Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][SH:25])([CH3:19])([CH3:18])[CH3:17].[Cl-].[NH4+]>CN(C)C=O>[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][S:25][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH2:1])[N:7]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A mixture of commercially available 2-amino-4,6-dichloropyrimidine (428 mg, 2.61 mmol), potassium carbonate (361 mg, 2.61 mmol), N,N-dimethylformamide (5.0 ml), and (2-mercaptoethyl)carbamic acid tert-butyl ester (356 mg, 2.0 mmol) was stirred in a reaction vessel at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was separated, and then sequentially washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=5:1 to 2:1) to yield [2-(2-amino-6-chloropyrimidin-4-ylsulfanyl)ethyl]carbamic acid tert-butyl ester (548 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[S:7][C:8]2[C:13]([C:14](=[O:17])[C:15]=1[I:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO>[OH:4][CH2:5][C:6]1[S:7][C:8]2[C:13]([C:14](=[O:17])[C:15]=1[I:16])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CC(=O)OCc1sc2ccccc2c(=O)c1I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: O=c1c(I)c(CO)sc2ccccc12
Reaction time: 1 h
Yield: 72 %

Procedure:
The compound (0.027 mmol, 10 mg) obtained in (1) above was dissolved in methanol, to which potassium carbonate (0.015 mmol, 2.05 mg) was added at 0° C., and the resulting solution was stirred for 1 hour. After the disappearance of the starting materials was confirmed by thin-layer chromatography, a saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction. Then, extraction was performed with methylene chloride, the obtained organic layer was dried over sodium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound (0.019 mmol, 6.2 mg) was obtained in a 72% yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:37])([CH3:36])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[CH:9]=1.C1C(=O)N([I:45])C(=O)C1>C(#N)C>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][O:29][CH2:28][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:36])([CH3:1])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:45])=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate (450 mg, 0.81 mmol) was dissolved in ACN (15 mL) and NIS (200 mg, 0.88 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified with column (silica gel, 10% EtOAc/Hexane) gave the product, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate (541 mg) as yellowish oil. HPLC-MS tR=3.10 min (UV254 nm); mass calculated for formula C26H39IN4O5Si2 670.2, observed LCMS m/z 671.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.Br>>[Cl:19][C:7]1[CH:6]=[CH:5][C:4]2[N:3]3[CH2:21][CH2:22][CH2:23][CH2:24][N:1]=[C:2]3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])([OH:11])[C:9]=2[CH:8]=1
Reactant: NC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reactant: BrCCCCBr
Agent: Br
Product: OC1(c2ccccc2Cl)C2=NCCCCN2c2ccc(Cl)cc21
Yield: 24.1 %

Procedure:
2-Amino-5-chloro-3-(o-chlorophenyl)-3H-indol-3-ol (5.86 g) was heated under reflux with 1,4-dibromobutane (4.32 g) for 18 hours. On cooling the hydrobromide of the title compound (1.67 g) was deposited m.p. 295°-300°C (decomp.).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O-:11])(=[O:10])=[O:9].[NH3+]C1C=CC=CC=1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]>>[SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O-:11])(=[O:10])=[O:9].[CH2:19]([NH+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]
Reactant: CCN(CC)CC
Agent: O=S(=O)([O-])c1ccccc1S
Agent: [NH3+]c1ccccc1
Product: CC[NH+](CC)CC

Procedure:
Then, 2.0 g of the resulting anilinium 2-mercaptobenzenesulfonate was subjected to ion-exchange column chromatography (about 30 ml of Dowex 50W-X2, 100-200 mesh, H-form was filled into a column) and eluted with a mixed solvent of methanol and water (4/1, v/v). Acidic fractions were concentrated under reduced pressure, and about 50 ml of isopropanol was added to the resulting syrup. The solvent was evaporated under reduced pressure. To 1.1 g of the resulting syrup, about 4 ml of isopropanol was added to form a solution. Triethylamine (0.58 g) was added to the solution, and the resulting crystals were collected by filtration to give 0.84 g of the captioned compound as colorless crystals (melting point: 89° to 90° C.)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][C:27]#[N:28])[CH:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH4+].[Cl-].[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[N:28]1[NH:35][N:36]=[N:37][C:27]=1[CH2:26][CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCc1nn[nH]n1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 0.12 mmol) in anhydrous DMF (2.6 mL) was added NH4Cl (230 mg, 4.3 mmol) and NaN3 (280 mg, 4.3 mmol). The reaction mixture was stirred for 30 min at 110° C. in the microwave, filtrated, and purified by preparative HPLC. The solid residue was dissolved in CDCl3 (3 mL) and briefly (2 to 4 min) exposed to daylight, which initiated a color change (purple). After 2 h of stirring open to the atmosphere at room temperature, the solvent was removed and the residue was purified by preparative HPLC to give N-(1-(2-(2H-tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 473.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].COC(C1C=C(C2C=CC=C(NCCNC[C@@H](C3C=CC=C(Cl)C=3)O)C=2)C=CC=1)=O.Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:29])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2cccc(NCCNCC(O)c3cccc(Cl)c3)c2)c1
Agent: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.36 %

Procedure:
3′-(2 (2 (3 chlorophenyl)-2-hydroxyethylamino)ethylamino)biphenyl-3-carboxylic acid (solabegron): A solution of 10% lithium hydroxide monohydrate in water (2 mL) was added to a solution of (R)-3′-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]ethylamino}-biphenyl-3-carboxylic acid methyl ester (50 mg, 0.12 mmol, 1.00 equiv) in ethanol (4 mL). The solution was stirred at ambient temperature for about 16 hours, and then the pH value of the solution was adjusted to 7-8 with concentrated hydrogen chloride. After concentrating the solution in vacuo, the resulting crude residue was purified by prep-HPLC to give the title product of as a white solid (20 mg; yield=41.36%). LC-MS: m/z=411 (MH)+. Retention time: 1.69 minute. [α]20.4D −20° (c=0.075, MeOH). [α]=−20° (c=0.075 g/100 ml in methanol, T=20.4). 1H NMR (300 MHz, CD3OD) δ: 8.22 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.29-7.38 (m, 4H), 7.20 (t, J=8.1 Hz, 1H), 6.97 (m, 2H), 6.68 (d, J=1.5 Hz, 1H), 5.00 (m, 1H), 3.56 (t, J=6.0 Hz, 2H), 3.23-3.33 (m, 3H), 3.12 (m, 1H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])=O>>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(Cl)cc3Cl)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 72 mg (0.269 mmol) of 2-bromo-1-(2,4-dichlorophenyl)ethanone were reacted according to the General Method 3. Yield: 43 mg (34% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[N:27]([CH:30]([CH3:32])[CH3:31])=[C:28]=[O:29]>CN(C)C=O>[O:23]=[C:21]1[NH:20][C:19]2[CH:24]=[CH:25][C:16]([NH:15][C:14]3[C:9]4[C:6]5[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:28]([NH:27][CH:30]([CH3:32])[CH3:31])=[O:29])[CH2:4][C:5]=5[S:26][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][C:18]=2[S:22]1
Reactant: CC(C)N=C=O
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 56 %

Procedure:
A mixture comprising 75 mg (196 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 6 mL N,N-dimethylforamide and 19.2 μL 2-isocyanatopropane was stirred at 23° C. overnight. The solvent was removed and the residue purified by chromatography to give 54 mg (56%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:20])[CH:18]=[CH2:19]>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:20][CH2:17][CH:18]=[CH2:19])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: C=CCN
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Product: C=CCNC1CCc2c(cccc2NC(C)=O)C1

Procedure:
Starting from 3.04 g (0.015 mol) of 5-acetylamino-2-tetralone and 4.2 g (0.045 mol) of allylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 3.30 g (78.4% of theory) and with a melting point of 263° C. which does not change after recrystallisation from methanol/water/ether.
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=1)(=[O:12])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[CH2:3]([S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1)(=[O:11])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCNS(=O)(=O)Cc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1COc1ccc(CCNS(=O)(=O)Cc2ccccc2)cc1
Yield: 61.8 %

Procedure:
Lithium hydroxide (2 mg, 0.077 mmol) in water (0.5 ml) was added into methyl 2-[(4-{2-[(benzylsulfonyl)amino]ethyl}phenoxy)methyl]benzoate (17 mg, 0.038 mmol) dissolved in THF (1 ml). The mixture was then in irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and dried with MgSO4 and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 500 mg/3 ml) using DCM, then MeOH/DCM (0.5:99.5) as eluant gave 10 mg the desired product, yield 61%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Cl
Yield: 41.8 %

Procedure:
8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55 mg, 0.22 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (69 mg, 0.23 mmol), and a 4 M solution of hydrogen chloride in dioxane (0.06 mL, 1.1 eq), were added to isopropyl alcohol (2 mL). The reaction mixture was microwaved on 300 watts, at 130° C. for 40 minutes. The reaction mixture was partitioned between aqueous saturated Na2CO3 and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and then concentrated on SiO2. Flash chromatography on SiO2 (MeOH/dichloromethane 0-15%) gave 2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a white solid (47 mg, 42%). MP: 109-112° C.; 1H-NMR (CDCl3) δ 10.98 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.10 (s, 1H), 8.09 (d, J=7.4 Hz, 1H), 7.40-7.54 (m, 3H), 7.07 (d, J=7.6 Hz, 1H), 6.64 (s, 1H), 6.20 (m, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 3.57 (m, 2H), 3.37 (s, 3H), 3.03 (d, J=4.8 Hz, 3H), 2.60-2.98 (m, 10H); LC/MS (ESI+): 510.99 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:37]([N:40]1[CH:44]([C:45]2[CH:46]=[CH:47][C:48]([O:56][CH3:57])=[C:49]([CH:55]=2)[O:50][CH2:51][C:52](O)=[O:53])[CH2:43][C:42]([C:58]2[CH:63]=[C:62]([O:64][CH3:65])[C:61]([O:66][CH3:67])=[C:60]([O:68][CH3:69])[CH:59]=2)=[N:41]1)(=[O:39])[CH3:38]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:52](=[O:53])[CH2:51][O:50][C:49]3[CH:55]=[C:45]([CH:44]4[N:40]([C:37](=[O:39])[CH3:38])[N:41]=[C:42]([C:58]5[CH:63]=[C:62]([O:64][CH3:65])[C:61]([O:66][CH3:67])=[C:60]([O:68][CH3:69])[CH:59]=5)[CH2:43]4)[CH:46]=[CH:47][C:48]=3[O:56][CH3:57])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 787.1 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10j) (531 mg, 80% yield).
Reaction SMILES: ClC1C=C(SCC2[C:20]3[C:15](=[CH:16][CH:17]=[C:18](C4C=CC=CC=4OC)[CH:19]=3)[NH:14]C(C)(C)C=2)C=C(Cl)C=1.Br[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])[CH:41]=2)[NH:36][C:35]([CH3:52])([CH3:51])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=C(S)C=C(Cl)C=1>>[CH3:50][O:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:52])([CH3:51])[CH:34]=[C:33]2[CH2:32][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1cc(Cl)cc(Cl)c1)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1cc(Cl)cc(Cl)c1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(3,5-Dichlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 50 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 33 mg of 3,5-dichlorothiophenol reacted to give 15 mg of the title compound as a foam.
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[C:17]([C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)N1N(C2CCCCC2)C(=O)C1(C)C

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 68 and 2-methylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:6]=2[CH2:5][CH:4]=[N:3]1.[BH4-].[Na+].B(O)(O)O>C1COCC1>[CH3:1][N:2]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: CN1N=CCc2c(-c3ccccn3)ncnc21
Agent: OB(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1NCCc2c(-c3ccccn3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a stirred solution of 1-methyl-5-(pyridin-2-yl)-1,4-dihydropyrimido[4,5-c]pyridazine (100 mg) in dry THF (5.0 mL), sodium borohydride (84 mg) was slowly added, followed by boric acid (137 mg) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours and solvents were removed under reduced pressure. The resulting oil was diluted with dichloromethane (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a residue which was purified by column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to afford 1-methyl-5-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimido[4,5-c]pyridazine (35 mg) as white solid. 1H NMR (DMSO-d6): δ 2.92-2.93 (m, 4H), 3.22 (s, 3H), 5.49 (t, 1H), 7.41-7.44 (t, 1H), 7.90-7.92 (m, 2H), 8.38 (s, 1H), 8.62-8.64 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH2:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH:33][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=2[NH:12][S:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])(=[O:11])=[O:10])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Product: CC(CNC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared from 2-(2,6-difluorobenzenesulfonylamino)-4-iodo-benzoic acid and 2-(3,4-dichloro-phenyl)-propylamine as in EXAMPLE 1, Part C. HPLC: RT=11.98 min. MS (ESI−): mass calcd. for C22H17Cl2F2IN2O3S, 625.3; m/z found, 624 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.63 (s, 1H), 8.02 (d, J=1.5, 1H), 7.54-7.45 (m, 1H), 7.39 (d, J=8.2, 1H), 7.34 (d, J=1.6, 1H), 7.32 (d, J=1.8, 1H), 7.09 (dd, J=8.3, 2.1, 1H), 7.02-6.94 (m, 3H), 6.34-6.32 (br m, 1H), 3.743.65 (m, 1H), 3.40 (ddd, J=13.7, 8.5, 5.6, 1H), 3.14-3.04 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([N:8]([C:32]1([CH3:41])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)[CH2:9][C@H:10]([O:28][C:29](=[O:31])[CH3:30])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([N+:25]([O-])=O)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([C@@H](O)CN(CC2C=CC=CC=2)C2CC3C(=CC(CC)=C(CC)C=3)C2)C=CC=1OCC1C=CC=CC=1>>[NH2:25][C:13]1[CH:12]=[C:11]([C@@H:10]([O:28][C:29](=[O:31])[CH3:30])[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:32]2([CH3:41])[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40]2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2ccccc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(N)c1)C2
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2ccccc2C1)c1ccc(OCc2ccccc2)c(N)c1
Reaction time: 6 h

Procedure:
The title compound is prepared from acetic acid (R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethyl ester (2.90 g) by an analogous procedure to that used to prepare (R)-1-(3-amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanol in Example 19. The reaction is shown to be complete by TLC after 6 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 2:1 Rf=0.60).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]4[C:19]=3[CH:18]=[CH:17][C:16]([O:20]C)=[N:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1>N1CCOCC1>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]4[C:19]=3[CH:18]=[CH:17][C:16]([OH:20])=[N:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Solvent: C1COCCN1
Product: Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Yield: 82.4 %

Procedure:
A solution of N-cyclopropyl-4-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine (510 mg, 1.81 mmol) in morpholine (15 mL) was heated at an oil bath temperature of 130° C. for about 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue was disolved in CH2Cl2 and triturated with diethylether to give the title compound as a yellow solid (400 mg, 82%). 1H-NMR (300 MHz, d6-DMSO) δ 8.96 (d, 1H, J=9.7 Hz), 8.49 (s, 1H), 8.23 (d, 1H, J=5.0 Hz), 7.35 (s, 1H), 7.06 (d, 1H, J=5.1 Hz), 6.97 (d, 1H, J=9.5 Hz), 2.74 (m, 1H), 0.73 (m, 2H), 0.49 (bs, 2H); MS (ESI) (M+H)+ 269.