Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20](=[O:35])[N:21]([CH:28]3[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH3:3].[CH:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([C:41]([N:25]2[CH2:26][CH2:27][CH:22]([N:21]([CH:28]3[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]3)[C:20]([NH:19][C:17]3[S:18][C:14]([CH2:13][N:10]4[CH2:11][CH2:12][N:7]([S:4]([CH2:2][CH3:3])(=[O:5])=[O:6])[CH2:8][CH2:9]4)=[CH:15][N:16]=3)=[O:35])[CH2:23][CH2:24]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCNCC3)C3CCC(C)CC3)s2)CC1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)C4CCCC4)CC3)s2)CC1
Yield: 40 %

Procedure:
Prepared as described in general procedure (N) using 3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-1-piperidin-4-yl-urea hydrochloride (48 mg, 0.078 mmol), TEA (24 μL, 0.17 mmol) and cyclopentane carbonylchloride (11 μL, 0.086 mmol) and to afford 19 mg (40%) of the desired product after purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH2:8]C)[O:5][N:4]=1.[OH:10][CH2:11][C:12]([N:14]([CH2:16][C@H:17]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH3:38])[CH:32]=1)=[N:23][CH:24]=[N:25]2)[CH3:18])[CH3:15])=[O:13]>>[OH:10][CH2:11][C:12]([N:14]([CH3:15])[CH2:16][C@H:17]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)=[C:33]([CH3:38])[CH:32]=1)=[N:23][CH:24]=[N:25]2)[CH3:18])=[O:13]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Reactant: CCc1cc(CCl)no1
Product: Cc1cc(COc2ccc(Nc3ncnc4cccc(O[C@H](C)CN(C)C(=O)CO)c34)cc2C)no1
Yield: 7 %

Procedure:
The procedure described in Example 3 was repeated using 3-(chloromethyl)-5-ethylisoxazole and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described in Example 90, preparation of starting materials) to give the title compound as a white solid in 7% yield; NMR spectrum (DMSO-d6 373K) 1.44 (d, 3H), 2.22 (s, 3H), 2.42 (s, 3H), 2.98 (s, 3H), 3.58 (m, 1H), 4.17 (m, 3H), 5.11 (m, 1H), 5.15 (s, 2H), 6.29 (s, 1H), 7.07 (d, 1H), 7.11 (d, 1H), 7.33 (d, 1H), 7.57 (m, 2H), 7.69 (t, 1H), 8.44 (s, 1H), 9.83 (s, 1H); Mass spectrum MH+ 492.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([O:9][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.59 g (5.7 mmol) of N-benzyloxycarbonyl-4-hydroxy-L-cis-proline methyl ester are dissolved in 50 ml of abs. pyridine and cooled to 0° C. 0.6 ml (7.7 mmol) of methanesulphonyl chloride is added dropwise at 0° C., and the mixture is subsequently stirred at room temperature for 3 hours. The mixture is then concentrated and 100 ml of methylene chloride are added to the residue, and this latter mixture is then extracted 2 x by shaking with a 10% solution of NaHCO3, dried over sodium sulphate and concentrated once again, with the residue being subsequently distilled repeatedly with toluene. Yield: quantitative Rf : 0.33, eluent, toluene/EtOH (10:1)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:27][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCC3CCOC(C)(C)C3)c2n1
Yield: 99.1 %

Procedure:
To a solution of N2-butyl-9-[2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethyl]-8-(methyloxy)-9H-purine-2,6-diamine (135 mg, 0.359 mmol) in methanol (10 ml) was added 4M HCl solution in dioxane (2.241 ml, 8.96 mmol) and the mixture was left standing at 20° C. After 6 hours the solvent was evaporated under a stream of nitrogen. The residue was loaded in methanol onto a 10 g aminopropyl SPE cartridge and eluted with methanol. The solvent was removed by evaporation to give the title compound (129 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=S)[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14].C(Cl)Cl.CC[O:28]C(C)=O>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:28])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=S
Solvent: ClCCl
Product: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=O

Procedure:
Dimethyl 2-(1,3-dihydro-1-oxo-3-thioxo-2H-isoindol-2-yl) -pentanedioate (208) and Dimethyl 2-(1,3-dihydro-1,3-dithioxo-2H-isoindol-2-yl)-pentanedioate (209). A mixture of compound 207 (144 mg, 0.47 mmol) and LR (191 mg, 0.47 mmol) in toluene was stirred in a 110° C. oil bath for 10 h. The solvent was then evaporated and the residue was purified by column chromatography, (silica gel) using CH2Cl2 as the eluent, to obtain compound 209 (17 mg, 11%) as a dark red oil. Thereafter, using CH2Cl2:EtOAc (10:1) as the eluent the more polar component 208 (105 mg, 70%) was obtained as a red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1>>[Br:24][C:25]1[CH:30]=[C:29]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[C:4]([CH3:23])[CH:3]=2)(=[O:33])=[O:32])[CH:28]=[N:27][CH:26]=1
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Product: Cc1cc(NS(=O)(=O)c2cncc(Br)c2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from D7 and 3-bromopyridine-5-sulfonyl chloride using a method similar to that described for D15 except that the reaction time was overnight and column chromatography was carried out eluting with 0-100% Et2O/petroleum ether. δH (CDCl3, 400 MHz) 8.83 (1H, d), 8.80 (1H, d), 8.12 (1H, t), 7.16 (1H, d), 7.13 (1H, br.s), 6.92 (1H, d), 6.86 (1H, dd), 4.17 (1H, br.s), 3.77 (1H, d), 3.34 (2H, s), 2.99 (1H, m), 2.64 (1H, m), 2.51 (1H, d), 2.31 (3H, s), 2.14 (1H, m), 1.96 (1H, m), 1.46 (9H, s), 1.17 (3H, d). MS (ES+): MH+ 539/541.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[OH:10][C:11]([CH3:44])([CH3:43])[CH2:12][C@@:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:18][C:17](=[O:19])[N:16]([C@H:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH3:21])[CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[OH:10][C:11]([CH3:43])([CH3:44])[CH2:12][C@@:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:18][C:17](=[O:19])[N:16]([C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=3)=[CH:26][CH:27]=2)[CH3:21])[CH2:15][CH2:14]1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 27.7 %

Procedure:
A mixture of 4-iodo-1-methylpyridin-2(1H)-one (0.909 g, 3.76 mmol), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.5 g, 3.13 mmol), 2 M aq Cs2CO3 (3 mL, 6 mmol), and PdCl2(PPh3)2 (0.201 g, 0.282 mmol) in 1,4-dioxane (15 mL) was refluxed under N2 for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to obtain the crude compound, which was purified by preparative HPLC and chiral HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (399 mg, 28%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1. The compound was recrystallized using below methods.
Reaction SMILES: [C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15](CC3C4C(=CC=C(NC(=O)CC5CCCC5)C=4)N(CC)C=3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:48]1([O:53][C:54]([NH:56][C:57]2[CH:65]=[C:64]3[C:60]([CH:61]=[N:62][N:63]3[CH2:66]C3C=CC(C(O)=O)=CC=3OC)=[CH:59][CH:58]=2)=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15]([CH2:66][N:63]3[C:64]4[C:60](=[CH:59][CH:58]=[C:57]([NH:56][C:54]([O:53][CH:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)=[O:55])[CH:65]=4)[CH:61]=[N:62]3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCn1cc(Cc2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Reactant: COc1cc(C(=O)O)ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Product: COc1cc(C(=O)OC(=O)N(c2ccccc2)c2ccccc2)ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Yield: 96 %

Procedure:
Using a procedure similar to part (f) of Example 4, but using 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoic acid (N) instead of acid (J), there was obtained 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (K) as a pink solid (2.14 g, 96%); partial NMR: (80 MHz, DMSO-d6): 3.86(s, 3H, OCH3), 5.49(s, 2H, ArCH2N), 7.42(s, 10H, NArH), 9.69(s, 1H, CONH).
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].C(O[C:20]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)(C)(C)C>[OH-].[K+].C(O)C>[C:26]([O:25][C:23]([O:22][C:20]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 28 °C
Yield: 63 %

Procedure:
A solution comprising 0.49 grams potassium hydroxide, 40 grams of 4-acetoxystyrene, and 100 grams of absolute ethanol was refluxed for 4 hours. The reaction solution was cooled to 28° C. and 13 grams of potassium hydroxide pellets were added over a period of 10 minutes. After an additional 30 minutes of reaction, 64 grams di-tertiary-butyl-dicarbonate was charged portionwise over 20 minutes and the reaction was stirred for an additional hour at 28° C. After aqueous washing, the reaction product was extracted with ethyl acetate. The ethyl acetate was stripped from the extraction mixture on a rotary evaporator and the residual oil was charged with 0.07 grams phenothiazine. Distillation at 0.1 Mm Hg gave 34.2 grams (64%) 4-tertiary-butoxycarbonyloxystyrene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I

Procedure:
A solution of 3-iodo-4-methylaniline (1.22 g, 5.25 mmol), 3-(trifluoromethyl)benzoic acid (0.95 g, 5 mmol), HOBt (0.68 g, 5 mmol), and EDCI (1.05 g, 5.5 mmol) in THF (20 mL) was stirred overnight at rt. Water was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (3:1 hexane/ethyl acetate) yielding the desired product.
Reaction SMILES: O.[NH2:2]N.[CH2:4]([O:11][C:12]1[C:13]([CH:27]=O)=[C:14]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:15]([N:17](CC)CC)=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([O:11][C:12]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:14]2[C:13]=1[CH:27]=[N:2][NH:17][C:15]2=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(=O)[nH]ncc2c1OCc1ccccc1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Glacial acetic acid (285 ml) at 10-20° C. was dropwise added with hydrazine monohydrate (10.16 ml, 209 mmoles) and added with 3-benzyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide (14.27 g, 41.8 mmoles), prepared as described in example 56. The mixture was left to stand for 2 hours, then evaporated, dissolved in CH2Cl2, washed with water, anhydrified over Na2SO4, brought to dryness, and the crude was triturated in petrolatum/ethyl ether 2:1 (150 ml) and filtered to give 11.3 g of the title compound (yield: 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[F:1][C:2]1[C:10]([NH:11][C:22](=[O:23])[CH2:21][O:20][CH3:19])=[CH:9][C:8]2[C:4](=[CH:5][C:6](=[O:12])[N:7]=2)[CH:3]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc2c(cc1F)=CC(=O)N=2
Temperature: 25 °C
Yield: 40.9 %

Procedure:
5-Fluoro-6-Amino-indol-2-one 9d (2.028 g, 12.2 mmol) was dissolved in 30 mL of tetrahydrofuran under stirring at room temperature, and 1.3 mL of pyridine was then added to the solution. The reaction system was cooled down to −50° C. in a dry ice-ethanol bath. Methoxy-acetyl chloride (1.35 g, 12.5 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the dry ice-ethanol bath was removed. The reaction system was allowed to warm up to room temperature and stirred overnight until TLC showed the disappearance of starting materials. The resulting solid was filtered, washed with water (10 mL ×3) and recrystallized from methanol to give the title compound 5-fluoro-6-methoxyacetamido-2-oxoindole 13a (1.18 g, yield 40.6%) as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1>C(O)(=O)C.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Yield: 45.2 %

Procedure:
2-(2-Chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2 mmol, 1 equiv) and 8.44 g iron (151.1 mmol, 5 equiv) in 100 mL acetic acid and 50 mL EtOAc were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52%) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), 6.80 (d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMS RT=0.89 min; [M+H]+=235.1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][C:21]1([CH3:24])[CH2:22][C@H:18]([O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[C:11]([F:31])[CH:12]=2)[C@@H:19]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[CH2:20]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(C)(C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(C)(C)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 90.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (309 mg, 0.504 mmol) prepared in Example 93f, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (212 mg, 91%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:36]1(N)CCCC1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH:32]4[CH2:33][CH2:35][CH2:34][CH2:36]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: NC1CCCC1
Product: Cc1cc(-c2cn(CCNC3CCCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using cyclopentylamine instead of cyclopropylmethylamine. LC-MS: (M+1=489, obsd.=489).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:12]([O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@@H:20]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into the THF (5 mL) solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (140 mg, 0.500 mmol), 4-hydroxycyclohexanecarboxylic acid ethyl ester (104 mg, 0.600 mmol; Aldrich, cis/trans mixture), and PPh3 (263 mg, 1.00 mmol) was added DIAD (203 mg, 1.00 mmol) dropwise at 0° C. under N2 over 5 min. The reaction was then stirred at rt for 2 days. After that time, the solvent was evaporated, and the residue was purified by chromatography on silica gel, eluting with 200 mL of 5%, 10%, 20% and 30% EtOAc/hexane to obtain cis-4-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester as a white solid, which was further purified by HPLC. 1H NMR (CDCl3, 400 MHz): δ=1.32 (t, 3H, J=7.2 Hz), 1.74-1.78 (m, 2H), 1.88-1.98 (m, 4H), 2.33-2.36 (m, 2H), 2.75-2.77 (m, 1H), 4.23 (q, 2H, J=7.2 Hz), 4.73-4.81 (m, 1H), 7.45 (s, 1H), 8.60 (s, 1H). MS (ES+): 433.9/435.9 [MH+]. HPLC: tR=4.0 min (polar—5 min).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]P(=O)([O-])[O-])[CH:2]=1.[H-].[Na+].[CH:18]([C:20]1[CH:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:23]([CH3:25])[CH:24]=1)=O.O>C1COCC1>[CH3:25][N:23]1[CH:24]=[C:20](/[CH:18]=[CH:11]/[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:21]=[C:22]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=P([O-])([O-])Cc1cnc2ccccc2c1
Reactant: CCOC(=O)c1cc(C=O)cn1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(/C=C/c2cnc3ccccc3c2)cn1C
Reaction time: 0.17 h

Procedure:
3-Quinolinylmethylphosphonate (0.503 g, 1.93 mmol; see step (iii) above) was dissolved in anhydrous THF (2 mL) and NaH (0.273 g, 11.37 mmol) was then added in small portions to the solution and the resulting mixture was then aged for an additional 10 min. Ethyl 4-formyl-1-methyl-1H-pyrrole-2-carboxylate (0.313 g, 1.92 mmol; see Preparation 11 above) in anhydrous THF (3 mL) was added dropwise and the solution allowed to stir for 16 h. Water (5 mL) was added to the mixture (dropwise initially) during which time the sub-title compound precipitated as a yellow solid (0.201 g, 34%).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:12]=1
Reactant: NCc1ccc(F)cc1
Reactant: N#Cc1cccnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1NCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
To a stirred suspension of 2-chloro-nicotinonitrile (Aldrich, 3.30 g, 23.82 mmol) in 2-propanol (30 ml) was added 4-fluoro-benzylamine (3.00 ml, 26.25 mmol) and N,N-diisopropylethylamine (8.30 ml, 47.65 mmol). The reaction mixture was heated to 80° C. for 24 hours. More 4-fluoro-benzylamine (0.55 ml, 4.81 mmol) was added and stirring was continued at 80° C. for another 24 hours. The reaction mixture was cooled to room temperature and the precipitated material was isolated by filtration and washed with 2-propanol. Residual 2-propanol was removed in vacuo affording the title compound (3.04 g) as a white crystalline material. 1H-NMR (DMSO-d6) δ 8.23-8.25 (m, 1H), 7.91 (dd, 1H), 7.73 (t, 1H), 7.34-7.38 (m, 2H), 7.08-7.14 (m, 2H), 6.63-6.67 (m, 1H), 4.57 (d, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>CN(C)C=O>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=3)[N:9]([CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)Nc1ccc(F)cc1S2
Reactant: CN1CCN(CCCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCN2c3ccc(F)cc3Sc3ccc(S(=O)(=O)N(C)C)cc32)CC1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
12 grams of N,N-dimethyl-7-fluoro-phenothiazine-2-sulphonamide were dissolved in 50 milliliters of dry dimethylformamide, 1.9 grams of 50% sodium hydride in oil added and the mixture stirred for 1 hour. 7.2 grams of 1-(3-chloropropyl)-4-methylpiperazine were then added and the mixture heated for two hours on a steam bath. Then the mixture was poured onto crushed ice, the resulting mixture extracted with ether, the ether phase washed, dried over anhydrous magnesium sulphate and the ether evaporated. 13 grams of 2-dimethylsulphamoyl-7-fluoro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine was thus obtained as a yellow oil. The dimaleate was made from an ethanol solution of the base and melted at 166°-169° Centigrade.