Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH2:21][C:22]([CH2:51][O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]/[CH:61]=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[NH:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[C:79]1(=[O:85])[O:84][C:82](=[O:83])[CH2:81][CH2:80]1>C1COCC1>[C:1]([O:20][CH2:21][C:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH2:51][O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]/[CH:61]=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[N:23]([CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])[C:79](=[O:85])[CH2:80][CH2:81][C:82]([OH:84])=[O:83])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)(COC(=O)CCCCCCC/C=C\CCCCCCCC)NCCS(=O)(=O)O
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)(COC(=O)CCCCCCC/C=C\CCCCCCCC)N(CCS(=O)(=O)O)C(=O)CCC(=O)O
Reaction time: 18 h

Procedure:
To 566 mg (0.553 mmol) of 2-[tris(oleoyloxymethyl) methylamino]-1-ethanesulfonic acid in 10 mL THF was added 410 mg (4.06 mmol) of triethylamine. After 5 min 96 mg (0.960 mmol) of succinic anhydride was added. The yellow solution was stirred for 18 h under reflux. The solvent was removed under reduced pressure. The residual oil was purified by chromatography on silica gel, eluted with an ethyl acetate/methanol gradient (25:75 vol/vol to 0:100 vol/vol). N-[tris(oleoyloxymethyl)methyl]-N-(2-sulfoethyl) succinic acid monoamide was isolated as a yellow heavy viscous oil with a yield of 240 mg (38%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:15]1C=C[CH:17]=[C:16]1CC(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:16](=[S:15])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h

Procedure:
A solution of 2.2 g of N—BOC-3-(R)-hydroxy-piperidine in 10 ml of THF is added under argon and 1 ml of thiolacetic acid to a solution of 3.4 g of triphenylphosphine and 2.65 ml of azadicarbonic acid-isopropylate in 10 ml of THF. The mixture obtained is kept for 18 hours at 70°, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. N—BOC-3-(S)-thioacetoxy-piperidine is obtained. 1H-NMR (CDCl3): 3.78 (dd,1H,NCH2CHS, J=3.1 Hz, J=13.3 Hz), 3.5-3.6 (m,2H, CHSC═O, NCH2CH2), 2.32(s,3H,SC═OCH3),1.46(s,9H, tert.butyl)
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)[C:2]#[CH:3]
Reactant: C#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
To a stirred solution of propargyl alcohol (5g, 90 mmol) and dihydropyran (37.5 g, 0.44 mol, 5 equiv) in CH2Cl2 (300 ML), was added p-toluenesufonic acid (30 mg). The mixture was stirred at 20° C. for 1.5 hours. The solvent was removed by rotary evaporation. The residue was taken up in ether (150 mL) and washed with aqueous saturated NaHCO3 (120 mL), saturated NaCl (120 mL), water (200 mL). The organic layer was dried (MgSO4) and concentrated to yield a yellow oil. Purification by distillation under reduced pressure gave Tetrahydro-2-(2-propynyloxy)-2H-pyran (47) (12 g, 97%) as a colorless oil: bp: (40° C., 0.05 mm Hg). ##STR20##
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27][NH:26][CH2:25]5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH:2]([N:5]1[C:9]([C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27][N:26]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:25]5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNC3)ccc1-2
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(S(C)(=O)=O)C3)ccc1-2

Procedure:
Following the procedure for 395, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene hydrochloride salt and methanesulfonyl chloride gave 396 isolated as a pale orange solid (28 mg, 48%). LCMS: RT=11.27 min, [M+H]+=460. 1H NMR δ (ppm) (CDCl3): 8.33 (1H, d, J=8.21 Hz), 7.90 (1H, s), 7.05 (1H, dd, J=8.24, 1.91 Hz), 6.94 (1H, d, J=1.87 Hz), 5.93-5.83 (1H, m), 4.42-4.36 (2H, m), 3.79 (1H, dd, J=9.53, 7.31 Hz), 3.61 (1H, ddd, J=9.97, 8.27, 3.30 Hz), 3.50-3.31 (5H, m), 2.86 (3H, s), 2.41-2.32 (1H, m), 2.15-2.03 (1H, m), 1.61 (6H, d, J=6.63 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[C:17]([CH3:22])=[N:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:18]3[C:17]([CH3:22])=[N:16][N:15]([CH3:14])[CH:19]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cc1nn(C)cc1C=O
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (3 g, 15.1 mmol, 1 eq) and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (2.0 g, 16.6 mmol, 1.1 eq) in 1,2-dichloroethane (75 mL) add sodium triacetoxyborohydride (4.8 g, 22.6 mmol, 1.5 eq) and stir at room temperature over the weekend. Add 2 N sodium hydroxide (100 mL), separate the layers, extract the aq. layer twice with DCM (75 mL), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 methanol:DCM). Combine only the fractions which contain the main component and concentrate to give 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a viscous yellow oil (2.14 g, 46%). Combine all other fractions which contain main component plus impurities, concentrate then repeat the chromatography step to recover further material (1.6 g, 35%, total yield 81%). MS (ES): m/z=307.1 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C@@H:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][O:28][C:27]3=[O:34])[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH:31]([C@H:30]1[CH2:29][O:28][C:27](=[O:34])[N:26]1[C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C@H:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH3:18])[N:25]=1)([CH3:32])[CH3:33]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(C(=O)OCc3ccccc3)CC2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of 4-{(S)-1-[4-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid benzyl ester (22 mg) in methanol (5 mL) was added palladium hydroxide on carbon (7 mg, 0.05 mmol). The reaction was then stirred at room temperature for 16 hours. The reaction is then filtered and then concentrated under vacuum. The crude material was then purified using reverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier to give (S)-4-isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one (11 mg) in 70% yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[O:20][CH2:21][CH3:22])/[C:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.CO[C:25](C)(C)[CH3:26]>[Pd]>[CH2:25]([O:19][C:17](=[O:18])[CH:16]([O:20][CH2:21][CH3:22])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH3:26]
Reactant: COC(C)(C)C
Reactant: CCO/C(=C\c1ccc(OCc2ccccc2)cc1)C(=O)[O-]
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 99 %

Procedure:
Ethyl E/Z-3-(4-benzyloxyphenyl)-2-ethoxyacrylate (20.0 g, 61.3 mmol) dissolved in tert-butyl methyl ether (40 mL) charged with palladium on carbon (5%) (1.0 g, Engelhard Tech code no. 4531) was hydrogenated with vigorous stirring at atmospheric pressure at room temperature for 2-3 days. The catalyst was filtered off and washed with a few milliliters of tent-butyl methyl ether. The combined filtrates were concentrated in vacuo to yield 14.5 g (99% yield) of the title compound as a viscous oil, which crystallizes upon standin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CC=C(c3ccc(F)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
A solution of 3.6 g (0.020 mol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine in 100 ml of tetrahydrofuran was treated with 13.9 ml (0.10 mol) of triethylamine and 7.3 g (0.020 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 3.5 g (58%) of 5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as brownish crystals; m.p. 265°.
Reaction SMILES: C(O[C:4](=[O:19])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:14]1[CH:13]=[C:12]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 8 %

Procedure:
A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.70 g, 6.05 mmol) and methyl urea (673 mg, 9.08 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 17.3 mL, 12.1 mmol) was heated under reflux at 100° C. for 6 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[2-(3-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (149.1 mg, 8%) as a white solid: mp 52–55° C.; EI-HRMS m/e calcd for C16H21ClN2O2 (M+) 308.1292, found 308.1287. The methyl ester of the starting material was recovered from the reaction mixture due to transesterification.
Reaction SMILES: C(OC[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12]OCC)[C:7]1=[S:16])C.[S]>>[CH2:9]([N:8]([CH2:11][CH3:12])[CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][N:6]([CH3:5])[C:7]1=[S:16])[CH3:10]
Reactant: CCOCCN1CCN(CCOCC)C1=S
Agent: [S]
Product: CCN(CC)CCN1CCN(C)C1=S
Yield: 89 %

Procedure:
Using a method similar to the preparation of 1,3-bis(2-ethoxyethyl)imidazoline-2-thione (7c), 80 mg (2.5 mmol) of sulfur are admixed with 1-(2'-diethylaminoethyl)-3-methylimidazolin-2-ylidene solution (8). This gives (8b) (478 mg, 89% of theory) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@H:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[C@@H:18]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:17]([CH2:52][NH2:53])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@H:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[C@@H:18]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:17]([CH2:52][NH:53][C:1](=[O:3])[CH3:2])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CNC(C)=O)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 0.5 h

Procedure:
5.936 mmol of acetyl chloride are added to a solution of 5.396 mmol of (3R,4R,5R)-3-aminomethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy -propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester and 6.475 mmol of triethylamine in 80 ml of dichloromethane under argon at 0° C. After 30 minutes, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution and extracted with tert-butyl methyl ether (2×). The combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rt=4.98 (gradient I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH2:12][CH2:11]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1>C1COCC1>[CH3:17][N:16]([CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]2[CH:18]=[CH:19][C:20]([F:21])=[C:2]([F:1])[CH:3]=2)[CH2:15][CH2:14]1)[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)=[S:31]
Reactant: CNC1CCN(CCCCOc2ccc(F)c(F)c2)CC1
Reactant: Fc1ccc(N=C=S)cc1
Solvent: C1CCOC1
Product: CN(C(=S)Nc1ccc(F)cc1)C1CCN(CCCCOc2ccc(F)c(F)c2)CC1

Procedure:
The condensation of 1.2 g (4 mmol) of 1-[4-(3,4-difluorophenoxy)butyl]-4-(methylamino)piperidine with 0.61 g (4 mmol) of 4-fluorophenyl isothiocyanate in THF according to the protocol of Example 1.1 gives 1.75 g (Yd: 95%) of a powder of formula 13.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:20]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(Cl)cc2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3ccc(Cl)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 89A in analogy to the synthesis of the compound of Example 1. 31 mg (80% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CCO>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:3]3[S:11][C:10]4[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:25][CH2:24]1
Reactant: Nc1nc(Cl)c2sc3c(c2n1)CCCC3
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(c2nc(N)nc3c4c(sc23)CCCC4)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 44.5 %

Procedure:
To a solution of 4-chloro-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine (0.09 mg, 0.37 mmol) in EtOH (3.7 mL) was added K2CO3 (0.12 g, 0.84 mmol) followed by N-methylpiperazine (0.05 mL, 0.44 mmol). After stirring at rt for 22 h, EtOH was removed under reduced pressure and the mixture was dissolved in CH2Cl2 (5 mL) and poured over H2O (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, such as with a satd. aq. NaCl, (30 mL), dried, for example with Na2SO4, and concentrated to afford the title compound (0.05 g) as a pale yellow solid. MS: 304.2. 1H NMR (400 MHz, CD3OD) δ ppm 3.93-3.88 (m, 4H), 2.80 (t, J=6.0 Hz, 2H), 2.63 (t, J=6.1 Hz, 2H), 2.56-2.52 (m, 4H), 2.33 (s, 3H), 1.96-1.81 (m, 4H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1>C(OC(=O)C)(=O)C>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:30]=[CH:29][C:28]=1[C:12]1([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=[CH:10][CH:9]=2)[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:18]1
Reactant: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3cccn3-c3ccccc3)OC(=O)c3ccccc32)c(N(C)C)c1
Yield: 59.7 %

Procedure:
A mixture of 2.91 g (0.01 mole) of 2-[(1-phenyl-2-pyrrolyl)carbonyl]benzoic acid prepared in part A above, 2.34 g (0.017 mole) of 84.6 percent active N,N,N', N'-tetramethyl-m-phenylenediamine in 4.0 ml of acetic anhydride was interacted in a manner similar to that described in Example 1, part C to obtain 2.61 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-phenyl-2-pyrrolyl)phthalide (Formula IV: R0 =R1 =R2 =R3 =H; R=CH3 ; R4 =N(CH3)2 ; R7 =C6H5), a peach-colored powder melting at 193°-194° C. The infrared spectrum showed a maximum at 1760 cm-1 (C=O, s). A toluene solution of this product spotted on silica gel developed an imediate orange-red-colored image.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][O:11][S:23]([CH3:22])(=[O:25])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of 22.0 gm (125.6 mMol) (R)-N-tert-butoxycarbonyl-2-amino-1-propanol and 19.5 gm (150.7 mmol) diisopropylethylamine in 450 mL dichloromethane was cooled to 0° C. To this solution was added dropwise 10.7 mL (138.2 mMol) methanesulfonyl chloride at a rate to maintain the temperature of the reaction mixture at from 0° C. to 10° C. Once the addition was complete the reaction mixture was stirred at 0° C. for about one hour. The reaction mixture was washed twice with 200 mL portions of water, once with 200 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from hexane and ethyl acetate to provide 19.4 gm (61%) of the desired compound in two crops (m.p.=65–68° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:44](=[O:45])[C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:43]2[C:44](=[O:45])[N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=[CH:41][CH:42]=2)=[O:47])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:15][C:8]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (144.5 mg, 0.326 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (228.9 mg, 0.977 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (312.3 mg, 1.63 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (220.1 mg, 1.63 mmol), N-ethyl-N-isopropylpropan-2-amine (421.1 mg, 3.26 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (87.3 mg, 40.62%). LRMS (APCI pos): >95% purity, 254 nm, m/e 660 (M+1). 1H NMR (400 MHz, CD3Cl) δ 11.83 (s, 1H), 8.45 (d, 1H), 8.42 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.37-7.68 (m, 5H), 7.21-7.28 (m, 2H), 6.48 (d, 1H), 4.24 (m, 2H), 3.08 (m, 1H), 2.89 (m, 2H), 2.07 (m, 2H), 1.75 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19].C(OCC)(=O)C>C(#N)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6]1)=[O:25])([CH3:20])[CH3:19]
Reactant: c1ccc2ncc(N3CCNCC3)cc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3c2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 3-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless foam.