Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])(=O)=O.O>CN(C=O)C>[CH2:42]([N:43]([CH2:46][CH3:47])[CH2:44][CH2:45][O:26][C:22]1[CH:21]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:41]
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Reactant: CCN(CC)CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(diethylamino)ethyl methanesulfonate (30 mg, 0.15 mmol). The mixture was heated at 50° C. for 15 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated. The residue was purified by chromatography (silica, EtOAc) to give 6-(3-(2-(diethylamino)ethoxy)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (18 mg, 37%). 1H NMR (300 MHz, CDCl3): δ 8.64 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.59-7.53 (m, 3H), 7.45-7.36 (m, 2H), 7.28 (s, 1H), 7.04 (d, 1H, J=8.4 Hz), 6.23 (d, 1H, J=8.1 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.29-4.15 (m, 3H), 3.68 (brs, 1H), 3.52-3.49 (m, 1H), 2.97-2.93 (m, 2H), 2.72-2.65 (m, 4 h), 2.15-2.04 (m, 3H), 1.77 (brs, 3H), 1.26 (d, 3H, J=6.3 Hz), 1.11 (t, 6H, J=7.1 Hz). LC/MS: 486 [M+H]+, tR=1.48 min. HPLC: 95.50% at 214 nm, 96.62% at 254 nm, tR=5.45 min.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH2:24][CH2:25][NH2:26].O>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:26][CH2:25][CH2:24][CH2:23][C@@H:22]([C:27]([OH:29])=[O:28])[NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCNCCC[C@H](N)C(=O)O
Yield: 90.1 %

Procedure:
ornithine oleate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 29.1 g of Nδ-oleyl ornithine (yield 86.9%). This is designated Derivative B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]4[CH2:39][CH2:38][NH:37][C:36]4=[O:40])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=C1NCC[C@@H]1NS(=O)(=O)c1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@H]3CCNC3=O)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (S)-2-bromo-N-(2-oxopyrrolidin-3-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J=2.2, 1.3, 2H), 8.18 (dd, J=7.9, 1.3, 1H), 7.67-7.60 (m, 1H), 7.58-7.51 (m, 1H), 7.45-7.31 (m, 4H), 6.05 (d, J=9.3, 1H), 5.51 (dd, J=9.8, 3.3, 1H), 5.35 (d, J=3.1, 2H), 3.67-3.55 (m, 1H), 3.39-3.19 (m, 2H), 2.65-2.50 (m, 1H), 2.16-1.99 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:13]1[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11][CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 93.6 %

Procedure:
A solution of compound 81 (0.5 g, 1.346 mmol) in dry methanol (20 mL) was treated with hydrazine hydrate (0.41 mL, 13.461 mmol) followed by Raney-Ni (0.1 g) and the resulting mixture was refluxed for 30 min. The reaction was brought to room temperature, filtered through celite bed, washed with CH2Cl2:methanol (1:1, 3 20 mL). The combined organic layer was evaporated and crude was purified by column chromatography (EtOAC: Hexanes, 1:1) to obtain compound 98 (0.43 g, 94%) as a foam. 1H NMR (DMSO-d6) δ: 1.38-1.41 (m, 11H), 1.76-1.86 (m, 2H), 2.14-2.42 (m, 2H), 2.73 (s, 3H), 4.05-4.15 (m, 1H), 4.49 (s, 2H), 6.00 (brs, 1H), 6.48 (dd, 1H, J=1.8, 8.2 Hz), 6.99 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.16 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS m/z (%): 364 (M+Na+, 7), 342 (MH+, 11), 286 (100).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[C:6]2=[N:5][C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:3]1.O.NN>C(O)C>[NH2:12][CH:11]1[C:6]2=[N:5][C:4]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:3][C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCn2c1nc(-c1ccncc1)cc2=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1CCCn2c1nc(-c1ccncc1)cc2=O
Yield: 65.8 %

Procedure:
To a solution of 3.2 g (8.59 mmol) of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione dissolved in 24 mL of ethanol was added 2.09 mL (43 mmol) of hydrazine hydrate and the resulting mixture was stirred under reflux for 2 h. The mixture was filtered and the solid obtained was triturated with dichloromethane for 24 h, filtered, and the resulting filtrates were evaporated to dryness. The resulting residue was purified on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 98/2 to 96/4 to give 1.37 g (66%) of the desired compound as a brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(O)cc3c2c1COC
Product: CCOC(=O)c1ncc2[nH]c3ccc(Oc4ncccn4)cc3c2c1COC

Procedure:
Analogously to Example 8 from 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester and 2-chloropyrimidine, mp 128°-129° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:41][C:42]1[CH:46]=[CH:45][N:44]([CH2:47][C:48]([CH3:51])([OH:50])[CH3:49])[N:43]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:41][C:42]1[CH:46]=[CH:45][N:44]([CH2:47][C:48]([OH:50])([CH3:49])[CH3:51])[N:43]=1)[CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CC1CCOCC1)C(=O)O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of 2-t-butoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid (500 mg, 1.83 mmol) in dichloromethane (15 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (285 mg, 1.85 mmol) and 1-hydroxybenzotriazole (260 mg, 1.92 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 312 mg, 2.01 mmol). The reaction mixture was then stirred for 18 h at 25° C. under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, to afford [1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-2-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid t-butyl ester (700 mg, 93%) as a white solid: LR-ES-MS m/z calculated for C20H34N4O5 [M]+ 410, observed [M+H]+ 411.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:11][C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)=[O:13])[CH3:10]>C1COCC1.CO>[CH2:9]([O:11][C:12]([C:14]1[NH:15][C:16]([Br:8])=[CH:17][CH:18]=1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc[nH]1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Br)[nH]1
Reaction time: 2 h
Yield: 55.3 %

Procedure:
NBS (0.15 mg, 0.83 mmol) was added to a stirred cold (0-5° C.) solution of 1H-pyrrole-2-carboxylic acid ethyl ester (200 mg, 1.44 mmol) in THF: MeOH (2:1, 24 mL). Stirring was continued at same temperature for 2 hrs. Solvent was removed under vacuum to get the residue. The residue obtained was purified by column chromatography (using silica gel of 200-430 mesh and 10% Ether in Hexane as eluent) to afford 100 mg (31.95% yield) of 5-bromo-1H-pyrrole-2-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 9.4 (bs, 1H), 6.8 (s, 1H), 6.2 (s, 1H), 4.4-4.2 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[CH:13](O)=O>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:13][NH:10][C:5]=2[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=CO
Product: FC(F)(F)c1ccc2nc[nH]c2c1
Yield: 83 %

Procedure:
A mixture of 10 g (60 mmol) of 4-(trifluoromethyl)-1,2-phenylenediamine (Lancaster) and 50 mL of formic acid was refluxed for 2 h. Excess formic acid was then removed in vacuo. To the resultant concentrate was added 200 mL of water during which time a precipitate was discerned. This was filtered and discarded. The filtrate was concentrated in vacuo and redissolved in EtOAc. After repeated washing with saturated NaHCO3, the EtOAc solution was dried over MgSO4 and concentrated. The concentrate was put on a vacuum pump overnight. This resulted in 9.27 g (83%) of a yellow solid. 1H NMR (DMSO-d6) δ7.5 (d,1H, aromatic), 7.8 (d, 1H, aromatic), 8 (s, 1H, aromatic), 8.4 (s, 1H, CH), 12.8 (br s, 1H, NH).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(=O)C.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: O=C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Temperature: 52.5 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
In 1.2 g of acetic acid were dissolved 1.39 g of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine and 3.9 g of cyclohexanone. To the resulting solution was added 302 mg of 10% palladium carbon. Under a hydrogen pressure of 10 kg/cm2, the mixture was stirred at 50 to 55° C. for 12 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was filtered through Celite. Water was added to the filtrate and crystals so precipitated were collected by filtration with suction. The resulting crystals were recrystallized from a mixed solvent of ethanol and water, whereby 1.63 g of the title compound was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](Br)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.[F-].[Cs+]>COCCOC.CO.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>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:47]3[CH:48]=[CH:49][C:44]([CH2:43][OH:42])=[CH:45][CH:46]=3)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Temperature: 110 °C
Yield: 60.6 %

Procedure:
A mixture of compound 34C (0.135 g, 0.2 mmol), 4-(hydroxymethyl)phenylboronic acid (0.033 g, 0.22 mmol), Pd(PPh3)4 (0.012 g, 0.01 mmol) and CsF (0.091 g, 0.6 mmol) in the DME (2 mL) and MeOH (1 mL) were heated under microwave conditions (110° C., 20 minutes). The reaction mixture was concentrated, and partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 1:1/hexanes:EtOAc to provide 0.085 g of the desired product 34D, which was also a mixture of two regioisomers. MS (ESI(+)): m/z 701 (M+H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:10]=3[N:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>CCO>[CH2:4]1[CH2:5][CH2:6][CH:1]([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]3[N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:21])=[O:22])[CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c([N+](=O)[O-])cnc32)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(N)cnc32)cc1
Temperature: 75 °C
Yield: 78.6 %

Procedure:
To a mixture of N-cyclohexyl-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine (0.111 g, 0.268 mmol, prepared using K.1 from Example #21 Step D with 4-methylbenzene-1-sulfonyl chloride, L with cyclohexylamine) in EtOH (2.5 mL) was added tin (II) chloride dihydrate (0.060 g, 0.268 mmol). The reaction mixture was heated at about 75° C. for about 75 min. Tin (II) chloride dihydrate (0.030 g, 0.134 mmol) was added and the reaction mixture was heated at about 75° C. for about 5 h. Additional tin (II) chloride dihydrate (0.060 g, 0.268 mmol) was added and the reaction mixture was heated at about 75° C. for about 14 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic portion was separated. The aqueous portion was extracted with EtOAc (3×25 mL). The organic extracts were combined, dried over MgSO4, filtered, and concd under reduced pressure to give N-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.081 g, 79%) as a brown oil: LC/MS (Table 1, Method n) Rt=0.82 min; MS m/z 385 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[CH3:33][NH:34][NH2:35]>>[ClH:32].[F:27][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3([C:5]4[C:6](=[N:35][N:34]([CH3:33])[CH:4]=4)[C:7]=2[CH:8]=1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3
Reactant: CNN
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: Cn1cc2c(n1)-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (3.81 g, 8.71 mmol) was added hydrochloric acid (32.7 mL of 4.0 M in dioxane, 130 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with EtOH (1×30 mL). The resulting solid was suspended in EtOH (30.5 mL) and was treated with methylhydrazine (556 μL, 10.5 mmol) at 40° C. for 4 h. The mixture was then heated at 80° C. for 1 h resulting in a yellow solution with an off white precipitate. The solid was collected to give 8-fluoro-2-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] hydrochloride (798 mg, 26%). ESI-MS m/z calc. 273.1, found 274.5 (M+1)+. Retention time 0.83 minutes (3 min run). Note: The yellow mother liquor was evaporated to give a mixture of methyl regioisomers (1.71 g).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])[C:2]#[CH:3].[CH:13]([Mg]Br)=[CH2:14].[NH4+].[Cl-]>C1COCC1>[CH2:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]([OH:8])[CH:13]=[CH2:14])[C:2]#[CH:3]
Reactant: C#CCSc1ccccc1C=O
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCSc1ccccc1C(O)C=C
Temperature: 25 °C

Procedure:
To 35.2 g of 2-(2-propynylthio)benzaldehyde in dry THF cooled to between -60° and -70° C. was added 210 ml of a 1M solution of vinylmagnesium bromide solution dropwise at -60° C. and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into saturated NH4Cl and extracted twice with diethyl ether. The extracts are washed with water and then brine and dried over MgSO4 to afford 42.1 g of the subtitle compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1>CN(C=O)C>[Br:1][C:13]1[C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=[C:11]([CH2:10][Cl:9])[CH:12]=1
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CCl)cc(Br)c1O
Reaction time: 15 h

Procedure:
A solution of N-bromosuccinimide (10 mmol) in 8 mL of DMF is added dropwise to a solution of 1-(5-chloromethyl-2-hydroxy-phenyl)-ethanone 211 (10 mmol) in 20 mL DMF and the resulting mixture is stirred for 12-18 h. The solvent is evaporated under reduced pressure and the residue is diluted with water resulting in the formation of a solid. The solid is isolated and recrystallized from ethanol to yield 1-(3-Bromo-5-chloromethyl-2-hydroxy-phenyl)-ethanone 212.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14].C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:18][CH2:17][CH2:16][CH:12]2[C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (3 g, 19 mmol), L-proline (2.19 g, 19.0 mmol) and triethylamine (10.6 ml, 76 mmol) were dissolved in DMSO (15 ml) then heated at 90° C. for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue treated with water and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to a residue. Purification by column chromatography using dichloromethane/methanol (97:3) gave 1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (0.9 g, 20%).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.CNC>>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([N:21]([CH3:22])[CH3:19])=[O:3])[CH3:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Product: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)N(C)C
Yield: 66.6 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 25, 2.7 g of carbonyldiimidazole and 3.6 ml of 40% aqueous dimethylamine. The product was recrystallized from toluene to obtain 2.2 g of desired product, m.p. 136°-139°.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH:14]([OH:35])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:14]([OH:35])[CH2:13][S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][CH:2]=[N:1]4)[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Sc1cccc2ncccc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: OC(CSc1cccc2ncccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 20.3 %

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 220 mg of 5-quinolinethiol and 1.2 g of 4-(3-chloro-2-hydroxypropyl)-1-(diphenylmethyl)piperzine, in order to obtain 130 mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropylthio]quinoline.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A163) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][CH:16]=[CH2:17]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:17][CH:16]=[CH2:15])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: C=CCBr
Product: C=CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as a yellow solid in 95.1% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-1-propene.