Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[N:11]=[C:10](F)[C:9]([C:13](=[O:29])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=O.C[C:33](C)([O-:35])C.[K+]>CO.O>[NH2:5][C:6]1[N:11]=[C:10]([O:35][CH3:33])[C:9]([C:13](=[O:29])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc(N)ccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-{6-[(2,2-dimethylpropanoyl)amino]-2-fluoro-3-pyridinyl}-3-oxopropyl)-1-piperidinecarboxylate (step 2, 360 mg, 0.827 mmol) and potassium tert-butoxide (278 mg, 2.48 mmol) in methanol (8 ml) was refluxed for 1 h. After cooling to room temperature, the mixture was diluted with water (20 ml) and extracted with diethyl ether (100 ml×2). The combined organic layer was washed with water (50 ml) and brine (50 ml), and dried over magnesium sulfate. Removal of the solvent gave 300 mg (100%) of the title compound as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:25]([F:26])=[CH:24][C:19]2[N:20]=[C:21]([NH2:23])[S:22][C:18]=2[CH:17]=1.CCN(CC)CC.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1COCC1>C(C#N)(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:25]([F:26])=[CH:24][C:19]2[N:20]=[C:21]([NH:23][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:22][C:18]=2[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc4sc(N)nc4cc3F)c2cc1OC
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC(=O)C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc4sc(NC(=O)Cc5ccccc5)nc4cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (95 mg, 0.25 mmol), Et3N (0.10 ml, 0.72 mmol), phenylacetyl chloride (0.044 ml, 0.33 mmol), and THF (1.0 ml) were combined and stirred at room temperature for 1 hr. Additional phenylacetyl chloride (0.044 ml, 0.33 mmol) was added and the mixture heated to reflux for 1-2 hrs. After cooling to room temperature, the reaction mixture was diluted with 1:1 AcCN:H2O (1.0 ml) and the resulting solids filtered, washed with 1:1 AcCN:H2O and dried under high vacuum to give N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-phenyl-acetamide (72 mgs, 59%). 1H-NMR (400 MHz, DMSO): 12.80 (s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.91 (d, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.34 (m, 4H), 7.28 (m, 1H), 6.60 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.86 (s, 2H). LC/MS Calcd for [M+H]+ 490.1, found 490.0.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12]([O:17][CH3:18])=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[C:12]=2[O:17][CH3:18])=[N:22][CH:23]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)ccc2c1CCC(NCC(F)F)CC2
Yield: 32 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide to yield 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (33.59 mg, 32% yield) as a beige powder. 1H-NMR (CDCl3) δ 9.40 (s, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 6.82 (d, J=8.2 Hz, 1H) 5.83 (m, 1H), 3.73 (s, 3H), 3.23 (m, 1H), 3.02 (m, 2H), 2.83 (m, 2H), 2.73 (s, 3H), 2.67 (m, 1H), 2.49 (m, 1H), 2.09 (m, 2H), 1.30 (m, 2H). LC/MS (ESI+)=581 (M+H). MP=118° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol. (Intermediate FC) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113). MS (ES+) m/e 729.54 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[N:20]([C:21]2[N:22]([CH3:27])[N:23]=[C:24]([CH3:26])[CH:25]=2)[C:13]2[N:14]=[C:15](SC)[N:16]=[CH:17][C:12]=2[CH:11]=1)=[O:9].O[O:29][S:30]([O-:32])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:42]([O-])(O)=O.[Na+]>C1COCC1.O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[N:20]([C:21]2[N:22]([CH3:27])[N:23]=[C:24]([CH3:26])[CH:25]=2)[C:13]2[N:14]=[C:15]([S:30]([CH3:42])(=[O:32])=[O:29])[N:16]=[CH:17][C:12]=2[CH:11]=1)=[O:9]
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1ncc2cc(C(=O)c3ccccc3Cl)n(-c3cc(C)nn3C)c2n1
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-n2c(C(=O)c3ccccc3Cl)cc3cnc(S(C)(=O)=O)nc32)n(C)n1

Procedure:
To a solution of (2-chloro-phenyl)-[7-(2,5-dimethyl-2H-pyrazol-3-yl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 19, (0.13 g, 0.34 mmol) in THF:methanol (4 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (0.73 g, 1.19 mmol) in H2O (4 mL). After stirring the reaction for 1 hour at room temperature, the solution is poured into aqueous saturated NaHCO3. The aqueous phase is twice extracted with CHCl3 and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to afford 0.12 g of the desired product which is used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O-:9])=O)[C:2]=1[C:10]([O:12]C)=O.[NH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17]>CCO>[OH:17][CH2:16][CH:15]([NH:14][C:7]([C:3]1[C:2]([C:10]([NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[O:12])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9])[CH2:18][OH:19]
Reactant: NC(CO)CO
Reactant: COC(=O)c1nccnc1C(=O)[O-]
Solvent: CCO
Product: O=C(NC(CO)CO)c1nccnc1C(=O)NC(CO)CO
Yield: 62.4 %

Procedure:
Methyl pyrazine-2,3-dicarboxylate (2 g, 10.2 mmol) was dissolved in EtOH (5 mL). 2-Amino-1,3-propanediol (1.86 g, 20.4 mmol) was added and the mixture was heated under reflux for 4 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 8:2) to afford the title compound (2 g, 62.5%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[O:38][CH:39]([CH3:41])[CH3:40])/[C:31](=[N:33]/O)/[NH2:32]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([C:31]2[N:33]=[C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=3)[O:9][N:32]=2)[CH:35]=[CH:36][C:37]=1[O:38][CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: O=C(O)c1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CO)cc3)n2)cc1Cl
Temperature: 140 °C
Yield: 74.4 %

Procedure:
To a slurry of 4-(hydroxymethyl)benzoic acid (0.220 g, 1.443 mmol) in DMF (1.640 ml) was added EDC (0.277 g, 1.443 mmol) followed by HOBT hydrate (0.195 g, 1.443 mmol). After about 45 min. a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.300 g, 1.31 mmol) in DMF (1.640 ml) was added and the reaction mixture was heated to about 140° C. for about 2 h. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanol (0.336 g, 71%) as an off-white solid. LCMS (Table 1, Method c) Rt=2.80 min, m/z 345 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][C:12]([NH:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[I:20]N1C(=O)CCC1=O>C(#N)C>[I:20][C:16]1[S:17][CH:18]=[CH:19][C:15]=1[NH:14][C:12](=[O:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1cccc2ccccc12)Nc1ccsc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1I
Reaction time: 18 h

Procedure:
2-(naphthalen-1-yl)-N-(thiophen-3-yl)acetamide (7.50 g, 28.1 mmol) and N-iodosuccinimide (7.12 g, 31.6 mmol) in acetonitrile (100 ml) was placed into a preheated oil bath at 75° C. After stirring for 18 h, the solution was concentrated under reduced pressure. The residue was flash chromatographed with 99:1, 49:1, 24:1, and 23:2 methylene chloride:ethyl acetate as the eluant to yield impure N-(2-iodothiophen-3-yl)-2-(naphthalen-1-yl)acetamide. Method [1] Retention time 2.32 min by HPLC (MH+ 394).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cn1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-5-chloropyridine (Preparation is described in Example 85).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[NH2:31])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].O>CN(C)C(=O)C>[C:20]([C:19]1[CH:28]=[CH:29][C:30]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:17]([O:16][CH3:15])[CH:18]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(C(=O)c2ccccc2)ccc1N
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)c2ccccc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.52 g) in N,N-dimethylacetamide (5 mL) was rapidly added thionyl chloride (0.39 g) and the mixture stirred at -10 to -20° C. for 1 hour. 3-Methoxy-4-aminobenzophenone (0.50 g) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent methylene chloride then 2% ethyl ether in methylene chloride) gave the title compound (0.37 g) as an off-white solid; mp 126-128° C. Analysis for C18H16F3NO4.0.25 H2O: Calculated: C, 58.14; H, 4.47; N, 3.77; Found: C, 58.29; H, 4.48; N, 3.78.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=2)[N:11]=1.[OH-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of (S)-methyl 2-(benzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (100.0 mg, 0.39 mmol) in MeOH (20 mL) was added sodium hydroxide (49.2 mg, 1.23 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (20 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(benzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (50.9 mg, 53%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:10]([CH3:12])[N:11]=2)[N:8]=1)[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:16][S:13]([C:9]2[N:7]3[N:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]3=[N:11][C:10]=2[CH3:12])(=[O:14])=[O:15])=[O:29])[N:22]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCc1ccc2nc(C)c(S(N)(=O)=O)n2n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc2nc(C)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2n1
Temperature: 25 °C

Procedure:
As shown in the above reaction scheme, 6-ethyl-2-methylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.60 g, 2.50 mmol) and phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.76 g, 2.76 mmol) were suspended in acetonitrile (10 ml) and stirred under ice-cooling, during which DBU (0.46 g, 3.02 mmol) was added thereto. The temperature of the reaction solution was increased to room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was poured into ice-water (150 ml) and adjusted to pH 3 with conc. hydrochloric acid. The reaction mixture was stirred at room temperature for 5 minutes, and the precipitated crystals were washed with water, acetonitrile and diethyl ether in this order, and collected by filtration. The crystals were dried under reduced pressure to give the title compound as colorless crystals. The yield was 0.55 g (52%), and the melting point was 172 to 174° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[Br:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(C=C3CCNCC3)c2)nc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 8 h
Yield: 67 %

Procedure:
2-(3-Bromo-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (0.58 g, 1.4 mmol) and phenyl pyridin-3-ylcarbamate (0.3 g, 1.4 mmol) were dissolved in DMSO (3 mL). Triethylamine (0.59 mL, 4.21 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography (35% acetone in hexane) to give the title compound (0.5 g, 67%). 1H NMR (500 MHz, DMSO-d6): δ 8.44 (s, 2H), 8.25 (d, J=4.4 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.92 (d, J=10.45 Hz, 1H), 7.22 (m, 2H), 7.20 (s, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.93 (s, 1H), 6.83 (s, 1H), 6.34 (s, 1H), 3.60 (m, 2H), 3.52 (m, 2H), 2.56 (m, 2H), 2.44 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 165.16, 154.72, 153.51, 145.38, 143.81, 141.22, 140.33, 139.66, 136.99, 136.36, 128.85, 127.64, 123.63, 123.26, 122.83, 122.48, 120.73, 111.68, 45.59, 44.60, 35.71, 29.29, 29.17; m/z (533.2, 535.2, M+ H+); HPLC: 99.0%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:17][C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Oc1ccc2ccncc2c1
Solvent: CCO
Product: Oc1ccc2c(c1)CN(Cc1ccc(Cl)cc1)CC2
Reaction time: 8 h
Yield: 65.8 %

Procedure:
2.9 g of 7-hydroxyisoquinoline are heated under reflux for 8 hours with 3.5 g of 4-chlorobenzyl chloride in 30 ml of ethanol. After standing overnight, 5.7 g of the isoquinolinium salt crystallize out (melting point: 273°-274°). This salt is dissolved in 200 ml of methanol/water 9:1 and, with cooling, 6 g of sodium borohydride are added. After evolution of hydrogen has ended, the mixture is heated under reflux for 15 minutes. It is then concentrated to 1/3 of its volume, and this is poured into 200 ml of water, ammonium chloride is added to saturation, and the solid material which has precipitated out is filtered off. Recrystallization from ethanol gives 3.6 g of colorless crystals (67% of theory), melting point: 177°-178°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cncc(Br)c1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a 500 mL RBF containing 5-bromopyridin-3-amine (60.0 g, 347 mmol) was added diethyl 2-(ethoxymethylene)malonate (71.0 mL, 354 mmol) and 121 mL of toluene. The reaction mixture was heated to reflux for 3 h. The reaction mixture was allowed to cool RT overnight, and the resulting precipitate was collected by filtration and dried to give the desired product as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[N:14][C:8]=3[N:7]([CH2:15][O:16][CH3:17])[C:6]=2[CH:18]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[CH3:17][O:16][CH2:15][N:7]1[C:6]2[CH:18]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[S:10][C:9]2[N:11]=[CH:12][CH:13]=[N:14][C:8]1=2
Reactant: COCN1c2cc(N)ccc2Sc2nccnc21
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COCN1c2cc(NC(C)=O)ccc2Sc2nccnc21

Procedure:
200 mg of 8-amino-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was suspended in 10 ml of ethyl acetate. After adding 1 ml of acetic anhydride, the reaction mixture was subjected to ultrasonication. The crystals thus precipitated were filtered and washed with diethyl ether to thereby give 206 mg of the title compound as yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=[O:2].[CH3:21][Mg]Br.[NH4+].[Cl-]>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:10][N:11]=2)[N:8]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
In a 10 mL round bottom flask under N2 was dissolved tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (200 mg, 721 μmol) in 3 mL of THF then cooled at −78° C. and treated with methylmagnesium bromide (721 μl, 2164 μmol). After 30 minutes, the reaction mixture was warmed to 0° C. over 1 h. After 1 h the reaction mixture based on LC-MS was neutralized with NH4Cl (sat.). The aqueous phase was extracted 3× with DCM then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude tert-butyl (6-(1-hydroxyethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (202 mg, 95.5% yield) was used without further purification in the next step. MS m/z=294.4 [M+1]+. Calc'd for C13H19N5O3: 293.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:28]1([CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([N:14]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:21][CH:22]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)CCN(c1ccc(OCC2CCCCC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCN(c1ccc(OCC2CCCCC2)cc1)C1CCNCC1
Reaction time: 0.5 h

Procedure:
4-[(4-Cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (40e, 1.08 g, 2.36 mmol) was dissolved in CH2Cl2 (8 mL), treated with TFA (8 mL), and stirred for 30 minutes. The reaction was concentrated in vacuo, diluted with EtOAc (200 mL), washed three times with saturated bicarbonate solution and once with brine, dried over Na2SO4, and concentrated to give 0.78 (92%) of the desired product which was used without further purification.