Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]3[CH:9]([OH:18])[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:18][CH:9]1[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[CH:25]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]2[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]12)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2nc(C(N)=O)nc21
Reaction time: 2 h

Procedure:
To a solution of 0.38 g. of 8-chloro-4-hydroxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide (3/2 hydrate) in 5 ml. of pyridine is added 0.2 ml. of acetic anhydride and the mixture is left to stand at room temperature for 2 hours, followed by addition of water. The precipitated crystals are collected by filtration to yield 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo[1,5-a][1,4]-benzodiazepine-2-carboxamide as crystals. This product is identical with the product in Example 1 with respect to melting point and infrared absorption spectrum.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:6]=1[C:15]([F:18])([F:17])[F:16])[OH:4].[CH:19](OCC)=[O:20]>>[CH3:14][O:13][C:7]1[C:6]([C:15]([F:16])([F:17])[F:18])=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:19]=[O:20])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: CCOC=O
Reactant: COc1ccc([C@H](O)CN)c(C(F)(F)F)c1OC
Product: COc1ccc(C(O)CNC=O)c(C(F)(F)F)c1OC
Temperature: 25 °C

Procedure:
3.4-dimethoxy-2-(trifluoromethyl)-(N-methylamino)ethanol (12) was made according to methods known in the art. See Kirk et al. (2000). Specifically, a solution of (1S or 1R)-2-amino-1-(3,4-dimethoxy-2-trifluoromethylphenyl)ethanol (10) (MW=265.23, 3.00 g, 11.3 mmol) in ethyl formate (140 ml) was heated to reflux under an atmosphere of Ar for 3 hours with stirring. The suspension eventually goes into solution during the first hour of reflux. Upon completion, the reaction was allowed to cool to room temperature. Volatiles were removed in vacuo to afford 1-N-[2-(3,4-dimethoxy-2-trifluoromethylphenyl)-2-hydroxyethyl]formamide (11) as a low melting yellowish solid. To a cold (0° C.) suspension of LiAlH4 (MW=37.95, 95%, 2.4 g, 63.2 mmol) in THF (30 ml) under Ar a solution of formamide (11) (MW=293.24, 13.0 mmol, 3.81 g) in THF (70 ml) was added dropwise. The mixture was heated to reflux for 3 hours and then cooled to 0° C. and quenched by the addition of 2.4 ml H2O, 2.4 ml 15% NaOH and 7.2 ml H2O. The mixture was stirred at room temperature until all of the unreacted LAH has reacted. The solid was filtered and washed 5 times with 50 ml of hot EtOAc. The filtrate was concentrated and the residue was recrystallized from hex/EtOAc. For S isomer: mp=121-128° C. 1H NMR for S in CDCl3 (300 MHz) δ 7.53 (m, 1H, J=8.8), 7.06 (m, 1H, J=8.8), 5.16 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.80 (m, 1H), 2.56 (m, 1H), 2.42 (s, 3H). 13C NMR in CDCl3 (75 MHz) 152.5, 148.1, 133.8, 124.5 (q, J=274 Hz), 122.8, 121.3, 115.5, 66.8, 61.5, 59.2, 55.9, 35.5. 19F (282.8 Mz) −53.4. For R isomer: mp=125-127° C. 1H NMR for R in CDCl3 (300 MHz) δ 7.55 (m, 1H, J=8.8), 7.06 (m, 1H, J=8.8), 5.22 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 2.83 (m, 1H), 2.62 (m, 1H), 2.47 (s, 3H). 13C NMR in CDCl3 (75 MHz) 152.3, 148.1, 133.6, 124.5 (q, J=274 Hz), 122.9, 121.3, 115.5, 66.6, 61.6, 58.9, 56.0, 35.2. 19F (282.8 Mz) −53.4.
Reaction SMILES: [CH:1]([N:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][CH2:4]1)=[O:2].[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:14][CH2:15][CH2:16][C:17]([C:11]1[CH:12]=[CH:13][C:7]2[O:6][CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:9][C:8]=2[CH:10]=1)=[O:18]
Reactant: O=CN1CCOc2ccccc2C1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=CN1CCOc2ccc(C(=O)CCCl)cc2C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 75.9 %

Procedure:
To a solution of 1.7 g of 4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine and 1.28 g of 3-chloropropionyl chloride in 20 ml of 1,2-dichloroethane was added 3.0 g of aluminum chloride by portions. The mixture was stirred for 6 hours under reflux. The reaction mixture was poured into ice-water, and the resultant was subjected to extraction with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent: ethyl acetate) to give 1.95 g of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.COC(=O)C1C=C([S:44](=[O:49])(=[O:48])[N:45]([CH3:47])[CH3:46])C(C(C)(C)C)=CC=1OCC.C[Al](C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:31][CH2:32][CH3:33])=[CH:23][C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])=[C:25]([S:44]([N:45]([CH3:47])[CH3:46])(=[O:49])=[O:48])[CH:26]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C(=O)OC
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: C[Al](C)C
Product: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1

Procedure:
In a manner analogous to the method described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) was reacted with 4-tert-butyl-5-dimethylsulfamoyl-2-ethoxy-benzoic acid methyl ester (prepared in an analogous manner as described in example 43) in the presence of trimethylaluminum to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-N,N-dimethyl-benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)=O.[OH-].[NH4+:19]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([NH2:19])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of (3,4-dichloro-phenyl)-methanesulfonyl chloride (500 g, 1.93 mol) and acetone (470 mL) was added over 2 h to cooled (0-5° C.), stirred concentrated ammonium hydroxide (28%, 900 mL, 227 g NH3, 13.3 mol). The reaction mixture was maintained below 12° C. during the addition. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Water (900 mL) was added to the reaction mixture and it was stirred for 1 h. The white solid was collected by filtration, washed with cold water (2×500 mL), and vacuum dried to give 375 g (81%) of (3,4-dichloro-phenyl)-methanesulfonamide with 99% purity (as determined by HPLC).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([OH:20])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:20]
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1cc(C(=O)O)ccn1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cc(C(=O)NC2CCOCC2)ccn1
Yield: 73 %

Procedure:
As described for example 7b, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid (50 mg; 0.16 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted (using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 46 mg, 73%) which was obtained as a yellow solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: N1C=CC=C(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH:24][C:25]([CH:27]5[CH2:29][CH2:28]5)=[O:26])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)C=1>CO.[Pd]>[N:20]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(Nc1nc2cccc(-c3ccc(/C=C/c4cccnc4)cc3)n2n1)C1CC1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1nc2cccc(-c3ccc(CCc4ccccn4)cc3)n2n1)C1CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
Cyclopropanecarboxylic acid {5-[4-((E)-2-pyridin-3-yl-vinyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide (320 mg, 0.84 mol) was dissolved in 10 mL MeOH. Pd/C (50 mg) was added and the reaction is put under H2 at normal pressure. The reaction was stirred for 2 hrs. The reaction mixture was filtered through Celite®. The organic solvent was removed under pressure. NaHCO3 saturated solution was added to resulting mixture. The compound was extracted with EtOAc. The organic phase was dried over MgSO4, filtered and removed under vacuum to afford the title compound in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=C[C:36]2N(O)N=[N:39][C:37]=2C=1.CCN=C=NCCCN(C)C.C(N)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:39][CH2:37][CH3:36])=[O:32])[CH2:27][CH2:28]4)=[O:22])=[CH:19][CH:20]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.5 h

Procedure:
2-{4-[(4-{[4-(4-Chlorophenyl)pyrimidin-2-yl]amino}phenyl) carbonyl]piperazinyl}acetic acid (0.200 g, 0.44 mmol) was dissolved in DMF then stirred for 15 minutes in ice-brine solution, then the HOBT (0.072 g, 0.53 mmol] then EDCI(0.102 g, 0.53 mmol) were added and stirred for another 30 minutes. Ethylamine (0.030 mL, 0.53 mmol) was added and the reaction was left to stir at room temp overnight. The reaction was quenched with 10 mL of water and a precipitate formed. The precipitate was colleted by filtration, and purified by preparative HPLC to yield 2-{4-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]piperazinyl}N-ethylacetamide: HPLC Retention time; 9.508 min. (Method B) M+1; 479.2
Reaction SMILES: Cl.Cl.N[C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]4[C:25]=3[CH3:26])[CH:10]=[CH:9][C:7]=2[N:8]=1.[OH2:27]>Cl>[OH:27][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]4[C:25]=3[CH3:26])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: COc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Reactant: O
Agent: Cl
Product: COc1ccn2c(C)c(CCc3ccc4nc(O)oc4c3)nc2c1

Procedure:
A mixture of 2-amino-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole dihydrochloride (2.0 g) in 1N hydrochloric acid (25.3 ml) was was refluxed for 21 hours. The reaction mixture was added to water (50 ml) under ice-cooling and the resulting precipitate was collected by filtration. A mixture of obtained residue and water was adjusted to pH 8 with 20% potassium carbonate aqueous solution under stirring. A precipitate was collected by filtration and dried to give 2-hydroxy-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.98 g).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]2[CH:7]=[C:8]3[O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][C:9]3=[CH:10][C:11]=2[N:12]=[CH:13][CH:14]=1.CN(C=O)C>[Pd].CO>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[C:6]3[CH:7]=[C:8]4[O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][C:9]4=[CH:10][C:11]=3[N:12]=[CH:13][CH:14]=2)=[C:2]([F:1])[CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc4c(cc23)OCCOCCOCCO4)c(F)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc4c(cc23)OCCOCCOCCO4)c(F)c1

Procedure:
To a par hydrogenation reaction vessel was 4-(2-Fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene (0.800 g, 1.6 mmol, 1.0 eq.), DMF (50 ml), EtoAc (50 ml), MeOH (50 ml), TEA (5 ml) and 10% Pd/C (200 mg). The vessel was placed on the par hydrogenator at 35 psi overnight. The Pd was filtered and the solvent removed to give 4-(4-Amino-2-Fluoro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene as an off yellow solid (0.78 g, 99% yield). 1HNMR (400 MHz, DMSO): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.88 (m, 1H), 6.50 (m, 2H), 5.40 (br s, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+401.4. found 401.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ncc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Yield: 64 %

Procedure:
A mixture of 5-nitroindazole (2 g, 12 mmol) and potassium carbonate (5.1 g 37 mmol) in DMF (40 mL) was stirred for 30 minutes after which 2-(dimethylamino)ethylchloride hydrochloride (2.65 g 18.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and was filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (1.8 g, 64% yield). 1H NMR (300 MHz, DMSO-d6) ppm 2.73(t, J=6.44, 2H), 3.33 (s, 6H), 4.57 (t, J=6.44, 2H), 7.93 (m, 1H), 8.21 (m, 1H), 8.40 (m, 1H), 8.82 (m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[S:25][C:26]1[S:27][C:28]([NH2:31])=[N:29][N:30]=1)[C@H:20]([NH:32][C:33](=[O:63])[C:34]([C:56]1[N:57]=[C:58]([NH2:62])[S:59][C:60]=1[Cl:61])=[N:35][O:36]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]2=[O:64])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:62][C:58]1[S:59][C:60]([Cl:61])=[C:56]([C:34](=[N:35][OH:36])[C:33]([NH:32][C@@H:20]2[C:19](=[O:64])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([S:25][C:26]2[S:27][C:28]([NH2:31])=[N:29][N:30]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:63])[N:57]=1
Reactant: Nc1nnc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC(c4ccccc4)(c4ccccc4)c4ccccc4)c4nc(N)sc4Cl)C3SC2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NO)c4nc(N)sc4Cl)C3SC2)s1
Temperature: 0 °C

Procedure:
To a solution of (7R)-7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-trityloxyiminoacetylamino ]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (150 mg, 0.17 mmol) in dichloromethane (7.5 mL) was added triethylsilane (1.5 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (7.5 mL) was added. After 2 hr at 0° C. the reaction mixture was concentrated under vacuum and disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with additional diisopropyl ether and dried under vacuum (85 mg, 65%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][C:16]([C:20](O)=O)=[CH:17][CH:18]=2)[NH:13][C:12](=[O:23])[CH2:11]1.N>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C(O)C>[CH3:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][C:16]([C:20]3[NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[N:8]=3)=[CH:17][CH:18]=2)[NH:13][C:12](=[O:23])[CH2:11]1
Reactant: Nc1ccccc1N
Reactant: CC1(C)CC(=O)Nc2cc(C(=O)O)ccc21
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc(-c3nc4ccccc4[nH]3)ccc21
Yield: 37.2 %

Procedure:
One stirs ortho-phenylenediamine (1.30 g, 12.0 mmol) and 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid (2.60 g, 12.0 mmol; preparation see DE-A-3,818,830) in a mixture of polyphosphoric acid (50 g) and diphosphorus pentoxide (10 g) for 3 hours at 160° C. One allows to cool to 80°-90° C., carefully adds ice and water thereto and filters off the precipitate with suction. One takes up in water (200 ml), adds conc. ammonia thereto, filters off with suction, dissolves the residue in hot ethanol, filters and allows to crystallise. One dries the colourless crystals at 120° C. in a vacuum and obtains 1.30 g (37%) of the title compound with the m.p. 314°-316° C. which, per mole, still has adhering a half mol of water.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[CH:28]=5)[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.N1CC[O:52][CH2:51]C1.C(OCC)(=O)C>O>[CH3:48][C:25]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[C:14]3[N:11]2[CH2:10][CH2:9][N:8]([C:6]([N:1]3[CH2:5][CH2:4][O:52][CH2:51][CH2:2]3)=[O:7])[CH2:13][CH2:12]2)=[CH:28][N:27]([C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:26]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)n4ccnc4)CC3)c2c1
Reactant: C1COCCN1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)N4CCOCC4)CC3)c2c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg 1H-1-imidazolyl{4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]piperazin-1-yl}methanone obtained in Example 195 and 1 mL morpholine was stirred overnight at 140° C. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 96 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Na].[C:2]([S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)(=O)[CH3:3].[N+:13](CCOC(=O)C)([O-:15])=[O:14]>C(O)C>[N+:13]([CH2:3][CH2:2][S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)([O-:15])=[O:14]
Reactant: CC(=O)SC1C=CCCCC1
Reactant: CC(=O)OCC[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])CCSC1C=CCCCC1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To 40 ml of absolute ethanol was added 1.38 g (0.060 gram atom) metallic sodium. When the reaction was completed, 10.2 g (0.060 mole) of 3-acetylmercaptocycloheptene in 20 ml of absolute ethanol was added and the reaction mixture was brought up to reflux for 15 minutes. The solution was then cooled to 0° and 7.98 g (0.060 mole) of 1-nitro-2-acetoxyethane in 20 ml absolute ethanol was added. The reaction was allowed to proceed for 3.0 hours at 0° and then was partitioned between 1 N HCl and methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic phases were pooled, dried over sodium sulfate, and evaporated to afford 12 g (99%) of pure 3-[2-nitroethylthio]cycloheptene as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[C:5]2[CH2:20][CH2:21][CH2:22][CH2:23][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:45]=[CH:44][C:37]2[NH:38][C:39]([C@@H:41]([NH2:43])[CH3:42])=[N:40][C:36]=2[CH:35]=1.ClCl>CN(C)C=O>[Cl:33][C:34]1[CH:45]=[CH:44][C:37]2[NH:38][C:39]([C@@H:41]([NH:43][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([N:6]4[C:5]5[CH2:20][CH2:21][CH2:22][CH2:23][C:4]=5[N:3]=[C:2]4[CH3:1])=[C:8]([C:16]([F:18])([F:19])[F:17])[CH:9]=3)[CH3:42])=[N:40][C:36]=2[CH:35]=1
Reactant: Cc1nc2c(n1-c1ccc(C(=O)O)cc1C(F)(F)F)CCCC2
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(n1-c1ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc1C(F)(F)F)CCCC2
Yield: 45 %

Procedure:
Prepared analogously to Example 1d from 4-(2-methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl)-3-trifluoromethylbenzoic acid, PFTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 45%; C25H23ClF3N5O (501.938); mass spectrum: (M−H)−=500/502 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+].[H][H]>[Ni].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(Cc2cccc(C#N)c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1(Cc2cccc(CN)c2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of methyl N-tert-butoxycarbonyl-4-(3-cyano-benzyl)piperidine-4-carboxylate (0.6 g, 1.67 mmol), Raney nickel (3 g) in a mixture of ethanol (20 mL) and concentrated aqueous ammonium hydroxide (0.6 mL) was stirred under a balloon of hydrogen gas at room temp. overnight. The slurry was filtered, and the filtrate concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[C:3]([C:14]2[CH:19]=[CH:18][N+:17]([O-])=[CH:16][CH:15]=2)=[N:2]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[CH:19]=[C:14]([C:3]2[C:4]3[CH2:5][CH2:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[NH:1][N:2]=2)[CH:15]=[CH:16][N:17]=1
Reactant: [O-][n+]1ccc(-c2n[nH]c3c2CCc2ccccc2-3)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2n[nH]c3c2CCc2ccccc2-3)ccn1

Procedure:
The N-oxide product from Example 14 (150 mg) was dissolved in phosphorus oxychloride (6 ml). The mixture was boiled under reflux for 4 hours. Excess phosphorus oxychloride was removed under reduced pressure and the residue was washed with saturated sodium carbonate solution and the product was extracted into chloroform, washed, dried and evaporated to give 3-(2-chloro-4-pyridyl)-4,5-dihydro-1H-benzo[g]indazole.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]([O:13][C:14]1[CH:15]=[C:16]([N:22]2[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])([CH3:12])[CH3:11]>>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH:10]([CH3:11])[CH3:12])[CH:15]=3)[CH2:23][C@@H:24]2[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:9])[N:3]=[CH:2]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](CC(C)C)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-isopropoxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 35, Compound 123) as starting materials. Product as an off-white solid (32%). LC/MS (Method B) 2.52 min, [M+1]+ 415.1. Potency class B.