Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]2[C@@H:5]([CH2:6][NH:7][CH2:8]2)[CH2:4][CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=1.C(N(CC)CC)C>C(O)C>[CH3:1][C@:2]1([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:8]2)[CH2:4][CH2:3]1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CNC[C@@H]21
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 75 °C

Procedure:
N-[(3aR,4R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-4-yl]benzamide (118 mg, 0.483 mmol, Example 8) was combined with 2-bromo-6-(trifluoromethyl)pyridine (131 mg, 0.580 mmol) and triethylamine (0.202 mL, 1.449 mmol) in ethanol (0.2 mL). The reaction was heated at 75° C. for 72 hours. The reaction mixture was partitioned between water (1 mL) and dichloromethane. The crude brown material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane as eluent to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.71 (s, 1H), 8.16 (dd, J=5.3, 3.3, 2H), 7.47 (t, J=7.9, 1H), 7.43-7.30 (m, 3H), 6.96 (d, J=7.2, 1H), 6.46 (d, J=8.6, 1H), 3.79-3.64 (m, 2H), 3.60 (dd, J=11.1, 7.3, 1H), 3.56-3.45 (m, 2H), 2.80-2.69 (m, 1H), 2.25 (dd, J=21.5, 9.6, 1H), 2.00-1.78 (m, 2H), 1.64 (s, 3H), 1.45-1.33 (m, 1H); MS (ESI+) m/z 390 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH3:16]I>CN(C=O)C.O>[CH3:16][O:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: N#Cc1ccc(C2(O)COC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(C#N)cc2)COC1

Procedure:
To a solution of 4-(3-hydroxyoxetan-3-yl)benzonitrile (Step 1 of Intermediate O, 600 mg, 3.43 mmol) in DMF (12.5 mL) was added sodium hydride (60% suspension in mineral oil, 151 mg, 3.77 mmol) at a temperature of ˜5° C. The reaction mixture was allowed to stirr for 1 h at this temperature, before methyl iodide (256 μL, 4.11 mmol) was added. Stirring was continued at rt over night. The mixture was diluted with water and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (566 mg, 87%): 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, 2H), 7.68 (d, 2H), 4.81 (d, 2H), 4.73 (d, 2H), 3.05 (s, 3H); ES-MS m/z 190 (MH)+; HPLC RT (Method E) 1.22 min.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)P(=O)(N(C)C)N(C)C.CCOCC>[CH2:18]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCBr
Reactant: Oc1cccc2c1NCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCCCCCCCCCN1CCCc2cccc(O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
A mixture of 499.2 mg (3.35 mmol) of 1,2,3,4-tetrahydro-8-quinolinol (see Example 7A), 425 mg (5.05 mmol, 1.5 eq.) of sodium bicarbonate, and 780 μl (3.69 mmol, 1.1 eq.) of 98% 1-bromodecane in 10 ml of hexamethylphosphoric triamide under argon was stirred for three hours at room temperature, followed by 44 hours at 50° C. The reaction was diluted with 80 ml of 1:1 ether:petroleum ether and the organic layer was washed with five 40 ml portions of water and 40 ml of brine, dried over sodium sulfate and evaporated to yield 1.04 g of a brown oil. Purification by flash chromatography on 110 g of silica, eluted with 5:95 ethyl acetate:petroleum ether afforded 624.4 mg of the title compound as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]>CO>[Br:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[OH:6]
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
0.826 g (21.8 mmol) of sodium borohydride was added to 2-bromo-4′-methoxy-acetophenone (10 g, 43.7 mmol) in methanol (200 ml) and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and saturated aqueous sodium chloride was added to the residue and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 2-bromo-1-(4′-methoxyphenyl) ethanol (11.05g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13](=O)[CH2:14][CH2:15][CH3:16].[OH-].[K+].Cl>C(O)C.O>[CH:13](=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CCCC=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC=C1Cc2ccc(OC)cc2C1=O
Reaction time: 1 h

Procedure:
To a 0° C. mixture of 9.66 g (59.6 mmol) of 6-methoxy-1-indanone and 4.29 g (59.6 mmol) of butyr-aldehyde in 10 ml ethanol is added 9.66 ml of a 4% KOH in ethanol solution. The reaction is stirred 1 hour and then added to 300 ml water and the pH of the quench adjusted to 2 with 1N hydrochloric acid. The resultant mixture is extracted with 3×300 ml ether, and the extracts combined, dried over MgSO4, evaporated and the residue triturated with ether to yield present title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10]C=2)=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]([CH2:19][CH3:20])[C:4]([C:21]([S:23][CH2:24][CH3:25])=[O:22])=[C:3]1[CH2:26][CH3:27].II>[N+](C)([O-])=O>[CH3:1][N:2]1[C:7]([CH:8]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]([CH2:19][CH3:20])[C:4]([C:21]([S:23][CH2:24][CH3:25])=[O:22])=[C:3]1[CH2:26][CH3:27]
Reactant: CCOC(=O)C1=C(c2ccccc2)N(C)C(CC)=C(C(=O)SCC)C1CC
Agent: II
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)C1=C(C2CCCC2)N(C)C(CC)=C(C(=O)SCC)C1CC
Reaction time: 24 h
Yield: 30 %

Procedure:
Chemical Transformation of 24 to 11 through Oxidation with Iodine (Scheme 1): A solution of 24 (5 mg, 0.013 mmol) in 0.5 mL of dry nitromethane was treated with iodine (10 mg, 0.040 mmol) at room temperature with stirring for 1 day (monitor by TLC). At completion the reaction mixture was applied to TLC separation (ethyl acetate:petroleum ether=1:4 v/v for the first development then 1:1 for a second development), and 2 mg of a yellow solid was obtained (yield: 30%), with 1H-NMR and MS data consistent with those of compound 11.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:26])[N:11]([CH2:14][C:15]3[N:24]=[C:23]([CH3:25])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[N:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[NH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:9]3[C:10](=[O:26])[N:11]([CH2:14][C:15]4[N:24]=[C:23]([CH3:25])[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]=4)[N:12]=[CH:13][C:8]=3[N:7]=2)[CH2:28]1
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 17.2 g (31.7 mmol) tert-butyl (R)-{1-[1-(but-2-ynyl)-6-(4-methyl-quinazolin-2-ylmethyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]-piperidin-3-yl}-carbamate in 400 ml dichloromethane was combined with 85 ml trifluoroacetic acid and stirred for three hours at ambient temperature. The mixture was evaporated to dryness at 30° C., the residue was dissolved in dichloromethane and the solution was made basic with ice-cooled saturated sodium carbonate solution. The organic phase was separated off and the aqueous phase was extracted twice more with dichloromethane. The combined organic phases were dried over sodium sulphate and the solvent was removed. The residue was purified by chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide 95:5:0.1).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13][C:12]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[N:34]1>CN(C)C(=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([NH:39][CH2:38][C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:23][C:12]=2[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: Cn1cc(CN)cn1
Reactant: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(Cl)c2CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(NCc3cnn(C)c3)c2CC1

Procedure:
A solution of ethyl 2-benzyl-4-chloro-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylate of Step B (50 mg, 0.14 mmol), triethylamine (0.10 ml, 0.72 mmol) and C-(1-Methyl-1H-pyrazol-4-yl)-methylamine (50 mg, 0.45 mmol) in N,N-dimethylacetamide (2.0 ml) was stirred for 18 h at 60° C. The solvent was removed in vacuo and the crude product was deprotected without further purification. LRMS APCI m/z 421 [MH]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])[CH2:25][CH2:24]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH2:27][CH2:28]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C1CCCN1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N2CCCC2=O)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidin-4-yl-pyrrolidine-2-one, hydrochloride, praeparative HPLC (Method C) (55%, semi-crystaline oil). HPLC-MS m/z=450.1 (M+1), Rt: 3.81 min.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])=[CH:4][C:3]=1[N:22]1[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]2=[N:23]1.[OH:31][C:32]1[CH:45]=[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:43]=[CH:42][C:33]=1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>>[N:23]1[N:22]([C:3]2[CH:4]=[C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH3:16])[CH:6]=[C:7]([CH2:8][C:45]3[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:43][CH:42]=[C:33]([C:34](=[O:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:32]=3[OH:31])[C:2]=2[OH:1])[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=12
Reactant: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 2 and 2-hydroxy-4-dodecyloxybenzophenone, the title compound is obtained as a yellow crystalline solid melting at 78°-82° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]2[CH:16]=[N:17][S:18][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.CCN(C(C)C)C(C)C.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[S:18][N:17]=[CH:16][C:15]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:32]
Reactant: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid (240 mg, 0.58 mmol) in THF (6 mL) was added DIPEA (396 μL, 2.34 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (119 mg, 1.15 mmol), HOBt (156 mg, 1.15 mmol) and EDCI (221 mg, 1.15 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between ethyl acetate and water. The organic extract was washed with aqueous saturated sodium bicarbonate solution then water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound (258 mg, 89%). LCMS (Method B): RT=3.83 min, [M+H]+=500.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:30].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16]2)=[O:19]
Reactant: Nc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.8 g) and benzo[d]thiazol-2-amine (5.52 g) in dichloromethane (80 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (9.4 g) and 4-dimethylaminopyridine (6 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (400 mL), washed with 5% aqueous HCl, water, and brine, and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4].O.O.Cl[Sn]Cl>C(O)(=O)C>[CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])(=[O:4])=[O:5]
Reactant: COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: COS(=O)(=O)c1ccccc1N

Procedure:
A reaction vessel equipped with a stirrer, a thermometer, and a nitrogen inlet tube was charged with 688 g of 2-nitrobenzene sulfonic acid methyl ester, 4.7 L of acetic acid, and 2.18 kg of SnCl2.2H2O, and the resultant mixture was cooled to 10° C. or less. Hydrochloric acid gas was bubbled through the mixture for 4 hours under stirring. Then, the mixture was stirred for 10 hours at 10° C. or less. Subsequently, 8.4 L of chloroform was added into the reaction mixture, and then while maintaining the temperature at 10° C. or less, the mixture was neutralized with aqueous 20% NaOH. The mixture was separated by further adding 56 L of water. The aqueous phase was extracted with 4 L of chloroform, and then the mixture including the chloroform layer was washed twice with 4 L of water, and separated. The mixture was dried by anhydrous magnesium sulfate, and then filtered to obtain 2-aminobenzene sulfonic acid methyl ester in chloroform solution. The obtained solution was charged along with 950 g of diethylaniline into a reaction vessel equipped with a stirrer, a thermometer, and a nitrogen inlet tube, and then 287 g of acrylic acid chloride was dropped for 15 minutes at a temperature of 5° C. or less. The mixture was stirred for 6 hours while maintaining the temperature at 5° C. or less. Then, 800 ml of concentrated hydrochloric acid and 12.8 L of water were added into the reaction mixture to separate the mixture. The organic layer was washed with, in order, 6.4 L of 2% hydrochloric acid, 6.4 L of water, 6.4 L of aqueous 3% sodium hydrogen carbonate, and 6.4 L of water. The product was dried by anhydrous magnesium sulfate, then filtered, and dried under reduced pressure at 30° C. to obtain 796 g of crystals. These were purified by column chromatography (5 kg silica gel, mobile phase hexane:ethyl acetate=2/1), to obtain 406 g of the monomer 4B represented by Formula (4B).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:20]#[C:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[O:1]([CH2:2][C:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]([C:20]#[C:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:13]=2)[CH2:5][CH2:4]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: CC#CC(CC(=O)OC)c1ccc(OCC2(CO)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC#CC(CC(=O)OC)c1ccc(OCC2(COc3ccccc3)CC2)cc1
Reaction time: 0.17 h

Procedure:
100 mg of methyl 3-[4-(1-hydroxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate were dissolved in 10 ml of DCM and used to charge a microwave vessel, then 46.7 mg of phenol and 130 mg of triphenylphosphine (polymer-bound, Reagentplus 99%) were added, and the mixture was stirred for 10 min to swell the resin. Subsequently, 98 μl of diisopropyl azodicarboxylate were added and the mixture was stirred at 120° C. under microwave irradiation for 15 min. The cooled reaction mixture was filtered and the filtercake was washed 3× with 10 ml each time of DCM. The combined filtrates were washed with 30 ml of water, then dried using a ChemElut cartridge and concentrated under reduced pressure. The residue was purified by means of RP-HPLC. This gave 68 mg of methyl 3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:19]2[CH:18]=[C:17]([NH:20]CC3C=CC(OC)=CC=3)[N:16]=[CH:15][C:14]=2[N:13]=[CH:12]1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([N:11]1[C:19]2[CH:18]=[C:17]([NH2:20])[N:16]=[CH:15][C:14]=2[N:13]=[CH:12]1)([CH3:10])[CH3:9]
Reactant: COc1ccc(CNc2cc3c(cn2)ncn3C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1cnc2cnc(N)cc21
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (2.42 ml, 31.4 mmol) was added to a solution of 1-isopropyl-N-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-6-amine (intermediate 25, 596 mg, 2.01 mmol) in DCM (12 ml) and then the mixture was stirred at 40° C. for 24 h. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3 (strong gas evolution) and H2O. The aqueous phase was extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and evaporated. The crude material was applied to a 24 g RediSep® silica column and purified by normal phase chromatography, eluting with 9:1 CH2Cl2/MeOH. Product-containing fractions were combined and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 0.33; ESI-MS 177.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:10]=1
Reactant: O=c1cc(-c2ccncc2)c(-c2ccc(F)cc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2nnc(Cl)cc2-c2ccncc2)cc1

Procedure:
A stirred mixture of 6-(4-fluorophenyl)-5-(4-pyridyl)-2H-pyridazin-3-one (105 mg, 0.40 mmol) and phosphorus oxychloride (2 ml) was heated at reflux for 2 h. It was evaporated, followed by co-evaporation with toluene and drying of the resultant product in an oil pump vacuum for several hours. Then dichloromethane was added and dil. ammonium hydroxide to neutrality with cooling. The organic solution was washed with water, dried and evaporated to leave the title compound. MS (m/z): 286.0 (M)+; C15H9ClFN3 requir. 285.7.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: OCCCc1cccc2nc(Cc3ccccc3Cl)oc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCCCc1cccc2nc(Cc3ccccc3Cl)oc12
Reaction time: 1 h

Procedure:
A solution of 2-(2-chlorobenzyl)-7-(3-hydroxy-1-propyl)benzoxazole (10 g, 0.033 mole) in ether (50 ml) was treated with methanesulfonyl chloride (4.4 g, 0.037 mol) and triethylamine 3.7 g, 0.037 mol). After stirring for 1 hour, the triethylamine hydrochloride was filtered and the ether was evaporated to give the title compound which was pure by TLC.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, white solid (61 mg, 81%), MS (ISP) m/z=302.5 [(M+H)+], mp 285.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=1)[CH3:17]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A 50 ml three-necked round-bottomed flask equipped with temperature probe and nitrogen bubbler was charged with Sodium Hydride (785 mg, 19.6 mmol) and DMF (10.0 ml) and cooled to 0° C. A solution of 3-Fluorophenol (2.00 g, 17.8 mmol) in DMF (2.0 ml) was added dropwise maintaining reaction temperature below 10° C. The mixture was stirred for an additional 15 minutes then Ethyl bromoacetate (2.48 ml, 22.3 mmol) was added dropwise maintaining the reaction temperature below 10° C. The reaction was stirred at room temperature for 4 hours. The reaction was then concentrated under reduced pressure and the crude product was taken up in Ethyl acetate, washed with water, dried (Na2SO4), filtered, concentrated and further purified via flash chromatography using 4:1/heptane:Ethyl acetate as eluant. Fractions containing product were combined and concentrated to afford (3-Fluoro-phenoxy)-acetic acid ethyl ester (2.26 g, 69%) as a clear oil.