Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:6]2[C:5]=1Cl)(=[O:3])[NH2:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]1([CH3:34])[CH3:33]>>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][C@@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[C:21]([CH3:34])([CH3:33])[CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Product: CCOC(=O)c1cc2c(N[C@@H]3CCN(C(=O)OC(C)(C)C)CC3(C)C)c(C(N)=O)cnn2c1
Yield: 98.6 %

Procedure:
Following the conditions described in Step 2 of Example 1, ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (Intermediate 1, 0.7 g, 2.62 mmol,) was reacted with (R)-tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (Intermediate 6, 0.657 g, 2.88 mmol) to give (R)-ethyl 4-((1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (1.187 g, 99% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.05 (d, J=1.8 Hz, 1H), 7.92 (s, 1H), 7.22 (d, J=1.5 Hz, 1H), 5.44 (br. s., 2H), 4.38 (q, J=7.1 Hz, 2H), 4.14-3.93 (m, J=9.6, 9.6, 3.7 Hz, 2H), 3.73 (br. s., 1H), 3.14 (br. s., 1H), 2.89 (br. s., 1H), 2.09-2.00 (m, 1H), 1.84-1.72 (m, 1H), 1.49 (s, 9H), 1.40 (t, J=7.2 Hz, 3H), 1.11 (s, 3H), 1.03 (s, 3H); MS (ES+) m/z: 460.3 (M+H); LC retention time: 4.250 min (analytical HPLC Method H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[OH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[O:29][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Oc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C
Temperature: 155 °C
Yield: 19.2 %

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmol) was dissolved in 2 mL DMF. 2,6-Dimethylphenol 8b (0.034 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate and solvent removed and purified to obtain 106 as a white solid (10 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.77 (s, 1H), 7.58 (t, J=7.2, 2H), 7.48 (dd, J=11.8, 19.0, 2H), 7.18 (s, 3H), 6.97 (d, J=23.8, 1H), 4.22 (s, 3H), 2.19 (s, 6H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([NH:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]3[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=3)[N:13]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1cccc(COCc2cccc(F)c2)n1
Product: O=S(=O)(Nc1cccc(COCc2cccc(F)c2)n1)c1cccc(Cl)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.06 g) and 3-chloro-benzenesulfonyl chloride (0.06 g) as a yellow gum (0.07 g). MS (ESI−): 405.1 ([M−H]−).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][CH3:27]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CCC(N)CO
Product: CCC(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 40 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-butan-1-ol according to the GPA affording 14.5 mg (40%) of a red powder. Rt=3.60 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:19]#[N:20])([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21].O1CCOCC1>>[ClH:21].[C:19]([C:11]1([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccs2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2cccs2)CCNCC1

Procedure:
Prepare by the method of example 30.3 using 1-tert-butoxycarbonyl-4-cyano-4-(thiophen-2-yl)-piperidine (3 mmol) and HCl in dioxane (4N, 40 mmol). Concentrate the solvent in vacuo and dry under high vacuum to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][NH:27][CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32]>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([C:31](=[O:33])[CH3:32])[CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)(C)C(=O)OCC)ccc1OC
Reactant: CC(=O)Cl
Product: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: 2-(2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid ethyl ester and acetyl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCc2ccc(OCCCCCBr)cc2N1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(OCCCCCN3CCC(Cc4ccccc4)CC3)cc2N1
Yield: 88 %

Procedure:
2.7 Grams of 7-(5-bromopentoxy)-3,4-dihydrocarbostyril, 2.0 g of 4-benzylpiperidine and 1.5 g of triethylamine were mixed with 30 ml of dimethylformamide and the mixture was heated at 60°-70° C. for 6 hours. The reaction mixture was then concentrated under a reduced pressure to dryness, and to the residue thus obtained was added a 5%-sodium hydrogencarbonate aqueous solution and stirred. The insoluble matters thus formed were collected by filtration, washed with water and dried. Recrystallization from ligroin to obtain 3.6 g (yield: 88%) of 7-[5-(4-benzyl-1-piperidyl)pentoxy]-3,4-dihydrocarbostyril as in the form of colorless plate-like crystals. Melting point: 100°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:10])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(N)nc(C)c1Br
Reaction time: 3 h

Procedure:
6.1 g (50 mmol) of 2-amino-4,6-dimethylpyridine are dissolved in 50 ml of acetic acid. A solution of 8 g (50 mmol) of bromine in 50 ml of acetic acid is added dropwise using a dropping funnel. The reaction medium is allowed to return to room temperature and the stirring is continued for 3 hours. The mixture is cooled in an ice bath and 40% sodium hydroxide is then added until the pH is basic. The mixture is filtered and dried. The residue is taken up in a little isopropyl ether and then chromatographed on silica gel, eluting with this same solvent. The expected product is collected in the form of white crystals. It is recrystallized from absolute ethanol.
Reaction SMILES: [CH:1]([C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[OH:27][N:26]=[CH:1][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(c1ccccc1)N1COC(C=O)=C(c2ccccc2)C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(c1ccccc1)N1COC(C=NO)=C(c2ccccc2)C1=O
Reaction time: 1 h
Yield: 86 %

Procedure:
6-Formyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 121, 2.87 g) was dissolved in ethanol (30 ml), and an aqueous solution (15 ml) of hydroxylamine hydrochloric acid (0.65 g) and sodium acetate (1.30 g) was added slowly thereto at room temperature. After stirring for one hour, ethanol was removed by evaporation, and filtered after adding water. The solid product obtained was rinsed with water and dried to afford the captioned compound (2.59 g, yield 86%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 39.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0306 g, 0.0663 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chlorobenzenesulfonyl chloride (0.0275 mL, 0.195 mmol) to obtain 4-(3-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0168 g, yield 40%).
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>N1C=CC=CC=1>[Br:15][C:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:2][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [Br-]
Reactant: COC(=O)c1cc2cccnc2[nH]1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1[nH]c2ncccc2c1Br
Temperature: 0 °C
Yield: 32.5 %

Procedure:
To a solution of 3.2 g of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride in 165 mL of pyridine is added dropwise, at 0° C. under an argon atmosphere, a solution of 5.04 g of pyridinium tribromide in 35 mL of pyridine. The reaction mixture is then stirred at 0° C., and then poured onto a mixture of 250 g of crushed ice and 750 ml of distilled water. The suspension is filtered and the solid is washed with twice 25 mL of distilled water and then dried in the open air. 0.87 g of methyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate is obtained in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([NH:27][CH3:28])=[O:26].FC(F)(F)C(O)=O>CC(O)C>[F:20][C:5]1[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=2)[C:25]([NH:27][CH3:28])=[O:26])=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1ccc(OC2CN(c3nc(Cl)ncc3F)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ncc(F)c(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To 2-chloro-5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (90.0 mg, 0.302 mmol) and 3-amino-N-methylbenzamide (49.9 mg, 0.333 mmol) in a disposable sealed tube in 2-propanol (2.50 mL) was added trifluoroacetic acid (0.070 mL, 0.907 mmol). The resulting reaction mixture was heated at 84° C. for 3 d, cooled to RT and concentrated. The residue was stirred in EtOAc and saturated aqueous NaHCO3 for 10 min and transferred to a reparatory funnel. The organic layer was washed with brine, dried and concentrated giving 3-(5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-2-ylamino)-N-methylbenzamide (124.8 mg).
Reaction SMILES: C(O[C:4](=[O:15])[CH2:5][N:6]1[C:10]([I:11])=[C:9]([I:12])[C:8]([I:13])=[C:7]1[I:14])C.[CH2:16]([NH2:38])[CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]>>[CH2:16]([NH:38][C:4](=[O:15])[CH2:5][N:6]1[C:7]([I:14])=[C:8]([I:13])[C:9]([I:12])=[C:10]1[I:11])[CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]
Reactant: CCOC(=O)Cn1c(I)c(I)c(I)c1I
Reactant: COCCOCCOCCOCCOCCOCCOCCN
Product: COCCOCCOCCOCCOCCOCCOCCNC(=O)Cn1c(I)c(I)c(I)c1I
Yield: 114.2 %

Procedure:
According to the procedure described in Ex. 2, 2.3 g of 2,3,4,5-tetraiodopyrrol-1-acetic acid ethyl ester (prepared according to the procedure described in Ex. 1) (0.00457 mol) and 23.27 g of compound B, 3,6,9,12,15,18,21-heptaoxadocosylamine, (0.0685 mol) are reacted. 3.82 g of N-[3,6,9,12,15,18,21-heptaoxadocos-1-y1]-2,3,4,5-tetraiodopyrrol-1-acetamide (0.0040 mol) are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:43][C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[O:35])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C=Nc1ccc(F)cc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccc(F)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-fluorophenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (44.5 mg, 0.15 mmol) and 1-fluoro-4-isocyanatobenzene (20.4 mg, 0.15 mmol) according to General Procedure G to give 46 mg (70.8%) of pale yellow solid. Anal. Calcd. for C25H30FN5O m/z 435.2, found: 436.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (s, 1H), 7.41 (m, 4H), 7.06 (t, J=8.9 Hz, 2H), 6.93 (d, J=9.1 Hz, 2H), 6.05 (d, J=7.8 Hz, 1H), 3.88 (d, J=11.6 Hz, 1H), 3.76 (d, J=12.7 Hz, 1H), 3.26 (m, 1H), 2.79 (m, 1H), 2.59 (m, 1H), 2.42 (m, 1H), 1.89 (m, 1H), 1.68 (m, 3H), 1.60 (m, 1H), 1.46 (m, 1H), 1.22 (m, 4H), 1.11 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=[O:33])=O)[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][N:39]([CH3:40])[S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:34])=[O:33]
Reactant: CNCCN(C)C
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)N(C)CCN(C)C)n2C)n(CCC)c1=O
Yield: 49.5 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 500 mg (0.98 mmol) of Compound 1 obtained in Example 1 and 0.62 mi (4.9 mmol) of N,N,N'-trimethyl-ethylenediamine. The resulting crude crystals were recrystallized from cyclohexane/toluene to give 280 mg (yield 48%) of Compound 6 as yellow needles.
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:16][CH2:15]1>C1COCC1>[C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:16][CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: C1CCOC1
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(=O)Nc2cccc3ccccc23)CC1
Temperature: 25 °C

Procedure:
2.6 g (17.7 mmol) 1-naphthyl isocyanate are dissolved in 15 ml abs. THF and cooled to 0° C. under moisture exclusion. 5.1 g (17.7 mmol) N-(4-piperidine-4-yl-butyl)-3-(pyridine-3-yl)-propionamide are dissolved in 35 ml abs. THF and added dropwise under ice cooling. The mixture is stirred without further cooling at RT overnight. Subsequently, the solution is drawn off under vacuum to a large extent and the residue is chromatographically purified over silica gel with CHCl3/CH3OH (90/10) and further purified by flash-chromatography with CHCl3/CH3OH (95/5 to 90/10). After drawing off the solvent, crystallization occurs from isopropanol/diisopropanol. Colorless crystals with a MP of 143-144° C. were recovered; yield 0.77 g (9%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]([CH2:41][Cl:42])[CH2:21][N:22]2[C:25](=[O:40])/[CH:26]=[CH:27]/[C:28]2[N:29]([CH3:39])[CH:30]=[C:31]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:32]=2)=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:34]([NH:33][C:31]1[CH:32]=[C:28](/[CH:27]=[CH:26]/[C:25]([N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16]([NH:15][C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=4)=[O:3])[CH:24]=3)[CH:20]([CH2:41][Cl:42])[CH2:21]2)=[O:40])[N:29]([CH3:39])[CH:30]=1)(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)Nc1cc(/C=C/C(=O)N2CC(CCl)c3ccc(N)cc32)n(C)c1
Solvent: O
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cc(/C=C/C(=O)N2CC(CCl)c3ccc(NC(=O)OCc4ccc([N+](=O)[O-])cc4)cc32)n(C)c1
Temperature: 20 °C
Yield: 70.4 %

Procedure:
4-Nitrobenzyl chloroformate (52 mg, 0.24 mmol) was added to a solution of 8 (48 mg, 0.12 mmol) in dry pyridine (6 mL) and the yellow solution was stirred at 20° C. More 4-nitrobenzyl chloroformate (52 mg, 0.24 mmol) was added after 30 min. After a further 1 h water was added and the mixture stirred for 30 min until the oil that separated had solidified. The solid was filtered off, washed with water, dried, and triturated with hot EtOAc to give 1-[(E)-4-butyramido-1-methyl-2-pyrroleacryloyl]-3-(chloromethyl)-6-[(4-nitrobenzyloxy)carbonyl]aminoindoline (8a) (49 mg, 71%) as a yellow solid, mp 207-209.5° C. 1H NMR [(CD3)2SO] δ6 9.91 (s, 1 H, NH), 9.76 (s, 1 H, NH), 8.40 (s, 1 H, H-7), 8.27 (d, J=8.7 Hz, 2 H, ArHo to NO2), 7.70 (d, J=8.7 Hz, 2 H, ArHm to NO2), 7.54 (d, J=15.0 Hz, 1 H. H-β) 7.28 (d, J=8.2 Hz, 1 H, H-4), 7.22 (d, J=1.5 Hz, 1 H, H-5′), 7.16 (d, J=8.2 Hz, 1 H, H-6), 6.71 (d, J=1.4 Hz, 1 H. H-3′), 6.64 (d, J=15.0 Hz, 1 H, H-α), 5.30 (s, 2 H, ArCH2O), 4.48-4.39 (m, 1 H, H-2), 4.12 (dd, J=10.5, 4.1 Hz, 1 H, ArCH2O), 4.48-4.39 (m, 1 H, H-2), 4.12 (dd, J=10.5, 4.1 Hz, 1 H, H-2), 3.98-3.92 (m, 1 H, CHCH2Cl), 3.85-3.76 (m, 2 H, CHCH2Cl), 3.68 (s, 3H, NCH3), 2.20 (t, J=7.3 Hz, 2 H, CH2CH2CH3), 1.58 (sx, J=7.4 Hz, 2 H, CH2CH2CH3), 0.89 (t, J=7.4 Hz, 3 H, CH2CH2CH3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:25])[CH3:24]>CO.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:1]([OH:5])([CH3:3])[CH3:2])[C:20]([NH:25][CH2:23][CH3:24])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Solvent: CCOCC
Solvent: CO
Product: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.08 mmoles) of (5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-one (prepared as described in Preparation 5) in 20 ml of methanol was saturated with ethylamine. After it had been allowed to stand at room temperature overnight, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue obtained, as an oily substance was dissolved in warm diethyl ether. The solution was then allowed to stand, and the needle-like crystals which deposited were collected by filtration, to give 317 mg of the title compound, melting at 155°-157° C.
Reaction SMILES: [BH4-].[Na+].[H][H].[Si:5]([O:12][CH:13]([C:27]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:28]=1[CH3:36])[CH:14]([CH2:23][N+:24]([O-])=O)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:24][CH2:23][CH:14]([CH:13]([C:27]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:28]=1[CH3:36])[O:12][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(O[Si](C)(C)C(C)(C)C)C(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(N)cc1C(O[Si](C)(C)C(C)(C)C)C(CN)CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Adapting literature known protocols (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2.6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of tert-butyl 4-(tert-butyl(dimethyl)silyl)oxy-4-(2-methyl-5-nitro-phenyl)-3-(nitromethyl)butanoate (17c) (4.69 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS till completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are evaporated to dryness under reduced pressure using a rotary evaporator. The crude tert-butyl 3-(aminomethyl)-4-(5-amino-2-methyl-phenyl)-4-(tert-butyl(dimethyl)silyl)oxy-butanoate (17d) is used directly in the next step without further isolation and purification procedures.