Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39]([C:41]1[C:50]2[CH2:49][CH2:48][CH2:47][C@@H:46]([OH:51])[C:45]=2[CH:44]=[CH:43][CH:42]=1)=[NH:40]>CN(C=O)C.CC(=O)OCC>[OH:51][C@@H:46]1[CH2:47][CH2:48][CH2:49][C:50]2[C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)=[CH:42][CH:43]=[CH:44][C:45]1=2
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1cccc2c1CCC[C@H]2O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4O)no2)cc1C#N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Prepared using General Procedure 2. To a stirring solution of 3-cyano-4-isopropoxybenzoic acid (16.7 mg, 0.08 mmol) in DMF (1 mL) were added HOBt (14.3 mg, 0.11 mmol) and EDCI (20.3 mg, 0.11 mmol). After stirring for 30 min, (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-4 (27.3 mg, 0.09 mmol) was added as a solution in DMF (1.5 mL). After stirring at room temperature for an additional 60 min, the mixture was heated to 90° C. for 15 h. The mixture was diluted with EA and washed with NaHCO3. The combined organic layers were dried, concentrated, chromatographed (EA/hexanes) to provide 12.72 mg (42.4%) (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m/z) calculated for C22H21N3O3: 375.4; found 376.1 [M+H]+, tR=3.73 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.97 (dd, J=7.7, 1.3 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.91-4.83 (m, 1H), 4.79 (dq, J=12.0, 6.0 Hz, 1H), 3.20 (dt, J=17.8, 5.4 Hz, 1H), 3.01 (dt, J=13.3, 6.4 Hz, 1H), 2.13-1.81 (m, 4H), 1.79 (d, J=7.2 Hz, 1H), 1.47 (d, J=5.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.70, 169.48, 162.75, 140.10, 137.4, 134.13, 133.88, 131.68, 129.96, 126.18, 125.97, 116.82, 115.26, 113.54, 103.95, 72.73, 68.47, 31.62, 28.50, 21.73, 18.57. Chiral HPLC: (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile was eluted with 10% IPA/hexane: 99.4% ee, tR=40.85 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].CN1CCOCC1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([C:34](=[O:37])[CH2:35][CH3:36])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]n2)cc1Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.4 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-pyrazol-3-yl)-propionamide (prepared in example 2, 100 mg, 0.25 mmol) was dissolved in methylene chloride (2 mL). N-Methyl-morpholine (31 μL, 0.28 mmol) was added followed by propionyl chloride (26 μL, 0.28 mmol). The reaction stirred at 25° C. for 2.5 h. The solution was diluted with ethyl acetate (25 mL), washed with water (2×15 mL), saturated aqueous saturated aqueous brine solution (2×15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-propionyl-1H-pyrazol-3-yl)-propionamide (49 mg, 43%) as a white powder: ESI-LRMS m/e calcd for C21H26ClN3O4S [M+] 451.1, found 452.2 [M+H+], 396.0 [M−COCH2CH3+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.24 (m, 2H, CH2), 1.27 (t, J=7.3 Hz, 1H, CH3), 1.44-1.97 (m, 8H, 4×CH2), 2.14-2.32 (m, 1H, CH), 2.99 (q, J=7.3 Hz, 2H, CH2), 3.27 (s, 3H, SO2CH3), 3.57 (t, J=7.5 Hz, 1H, CH), 6.98 (d, J=2.1, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.5 Hz. 1H, Ar), 7.59 (d, Jm=1.5 Hz, 1 H, Ar), 7.81 (s, 1H, NH), 8.10-8.15 (m, 2H, Ar).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])=[O:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])=[O:2]
Reactant: COc1c(C=O)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C=O)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 6.5 h

Procedure:
To 3-formyl-4-methoxy-5-trifluoromethylbenzoic acid (2.05 g), toluene (20 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.70 mL) were added, and then the mixture was stirred at 60° C. for 6.5 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (2.42 g) as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[Br:9][CH2:10][CH2:11][CH2:12][OH:13]>>[BrH:9].[NH:8]=[C:4]1[N:3]([CH2:10][CH2:11][CH2:12][OH:13])[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]1
Reactant: OCCCBr
Reactant: Cc1nc(N)sc1C
Product: Br
Product: Cc1sc(=N)n(CCCO)c1C

Procedure:
4,5-dimethyl-thiazol-2-ylamine (2.0 g, 16 mmol) and 3-bromo-propan-1-ol (1.6 mL, 19 mmol) were processed according to the method of Example 46A to afford the title compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[C:3]2([CH2:1][CH3:2])[CH2:13][CH3:14]
Reactant: CCC1(CC)C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(CC)C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, then brine, dried (MgSO4) and evaporated to afford the crude product (7.6 g, 75%). A sample was recrystallized from EtOAc/hexane to obtain the subtitled compound, m.p. 164-165° C.; 1H-NMR (DMSO-d6) δ 10.45 (s, 1H), 7.41-7.40(d, 1H, J=2.2 Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H J=8.2 Hz), 1.78-1.65 (m, 4H), 0.50-0.46 (m, 6H); MS (−ESI) m/z 266/268 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].N1C=CC=CC=1>CC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1F
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a stirred solution of methyl 4-amino-2-fluorobenzoate (800 mg, 4.6 mmol, 1.0 eq) in acetone (10 mL) was added phenyl chloroformate (0.6 mL, 4.6 mmol, 1.0 eq) and followed by pyridine (1.1 mL, 13.8 mmol, 3.0 eq) at 0° C. and stirred at RT for 1 h. The acetone in the RM was evaporated and diluted with water (50 mL) extracted with EtOAC (2×100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was washed with n-pentane to yield methyl 2-fluoro-4-(phenoxycarbonylamino)benzoate (1.2 g, 89.6%) as white solid (TLC: EtOAc/PE (2:3); Rf: 0.3).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Br-:6].[OH:7][C@@H:8]1[C@@H:25]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:24][C@@:23]2([CH3:32])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N+:38]3([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C@@H:17]2[O:33][C:34](=[O:37])[CH2:35][CH3:36])[CH2:9]1>ClCCl>[Br-:6].[N:26]1([C@H:25]2[CH2:24][C@@:23]3([CH3:32])[C@@H:10]([CH2:11][CH2:12][C@@H:13]4[C@@H:22]3[CH2:21][CH2:20][C@@:18]3([CH3:19])[C@H:14]4[CH2:15][C@H:16]([N+:38]4([CH3:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]4)[C@@H:17]3[O:33][C:34](=[O:37])[CH2:35][CH3:36])[CH2:9][C@@H:8]2[O:7][C:1](=[O:4])[CH2:2][CH3:3])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CCC(=O)O[C@H]1[C@@H]([N+]2(C)CCCCC2)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CCC(=O)Cl
Agent: [Br-]
Solvent: ClCCl
Product: CCC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3C[C@H]([N+]3(C)CCCCC3)[C@@H]4OC(=O)CC)[C@@]2(C)C[C@@H]1N1CCOCC1
Reaction time: 20 h

Procedure:
Propanoyl chloride (5.24 ml) was added to a solution of 1-[(2β,3α,5α,16β,17β)-3-hydroxy-2(4-morpholinyl)-17-(1-oxopropoxy)-androstan-16-yl]-1-methylpiperidinium bromide (2.62 g) in dichloro-methane (33 ml) and the solution was set aside at room temperature for 20 h. The solution was evaporated to dryness under reduced pressure to give a gum, which was taken up in dichloromethane (15 ml) and purified by chromatography on alumina (Fluka type 5016A) (62 g) to give 1-[(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-3,17-bis(1-oxopropoxy)-androstan-16-yl]-1-methylpiperidinium bromide as a non-crystalline solid (1.99 g), [α]D20 =-16.7° (c 1.09 in CHCl3).
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)C.[BrH:20].O>C(OCC)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][Br:20])=[CH:13][CH:14]=1
Reactant: Br
Reactant: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1
Solvent: CCOCC
Solvent: O
Product: BrCc1ccccc1Oc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 413.0 g of the 2-(4-bromophenoxy)benzyl alcohol and 1290 ml of 48% hydrobromic acid is boiled under reflux for 4 hours, then cooled and poured onto 2000 ml of ice and water. The greenish oil that separates out is dissolved in 2000 ml of diethyl ether. The organic phase is washed twice with 400 ml of water and with 400 ml of a 1N aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation at 40° under 11 mm Hg. The 2-(4-bromophenoxy)benzyl bromide, obtained in the form of an oily residue, is used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Br[CH2:18][C:19]([OH:21])=O.Cl.[C:23](=[S:25])=[S:24]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:19](=[O:21])[CH2:18][S:25][C:23]1=[S:24]
Reactant: S=C=S
Reactant: O=C(O)CBr
Reactant: Cc1ccc(N)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(N2C(=O)CSC2=S)c(C)c1
Reaction time: 12 h

Procedure:
At 0° C., 1 g of 2,4-dimethylaniline (8.04 mmol) was mixed with 54 mL of a 0.2 M solution of triethylamine in ethyl acetate, and 0.65 mL of a carbon disulfide (CS2) solution was dropwise added to the mixture with slowly stirring. After completion of the addition, stirring was continued for an additional 12 hrs. The reaction mixture was filtered, and the filtrate was dissolved in an aqueous sodium bicarbonate solution (NaHCO3) and mixed with 2.2. g of bromoacetic acid (15.83 mmol) for 2 hrs by stirring. The resulting reaction mixture was acidified (pH 2) with a 35% HCl solution and heated for 6 hrs. After extraction with methylene chloride (CH2Cl2), the organic layer was pooled, washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo. Purification of the concentrate by silica gel column chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][CH:33]=1.ClC1C=CC(C2N=C(C)N3C(=O)N(CC4C=CC(C(F)(F)F)=CC=4)N=C3C=2C2C=CC(Cl)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[N:16]([CH2:27][C:28]4[CH:33]=[N:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=4)[N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Agent: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12
Product: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12

Procedure:
The title compound was prepared by coupling 7,8-bis(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one with 5-(chloromethyl)-2-(trifluoromethyl)pyridine in a manner analogous to that in which 7,8-bis(4-chlorophenyl)-5-methyl-2-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one was prepared. HPLC/MS: retention time=4.188 min, [M+H]30 =530.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.C[O-].[Na+].[Cl-].[NH4+:24]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]([NH2:24])=[NH:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: [NH4+]
Reactant: N#Cc1cccc(-c2cnn(-c3cccnc3)c2)n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N=C(N)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
With heating, 0.7 g (2.8 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbonitrile was dissolved in 150 ml of abs. methanol, and 1 ml of a solution of sodium methoxide in methanol (30%, corresponds to 5.4 mmol) was added. The mixture was stirred at 65° C. until the thin-layer chromatogram (TLC) showed complete conversion, 1.5 g of ammonium chloride was added and the mixture was concentrated. The residue was boiled twice with in each case 30 ml of ethanol, the hot mixture was filtered and the combined filtrates were concentrated slightly. The mixture was allowed to stand at RT for 20 min, and the precipitate formed was filtered off with suction, washed with MTBE and dried on a rotary evaporator.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate (1.17 g, 3.43 mmol) and lithium hydroxide monohydrate (0.58 g, 13.70 mmol) in tetrahydrofuran (60 mL) and water (10 mL) was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL); washed with 1 M aqueous hydrochloric acid (80 mL) and brine (80 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo to afford the title compound which was used without further characterization. MS (ES+) m/z: 328.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([C:15](SC)=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:17]#[N:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:33][CH:34]([NH2:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C>C(#N)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([C:15]([NH:39][CH:34]([CH3:33])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:17]#[N:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CSC(=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(N)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NC(=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Temperature: 80 °C
Reaction time: 68 h
Yield: 43.1 %

Procedure:
To a solution of 3-[N-(3,5-Bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.58 mmol) in dry acetonitrile (2 ml) was added 1,2,2-trimethylpropylamine (0.12 g) and dry triethylamine (89 μl). The mixture was stirred for 68 h at 80° C. under nitrogen. The reaction mixture was concentrated. Purification by flash chromatography using ethyl acetate/heptane 1:4 and 1:3 as eluent gave a syrup (142 mg) which was crystallised in ethanol/water to give 110 mg (33%) of the title compound. Mp 151.5-154° C. 1H NMR (300 MHz, CDCl3): δ=0.9 (s, 9H), 1.10 (d, 3H), 3.11 (m, 1H), 3.30 (s, 3H), 7.10 (s, 2H), 7.46 (s, 1H), 7.55 (d, 2H), 7.85 (d, 2H), 8.1 (br d, 1H); MA calc for C24H24ClF6N3O2S: C, 50.75%; H, 4.26%; N, 7.40%; Cl, 6.24%. Found: C, 50.79%; H, 4.28%; N, 7.24%; Cl, 6.19%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:17][O:18][C:19](=[O:43])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:39](=[CH:40][CH:41]=1)[O:38][C:27]1([CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1)[CH2:26][C:25]2=[O:42]>C(#N)C>[CH3:17][O:18][C:19](=[O:43])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:39](=[CH:40][CH:41]=1)[O:38][C:27]1([CH2:30][N:29]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:28]1)[CH2:26][C:25]2=[O:42]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2
Temperature: 70 °C
Reaction time: 54 h
Yield: 29.2 %

Procedure:
K2CO3 (285 mg, 2.06 mmol) and 1-(2-bromoethyl)-4-fluorobenzene (0.43 ml, 3.1 mmol) were added to a suspension of Intermediate 4 (320 mg, 1.04 mmol) in acetonitrile (30 ml) and the mixture was stirred at 70° C. for 54 h. The solvent was evaporated and the residue was partitioned between water and DCM. The organic phase was dried over Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (eluent:petroleum ether:EtOAc 6:4) to give (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-acrylic acid methyl ester (120 mg) as a brown oil.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[CH3:40][N:41]1[C:45]([C:46]([C:48]2[N:52]([CH3:53])[CH:51]=[N:50][CH:49]=2)=[O:47])=[CH:44][N:43]=[CH:42]1.[NH4+].[Cl-]>C1COCC1.O>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[N:41]([CH3:40])[CH:42]=[N:43][CH:44]=3)([C:48]3[N:52]([CH3:53])[CH:51]=[N:50][CH:49]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1cncc1C(=O)c1cncn1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3cncn3C)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (1.6 M in hexanes, 0.34 mL, 0.56 mmol) was added dropwise to a mixture of 6-bromo-2,4-dichloro-3-(4-(trifluoromethyl)benzyl)quinoline (0.20 g, 0.467 mmol, Intermediate 12: step d) and bis(1-methyl-1H-imidazol-5-yl)methanone (0.097 g, 0.513 mmol, Intermediate 55: step b) in dry THF at −78° C. over a 30 minute period. Stirring was continued at −78° C. for 10 minutes. The reaction mixture was warmed up to 0° C., stirred for 35 minutes and then saturated aqueous NH4Cl was added. The mixture was warmed to room temperature, H2O was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, evaporated in vacuo and chromatographed (10% MeOH in CH2Cl2) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.21 (br. s., 1H), 7.75 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.36-7.46 (m, 3H), 7.27-7.32 (m, 2H), 6.33 (br. s., 2H), 4.31 (br. s., 2H), 4.07 (s, 3H), 3.44-3.56 (m, 6H); MS (ESI) [M+H]+
Reaction SMILES: [CH:1]1[C:13]2[O:12][C:11]3[C:10]4[C:14]5[C:19]([NH:20][C:9]=4[CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:18][CH:17]=[CH:16][CH:15]=5.[H-].[Na+].Cl[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]=1>CN(C)C=O.C1COCC1>[C:36]1([C:26]2[N:27]=[C:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:29]=[C:24]([N:20]3[C:9]4[CH:8]=[CH:7][C:6]5[C:5]6[CH:4]=[CH:3][CH:2]=[CH:1][C:13]=6[O:12][C:11]=5[C:10]=4[C:14]4[C:19]3=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:25]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: c1ccc2c(c1)[nH]c1ccc3c4ccccc4oc3c12
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-n3c4ccccc4c4c5oc6ccccc6c5ccc43)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 g (50.5 mmol) of 7H-12-oxa-7-azaindeno[1,2-a]fluorene are dissolved in 150 ml of dimethylformamide under a protective-gas atmosphere, and 2.4 g of 60% NaH in mineral oil (60.6 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (14.9 g, 55.6 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 18.4 g (75%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([Cl:14])=[CH:9][N:8]=1.CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C1COCC1>[Cl:6][C:7]1[N:12]=[C:11]([NH:1][CH2:2][CH:3]([NH:5][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:4])[C:10]([Cl:14])=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)CN
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 32 %

Procedure:
1,2-Diaminopropane (2.00 g, 27.03 mmol, 2.30 mL, 1.5 eq.) in THF (100 mL) was cooled to 0° C. and 2,4,5-trichloropyrimidine (3.30 g, 18.02 mmol, 2.06 mL, 1.0 eq.) was added. A precipitate formed and the reaction was stirred for 5 minutes before NEt3 and mesyl chloride were added simultaneously via two syringes. After 5 minutes, external cooling was removed and the reaction was stirred under a nitrogen atmosphere for 45 minutes. The reaction was then partitioned between CH2Cl2 (100 mL) and sat. NaHCO3 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure onto silica gel. Purification by silica gel chromatography (dry loaded) using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1-methyl-ethyl]-methanesulfonamide as a white solid (1.75 g, 32%). m.p.=160° C.; LCMS (m/e) 299 (M+1); 1H-NMR (d6-DMSO, 400 MHz) δ 8.20 (s, 1H), 7.94-7.77 (m, 1H), 7.23-7.07 (m, 1H), 3.65 (m, 1H), 3.42-3.35 (m, 2H), 2.93 (s, 3H), 1.11 (d, 3H, J=6.5 Hz).