Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-piperidin-4-yl-morpholine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as an off white solid (50% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography to give 336 as an off white solid (21% yield). NMR (CDCl3, 400 MHz), 1.60-1.67 (2H, m),1.86 (2H, d, J=12.2), 2.14 (2H, t, J=10.6), 2.17-2.23 (1H, m), 2.57-2.59 (4H, m), 3.05 (2H, d, J=11.7), 3.73-3.75 (4H, m), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=497
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:60]1[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][C:61]=1[C:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:68]>C1(C)C=CC=CC=1>[Cl:66][C:63]1[CH:64]=[CH:65][C:60]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:61]([C:67]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)=[O:68])[CH:62]=1
Reactant: C1CNCCN1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1N1CCNCC1
Temperature: 110 °C

Procedure:
Piperazine (3.6 g, 42.5 mmol), Pd(II)acetate (0.007 g, 0.043 mmol), sodium t-butoxide (0.22 g, 2.4 mmol) and BINAP (0.042 g, 0.068 mmol) were stirred at room temperature in 10 mL dry toluene for 15 min. (2-Bromo-5-chloro-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol) in 10 mL dry toluene was then added into the reaction mixture. The reaction mixture was refluxed at 110° C. for 20 hrs, filtered through a celite bed, washed with toluene, concentrated, taken in ethyl acetate and extracted with 1.5 (N) HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (eluted with CHCl3-MeOH) afforded the title compound as product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:12][C:10]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:3][CH2:1][CH3:2])[N:11]=1
Reactant: COC(OC)N(C)C
Reactant: CCOc1nc(C)c([N+](=O)[O-])cc1C#N
Solvent: CN(C)C=O
Product: CCOc1nc(C=CN(C)C)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C

Procedure:
To a stirred solution of the compound prepared in Example 444 (0.86 g) in N,N-dimethylformamide (10 mL) at ambient temperature was added N,N-dimethylformamide dimethyl acetal (94%, 0.65 mL). The resulting solution was stirred and heated to reflux for 30 minutes. After cooling to ambient temperature, the solution was concentrated to provide the title compound (1.07 g) with the following physical data.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(C(F)(F)F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (79 mg, 80%), MS (ISP) m/z=397.4 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].CCN(CC)CC.[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: COc1ccccc1N
Reactant: O=C(Cl)c1ccccc1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a solution of 2-methoxyaniline 5 (2.46 g, 20 mmol) in dry CH2Cl2 (50 mL) was added Et3N (6.14 mL, 44 mmols) at 0° C. and under dry N2 atmosphere. A solution 2-iodobenzoyl chloride 2 (5.33 g, 20 mmol) in dry CH2Cl2 (25 mL) was slowly added to the reaction mixture keeping the temperature at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and stirred overnight. Reaction mixture was diluted with CH2Cl2 (100 mL), washed with H2O (40 mL) and saturated aqueous NaCl solution (40 mL), dried (Na2SO4) and evaporated to yield a light pink solid. Recrystallization from ethyl acetate-hexanes (1:3) provided 3 as white needles (5.7 g). The filtrate was concentrated and the residue was purified by flash chromatography on silica, eluting with 15% ethyl acetate (EtOAc) in hexanes, to provide additional pure product (1.25 g). Total yield: 6.95 g, 98%; 1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (br s, 1H), 7.92 (dd, J=8.0, 1.2 Hz, 1H), 7.52 (dd, J=7.6, 1.2 Hz, 1H), 7.43 (ddd, J=8.8, 7.6, 1.2 Hz, 1H), 7.17-7.09 (m, 2H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.10, 148.29, 142.58, 140.30, 131.49, 128.52, 128.43, 127.58, 124.45, 121.33, 120.12, 110.25, 92.70, 55.92; MS (ESI): m/z 376.20 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:12]([B:13]([OH:15])[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:21][N:20]=1.CC(O)CC>CCCCCC>[C:29]1([C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]([NH:1][C:2]3[CH:17]=[CH:16][C:5]([O:6][C:7]4[C:12]([B:13]([OH:15])[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)=[CH:4][CH:3]=3)=[N:20][N:21]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: Nc1ccc(Oc2ncccc2B(O)O)cc1
Solvent: CCC(C)O
Solvent: CCCCCC
Product: OB(O)c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
2-(4-Aminophenoxy)pyridin-3-ylboronic acid (478 mg, 2.08 mmol), 1-chloro-4-phenylphthalazine (500 mg, 2.08 mmol) and butan-2-ol (4.16 ml, 2.08 mmol) were placed in a sealed tube. The reaction vessel was sealed and the mixture heated to 100° C. After 1 h 45 min, the reaction was cooled to rt. Hexane was added and the precipitated tan solid was filtered off with hexanes. LCMS of the solids indicated product, 2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid. MS Calculated for C25H19BN4O: [M]+=434. Found: [M+1]+=435.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:22])[CH2:5][CH:6]([OH:21])[CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19].[C:23](=O)(O)[O-].[Na+]>CO>[OH:1][CH2:2][CH:3]=[C:4]([CH3:22])[CH2:5][CH:6]([O:21][CH3:23])[CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC(O)CC(C)=CCO
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C=C(C)C=CC1=C(C)CCCC1(C)C)CC(C)=CCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
1.52 g (5 mmol) of 1,5-dihydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8-nonatriene (I) was dissolved in 20 ml of methanol and the mixture was cooled to 0° C. To the mixture was then added 47.6 mg (0.25 mmol) of paratoluenesulfonic acid hydrate. After the mixture was stirred at 0° C. for 3 hours, a saturated aqueous sodium bicarbonate solution was added to the mixture and the resulting mixture was subjected to extraction with ether, followed by washing with a saturated brine. The resulting product was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain 1-hydroxy-5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene- 1-yl) -2,6,8-nonatriene (IV) as a mixture of E and Z isomers in a yield of 85%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:43][CH3:44])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:41][CH2:40][CH2:39][N:38]([CH3:42])[CH2:37][CH2:36]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][N:17](C2CCCCO2)[CH:18]=1)=[O:12])[CH3:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:10]([CH2:8][CH3:9])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:41][CH2:40][CH2:39][N:38]([CH3:42])[CH2:37][CH2:36]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][NH:17][CH:18]=1)=[O:12])[CH3:44]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCN(C)CC3)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCCN(C)CC3)cc2[nH]1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 39 mg of 1,1-diethyl-3-[3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl}urea in solution in 1 mL of dichloromethane. The reaction medium is stirred at 22° C. for 16 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-4 cartridge. The elution is carried out with pure dichloromethane and then with dichloromethane containing 5% of ammoniacal methanol. 12 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea trifluoroacetate salt are obtained in the form of a black resin. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.10 (t, J=7.0 Hz, 6H); 2.20 (broad m, 2H); 2.89 (s, 3H); from 3.07 to 3.68 (m, 8H); 3.34 (q, J=7.0 Hz, 4H); 7.22 (d, J=7.5 Hz, 1H); 7.55 (d, J=12.0 Hz, 1H); 7.96 (s, 1H). EI mass spectrum: m/z=428 M+., m/z=355 (M−C4H11N)+, m/z=69 CF3+ (relative to TFA), m/z=58 C3H8N+ (base peak), m/z=45 CO2H+ (relative to TFA).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:19]=[CH:18][C:16]([NH2:17])=[N:15][C:13]1=[O:14]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:17][C:16]1[CH:18]=[CH:19][NH:12][C:13](=[O:14])[N:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Over a period of about 1 h, benzyloxycarbonyl chloride (52 ml; 0.36 mol) was added dropwise to a suspension of cytosine (8, 20.0 g; 0.18 mol) in dry pyridine (1000 ml) at 0° C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 ml) and 4 N hydrochloric acid were added to reach pH ˜1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The still-wet precipitate was boiled with absolute ethanol (500 ml) for 10 min, cooled to 0° C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250° C. Anal. for C12H11N3O3. Found(calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
Reaction SMILES: N1([NH:7][C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.N[C:42]1[CH:51]=[C:50]2[C:45]([C:46]([CH3:53])=[CH:47][C:48](=[O:52])[O:49]2)=[CH:44][CH:43]=1>>[CH3:53][C:46]1[C:45]2[C:50](=[CH:51][C:42]([NH:7][C:8]([C:10]3[CH:40]=[CH:39][C:13]4[N:14]([CH:33]5[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]5)[C:15]([C:17]5[CH:18]=[C:19]6[C:24](=[CH:25][CH:26]=5)[N:23]=[C:22]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:21]=[N:20]6)=[N:16][C:12]=4[CH:11]=3)=[O:9])=[CH:43][CH:44]=2)[O:49][C:48](=[O:52])[CH:47]=1
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Product: Cc1cc(=O)oc2cc(NC(=O)c3ccc4c(c3)nc(-c3ccc5nc(-c6ccccc6)cnc5c3)n4C3CCCCC3)ccc12
Yield: 27 %

Procedure:
The general procedure described for Compound 574 was used with 7-Amino-4-methyl-chromen-2-one (17.5 mg), producing 8 mg of the title compound (27% yield). MS: 606.29 (M+H+) HPLC Procedure A, retention time=19.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:16])[C@@H:10]([N+:13]([O-])=O)[CH2:11][CH3:12])=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:13][C@@H:10]([CH2:11][CH3:12])[C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:16]
Reactant: CC[C@@H]([C@@H](O)c1ccc(OC)cc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](N)[C@@H](O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
A solution of (1S*,2S*)-1-(4-methoxyphenyl)-2-nitrobutan-1-ol (1.0 g, 4.44 mmol) in ethanol (20 mL) was purged with argon, and Pd/C (100 mg, 0.094 mmol) was added at room temperature. The sealed vessel was then purged and refilled with H2 and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered over celite, washed with ethanol and concentrated. The residue was purified by column chromatography using CH2Cl2/MeOH/(NH4OH in H2O) from 100:0:0 to 80:20:1 to yield the title compound as a white solid (450 mg, 51.4%). LC-MS: [M+H] 196.1; Rt 0.44 min; (LCMS method 2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(O)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(O)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-hydroxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1.O.[NH2:16][NH2:17]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:16][NH2:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CC=CCC2)c(Cl)nn1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(N2CC=CCC2)c(Cl)nn1
Yield: 88 %

Procedure:
A mixture of 3,6-dichloro-4-(3,6-dihydro-2H-pyridin-1-yl)pyridazine (1.7 g, 7.4 mmol) and hydrazine hydrate (2.2 ml) in dioxan was stirred and heated at reflux under nitrogen for 24 hours. Upon cooling the dioxan was removed in vacuo and the residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (×3). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with ether/MeOH and dried in vacuo to afford the title pyridazine (1.5 g, 88%). 1H NMR (250 MHz, d6-DMSO) 7.8 (1H, br s), 6.48 (1H, s), 5.76 (2H, m), 4.21 (2H, br s), 3.51 (2H, m), 3.24 (2H, m), 2.16 (2H, m). MS (ES+) 226 [MH]+, 228 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCc1ccccc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
Example 8 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and (2-isocyanatoethyl)benzene (18.9 μl) to give the title compound (0.0312 g). LC-MS (System A): Rt 2.29 mins, Mass Spectrum m/z 422 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:43](OC)(OC)(OC)[CH2:44][CH2:45][CH3:46].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:33][C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[C:16]=4[N:42]=[C:43]3[CH2:44][CH2:45][CH3:46])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 39.9 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), trimethyl orthobutyrate (2.4 g, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined and treated according to the method described in Part E of Example 18 with the modification that no additional trimethyl orthobutyrate was added. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (2.62 g) was obtained as a yellow solid.
Reaction SMILES: [F-].[K+].[O:3]=[S:4]1(=[O:38])[N:8](S(C2C=CC(C)=CC=2)(=O)=O)[C:7]2[CH:19]=[C:20]([CH2:23][N:24]([C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)[N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[CH:21]=[CH:22][C:6]=2[O:5]1>O.C(#N)C>[O:38]=[S:4]1(=[O:3])[NH:8][C:7]2[CH:19]=[C:20]([CH2:23][N:24]([C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)[N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[CH:21]=[CH:22][C:6]=2[O:5]1
Reactant: Cc1ccc(S(=O)(=O)N2c3cc(CN(c4ccc(C#N)cc4)n4ccnc4)ccc3OS2(=O)=O)cc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc3c(c2)NS(=O)(=O)O3)n2ccnc2)cc1
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Potassium fluoride (0.36 g, 6.14 mmol) in water (5 ml) was added to 4[N-[(2,2-dioxido-3-tosyl-3H-1,2,3-benzoxathiazol-5-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile (1.60 g, 3.07 mmol) in acetonitrile (15 ml) at room temperature. The solution was stirred overnight, concentrated, extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel (toluene/dioxane: 5/5) yielded an oil and crystallization from ethanol yielded the expected product (0.17 g, 15%, mp: 230° C.).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].Cl>N1C=CC=CC=1>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.36 g of 4-isopropylbenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization. Thereupon, the mixture was boiled with 0.5 g of active charcoal and the active charcoal and insoluble constituents were filtered off. Crystals separated upon cooling and, after recrystallization from 40 ml of 50% ethanol, yielded 0.17 g of 4-isopropyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as colourless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([S:19]([CH2:22][CH2:23]O)(=[O:21])=[O:20])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCO)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Temperature: 2.5 °C
Yield: 43.5 %

Procedure:
To a 0-5° C. stirred suspension of 2-[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidine-6-sulfonyl]-ethanol (41 mg, 0.1 mmol), and triethylamine (31 μL, 0.22 mmol) in dichloromethane (0.5 mL) under N2 was added dropwise methanesulfonyl chloride (9.3 μL, 0.12 mmol). Additional charges of methanesulfonyl chloride (9.3 μL, 9.3 μL) were added after 45 minutes, and 1.5 hours, the latter with additional triethylamine (50 μL). After reaction for a total of 2.5 hours, the cold solution was quenched with 5% aqueous sodium bicarbonate, then extracted with ethyl acetate (2×). The combined organic extracts were dried (MgSO4) then filtered through a pad of flash SiO2. The filtrate was concentrated to a solid that was crystallized from ethyl acetate to leave the product (17 mg, 44%), mp 214-217° C.