Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:13]2[C@H:18]([CH3:19])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:19][C@@H:18]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[C:1]1[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 90.5 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-piperidine-1-carboxylate (27.9 g, 78 mmol) in 1,4-dioxane (400 mL) was added HCl (4 N in 1,4-dioxane, 58.9 mL, 235 mmol). The resulting suspension was heated at about 60° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then was filtered, washed with 1,4-dioxane (100 mL) followed by Et2O (100 mL), to give 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (20.6 g, 89%) as a tan solid: LC/MS (Table 1, Method b) Rt=1.27 min; MS m/z: 256 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20]C)=[O:19])=[CH:7][N:8]2C(OC(C)(C)C)=O)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([OH:20])=[O:19])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(-c3ccc(OCc4cccnc4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCc4cccnc4)cc3)cc12
Temperature: 75 °C
Yield: 22.5 %

Procedure:
A mixture of crude 1-tert-butyl 3-methyl 6-chloro-5-[4-(pyridin-3-ylmethoxy)phenyl]-1H-indole-1,3-dicarboxylate (37 mg, 0.075 mmol), methanol (0.8 mL) and 1M aqueous sodium hydroxide (0.45 mL, 0.45 mmol) was sealed in a vial and heated at 75° C. for 17 hours, causing a solution to form. After cooling to room temperature, the reaction mixture was concentrated via a stream of nitrogen, and diluted with ethyl acetate and saturated aqueous citric acid slowly. The layers were separated, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were combined, concentrated in vacuo, and the resulting clear oil was dissolved in DMSO (0.9 mL) and purified via reverse phase prep-HPLC to give the title compound (6.4 mg, 23% over two steps). MS (ES+) 379.1 (M+H)+. Retention time: 2.28 min. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:36](=[O:49])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:50]1[CH2:55][CH2:54][NH:53][CH2:52][C:51]1=[O:56]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:53]4[CH2:54][CH2:55][NH:50][C:51](=[O:56])[CH2:52]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:49])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[S:38]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C1CNCCN1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-2-(2-trimethylsilanyl-ethoxymethyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (240 mg, 0.3 mmol) was treated as described in general procedure R using excess piperazin-2-one (301 mg, 3 mmol) to give 4-[4′-(4-(2,4-dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7](OC(=O)C)[CH2:6][CH2:5][C:4]([CH3:13])([CH3:12])[C:3]=1[C:14]#[C:15][CH:16](OC(=O)C)[CH3:17].C(Cl)Cl.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1>O>[C:14]([C:3]1[C:4]([CH3:13])([CH3:12])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:32])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC(=O)OC(C)C#CC1=C(C)C(OC(C)=O)CCC1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Yield: 60 %

Procedure:
In a 100 ml. three-necked flask fitted with a mechanical stirrer and a Dean-Stark water separator provided with a reflux condenser, a solution of 7 g. of 2,6,6-trimethyl-3-acetoxy-1-(3-acetoxy-but-1-ynyl)cyclohex-1ene in 70 ml. of methylene chloride is refluxed while stirring. Then 0.7 g. of p-toluenesulfonic acid is added and the reaction mixture is refluxed for an additional 7 hours. The reaction mixture is cooled and then poured into 70 ml. of water. The organic layer is separated, washed with 10% sodium bicarbonate solution and water. Drying over sodium sulfate and subsequent concentration yields 5 g. of a residue which gives, upon distillation using a short Vigreux column, 3 g. or 60% yield of 1-crotonoyl-2,6,6-trimethylcyclohexa-1,3-diene, b.p. 75°-80° C./0.1 mm, nD20 1.5150.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24](OC)=[O:25])=[O:19])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[OH:25][CH2:24][C:23]1[CH:22]=[C:21]([NH:20][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:19])[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(CO)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 15 %

Procedure:
Under a nitrogen gas stream, to a solution of methyl 3-({[4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazin-1-yl]carbonyl}amino)benzoate (300 mg, 0.710 mmol) in tetrahydrofuran (7.0 ml) was added, under ice-cooling, a 1.5 M solution of diisobutylaluminum hydride in toluene (4.7 ml, 7.10 mmol), and the mixture was stirred at room temperature for 2 hours. An aqueous saturated ammonium chloride solution was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 42 mg (15.0%) of the desired product as a solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.Cl.[NH2:21][C@@H:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:21][C@@H:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Agent: Cl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and (2S)-2-amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 99145-71-8) as starting materials, MS (EI): m/e=390.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:24][C:25]1[CH:30]=[CH:29][NH:28][C:27](=O)[CH:26]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[I:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([O:4][CH:2]([CH3:3])[CH3:1])[CH:26]=1
Reactant: CC(C)O
Reactant: O=c1cc(I)cc[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1cc(I)ccn1
Reaction time: 0.08 h

Procedure:
0.88 mL (11.4 mmol) 2-propanol and 3.00 (11.4 mmol) triphenylphosphine are added to 2.30 g (10.4 mmol) 4-iodo-1H-pyridin-2-one (XXI.1) in 130 mL DCM. Finally, 2.23 mL (11.4 mmol) DIAD are added at 0° C. After 5 min stirring, cooling is suspended and the mixture is stirred at rt for 2 h. After that time, the mixture is washed with water and brine, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silicia gel; heptane/EtOAc 90/10).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]3[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][C:22]2[NH:23][C:24]3[CH:30]=[C:29]([C:31]4[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=4)[CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCc2nc3ccc(C4=NNC(=O)CC4C)cc3[nH]2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27]C(OCC)C)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:33][C@H:23]([CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:35]2([CH3:41])[C@H:16]([C@H:15]3[C@H:38]([CH2:37][CH2:36]2)[C@:39]2([CH3:40])[C:12]([CH2:11][C@@H:10]([OH:42])[CH2:9][C@@H:8]2[OH:7])=[CH:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:34])[C:24]([OH:27])([CH3:25])[CH3:26]
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C[C@H](CC[C@@H](F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A mixture of 3.56 g. (0.0053 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, 140 ml. of methanol and 0.58 g. of p-toluenesulfonic acid monohydrate was stirred at 25° C. for 3 hr. The mixture was quenched by adding 1.0 g. of sodium bicarbonate and stirring for 0.5 hr. The mixture was then evaporated to dryness. The residue was triturated with ethyl acetate, filtered, and evaporated to dryness. The crude solid was recrystallized from ethyl acetate to yield [1α,3β,24R]-24-fluorocholest-5-en-1,3,25-triol, mp 156°-158°, [α]D21 +4° (c 0.5, MeOH).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[C:5]([N+:11]([O-])=O)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CO.C(OCC)(=O)C.[Fe]>[Br:2][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]([NH:7][CH3:8])=[CH:9][CH:10]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(Br)cc1N
Temperature: 25 °C

Procedure:
A mixture of iron (5.88 g, 105 mmol), ethanol (16 mL) and 2 M hydrochloric acid (3.1 mL) was sparged with nitrogen for 10 min, then heated to reflux. A solution of 4-bromo-N-methyl-2-nitroaniline (1.43 g, 6.19 mmol) in ethanol (14 mL), methanol (3 mL) and ethyl acetate (2 mL) was added to the hot mixture and the reaction stirred at reflux for 1 h. After this time, the reaction was cooled to room temperature and adjusted to pH 8-9 with potassium carbonate (˜850 mg). The mixture was filtered through diatomaceous earth and the filter cake washed with methanol (300 mL). The filtrate was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, methylene chloride to 19:1 methylene chloride/methanol) to afford 4-bromo-N1-methylbenzene-1,2-diamine. 1H NMR (400 MHz, DMSO-d6) δ 6.65 (d, J=2.4 Hz, 1H), 6.60 (dd, J=8.4, 2.4 Hz, 1H), 6.26 (d, J=8.4 Hz, 1H), 4.74 (s, 2H), 4.72-4.69 (m, 1H), 2.67 (d, J=5.2 Hz, 3H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][OH:31])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]([CH3:36])=[CH2:35]>C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][C:34]([CH3:36])([O:33][CH3:32])[CH3:35])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)OC
Reactant: O=C(O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Product: COC(C)(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 12.9 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetic acid, 120 ml of methylene chloride and 12 ml of 2-methoxy-propene was stirred for 20 minutes at room temperature and was then evaporated to dryness. The residue was stirred for another 30 minutes in 60 ml of methylene chloride and 12 ml of 2-methoxypropene and the mixture was evaporated to dryness under reduced pressure to obtain the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxyethoxyimino)-acetic acid which was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:21]([O-:23])=[O:22])[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].S(Cl)([Cl:26])=O>ClCCCl>[Cl:26][C:6]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[C:21](=[O:22])[O:23]1
Reactant: O=S(Cl)Cl
Reactant: COCC(CC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Solvent: ClCCCl
Product: COCC1CC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)OC1=O

Procedure:
A 340 mg portion of the Compound (78) obtained in Example 78 was dissolved in 14 ml of 1,2-dichloroethane. To the solution was added 0.34 ml of thionyl chloride, and the mixture was heated for 5 hours under reflux. The solvent was evaporated off, and the residue was subjected to a column chromatography using Florisil, followed by elution with hexane-ethyl acetate (5:1) to give 152 mg of the subject Compound (79) as colourless oily product.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([CH2:23][S:24]C(=O)C)[CH:6]([C:10]1[CH:11]=[N:12][C:13]([NH:16]C(=O)C(C)(C)C)=[CH:14][CH:15]=1)[CH2:7][CH2:8][CH3:9])C>Cl>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH:5]([CH2:23][SH:24])[C:4]([OH:28])=[O:3])=[CH:15][CH:14]=1
Reactant: CCCC(c1ccc(NC(=O)C(C)(C)C)nc1)C(CSC(C)=O)C(=O)OCC
Agent: Cl
Product: CCCC(c1ccc(N)nc1)C(CS)C(=O)O

Procedure:
2-Acetylsulfanylmethyl-3-[6-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-hexanoic acid ethyl ester (40.4 mg, 99 μmol) was dissolved under argon in aqueous hydrochloric acid (37%, 4.2 mL) and heated under reflux for 2 h. Concentration under reduced pressure (0.3 torr, 40° C.) gave the title compound as the hydrochloride salt (28 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:14])[NH:6]1)=[O:4].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:14])[N:6]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH3:28])=[O:4]
Reactant: COC(=O)C1Cc2c(F)cccc2N1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(F)c2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-fluoroindoline-2(R/S)-carboxylic acid methyl ester (0.43 g, 2.205 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (0.47 g, 2.33 mmol) dissolved in dried dichloromethane(10 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (0.36 ml, 2.33 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown solid which was purified by column chromatography on silica gel using 10:1 dichloromethane: diethyl ether as eluent. An off-white foam was obtained which was the mixture of the two diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH3:15])[C:10](=O)[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:35]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH3:15])[C:10](=[S:35])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Solvent: Cc1ccccc1
Product: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=S

Procedure:
7-(2-Chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-2H-1,4-benzoxazine-3 (4H)-one (2.5 g) prepared in Example 6 was dissolved in toluene (30 ml), and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (1.9 g) was added thereto, and the resultant mixture was refluxed for 2 hr. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to prepare the title compound (2.9 g) as a colorless crystal.
Reaction SMILES: CN1C2C(=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=N1.[CH3:18][N:19]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([CH:22]=[C:23]([N+:32]([O-:34])=[O:33])[CH:24]=[CH:25]2)=[N:20]1.[OH-].[Na+].Cl>C(O)C.O>[CH3:18][N:19]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([CH:22]=[C:23]([N+:32]([O-:34])=[O:33])[CH:24]=[CH:25]2)=[N:20]1
Reactant: COC(=O)c1c2ccc([N+](=O)[O-])cc2nn1C
Agent: COC(=O)c1nn(C)c2cc([N+](=O)[O-])ccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1nc2cc([N+](=O)[O-])ccc2c1C(=O)O
Reaction time: 2 h

Procedure:
670 mg of a mixture of methyl 1-methyl-6-nitro-1H-indazole-3-carboxylate and methyl 2-methyl-6-nitro-2H-indazole-3-carboxylate (Example XX) are dissolved in 20 ml of ethanol, combined with 10 ml 1 M sodium hydroxide solution and stirred for 2 hours. Then 10 ml of 1 M hydrochloric acid are added, the mixture is diluted with water and the precipitated solid is suction filtered. Then the solid is dissolved in dichloromethane/methanol 90:10. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is dried in vacuo. 640 mg of a mixture of 1-methyl-6-nitro-1H-indazole-3-carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid is obtained which is further reacted directly in Example XV (1) or in XV (2), respectively.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[N:12]=[C:11]([CH3:13])[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:21]=1)=[O:4].[F:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27](O)[CH2:28][CH2:29][O:30]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[F:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]([O:22][C:7]1[C:8]3[N:12]=[C:11]([CH3:13])[NH:10][C:9]=3[CH:21]=[C:5]([C:3]([N:2]([CH3:1])[CH3:23])=[O:4])[CH:6]=1)[CH2:28][CH2:29][O:30]2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C(=O)OC(C)(C)C
Reactant: OC1CCOc2cccc(F)c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc2c(OC3CCOc4cccc(F)c43)cc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a stirred mixture of 1,1-dimethylethl 6-[(dimethylamino)carbonyl]-4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (1.00 g, 3.13 mmol, STEP 2), 5-fluoro-3,4-dihydro-2H-chromen-4-ol (948 mg, 5.64 mmol, STEP 3-1) and triphenylphosphine (2.57 g, 9.79 mmol) in toluene (50 mL) was added diisopropyl azodicarboxylate (DIAD) (1.98 g, 4.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuum. The residue was dissolved in tetrahydrofuran (30 mL) and methanol (15 mL), and sodium hydroxide (750 mg, 18.8 mmol) was added to the mixture at room temperature. After stirring at room temperature for 1 hour, the mixture was quenched with saturated sodium dihydrogenphosphate aqueous solution, and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (dichloromethane only then ethyl acetate methanol 10:1 as an eluent) to afford the title compound as a white solid (510 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>>[CH2:17]([O:16][C:10](=[O:15])[C:11](=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[C:12](=[O:13])[CH3:14])[CH3:18]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-fluorobenzonitrile and ethyl acetoacetate: MS (m/z) 252.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[O:30][CH:29]=[N:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[S:11](=[O:40])(=[O:39])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41]>C(OCC)(=O)C>[ClH:41].[O:30]1[C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[S:16][C:15]([C:12]4([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:11](=[O:40])(=[O:39])[CH2:10][CH2:9][NH:8][CH2:14][CH2:13]4)=[CH:19][CH:18]=3)=[CH:25][CH:24]=2)=[CH:27][N:28]=[CH:29]1
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)OC(C)(C)C)CCS1(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCNCCS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-[4-tert-butoxycarbonyl-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (4.7 g) in ethyl acetate (40 ml) was added dropwise a solution 4N-hydrogen chloride in ethyl acetate (40 ml) under ice-cooling. After being stirred at 0° C. for 30 minutes and at ambient temperature for 1 hour, reaction mixture was concentrated in vacuo and hydrogen chloride was azeotropically removed with toluene to give tert-butyl 2-[7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate hydrochloride (4.2 g) as an oil.