Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C:23]2[CH:28]=[C:27]([N:29]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:26]3[N:46]=[CH:47][C:48]([C:49]4[CH:50]=[N:51][C:52]5[C:57]([CH:58]=4)=[CH:56][C:55]([F:59])=[CH:54][CH:53]=5)=[C:25]3[N:24]=2)[C:16](=[O:22])[O:17][C:18]([CH3:21])(C)C)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].[CH2:64](O)[CH3:65]>[OH-].[OH-].[Pd+2]>[CH3:35][Si:34]([CH3:36])([CH3:37])[CH2:33][CH2:32][O:31][CH2:30][N:29]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:27]1[N:26]2[N:46]=[CH:47][C:48]([C:49]3[CH:50]=[N:51][C:52]4[C:57]([CH:58]=3)=[CH:56][C:55]([F:59])=[CH:54][CH:53]=4)=[C:25]2[N:24]=[C:23]([N:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16](=[O:22])[O:17][CH2:18][CH2:21][CH2:64][CH3:65])[CH:28]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N(CC1CCN(Cc2ccccc2)CC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCCCOC(=O)N(CC1CCNCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 25 °C

Procedure:
This material, tert-butyl (1-benzylpiperidin-4-yl)methyl(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)carbamate, was then stirred with Pd(OH)2/C (0.2 equiv) and ammonium formate (20 equiv) in ethanol at 80° C. until the reaction was deemed complete by HPLC, LC-MS, or TLC analysis. The mixture was allowed to cool to room temperature, filtered through a pad of celite, concentrated and purified on silica gel to afford compound tea-butyl 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl(piperidin-4-ylmethyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16](=[O:19])[CH2:17][CH3:18])[C:9](=[N:12][N+:13]([O-:15])=[O:14])SC)=[CH:5][N:6]=1.[CH3:20][NH2:21].CO.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16](=[O:19])[CH2:17][CH3:18])[C:9]([NH:21][CH3:20])=[N:12][N+:13]([O-:15])=[O:14])=[CH:5][N:6]=1
Reactant: CN
Reactant: CCC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])SC
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])NC
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a solution of N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitro-N-propionylisothiourea (310 mg) in toluene (5 ml) was added 40% methylamine-methanol solution (75 mg) below -10° C. and the mixture was stirred at the same temperature for 3 hours. After addition of 2N hydrochloric acid (5 ml) under ice-cooling, the mixture was extracted with AcOEt (10 ml). The organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with AcOEt. The fractions containing the desired compound were concentrated and the residue was dissolved in toluene. Crystallization by addition of n-hexane gave 120 mg of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitro-1-propionylguanidine (Compound No. 32) as a white crystal, m.p. 89°-90° C.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.[Si:20]([C@@:27]1([OH:67])[C@@H:31]([CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[O:30][C@@H:29]([N:41]2[CH:48]=[C:47]([CH2:49][O:50][C@H:51]([C:56]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=3[N+:64]([O-:66])=[O:65])[C:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=O)[NH:44][C:42]2=[O:43])[CH2:28]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C([N:70](CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:20]([C@@:27]1([OH:67])[C@@H:31]([CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35])[O:30][C@@H:29]([N:41]2[CH:48]=[C:47]([CH2:49][O:50][C@H:51]([C:56]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=3[N+:64]([O-:66])=[O:65])[C:52]([CH3:53])([CH3:55])[CH3:54])[C:45]([NH2:70])=[N:44][C:42]2=[O:43])[CH2:28]1)([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21]
Reactant: COc1ccc([N+](=O)[O-])c([C@@H](OCc2cn([C@H]3C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c(=O)[nH]c2=O)C(C)(C)C)c1
Reactant: CCN(CC)CC
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c([C@@H](OCc2cn([C@H]3C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c(=O)nc2N)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
2,4,6-Triisopropyl benzenesulfonyl chloride (363 mg, 1.2 mmol) was added to a solution of compound 48 (170 mg, 0.24 mmol), DMAP (32 mg, 0.26 mmol), and triethylamine (0.34 mL, 2.4 mmol) in anhydrous CH2Cl2 (8.0 mL). The mixture was stirred at room temperature overnight under a nitrogen atmosphere, concentrated in vacuo, and the residue was dissolved in a solution of NH3 in 1,4-dioxane (0.5 M, 20 mL). The mixture was transferred into a sealed tube and was heated at 90° C. overnight. The mixture was cooled to room temperature, concentrated in vacuo, dissolved in CH2Cl2 (20 mL), and washed with brine (50 mL). The organic and aqueous phases were separated, and the aqueous phase was extracted with CH2Cl2 (30 mL) three times. The combined organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 3′,5′-O-bis-(tert-butyldimethylsilyl)-5-[(S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-propyloxy]methyl-2′-deoxycytidine 49 (110 mg, 65% for two steps). 1H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J=8.8 Hz, 1H, Ph-H), 7.50 (br s, 1H, NH2), 7.38 (s, 1H, H-6), 7.08 (dd, 1H, J=2.8 and 8.8 Hz, Ph-H), 7.04 (d, 1H, J=2.8 Hz, Ph-H), 6.80 (br s, 1H, NH2), 6.13 (t, 1H, J=6.4 Hz, H-1′), 5.09 (s, 1H, Ph-CH), 4.31 (m, 1H, H-3′), 4.25 (d, 1H, J=12.8 Hz, 5-CH2a), 4.08 (d, 1H, J=12.8 Hz, 5-CH2b), 3.87 (s, 3H, OCH3), 3.76 (m, 1H, H-4′), 3.64 (m, 2H, H-5′), 3.76 (dd, 1H, J=2.8 Hz, H-5′b), 2.10 (m, 1H, H-2′a), 2.00 (m, 1H, H-2′b), 0.87 (s, 9H, C(CH3)3), 0.78 and 0.76 (2 s, 18H, SiC(CH3)3), 0.07, 0.06, −0.01, and −0.04 (4 s, 12H, SiCH3).
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:15]3[C:10](=[C:11]([NH:29]C(=O)C(F)(F)F)[C:12]([F:28])=[C:13]([NH:18][CH2:19][CH2:20][NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[O:16][CH3:17])[C:9](=[O:36])[C:8]([C:37]#[N:38])=[CH:7]2)[CH2:5][CH2:4]1.O>CO>[NH2:29][C:11]1[C:12]([F:28])=[C:13]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([O:16][CH3:17])=[C:15]2[C:10]=1[C:9](=[O:36])[C:8]([C:37]#[N:38])=[CH:7][N:6]2[CH:3]1[CH2:4][CH2:5]1
Reactant: COc1c(NCCNc2ccccn2)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C#N)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
1 M aq. NaOH (1 mL) was added to a suspension of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]-5-(trifluoroacetamido)quinoline-3-carbonitrile (100 mg, 0.198 mmol) in MeOH (5 mL). After stirring at room temperature for 8 h, water (10 mL) was added. The resulting precipitate was collected by filtration, washed with water and MeOH, and dried to give 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carbonitrile (60.1 mg, 74%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[C:9]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:8]2[C:9]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:10][CH:11]=[CH:12][CH:13]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1-n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1cccnc1-n1ccnc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 4.8 g of 3-(4-chlorobenzoyl)-2-(1-imidazolyl)pyridine in 35 ml of ethanol and 5 ml of water is added 0.64 g of sodium borohydride. After the mixture is stirred at room temperature for an hour, the reaction mixture is poured into water and extracted with chloroform. The chloroform is distilled off and the residue is recrystallized from toluene to give 4.3 g of α-(4-chlorophenyl)-2-(1-imidazolyl)-3-pyridinemethanol as white crystals, melting at 133°-134° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](O)=[O:8].S(Cl)([Cl:21])=O>ClCCCl>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:21])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: ClCCCl
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoic acid (43.9 g, 0.075 mol) was suspended in 1,2-dichloroethane (40 ml) and thionyl chloride (24.9 ml, 0.34 mol) was added. The mixture was heated to reflux temperature for 3 h. After evaporation to dryness, the residue was dissolved in tetrahydrofuran (50 ml). Sodium hydrogen carbonate (15 g) and crystalline sodium carbonate (5 g) were added to the solution and the mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate evaporated to dryness. After pump-drying, a foam was formed, yield 44.6 g (98%). This material was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(C(C)=O)C(C)C>[N:26]1([C:32]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Yield: 98.2 %

Procedure:
To 6.50 g (23.5 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 39 g of methyl isobutyl ketone and 3.57 g (25.9 mmol) of potassium carbonate, and the resultant mixture was stirred at 50° C. To the mixture was added dropwise 3.87 g (25.9 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 50° C. for 4 hours. After completion of the reaction, the resultant opaque mixture was subjected to filtration, and washed with methyl isobutyl ketone, and then the resultant organic phase was quantitatively determined by an HPLC internal standard analysis method, which showed that 9.00 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 98%) was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:29]S(C(C)(C)C)=O)([C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:15]=2[N:16]=1)[CH3:11])(C(C)(C)C)(C)C.Cl>CO>[NH2:29][C:10]([C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:15]=2[N:16]=1)([CH3:11])[CH2:9][OH:8]
Reactant: CCCCCCCCc1ccc2nc(C(C)(CO[Si](C)(C)C(C)(C)C)NS(=O)C(C)(C)C)sc2c1
Agent: Cl
Solvent: CO
Product: CCCCCCCCc1ccc2nc(C(C)(N)CO)sc2c1
Yield: 20.6 %

Procedure:
A methanol (5 mL) solution of N-(1-(tert-butyldimethylsilyloxy)-2-(6-octylbenzo[d]thiazol-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (90 mg) and 4N HCl (0.325 mL, 1.3 mmol) was stirred at r.t. for 24 h. Then the mixture was extracted with EtOAc and purified by silica gel chromatography using PE/EA (1/2) to give product the title compound (11 mg, 26%). EDI-MS (M+1): 321. 1H NMR (300 MHz, CDCl3) δ 7.840 (d, 1H), 7.699 (s, 1H), 7.276 (d, 1H), 4.031 (d, 1H), 3.722 (d, 1H), 2.730 (t, 2H), 2.632 (b, 3H), 1.666 (t, 2H), 1.564 (s, 3H), 1.330-1.283 (m, 1011), 0.866 (t, 3H). HPLC: 96.9% (214 nm); 98.0% (254 nm).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:6]=2[O:5][C:4]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:3]1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)CC(=O)c2ccc(OCCCOc3ccccc3)cc2O1
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Product: O=C(O)CCC1(CCC(=O)O)CC(=O)c2ccc(OCCCOc3ccccc3)cc2O1

Procedure:
The title compound was prepared by the method of Example 22 substituting the title product of Example 26 for the title product of Example 21. Crystallization from 60% by volume ethyl acetate/hexane yielded 219 mg, m.p. 132°-133° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3(C=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:18]([F:30])[C:17]=2[F:31])=[C:12]([F:32])[C:11]=1[F:33])[CH3:8].O>C1COCC1>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25](/[CH:17]=[CH:18]/[CH2:19][CH2:1][C:2]4[CH:5]=[CH:16][C:13]([CH2:12][CH2:11][CH3:10])=[CH:14][CH:3]=4)[CH2:24][CH2:23]3)=[C:18]([F:30])[C:17]=2[F:31])=[C:12]([F:32])[C:11]=1[F:33])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCOc1ccc(-c2ccc(C3(C=O)CCCCC3)c(F)c2F)c(F)c1F
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(CC/C=C/[C@H]2CC[C@H](c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)CC2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Well-dried compound (s5) (6.4 g) was mixed with THF (100 ml) under an atmosphere of nitrogen, and the solution was cooled to −10° C. Potassium t-butoxide (t-BuOK; 1.4 g) was added in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., the compound (s78) (4.0 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was mixed with sodium benzenesulfonate dihydrate (20.2 g) and Solmix A-11 (100 ml). Then, 6N-hydrochloric acid (16.8 ml) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (ethyl acetate:Solmix=1:4 by volume) to give (E)-4-ethoxy-2,2′,3,3′-tetrafluoro-4′-(trans-4-(4-(4-propylphenyl)but-1-en-1-yl)cyclohexyl)-1,1′-biphenyl (No. 262) (3.6 g). The yield based on the compound (s78) was 65.3%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[S:19][CH:20]=[C:21]([C:23]([O:25]CC)=O)[N:22]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]5[S:19][CH:20]=[C:21]([C:23]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[O:25])[N:22]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)n1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5nc(C(=O)N6CCCC6)cs5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 47 starting from ethyl 2-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydro isoquinolin-7-yl}-1,3-thiazole-4-carboxylate and pyrrolidine. LCMS (M+H)+: m/z=505.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:23])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[CH2:20]([O:19][C:17]([C:16](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:14]1[N:15]=[C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[S:23])[S:12][CH:13]=1)=[O:18])[CH3:21]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccccc2F)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 7 g of ethyl 2-(3-o-fluorophenylthioureido)thiazol-4-ylglyoxylate, 3.8g of rhodanine-3-acetic acid, 2 g of ammonium chloride, ml of 28% v/v aqueous ammonia and 100 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH:9]1[CH:10]=[CH:11][C:12]2[C:23](=[O:24])[C:22]3[C:17](=[C:18](O)[CH:19]=[CH:20][C:21]=3O)[C:15](=[O:16])[C:13]=2[CH:14]=1>>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:18]1[C:17]2[C:15](=[O:16])[C:13]3[C:12](=[CH:11][CH:10]=[CH:9][CH:14]=3)[C:23](=[O:24])[C:22]=2[C:21]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[CH:20][CH:19]=1)[CH3:2]
Reactant: CCN(CC)CCN
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Product: CCN(CC)CCNc1ccc(NCCN(CC)CC)c2c1C(=O)c1ccccc1C2=O

Procedure:
A mixture of 42 ml. of N,N,N',N'-tetramethylenediamine, 17.43 g. of N,N-diethylethylenediamine and 12.01 g. of quinizarin is stirred and heated under reflux for 15 hours. The resulting solution is evaporated to dryness and a chloroform solution of the residue is filtered through 300 g. of alumina. The blue filtrate is chromatographed on silica gel in a Nylon® film column, developing with a chloroform:methanol (6:1) mixture. The major blue band is cut out and then eluted with a chloroform:methanol:triethylamine (6:2:1) mixture. The eluate is evaporated. The residue is crystallized from hexane and washed with petroleum ether, giving 1.43 g. of the desired product as blue-black plates, mp. 109° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:8]2[CH2:15][C:11]3[S:12][CH:13]=[CH:14][C:10]=3[C:9]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[CH2:15][C:11]4[S:12][CH:13]=[CH:14][C:10]=4[C:9]=3[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(F)cc1)C1Cc2sccc2C1=O
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
5-(4-Fluoro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol), hydrazine monohydrate (0.15 mL, 3.1 mmol), glacial acetic acid (0.5 mL) and ethanol (10 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(4-Fluoro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.7 mmol) as yellow solid in 81% yield.
Reaction SMILES: C([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]([O:20]C)=O)[CH:9]=1)C1C=CC=CC=1.[CH2:22]([Mg]Cl)[CH:23]([CH3:25])[CH3:24].CCOCC>C1COCC1>[CH3:22][CH:23]([CH3:25])[CH2:24][C:18](=[O:20])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COC(=O)Cn1cc(Cc2ccccc2)c2ccccc21
Reactant: CC(C)C[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(=O)Cn1ccc2ccccc21
Temperature: 0 °C

Procedure:
To a solution of methyl indol-1-ylacetate (1.13 g, 5.9 mmol) from Example 1, Step 1, in THF at -78° C. was added dropwise a solution of 2M isobutyl magnesium chloride in Et2O (3.3 mL, 6.6 mmol). The reaction mixture was warmed up to 0° C. and kept at this temperature until the starting material disappeared. The reaction mixture was quenched with a 0.5M solution of Na and K tartrate and extracted with EtOAc. The extract was washed with a solution of NH4OAc, dried over MgSO4 and evaporated to dryness. The crude residue was chromatographed on flash silica gel column eluting with EtOAc-hexane (1:9) to afford the pure title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18](OC(=O)C)(=[O:20])[CH3:19].C([O-])(=O)C.[Na+]>S(=O)(=O)(O)O>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])(=[O:20])[CH3:19]
Reactant: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
3.0 G. 2-amino-4-phenylthio-1-nitrobenzene (prepared according to Example XII) is dissolved in 40 ml. of acetic anhydride and two drops of sulfuric acid added. The mixture is left at room temperature for two hours then neutralized with a little sodium acetate and concentrated under vacuum. Water is added to the residue and the crude product filtered off. Recrystallization from methanol gives pure 2-acetamido-4-phenylthio-1-nitrobenzene.
Reaction SMILES: [N+:1]([C:4]1[C:5](F)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[OH:21][CH:22]([CH2:32][OH:33])[CH2:23][NH:24][C:25]([CH3:31])=[CH:26][C:27]([O:29][CH3:30])=[O:28]>C(O)(C)C>[OH:21][CH:22]([CH2:32][OH:33])[CH2:23][NH:24][C:25]([CH3:31])=[C:26]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=[N+]([O-])c1cnc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)C=C(C)NCC(O)CO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)C(=C(C)NCC(O)CO)c1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 g (0.0026 m) 3,5-dinitro-2-fluoropyridine (1) and 0.3 g (0.0026 m) triethylamine in 10 ml isopropanol is added 0.48 g (0.0025 m) methyl 3-(2,3-dihydroxypropyl)amino-2-butenoate (2). This solution is stirred at room temperature for two days, concentrated to an oil in vacuo and the residue is chromatographed on silica gel with 8% methanol/chloroform. The material with Rf =0.5 is collected. This reddish brown material is recrystallized from acetonitrile/n-butylchloride, m.p. 128°-9°.