Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:50]1[CH2:53][CH:52]([O:54][C:55]2[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=2[CH3:63])[C:58]#[N:59])[CH2:51]1>CN(C=O)C>[C:58]([C:57]1[CH:60]=[CH:61][C:62]([CH3:63])=[C:55]([CH:56]=1)[O:54][CH:52]1[CH2:51][N:50]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:53]1)#[N:59]
Reactant: Cc1ccc(C#N)cc1OC1CNC1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C#N)cc1OC1CN(C(=O)CNC(=O)c2cn(-c3ccccc3)cn2)C1
Reaction time: 0.03 h
Yield: 18.7 %

Procedure:
DIPEA (193.9 mg, 1.5 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (92 mg, 0.37 mmol) in DMF (3 mL) followed by HOBt (53.2 mg, 0.39 mmol) and EDCI (75.5 mg, 0.39 mmol). After 2 minutes of stirring, 3-(azetidin-3-yloxy)-4-methyl-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (84 mg, 0.37 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Partitioning with cold water and ethyl acetate and concentration of the organic layer after drying over sodium sulfate afforded a residue which was purified by preparative HPLC to afford 29 mg (18.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(5-cyano-2-methyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 416, 98.6%. 1H NMR (300 MHz, DMSO-d6): δ 8.38 (d, 1H), 8.28 (d, 1H), 8.12 (t, 1H), 7.7 (d, 2H), 7.5 (t, 2H), 7.38 (m, 3H), 7.16 (s, 1H), 5.2 (m, 1H), 4.7 (t, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: [CH3:1]OC(C1CC2C(=CC=C(S)C=2)C1)=O.[CH3:15][O:16][C:17](=[O:48])[CH2:18][CH:19]1[C:27]2[C:22](=[CH:23][C:24]([S:30]CC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)=[C:25]([O:28][CH3:29])[CH:26]=2)[CH2:21][CH2:20]1>>[CH2:15]([O:16][C:17](=[O:48])[CH2:18][CH:19]1[C:27]2[C:22](=[CH:23][C:24]([SH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[CH2:21][CH2:20]1)[CH3:1]
Reactant: COC(=O)C1Cc2ccc(S)cc2C1
Reactant: COC(=O)CC1CCc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)c(OC)cc21
Product: CCOC(=O)CC1CCc2cc(S)c(OC)cc21

Procedure:
19C was prepared analogously to compound 1C. Used as unpurified oil. MS: 267 (M+1)+. Preparation of {6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-1-yl}-acetic acid methyl ester (Compound 19D)
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:28]=[CH:29][N:30]=[CH:31][C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:17][CH:18]=2)[CH2:23][CH2:24]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (174 uL, 1.0 mmol) and acetyl chloride (43 uL, 0.60 mmol) in DMF (2 mL) at 0° C. and the resulted mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated and the residue was washed with water (sonicated) and the solid was collected by filtration, dried under high vacuumn to give compound 186 (170 mg, 74% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.82 (1H, s), 9.27 (1H, s), 9.01 (1H, s), 8.44 (1 H, d, J=5 Hz), 8.21 (1H, d, J=10 Hz), 8.07 (1H, d, J=2 Hz), 8.04 (1H, d, J=5 Hz), 7.52 (1H, dd, J=10 Hz, J=2 Hz), 5.37 (1H, p, J=10 Hz), 3.61 (4H, q, J=5 Hz), 3.17 (2H, t, J=5 Hz), 3.10 (2H, t, J=5 Hz), (3H, s), 2.40 (2H, m), 2.08 (4H, m), 2.06 (3H, s), 1.78 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 456.1, Calculated 456.2.
Reaction SMILES: [I:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][NH:6][C:7]2=O.P(Cl)(Cl)([Cl:16])=O>CCOC(C)=O>[Cl:16][C:7]1[C:8]2[C:3](=[C:2]([I:1])[C:11]([CH3:12])=[CH:10][CH:9]=2)[CH:4]=[N:5][N:6]=1
Reactant: Cc1ccc2c(=O)[nH]ncc2c1I
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2c(Cl)nncc2c1I
Temperature: 108 °C
Yield: 62 %

Procedure:
A suspension of 5-iodo-6-methylphthalazin-1(2H)-one (8.51 g, 29.7 mmol) in phosphorous oxychloride (200 ml, 2146 mmol), charged to a 500 mL was stirred at 108° C. (reflux) for 90 min. The POCl3 was then removed under vacuum, and the resulting residue was azeotroped 2× with toluene. The resulting residue was dissolved in a mixture of DCM and MeOH and water. The layers were separated the aqueous layer was washed with DCM 3×. The combined organics were washed with saturated aqueous sodium carbonate and brine. The organic layer was then dried over magnesium sulfate, and loaded on to silica. 1-Chloro-5-iodo-6-methylphthalazine (5.604 g, 61.9% yield) was obtained by column chromatography (ISCO 330 g 15%-60% EtOAc in Hex 60 min) as a yellow solid. MS (M+H)+ 305.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: O=[N+]([O-])O
Reactant: COCc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: COCc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a cooled (0° C.) solution of 2-methoxymethyl-benzothiazole (2.4 g, 13.4 mmol) in concentrated sulfuric acid (8 mL) was added a mixture of 90% fuming nitric acid (2 mL) and concentrated sulfuric acid (1.3 mL) at a rate to keep the internal temperature below 5° C. After the addition was completed, the reaction mixture was stirred for 15 min at 0° C. and then at RT for 2 h. The mixture was poured into ice cold water. Collection of the precipitated solid by filtration, washing with cold water until the pH of the eluent was neutral, afforded 2.6 g (79%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.8 (d, J=2.1 Hz, 1H), 8.36 (dd, J=9, 2.1 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 4.90 (s, 2H), 3.59 (s, 3H).
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:14][CH2:15][CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCBr
Reactant: CCOC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCOc1ccccc1C(=O)O

Procedure:
The reaction of ethyl salicylate and 4-bromo-1-butene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-But-3-enyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.57 (s, —CO2H); 7.63 (m, 1 arom. H); 7.46 (m, 1 arom. H); 7.12 (m, 1 arom. H); 6.99 (m, 1 arom. H); 5.92 (m, —CH═CH2); 5.18, 5.08 (2 d-like, —CH═CH2); 4.07 (t, J=6.4, OCH2—CH2—CH═CH2); 2.49 (m, OCH2—CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 167.33 (—C═O); 157.18; 134.77; 132.85; 130.52; 121.75; 120.16; 117.01; 113.60; 67.70; 33.20.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH:13]1[CH:18]=[C:17]2[C:19]([C:21](O)([OH:24])[C:22](=[O:23])[C:16]2=[CH:15][CH:14]=1)=[O:20]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:21]2([OH:24])[C:19](=[O:20])[C:17]3[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=3)[C:22]2=[O:23])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(NC(C)=O)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=S(=O)(O)O
Product: CCc1ccc(C2(O)C(=O)c3ccccc3C2=O)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
N-(3-ethylphenyl)acetamide (500 mg, 3.06 mmol) and ninhydrin (546 mg, 3.06 mmol) were dissolved in conc. sulfuric acid (10 mL) and stirred at room temperature for 3 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (90 mg, 9%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
In a 60-mL vial, tert-butyl-4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0 g, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was filtered through a bed of celite and the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4×25 mL), dried over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]4[C:12]=3[CH2:13][N:14]([CH3:24])[C:15]4=[O:23])=[CH:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1.CCOC(C)=O>[CH3:24][N:14]1[CH2:13][C:12]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=2[C:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=2)[C:15]1=[O:23]
Reactant: CN1Cc2c(C3=CCC4(CC3)OCCO4)ccc([N+](=O)[O-])c2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1Cc2c(C3=CCC(=O)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 193E, 515 mg, 1.56 mmol) was dissolved in THF (10 mL) and aq. 3N HCl (3 mL). The resulting mixture was stirred at rt for 4 h. The mixture was diluted with EtOAc (40 mL), washed with brine (2×10 mL), and dried over anhydrous sodium sulfate. Evaporation afforded a yellow oil, which was used to next step without further purification. MS (ES+): m/z=287.10 [MH+]. HPLC: tR=3.13 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:15]#N)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2].C(O)(=[O:21])C.N1C=CC=CC=1>[Ni].O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH:15]=[O:21])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)oc2ccc(C#N)cc12
Reactant: CC(=O)O
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1c(C)oc2ccc(C=O)cc12
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of (5-cyano-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (4.31 g, 17.7 mmol), NaPH2O2.H2O (14.99 g, 141 mmol) and Raney nickel (3.06 g, 35.4 mmol) in a mixture of water (50 mL), acetic acid (50 mL) and pyridine (100 mL) is heated for 2 h at 100° C. under an argon atmosphere. After cooling to room temperature the reaction mixture is filtered over hyflo and the filtrate concentrated by rotary evaporation. The residue is partitioned between water and TBME, the layers are separated and the aqueous phase is extracted with TBME. The combined organic layers are washed with a 1 M aqueous HCl solution, a saturated aqueous NaHCO3 solution and brine. After drying over Na2SO4 and evaporation of the solvent in vacuo the crude product is obtained as a brown oil. Further purification by flash column chromatography (silica gel gradient of cyclohexane/EtOAc 100:0 to 6:1) affords the title compound as colorless crystals (2.59 g, 10.5 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=10.08 (s, 1H), 8.07 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.49 (s, 3H), 1.27 (t, J=7.1 Hz, 3H). MS (ES+): 247 (M(C14H14O4)+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][CH2:18][CH2:17]2)[CH:3]=1.[NH3:27]>O1CCCC1.CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:27])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: N
Reactant: COC(=O)c1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a mixture of methyl 4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (400 mg, 1.04 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) in tetrahydrofuran (5 mL) and a saturated solution of ammonia in methanol (30 mL) was heated with stirring for 16 hours at 120° C. in a sealed tube. The reaction mixture was concentrated in vacuo to afford 300 mg of the product (yield was 78%).
Reaction SMILES: Br[C:2]1[S:11][C:10]2[C:9]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](#[N:26])[CH3:25]>CCOC(C)=O.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>[CH3:25][C:24]1[CH:10]=[C:4]([C:2]2[S:11][C:10]3[C:9]4[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:8]=4[O:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)[CH:3]=[CH:2][N:26]=1
Reactant: CC#N
Reactant: N#Cc1ccc2c(c1)OCCc1cc(Br)sc1-2
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
Product: Cc1cc(-c2cc3c(s2)-c2ccc(C#N)cc2OCC3)ccn1
Yield: 17 %

Procedure:
A 2 ml microwave vial was loaded with a slurry of 2-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carbonitrile (170 mg, 0.55 mmol) and pyridine-2-amino boronic acid pinacolester (130 mg, 0.61 mmol) in 0.800 ml of aqueous 2M Sodium carbonate and 1.2 ml of ACN. The reaction mixture was degassed by bubbling nitrogen through the solution for several minutes. Next palladium tetrakis (51 mg, 2 mmol) was added to the reaction mixture and the vial was tightly capped and flash heated a Biotage microwave at 180 C for 10 minutes. The cooled reaction mixture was diluted with a large volume of EtOAc and the organic was washed with water and saline and concentrated in vacuo. The resulting residue was taken into DMF and purified by preparative RP-HPLC to give 32 mg (17%) of 2-(2-methylpyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[C:20](=[O:28])[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Fc1cc(F)cc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4ccccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 491.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:19])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitro-pyridine (2.4 g, 10.1 mmol), benzene-1,3-diamine (2.7 g, 25 mmol) and DIPEA (5.3 ml, 30 mmol) in dry NMP (20 ml) was stirred and heated at 120° C. under N2 for 2 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→50% EtOAc/petrol) to give the title compound (2.5 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.78 (1H, s), 8.66 (1H, d), 8.60 (1H, d), 7.00 (1H, t), 6.83-6.71 (2H, m), 6.39 (1H, d), 5.13 (2H, s).
Reaction SMILES: CO.[CH3:3][NH:4][CH3:5].[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19])(=[O:8])[CH3:7]>CO.O1CCCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([S:18](=[O:20])(=[O:19])[N:4]([CH3:5])[CH3:3])=[C:11]([CH:16]=1)[CH2:10][NH:9][C:6](=[O:8])[CH3:7]
Reactant: CNC
Reactant: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Step 1) To a solution of 2N dimethylamine methanol solution (7.51 ml) in methanol (15 ml) was added dropwise a suspension of 2-[(acetylamino)methyl]-4-chlorobenzenesulfonyl chloride (2.12 g) in tetrahydrofuran (5 ml) under ice-cooling. The mixture was allowed to warm to room temperature, and stirred for 3 hr. The reaction mixture was quenched with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-[5-chloro-2-(dimethylsulfamoyl)benzyl]acetamide (1.77 g) as a white solid.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4]([CH3:6])=[O:5].[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24](=O)[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17]>C(O)C>[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24]2[CH2:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:6][C:4](=[O:5])[CH:3]=2)[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(O)COc1ccc(C(=O)C=Cc2ccccc2)c(Cl)c1Cl
Agent: [Na]
Solvent: CCO
Product: O=C(O)COc1ccc(C2=CC(=O)CC(c3ccccc3)C2)c(Cl)c1Cl

Procedure:
To a stirred solution of sodium (1.21 g, 0.0526 mole) in ethanol (150 ml) and ethyl acetoacetate (6.85 g, 0.0526 moles) was added [2,3-dichloro-4-(1-oxo-3-phenyl-2-propenyl)phenoxy]acetic acid (8.7 g, 0.0248 mole)(Step A). The reaction mixture was heated at reflux for 3 hours, then the solvent was distilled at reduced pressure. The residue was dissolved in water, extracted with ether, acidified with hydrochloric acid, extracted with methylene chloride and ethyl acetate, dried over magnesium sulfate and evaporated at reduced pressure to give [2,3-dichloro-4-(5-phenyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 197°-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[CH2:15]([OH:17])[CH3:16]>>[ClH:1].[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:10])([CH3:11])[C:8](=[NH:9])[O:17][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)Oc1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
Commercially available 2-(4-chlorophenoxy)-2-methylpropanenitrile (Maybridge), HCl gas and ethanol were processed using the method described for Example 4A to obtain the titled compound. MS (ESI+) m/z 242 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[C:20]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Yield: 77.1 %

Procedure:
A mixture of 2-methoxy-4-nitroaniline (2.23 g, 13.3 mmol), triethylamine (2.00 ml, 14.6 mmol) and benzoyl chloride (1.70 ml, 14.6 mmol) were stirred in toluene (50 ml) for 24 hours under an inert atmosphere at ambient temperature. The solid was collected by suction filtration and washed with toluene (3×50 ml) and diethyl ether (50 ml). Purification of the crude product by flash chromatography on silica gel, eluting with dichloromethane, yielded N-benzoyl 2-methoxy-4-nitroaniline (2.79 g, 77% yield) as a white solid:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[NH:14])[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:16](=[CH:19]OC(C)C)[CH:17]=[O:18].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O>[CH:1]1([N:4]2[C:16]([CH:17]=[O:18])=[CH:19][N:14]=[C:5]2[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=N)NC2CC2)cc1
Reactant: CC(C)OC=C(Br)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ncc(C=O)n2C2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
N-cyclopropyl-4-methoxy-benzamidine (0.90 g, 4.75 mmol), 2-bromo-3-isopropoxy-propenal (1.37 g, 7.12 mmol) and K2CO3 (0.98 g, 7.12 mmol) were mixed with chloroform (10 ml) and water (1.2 ml), followed by stirring at r.t. for 24 h. After drying of the reaction mixture (Na2SO4), filtration and concentration of the filterate in-vacuo, the crude residue was purified via flash chromatography (40% EA in hex.) to isolate the title compound (973 mg, 85%). 1H-NMR: 9.83 (s, 1H), 7.82 (m, 3H), 7.02 (d, 2H), 3.89 (s, 3H), 3.58 (m, 1H), 1.13 (m, 2H), 0.64 (m, 2H).