Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH2:41][CH2:40][C:39]2[CH:45]=[CH:46][C:36]([Cl:35])=[CH:37][CH:38]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(CCc2ccc(Cl)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), (E)-4-chlorostyrylboronic acid (54.8 mg, 0.301 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(4-chlorophenethyl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (31 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.82 Hz, 2H), 1.62 (d, J=7.58 Hz, 1H), 1.66-1.80 (m, 3H), 1.80-2.02 (m, 2H), 3.74 (br s, 1H), 4.41 (d, J=2.27 Hz, 1H), 4.50 (br s, 1H), 6.86 (d, J=5.56 Hz, 1H), 7.50 (d, J=8.59 Hz, 1H), 7.56-7.68 (m, 2H), 7.69 (s, 1H), 7.76 (br s, 3H), 8.21 (d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H22ClFN4O, 401. found, 401.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([Cl:26])[CH:24]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)c(Cl)c4)cc3CC[C@@H]12
Yield: 64.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 156 mg (64%) of the title compound as a foam. mp 129°-135°. FDMS: m/e=374. α[D]589 =+68.66 (c=1.03, chloroform).
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=1>>[O:69]1[C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=[C:68]1[S:67][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:54])[F:55])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:47])([F:48])[F:49])=[O:36])[CH2:30][CH2:29]1
Reactant: Sc1nc2ccccc2o1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(OCC(F)(F)F)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a colorless crystalline powder.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:2][CH3:3].O>C(O)C.[Ni]>[CH2:1]([C:4]1[N:5]=[C:6]([S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(SCCCC(=O)OCC)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCCc1nc(SCCCC(=O)OCC)sc1Cc1ccc(N)cc1
Yield: 21.6 %

Procedure:
3 g of ethyl 4-[[4-propyl-5-(4-nitrobenzyl)thiazol-2-yl]mercapto]butyrate in 50 ml of ethanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the filtrate, the brown oil obtained is taken up with acidified water. The aqueous phase is extracted with chloroform, rendered basic with dilute sodium hydroxide and extracted with ether. The ether solution is dried and concentrated to give a yellow oil, which is purified on a silica column (eluent: 7/3 cyclohexane/ethyl acetate) to give 0.6 g of ethyl 4-[[4-propyl-5-(4-aminobenzyl)thiazol-2-yl]mercapto]butyrate in the form of a pink oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[N:30]1[C:39]2[C:34](=[C:35]([NH:40][NH2:41])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[N:23]1([S:20]([C:16]2[CH:15]=[C:14]([N:9]3[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]4[N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[C:39]6[C:34]=5[CH:33]=[CH:32][CH:31]=[N:30]6)[N:41]=[CH:3][CH:4]=4)=[N:8]3)[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Reactant: NNc1cccc2ncccc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=513.4 (M+H)+
Reaction SMILES: [Mg].CO[CH:4]([O:12]C)[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:12])=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Under argon, 9.2 g (379 mmol) of magnesium are placed in 84 ml of THF and heated to 60° C. A solution of 82.6 g (357 mmol) of 4-bromobenzaldehyde dimethyl acetal (for preparation see J. Org. Chem. 56, 4280 (1991)) in 677 ml of THF is added dropwise thereto within a period of 30 min and the mixture is stirred at boiling temperature for a further 40 min. The Grignard solution is cooled, decanted into a dropping funnel and added dropwise within a period of 30 min to a reddish suspension of 31.7 ml (338 mmol) of 2-bromothiazole (Fluka, Buchs, Switzerland) and 5.39 g (9.95 mmol) of DPPP in 1.68 liters of THF. The mixture is stirred at room temperature for 12 hours; a further 5.39 g of DPPP are added and the mixture is stirred for a further 7 hours. 840 ml of water are added and the mixture is stirred for 10 min; the THF is evaporated off using a rotary evaporator and the residue is stirred for 1.5 hours in 1.0 liter of ether and 340 ml of 2N HCl. The aqueous phase is separated off and extracted 2× with ethyl acetate. The organic phases are washed 2× with 0.5N HCl, water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Chromatography (SiO2 ; hexane/ethyl acetate 4:1) and digestion in hexane yield the title compound: TLC: Rf =0.21 (hexane/ethyl acetate 3:1); m.p: 91-92° C.; Anal. (C10H7NOS) calc. C 63.47, H 3.73, N 7.40, S 16.94: found C 63.14, H 3.79, N 7.27, S 17.08; 1H-NMR (CDCl3) δ 10.05(S, HCO), 8.15 (d, J=8, 2H), 7.95 (m, 3H), 7.45 (d, J=3, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C@H:4]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[C@H:3]1/[CH:19]=[CH:20]/[C@@H:21]([OH:29])[CH2:22][C@@H:23]([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27].O[C@@H](C[C@@H](C)CCCC)/C=C/[C@H]1CCC(=O)[C@@H]1CCSC1SC=C(C(OCC)=O)N=1>>[OH:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C@H:4]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C@H:3]1/[CH:19]=[CH:20]/[C@@H:21]([OH:29])[CH2:22][C@@H:23]([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)OC
Agent: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCSc1nc(C(=O)OCC)cs1
Product: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O

Procedure:
By the same procedure as the reaction of Example 30 using methyl 7-{(1R,2R,3R)-3-hydroxy-2-[(1E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl}-6-oxoheptanoate (Reg No.70667-26-4) instead of the compound 29, the title compound having the following physical data was obtained.
Reaction SMILES: Cl[C:2]([F:32])([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18]CC2C=CC=CC=2)[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C.Cl>C(O)C.[Pd]>[F:32][CH:2]([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH2:18])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OCC)c1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reaction time: 18 h

Procedure:
A mixture of 340 g (0.722 mol) of product from Example 99, 87.67 g (0.866 mol) of triethylamine and 10.00 g of 5% Pd/C (50% water coated) in 700 ml of ethanol was hydrogenated at 50° C. under 446 kPa of H2 pressure for 18 hours. Then 150 ml of 18% HCl (0.722 mol) was added, and the mixture was hydrogenated at 50° C. under 446 of H2 pressure for 2 hours. The reaction mixture was filtered through celite, and concentrated in vacuo to remove the ethanol. The residue was taken up in H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concentrated in vacuo to 161.7 g (65%) of a brown oil, 90% pure by GC analysis. Then 5.0 g were purified by HPLC in 5% ethyl acetate/cyclohexane affording 3.9 g of product as a yellow solid; mp 29°-30° C.
Reaction SMILES: CC1C=CC=C2C=1C=C(C(OCC)=O)N2.[CH3:16][C:17]1[CH:25]=[CH:24][C:23]2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH2:30][N:21]3[C:22]=2[C:18]=1[CH:19]=[C:20]3[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Br:37]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:37][CH2:16][C:17]1[CH:25]=[CH:24][C:23]2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH2:30][N:21]3[C:22]=2[C:18]=1[CH:19]=[C:20]3[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCCCC3=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCOC(=O)c1cc2c(C)cccc2[nH]1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc2c(CBr)ccc3c2n1CCCCC3=O

Procedure:
In accordance with the process described in Example 22(a)-(c) except for using ethyl 4-methyl-1H-indole-2-carboxylate as a starting material, ethyl 5,6,7,8-tetrahydro-11-methyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (m.p. 98° C., recrystallized from isopropyl alcohol) was synthesized. Ethyl 5,6,7,8-tetrahydro-11-methyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (2.50 g, 8.76 mmol) was then dissolved in carbon tetrachloride (80 ml) and N-bromosuccinimide (1.72 g, 9.64 mmol) and 2,2′-azobisisobutyronitrile (43 mg) were added therein under refluxing condition to heat at reflux for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the obtained residue was purified with silica gel column chromatography (eluated with ethyl acetate/n-hexane=1/10) to give ethyl 5,6,7,8-tetrahydro-11-bromomethyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (3.12 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([NH:14][CH:15]=O)[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[BH4-].[Na+]>C(O)(=O)C>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CNc1nc(SCc2ccccc2)nn1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CNc1nc(SCc2ccccc2)nn1-c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
The product of stage (a) (31 g) was mixed with dioxan (200 ml) and 96% sodium borohydride (19.6 g) at room temperature, and acetic acid (30 ml) was added with vigorous stirring. The mixture was stirred at 100° C. for 2 hours, after which the solvents were removed and the mixture was added carefully to water. The product was then extracted with ethyl acetate and chromatographed on silica gel to give 21.4 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][NH:7][C:6]=2[CH:20]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:31]([C:28]3[CH:29]=[CH:30][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[C:6]=2[CH:20]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc2c(n1)Nc1ccc(Br)cc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1

Procedure:
A solution of 8-bromo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (5.16 g, 15 mmol, intermediate 36), (4-tert-butylphenyl)sulfonyl chloride (10.5 g, 45 mmol), pyridine (7.11 g, 90 mmol), DMAP (0.366 g, 3 mmol in DCM (75 mL) was stirred at rt for 24 h. The reaction was quenched with water, and the product was extracted with EtOAc (3×). The combined extracts were washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from DCM and hexanes to afford the title compound. LC/MS: m/e 542.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.76 (1H, d, J=2.3 Hz), 7.56 (1H, d, J=7.3 Hz), 7.36 (1H, dd, J=8.7, 2.3 Hz), 7.11 (2H, d, J=8.5 Hz), 7.09 (1H, d, J=7.5 Hz), 6.96 (2H, d, J=8.4 Hz), 6.72 (1H, s), 6.62 (1H, d, J=8.7 Hz), 4.70-4.90 (2H, br), 1.25 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:25])CC>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:16][CH2:15][CH:14]([F:25])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=c1c2ccc(Br)cc2nc2n1CCC(O)CC2
Solvent: ClCCl
Product: O=c1c2ccc(Br)cc2nc2n1CCC(F)CC2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-bromo-8-hydroxy-7,8,9,10-tetrahydroazepino[2,1-b]-quinazolin-12(6H)-one (200 mg, 0.64 mmol, 1 equiv) in DCM was added excess DAST under N2 at −78° C. After that, the resulting mixture was stirred at −78° C. for 3 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extract was dried over Na2SO4. After filtration and concentration, the crude product was purified by silica gel chromatography to give 200 mg of the desired product. MS (ESI): 311, 313 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]([CH3:17])[N:15]=[N:16][C:12]3=[CH:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)([OH:3])=O.C(Cl)(=O)C([Cl:29])=O>ClCCl>[Cl:29][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]([CH3:17])[N:15]=[N:16][C:12]3=[CH:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1N=NC2=CN=C(c3ccccc3Cl)c3cc(C(=O)O)ccc3N21
Solvent: ClCCl
Product: CC1N=NC2=CN=C(c3ccccc3Cl)c3cc(C(=O)Cl)ccc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
3.5 g (0.01 mol) of 8-carboxy-6-(2-chlorophenyl)-1-methyl[1,2,4]triazolo-[4,3-a][1,4]benzodiazepine are suspended in 40 ml of dichloromethane. While cooling in ice, 2.5 g (0.02 mol) of oxalyl chloride are added dropwise, and the mixture is stirred at room temperature for 2 hours. It is then concentrated and subsequently distilled twice with anhydrous chloroform. The crystalline residue is triturated with petroleum ether and filtered off with suction. 3.7 g (100%) of 8-chlorocarbonyl-6-(2-chlorophenyl)-1-methyl[1,2,4]- triazolo[4,3-a][1,4]benzodiazepine of melting point 295°-297° C. are obtained.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([NH:31]/[C:32](/[CH3:42])=[CH:33]\[C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:42]/[C:32](/[NH:31][CH:5]([CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:43])=[O:3])=[CH:33]/[C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)N/C(C)=C\C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C(=C/C(=O)c1ccccc1)NC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
0.333 g (0.56 mmol) [rac]-2-[1-Methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester were dissolved in THF/EtOH 1:1 (10 ml) and treated with 1.4 ml (1.4 mmol) aqueous sodium hydroxide solution (1 molar) and the reaction mixture was stirred for 1 hour at room temperature. It was then acidified with 1N hydrochloric acid and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. Purification by flash-chromatography (silica gel, eluent: gradient of dichloromethane and methanol) gave 0.218 g (69%) [rac]-2-[1-methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid as light yellow amorphous solid.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[NH:21][C:20]2=[O:27])=[CH:14][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][C:6]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[N:21]([CH:2]([F:4])[F:3])[C:20]2=[O:27])=[CH:14][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 80 °C

Procedure:
103 g of chlorodifluoromethane are conducted into a suspension of 145.0 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-4-methyl-1(2H)-pyrimidinyl]-benzoate and 59.0 g of anhydrous, finely powdered potassium carbonate in 1 l of dimethylformamide for 6 hours while stirring at 80° C. After cooling the solid constituent is filtered off under suction and rinsed with 100 ml of dimethylformamide. The filtrate is concentrated to a large extent under reduced pressure at 55° C., the residue is poured into 2 l of water and the aqueous mixture is adjusted to pH 3 with concentrated hydrochloric acid. The mixture is extracted with 1.5 l of ethyl acetate and the organic phase is washed twice with 1 l of water each time. dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:1) as the eluent. The product is dissolved in 1500 ml of hot n-hexane and the solution is treated with charcoal, filtered and concentrated to 700 ml at an elevated temperature. It is subsequently seeded and cooled to 5° C. while stirring. The resulting crystals are filtered off under suction, washed with n-hexane and dried. There is obtained isopropyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-2,6-dioxo-4-methyl-1(2H)-pyrimidinyl]-4-fluorobenzoate, m.p. 90°-93° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>C(O)C.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[S:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1SCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a mixture of 225.6 g of 4-chloro-3-nitrobenzotrifluoride and 136 g of benzyl mercaptan in 1.5 l of ethyl alcohol, at reflux, was added a solution of 72.5 g of 85% KOH in 120 ml of water over a 45 minute period. Reflux was continued for an additional three hours. The reaction mixture was cooled to 5° C. The precipitate was filtered off, washed with ethanol and water and dried to give 273.2 g of 2-nitro-1-[(phenylmethyl)thio]-4-trifluoromethylbenzene as a bright yellow solid, m.p. 132°-136°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][C:15]([CH3:28])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][C:15]([CH3:28])([C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1)[CH2:14][CH:11]1[CH2:13][CH2:12]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: CC(CNC(=O)c1ccccc1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.