Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:21]=2)[CH:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)=O.[C:40]([O-])(=[S:42])[CH3:41].[K+].O>CN(C=O)C>[C:40](=[S:42])([O:5][CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:31])=[O:32])[CH:21]=2)[CH:14]=1)[C:8]([CH3:10])([CH3:9])[CH3:11])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=S)OC[C@@H](Nc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutyl methanesulfonate, 55a, (10.5 g, 18.11 mmol) in dry DMF (200 mL) was added potassium thioacetate (3.1 g, 27.1 mmol). The brown solution was heated with stirring at 80° C. for 1 hour. The thick brown suspension was poured into water and extracted with EtOAc (3×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 6.8 g of the desired product, 56a, as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 8.41 (m, 2H), 8.23 (s, 1H), 8.01 (m, 3H), 7.23-7.16 (m, 2H), 4.99 (d, J=10.1 Hz, 1H), 4.37 (m, 1H), 3.21 (dd, J=13.8, 2.3 Hz, 1H), 3.09-2.95 (m, 1H), 2.31 (s, 3H), 2.16 (s, 3H), 1.02 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 560.99 (M+H) RT=4.14 minutes.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)=[CH:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)=[CH:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)cn2C1CCOCC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: N#CCc1ccc(-c2cn(C3CCOCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of (4-(4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)phenyl)acetonitrile (10.2 mg) in acetonitrile (1 mL) were added sodium iodide (10.8 mg) and chloro(trimethyl)silane (0.037 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (5.7 mg).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[Cl:33]>>[Cl:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Nc1ccncc1Cl
Product: CCc1cc2c(C(=O)Nc3ccncc3Cl)cnc(OC)c2o1
Yield: 72.2 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) and 4-amino-3-chloropyridine (0.15 g). Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (0.14 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1>>[OH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:11]1
Reactant: OCC1CNCCO1
Reactant: Clc1ccccn1
Product: OCC1CN(c2ccccn2)CCO1
Yield: 71.1 %

Procedure:
The title compound (33.0 g, 72%) was prepared as a thick liquid from 2-chloropyridine (54.32 g) and 2-hydroxymethyl morpholine (28.0 g) by a similar procedure to that described in preparation 1.
Reaction SMILES: C(=O)(O)[O-].[K+].C(OC(Cl)=O)C1C=CC=CC=1.[CH2:17]([O:24][C:25]([N:27]1[C@@H:35]2[C@@H:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][C@H:28]1[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(ON1[C@H]2[C@H](CCCC2)C(=C=O)[C@@H]1C(OCC)=O)C1C=CC=CC=1>C(OCC)(=O)C.O>[CH2:17]([O:24][C:25]([N:27]1[C@H:35]2[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][C@@H:28]1[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1C(=O)OCc1ccccc1
Agent: CCOC(=O)[C@H]1C(=C=O)[C@H]2CCCC[C@H]2N1OCc1ccccc1
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@H]2CCCC[C@H]2N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
In 38.8 g of ethyl acetate was dissolved 15.6 g (78.0 mmol) of the mixture of the enantiomers obtained in Reference Example 1. To the resulting solution were added 38.8 g of water and 15.5 g of potassium bicarbonate and mixed. To this solution cooled to 0° C. was dropped 15.0 g of benzyloxycarbonyl chloride over 1 hour. After the completion of dropping, the solution was raised to room temperature, and then agitated at room temperature for 4 hours to complete the reaction. After the completion of reaction, to the reaction mixture was added 40 g of ethyl acetate to separate the resultant solution. From the resulting organic phase the solvent was removed by distillation to obtain an oily mixture of ethyl (2S, 3aS, 7aS)-N-benzyloxycarbonyl-octahydro-1H-indole-2-carboxylate and ethyl (2R, 3aR, 7aR)-N-benzyloxy-carbonyl-octahydro-1H-indole-2-carboxylate. This oily mixture was purified using n-hexane/ethyl acetate (eluate of the volume ratio of 85:15) by silica gel column chromatography to yield 24.3 g of a mixture of ethyl (2S, 3aS, 7aS)-N-benzyloxycarbonyl-octahydro-1H-indole-2-carboxylate and ethyl (2R, 3aR, 7aR)-N-benzyloxycarbonyl-octahydro-1H-indole-2-carboxylate [contained pure compounds were 22.8 g, 68.8 mmol (yield 88.2%)].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)[NH:5][C:4](=[O:16])[CH:3]=1.N1C=CC=CC=1.[S-:23][C:24]#[N:25].[K+].BrBr>CN(C=O)C>[NH2:25][C:24]1[S:23][C:3]2[C:4](=[O:16])[NH:5][C:6]([S:8][CH2:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[N:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nc(CSc2nc3nc(N)sc3c(=O)[nH]2)cs1
Yield: 29.2 %

Procedure:
The product from step (a) (24.3 g) was stirred in dry DMF (400 ml) with pyridine (13.1 ml) and potassium thiocyanate (37.1 g) at 0C. Bromine (4.5 ml) was added over 1 hr and the mixture kept at 0C for a further 2 hrs. The mixture was poured onto water to give a solution which was then evaporated to low volume. Water was added to give a precipitate which was collected. The solid was dissolved in dilute hydrochloric acid and reprecipitated by the addition of sodium bicarbonate solution. The solid was collected, washed with water and dried to afford the sub-title compound (8.7 g)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl>CCO.[Fe]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[O:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)oc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(N)cc2)oc1C
Yield: 88.7 %

Procedure:
A mixture of ethyl 2-methyl-5-(4-nitrophenyl)-3-furanecarboxylate (500 mg, 1.82 mmol), iron powder (325 mesh, 811 mg, 14.5 mmol) and aqueous 1 N HCl solution (0.36 mL, 0.36 mmol) in EtOH (5 mL) was heated to reflux for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (396 mg, 89% yield) as a brown oil.
Reaction SMILES: [Cl-:1].[OH:2][C@H:3]([CH2:9]O)[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].S(Cl)([Cl:13])=O>CN(C)C=O>[Cl-:13].[Cl:1][CH2:9][C@@H:3]([OH:2])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: C[N+](C)(C)C[C@H](O)CO
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[N+](C)(C)C[C@H](O)CCl
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
There was suspended 10.73 g of the obtained (S)-2,3-dihydroxypropyltrimethylammonium chloride in 50 ml of dimethylformamide, and then 7.66 g of thionyl chloride was added thereto at a temperature from 5° to 10° C. After stirring for 20 minutes, it was heated for 5 hours at 100° C. After cooling the reaction mixture to room temperature, the reaction mixture was evaporated to dryness to give 10.56 g of (S)-3-chloro-2-hydroxypropyltrimethylammonium chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[N:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCNCC2)nc1)C1CC1
Yield: 50.2 %

Procedure:
Following general procedure F, tert-butyl 4-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperazine-1-carboxylate (8.4 g, 15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5.0 g, 18 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (3.9 g, 53% over 2 steps) as a yellow/orange solid: 1H NMR (300 MHz, MeOD) δ 9.26 (s, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.89 (s, 2H), 7.75 (s, 1H), 7.47 (dd, J=9.0, 2.8 Hz, 1H), 7.02 (s, 1H), 6.96 (d, J=9.0 Hz, 1H), 6.84 (dd, J=12.2, 2.4 Hz, 1H), 3.72 (t, J=5.2 Hz, 5H), 3.12 (t, J=5.2 Hz, 5H), 2.92 (m, 1H), 1.22 (m, 2H), 1.12 (m, 2H); ESI MS m/z 518 [C28H25ClFN5O2+H]+; HPLC 98.7% (AUC), tR=8.67 min.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH2:8])[CH2:2]1.[C:9]([O:13][C:14](ON1C(=O)CCC1=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(=O)NC(=O)CC1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.[NH4+].[OH-]>C(Cl)Cl.CO>[C:9]([O:13][C:14]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH2:8])[CH2:2]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: N[C@H]1CCCCNC1
Reactant: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: O=C1CCC(=O)N1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@H](N)C1
Temperature: -78 °C
Yield: 54.3 %

Procedure:
(S)-Azepan-3-ylamine (5 g; 43.8 mmol) was dissolved in 100 mL of anhydrous CH2Cl2 and cooled to −78° C. while stirring with a magnetic stirring bar. In another flask N-(tert-butoxycarbonyloxy)succinimide [Boc-OSu] (9.7 g; 45 mmol) was dissolved in 50 mL of anhydrous CH2Cl2. To the stirred solution of the amine was added the solution of the succinimide over a period of 10-15 minutes so as to keep the reaction mixture at −78° C. while stirring. After the addition was complete, the reaction was allowed to warm to room temperature and then stirred for an additional 4 h or until the reaction was complete by TLC (Ninhydrin; Rf 0.3; 0.1:1:10 NH4OH, MeOH; CH2Cl2). The reaction mixture was washed with 50 mL of H2O. The aqueous layer was brought to a pH >13 by the addition of 6N NaOH and extracted with CH2Cl2 (3×100 mL). The organic layer was dried over Na2CO3, filtered, and concentracted in a vacuum to yield pure (S)-3-amino-azepane-1-carboxylic acid tert-butyl ester as a viscous oil (5.1 g, 54%). 1H NMR (d6-DMSO, d 3.4, m, 2H; d 2.89, m, 1H; d 2.71, m, 1H; d 2.54, m, 1H; d 1.54, m, 3H; d 1.34, m, 3H; d 1.27, s, 9H; d 1.12, m, 2H), LC/MS (APCI, ES, M+H=215).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(c3cccnc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine, copper (II) acetate and pyridine in the same manner as in Example 32.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([O:27]CC4C=CC=CC=4)=[O:26])=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2)=[O:8])=[O:4]>O1CCOCC1.[Pd]>[CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:35]12[CH2:36][CH:37]3[CH2:43][CH:41]([CH2:40][CH:39]([CH2:38]3)[CH2:44]1)[CH2:42]2)=[O:8])=[O:4]
Reactant: COC(=O)CNC(=O)c1ccc(-c2cccc3cc(C(=O)OCc4ccccc4)ccc23)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)c1ccc(-c2cccc3cc(C(=O)O)ccc23)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 12 h

Procedure:
1.25 g (2.1mmol) of the benzyl ester obtained in Example 48, in 50 ml of dioxane, are hydrogenated at 70° C. in the presence of 190 mg of palladium on carbon (10%), under a hydrogen pressure of 7 bar, for 12 h. After the same treatment as in Example 5 followed by a recrystallization from the ethyl acetate/hexane mixture, 742 mg (71%) of the expected derivative are isolated, which derivative melts at 272° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][CH2:14][CH2:15]Br>>[Br:13][CH2:14][CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: Cc1ccc2c(O)cccc2n1
Reactant: BrCCBr
Product: Cc1ccc2c(OCCBr)cccc2n1
Yield: 91 %

Procedure:
The title compound was prepared from 5-hydroxy-2-methylquinoline and 1,2-dibromoethane using a similar procedure to Description 16, in 91% yield.
Reaction SMILES: Cl.[N+:2]([CH:5]=[C:6]([S:16][CH3:17])[NH:7][CH2:8][CH:9](OCC)OCC)([O-:4])=[O:3].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH3:17][S:16][C:6]1[NH:7][CH:8]=[CH:9][C:5]=1[N+:2]([O-:4])=[O:3]
Reactant: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CSc1[nH]ccc1[N+](=O)[O-]
Yield: 53.7 %

Procedure:
Dry hydrogen chloride was passed through a stirred solution of 1-nitro-2-methylthio-2-(2,2-diethoxyethylamino)-ethylene (9.7 g, 0.04 mol) in dry ether (250 ml) at 5°-10° for 3 hours. The resulting mixture was basified by pouring it into potassium carbonate solution (300 ml). The mixture was filtered to give a yellow solid, and the aqueous phase of the filtrate was separated and extracted with ether (2×150 ml). The combined ether solutions were evaporated to a residue. This residue and the solid filtered off earlier were recystallised from acetone-chloroform to give 2-methylthio-3-nitropyrrole (3.4 g, 54%) m.p. 212°-213°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([SiH2:27][O:28][C:29]([CH3:40])([CH3:39])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:33][NH2:34])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.[F:50][C:51]([F:57])([F:56])[CH2:52][C:53](O)=[O:54]>C(Cl)Cl>[C:23]([SiH2:27][O:28][C:29]([CH3:40])([CH3:39])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:33][NH:34][C:53](=[O:54])[CH2:52][C:51]([F:57])([F:56])[F:50])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
TBTU (3.37 g, 10.5 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (2.00 g, 7.00 mmol), DIPEA (4.80 mL, 28.0 mmol) and 3,3,3-trifluoropropionic acid (0.927 mL, 10.5 mmol) in CH2Cl2 (70 mL). The mixture was stirred at rt for 1 h. CH2Cl2 (30 mL) was added, and the mixture was washed with aq. sat. NH4Cl (2×), aq. 1M NaOH (1×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 40:60) yielded the title compound (1.80 g, 65%). LC-MS: tR=1.10 min; ES+: 396.15.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>C(O)(=O)C>[O:2]=[CH:3][CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15]
Reactant: COC(C[C@H]1NC(=O)[C@@H]1N1C(=O)c2ccccc2C1=O)OC
Solvent: CC(=O)O
Product: O=CC[C@H]1NC(=O)[C@@H]1N1C(=O)c2ccccc2C1=O
Yield: 76.1 %

Procedure:
A solution of (3R,4R)-4-(2,2-dimethoxyethyl)-3-phthalimido-2-oxoazetidine (65 mg) in 80% aqueous acetic acid (1.5 ml) was heated at 64° for two hours. After evaporation of the solvent in vacuo, the residue was crystallized from a mixture of diethyl ether and ethyl acetate to afford (3R,4R)-4-(2-oxoethyl)-3-phthalimido-2-oxoazetidine (42 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([C:36]([O:38]CC)=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:24]([O:41][CH3:42])[CH:23]=2)[C:8]2=[N:9][C:10]([CH3:19])=[C:11]([NH:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([C:36]([OH:38])=[O:37])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:24]([O:41][CH3:42])[CH:23]=2)[C:8]2=[N:9][C:10]([CH3:19])=[C:11]([NH:13][C:14]([N:16]([CH3:17])[CH3:18])=[O:15])[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(NC(=O)N(C)C)c(C)nc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cc(NC(=O)N(C)C)c(C)nc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(OC)c1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-3-[4-[(α-ethoxycarbonyl)benzyloxy]-3-methoxybenzyl]-5-methyl-6-dimethylaminocarbonylamino-imidazo[4,5-b]pyridine and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CCOC(C)=O>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1COc2ccc(CCCl)cc2N1
Temperature: 45 °C
Reaction time: 40 h
Yield: 95.8 %

Procedure:
To a dried flask under N2 atmosphere equipped with addition funnel was added 6-(2-chloroethanoyl)-4H-benzo[1,4]oxazin-3-one (10.0 g, 44.4 mmol) in trifluoroacetic acid (34 mL, 0.44 mol). To the resulting mixture at 0° C. was added triethylsilane (15.3 mL, 0.1 mole) dropwise over 5 min. The resulting mixture was warmed to 45° C. for 30 min and stirred at room temperature for 40 h. Reaction was poured onto ice water and layered with EtOAc. The organic layer was washed with water, brine, and dried over MgSO4. Solvent was removed on vacuum to give the desired compound as white solid (9.0 g, 93%). LC-MS (ES): m/e 212 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.Cl.[N:13]1([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C1COCC1>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([C:27]2[CH:26]=[N:25][N:24]([CH:20]([CH2:21][C:22]#[N:23])[CH2:19][N:13]3[CH2:18][CH2:17][N:16]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[CH3:11])=[O:10])[CH2:15][CH2:14]3)[CH:28]=2)=[N:34][CH:33]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: Cc1cc(F)ccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1NC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reaction time: 1 h

Procedure:
4-Fluoro-1-isocyanato-2-methylbenzene (10 mg, 0.068 mmol) was added to a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (20 mg, 0.034 mmol; from Example 12, Step 2) and triethylamine (28 uL, 0.20 mmol) in THF (0.39 mL). The reaction was stirred for one hour, then solvent was removed in vacuo. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product as the free base (11 mg, 67%). 1H NMR (400 MHz, d6-dmso): δ 12.12 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.61 (d, 1H), 7.11 (dd, 1H), 7.02 (dd, 1H), 6.98 (d, 1H), 6.92 (dt, 1H), 5.01 (tt, 1H), 3.42-3.29 (m, 4H), 3.26-3.19 (m, 2H), 2.86 (dd, 1H), 2.81 (dd, 1H), 2.54-2.46 (m, 2H), 2.43-2.34 (m, 2H), 2.11 (s, 3H); LCMS (M+H)+: 488.3.