Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11](#[N:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:10][C:11]([CH3:12])=[N:13][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CC#N
Product: Cc1ncc(-c2cccc(Cl)c2)o1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of Tl(OAc)3 (4.2 g, 11.1 mmol) in acetonitrile (80 ml), trifluoromethanesulfuric acid (5 g, 33.3 mmol) was added dropwise at room temperature and stirred for 15 min. The reaction mixture was then heated to 80° C. and 1-(3-chloro-phenyl)-ethanone (1.14 g, 7.4 mmol) in acetonitrile (40 ml) was added. After one h, the reaction was quenched with dichloromethane and saturated sodium bicarbonate. The organic layer was dried, purified by column chromatography with 5˜19% ethyl acetate in hexanes to give 1.2 (83.9%) g of 5-(3-chloro-phenyl)-2-methyl-oxazole as yellow oil. 1H-NMR(CDCl3) d(ppm): 7.60 (s, 1H), 7.48 (d, 1H), 7.29 (m, 2H), 7.23 (s, 1H) and 2.34 (s, 3H). Step 2: 2-Bromomethyl-5-(3-chloro-phenyl)-oxazole: 5-(3-chloro-phenyl)-2-methyl-oxazole (580 mg, 3 mmol) was mixed with NBS (531 mg, 3 mmol) and BPOA (36.3 mg, 0.15 mmol) in CCl4 at room temperature. The reaction mixture was heated at 75° C. for 2 h and then quenched with water and dichloromethane. The organic layer was dried, concentrated, purified by column chromatography with 2˜5% ethyl acetate in hexanes to give 562 mg (68.3%) of 2-bromomethyl-5-(3-chloro-phenyl)-oxazole as yellow oil. 1H-NMR(CDCl3) d(ppm): 7.67 (s, 1H), 7.54 (d, 1H), 7.35(m, 3H) and 4.56 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1>C(O)C.Cl>[CH3:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(CCc2ncccc2C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Cc1cccnc1CCc1ccc(N)c([N+](=O)[O-])c1
Yield: 90.2 %

Procedure:
A mixture of 3-methyl-2-[2-(4-acetamido-3-nitrophenyl)ethyl]pyridine (12.0 g) in ethanol (100 ml) and 17% hydrochloric acid (100 ml) was heated at 80° to 85° C. for 6 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in water. The resultant solution was adjusted to pH 8.0 with aqueous 20% potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 3-methyl-2-[2-(4-amino-3-nitrophenyl)ethyl]pyridine (9.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)=[O:20])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1cccc2c1CCNC2
Product: COc1cccc2c1CCN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 5-methoxy-1,2,3,4-tetrahydro-isoquinoline (CA [103030-70-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[C:44]#[N:45]>CN(C=O)C.O>[C:44]([C:43]1[CH:42]=[C:41]([NH:40][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:48]=[CH:47][CH:46]=1)#[N:45]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: N#Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cccc(C#N)c2)cc1
Reaction time: 0.25 h

Procedure:
5.0 g (33 mmol) 4-methoxybenzoic acid were dissolved in 50 ml DMF. 12.8 g (66 mmol) EDCI, 9.2 g (66 mmol) HOBt and 14.8 ml (132 mmol) 4-methylmorpholine were added and the mixture was stirred for 15 min. Subsequently, 3.9 g (33 mmol) 3-aminobenzonitrile were added and the mixture was stirred for 48 h at room temperature and 6 h at 80° C. The reaction mixture was poured in 500 ml water and the precipitate was filtered, washed and dried.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])[CH:26]=4)[CH2:21][CH2:20][N:19]3[N:38]=O)[CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>O1CCCC1>[NH2:38][N:19]1[CH2:20][CH2:21][C:22]2[C:27](=[CH:26][C:25]([O:28][CH2:29][CH2:30][NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:24][CH:23]=2)[CH:18]1[C:14]1([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(N=O)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(N)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A reaction vessel was charged with lithiumaluminium hydride (23.5 mg, 0.618 mmol) and dry tetrahydrofuran (1 mL). N-[2-({1-[1-(4-fluorophenyl)cyclobutyl]-2-nitroso-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (49 mg, 0.103 mmol, cf. example 75) was added dropwise as a solution in dry tetrahydrofuran (1 mL) at 0° C. After the addition was completed the reaction mixture was stirred at room temperature for 1 h and then at 40-50° C. for 1 h. After cooling to room temperature the reaction mixture was poured on ice water (15 mL) and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (RP, acetonitrile, water). Yield: 1 mg (2.2 μmol, 2%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:28]([CH3:27])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-methyl-1-phenylmethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-benzyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methylterephthalamide. MS (Q1) 490.1 (M)+.
Reaction SMILES: [N:1]([CH2:4][N:5]1[C:15]2[C:10](=[CH:11][C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])(=[O:18])=[O:17])=[CH:13][CH:14]=2)[C:8](=[O:9])[C:6]1=[O:7])=[N+:2]=[N-:3].[F:34][CH2:35][C:36]#[CH:37].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>[O-]S([O-])(=O)=O.[Cu+2].CN(C=O)C>[F:34][CH2:35][C:36]1[N:3]=[N:2][N:1]([CH2:4][N:5]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[C:8](=[O:9])[C:6]2=[O:7])[CH:37]=1
Reactant: [N-]=[N+]=NCN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)ccc21
Reactant: C#CCF
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
is prepared as illustrated in FIG. 2(ii), by reaction of (S)-1-(azidomethyl)-5-(2-(2,4-difluorophenoxymethyl)-pyrrolidine-1-sulfonyl)isatin] (compound 37) with 3-fluoroprop-1-yne (compound 28). The reagents are as follows: (a) CuSO4, L-ascorbic acid, DMF. For the preparation of [18F]6, 3-[18F]fluoroprop-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([OH:12])=O)[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C[N+](C)=CCl.[Cl-].ClCCl.[CH2:28]([O:31][C:32]([NH:34][CH2:35][C:36]1[N:43]2[C:39]([S:40][CH:41]=[C:42]2[CH2:44][NH:45][CH3:46])=[CH:38][N:37]=1)=[O:33])[CH:29]=[CH2:30]>C(N(CC)CC)C>[C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([N:45]([CH2:44][C:42]2[N:43]3[C:36]([CH2:35][NH:34][C:32]([O:31][CH2:28][CH:29]=[CH2:30])=[O:33])=[N:37][CH:38]=[C:39]3[S:40][CH:41]=2)[CH3:46])=[O:12])[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Reactant: C=CCOC(=O)NCc1ncc2scc(CNC)n12
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)NCc1ncc2scc(CN(C)C(=O)[C@@H]3C[C@H](SC(C)=O)CN3C(=O)OCC=C)n12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.5 %

Procedure:
The procedure of Synthesis Example 1 is repeated, except that 255 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonylpyrrolidin-5-carboxylic acid, 0.93 ml of a 1.1 M Vilsmeier reagent/dichloromethane solution, and 262 mg of 5-allyloxycarbonylaminomethyl-3-(N-methylamino-methyl)imidazo[5,1-b]thiazole are used and 0.145 ml of triethylamine is finally added at 4° C. followed by stirring at room temperature for additional 50 min. Thus, 327.5 mg of the title compound is prepared as a colorless amorphous material.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:15]([NH:14][CH:11]([CH3:13])[CH3:12])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(F)c(F)cc2[nH]1
Yield: 53 %

Procedure:
4,5-Difluoro-1,2-phenylenediamine (2.87 g, 19.91 mmol), isopropyl isothiocyanate (2.19 g, 21.65 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (11.38 g, 26.87 mmol) and pyridine (75 mL) were used according to general method I. The product was recrystallized from 1,4-dioxane to afford 2.23 g (53%) of a white solid; m.p. 188-189° C. Anal. Calcd for C10H11F2N3: C, 56.87; A, 5.25; N, 19.89. Found C, 56.95; H, 5.25; N, 19.98.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.C(Cl)Cl.[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C@H:34]1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][OH:75])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.S(=O)(=O)(O)O>C(O)C>[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C@H:34]1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[O:75])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCl
Product: O=CCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
(b)(i) PDC oxidation of 10-(2,3,4,6-tetra-O-benzyl-β-D-cralactopyranosyloxy)-n-decanol. Under an atmosphere of nitrogen, pyridinium dichromate (460 mg, 1.222 mmol) was added to a dry methylene chloride solution (10 mL) of 10-(2,3,4,6-tetra-O-benzyl-β-D-galactopyrano-syloxy)-n-decanol (570 mg, 0.818 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 20 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 20% ethyl acetate in hexanes) afforded 374 mg (0.539 mmol, 66%) of 10-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-decanal as a clear oil. Rf =0.61 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3 300 MHz) δ: 9.77 (t, J=1.5 Hz, 1H), 7.30 (m, 20 H), 4.97 (dd, J=12.0, 2.7 Hz, 2H), 4.78 (d, J=11.1 Hz, 1H), 4.77 (d, J=4.5 Hz, 1H), 4.65 (d, J=12 Hz, 1H), 4.46 (d, J=4.2 Hz, 2H), 4.38 (d, J=7.8 Hz, 1H), 3.95 (m, 1H), 3.84 (dt, J=10.2, 1.8 Hz, 1H), 3.50 (m, 6H), 2.40 (dt, J=7.5, 1.8 Hz, 2H), 1.65 (m, 6H), 1.30 (m, 10 H); MS (FAB+): 701.0 ((M+Li)+, 100), 455.1 (4), 181.1 (19), 160.0 (8).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10]>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([C:11]1[NH:15][CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Solvent: CCO
Product: Cc1cccc([C@@H](C)c2ncc[nH]2)c1C
Yield: 49.3 %

Procedure:
The compound of Example 1 (750 mg, 3.75 mmol) was dissolved in ethanol (4 ml) and the enantiomers were separated by automated preparative liquid chromatography (Gilson system, 50×50 mm ID Chiralcel OD, 20 μm column, 50 ml/min) using ethanol:hexane [10:90] as the mobile phase. The appropriate fractions were combined and concentrated to give the title compound (370 mg).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([F:26])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[F:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2cccc3cncc(F)c23)CC1
Agent: Cl
Solvent: CO
Product: NC1CCC(Nc2cccc3cncc(F)c23)CC1
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 77 (90.8 mg) and 10% hydrogen chloride/methanol solution (2 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (75.4 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[Cl:13][CH2:14][CH2:15][NH2:16].[Cl:17][CH2:18][CH2:19]N.C(N(CC)CC)C>ClCCl.O1CCCC1>[Cl:13][CH2:14][CH2:15][N:16]([CH2:19][CH2:18][Cl:17])[C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCCl
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CCCl)CCCl
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
13.2 ml (92 mmol) of benzyl chloroformate are added slowly to a solution, cooled to 0° C., of 15 g (84 mmol) of bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran, stirred beforehand for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 20 g of crude residue are obtained and purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 6 g (26%) of benzyl bis(2-chloroethyl)carbamate are thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)[CH:7]=1.C(OCC)(=O)C.O.[CH3:33][N:34](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([C:33]#[N:34])=[CH:7][C:6]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2
Reactant: Cc1ccc(Br)cc1C1SCCNc2c1c(-c1ccccn1)nn2C
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)cc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 120 °C
Yield: 20 %

Procedure:
To a degassed solution of 4-(5-bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.250 g, 0.6 mmol, Example D.27) in anhydrous DMF (3 mL) was added zinc cyanide (0.0511 g, 0.43 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.0346 g, 0.03 mmol). The resulting mixture was heated, in a sealed microwave vessel, for about 1 h, at about 120° C. in a microwave. After cooling to rt, ethyl acetate (50 mL) and water (50 mL) were added, and the mixture was filtered through a pad of Celite®. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate 1:1) followed by trituration with diethyl ether to give 4-methyl-3-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzonitrile (0.042 g, 0.117 mmol, 20%). LC-MS (Table 1, Method e) Rt=8.10 min, m/z 362 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 2.57-2.66 (1 H, m) 2.63 (3 H, s) 2.70 (1 H, dd, J=14.7, 4.4 Hz) 3.04 (1 H, ddt, J=13.1, 10.6, 1.6 Hz) 3.68-3.77 (1 H, m) 3.79 (3 H, s) 5.87 (1 H, d, J=5.5 Hz) 6.87 (1 H, s) 7.17 (1 H, ddd, J=7.4, 4.9, 1.3 Hz) 7.34 (1 H, d, J=8.0 Hz) 7.46 (1 H, dd, J=7.8, 1.8 Hz) 7.54 (1 H, d, J=1.8 Hz) 7.70 (1 H, ddd, J=9.4, 7.3, 1.8 Hz) 7.86 (1 H, dt, J=8.0, 1.0 Hz) 8.46 (1 H, ddd, J=4.9, 1.9, 0.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][NH:11][C:10]2=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24].O>CN(C)C=O>[CH2:23]([O:25][C:26]([N:12]1[C:13](=[O:14])[N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:10](=[O:15])[NH:11]1)=[O:27])[CH3:24]
Reactant: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 2.5 g of 4-(3',5'-dichlorophenyl) urazole and 1 g of triethylamine in 10 ml of N,N-dimethylformamide was added dropwise 1.1 g of ethylchloroformate with agitation. The reaction and agitation were continued at room temperature for one hour. The reaction mass was mixed with water to precipitate crystals which were filtered and recrystallized from acetone-ethanol to obtain 2.3 g of 1-ethoxycarbonyl-4-(3',5'-dichlorophenyl) urazole, which constituted a yield of 72%.
Reaction SMILES: [Cl-:1].[Ca+2].[Cl-].[Cl:4][C:5]1[C:6]([F:22])=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:12]=3[CH2:11][CH:10](O)[C:9]=2[CH:21]=1.Cl>C(Cl)Cl>[Cl:4][C:5]1[C:6]([F:22])=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:12]=3[CH2:11][CH:10]([Cl:1])[C:9]=2[CH:21]=1
Reactant: [Cl-]
Reactant: OC1Cc2ccc(F)cc2Sc2cc(F)c(Cl)cc21
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: Fc1ccc2c(c1)Sc1cc(F)c(Cl)cc1C(Cl)C2
Reaction time: 8 h

Procedure:
Powdered anhydrous calcium chloride (5 g) was added to a solution of the alcohol from the preceding preparation (7.6 g) in methylene chloride (100 ml) and anhydrous hydrogen chloride introduced into the suspension for 2 hours. The mixture was then allowed to stand overnight and filtered. The filtrate was evaporated, yielding 7.5 g of the desired 8,10-dichloro-3,7-difluoro-10,11-dihydrodibenzo(b,f)thiepine which is crystallized from cyclohexane. The pure compound melts at 118.5°-119.5° C.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][C:28]=2[Cl:33])=[C:23]([F:34])[CH:22]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][C:28]=2[Cl:33])=[C:23]([F:34])[CH:22]=1)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1ncc(Cl)c1-c1ccc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)NC(CN)Cc2ccccc2)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl]carbonyl}amino)-3-phenylpropyl]carbamate in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [F:1][C:2]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[C:42]([O:48]COC)[C:3]=1[C:4]([C:6]1[CH:41]=[CH:40][C:9]([C:10]([O:12][C@@H:13]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C@H:14]2[NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35]COC)=[CH:31][CH:30]=2)=[O:11])=[CH:8][CH:7]=1)=[O:5].C(O)(C)C.[ClH:56]>C(COC)OC>[ClH:56].[OH:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([NH:27][C@H:14]2[C@H:13]([O:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:4](=[O:5])[C:3]4[C:42]([OH:48])=[CH:43][CH:44]=[C:45]([O:46][CH3:47])[C:2]=4[F:1])=[CH:41][CH:40]=3)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[O:39])=[CH:34][CH:33]=1
Reactant: COCOc1ccc(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)CCC[C@H]2OC(=O)c2ccc(C(=O)c3c(OCOC)ccc(OC)c3F)cc2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: COCCOC
Product: COc1ccc(O)c(C(=O)c2ccc(C(=O)O[C@@H]3CCCNC[C@H]3NC(=O)c3ccc(O)cc3)cc2)c1F
Reaction time: 24 h

Procedure:
639.7 mg of tert-butyl (3R,4R)-4-[4-(2-fluoro-3-methoxy-6-methoxymethoxy-benzoyl)-benzoyloxy]-3-(4-methoxymethoxy-benzoylamino)-azepane-1-carboxylate were dissolved in 9 ml of dimethoxyethane and 9 ml of isopropanol and, after cooling to 0° C., saturated slowly with HCl gas and stored in a refrigerator for 24 hours. The solvent was removed completely under reduced pressure and the product was triturated with diethyl ether. The suspension obtained was stirred for several hours; the solvent was decanted off and, after the addition of a further amount of fresh solvent, the stirring was continued overnight. The product was filtered off, washed several times with diethyl ether and dried at 0.1 mbar and 50° C. There were obtained 479 mg of 4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12]([CH3:14])=[N:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.[S]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([CH3:15])[N:11]=[C:12]([CH3:14])[N:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(C)N=C(C)NC1c1ccc(F)cc1
Agent: [S]
Product: CCOC(=O)c1c(C)nc(C)nc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
Ethyl 6-(4-fluorophenyl)-1,6-dihydro-2,4-dimethyl-5-pyrimidinecarboxylate (75.7 g, 0.274 mol) and 9.67 g (0.3 mol) of powdered sulfur were heated together at 130°-150° C. for three and one-half hours. Afterhydrogen sulfide evolution had ceased, the melt was cooled to room temperature and flash chromatographed on silica gel, eluting with 10% ethyl acetate/hexane, to yield 48.7 g of ethyl 4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinecarboxylate.