Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:21])([CH2:19][CH3:20])[C:14]2=[O:22])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:21])([CH2:19][CH3:20])[C:14]2=[O:22])[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCC(=O)Nc1cccc(N2C(=O)CC(C)(CC)C2=O)c1

Procedure:
Two and eight-tenths g. of propionylchloride was added dropwise to a well-stirred solution of 7 g. of N-m-aminophenyl-2-methyl-2-ethylsuccinimide and 3.5 g. of triethylamine in 50 ml. of acetone in a water bath. When the reaction was complete (after approximately 30 minutes), the mixture was poured into approximately 500 ml. of water and the product extracted with approximately 50 ml. of methylene chloride, dried and the solvent stripped under vacuum. The yield was 7.7 g. of a thick oil having a nD30 of 1.5510. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[CH:32]=[CH:31][C:8]([C:9]([N:11]2[CH2:30][CH2:29][C:14]3([C:19]4=[CH:20][CH:21]=[CH:22][N:18]4[C:17]4[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:16]=4[O:15]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:33][CH3:34])[CH3:4]>CO.O.O.O.O.O.O.Cl[Co]Cl>[NH2:28][CH2:27][C:25]1[CH:24]=[CH:23][C:17]2[N:18]3[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]3([CH2:29][CH2:30][N:11]([C:9]([C:8]4[CH:31]=[CH:32][C:5]([CH2:3][CH3:4])=[C:6]([O:33][CH3:34])[CH:7]=4)=[O:10])[CH2:12][CH2:13]3)[O:15][C:16]=2[CH:26]=1
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C#N)ccc2-n2cccc23)cc1OC
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CN)ccc2-n2cccc23)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaBH4 (17.7 mg, 0.47 mmol) was slowly added to a solution of 1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carbonitrile (20 mg, 0.050 mmol) and dichlorocobalt hexahydrate (22 mg, 0.090 mmol) in MeOH (1 mL) and was stirred at room temperature for 10 minutes. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O) to yield (7-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanone. ESI-MS m/z calc. 431.5, found 432.5 (M+1)+; Retention time: 1.44 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:8]([OH:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C1COCC1.C(N(C(C)C)C(C)C)C.[C:41]1([C:47]#[CH:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CCOC(C)=O.[Cu]I>[OH:14][C:8]1[C:9]([CH3:12])([CH3:13])[C:10]2[C:5]([C:6](=[O:26])[C:7]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])=[CH:4][CH:3]=[C:2]([C:48]#[C:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:11]=2
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(Br)ccc2C1=O
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(C#Cc3ccccc3)ccc2C1=O
Temperature: 80 °C

Procedure:
To a mixture of tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (120 mg, 283 μmol, Example 53A-E), palladium dichloride bistriphenylphosphine (20 mg, 28 μmol), and copper(I) iodide (11 mg, 57 μmol) was added THF (1414 μL), N-ethyl-N-isopropylpropan-2-amine (148 μL, 848 μmol), and phenylacetylene (62 μL, 566 μmol). The reaction was heated at 80° C. for 2 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated to give crude product which was purified via flash chromatography to give the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H-].[Na+].Br[CH2:12][C:13]([CH3:24])=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[C:13]([CH3:24])[CH2:12][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)=[CH:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: CC(=Cc1ccc(C(C)C)cc1)CBr
Reactant: Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccc(C(C)C)cc1)COc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of p-cresol (3.50 g, 32.3 mmol) in DMF (70 mL) was added sodium hydride (a 60% liquid paraffin dispersion, 1.42 g, 35.5 mmol) under nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 1-(3-bromo-2-methyl-1-propenyl)-4-isopropyl benzene (9.0 g, 35.5 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 8.20 g (yield 91%) of the title compound. Oily matter.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[F:32][C@H:33]1[C@@H:38](OS(C)(=O)=O)[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34]1.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][C@@H:38]3[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:34][C@H:33]3[F:32])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2cccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (25 mg, 0.061 mmol; prepared according to Example 17, Step A) in DMA (2 mL) was added a mixture (approximately 9:1) of (3R,4S)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (prepared as described in WO 2008/124323) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (27 mg). Cs2CO3 (39 mg, 0.12 mmol) was added, the reaction vial was sealed, and the mixture was heated to 90° C. and stirred for 6 hours. DMA was removed under reduce pressure. The residue was diluted with EtOAc (20 mL), washed with saturated NaHCO3 aqueous solution and brine, and concentrated. Silica gel chromatography (DCM/MeOH 10:0.5) gave the desired product (12 mg). (The non-fluorinated product, which was also isolated, was utilized in Example 19, Step A).
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C@@H:17]2[OH:26])[CH2:9][CH2:8]1)(=O)C.O>CO>[N:27]1([C@H:16]2[CH2:15][C@H:14]3[C@H:13]4[C@H:22]([CH2:21][CH2:20][C@:18]3([CH3:19])[C@H:17]2[OH:26])[C@:23]2([CH3:25])[C@H:10]([CH2:9][CH2:8][C@@H:7]([OH:6])[CH2:24]2)[CH2:11][CH2:12]4)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(=O)O[C@@H]1CC[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](O)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Temperature: 25 °C
Yield: 76.4 %

Procedure:
Sodium hydroxide solution (60 ml; 4N) was added to a solution of 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol 2-acetate (25.49 g) in methanol (120 ml) and the mixture was heated under reflux for 1 h. When the solution had cooled to room temperature, water (200 ml) was added to precipitate the product, which was filtered off and washed with water (3×200 ml). A solution of the crude solid in diethyl ether (150 ml) was washed neutral with water (2×200 ml), dried (MgSO4) and evaporated to dryness. Crystallisation of the resulting white solid from methanol acetone afforded 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol (17.51 g), m.p. 215°-219° C.; [α]D +36.1° (c 0.48 in CHCH3).
Reaction SMILES: [C:1]([N:5]1[C@@H:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@@H:8]2[O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].C([Mg]Cl)(C)(C)C.C(O[C@H:28]1[NH:31][C:30](=[O:32])[C@@H:29]1[C@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH3:34])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[Si:36]([O:35][C@@H:33]([C@@H:29]1[C@@H:28]([C@@H:2]([CH3:3])[C:1]([N:5]2[C@@H:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@@H:8]3[O:7][C:6]2=[O:17])=[O:4])[NH:31][C:30]1=[O:32])[CH3:34])([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:37])[CH3:38]
Reactant: CCC(=O)N1C(=O)O[C@H]2Cc3ccccc3[C@H]21
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)O[C@H]2Cc3ccccc3[C@H]21
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
Under a nitrogen atmosphere, 231 mg (1. 0 mmol) of 3-propionyl-(3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.75 ml (2.2 mmol) of a tetrahydrofuran solution (0.8M) of t-butylmagnesium chloride was slowly added dropwise at room temperature. After the resulting mixture was allowed to react for 20 minutes under the same conditions, the reaction mixture was cooled to 5° C. and added with 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one at the same temperature. After stirring for 10 minutes, 10 ml of ethyl acetate was added to the reaction mixture, followed by the dropwise addition of 2ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 83 mg (0.18 mmol) of a condensation product was obtained (yield: 18%, β:α=64:46).
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[OH:22][CH2:23][CH:24]([NH2:26])[CH3:25]>>[CH2:23]([CH2:24][NH2:26])[OH:22].[OH:22][CH2:23][CH:24]([NH:26][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])[CH3:25]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Reactant: CC(N)CO
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(C)CO)on1
Product: NCCO
Yield: 102.7 %

Procedure:
As described for example 24b, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (201 mg, 0.68 mmol), was converted using 1-hydroxymethylethylamine (62 mg, 0.82 mmol), instead of ethanolamine, to the title compound (142 mg, 62%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=1:1 to 0:1). MS: m/e=338.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][C:14](OCC)=[N:13][CH2:12][CH2:11]1)=[O:9].O.[NH2:20][NH2:21]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:11][CH2:12][NH:13][CH:14]([NH:20][NH2:21])[CH2:15]1)=[O:9]
Reactant: CCOC1=NCCN(C(=O)c2ccccc2Cl)C1
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: NNC1CN(C(=O)c2ccccc2Cl)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[(2-chlorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (I39) (0.755 g, 2.83 mmol) dissolved in Dichloromethane (DCM) (10 mL) was added to hydrazine hydrate (0.220 mL, 7.08 mmol, commercially available from e.g. Alfa Aesar, Acros or Fluka) dissolved in Dichloromethane (DCM) (5 mL) and stirred at 25° C. for 4 hr. The solvents were removed in vacuo and the residue azeotroped with toluene (3×25 mL), to afford product in 715 mg that was used in the subsequent step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]([NH:5][C:6]2[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=2[S:12][CH3:13])=[O:4])[CH2:22][CH2:21]1
Reactant: OCCN1CCNCC1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (6.41 g, 0.02 mol) in acetonitrile (120 ml) was added 1-(2-hydroxyethyl)piperazine(3.53 g, 0.027 mol), and then added potassium carbonate (3.75 g, 0.027 mol) with ice-cooling and the mixture was stirred at room temperature for 23 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was recrystallized from ethanol-ether to provide 7.19 g (yield 97%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][NH:14][CH3:15].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:13][CH3:12])[CH3:15])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CNOC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
A mixture of 4-bromo-3-methyl-benzoic acid (15 g, 0.069 mol), O,N-dimethyl hydroxylamine (6.5 g, 0.1 mol) HATU (38 g, 0.1 mol), and triethylamine (20 g, 0.2 mol) dissolved in DMF (50 mL) was stirred at RT for 12 h, concentrated, and purified by silica gel chromatography (1:1 EtOAc:petroleum ether) to provide the title intermediate (11 g, 61% yield) 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.52 (m, 2H), 7.32 (m, 1H), 3.50 (s, 3H), 3.29 (m, 3H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[CH3:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])[CH2:7][C:6]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccc4)CC3)n1-2
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccc3)CC2)C1
Reaction time: 16 h

Procedure:
To a stirred solution of the compound from example 5 (270 mg, 0.71 mmol) in dichloromethane (20 mL) was added triethylamine (118.8 μL, 0.86 mmol) followed by dimethylsulfamoyl chloride (84 μL, 0.78 mmol) and the reaction mixture was stirred for 16 hours. Dimethylsulfamoyl chloride (84 μL, 0.78 mmol) was then added and the reaction stirred for a further 72 hours. The reaction was diluted with water (20 mL) and the phases separated. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using ethyl acetate and then dichloromethane methanol (95:5) as eluent gave the product as a white crystalline solid, 217 mg (63%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]([CH3:17])[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.CO>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:2]=1[F:1])=[O:22]
Reactant: CN1CCC(N(C)c2cccc(N)c2F)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2F)CC1
Yield: 100 %

Procedure:
Heat 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 22, 44 mg) with 2-chloro-4-fluorobenzoyl chloride (40 mg) in 1,4-dioxane (5 mL) at reflux for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a SCX column (10 g). After wash with methanol, elute the product with 2 M NH3 in methanol, evaporate to give 73 mg of the title compound: mass spectrum (electric spray) m/z=394 (M+1); 1H NMR (CDCl3): 8.29 (br d, 1H), 7.94 (t, 1H), 7.81 (dd, 1H), 7.18 (dd, 1H), 7.05 (m, 2H), 6.77 (ddd, 1H), 3.15 (m, 1H), 2.72 (s, 3H), 2.26 (s, 3H), 1.96 (m, 2H), 1.83 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)c2cc[nH]c2c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccn(COCC[Si](C)(C)C)c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A solution of 4-bromo-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.967 g, 4.26 mmol) in N,N-dimethylformamide (30.6 mL) at 0° C. was treated with sodium hydride (0.255 g, 6.38 mmol) and stirred at 0° C. for 30 min. After this time the reaction mixture was treated with [β-(trimethylsilyl)ethoxy]methyl chloride (1.13 mL, 6.39 mmol) and subsequently stirred at 20° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with water (3×), dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (1.03 g, 68%) as a white solid. LCMS calculated for C14H22BrN2O2Si (M+H)+: m/z=357.1, 359.1. found: 357.0, 359.0.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]([OH:12])=O)[C:4]=2[CH:3]=1.C(Cl)(=O)[C:16]([Cl:18])=O.[N+](=C)=[N-].Cl>>[Cl:18][CH2:16][C:10](=[O:12])[CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=2[S:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1csc2ccc(Cl)cc12
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(CCl)Cc1csc2ccc(Cl)cc12
Yield: 97.1 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting 5-chlorobenzo[b]thiophen-3-yl acetic acid (4.00 g, 17.6 mmol) with oxalyl chloride (1.7 mL, 2.5 g, 19 mmol), then ethereal diazomethane, then dry HCl gas. Work-up of the reaction mixture gave pure product as a light golden-yellow solid (4.43 g, 97% yield): 1H NMR (400 MHz, CDCl3) δ 4.12 (s, 2H) 4.15 (s, 2H) 7.35 (dd, J=8.6, 2.1 Hz, 1H) 7.43 (s, 1H) 7.65 (d, J=2.1 Hz, 1H) 7.79 (d, J=8.6 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30]([NH:29][C:25]3[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)c1
Yield: 42 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 3-tolyl isocyanate in a yield of 42%, according to the procedure for the synthesis of example 42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.BrC1C=C2C3(CCNC3)CN([C:38](NC3SC(Cl)=CN=3)=[O:39])C2=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH:38]=[O:39])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: O=CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 23, with the exception that the 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 39 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide.
Reaction SMILES: [NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH2:4][CH2:3]1.C1C(=O)N([O:25][C:26]([O:28][CH2:29][CH:30]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=O)C(=O)C1.CCN(CC)CC>[OH-].[Na+].C(#N)C.C(#N)C.O>[CH:41]1[C:42]2[CH:30]([CH2:29][O:28][C:26]([NH:1][C:2]3([C:15]([OH:17])=[O:16])[CH2:14][C:13]4[C:12]5[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=5)[NH:6][C:5]=4[CH2:4][CH2:3]3)=[O:25])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CCc2[nH]c3ccccc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1(C(=O)O)CCc2[nH]c3ccccc3c2C1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid in 26 ml of 1N NaOH and 26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile are combined at room temperature and diluted with 130 ml of acetonitrile/H2O 1:1. After two hours, the pH is readjusted to 9 (1.5 ml) with NEt3 and stirred overnight at room temperature. Then, another 6.3 g (18.7 mmol) of Fmoc-ONSu, dissolved in 19 ml of acetonitrile, is added and stirred for another two hours while the pH is monitored. After distillative removal of the acetonitrile, it is acidified with 0.01 M HCl and extracted with ethyl acetate. The extract is washed neutral, dried with Na2SO4 and spun in until a dry state is reached. Recrystallization is carried out from ether/hexane. Yield: 10.7 g.