Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[H-].[Na+].[C:24](Cl)(=[O:26])[CH3:25]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([S:18]([NH:21][C:24](=[O:26])[CH3:25])(=[O:19])=[O:20])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: NS(=O)(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NS(=O)(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-[1-(Pyridin-3-yl)-1H-pyrazol-4-yl]pyridin-2-sulphonamide (0.15 g, 0.44 mmol) was initially charged in acetonitrile (1.5 ml) under argon, and sodium hydride (0.026 g, 0.66 mmol, 60%) was added in portions. The reaction mixture was stirred at room temperature for 1 h, then acetyl chloride (0.052 g, 0.66 mmol) was added dropwise. The reaction mixture was stirred at 82° C. for 33 h and, after cooling, the solvent was removed under reduced pressure. The residue was taken up in saturated sodium hydrogencarbonate solution, dichloromethane was added and the precipitated solid was filtered off. The phases of the filtrate were separated; the aqueous phase was adjusted to pH 3 with hydrochloric acid and left to stand for 16 h. The precipitated crystals were filtered off with suction. Yield 0.02 g (12% of theory) of N-({6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridin-2-yl}sulphonyl)acetamide.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]>C(O)C.Cl.O>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:13]2
Reactant: CC(=O)OC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)OC1Cc2ccc(N)cc2C1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A slurry of 8.0 g (0.045 moles) of 2-acetoxy-5-nitroindan in 25 ml of absolute ethanol and 32 ml of concentrated hydrochloric acid was treated over 1 hr with a solution of 24 g (0.11 moles) of stannous chloride in 32 ml of absolute ethanol, with water bath cooling to maintain T=20°C. The mixture was stirred for 1 day at room temperature, diluted with 100 ml of water and extracted twice with ether. The aqueous phase was basified with 10% sodium hydroxide until the hydroxides redissolved, then extracted with chloroform, dried (sodium sulfate) and evaporated to an oil which crystallized to 3.9 g (82%) 5-amino-2-hydroxyindan, the hydrochloride of which had mp 237°-239° after one crystallization from ether-methanol isopropanol.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=[O:21])=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CO>>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH2:20][OH:21])=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cccnc32)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(CO)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To a stirred solution of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde [956716-93-1] (2.0 g, 6.66 mmol) in methanol (20 mL) NaBH4 (0.756 g, 20 mmol) was added in portions at 0° C. Then the mixture was allowed to warm to rt and stirred for 18 h. Methanol was evaporated under reduced pressure and water was added to the stirred residue. The resulting precipitate was filtered off and dried under vacuum to yield the title compound as a white solid (1.6 g, 80%). [1H NMR (400 MHz, CHLOROFORM-d) ♀ ppm 8.45 (dd, J=4.8, 3.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.96 (dd, J=8.0, 1.6 Hz, 1H), 7.70 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.20 (dd, J=7.6, 4.8 Hz, 1H), 4.83 (d, J=5.2 Hz, 2H), 2.37 (s, 3H), 1.73 (t, J=5.2 Hz, 1H); LCMS RtE=0.85, [M+H]+=302.8].
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:23]#[N:24])[CH2:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:8]1)C.C([O-])(=O)C.[NH4+:30]>CO.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:9]2[CH2:10][CH2:11][C:12]3[NH:30][C:4](=[O:3])[CH:5]([C:23]#[N:24])[CH2:6][C:7]=3[CH2:8]2)=[CH:16][CH:17]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C(C#N)CC1CC(Cc2ccc(OC)cc2)CCC1=O
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC2CCC3=C(C2)CC(C#N)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Cyano-3-[3-(4-methoxyphenyl)methyl-6-oxocyclohexanyl]propanoic acid ethyl ester (1 g) (prepared as described in Example 5(a)) in methanol (10 ml) was treated with ammonium acetate (2.2 g) and left to stir at room temperature for 2 hours. The reaction mixture was diluted with water and a solid crystallised out. The solid was mixed with water and methanol, and the methanol removed under reduced pressure. The mixture was extracted into ethyl acetate, dried (MgSO4), and solvent evaporated to give the title compound as the quarterhydrate, mp 158°-9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.Cl>C(O)(C)C>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:18][CH:16]([OH:17])[CH2:15][O:14][C:13]3[C:3]([O:2][CH3:1])=[CH:4][C:5]4[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=4[CH:12]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1cc2oc(=O)ccc2cc1OCC1CO1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2oc(=O)ccc2cc1OCC(O)CN1CCN(c2cccc(Cl)c2)CC1
Yield: 85 %

Procedure:
Method C (3 d at 40° C.); starting materials: 7-methoxy-6-(oxiranylmethoxy)-2H-1-benzopyran-2-one and 1-(3-chlorophenyl)-piperazine; yield 85%; fusion point 140°-141° C. (from isopropanol). Hydrochloride (×1.7 HCl): method F; yield 88%; fusion point 222°-224° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:34][C:35]1[CH:40]=[C:39]([CH:41]([CH:43]2[CH2:45][CH2:44]2)[OH:42])[C:38]([S:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:37][N:36]=1)(=[O:33])=[O:32]>ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:34][C:35]1[CH:40]=[C:39]([C:41]([CH:43]2[CH2:44][CH2:45]2)=[O:42])[C:38]([S:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:37][N:36]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Nc1cc(C(O)C2CC2)c(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)cn1)c1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Dess Martin periodinane (60 mg, 0.14 mmol) was added to a stirred solution of 2,4-dichloro-N-{4-(cyclopropyl-hydroxy-methyl)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide (74 mg, 0.12 mmol) in dichloromethane (5 ml) and the mixture stirred at room temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (30 ml), washed with NaHCO3 solution (20 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to give 2,4-dichloro-N-{4-cyclopropanecarbonyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin -2-yl}-benzenesulfonamide as a yellow solid (38 mg, 51%). 1H NMR (CDCl3): 8.32 (1 H, s, py); 8.08 (1 H, d, Ar); 7.57 (2 H, d, Ar); 7.46 (1 H, s, py); 7.36 (1 H, d, Ar); 7.27 (2 H, d, Ar); 2.89 (4 H, m, 2×CH2 pip); 2.17 (1 H, m, COCH); 1.54 (4 H, m, 2×CH2 pip); 1.33 (2 H, m, CH2 pip); 0.82 (4 H, m, 2×CH2 cprop). HPLC (Luna 2, Gradient 5): rt=6.47 minutes. LCMS rt=7.24 minutes, 627 (M+H)+. By a similar method using the appropriate starting materials the following can be prepared:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.O[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([O:6][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 3-cyclopenten-1-ol (15.3 g), N-hydroxyphthalimide (29.7 g) and triphenylphosphine (47.7 g) in tetrahydrofuran (250 ml) was added diethyl azodicarboxylate (31.7 g) at 40° to 50° C. After stirring at 45° C. for 2 hours, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The separated organic layer was washed with 5% aqueous solution of sodium bicarbonate, brine, successively and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residual oil was subjected to column chromatography on silica gel. The desired product was eluted with 15% ethyl acetate in n-hexane to give N-(3-cyclopenten-1-yloxy)phthalimide (25.6 g).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[NH2:26][CH:27]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].N1C=CN=C1.C(C(N1C(=O)C2C3C4C(=CC=2)C2C5C(C=CC=2)=CC=CC=5C=4C=CC=3C1=O)CCCCCC)CCCCC>C(Cl)(Cl)Cl>[CH2:28]([CH:27]([N:26]1[C:24](=[O:23])[C:3]2[C:4]3[C:19]4[C:18](=[CH:1][CH:2]=2)[C:17]2[C:20]5[C:13]([CH:14]=[CH:15][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=5[C:8]=4[CH:7]=[CH:6][C:5]=3[C:21]1=[O:22])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCC(N)CCCCCCCCC
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: CCCCCCC(CCCCCC)N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(CCCCCCCCC)N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54

Procedure:
230 mg (0.70 mmol) of perylene-3,4-dicarboxylic anhydride are reacted with 400 mg (1.40 mmol) of 10-aminononadecane (prepared according to DE-A 4,007,618) and 1.0 g of imidazole under an argon inert atmosphere as in 2c, followed by workup. After chromatography on silica gel using chloroform, the reaction product is applied to silica gel using petroleum ether, and the purely aliphatic by-products are washed off with about 11 of petroleum ether. The reaction product is then eluted with toluene, and is then recrystallized by extraction with pentane. Yield 400 mg (85%), m.p. 143°-143.5° C. Rf (silica gel/CHCl3)=0.94. UV (CHCl3): λmax (ε)=507 nm (31319), 482 (32213), 453 (sh, 17450). Fluorescence (CHCl3, exc. 507 nm) λmax (Irel)=539 (1), 557 (0.47).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCO>C(COC)OC.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>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH2:17][N:18]5[C:19](=[O:28])[C:20]6[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:26]5=[O:27])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:30]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCCO
Solvent: COCCOC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1

Procedure:
A mixture of 2-[1-(3-bromophenyl)-1H-benzimidazol-5-ylmethyl]-isoindole-1,3-dione (1.10 g, 2.54 mmol), 3-pyridineboronic acid (0.47 g, 3.82 mmol), potassium carbonate (1.06 g, 7.63 mmol), 1,3-propanediol (0.92 ml, 12.72 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g) in a mixture of dimethoxyethane (20 ml) and water (10 ml) was stirred at reflux in a nitrogen atmosphere for 20 min. The resultant mixture was cooled and volatile material was removed in vacuo. The product precipitated from the residual solvent and was filtered off, washed with water and dried in the air to afford 0.56 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[F:26][C:27]([F:46])([F:45])[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:25])=[C:2]([C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([C:28](=[O:29])[C:27]([F:46])([F:45])[F:26])[CH:31]=5)[N:7]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: CC1(C)OB(c2cccc(C(=O)C(F)(F)F)c2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)C(F)(F)F)c1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (163 mg, 0.444 mmol) was dissolved in 1,2-dimethoxyethane (4.0 mL) in a reaction tube. 2,2,2-Trifluoro-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone (200 mg, 0.666 mmol), aqueous 2 M sodium carbonate (0.444 mL), and (Ph3P)4Pd (26 mg, 0.022 mmol) were added and the reaction mixture was heated at 120° C. under N2 atmosphere for 30 minutes in the microwave. The resulting material was cooled to room temperature, filtered, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(3-(2,2,2-trifluoroacetyl)phenyl)-pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 522.1. found 523.5 (M+1)+. Retention time 1.92 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:18]([O-])=O)=[CH:5][C:6]([CH3:17])=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:18][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[O:10])=[C:6]([CH3:17])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)N2CCOCC2)c(C)cc1N
Temperature: 90 °C
Yield: 83.1 %

Procedure:
To (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (1.76 g, 6.3 mmol) in ethanol (25 mL) and water (25 mL) was added ammonium chloride (1.72 g, 31.5 mmol) and iron powder (1.41 g, 25.2 mmol). The mixture was heated to 90° C. for 2 hours and then filtered through celite, washed through with ethanol. The solvent was removed in vacuo and the residue was partitioned between water (50 mL) and DCM (50 mL). The layers were separated and the aqueous phase was washed with DCM (3×50 mL). The combined organic phases were dried over MgSO4, filtered and the solvent removed in vacuo. The residue was triturated with diethyl ether/40-60 petroleum ether and dried to give (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (1.31 g, 82%) as an off-white solid.
Reaction SMILES: BrCCC1C=CC([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=CC=1.[C:26]([O:30][C:31]([NH:33][C:34]([CH3:52])([CH3:51])[CH2:35][C:36]([NH:38][C@@H:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=2[NH:41][C:40]1=[O:50])=[O:37])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[N+:23]([C:20]1[CH:19]=[CH:22][CH:17]=[CH:18][C:21]=1[C:22]1[CH:15]=[CH:10][C:11]([CH2:12][N:41]2[C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[CH2:44][CH2:45][C@@H:39]([NH:38][C:36](=[O:37])[CH2:35][C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:52])[CH3:51])[C:40]2=[O:50])=[CH:18][C:17]=1[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:10]=1)([O-:25])=[O:24]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccc(CCBr)cc2)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3[N+](=O)[O-])c(Oc3ccccc3)c2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 4'-bromoethyl-2-(4-nitrophenoxy) -1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl -N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-(R) -yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1NMR (200 MHz, CDCl3): 1.32 (s,6H), 1.38 (s,9H), 1.78 (m,1H), 2.3-2.7 (m,5H), 4.47 (m,1H), 4.75 (d,15 Hz,1H), 5.13 (d,15 Hz,1H), 6.63 (d,7 Hz,1H), 6.75 (d,8 Hz,2H), 7.05-7.50 (m,/11H), 7.97 (s,1H), 7.98 (d,8 Hz,2H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].N12CCN(CC1)CC2.O>CN(C)C=O>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:7][CH:6]=1)=[O:14]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)C(=O)Nc1ccc(O)nc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)C(C)(C)C)cn1)c1ccccc1
Yield: 56 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-2,2-dimethyl-propionamide (0.58 g, 3.00 mmol), N -methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 1 hour. Water was added and a thick oil was being formed. The water was decanted and the residue was dissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo yielding the title compound (0.55 g, 56% yield) as a brown oil that solidified upon standing.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:16].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:13]1[C:14]2[C:9](=[C:8]3[C:3](=[C:2]([O:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=2)[CH2:4][CH2:5][CH2:6][C:7]3=[O:16])[CH2:10][CH2:11][CH2:12]1
Reactant: O=C1CCCc2c(O)cc3c(c21)CCCC3
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2c(c3c1CCCC3=O)CCCC2

Procedure:
40.44 g (0.19 mol) of the compound from Example 6 is heated to reflux with 38.64 g (0.23 mol) of ethyl bromoacetate and 31.97 g (0.23 mol) of potassium carbonate in 190 ml of butanone for 5 h. After cooling, the precipitate is filtered off and washed well with acetone and the solution is evaporated. The residue is taken up in 100 ml of CH2Cl2, shaken 3 times with 50 ml of 10% strength NaOH solution each time, dried over Na2SO4 and evaporated. The residue is dried in a high vacuum.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH:9]2[C:21]2([OH:32])[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)C=CC=CC=1.[H][H]>CO.[Pd]>[OH:32][C:21]1([CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CN(Cc3ccccc3)CCN2Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)(C2CNCCN2)C1
Yield: 94.6 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate (408 mg, 0.93 mmol) in methanol (15 mL) was added 10% palladium on carbon (wet), and the resulting suspension was subjected to an atmosphere of hydrogen for 21 hours. The catalyst was removed by filtration through celite, and the filter cake was rinsed with methanol. The combined filtrate was concentrated to provide 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate as a brown syrup (227 mg, 0.88 mmol, 95% yield). 1H NMR, (400 MHz, CDCl3): 3.94-3.76 (m, 5H), 3.12 (m, 1H), 3.01 (m, 1H), 2.94-2.81 (m, 3H), 2.78-2.70 (m, 2H); MS (EI) for C12H23N3O3: 258 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:55]=[CH:56][CH:57]=1)[O:5][C:6]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=3[C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)[CH2:35][CH2:34]2)[CH:30]=[CH:29][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=1)(=[O:13])=[O:12])=[O:9].[CH2:58]=O>O1CCCC1.C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:55]=[CH:56][CH:57]=1)[O:5][C:6]1[CH:32]=[C:31]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]3[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=3[C:48]3[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=3)[CH2:37][CH2:38]2)[CH:30]=[CH:29][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23]([CH3:58])[CH2:22]2)=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=1)(=[O:12])=[O:13])=[O:9]
Reactant: C=O
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@H]5CCNC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@H](Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cccc(Cl)c3)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 194C (470 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added 37% formaldehyde solution in water (0.42 mL) and MP-CNBH3 resin (947 mg, 2.38 mmol/g)). The reaction mixture was stirred overnight at room temperature. The resin was filtered off and reaction mixture was then concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate, followed by a gradient of 3-10% methanol/dichloromethane. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 8.42 (d, 1H), 8.34 (m, 1H), 7.78 (dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.19 (t, 1H), 7.08 (m, 3H), 6.95 (m, 1H), 6.76 (dd, 1H), 6.67 (m, 2H), 6.45 (d, 1H), 3.53 (m, 2H), 3.16 (m, 7H), 2.83 (m, 4H), 2.61 (br m, 1H), 2.27 (m, 4H), 2.18 (m, 3H), 1.98 (m, 3H), 1.41 (m, 2H), 0.94 (s, 6H).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 116) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 486.3 (MH+).