Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([F:11])([F:10])[F:9])[CH2:3][OH:4].[N:18]#[C:19]Br>>[F:11][C:8]([F:9])([F:10])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5][C@H:2]1[CH2:3][O:4][C:19]([NH2:18])=[N:1]1
Reactant: N#CBr
Reactant: N[C@H](CO)CCC(c1ccccc1)C(F)(F)F
Product: NC1=N[C@@H](CCC(c2ccccc2)C(F)(F)F)CO1

Procedure:
In analogy to example 1d (S)-2-amino-6,6,6-trifluoro-5-phenyl-hexan-1-ol was reacted with cyanogen bromide to give (4S)-4-(4,4,4-trifluoro-3-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 273.1 ([M+H]+))
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:13][CH:14]([C:19]([CH3:21])=[O:20])[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:21][C:19](=[O:20])[CH:14]([CH3:13])[CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C(C)CC(=O)O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C=CC(=O)C(C)CC(=O)O)cc1
Yield: 51.6 %

Procedure:
A solution of 8.2 g (0.05 mol) of 4-acetamidobenzaldehyde, 7.2 g (0.055 mol) of β-methyl levulinic acid, 6.3 g (0.075 mol) of piperidine in a mixture of 125 ml of toluene and 75 ml of tetrahydrofuran is heated under relux with a Dean Stark apparatus for two hours. The solution is evaporated under vacuo and the residue is taken up with dilute aqueous K2CO3 solution. The insoluble material is extracted with ether and discarded. The pH of the solution is adjusted to 5.6 and the gummy material is extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried, and evaporated. The residue is crystallized from 2-propanol to give 7.1 g of 6-[4(acetylamino) phenyl]-3-methyl-4-oxo-5-hexenoic acid, mp 189°-190° C.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O.O1CCOCC1>[O:1]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-phenoxybenzoate (0.144 g; 0.630 mmol) was added to a mixture of NaOH in water (1 mL; 2M) and dioxane (1 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipitated product was collected by filtration to yield 0.136 g (quantitative) of the title compound as a white solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:20]>N1C=CC=CC=1>[NH2:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:3]([C:4]#[N:5])[C:6](=[S:20])[NH2:7]
Reactant: S
Reactant: N#CC(C#N)=C(N)N1CCCC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#CC(C(N)=S)=C(N)N1CCCC1
Reaction time: 64 h

Procedure:
A mixture of 93.3 g of 3-amino-2-cyano-3-(1-pyrrolidinyl)propenenitrile, 58.2 g of triethylamine and 400 ml of pyridine was heated at 60°-65° and hydrogen sulfide passed in for 21/2 hours. While continuing the addition of hydrogen sulfide, the temperature of the mixture was increased to 80°, where it was maintained for two and a half hours. The mixture stood for 64 hours at ambient temperature, then was heated at 90° for 21/2 hours. The mixture was concentrated under reduced pressure. The tan solid residue was stirred with 750 ml of ice-water, the cold slurry was filtered and the solid was washed with cold water. The washed solid was recrystallized from 1200 ml of ethanol to give 87.4 g (three crops) of 3-amino-2-cyano-3-(1-pyrrolidinyl)propenethioamide, m.p. 164°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[N:55]=[C:54]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[O:53][N:52]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43]>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:59]1[CH2:58][CH2:57][CH:56]([C:54]2[O:53][N:52]=[C:51]([C:48]3[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:43])=[O:44])=[CH:46][CH:47]=3)[N:55]=2)[CH2:61][CH2:60]1)=[O:8]
Reactant: CS(=O)(=O)c1ccc(-c2noc(C3CCNCC3)n2)cc1
Reactant: O=C(O)CCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2noc(C3CCN(C(=O)CCCC(F)(F)F)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and diisopropylethylamine (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 4-(3-[4-(methylsulfonyl)phenyl-]1,2,4-oxadiazol-5-yl]piperidine (34c) (0.85 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Yield 69%; 1H NMR (CD2Cl2) δ 8.32 (d, J=8.7 Hz, 2H), 8.08 (d, J=8.7 Hz, 2H), 4.52-4.57 (m, 1H), 3.92-3.96 (m, 1H), 3.23-3.39 (m, 2H), 3.11 (s, 3H), 2.92-3.01 (m, 1H), 2.46 (t, J=7.2 Hz, 2H), 2.16-2.32 (m, 4H), 1.82-2.01 (m, 4H). tR LCMS 5.7 min. Purity >99%; MS [M+H]+ m/z 446.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1C=C[C:9](OC)=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].CCO[C:20]([CH3:22])=[O:21]>C(Cl)Cl>[Br:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=[CH:22][C:20]=1[OH:21]
Reactant: CCOC(C)=O
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(O)c1Br
Reaction time: 23 h
Yield: 79 %

Procedure:
BBr3 (1 M in CH2Cl2, 77 mL, 77 mmol) was added dropwise, over 1 h, to a stirred solution of 4-bromo-3-nitroanisole (5.0 g, 22 mmol) in 30 mL CH2Cl2 at -70° C. under nitrogen. The resulting deep burgundy-colored reaction was stirred overnight (23 h) and then poured onto 300 g crushed ice. EtOAc (250 mL) was added and the organic fraction washed with brine (250 mL), dried (MgSO4) and concentrated in vacuo to 5.06 g of a yellow-brown solid. Purification by column chromatography (EtOAc/hexane, gradient elution 5:95 to 15:85) afforded 3.77 g (79%) of 2-bromo-3-nitrophenol as a yellow solid: TLC (EtOAc/hesane 20:80) Rf =0.12; HPLC (Tr =12.2); 1H-NMR (CDCl3) δ 5.57 (s, 1H, --OH), δ 6.95 (dd, J=8 Hz, J=3 Hz, 1H), δ 7.36 (d, J=3 Hz, 1H), δ 7.58 (d, J=8 Hz, 1H); MS m/z (relative intensity) 218 (MH+, 100), 220 (MH+ +2.56).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@@H:10]([CH3:13])[O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][CH3:19].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:18]([CH3:19])[CH3:17])=[O:16])[C@@H:10]([CH3:13])[O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-threonine (2.33 g), 50% aqueous dimethylamine solution (1.08 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.58 g) in DMF (30 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.18 g) under ice-cooling. The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.02 g).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C@H:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:4]1>C(O)C.[H][H].[Pt](=O)=O>[CH3:1][N:2]([CH3:24])[C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C@H:5]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:4]1
Reactant: [H][H]
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(N)cc2)C1
Reaction time: 0.5 h
Yield: 107.1 %

Procedure:
370 mg of platinum dioxide were added to a solution of 3.7 g of cis N,N-dimethyl-5-[4-nitrophenoxy]-6,7,8,9-tetrahydro-benzocycloheptene-7-amine in 200 ml of ethanol and one liter of hydrogen was bubbled therethrough for 30 minutes with stirring. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 3.6 g of cis N,N-dimethyl-5-[4-aminophenoxy]-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-amine in the form of an orange oil. The said oil was dissolved in 20 ml of ethyl acetate and a solution of ethyl acetate saturated with gaseous hydrogen chloride was added thereto to adjust the pH to 1. The mixture stood for one hour at room temperature and was then vacuum filtered to obtain 4.1 g of the dihydrochloride of the cis compound in the form of colorless crystals melting at ≈260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[OH-].[K+].[C:13](=S)=[S:14].C>O.C(O)C>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[N:1]=[C:13]([SH:14])[NH:10][C:3]=2[CH:4]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(Cl)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1cc2nc(S)[nH]c2cc1Cl
Reaction time: 4 h
Yield: 575.7 %

Procedure:
The procedure of Van Allan and Deacon, Org. Synth. Coll. Vol. IV, 569, was adapted. A mixture of 1,2-diamino-4-chloro-5-fluorobenzene (528 mg, 3.29 mmol, Aldrich), potassium hydroxide (202 mg, 0.36 mmol), carbon disulfide (280 mg, 0.36 mmol), 95% ethanol (3 mL) and water (0.45 mL) was heated under reflux for 3 h. Activated charcoal (120 mg) was then added cautiously, and after the mixture has been heated at the refluxing temperature for 10 min the activated charcoal was removed by filtration. The filtrate was heated to 60°-70° C., warm water (3 mL) was added, and then acetic acid (0.25 mL) in water (0.5 mL) was added with good stirring for 4 h. The mixture was placed in a refrigerator overnight to give a mixture of brown and white crystals. The brown crystals were removed by washing with chloroform (5 mL). Recrystallization from hot EtOH/H2O gave pure title compound (420 mg, 63.5%, purity >99.57% by HPLC) as a white cubic crystals; top: 294°-6° C. (sub. from 250° C.). IR (KBr, cm-1): 3443, 3131, 3075, 1618, 1506, 1487, 1462. 1H NMR (DMSO-d6): δ 7.169 (d, J=9 Hz, 1H); 7.245 (d, J=6.6 Hz, 1H); 12.758 (s, 2H). HRMS: calcd for C7H4ClFN2S (M+) m/z: 201.9766, Found: 201.9779.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1.N1C2C(=NC=CC=2OC2C=CC(NC(NC(=O)CC3C=CC=CC=3)=S)=CC=2F)C=C1.[N-]=C=S.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[C:54]=1[CH2:60][C:61]([N:63]=[C:64]=[S:65])=[O:62].[ClH:66]>CO>[ClH:52].[ClH:66].[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:64]([NH:63][C:61](=[O:62])[CH2:60][C:54]3[C:53]([Cl:52])=[CH:58][CH:57]=[CH:56][C:55]=3[Cl:59])=[S:65])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1
Reactant: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: [N-]=C=S
Solvent: CO
Product: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Yield: 48 %

Procedure:
Starting from the compound 268 and following the procedure described above for the synthesis of compound 269a (example 221) but replacing 2-phenylacethyl isothiocyanate with 2-(2,6-dichlorophenyl)acetyl isothiocyanate, a white solid was obtained. This material was dissolved in MeOH and treated with HCl (1 mL, 1.0M in ether). Solvents were removed under the reduced pressure and the residue was lyophilized, to afford the title compound 269b (48% yield) as a yellowish solid. 1H NMR (DMSO-d6) δ (ppm): 13.29(s, 1H), 12.32(s, 1H), 12.05(s, 1H), 8.52(d, 1H,), 8.14(m, 2H), 7.64(m, 2H), 7.51(d, 1H), 7.37(dd, 1H), 6.86(m, 1H), 6.81(dd, 1H), 4.22(s, 2H), MS (m/z): 489.1(M+H) (found).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[C:19](O)(=[O:21])[CH3:20]>>[C:19]([O:11][CH:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][CH3:10])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CCC(O)c1cccnc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCC(OC(C)=O)c1cccnc1F
Temperature: 130 °C

Procedure:
2.75 g (17.7 mmol) of the product from example 48A are dissolved in 12 ml of glacial acetic acid and admixed with 4 ml of concentrated sulfuric acid. The mixture is heated to 130° C. for 30 min and, after cooling, stirred into ice-water. A pH of 8 is established with sodium hydroxide solution, and then extraction is effected with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated cautiously. This affords 3.30 g (94% of theory) of the title compound, which is converted further without purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([CH2:25][C:26]2[C:27](=[O:34])[NH:28][C:29](SC)=[N:30][CH:31]=2)=[CH:23][CH:22]=1.C(Cl)(Cl)Cl.CO.N.C(O)(=O)/C=C\C(O)=O>CC(C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[C:27](=[O:34])[NH:28][C:29]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]3[N:11]=[C:7]([NH:6][C:5]([NH2:17])=[N:4][CH2:3][C:2]([F:1])([F:18])[F:19])[S:8][CH:9]=3)=[N:30][CH:31]=2)=[CH:35][CH:36]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Agent: N
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CO
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNc2ncc(Cc3ccc(Cl)cc3)c(=O)[nH]2)cs1

Procedure:
An intimate mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.39 g.) and 5-(4-chlorobenzyl)-2-methylthiopyrimid-4-one (0.39 g.) was heated at 150°-160° for 20 min. during which time effervescence occurred. The residue obtained on cooling was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform (50:50 v/v; 200 ml.). Evaporation of the eluate gave a glass which was dissolved in acetone (0.3 ml.) and treated with an excess of a saturated solution of maleic acid in acetone to give a maleate salt of 5-(4-chlorobenzyl)-2-{4-[2-(2,2,2-trifluoroethyl)guanidinothiazol-4-yl]butylamino}-pyrimid-4-one as a white powder (0.1 g.) which contained 1.5 moles of maleic acid and 1.5 moles of water of crystallisation. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethylsilane (δ=0) as internal standard included the following resonances (δ): 3.45 (2H, singlet); 4.1 (2H, multiplet); 7.1 (3H, singlet-maleic acid); 7.45 (1H, singlet) and 8.2 (4H, singlet).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[CH2:2]([N:9]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:10][C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CNCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
N-Benzylglycine hydrochloride was taken up in 2-N sodium hydroxide and the mixture was stirred at -5° C. while 4-N sodium hydroxide and benzyl chloroformate were simultaneously added dropwise. The mixture was stirred in the cold for 2 hours and then stirred at room temperature for 0.5 hour. Excess benzyl chloroformate was removed by extraction with ether. The aqueous layer was cooled to -5° C. and acidified with concentrated hydrochloric acid. The mixture was stirred in the cold for 1 hour, then brought to room temperature and extracted 4 times with diethyl ether. The diethyl ether extracts were back-washed with water, filtered and then dried over anhydrous sulphate and again filtered. Evaporation gave N-benzyl-N-benzyloxycarbonyl-glycine in the form of an oil.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.C1C2C3C=CC(C2C=C1)C3.[CH3:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:22]1([C:5]2[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=2[NH2:7])[CH2:23][CH2:24][CH:20]=[CH:21]1
Reactant: CCCCC
Reactant: Cc1ccc(N)cc1N
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: Cc1cc(C2C=CCC2)c(N)cc1N
Temperature: 205 °C

Procedure:
A 200g (1.64 mol) portion of 2,4-toluenediamine, 162g (1.23 mol, 2,45 equiv) of dicyclopentadiene, 200g (2.78 mol) of pentane, and 20.0g of an amorphous alumina-silica catalyst comprised of 13% alumina and 87% silica were charged to a 1000cc pressure vessel equipped with a mechanical stirrer. The vessel was sealed and purged with nitrogen leaving a 32 psig nitrogen blanket. The vessel contents were heated to 205° C. with stirring and were maintained at that temperature for 22 hours. The contents were cooled to 150° C. and isolated catalyst free by hot filtration. Selective removal of residual hydrocarbons by vacuum distillation and analysis by gas chromatography (GC) provides the following product mixture.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[C:10]([F:18])[CH:9]=[CH:8][C:7]=1[S:6]2(=[O:20])=[O:19])#[N:2].[CH2:21](N)[CH2:22][NH2:23].C[O-].[Na+]>CO>[NH:2]1[CH2:21][CH2:22][N:23]=[C:1]1[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[C:10]([F:18])[CH:9]=[CH:8][C:7]=1[S:6]2(=[O:20])=[O:19]
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1C2=O
Reactant: NCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2cc(F)ccc2S(=O)(=O)c2cc(C3=NCCN3)ccc21
Reaction time: 120 h

Procedure:
A mixture of 6-cyano-2-fluorothioxanthen-9-one 10,10-dioxide, 5.2 g (0.02 mol), ethylenediamine, 1.2 g (0.02 mol), and sodium methoxide, 0.08 g (0.0015 mol), in methanol, 76 ml, was refluxed for 4 days. Additional ethylenediamine, 1.2 g (0.02 mol), was added and reflux continued for 5 days. The mixture was poured into ice and the precipitate was filtered, dried and recrystallised from ethanol, DMSO and H2O; affording 2.6 g of 6-(2-imidazolin-2-yl)-2-fluorothioxanthen-9-one 10,10-dioxide, m.p. 248°-249° C.; TLC on silica gel (triethylamine; ethanol; hexane/1:1:2), Rf =0.8.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([OH:38])=O)=[CH:31][CH:30]=2.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([NH:2][CH3:1])=[O:38])=[CH:31][CH:30]=2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2cnc(Cl)cc2c1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2cnc(Cl)cc2c1
Reaction time: 18 h
Yield: 60.4 %

Procedure:
HATU (17.6 mg, 0.046 mmol) was added to a solution of 3-chloroisoquinoline-6-carboxylic acid (Preparation 54, 8 mg, 0.039 mmol), DIPEA (54 uL, 0.31 mmol) and methanamine hydrochloride (15.6 mg, 0.231 mmol) in DMF (4 mL) and the reaction was stirred for 18 hours. The reaction was partitioned between EtOAc and brine, the separated organic phase was washed with saturated NaHCO3 solution, citric acid and brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as yellow oil (5.2 mg, 61%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:9]([F:19])[CH:8]=1.[O:20]=[C:21]1[CH2:24][CH:23]([C:25]([OH:27])=O)[CH2:22]1.[CH2:28]([NH2:32])[CH:29]([CH3:31])[CH3:30].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[CH2:28]([NH:32][C:25]([CH:23]1[CH2:22][C:21]([C:7]2[CH:18]=[CH:17][C:10]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:9]([F:19])[CH:8]=2)([OH:20])[CH2:24]1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: O=C1CC(C(=O)O)C1
Reactant: Fc1cc(Br)ccc1CN1CCCC1
Reactant: CC(C)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A 2.5 M solution of n-BuLi in hexanes (155 ml, 388 mmol) was added over 30 min to a solution of 1-(4-bromo-2-fluoro-benzyl)-pyrrolidine (100 g, 388 mmol) in THF (600 ml) in a 2 L round bottomed flask under a flow of nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 60 min. Then a −78° C. chilled solution of 3-oxocyclobutanecarboxylic acid (22 g, 194 mmol) in THF (264 ml) was cannulated under nitrogen and at −78° C. The mixture was warmed to RT slowly and left stirring for 18 h. Isobutylamine (38.5 mL 388 mmol) and T3P (148 ml, 233 mmol, 50 wt % solution in EtOAc) were added. The mixture was stirred for 60 min and then quenched with 1N NaOH (800 ml) and diluted with another 800 ml of EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (2×1 L) to recover crude product. This was purified by flash column chromatography using a 75 L Biotage™ column eluting with 100% EtOAc, followed with 25%, 30%, and 40% MeOH/EtOAc. The fractions containing the product were combined and concentrated under reduced pressure to obtain a semi solid which was triturated in Et2O and filtered to obtain the title compound as a white solid (43 g, 61% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CS(O[CH2:19][C:20]1[S:28][C:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=2[CH:21]=1)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:19][C:20]2[S:28][C:27]3[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=3[CH:21]=2)[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(Cc2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)CC1
Yield: 50 %

Procedure:
Potassium carbonate (26.5 mmol) and N-methylpiperazine (6.36 mmol) was added to a solution of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) in toluene (30 ml). The reaction mixture obtained was heated under reflux for 16 hours. The reaction temperature was then reduced to 25° C. and the reaction mixture was diluted with ethyl acetate. The reaction mixture was washed with water and saturated sodium chloride solution and dried over sodium sulfate. After the solvent had been removed under reduced pressure, the crude product obtained was purified by column chromatography (5% methanol in methylene chloride). The desired product was obtained in a yield of 50%.
Reaction SMILES: C([O:4][CH:5]([C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:6])(=O)C>P([O-])([O-])([O-])=O>[OH:4][C@@H:5]([C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]
Reactant: C=C(C(=O)OCC)C(C)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Product: C=C(C(=O)OCC)[C@@H](C)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 38.5 %

Procedure:
A mixture of ethyl 2-(1-acetoxyethyl)acrylate (1 g) and Lipase (0.25 g) in 0.1M phosphate buffer solution (pH 7.0) (80 ml) was stirred at room temperature for 60 hours. The whole mixture was extracted three times with ethyl acetate and the combined extracts were dried over magnesium sulfate. After removal of the solvent in vacuo, the crude product was purified by column chromatography on silica gel (eluent : a mixture of hexane and ethyl acetate, 2:1) to give ethyl 2-[(1R)-1-hydroxyethyl]acrylate (298 mg).