Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)[CH:18]=[C:17]([Cl:31])[N:16]=1.C(NC(C)C)(C)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([N:21]3[CH2:30][CH2:29][C:24]4([O:25][CH2:26][CH2:27][O:28]4)[CH2:23][CH2:22]3)[CH:18]=[C:17]([Cl:31])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(Cl)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCN(Cc3ccccc3)CC2)n1
Yield: 83.6 %

Procedure:
1-Benzylpiperazine (7.59 g, 43.1 mmol) was added to a solution of 8-(2,6-dichloro-4-pyrimidinyl)-1,4-dioxa-8-azaspiro[4.5]decane (10.0 g, 34.5 mmol) in tetrahydrofuran (100 mL), followed by diisopropylamine (9.26 g, 71.7 mmol). The reaction mixture was then heated at reflux overnight. The crude product was concentrated under reduced pressure and the residue was re-dissolved in CH2C12 and then washed with aqueous citric acid (2×100 mL) and brine (2×200 mL). The organic layer was dried over -anhydrous Na2SO4 and filtered. Upon standing, crystallization occurred, giving the desired product (12.4 g, 84%).
Reaction SMILES: C(NC(=O)[C@H](C)NC(OCC1C=CC=CC=1)=O)C.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:32]([OH:34])=O)[CH3:31])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:35]([NH:38][C:39](=[O:50])[C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:45](=[O:49])[C@H:46]([CH3:48])[NH2:47])[CH2:36][CH3:37]>CN(C)C=O>[CH2:35]([NH:38][C:39](=[O:50])[C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:45](=[O:49])[C@H:46]([CH3:48])[NH:47][C:32](=[O:34])[C@H:30]([CH3:31])[NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28])[CH2:36][CH3:37]
Reactant: CCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 71 %

Procedure:
This compound was prepared by a process analogous to that employed in preparing benzyloxycarbonyl alanine ethylamide from benzyloxycarbonyl alanine and alanyl proline propylamide in a 71% yield with a melting point of 101 to 103 degrees C. [α]D20 -47.7 degrees (c 0.3; dimethylformamide).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+].O>O1CCCC1>[CH:1]1([CH2:7][C:8]([CH3:19])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(CC1CCCCC1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CC1CCCCC1)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of Example 41A (4.02 g, 15.4 mmol) and potassium trimethyl silanolate (11.0 g, 77.2 mmol) in tetrahydrofuran (80 mL) was heated to reflux for 18 hours. The mixture was cooled to 25° C., treated with water (10 mL), and concentrated in vacuo to remove the tetrahydrofuran. The residue was dissolved in water and washed with hexane. The aqueous layer was acidified to pH 1 with 1N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound (3.80 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 1.10 (m, 6H) 1.57 (m, 8H) 1.82 (m, 1H) 2.04 (m, 1H) 7.32 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>ClCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Br:43]
Reactant: Cc1ccc(-c2nc(Cc3cccc(CO)c3)c(C)o2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(Cc3cccc(CBr)c3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}-benzyl alcohol (3.52 g) was dissolved in 60 ml of dichloromethane. After addition of 3.77 g of triphenylphosphine and 5.17 g of carbon tetrabromide, the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=4:1) to provide 3.96 g of the objective compound as colorless crystals. M.p. 101-102° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([O:32][CH3:33])[C:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[C:25]3[Cl:45])([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[OH:13])[CH2:9]1)=O)(C)(C)C.C(O)=O.Cl>CO>[NH:8]1[CH2:11][CH:10]([C:12]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([O:32][CH3:33])[C:26]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=2)=[C:25]3[Cl:45])([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[OH:13])[CH2:9]1
Reactant: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.75 h

Procedure:
To a flask containing tert-butyl 3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidine-1-carboxylate (700 mg, 1.09 mmol, Example 125) was added formic acid (10 mL, 265 mmol) at room temperature followed by 6 N aqueous HCl (500 μL). After 45 minutes, MeOH was added (10 mL) and the mixture was stirred for 15 minutes and then concentrated to provide the title compound as a crude product. MS (ESI): mass calcd. Chemical Formula: C29H27ClF3N3O2; Exact Mass: 541.2. m/z found 541.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1.[N:28]1([OH:37])C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.NO.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:28][OH:37])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1
Reactant: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)O)cc2)nc(N)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)NO)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a stirred solution of 4-[2-amino-6-(5-bromo-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzoic acid (0.086 g, 0.20 mmol) in dimethylformamide (3.0 ml) was added benzotriazol-1-ol (0.054 g, 0.40 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.086 g, 0.44 mmol). After stirring at room temperature for 1 hour, hydroxylamine hydrochloride (0.070 g, 1.0 mmol) was added followed by triethylamine (0.1 g, 1.0 mmol). After stirring for 16 hours, the solvent was evaporated under reduced pressure and the residue was treated with 1 M aqueous sodium carbonate solution (10 ml). Filtration provided the title compound (0.065 g, 73% yield) as a light brown solid. 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=6.9 Hz, CH3), 4.12 (q, 2H, J=6.9 Hz, CH2), 6.32 (s, 2H, NH2), 6.79 (s, 1H, Ar), 7.08 (d, 1H, J=8.9 Hz, Ar), 7.52 (dd, 1H, J=8.9 Hz, J=2.6 Hz, Ar), 7.66 (b, 4H, Ar), 8.04 (d, 1H, J=2.6 Hz, Ar), 9.24 (s, 1H, NH).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:28]\O)/[C:24]([O:26][CH3:27])=[O:25])[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:28]\[O:6][CH3:7])/[C:24]([O:26][CH3:27])=[O:25])[CH:12]=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
Dimethyl sulphate (0.4 ml, 4.2 mmol) was added dropwise to a mixture of (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (1.04 g, 2.9 mmol) and anhydrous potassium carbonate (0.78 g, 5.6 mmol) in dry DMF (10 ml). After stirring at room temperature for 3 hours, the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and concentrated to give an oil which was purified by column chromatography (silica eluted with 20% ethyl acetate in hexane) to give (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-methoxyacrylate (Compound No.244 in Table I of EP-A-0278595) (0.72 g, 74%) as a cream solid; mp 91-92° C.; 1H NMR (270 MHz)δ: 3.69(3H,s), 3.83(3H,s), 5.26(2H,s), 6.63(1H,d), 6.90(1H,s), 7.15-7.55(5H,m), 7.56(1H,s) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][C@H:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:31][C@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (19.4 g, 78.5 mmol) in DMF (100 mL) with triethylamine (32 mL, 0.235 mol) and (S)-(−)-α-methylbenzylamine (11.5 g, 94.2 mmol) with the modification that the reaction was allowed to warm to room temperature and stirred for two hours. After the isolated precipitate was washed with water, it was dried under high vacuum overnight to provide 25.1 g of 2-chloro-3-nitro-N-[(1S)-1-phenylethyl]quinolin-4-amine as an orange solid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[N:29]=[C:28]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Cl:23][C:24]1[N:29]=[C:28]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(Cl)n2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (6-chloro-2-pyridinyl)acetic acid (76 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. The resulting suspension was poured into water (10 mL) and stirred for 30 min. The resulting precipitate was collected by filtration, and the residue was washed with water (10 mL), dried at the pump for ca. 1 hour. The solid residue was dissolved in acetone and adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-{1-[(6-chloro-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (99.8 mg, 53.7% yield) as a beige solid. LC-MS (ES) m/z=419 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (t, J=8.34 Hz, 2H), 3.74 (s, 3H), 4.08 (s, 2H), 4.27 (t, J=8.46 Hz, 2H), 5.92-6.22 (m, 2H), 7.20-7.28 (m, 2H), 7.33 (s, 1H), 7.38-7.46 (m, 2H), 7.87 (t, J=7.83 Hz, 1H), 8.10 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][N:6]=1)=[O:4].[CH:11]1([C:14]([CH3:16])=[O:15])[CH2:13][CH2:12]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:11]1([C:14](=[O:15])[CH2:16][C:3]([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][N:6]=2)=[O:4])[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccncn1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1ccncn1

Procedure:
A stirred mixture of 1.4 g. of methyl-4-pyrimidinecarboxylate, 1.7 g. of cyclopropylmethyl ketone, 1.2 g. of sodium methoxide and 40 ml. of benzene is heated under reflux for 4 hours. The mixture is diluted with 40 ml. of water and the benzene phase is removed. The aqueous mixture is made weakly acidic with dilute hydrochloric acid and extracted with chloroform. The cloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give light brown crystals, which are recrystallized from hexane to provide straw-colored crystals, melting point 81°-84°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1200 mg) in N,N-dimethylformamide (20 ml) were added potassium carbonate (1710 mg) and ethyl 2-bromopropionate (1.5 ml). The mixture was stirred at 100° C. for 12 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (882 mg, yield 60%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CN(C)C=O.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23])[CH3:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Diethylamine (230 μl, 2.22 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (211 mg, 1.01 mmol, commercially available product). The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=8/1). Thus, 1-diethylamino-2-nitro-4-(trifluoromethyl)benzene (258 mg, 98.3%) was yielded as an orange-colored oily material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH2:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].[N:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[C:15]=[O:16]>>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:14][C:15]([NH:12][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:11][N:10]=1)=[O:16]
Reactant: Nc1nsc2ccc([N+](=O)[O-])cc12
Reactant: Cc1ccccc1CN=C=O
Product: Cc1ccccc1CNC(=O)Nc1nsc2ccc([N+](=O)[O-])cc12

Procedure:
In analogy to example 6, 100 mg (0.51 mmol) of 5-nitrobenzo[d]isothiazol-3-ylamine were reacted with 90.4 mg (0.61 mmol) of 1-isocyanatomethyl-2-methylbenzene. Yield: 11 mg (6%), M+H+: 343.16.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]=12>>[Cl:18][C:16]1[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]2=[C:12]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:17]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: NCCOc1ccccc1
Product: Cn1ncc2c(NCCOc3ccccc3)nc(Cl)nc21

Procedure:
Reaction of 2-phenoxyethylamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-phenoxy-ethyl)-amine.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH2:6]([SH:10])[CH2:7][CH2:8][SH:9].B(F)(F)F.CCOCC>ClCCl>[CH:2]([CH:1]1[S:10][CH2:6][CH2:7][CH2:8][S:9]1)([CH3:4])[CH3:3]
Reactant: SCCCS
Reactant: CC(C)C=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a mixture of isobutyraldehyde (9.1 mL, 100 mmol) and 1,3-propanedithiol (10 mL, 100 mmol) in dichloromethane at 0° C. was added boron trifluoride diethyl etherate (6.4 mL, 50 mmol). The resulting mixture was stirred at 0° C. for 30 min and at room temperature for 30 min. The reaction mixture was washed with brine, 5% NaHCO3, and brine again. The organic phase was separated and dried over Na2SO4, then concentrated to give 16 g (100%) of the title compound as a yellow liquid. This was carried to the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.057 (d, J=7.2 Hz, 3H), 1.059 (d, J=7.2 Hz, 3H), 1.80 (m, 1H), 1.97–2.08 (m, 2H), 2.82 (m, 4H), 4.00 (d, J=5.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1>C1COCC1.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:9]([C:17]([NH2:19])=[O:18])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:5]=[CH:6][CH:7]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: NC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)Nc2cccc(-c3cc4ccccc4n3C(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(3-aminophenyl)-1H-indole-1-carboxamide (50.2 mg, 0.2 mmol, 1 eq) in anhydrous THF (2 mL) was added m-tolyl isocyanate (25 μL, 1 eq) and the reaction solution was stirred at room temperature for one hour. It was then diluted with ethyl acetate, washed with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated and the oily residue was treated with small amount of dichloromethane. The white solid appeared during this process was filtered to yield 2-[3-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-1-carboxamide in amount of 36 mg.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:22]I>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:22])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1ccc2[nH]c(C(=O)OCC)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)cc(C(=O)OCC)n2C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Sodium hydride (60%-suspension, 144 mg, 3.6 mmole) was added to a stirred solution of 1H-indole-2,5-dicarboxylic acid diethyl ester 16 (784 mg, 3.0 mmole) in dry DMF (15.0 ml) and kept at ambient temperature for 30 min. To a resulted reaction mixture MeI (280 μl, 4.5 mmol) was added and kept at ambient temperature for 16 hours and evaporated. The residue was suspended in AcOEt (100 ml) and washed with water (2×20 ml), 0.01 M HCl (3×20 ml) and brine (2×100 ml). The organic layer was dried over sodium sulfate and evaporated to give 800 mg (97%) of 1-methyl-indole-2,5-dicarboxylic acid diethyl ester 17 as a yellow oil. 1-NMR (DMSO-d6): 8.45 (m, 1H, H-4, indole); 8.03 (m, 1H, H-6, indole); 7.40 (m, 1H, H-7, indole); 7.38 (s, 1H, H-3, indole); 4.40 (m, 4H, —OCH2CH3); 4.10 (s, 3H, NCH3, indole); 1.42 (m, 4H, —OCH2CH3).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]([C:12]1[S:16][C:15]([C:17]([O:19]C)=O)=[CH:14][CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[C:1]([O:5][C:6](=[O:7])[CH2:8][NH:9][C:10]([C:12]1[S:16][C:15]([C:17]([NH:22][NH2:23])=[O:19])=[CH:14][CH:13]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCC(=O)OC(C)(C)C)s1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(C(=O)NN)s1
Temperature: 25 °C
Yield: 71 %

Procedure:
Methyl 5-(tert-butoxycarbonylmethylcarbamoyl)thiophene-2-carboxylate (63 mg, 0.21 mmol) in ethanol (3.0 mL) was refluexed with heating with hydrazine monohydrate (0.13 mL) for 8 hours and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and water was added. The precipitated solid was collected by filtration, washed with water and dried to give 44 mg of the desired product (yield 71%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([CH:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].[CH2:38](I)[CH3:39]>>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH2:38][CH3:39])[S:27]([CH:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CCC2)C1=O
Reactant: CCI
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(CC)S(=O)(=O)C2CCC2)C1=O

Procedure:
By the method of Example 290, Step A, N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide (Example 298, Step A) was treated with ethyl iodide to afford the title compound as a white foam. LCMS (ESI) m/z=591.2 (M+H).