Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:27][CH2:26][CH2:25][CH2:24][C:19]54OCC[O:20]5)[NH:13][C:12]4=[N:28][NH:29][CH:30]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.O1CCOCC1.Cl>CO>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:27][CH2:26][CH2:25][CH2:24][C:19]4=[O:20])[NH:13][C:12]4=[N:28][NH:29][CH:30]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CC1=C(C2CCCCC23OCCO3)Nc2n[nH]cc2C1c1cccc2nonc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#CC1=C(C2CCCCC2=O)Nc2n[nH]cc2C1c1cccc2nonc12
Temperature: 60 °C
Yield: 2.2 %

Procedure:
To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in methanol (30 mL) was added 4N HCl dioxane solution (6.0 mL) at room temperature and the mixture was heated at 60° C. for two hours. After alkalification with sodium bicarbonate, the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (20 mg) as colorless crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCCCCC.O1CCCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:7]2[C:16]3[O:15][CH2:14][CH2:13][O:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccc2c1OCCO2
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OC1(c2cccc3c2OCCO3)CCN(Cc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
23.3 ml of a 1.6 M solution of butyllithium in hexane are added dropwise to a solution, previously cooled to -60° C., of 8 g of 5-bromo-1,4-benzodioxane in 400 ml of tetrahydrofuran. When the addition is complete, the mixture is stirred at -60° C. for 5 minutes and a solution of 8 g of 1-benzylpiperid-4-one in 100 ml of tetrahydrofuran is then added dropwise. The mixture is stirred for 2 hours at -40° C. and then for 2 hours at ambient temperature before hydrolyzing using 80 ml of water.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[C:14]([N:11]1[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][OH:4])[CH2:13][CH2:12]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OCCCC1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N1CCC(CCCO)CC1

Procedure:
1-Acetoxy-3-(N-acetyl-4-piperidinyl)propane was saponificated by potassium carbonate.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10](C(OCC3C=CC=CC=3)=O)[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[NH:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])[C:7]=2[CH:8]=[CH:9]1
Reactant: CCC(=O)Cl
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Product: CCC(=O)Nc1nccc2[nH]ccc12

Procedure:
N-(1H-pyrrolo[3,2-c]pyridin-4-yl)propanamide (Intermediate 26) was prepared from benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate in an analogous manner using propanoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CN=C1>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 5.7 mg (0.03 mmol) of p-toluenesulfonic acid.1H2O and 10.2 mg (0.15 mmol) of imidazole, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][O:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][C:21]([NH:23][CH3:24])=O)[NH:12][N:11]=1.FC(F)(F)C(O)=O.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:8][O:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:21][NH:23][CH3:24])[NH:12][N:11]=1
Reactant: CNC(=O)CC(c1ccccc1)c1cccc2[nH]nc(OC)c12
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(c1ccccc1)c1cccc2[nH]nc(OC)c12

Procedure:
[3-(3-Methoxy-1H-indazol-4-yl)-3-phenyl-propyl]-methyl-amine CXC was prepared as a trifluoroacetate from 3-(3-methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide and trifluoroacetic acid, using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=297.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]=O)[CH:9]=O)=[CH:4][CH:3]=1.[CH3:13][NH:14][NH2:15]>C(O)C>[CH3:13][N:14]1[CH:11]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:9]=[N:15]1
Reactant: Cc1ccc(C(C=O)C=O)cc1
Reactant: CNN
Solvent: CCO
Product: Cc1ccc(-c2cnn(C)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 2-(4-methylphenyl)-malondialdehyde (3.05 g), absolute ethanol (40 ml), and methylhydrazine (1.09 g) was stirred at room temperature for 18 hours and the volatiles removed at room temperature. Water was added and the mixture was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solution was filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (2.91 g), m.p. 107-108° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:11]([C:8]1([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH2:10][CH2:9]1)=[O:13]
Reactant: O=C(O)C1(c2cccc(Br)n2)CC1
Reactant: CNC
Product: CN(C)C(=O)C1(c2cccc(Br)n2)CC1
Yield: 70 %

Procedure:
The title compound was prepared from 1-(6-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 70% of theory; LC (method 3): tR=2.97 min; Mass spectrum (ESI+): m/z=255/257 (Br) [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11](B2OC(C)(C)C(C)(C)O2)=[C:10]([NH2:24])[CH:9]=1.[C:28]([O:32][C:33](=[O:54])[NH:34][C:35]([C:37]1[S:38][C:39]([S:52][CH3:53])=[C:40]([S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47](Br)[CH:46]=2)(=[O:44])=[O:43])[CH:41]=1)=[NH:36])([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.O.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:27][Si:2]([CH3:1])([CH3:26])[CH2:3][CH2:4][O:5][C:6](=[O:25])[NH:7][C:8]1[CH:9]=[C:10]([NH2:24])[C:11]([C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([S:42]([C:40]3[CH:41]=[C:37]([C:35]([NH:34][C:33]([O:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:54])=[NH:36])[S:38][C:39]=3[S:52][CH3:53])(=[O:43])=[O:44])[CH:50]=2)=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OCC[Si](C)(C)C)cc(N)c1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2N)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
A flask with a stirbar was charged with [3-amino-5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester ((Example 294: step e) 2.34 g, 5.96 mmol), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) 2.93 g, 5.96 mmol), aqueous Na2CO3 (2M, 11.9 mL, 23.8 mmol), ethanol (12 mL) and toluene (24 mL). The solution was sparged with argon for 10 min and Pd(PPh3)4 (689 mg, 0.6 mmol) was added. The biphasic solution was vigorously stirred under inert atmosphere at 80° C. for 16 h, then was cooled to rt. EtOAc (80 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with saturated NaHCO3 (2×20 mL), brine (20 mL) and was dried over sodium sulfate. Removal of the solvents in vacuo followed by column chromatography (85:15 DCM/EtOAc) of the residue yielded the title compound (2.24 g, 55%) as a light brown solid. 1H-NMR (CDCl3): δ 7.98 (ddd, 1H, J=1.3, 1.9, 7.8 Hz), 7.89 (m, 2H), 7.61 (t, 1H, J=7.7 Hz), 7.5 (dt, 1H, J=1.3, 7.7 Hz), 6.88 (s, 1H), 6.55 (d, 1H, J=1.7 Hz), 6.47 (s, 1H), 4.26 (m, 2H), 3.42 (s, 2H), 2.56 (s, 3H), 1.9 (s, 3H), 1.52 (s, 9H), 1.06 (m, 2H), 0.08 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH2:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:29]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]5[C:16]([CH:17]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:18][CH2:19][O:20]5)=[CH:15][C:14]=4[Cl:13])=[CH:33][CH:32]=3)=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc5c(c4)OCO5)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 93.2 %

Procedure:
2-(Benzo[d][1,3]dioxol-5-yl)ethanamine (32.9 mg, 0.199 mmol) in DMF (0.1 M) was treated sequentially with 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (1327 μL, 0.133 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) at ambient temperature. After 16 hours, the reaction was applied directly to a silica gel column and eluted with a gradient (20% to 80%) of ethyl acetate-hexanes to provide the title compound (65 mg, 0.124 mmol, 93.5% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][C:6]#[N:7].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl>C(Cl)Cl>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][C:6]1[NH:26][CH2:25][CH2:24][N:7]=1
Reactant: NCCN
Reactant: N#CCNc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: Clc1ccc(NCC2=NCCN2)c(Cl)c1
Reaction time: 1.17 h
Yield: 84.1 %

Procedure:
A mixture of 21.5 grams (g) of 2,4-dichloroanilinoacetonitrile, 23.3 g of ethylenediamine p-toluenesulfonate and 75 milliliters (ml) of 1,2-dichlorobenzene was heated with stirring in a round-bottomed three-necked flask at from about 140°-170° C. for about 70 minutes under a small flow of nitrogen. The reaction mixture was cooled and then diluted with methylene chloride. The mixture was cooled and then filtered, which gave 35.1 g of 2-((2,4-dichloroanilino)methyl)-2-imidazoline p-toluenesulfonate as white crystals. The p-toluenesulfonate salt was slurried in water and CH2Cl2 and then basified. The CH2Cl2 layer was separated and the remaining aqueous portion extracted with CH2Cl2 and then CHCl3. The extracts were combined, treated with diatomaceous earth and activated charcoal, and then filtered. Concentrating the filtrate to dryness, left 17.0 g of crystals. Recrystallization from ethylene dichloride gave 14.0 g of purified 2-((2,4-dichloroanilino)methyl)-2-imidazoline as white crystals, having a melting point (m.p.) of 154°-156° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:40][CH2:39][CH2:38][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: CN1CCN(CCCO)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Di-tert-butyl azodicarboxylate (0.478 g, 2.08 mmol) was added portionwise to a mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.350 g, 1.66 mmol), 3-(4-methyl-piperazin-1-yl)-propan-1-ol (Intermediate 9, 0.276 g, 1.74 mmol), and triphenylphosphine (0.544 g, 2.08 mmol) in dichloromethane (20 mL) at r.t. If necessary, further alcohol was added. After stirring for 2 h, the solution was concentrated to 10 mL, mounted on silica and chromatographed (gradient, dichloromethane to dichloromethane:methol=3.2 within 1 h) to obtain 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (brownish solid, 0.431 g, 1.23 mmol, 74%). LC/ESI-MS: m/z=351 [M(35Cl)+H]+; Rt=1.88 min Cf. also WO 04/143472, page 32,
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
2-Acetylthiomethyl-3-phenylpropionic acid (11.9 g) and ethyl 3-aminobenzoate (8.26 g) are dissolved in dichloromethane (150 ml), and thereto are added 4-dimethylaminopyridine (0.61 g) and EDC·HCl (10.54 g), and the mixture is stirred at room temperature overnight. The reaction mixture is washed with saturated aqueous citric acid solution, saturated aqueous sodium chloride solution and saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is washed with diethyl ether to give the title compound (13 g).
Reaction SMILES: CC1(C)COB([C:8]2[C:9]([C:15]#[N:16])=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)OC1.Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.[F-].[Cs+]>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.[Cu]I.O1CCOCC1>[CH3:14][C:11]1[N:10]=[C:9]([C:15]#[N:16])[C:8]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: Brc1ncccn1
Reactant: Cc1ccc(B2OCC(C)(C)CO2)c(C#N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ncccn2)c(C#N)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
An alternative route to make D18 is: 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methyl-2-pyridinecarbonitrile D17 (50.6 mg) was dissolved 1,4-Dioxane (1 ml) under nitrogen in a vial, then 2-bromopyrimidine (42.0 mg, 0.264 mmol), CsF (67 mg, 0.441 mmol), Pd(Ph3P)4 (12 mg, 10.38 μmol) and CuI (7 mg, 0.037 mmol) were added in sequence. The vial was then capped and stirred at 65° C., after 1 hour the solvent was removed at reduced pressure and the residue partitioned between AcOEt (10 mls) and NaHCO3 (saturated solution, 10 ml). The phases were separated and the water was extracted with AcOEt (2×10 mls). The organic fraction were joined together, dried over Na2SO4 and evaporated at reduced pressure, obtaining an orange oily residue which was purified (Biotage, Snap 25 g silica gel column, AcOEt/Cy from pure Cy to 50:50 in 10 column volumes) to obtain the title compound D18 as pale yellow solid (27.6 mg).
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3[CH2:27][CH2:26]N[C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42](O)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36].N1CCOCC1>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([N:22]3[CH2:23][CH2:24][O:28][CH2:26][CH2:27]3)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Solvent: C1COCCN1
Product: O=C(c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1)N1CCOCC1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 21A. 1.5 equivalents of morpholine are used. 205 mg (59% of theory) of the title compound are obtained.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][CH2:20][NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=1)=[O:8]>CC(C)=O.O.CC(C)=O>[C:24]1([CH2:23][C:22]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH:18]=[C:9]([C:7]([OH:2])=[O:8])[CH:10]=[CH:11]3)=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)NCCc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added, at ambient temperature, to a solution of 6.88 mmol of the product obtained in Step B in 30 ml of acetone. The solution is stirred for 2 hours at ambient temperature and is then filtered. The filtrate is concentrated under reduced pressure and chromatographed on silica gel to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([C:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C.CO>[C:12]1([C:18]2[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Reaction time: 2 h

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 2.00 g (9.6 mmol) of benzil were placed in a four-necked flask, and were dissolved by adding a 1:1 mixed solvent of acetic acid/methanol thereto. Thereafter, reaction was allowed at 70° C. for 2 hr. After the reaction, the solvent was removed, and the reaction product was extracted on a silica gel column (ethyl acetate:hexane=1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([NH:12][C:20](=[O:21])[CH2:19][Br:18])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(Br)CBr
Reactant: COc1cccc(C(=O)O)c1N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cccc(C(=O)O)c1NC(=O)CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 3-methoxy-2-aminobenzoic acid (5.0 g, 30 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL-3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled with an ice-bath to -5° C. Bromoacetyl bromide (6.66 g, 2.90 mL, 30 mmol) was added dropwise, keeping the internal temperature between -5° to 0° C. over a 1/2 h period. After the addition of bromoacetyl bromide was completed, the solution was warmed to room temperature and then stirred overnight. To the solution was slowly added 150 mL of ice-water, causing a pale white solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum oven overnight to afford 6.26 g (72%) of the title compound as a pale-white solid, mp 178°--180° C. (decomp): 1H NMR (DMSO-d6) δ12.80 (bs, 1H), 9.80 (s, 1H), 7.30-7.25 (m, 3H), 4.05 (s, 2H), 3.81 (s, 3H); 13C NMR (DMSO-d6) δ167.37, 164.54, 153.67, 129.76, 126.56, 124.39, 121.18, 114.66, 56.03, 29.63; MS (EI, m/z) 287 (M+).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1.[NH3:20].C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:20][CH2:2][C@@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1
Reactant: N
Reactant: O=C1COCCN1c1ccc(NC[C@@H](O)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC[C@@H](O)CNc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
30.00 g of 4-[4-((R)-3-chloro-2-hydroxy-propylamino)-phenyl]-morpholin-3-one (MW=284.75; 1 eq.) were added to 1298 g of conc. aqueous ammonia (MW=17.03; 88 eq.). The reaction mixture was stirred for 2.5 h at room temperature. Then 3.0 g of charcoal were added and after 10 min of stirring, the suspension was filtered and the cake was washed with 90 mL of water. Filtrate and wash water were combined and concentrated in vacuo to a mass of 100 g. The concentrate was alkalized by addition of 21.84 g of potassium carbonate (MW=138.21; 1.5 eq.) and to the alkaline solution were added 200 mL of methylenechloride. After 10 min of stirring, the layers were separated and the aqueous layer was extracted once more with 100 mL of methylenechloride. The organic layers were combined and concentrated in vacuo. To the residue were added 150 mL of methyl tert-butyl ether and the resulting suspension was stirred for at least one hour at ambient temperature. Then the crystalline product was isolated by filtration and the filter cake was washed with 75 mL of methyl tert-butyl ether. After drying in vacuo at 30° C., 21.08 g of the crystalline title compound (MW 265.31) were isolated. Yield=75.4%.