Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1)([C:19](=[O:25])NC(C)(C)C)[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:14]C(C)(C)C(C)(C)[O:11]1)(=O)C.[ClH:38].[OH2:39]>O1CCOCC1>[ClH:38].[ClH:38].[NH2:4][C@@:5]([C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)([CH2:6][CH2:7][CH2:8][CH2:9][B:10]([OH:11])[OH:14])[C:19]([OH:25])=[O:39]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@](CCCCB(O)O)(C(=O)O)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
In a 50 ML round bottom flask, tert-butyl (3R)-3-[1-acetamido-1-(tert-butylcarbamoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl]pyrrolidine-1-carboxylate (1.41 g, 2.69 mmol) was dissolved in 1,4-dioxane (10 mL). To this solution was added a 6M aqueous solution of hydrogen chloride (10 mL) in a single portion and the reaction was heated under refluxing conditions for 18 h. At the end of 18 hours the reaction mixture was cooled to room temperature prior to dilution with water (10 mL). The aqueous layer was washed with ethyl acetate (20 mL) and concentrated in vacuo prior to lyophilization to afford (R)-2-amino-6-borono-2-((R)-pyrrolidin-3-yl)hexanoic acid dihydrochloride (0.657 g) as a mixture of diastereomers. The crude foam was used without purification in the next step. ESI MS found for C10H21BN2O4 m/z 227.2 (M+H-water)+.
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]#[C:28][CH2:29][N:30]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:22][CH2:21]2)=[CH:15][CH:14]=1.NN.O>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[N:20]2[CH2:21][CH2:22][N:23]([CH2:26][C:27]#[C:28][CH2:29][NH2:30])[CH2:24][CH2:25]2)=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: O
Product: NCC#CCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The reaction of the phthalimide to the amine occurs analogously to Example 21)d): 23.3 g (48 mmol) 2-(4-{4-[bis-(4-fluorophenyl)-methyl]-piperazin-1-yl}-but-2-inyl)-isoindolin-1,3-dione and 4.7 ml (96 mmol) hydrazine.hydrate. The purification occurs by chromatography on silica gel with CHCl3/CH3OH (90/10 to 85/15): Yield 9.8 g (58%).
Reaction SMILES: [CH3:1][NH2:2].CO[C:5](=[O:44])[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][N:18]=[C:19]([CH3:43])[C:20](=[N:39][O:40][CH2:41][CH3:42])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][Si:29]([CH3:38])([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[N:7][O:8][CH3:9]>C(O)C.CO>[CH3:1][NH:2][C:5](=[O:44])[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][N:18]=[C:19]([CH3:43])[C:20](=[N:39][O:40][CH2:41][CH3:42])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][Si:29]([CH3:38])([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[N:7][O:8][CH3:9]
Reactant: CCON=C(C(C)=NOCc1ccccc1C(=NOC)C(=O)OC)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CCON=C(C(C)=NOCc1ccccc1C(=NOC)C(=O)NC)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reaction time: 48 h

Procedure:
3 ml of a 8M solution of methylamine in ethanol are added to 2.9 g of 2-[[[(1-methyl-2-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-[ethoxyimino]ethylidene) amino]oxy]-methyl]-α-(methoxyimino)-phenylacetic acid methyl ester in 30 ml of methanol and stirring is carried out for 2 days at room temperature. The reaction mixture is concentrated to dryness by evaporation. Recrystallisation of the residue from hexane yields the title compound having a melting point of 88-90° C. (compound 5.23).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22][OH:23])=[C:16]([CH:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=1>C(Cl)Cl.CCOCC>[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH:22]=[O:23])=[C:16]([CH:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=1
Reactant: COc1cc(CO)c(C(C)Cc2ccccc2)cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C=O)c(C(C)Cc2ccccc2)cc1OC
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
A solution of pyridinium chlorochromate (1.253 g, 5.8 mmol) in 40 mL CH2Cl2 was cooled to 0° C. [4,5-Dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-methanol (1.110 g, 3.88 mmol) in 5.0 mL CH2Cl2 was added drop-wise and allowed to stir for 45 minutes. The mixture was diluted in 200 mL Et2O, filtered through celite and concentrated in vacuo to afford a dark brown oil. Purification via flash chromatography (9:1 hexane/ethyl acetate) gave 4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-benzaldehyde (0.840 g, 76%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1>CN(C=O)C.CO.CCOC(C)=O.[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1
Reactant: NC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1Cl
Agent: O=[Pt]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)Cc1ccccc1CCc1nc(Cl)ncc1Cl

Procedure:
A solution of 2-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)acetamide (A138) (1.2 g, 4.0 mmol) in DMF (40 mL) and MeOH (8 mL) was stirred with platinum(II)oxide (0.27 g, 1.2 mmol) under an atmosphere of hydrogen for 144 hours at ambient temperature. The reaction mixture was diluted with EtOAc and filtered through a plug of Celite. The solvents were removed in vacuo and the crude residue was purified by silica gel column chromatography (Combiflash Rf, 0-10% MeOH in DCM) to give the title compound (A139) as a light yellow solid (0.63 g, 51%). LCMS-C: rt 4.82 min; m/z 310 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]/[C:7](O)=[O:8])[CH3:2].[C:11]([OH:15])([CH3:14])([CH3:13])[CH3:12].C1CCC(N=C=NC2CCCCC2)CC1.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:7](=[O:8])/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of fumaric acid mono-ethyl ester (721 mg, 5 mmol) and tert-butanol (0.938 mL, 10 mmol) in 10 mL of DCM was added DMAP (122 mg, 1 mmol) followed by DCC (2.06 g, 10 mmol). The resulting mixture was stirred at rt for 16 h, taken to dryness under reduced pressure, stirred overnight with 50 mL acetone and filtered to remove DCU. The resulting filtrate was concentrated under reduced pressure, and the residue taken up in EtOAc. The EtOAc was washed twice with 30 mL 0.1 M KHSO4, and once with 30 mL saturated NaHCO3 and once with 30 mL of brine. The resulting EtOAc solution was treated with charcoal and dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel flash chromatography using a gradient of 0–15% EtOAc in hexanes as eluent to give essentially pure (one peak on HPLC) 4-1 (350 mg, 35% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16]C)=[C:11]([O:14]C)[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl.CO>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:14])[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2cc(O)c(O)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10 g, 34.6 mmol) in Dichloromethane (DCM) (150 mL) was added BBr3 (16.34 mL, 173 mmol) at −78° C. The mixture was allowed to warm up to rt, and stirred at rt overnight. LCMS indicated completion of the reaction. The mixture was diluted with MeOH and concentrated. This procedure was repeated several times to afford 1-cyclopropyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8.2 g, 31.4 mmol, 91% yield) as yellow solid. The crude product was used in next step reaction without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:33])=[CH:39][CH:38]=[CH:37][C:36]=3[F:40])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1c(F)cccc1F
Reactant: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 102), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluorophenyl)boronic acid gave 347. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.94 (s, 1H), 7.69-7.65 (m, 1H), 7.40-7.36 (m, 2H), 5.11-5.09 (m, 1H), 3.85-3.79 (m, 2H), 3.72 (s, 3H), 3.57 (s, 2H), 3.46-3.43 (m, 1H), 3.30 (s, 1H), 3.01 (s, 3H), 2.43-2.37 (m, 1H), 1.74-1.58 (m, 3H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][C:24](=[O:29])[N:25]2[CH3:28])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][C:24](=[O:29])[N:25]2[CH3:28])=[CH:20][C:19]=1[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Product: CCS(=O)(=O)NC1CCc2c(-c3cc4c(cc3F)N(C)C(=O)CC4)cncc21
Yield: 70 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)ethanesulfonamide (intermediate A-6) was reacted with 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-9). The Suzuki coupling had to be repeated three times to give the to give the title compound as off-white solid in 70% yield. MS: 404.1 (M+H+).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])([OH:3])=[O:2].[CH3:30]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:30][O:2][C:1](=[O:3])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1C
Reaction time: 2 h

Procedure:
To a solution of the carboxylic acid from Example 6 (0.080 g, 0.20 mmol) under a nitrogen atmosphere in dichloromethane (25 ml) at 0° C. were added DMF (20 μl) and oxalyl chloride (31 mg, 0.24 mmol). The mixture was stirred at 0° C. to room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in methanol (4 ml) and dichloromethane (16 ml) and the mixture stirred at room temperature for 16 h. The mixture was then washed with 1M KHSO4 (3 times), saturated sodium bicarbonate solution (3 times) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane:methanol 96:4) to give a white solid; yield 0.049 g (60%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=2)[CH:13]=[CH:12][C:11]=1[OH:25].C(Cl)Cl.[O:29]1C[CH2:32][CH2:31][CH2:30]1.C(Cl)(=O)C=C>O.C(N(CC)CC)C>[C:30]([O:25][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)(=[O:29])[CH:31]=[CH2:32]
Reactant: C1CCOC1
Reactant: Oc1ccc(-c2cc3ccccc3s2)cc1-c1cc2ccccc2s1
Agent: C=CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(-c2cc3ccccc3s2)cc1-c1cc2ccccc2s1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
1.31 g of the thus obtained 2,4-bis(2-benzothiophenyl)phenol is placed in a round bottom flask; 20 mL of methylene chloride and 2 mL of tetrahydrofuran are added to form a transparent solution; after ice cooling the flask, 0.44 g of triethylamine is added; 0.39 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=90/10 (volume ratio)) to concentrate a component having an Rf of 0.20, thereby obtaining 1.0 g (yield: 66%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 6.06 (dd=1.2 & 10.8 Hz, 1H), 6.38 (dd=10.8 & 17.2 Hz, 1H), 6.64 (dd=1.2 & 17.2 Hz, 1H), 7.31 to 7.40 (m, 5H), 7.59 (s, 2H), 7.70 to 7.85 (m, 5H), 8.05 (d=2.4 Hz, 1H)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.NC1C=CC(O)=CC=1F>>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([OH:12])=[CH:4][C:3]=1[S:2][CH3:1]
Reactant: CSc1cc(O)ccc1[N+](=O)[O-]
Agent: Nc1ccc(O)cc1F
Product: CSc1cc(O)ccc1N
Yield: 81.2 %

Procedure:
This compound was prepared from 3-(Methylsulfanyl)4-nitrophenol (3.2 g, 17.3 mmol) in the manner described for 4-amino-3-fluorophenol, affording 2.18 g (81.3%) of the title compound. 1H-NMR (DMSO-d6) δ 8.56 (s, 1H), 6.60 (d, J=2.7 Hz, 1H), 6.53 (d, J=8.7 Hz, 1H), 6.43 (dd, J=8.7, 2.4 Hz, 1H), 2.28 (s, 3H).
Reaction SMILES: CC(S([NH:7][C:8]([CH3:20])([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)[CH2:9][CH:10]1[CH2:13][O:12][CH2:11]1)=O)(C)C.Cl.O1CCOCC1>CO.C(OCC)(=O)C>[CH3:19][C:16]1[O:15][C:14]([C:8]([NH2:7])([CH3:20])[CH2:9][CH:10]2[CH2:11][O:12][CH2:13]2)=[N:18][N:17]=1
Reactant: Cc1nnc(C(C)(CC2COC2)NS(=O)C(C)(C)C)o1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nnc(C(C)(N)CC2COC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
To a solution of 2-methyl-N-[1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(oxetan-3-yl)ethyl]propane-2-sulfinamide (example 190c, 250 mg, 829 μmol) in methanol (8 ml) was added a 4M solution of hydrochloric acid in dioxane (415 μl, 1.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted twice with ethylacetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield the title compound (168 mg) as a crude oil which was used without any purification. MS (ESI, m/z): 198.3 (M+H+).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][C:20](Cl)=[O:21].O>CC(C)=O.O>[Cl:18][CH2:19][C:20]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)CCl
Reaction time: 2 h

Procedure:
38 Grams of methyl anthranilate and 35 g of potassium carbonate were dissolved in 300 ml of a mixture of acetone-water (2:1), then to this solution was added dropwise 30 g of chloroacetyl chloride under an ice-cooled condition with stirring. After completion of the addition, the reaction was carried out at a room temperature for 2 hours, then 200 ml of water was added to the reaction mixture, and the mixture obtained was ice-cooled, and the crystals precipitated were collected by filtration. The crystals collected were washed with water and ethanol, and recrystallized from methanol to obtain 48.6 g of methyl o-(α-chloroacetylamino)benzoate in the form of colorless needle-like crystals. Melting point: 97°-99° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[Cl:20][C:21]1[CH:22]=[N+:23]([O-:41])[CH:24]=[C:25]([Cl:40])[C:26]=1[CH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:40][C:25]1[CH:24]=[N+:23]([O-:41])[CH:22]=[C:21]([Cl:20])[C:26]=1[CH2:27][C@H:28]([O:18][C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=1)(=[O:10])=[O:11])=[O:19])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C=O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
To a stirred solution of (2S)-1-(4-formylphenyl)sulfonylpyrrolidine-2-carboxylic acid (283 mg, 1 mmol) in DMF (15 mL) was added (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (344 mg, 1 mmol), followed by DMAP (60 mg, 0.5 mmol) and EDC (385 mg, 2 mmol). The mixture was allowed to stir at room temperature for 18 hours and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate solution (15 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in isohexane followed by 10% methanol in DCM, to afford the title compound as an off-white solid (333 mg, 55%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC(C)C>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Clc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4,5]decane (51.2 ml), 4-chloropyridine hydrochloride (20 g) and potassium carbonate (18.4 g) in isoamyl alcohol (400 ml) was gently refluxed for 18 hr. The reaction mixture was cooled and filtered. The filtrate was evaporated to give a waxy solid which was triturated with hexane to give 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4,5]decane (24.16 g) as a colourless solid; NMR (d6 -DMSO) δ1.65-1.70 (4H, m), 3.45-3.55 (4H, m), 3.9 (4H, s), 6.90 (2H, m), 8.15 (2H, m); m/Z 221 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[NH:9]2)=[N:6][CH:7]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:10]1([CH3:15])[NH:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:23]#[C:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][N:6]=2)[C:12](=[O:13])[CH2:11]1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)CC(=O)N(c2ccc(Br)cn2)N1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)cn2)N1
Temperature: 65 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (27 mg, 39 μmol, 0.05 equiv.) was dissolved in 2 ml THF. (210 mg, 770 μmol) 2-(5-Bromo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (Example 1, step 2) and phenylacetylene (130 mg, 1.24 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (325 μl, 2.33 mmol, 3 equiv.), triphenylphosphine (6 mg, 23.3 μmol, 0.03 equiv.) and copper(I)iodide (4 mg, 23.3 μmol, 0.03 equiv.) were added and the mixture was stirred for 16 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 5,5-dimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (102 mg, 45% yield) was obtained as a white solid, MS: m/e=292.1 (M+H+).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8](N(CCCl)C)[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]([O-])([O-])=O.[K+].[K+].[CH3:27][N:28]([CH:30]=O)[CH3:29]>>[CH3:29][N:28]1[CH2:27][CH:8]2[N:7]([C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=32)[CH2:21][CH2:30]1
Reactant: CN(CCCl)C1Nc2ncccc2Cc2ccccc21
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN2c3ncccc3Cc3ccccc3C2C1

Procedure:
The crude 10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-yl-(2-chloroethyl)-methylamine obtained (some starting material present) was dissolved in DMF (10 ml). K2CO3 (800 mg) and Kl (500 mg) were added. The mixture was refluxed for 4 hours. Dilution with water (100 ml) and extraction with dichloromethane (2×100 ml) gave after drying with Na2SO4 and evaporation crude racemic mirtazapine as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)Nc1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
The 3-tert-butoxycarbonylaminopyridine (2.0035 g, 10.32 mmol) was dissolved in THF (100 mL). The solution was cooled to −30° C. in a dry ice/acetonitrile bath, then t-BuLi (13 mL, 22.1 mmol) was added dropwise. After 1 h, 4-chlorophenyl isocyanate (1.911 g, 12.44 mmol) was added. The reaction mixture was warmed to 0° C. After 1.5 h, the reaction was warmed to room temperature. After 3 h at room temperature, the reaction was quenched with water (100 mL) and extracted with EtOAc (800 mL). The organic layer was washed with water (2×50 mL), dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography (350 g silica, 30% EtOAc/-CH2Cl2) to give the amide (1.284 g, 3.69 mmol, 36%) as a pale yellow solid.