Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13]Cl)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.ClC1C=CC2OCC[NH:30][CH:29](C3C=CC=CC=3)C=2C=1.CN>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][NH:30][CH3:29])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)NCCO2
Reactant: O=C(CCl)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Agent: CN
Solvent: ClCCl
Product: CNCC(=O)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reaction time: 18 h

Procedure:
Crude 7-chloro-4-(2-chloroacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine, prepared as described in Example 4a starting with 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.82 g, 7.0 millimoles), was dissolved in 125 ml CH2Cl2 and the solution was saturated with gaseous monomethylamine. The reaction solution was stoppered and allowed to stand at room temperature for 18 hours, followed by unstoppering and warming on a steam bath for 30 minutes. The resulting CH2Cl2 solution was washed with two portions of saturated NaHCO3, dried over Na2SO4, filtered and rendered free of solvent to afford crude 7-chloro-4-(2-methylaminoacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as a light viscous oil which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][C@H:18]1[C@@H:23]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:22][CH2:21][NH:20][CH2:19]1>O.CCOCC>[CH2:1]([O:8][C:9]([N:20]1[CH2:21][CH2:22][C@H:23]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C@H:18]([CH3:17])[CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1CNCC[C@@H]1Nc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a rapidly stirred mixture of benzylchloroformate (0.39 ml, 2.76 mmol) and sodium bicarbonate (284 mg, 3.6 mmol) in water (4 ml) and ether (4 ml) is added cis-3-methyl-4-(2-fluoro-phenylamino)-piperidine (500 mg, 2.4 mmol) as a solution in ether (2 ml). The mixture is stirred for one hour at ambient temperature, the layers are separated, and the organics washed with 2N NaOH (2×) and brine (1×). The organics are dried over sodium sulfate and concentrated to give cis-1-benzyloxycarbonyl-3-methyl-4-(2-fluorophenylamino)-piperidine as an oil: 740 mg; 90%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([N:38]3[CH2:39][CH2:40][C:35]4([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=5[O:42][CH2:41]4)[CH2:36][CH2:37]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 74.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.363 mmol) obtained in Example 90, step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.082 g, 0.399 mmol), the title compound (0.148 g, 74%) was obtained.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:17]1([NH:20][C:8]([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)N(c1ccccc1)c1ccccc1

Procedure:
The thus formed solution of diphenylcarbamic acid chloride was then added dropwise upon stirring to a mixture of 114 g of cyclopropylamine, 202 g of triethylamine and 500 ml of toluene. During the addition the temperature inside the flask rose to 85° C. Subsequently the reaction mass was heated to boiling point for 15 minutes and then cooled. The precipitated triethylammoniumchloride was removed by suction and the solvent was distilled off in a vacuum. The remaining residue was subjected to recrystallization from diisopropylether. The yield in 1-cyclopropyl-3,3-diphenylurea was 440.2 g (87.2% of the theoretical value). The melting point was 98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc2c1OCCO2
Reaction time: 3 h

Procedure:
10% Pd/C (400 mg) was added to a solution of 7-fluoro-5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (2.0 g, 10 mmol) in methanol (50 mL) and stirring was continued at 25° C. under H2 atmosphere for 3 h. The reaction mixture was filtered over celite bed and washed with methanol. The filtrate and the washings were concentrated under reduced pressure to afford 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (Int-52) as pale brown liquid. MS (ESI): m/z 170.1 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[N:34]([CH3:35])[CH2:33][CH2:32][N:31]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)[CH2:30]1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl.CO>[CH3:28][C:29]1([CH3:44])[N:34]([CH3:35])[CH2:33][CH2:32][N:31]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:5])=[N:41][CH:42]=2)[CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1(C)C
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)C(C)(C)C4)cn3)c3nccnc23)c1F
Reaction time: 0.25 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 107.1), stirring the reaction mixture for 15 min at reflux, pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.1 [M+H]+; tR=3.72 min (System 1); TLC: Rf=0.33 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[CH2:21]([NH:24][CH:25]1[CH2:33][CH2:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH2:26]1)[CH2:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:15]1([CH:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH2:21][CH2:22][CH3:23])[CH:25]3[CH2:33][CH2:32][C:28]4[N:29]=[CH:30][S:31][C:27]=4[CH2:26]3)=[O:8])[CH2:10][CH2:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCCCNC(=O)N1CCC(c2ccccc2)CC1
Reactant: CCCNC1CCc2ncsc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CCCCNC(=O)N1CCC(c2ccccc2)CC1)C1CCc2ncsc2C1
Reaction time: 8 h
Yield: 34 %

Procedure:
A solution of 713 mg (2.6 mmol) N-(4-oxobutyl)-4-phenylpiperidine-1-carboxamide and 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine in 1,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of 1N aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:23]3[C:24]4[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=4[CH:20]=[CH:21][C:22]=3[F:25])[CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CN(C)C=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]2[N:18]=[CH:17][C:16](=[O:26])[N:15]3[CH2:14][C:13]([CH2:12][N:28]4[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]4)([OH:27])[C:23]=1[C:24]=23
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)cnc4ccc(F)c2c43)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)cnc4ccc(F)c2c43)CC1
Temperature: 50 °C

Procedure:
A mixture of (7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl 4-methylbenzenesulfonate (3.64 g, 9.3 mmol) (for a preparation, see Example 9(f)), 1,1-dimethylethyl 4-piperidinylcarbamate (2.0 g, 10.2 mmol) and sodium carbonate (2.9 g, 27.9 mmol) in ethanol (110 mL) and dimethylformamide (10 mL) was heated at 50° C. for 6 h. The mixture was evaporated to remove ethanol and the residue was partitioned between dichloromethane and half-saturated brine (200 mL each).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:13]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:8][CH:7]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:31](=[O:34])[CH2:32][CH3:33])[CH:15]=2)[CH2:10][CH2:11][CH:12]1[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)NC1CCc2ccc(OCCNC(=O)CC)cc2C1Cc1ccc(Cl)c(Cl)c1
Yield: 86.7 %

Procedure:
Ethyl 7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate hydrochloride (example 2.1, 100 mg, 0.229 mmol) and N,N-dimethyl amino pyridine (30.7 mg, 0.252 mmol) were dissolved in CH2Cl2 (20 ml) and propionyl chloride (30.7 mg, 0.252 mmol) was added at RT. After stirring at RT for 14 h 0.5 N HCl was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 and NaCl solution, dried over Na2SO4, and concentrated to afford a residue. White solid ethyl 1-(3,4-dichlorobenzyl)-7-(2-propionamidoethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (98 mg, 87%) was obtained from precipitation in ethyl acetate. Further transformation in analogy to example 2 and 97 finally gave N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-propionamide hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:14]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(C(C)=O)cc1)OCC
Temperature: 120 °C
Reaction time: 8 h
Yield: 133.4 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)ethanone (1.00 g, 7.34 mmol) in N,N′-dimethylformamide (24 mL), sodium hydride (purity 50%) (380 mg, 8.07 mmol), and bromoacetaldehyde diethyl acetal (1.30 mL, 8.81 mmol) were added under ice-cold conditions and stirred at 120° C. overnight. Under ice-cold conditions, the reaction solution was added water, and extracted with diethylether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (2.47 g (yield >100%)) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12]O)[N:11]=1.P(Br)(Br)[Br:15]>CCOCC.C(OCC)(=O)C>[Br:15][CH2:12][C:10]1[N:11]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[S:8][CH:9]=1
Reactant: BrP(Br)Br
Reactant: COCCOCc1nc(CO)cs1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCOCc1nc(CBr)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
A solution of (2-((2-methoxyethoxy)methyl)thiazol-4-yl)methanol (0.35 g, 1.72 mmol) in ether (15 mL) was treated with PBr3 (0.1 mL, 1.06 mmol) at RT. There is formation of a precipitate. The reaction was stirred at RT for 18 hours, then diluted with ethyl acetate and washed with sat. NaHCO3 (1×) and brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3×10 cm, 20% ethyl acetate/CH2Cl2) to give the title material (0.233 g, 51%) as a clear oil. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.27 (s, 1H), 4.83 (s, 2H), 4.55 (s, 2H), 3.73-3.76 (m, 2H), 3.57-3.60 (m, 2H), 3.39 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:8][CH:9]([OH:13])[C:10](=[N+:11]=[N-:12])[C:4]2=[CH:3][CH:2]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[OH:28].C(=O)(O)[O-].[Na+].Cl>O>[OH:13][C:9]1[CH:8]=[C:7]([S:14]([OH:17])(=[O:15])=[O:16])[C:5]2[C:4]([C:10]=1[N:11]=[N:12][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=1[OH:28])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: Oc1ccc2ccccc2c1
Reactant: [N-]=[N+]=C1c2ccccc2C(S(=O)(=O)O)=CC1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1cc(O)c(N=Nc2c(O)ccc3ccccc23)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a stirring solution of 1-diazo-2-naphthol-4-sulfonic acid (1.49 g, 5.95 mmol) and 2-naphthol (0.858 g, 5.95 mmol) in water (20 mL), sodium bicarbonate (1.50 g, 17.85 mmol) was added slowly. The resulting solution was heated at 60° C. with stirring overnight. The solution was cooled to room temperature, and was adjusted to pH=1 with 3 N hydrochloride solution. The purple precipitate was isolated by filtration and washed with water to provide the title compound (1.35 g, 58%) MS(ES) m/z 393 [M−H].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][S:7]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])(=[O:9])=[O:8].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C)C=O.O>[CH2:24]([N:10]([CH2:11][C:12]([NH2:14])=[O:13])[S:7]([CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=1)(=[O:9])=[O:8])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: NC(=O)CNS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(CC(N)=O)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.96 g of 3-trifluoromethylbenzylsulfonamidoacetamide was dissolved in 10 ml of dry dimethylformamide. To this ice-cooled solution was added 0.24 g of sodium hydride. The reaction mixture was stirred for 15 minutes at room temperature and then 0.95 ml of allyl bromide dissolved in 5 ml of dimethylformamide was added dropwise. Reaction was essentially instantaneous. After about 30 minutes, the reaction mixture was diluted with 150 ml of water and extracted twice with 75 ml portions of diethyl ether. Petroleum ether was added to the combined ether phases until cloudiness occurred, and this solution was washed with 100 ml of water. The organic phase was dried over magnesium sulfate and stripped to a white solid. Trituration with carbon tetrachloride afforded 2.8 g of the title compound, m.p. 91° to 92° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:12]=2[NH:11][CH:10]=[CH:9]3)[CH2:3][CH2:2]1.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:12]=2[NH:11][CH:10]=[C:9]3[C:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CC2)c2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: C1=C(c2c[nH]c3c(C4CC4)cccc23)CCNC1
Yield: 54.8 %

Procedure:
Beginning with 2.0 gm (12.7 mMol) 7-cyclopropyl-1H-indole and 3.9 gm (25.0 mMol) 4-piperidone hydrochloride monohydrate, 1.66 gm (55%) of the title compound were recovered as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:23](OCC)=[O:24])[N:11]([CH2:21][CH3:22])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.[NH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([NH:28][C:23]([C:10]2[N:11]([CH2:21][CH3:22])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Reactant: NN1CCCCC1
Product: CCn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole-2-carboxylate (25 mg, 0.06 mmol) from Step B in neat 1-aminopiperidine (2 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (1 mm, silica) (25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:11])[CH2:10][C:3]=12.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:10]3[C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[Cl:1])[NH:8][C:9]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Reactant: O=C1Cc2c(Cl)ccnc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2nccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A reaction mixture of 4-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (85 mg, 0.5 mmol), 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (125 mg, 0.5 mmol), 0.1 mL of piperidine and 10 mL of ethanol was stirred at room temperature overnight. The yellow precipitate was filtered after cooled with an ice bath, washed with cold ethanol and dried to give 185 mg (92%) of 5-(4-chloro-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
Reaction SMILES: CC1C(=CC(=CC=1)N=C=O)N=C=O.[OH:14][CH2:15][CH2:16][O:17][C:18](=[O:21])[CH:19]=[CH2:20].[N-:22]=[C:23]=[O:24]>NC(OCC)=O>[C:18]([OH:21])(=[O:17])[CH:19]=[CH2:20].[NH2:22][C:23]([O:14][CH2:15][CH3:16])=[O:24]
Reactant: C=CC(=O)OCCO
Reactant: [N-]=C=O
Agent: CCOC(N)=O
Agent: Cc1ccc(N=C=O)cc1N=C=O
Product: C=CC(=O)O
Temperature: 82 °C
Reaction time: 1 h

Procedure:
An amount of toluene diisocyanate was added to a reaction vessel suspended in a room temperature water bath and stirred. The above product from Stage 1 was added incrementally to control exothermic activity. When the exothermic activity ceased the batch was heated to 82° C. and cooked for 1 hour. After the one hour cook the batch was cooled to 70° C. and polycaprolactone acrylate was added followed by an addition of hydroxyethylacrylate (HEA). A small amount of dibutyltindilaurate, a urethane catalyst, was also added to aid bringing the reaction to completion. The batch was cooked at 82° C. until no free isocyanate was detected by FTIR. The equivalent ratio of TDI:Stage 1 product:polycaprolactone acrylate:HEA was 2.0:1.0:0.5:0.5.
Reaction SMILES: N#N.Br[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:16]3[CH:41]=[CH:40][N:39]([S:42]([C:45]4[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=4)(=[O:44])=[O:43])[C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[CH:24][C:23]=3[O:37][CH3:38])[N:20]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:52][N:53](C)C=O>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.[C-]#N.[Zn+2].[C-]#N>[C:52]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:16]3[CH:41]=[CH:40][N:39]([S:42]([C:45]4[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=4)(=[O:44])=[O:43])[C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH:34]([CH3:35])[CH3:36])[CH2:30][CH2:29]4)=[CH:24][C:23]=3[O:37][CH3:38])[N:20]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])#[N:53]
Reactant: COC(=O)c1c(Br)cccc1Nc1nc(Nc2ccc(N3CCN(C(C)C)CC3)cc2OC)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [C-]#N
Product: COC(=O)c1c(C#N)cccc1Nc1nc(Nc2ccc(N3CCN(C(C)C)CC3)cc2OC)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 120 °C
Yield: 86 %

Procedure:
To a N2 degassed solution of methyl 2-bromo-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoate (500 mg, 0.668 mmol) in N,N-Dimethylformamide (DMF) (10 ml) was added tetrakis(triphenylphosphine)palladium(0) (154 mg, 0.134 mmol) and zinc cyanide (94 mg, 0.801 mmol). The reaction was heated in the microwave at 120° C. for 10 min. The solvent was then removed, the residue redissolved in DCM (50 ml), washed with water (50 ml), adsorbed onto silica gel, and purified by silica gel chromatography (DCM to 5% MeOH/DCM) to afford methyl 2-cyano-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoate (0.4 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (d, J=6.62 Hz, 6 H) 2.33 (s, 3 H) 2.57-2.64 (m, 4 H) 2.65-2.72 (m, 1 H) 3.09-3.18 (m, 4 H) 3.63 (s, 3 H) 3.83 (s, 3 H) 6.53-55 (m, 1 H) 6.64-6.66 (m, 1 H) 6.81 (d, J=4.01 Hz, 1 H) 7.36 (d, J=8.03 Hz, 2 H) 7.38 (d, J=4.01 Hz, 1 H) 7.52-7.57 (m, 1 H) 7.58-7.65 (m, 1 H) 7.71-7.74 (m, 1 H) 7.91 (d, J=8.23 Hz, 2 H) 7.95 (s, 1 H) 7.99-8.04 (m, 1 H) 9.95 (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC2C(=CC=CC=2)[N:28]1C(OCC)=O)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([C:21]([NH2:28])=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: O=C(O)C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC(=O)C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Reaction time: 48 h

Procedure:
A mixture of 1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentanecarboxylic acid (300 mg, 0.948 mmol), NH4HCO3 and 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (469 mg, 3.49 mmol) in chloroform (5.0 ml) was stirred for 2 d. To the mixture was added sat NaHCO3 (3 ml) and the mixture was extracted with dichloromethane After the solvent was removed in vacuo, the residue was extracted with dichloromethane (30 ml). The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo . The residue was purified by column chromatography (SiO2, 200-350 mesh/21 g/dichloromethane:methanol=97:3) to provide a yellow oil (174 mg/58%).