Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:19][C:14]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[C:8]=1[CH3:7]
Reactant: Cc1cccc(N)c1S(C)(=O)=O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Br)ccc(N)c1S(C)(=O)=O
Yield: 82.7 %

Procedure:
400 g (2.9 mol) of potassium carbonate were added to a solution of 134 g (0.73 mol) of 3-methyl-2-methylsulfonylaniline in 1200 ml of acetonitrile. At room temperature, 320 g (0.65 mol) of tetrabutylammonium tribromide were then added a little at a time, with vigorous stirring. The resulting precipitate was separated off, methyl tert-butyl ether was added to the filtrate and the filtrate was extracted with dilute hydrochloric acid and then with water. The organic phase was concentrated to dryness under reduced pressure. The resulting residue was once more taken up in methyl tert-butyl ether and washed two more times with hydrochloric acid and water. The organic phase was dried and concentrated under reduced pressure, giving 142 g (74%) of 4-bromo-3-methyl-2-methylsulfonylaniline as a brown solid of melting point 103–106° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[OH:13])[CH2:3][CH2:2]1.[O:15]1[CH2:17][C@H:16]1[CH2:18]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[O:13][CH2:18][CH:16]2[CH2:17][O:15]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: O=C(NC1CC1)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(F)cc1OCC1CO1
Yield: 59.7 %

Procedure:
A mixturte of N-cyclopropyl-4-fluoro-2-hydroxybenzamide (195 mg, 1.0 mmol), (2S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (259 mg, 1.0 mmol) and Cs2CO3 (390 mg, 1.2 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-30% ethylacetate in petroleum ether) to give the subtitled compound (150 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1>C(O)(=O)C>[F:15][C:10]1[CH:9]=[C:5]2[C:4]([CH:3]=[C:1]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:2]=[C:6]2[OH:7])=[CH:12][C:11]=1[O:13][CH3:14]
Reactant: COc1cc(CC#N)c(C(=O)O)cc1F
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
2-Cyanomethyl-5-fluoro-4-methoxy-benzoic acid (1.75 g), 3-amino-5-methylpyrazol (1.63 g), acetic acid (15 ml), were sealed in a process vial. The mixture was heated at 130° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was dissolved in 5 ml MeOH. The resulting solution was added dropwise to 200 ml water. After stirred for 1 hour, the solid was collected, and dried to give product (1.85 g, 77% yield). LC-MS: m/e 289 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Reactant: NC1CCCC1
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)NC5CCCC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and cyclopentylamine (Aldrich Cat. No. C115002). LCMS (M+H)+: m/z=436.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:25][CH2:24][N:23](C)[C@@H:22]([CH2:27][CH2:28][O:29][CH3:30])[CH2:21]3)[C:8]=2[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:30][O:29][CH2:28][CH2:27][C@@H:22]1[NH:23][CH2:24][CH2:25][N:20]([C:9]2[C:8]3[N:7]=[C:6]([CH2:4][OH:3])[S:15][C:14]=3[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)[CH2:21]1
Reactant: CCOC(=O)c1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCOC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(CO)nc32)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Combine (S)-10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-4H-3-thia-1,4,9-triaza-benzo[f]azulene-2-carboxylic acid ethyl ester (0.49 g, 1.18 mmol) in 5.0 mL THF, add 2.95 mL of LiAlH4 (1.0 M THF) dropwise at ice-water bath. After addition, remove the ice bath, stir the reaction mixture at RT. After half hour, quench the reaction by adding 1.0 N NaOH cautiously until no gas evolves. Pass the suspension through celite plug, wash repeatedly with ether, and concentrate the organic solution to a residue. Purify by flash chromatography affords 0.22 g of the title compound: mass spectrum (electrospray) (m/e): 374.0 (M+1), 372.1 (M−1); 1H NMR (400 MHz, DMSO-d6): 7.79 (s, 1H), 6.86-6.75 (m, 3H), 6.69-6.66 (m, 1H), 5.89 (br, 1H), 4.50 (d, 2H, J=4.4 Hz), 4.04-3.93 (m, 2H), 3.38-3.33 (m, 2H), 3.30 (s, 3H), 2.84-2.60 (m, 4H), 2.46-2.41 (m, 1H), 1.49 (q, 2H, J=6.6 Hz).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:31]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and cyclohexyl isocyanate to give the title compound as a colorless solid. MS: 525.4 ([M+H]+)
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH:28]1([CH2:27][C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)C1(CC2CC2)CCN(C(=O)c2ccc(-c3ccc(F)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccc(-c2ccc(F)cc2)cc1)N1CCC(CC2CC2)(C(=O)O)CC1
Temperature: 75 °C

Procedure:
A mixture of 0.51 g (1.24 mmol) 4-cyclopropylmethyl-1-(4′-fluoro-biphenyl-4-carbonyl)-piperidine-4-carboxylic acid ethyl ester and 1.87 mL 4N NaOH aq. in 5 mL ethanol was stirred at 75° C. for a prolonged period of time. After concentration of the mixture ice-water was added and the pH was adjusted to pH=2 with HCl aq. The mixture was extracted with ethyl acetate, the combined organic layers were dried with Na2SO4, filtered, evaporated to dryness and purified by column chromatography on silica eluting with a gradient formed from ethyl acetate, heptane and formic acid to yield after evaporation of the product containing fractions 0.146 g (31%) of the title compound as white foam. MS ISP (m/e): 382.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:37])[CH2:35][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:27][CH3:28])[CH2:17][CH2:18]2)=[O:12])=[CH:7]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)OC(C)(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid tert-butyl ester gave the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:22]>O.[Cu]Br>[Br:22][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a mixture of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10 g, 39 mmol) in 40% HBr (100 mL) was added dropwise a solution of sodium nitrite (3.2 g, 46 mmol) in water (10 mL). The mixture was stirred for 20 minutes before it was poured into a solution of copper(I) bromide (8.4 g, 59 mmol) in 40% HBr (100 mL) at 0° C. The resulting dark brown mixture was stirred for 30 minutes and was then diluted with water. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (7.1 g, 57%). 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 4H), 3.58 (s, 1H). MS (ESI) m/z (M−H+) 321.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[I:14]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([I:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(C)nc(N)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)nc(C)c1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Ethyl 6-amino-2-methylisonicotinate (2.00 g, 11.1 mmol) was dissolved in DMF (20 mL), and the solution was stirred overnight at 60° C. after adding N-iodosuccinimide (2.50 g, 11.1 mmol). The reaction mixture was stirred at 60° C. for 5 hours after adding N-iodosuccinimide (1.25 g, 5.55 mmol). The reaction mixture was allowed to cool to room temperature, and extracted with a mixed solvent of ethyl acetate and hexane after adding a sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→50/50) to give ethyl 6-amino-3-iodo-2-methylisonicotinate (1.92 g, yield 57%).
Reaction SMILES: CI.FC(F)(F)C(O)=O.C(O[C:15](=O)[NH:16][C:17]1[C:18]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=1)(C)(C)C.C(O)(C)(C)C.[F:39][C:40]([F:58])([F:57])[C:41]1[CH:42]=[C:43]([C:51]([CH3:56])([CH3:55])[C:52](Cl)=[O:53])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>>[F:39][C:40]([F:58])([F:57])[C:41]1[CH:42]=[C:43]([C:51]([CH3:56])([CH3:55])[C:52]([N:16]([C:17]2[C:18]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=2)[CH3:15])=[O:53])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CSc1ncc(NC(=O)OC(C)(C)C)c(Oc2ccc(F)cc2)n1
Solvent: CI
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Oc2ccc(F)cc2)n1

Procedure:
In an analougous manner to that described in Examle 46 a) there was obtained from 4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidine-5-carboxylic acid, diphenylphosporylazide and t-butanol [4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-carbamic acid tert.-butyl ester, which was methylated with methyliodide and than deprotected with trifluoracetic acid according to Example 43b)c). The resulting [4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-methyl-amine was treated with 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride as described in Example 43e) to give 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-N-methyl-isobutyramide as a white foam, MS (EI): 547 (M+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[CH2:10]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:15][C@@H:11]1[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][OH:6])[CH2:10]1
Reactant: C[C@@H]1CCCN(CCO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1CCCN(CCO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of (R)-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methyl-piperidine (500 mg, 1.9 mmol) in THF (5 mL) at 0° C., TBAF (1M in THF, 2.8 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by silica gel column chromatography (MeOH/CH2Cl2=1/50) to give (R)-2-(3-methyl-piperidin-1-yl)-ethanol (0.23 g) as colorless oil. 1H NMR (DMSO-d6): δ 4.39 (br s, 1H), 3.48 (t, 2H), 2.80-2.77 (m, 2H), 2.38 (t, 2H), 1.88-1.86 (m, 1H), 1.65-1.47 (m, 5H), 0.81 (d, 3H), 0.82-0.78 (m, 1H); LCMS: 144.1 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[N+]([O-])(OC(=O)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.ClC(Cl)=C(Cl)Cl>[CH3:12][C:13]1[CH:17]=[C:16]([N+:8]([O-:11])=[O:9])[NH:15][N:14]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc[nH]n1
Agent: CC(=O)O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)=C(Cl)Cl
Product: Cc1cc([N+](=O)[O-])[nH]n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (96.2 mL, 104.58 g, 1.02 mol) was cooled to −15° C. with an ice/NaCl bath and to this was dropwise, very slowly, added red fuming HNO3 (40.7 mL, 61.8 g, 0.98 mmol). The reaction is strongly exothermic and care must be taken to keep the temperature below 0° C. (inside temperature). This solution was then rapidly transferred with a teflon tube of sufficient diameter (to prevent warming on transfer) to an addition funnel with a cooling mantle. This solution was kept <0° C. at all times and the addition funnel mounted on a flask containing methylpyrazole (35 g, 0.427 mol) in glacial acetic acid (40 mL) at −5° C. The chilled (−15° C.) acetyl nitrate solution was then dropwise added to the methylpyrazole 8 solution at 0° C. The reaction was highly exothermic until ca. 1 eq. acetyl nitrate had been added and it must not be allowed to warm above 5° C. After 3 hours stirring at 0° C. the mixture was poured into ice/water (500 mL) and neutralized to ca. pH 7 with sodium carbonate. Extraction with DCM (3×200 mL), drying (sodium sulfate) and evaporation in vacuo afforded a 90:10 mixture of N-nitro intermediates (42.8 g, 0.337 mol, 79%), which was dissolved in perchloroethylene (4 L), heated at 140° C. ext. temperature for 18 hours and for 5 hours at 165° C. Evaporation of the solvent and drying in vacuo gave pure 9 (39.0 g, 0.307 mol, 72% both steps).
Reaction SMILES: BrC1C=CN2C(C([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:29])[NH:21][CH2:22][CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[CH:16][C:15]=3[F:30])=O)=CN=C2C=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[CH:39][C:40]=2[C:41]([OH:43])=O)[CH:37]=1>>[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[CH:39][C:40]=2[C:41]([NH:13][C:14]2[CH:19]=[C:18]([C:20](=[O:29])[NH:21][CH2:22][CH2:23][O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:17]=[CH:16][C:15]=2[F:30])=[O:43])[CH:37]=1
Reactant: O=C(O)c1cnn2cc(Br)ccc12
Reactant: CC(C)(C)OCCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Product: CC(C)(C)OCCNC(=O)c1ccc(F)c(NC(=O)c2cnn3cc(Br)ccc23)c1

Procedure:
The title compound was prepared analogously to Intermediate 2A by replacing 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (step 2) with 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (commercially available);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]3[CH:20]=[C:19]([O:21][CH2:22]C)[C:18]([O:24][CH2:25]C)=[C:17]([O:27][CH2:28]C)[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][NH:47][C:48]([C:50]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[O:49])[CH2:41][CH2:40]1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[ClH:1].[O:39]1[CH2:40][CH2:41][N:42]([CH2:45][CH2:46][NH:47][C:48]([C:50]2([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH2:51][CH2:52][N:53]([CH2:32][CH2:31][C:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:24][CH3:25])=[C:17]([O:27][CH3:28])[CH:16]=4)[CH2:10]3)[CH2:54][CH2:55]2)=[O:49])[CH2:43][CH2:44]1
Reactant: O=C(NCCN1CCOCC1)C1(c2ccccc2)CCNCC1
Reactant: CCOc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OCC)c1OCC
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)NCCN4CCOCC4)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.8 g, 5.24 mmol) and 4-phenyl-piperidine-4-carboxylic acid (2-morpholino-ethyl)-amide hydrochloride (1.87 g, 35.2 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane and then 6% methanol/dichloromethane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-].P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc(Cl)n1
Temperature: 25 °C

Procedure:
2-Chloro-4-nitro-6-methyl-pyridine 1-oxide (6.2 g, 0.033 mol) was dissolved in chloroform (100 ml), phosphorus trichloride was added (22.6 g, 0.165 mol) and the mixture was heated under reflux for 2 days. The mixture was cooled to room temperature, poured into icewater and the mixture was neutralized with solid potassium carbonate. The phases were separated, the aqueous phase was extracted three times with chloroform, the combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure after which 5.326 g of a brown oil was obtained (0.031 mol, 94%) which was used directly in the next step.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].Cl.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:9]
Reactant: Fc1ccccc1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(C(=O)c2ccc(F)cc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 41 h

Procedure:
150 g of aluminum chloride were added over 30 minutes at 40°C under an argon atmosphere to a suspension of 107.8g of 2-methyl-3-nitro-benzoyl chloride (Step A - EXample IV) in 450 ml of fluorobenzene and the mixture was held at this temperature for 41 hours. After icing, the mixture was added to 1 liter of ice water and 250 ml of concentrated hydrochloric acid and after stirring for 30 minutes, the mixture was extracted with methylene chloride. The extract was washed with water, then with N sodium hydroxide and then with water until the wash water was neutral. The solution was dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 115.7 g of 2-methyl-3-nitro-4'-fluorobenzophenone in the form of white crystals. For analysis, a sample of the product was crystallized from n-pentane and had a melting point of 64°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH:33]([CH3:34])[CH3:35])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Solvent: Cc1ccccc1C
Product: CC(C)Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (265 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (230 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH3:22])[N:6]([CH2:7][CH:8]2[O:10][CH2:9]2)[C:5](=[O:11])[C:4]2([CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]2)[O:3]1.C(O)=[O:24]>>[CH3:1][C:2]1([CH2:21][CH3:22])[N:6]([CH2:7][CH:8]([OH:24])[CH2:9][OH:10])[C:5](=[O:11])[C:4]2([CH2:16][C:15]([CH3:17])([CH3:18])[NH:14][C:13]([CH3:19])([CH3:20])[CH2:12]2)[O:3]1
Reactant: O=CO
Reactant: CCC1(C)OC2(CC(C)(C)NC(C)(C)C2)C(=O)N1CC1CO1
Product: CCC1(C)OC2(CC(C)(C)NC(C)(C)C2)C(=O)N1CC(O)CO
Reaction time: 2 h

Procedure:
50 g of 2,7,7,9,9-pentamethyl-2-ethyl-3-(2,3-epoxypropyl)-1-oxa-3,8-diaza-spiro[4.5]decan-4-one in 200 g of formic acid were boiled under reflux for 4 hours. The formic acid was removed by distillation in vacuo and the residue was boiled for 2 hours in 100 ml of 10% strength NaOH. An oily layer was formed, this was separated off and it solidified after a little time. The product was pulverized, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][CH2:6][C:5]([NH:14]C(=O)OCC2C=CC=CC=2)([C:8]2[O:9][C:10]([CH3:13])=[CH:11][N:12]=2)[CH2:4][O:3]1>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:25])[O:7][CH2:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][N:12]=2)([NH2:14])[CH2:4][O:3]1
Reactant: Cc1cnc(C2(NC(=O)OCc3ccccc3)COC(C)(C)OC2)o1
Agent: [Pd]
Solvent: CCO
Product: Cc1cnc(C2(N)COC(C)(C)OC2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of 35 mg of benzyl [2,2-dimethyl-5-(5-methyl-1,3-oxazol-2-yl)-1,3-dioxan-5-yl]carbamate in 2 ml of ethanol was added 10 mg of 10% palladium-carbon (hydrated), followed by stirring at room temperature for 4 hours under a hydrogen atmosphere of 1 atm. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain 21.4 mg of 2,2-dimethyl-5-(5-methyl-1,3-oxazol-2-yl)-1,3-dioxan-5-amine.