (d, J=2.14 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J=8.24, 2.14 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 7.05 (m, 4H), 6.87 (m, 2H), 6.56 (m, 2H), 4.49 (s, 2H), 4.07 (s, 3H), 4.61 (m, 2H), 3.85 (s, 3H). MS (APCI+) m/z 527.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].NC1C=CC([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=C(F)C=1>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([Cl:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1F
Product: CCOC(=O)C=Cc1ccc(N)cc1Cl
Yield: 99 %

Procedure:
Using 4-bromo-3-chloroaniline (5.0 g), Compound 8a (5.43 g, 99%) was obtained as a yellow solid in the same manner as Compound 2a was obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][N:13]2C(=O)CS[C:14]2=[O:19])=[CH:7][CH:6]=1>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][NH:13][C:14](=[O:19])[NH:2][N:3]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(CN1C(=O)CSC1=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CO
Product: O=C1NCC(c2ccc(Cl)cc2)=NN1
Yield: 57 %

Procedure:
Hydrazine hydrate (8.0 g, 160 mmol) and 19.55 g of 3-(2-(4-chlorophenyl)-2-oxo-ethyl)-thiazolidine-2,4-dione in 100 mL of methanol were stirred at room temperature over a weekend, then refluxed for 8 hours. The reaction mixture was cooled and the solids were filtered, washed with methanol and dried to give 9.06 g of white solid 6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-3-one (57% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:40][CH:41]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42]1)(=O)=O.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH2:40][CH:41]5[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[CH2:42]5)=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Reactant: O=C(Cn1cc(Nc2ncnc3cc(O)ccc23)cn1)Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(Nc4cnn(CC(=O)Nc5cccc(F)c5)c4)ncnc3c2)C1
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A mixture of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.59 g, 1.2 mmol), cesium carbonate (1.95 g, 6.0 mmol) and tert-butyl 3-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (assumed 1.3 mmol) in dimethyl acetamide (10 ml) was heated at 80° C. for 6 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 4 to 7% methanol in dichloromethane to yield tert-butyl 3-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.435 g, 65% yield): MS (+ve ESI): 562 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][Si:14]([C:17]#[C:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.9 %

Procedure:
A mixture of methyl 2-(2-iodophenyl)acetate (I1) (4.65 g, 16.8 mmol), PdCl2(PPh3)2 (295 mg, 421 μmol), CuI (80.0 mg, 421 μmol) and (trimethylsilyl)acetylene (2.80 mL, 20.2 mmol) in dry degassed THF (20 mL) and Et3N (20 mL) was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure to give a black residue which was adsorbed onto silica gel and purified using column chromatography (0-5% EtOAc in petroleum benzine 40-60° C.) to give the title compound I2 as a light brown liquid (4.63 g, 99%); 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J=7.5, 0.8 Hz, 1H), 7.32-7.14 (m, 3H), 3.84 (s, 2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS-B: rt 6.64 min.
Reaction SMILES: C(=[N:14][C:15]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:21]=2)[CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[OH-].[Na+]>C1COCC1>[CH2:26]([O:25][C:24]1[C:15]([NH2:14])=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:19][CH:18]=2)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(COc2ccc3cc(N=C(c4ccccc4)c4ccccc4)c(OCc4ccccc4)cc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc2ccc(OCc3ccccc3)cc2cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Benzhydrylidene-(3,6-bis-benzyloxynaphthalen-2-yl)-amine (0.628 g, 1.208 mmol) is dissolved in 15 mL of THF. A solution of 1 N HCl (15 mL) is added and stirred for 30 min. The crude reaction mixture is basified to pH 14 with 1 N NaOH and extracted with EtOAc. The combined organic layers are dried and evaporated to afford an orange oil. The oil is purified on silica, eluting with 9:1 hexanes/EtOAc and then 1:1 hexanes/EtOAc, to afford 3,6-bis-benzyloxynaphthalen-2-ylamine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].B(F)(F)F.CCOCC>C(Cl)Cl>[C:2]1([CH:1]2[S:13][CH2:9][CH2:10][CH2:11][S:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: O=Cc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(C2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of benzaldehyde (10.6 g, 100 mmol) and 1,3-propane dithiol in CH2Cl2 (150 mL) at room temperature was dropwise added BF3.Et2O (6.3 mL, 50 mmol) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with CH2Cl2, filtered and the filtrate washed with brine, saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford a white solid, which was recrystallized from a 1:1 mixture of ether and hexane to afford 17.0 g (87%) of the title compound (65) as white crystalline needles. 1H NMR (CDCl3, 400 MHz): δ 1.91 (m, 1H), 2.14 (m, 1H), 2.89 (m, 2H), 3.04 (m, 2H), 5.16 (s, 1H), 7.35-7.28 (m, 3H), 7.46 (m, 2H).
Reaction SMILES: C(OP([CH:9]1[S:14][CH2:13][CH2:12]C[S:10]1)(OCC)=O)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.[OH-].[Na+]>ClCCl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[S:14]1[CH2:13][CH2:12][S:10][C:9]1=[CH:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: CCOP(=O)(OCC)C1SCCCS1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C=C2SCCS2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-diethoxyphosphoryl-1,3-dithiane (23.4 g) and 3,4-dimethoxybenzaldehyde (16.0 g) in dichloromethane (70 ml) is added to a mixture of dichloromethane (85 ml), a 50% aqueous solution of sodium hydroxide (170 ml) and triethylbenzylammonium chloride (1.4 g). The mixture is stirred for 24 hours at room temperature. The two phases are then separated. The aqueous solution is extracted with dichloromethane (100 ml) and the combined organic solutions are washed with a 10% aqueous solution of ammonium chloride (3×100 ml) and with water (2×100 ml). The dichloromethane is dried over magnesium sulphate and evaporated in vacuo. The residue is purified by column chromatography on silica gel using chloroform as eluant. The product is dried in vacuo to constant weight to yield (1,3-dithiolan-2-ylidene)-(3,4-dimethoxyphenyl)methane, m.p. 74°--75°.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:29](=[O:28])[C:24]5=[CH:23][C:22]([O:21][CH3:20])=[CH:32][CH:31]=[C:25]5[C:26]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)N(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and 4-methoxyphthalic anhydride (1.78 g, 0.01 mole) in dichloromethane (100 ml) is stirred at room temperature for 3 hours. The solvent is then removed under reduced pressure and the residual material is purified by flash chromatography. The product is purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxyphthalimide.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])[C:5](=[O:9])[C@@H:6]1[O:8][CH2:7]1)[CH:2]=[CH2:3].[F-].[NH4+].C1COCC1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([N:4]1[C@H:10]([S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])[C@@H:6]([CH2:7][OH:8])[C:5]1=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCN(CS(=O)(=O)C(C)(C)C)C(=O)[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1C(=O)[C@H](CO)[C@H]1S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 197 mg (0.757 mmol) of N-allyl-N-tert.-butylsulphonylmethyl-(R)-glycidic acid amide in 1 ml of tetrahydrofuran is introduced at 0°, with the exclusion of moisture, into 8 ml of a tetra-n-butyl; ammonium fluoride/THF solution which has been prepared from 5.0 g of tetra-n-butylammonium fluoride trihydrate by dehydrating at 60° C./0.1 torr and making up to 20 ml with tetrahydrofuran. The reaction mixture is stirred for 2 hours at room temperature and then partitioned between methylene chloride and phosphate buffer solution (pH 8.0). The crude product obtained by drying over sodium sulphate and concentration by evaporation of the organic phase is chromatographed over preparative silica gel plates using hexane/ethyl acetate (1:3). the title compound is obtained in the form of colourless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[O:15]1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.CCCCCC.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[CH:20][C:16]1[O:15][C:14]([CH3:21])([CH3:13])[C:18](=[O:19])[CH:17]=1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)OC(C=Cc2ccc(F)cc2F)=CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of dry diisopropylamine (3.3 mL, 24 mM) in dry tetrahydrofuran (25 mL) at -78° C., was added dropwise 2.3N solution of n-butyllithium in hexane (10.4 mL, 24 mM). After the reaction solution was stirred 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 16 mM) in tetrahydrofuran (10 mL) was added dropwise. Hexamethylphosphoramide (4.4 mL, 24 mM) was then added dropwise after 30 minutes. Finally, 2,4-difluorobenzaldehyde (3.5 mL, 31.8 mM) in tetrahydrofuran (10 mL) was added in one portion. The reaction solution was stirred 10 minutes when trifluoroacetic anhydride (11.87 g, 55.7 mM) was added in one portion. Again, the reaction solution was stirred 15, minutes when triethylamine (5.6 g, 55.7 mM) was added and was allowed to warm to room temperature. The reaction solution was partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL). The layers were separated. The organic layers were then washed with saturated aqeuous sodium chloride (2×25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an orange liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford a yellow crystalline solid (2.6 g, 65% yield), m.p. 98.5°-100° C.
Reaction SMILES: COC([N:5]1[CH2:10][C@@H:9]([CH2:11][C@@H:12]([CH2:16][CH3:17])[CH2:13][CH2:14][CH3:15])[C:8](=[O:18])N(C)[C@@H]1C(C)(C)C)=O.Cl.[O:25]1CCOCC1>>[NH2:5][CH2:10][C@@H:9]([CH2:11][C@@H:12]([CH2:16][CH3:17])[CH2:13][CH2:14][CH3:15])[C:8]([OH:18])=[O:25]
Reactant: CCC[C@H](CC)C[C@@H]1CN(C(=O)OC)[C@@H](C(C)(C)C)N(C)C1=O
Reactant: C1COCCO1
Agent: Cl
Product: CCC[C@H](CC)C[C@H](CN)C(=O)O
Temperature: 105 °C
Yield: 57 %

Procedure:
A stirred solution of (2S,5R)-2-tert-butyl-5-((S)-2-ethyl-pentyl)-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester (0.185 g, 0.567 mmol) in a 1:1 mixture of 6N HCl/dioxane (8 mL) was heated at 105° C. for 6 days. The reaction was cooled to room temperature and concentrated under reduced pressure. The product was dissolved in 1:1 MeOH/H2O and loaded onto an ion exchange chromatography column (Varian SCX-Prepacked 10 g, 60 mL) and eluted with 1:1 MeOH/H2O (95%)+NH4OH. The fractions containing product were collected and concentrated under reduced pressure to yield 0.06 g (57%) of product: 1H NMR (400 MHz, CD3OD) δ ppm 0.9 (m, 6 H), 1.3 (m, 5 H), 1.4 (m, 3 H) 1.7 (m, 1 H), 2.5 (m, 1 H), 2.9 (d, J=6.6 Hz, 2 H). MS: M+1 (188).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12]([OH:17])(=[O:16])[CH2:13][CH2:14][CH3:15].O.[OH-].[Ca+2:20].[OH-]>CO>[C:9]([O-:11])(=[O:10])[CH2:8][CH2:2][CH3:3].[Ca+2:20].[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6].[C:12]([O-:17])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)O
Agent: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
L-Carnitine (0.5 g, 0.003 mol) and butyric acid (0.54 g, 0.006 mol) were added to 5 mL of water and 1 mL of methanol. To the resulting solution was added calcium hydroxide (0.22 g, 0.003 mol). The resulting slurry clarified during 15 minutes of stirring at room temperature. After continued stirring at room temperature for four hr, the solution was filtered, and the filtrate was concentrated to dryness under vacuum at bath temperatures that were less than about 70° C. The solid, L-carnitine calcium butyrate, was obtained in greater than 90% yield and had a melting point of 97.6° C., with decomposition and evolution of trimethylamine. (The melting point of L-carnitine was 186-190° C. Butyric acid is a liquid.) The solid was not hygroscopic. The solid had no objectionable taste but had a somewhat bitter aftertaste. The 1H-NMR spectrum (FIG. 2) is consistent with the structure of the salt and shows the presence of L-carnitine and butyrate in a molar ratio of approximately 1:2. (Calcium is not detected by 1H-NMR.)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]=[CH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2C=NCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2ccnc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-4-[methoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-imidazole from Step 2 (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-4methoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole.
Reaction SMILES: [OH-].[Na+].ClCl.[SH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[Na]>>[CH:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([S:5][S:5][C:6]3[S:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[N:10]=3)=[N:10][C:9]=2[CH:11]=1
Reactant: Sc1nc2ccccc2s1
Agent: ClCl
Agent: [Na+]
Agent: [Na]
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Yield: 99.4 %

Procedure:
A 55 gal. reactor was filled with 40 gallons sodium mercaptobenzothiazole (9.69 g./100 ml.). The agitator was set at 335 RPM and a Beckman pH combination probe and a Beckman redox combination probe were immersed in the solution. Sodium hydroxide solution, 1.95N, was pumped in at 0.26 gal./min. and vaporized chlorine fed in until the pH was 8.9 and the redox potential was +90 mv. Sodium mercaptobenzothiazole solution (0.69 g./100 ml.) was then pumped in at 25° C. at a rate of 47.5 gal./min. The sodium hydroxide solution and chlorine flow were controlled to maintain the pH between 8.9 and 9.4 and the redox potential between +90 mv. and 150 mv. A slurry of benzothiazyl disulfide at 49° C. was continuously withdrawn at the overflow. After a steady state condition was obtained, benzothiazyl disulfide was produced at a yield of 99.4% having a purity of 96%.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]2[N:11]([C:12]=1[CH3:13])[CH2:10][CH2:9][CH2:8]2)=O.[BH3-]C#N.[Na+].OP(O)(O)=O>C(Cl)Cl.[Zn+2].[I-].[I-]>[CH2:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]2[N:11]([CH2:10][CH2:9][CH2:8]2)[C:12]=1[CH3:13])[CH:2]([CH3:20])[CH3:1]
Reactant: Cc1c(C(=O)C(C)C)c(-c2ccccc2)c2n1CCC2
Agent: O=P(O)(O)O
Agent: [BH3-]C#N
Agent: [I-]
Solvent: ClCCl
Product: Cc1c(CC(C)C)c(-c2ccccc2)c2n1CCC2
Reaction time: 16 h

Procedure:
A solution of 2-methyl-1-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)-propan-1-one (7.5 g, 28 mmol) in CH2Cl2 (140 ml) is treated successively with NaCNBH3 (7.4 g, 112 mmol) and ZnI2 (12.5 g, 40 mmol) and the mixture is stirred at RT for 2 h (TLC: SiO2/diethyl ether; starting material Rf 0.75; product Rf 8.8). The mixture is covered with a layer of H3PO4 (8%, 200 ml) with ice cooling and stirred for 16 h. The CH2Cl2 phase is separated and washed with water (50 ml), dried over Na2SO4 sicc. and concentrated in vacuo. The residue (7.5 g, 106%) is recrystallized from MeOH.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.CN.[CH:34]([N:37](CC)C(C)C)(C)C>O1CCOCC1>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:24])[N:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]([C@@H:11]([NH:10][C:8]([C:3]1[C:2]([NH:37][CH3:34])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9])[CH3:12])=[CH:22]2
Reactant: C[C@H](NC(=O)c1nccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: C1COCCO1
Product: CNc1nccnc1C(=O)N[C@@H](C)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide (12) (133 mg, 0.30 mmol) in anhydrous 1,4-dioxane (6 mL) in a sealed tube, methylamine hydrochloride (102 mg, 1.51 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.51 mmol) were added sequentially. The resulting mixture was stirred at 140° C. in a sealed tube for 14 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-8% MeOH-DCM) to afford the product (S)-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-3-(methylamino)pyrazine-2-carboxamide (compound 56). ESI-MS m/z: 434.0 [M+H]+.