Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][C:2]1[N:7]=[C:6]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Product: CC(C)(C)Nc1nc(NC(C)(C)C)nc(N2CC3CCC(CC3)C2)n1

Procedure:
3-(4,6-Dichloro-s-triazin-2-yl)-3-azabicyclo[3.2.2]nonane (8.2 g.; 0.03 mole) and 25 ml. (0.24 mole) of t-butylamine is placed in a glass liner in a bomb and then heated in an oil bath maintained at 160°-180° C. for 16 hours. After cooling, the contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo, column chromatography on silica gel and recrystallization of the pure fractions containing the more polar component from n-heptane gives 4.8 g. of fine colorless crystals, m.p. 217°-222° C.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:15]([O:19][C:20]([NH:22][C@H:23]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28](O)=[O:29])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([C:49]2[N:50]=[N:51][S:52][CH:53]=2)=[C:45]([CH2:47][NH2:48])[CH:46]=1>CN(C=O)C>[C:15]([O:19][C:20]([NH:22][C@H:23]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([NH:48][CH2:47][C:45]1[CH:46]=[C:41]([Cl:40])[CH:42]=[CH:43][C:44]=1[C:49]1[N:50]=[N:51][S:52][CH:53]=1)=[O:29])=[O:25])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Reactant: NCc1cc(Cl)ccc1-c1csnn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1csnn1)C1CCCCC1

Procedure:
EDC (0.388 g, 2.02 mmol), HOAt (0.275 g, 2.02 mmol), and 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 0.551 g, 1.55 mol) were added to a stirred solution of 1-[5-Chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]methanamine (0.351 g, 1.555 mmol) in DMF (7.8 mL). After 16 h the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by flash chromatography on silica (eluting with an EtOAc/hexanes gradient, 1–100% EtOAc). 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(1,2,3-thiadiazol-4-yl)benzyl]-L-prolinamide was obtained as a solid. MS m/z=562.6.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([NH:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([S:26]([NH:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(NCCO)c1cncc(Br)c1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cncc(S(=O)(=O)NCCO)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 5-bromo-N-(2-hydroxyethyl)pyridine-3-sulfonamide (Intermediate 31), the title compound was obtained as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)ON=1.CC1[O:18][N:17]=C(C(OCC)=O)C=1>>[CH3:1][C:2]1[O:18][N:17]=[C:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: Cc1cc(C2(C(=O)O)CC2)on1
Reactant: CCOC(=O)c1cc(C)on1
Product: Cc1cc(C2(C(=O)O)CC2)no1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 8, but using ethyl 5-methylisoxazole-3-carboxylate as the starting material. MS (ES+) (M+H) 168.0; LCMS retention time: 2.06 minutes. (Method L). 1H NMR (500 MHz, CD3OD) δ 1.38-1.42 (m, 2H), 1.58-1.62 (m, 2H), 2.39 (s, 3H), 6.32 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)=[CH:17][CH:16]=2)[C:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:13]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OC)cc3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(O)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 5-(4-methoxy-phenyl)-1-methyl-3-pentyl-2-phenyl-1H-indole (0.505 g, 1.317 mmol) was reacted with BBr3 (1.6 ml of a 1M solution in CH2Cl2) to give the product (0.375 g, 1.023 mmol, 78%) as a light-brown oil. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.14-1.22 (m, 4H), 1.51-1.57 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 3.55 (s, 3H), 6.84 (d, J=8.6 Hz, 2H), 7.39 (dd, J=1.7, 8.4 Hz, 1H), 7.43-7.50 (m, 6H), 7.54 (t, J=7.2 Hz, 2H), 7.68 (d, J=1.5 Hz, 1H), 9.37 (s, 1H); [ESI(+)], m/z 370 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])C.Cl>CO>[C:6]([OH:20])(=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19]
Reactant: CCOCCCCCSCCCCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCCCCCSCCCCC(=O)O
Reaction time: 7 h

Procedure:
NaOH (lM, 24 mL, 24 mmol) was added to a solution of the above ethyl-6-thia-12-oxatetradecanoate, (6.8 mmol) in MeOH (20 mL). After stirring for 7 h, the reaction mixture was acidified with 10% HCl (pH 1) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water (50 mL), brine (50 mL), and dried (Na2SO4). The crude product was recrystallized from hexane to afford the title compound, 6-thia-12-oxatetradecanoic acid; yield 82%; bp 144° C.-146° C./0.01 torr; IR(neat): 3000 (broad) and 1730 cm-1 ; NMR: 1.23 (3H, t, J=7.3 Hz), 1.46 (2H, quint, J=6.9 Hz), 1.55-1.69 (6H, m), 1.74 (2H, quint, J=7.3 Hz), 2.37 (2H, t, J=7.6 Hz), 2.51 (2H, t, J=7 Hz), 2.53 (2H, t, J=7 Hz)m 3,42 (2H, t, J=6.9 Hz), 3.48 (2H, q, J=7.3 Hz), and 10.6 ppm (lH, br s); Found: C, 58.07, H, 9.78%. Calcd for C13H26SO2 : C, 58.03, H, 9.74%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])[CH3:2].[C:17](Cl)(Cl)=[S:18]>O1CCCC1>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[C:17](=[S:18])[NH:15]2
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CN1Cc2c(C)cccc2NC1=S
Temperature: 25 °C

Procedure:
To a cooled solution of compound (10b) (15 g., 67 mmole) in 300 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere, is added 72 mmole of thiophosgene at about room temperature. Upon completion of the addition, the solution was refluxed for 10 hours, cooled to room temperature and the tetrahydrofuran removed in vacuo. The residue is dissolved in methylene chloride, washed with 5% aqueous hydrochloric acid, then water. The methylene chloride solution is dried over sodium sulfate, filtered and the solvent removed in vacuo to produce the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][NH:42]5)=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[F:47][C:48]([F:61])([F:60])[CH2:49][CH2:50][CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:52](O)=[O:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:59][O:58][C:56](=[O:57])[NH:55][CH:51]([C:52]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21]4[NH:20][C:19]([CH:15]5[CH2:16][CH2:17][CH2:18][N:14]5[C:12](=[O:13])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:46])[CH2:6][CH2:7][C:8]([F:9])([F:11])[F:10])=[N:23][CH:22]=4)=[CH:29][CH:28]=3)=[CH:31][CH:32]=2)=[CH:40][N:39]=1)=[O:53])[CH2:50][CH2:49][C:48]([F:47])([F:61])[F:60]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(CCC(F)(F)F)NC(=O)OC)[nH]4)cc3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a solution of crude [4,4,4-Trifluoro-1-(2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester (115 mg, 0.18 mmol) in dimethylformamide (0.5 mL) was added a solution of 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid (44 mg, 0.19 mmol) and HATU (72 mg, 0.19 mmol) in dimethylformamide (0.5 mL). Diisopropylethylamine (65 μL, 0.37 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield (4,4,4-Trifluoro-1-{2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester (35 mg, 23%). LCMS-ESI+: calculated for C40H44F6N8O6: 846.82; observed [M+1]+: 847.34. 1H-NMR: 400 MHz, (CD3OD) δ: 7.81-7.72 (m, 4H), 7.67-7.64 (m, 4H), 7.38-7.32 (m, 2H), 5.20-5.16 (m, 2H), 4.55-4.51 (m, 2H), 3.91-3.86 (m, 4H), 3.67 (s, 6H), 2.38-2.20 (m, 8H), 2.18-1.79 (m, 8H) ppm.
Reaction SMILES: [CH2:1]1[C:11]2[C:5]([C:6]([C:16](O)=[O:17])=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)=[CH:4][CH:3]=[CH:2]1.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][C@H:20]([NH:19][C:16]([C:6]3[C:5]4=[CH:4][CH:3]=[CH:2][CH2:1][C:11]4=[CH:10][CH:9]=[C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=34)=[O:17])[CH2:21]2)=[CH:32][CH:31]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C1=c2ccccc2=CC=C2CC=CC=C21
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1=c2ccccc2=CC=C2CC=CC=C21

Procedure:
Dibenzo[a,d]cycloheptene-5-carboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)dibenzo[a,d]cycloheptene-5-carboxamide, melting point 127-128° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Yield: 209.1 %

Procedure:
To a mixture of 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.3 g) and aminoguanidine hydrochloride (122 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 4 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 6-(2,5-dichlorothiophen-3-yl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 127) (0.41 g) as pale yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[Br:25][CH2:26][CH2:27][CH2:28]Br>C(#N)C>[Br:25][CH2:26][CH2:27][CH2:28][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: BrCCCBr
Reactant: O=C(Cc1ccccc1O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Cc1ccccc1OCCCBr)OCc1ccccc1

Procedure:
A solution of 100 g of 2-hydroxyphenylacetic acid, 75 cm3 of benzyl alcohol and 0.5 g of paratoluenesulphonic acid in 1400 cm3 of toluene is refluxed for 2 hours while removing the water formed. After cooling, treating with 3 g of animal black and filtering, the reaction mixture is concentrated to 150 cm3 and supplemented with 300 cm3 of isopropyl oxide. The crystals obtained by cooling to 0° C. are drained, washed and dried to give 82.5 g of benzyl 2-hydroxyphenylacetate. 174 g of potassium carbonate are added to a solution of 153 g of this ester in a mixture of 500 cm3 of 1,3-dibromopropane and 2500 cm3 of acetonitrile and the mixture is refluxed for 17 hours. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of ethyl acetate and the organic phase is washed twice with 400 cm3 of water and twice with 250 cm3 of a saturated solution of sodium chloride and then dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 9 cm, height 55 cm), eluting with a cyclohexane and ethyl acetate mixture (95/5 by volume) and collecting fractions of 500 cm3. Fractions 12 to 18 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 90 g of benzyl 2-(3-bromopropoxy)phenylacetate in the form of a yellow oil. A solution of 40 g of this product in 500 cm3 of acetonitrile is heated in an autoclave with 27 g of sodium iodide and 90 g of dimethylamine for 16 hours at 80° C. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by acid-base treatment to give 29.3 g of benzyl 2-(3-dimethylaminopropoxy)phenylacetate in the form of a yellow oil. Hydrogenation of this ester at atmospheric pressure at 40° C. in ethyl acetate in the presence of palladium hydroxide, followed by crystallization from ethyl acetate, lead to 17.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid in the form of white crystals; melting point 98° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:30][C@@H:31]1[CH2:40][CH2:39][C:38]2[C:33](=[C:34]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH:35]=[CH:36][CH:37]=2)[CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:33]=2[CH2:32][C@H:31]([NH:30][C:1]([C:4]2[N:5]=[C:6]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=4)[S:7][CH:8]=2)=[O:3])[CH2:40][CH2:39]3)[CH2:42][CH2:43]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1csc(-c2ccncc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2csc(-c4ccncc4)n2)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
To a solution of 4-carboxy-2-(4-pyridyl)thiazole (89 mg, 0.43 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 1,1'-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent gave 110 mg (61% yield) of the title compound as white crystals: mp 187-188° C.; [α]21D -82° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 433 (2, M+).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=Cc1ccncc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2Cc2ccncc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with 4-pyridine carboxaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-pyridin-4-ylmethyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 445.3 [M+H]+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:21][CH2:20][C@@H:19]([O:22][Si](C(C)C)(C(C)C)C(C)C)[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]1[NH2:33].C(O)(C)C>O>[NH2:33][CH:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C@H:19]([OH:22])[CH2:20][CH2:21][C@H:11]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)C(N)c2cccnc21)(C(C)C)C(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: NC1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Temperature: 82 °C
Yield: 124.2 %

Procedure:
To a 250 ml flask was charged (6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-amine di HCl salt (15 g, 25.88 mmol) and a solution of isopropanol:water (45 mL:15 mL). The mixture was heated to 82° C. for 6 h then dried via azeotropic distillation at atmospheric pressure using isopropanol until the KF was less than <3%. After fresh isopropanol (25 ml) was added, the mixture was heated to 70° C. and then isopropyl acetate (45 ml) was added that resulting in a white slurry. The slurry cooled to 22° C. for 15 min to afford a white solid (9.33 g, 99%). 1H NMR (500 MHz CD3OD) δ 8.77 (d, J=5.7 Hz, 1H), 8.47 (d, J=7.9 Hz, 1H), 8.11 (dd, J=6.0, 8.2 Hz, 1H), 7.21-7.32 (m, 3H), 5.53 (dd, J=3.8, 9.8 Hz, 1H) 5.33 (d, J=9.8 Hz, 1H), 3.5 (bm, 1H), 2.25-2.40 (m, 2H), 2.15 (bm, 1H), 1.90 (bm, 1H); 13C NMR (125 MHz, MeOD) δ 159.4, 153.9, 151.9 and 151.8, 149.7, 143.6, 141.8, 135.7, 130.6, 127.7, 126.8, 118.9, 70.0, 54.9, 42.2, 34.5, 33.4.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]2[NH:5]1.I[CH3:29]>C1COCC1>[CH3:29][N:5]1[C@@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H]2NC(=O)c3c(cccc3C(F)(F)F)[C@@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(cccc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a suspension of NaH (9 mg of 60% in mineral oil, hexane-washed, 0.22 mmol) in 2 mL of THF at ambient temperature was added (3aS,9bR)-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 13, Part A (52 mg, 0.145 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodomethane (0.023 mL, 0.36 mmol) and the reaction was allowed to stir at ambient temperature for 18 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 3:1 hexane/EtOAc) to afford 40 mg (74%) of the title compound. LRMS (ESI): 371.12 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=3)=[N:9][N:10]=2)[N:7]=1.O1[CH2:23][CH2:22]OCC1>>[N:6]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=4)=[N:9][N:10]=3)[N:7]=2)[CH2:23][CH2:22][CH2:14][CH2:15][CH2:16][CH2:11][CH2:8]1
Reactant: Clc1cccc(-c2nnc3ccc(Cl)nn23)n1
Reactant: C1COCCO1
Product: Clc1cccc(-c2nnc3ccc(N4CCCCCCC4)nn23)n1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A mixture of 6-chloro-3-(6-chloropyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (620 mg), heptamethylenimine (1.32 g) and 1,4-dioxane (20 ml) was stirred at 100° C. for 9 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The extract was washed successively with 5% aqueous solution of citric acid, water, saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant crude crystal was recrystallized from ethanol, to obtain 6-azocan-1-yl -3-(6-chloropyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (370 mg) as grayish white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1>C(O)(C)C>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Temperature: 85 °C
Yield: 76 %

Procedure:
A mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.5 g, 9.06 mmol) and 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.2 g, 8.23 mmol) in isopropanol (30 mL) was heated at 85° C. for 15 h. After the reaction was finished, it was filtered and the solid was washed with isopropanol to afford 282a as a white solid (2.9 g, 80%).LCMS: (M+H)+ 463
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.C1(C2[O:23]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12]([CH3:13])=[O:23])[N:9]=[C:8]([NH2:14])[N:7]=1
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1cc(-c2ccco2)nc(N)n1
Reaction time: 16 h
Yield: 90.2 %

Procedure:
To a stirred suspension of 3.00 g (14.5 mmol) 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-yl-amine in 150 ml dichloromethane was added 7.56 g (29.0 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The resulting crystals were collected by filtration and washed with dichloromethane to afford 2.92 g (90%) 4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine as a white crystalline solid. EI-MS m/e (%): 223 (M+, 50), 177 (32), 160 (25), 148 (23), 118 (100), 90 (23), 63 (24).