Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C@@H:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:17]=1.CCN(CC)CC.[CH3:38][C:39](OC(C)=O)=[O:40]>C(Cl)Cl>[C:39]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][N:19]=2)[C:15]([NH:14][CH2:13][C@H:12]([OH:30])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:29])[CH2:24][CH2:25]1)(=[O:40])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccnc(NC2CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccn2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (S)—N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(piperidin-4-ylamino)isonicotinamide (70 g), and Et3N (40 g) in DCM (2000 mL) was added Ac2O (17 g) dropwise over 1 h at 0° C. After addition, the mixture was warmed to 20° C. and stirring was continued for another 1 h, at which time TLC showed the reaction was completed. The reaction mixture was washed with water (500 mL), and the organic phase dried and concentrated. The residue was then purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give crude product. Five batches were run in parallel and produced a combined crude product weight of 400 g. This crude was further purified by preparative HPLC to give the pure product (310 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 7.94-7.92 (d, 7.0 Hz, 1H), 7.14-7.05 (m, 4H), 6.87 (s, 1H), 6.76-6.74 (m, 1H), 4.44 (m, 1H), 4.10 (m, 1H), 3.96-3.94 (m, 2H), 3.75 (s, 2H), 3.52 (m, 2H), 3.33-3.32 (m, 1H), 2.92-2.86 (m, 5H), 2.67 (m, 2H), 2.13-2.00 (m, 5H), 1.44-1.37 (m, 2H); LCMS (m/z): 452.3 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][N:46]=[C:47]2[NH2:52]>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:52][C:47]1[C:48]2[C:43](=[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)[CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:45][N:46]=1
Reactant: Nc1nccc2c(Br)cccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccc4c(N)nccc34)nc21
Temperature: 140 °C
Yield: 18.2 %

Procedure:
To a degassed mixture of 2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (256 mg, 0.386 mmol), 5-bromoisoquinolin-1-amine (86 mg, 0.386 mmol), copper(I) thiophene-2-carboxylate (74 mg, 0.386 mmol) in 1,4-dioxane (4 mL) was added Pd(PPh3)4 (45 mg, 0.039 mmol). The reaction mixture was heated in the microwave at 140° C. for 35 minutes. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was first washed with MeOH. The product was eluted with 2 M NH3 in MeOH and concentrated. The crude was further purified by RP-HPLC to give 147 (36.3 mg, 18.2%). LCMS: M+H+=517.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.28 (d, 1H), 8.11 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.53 (t, 1H), 6.80 (s, 2H), 4.23 (s, br, 4H), 4.09 (s, 1H), 3.81 (s, 3H), 3.73 (m, 6H), 2.90 (m, 2H), 2.02 (m, 2H), 1.66 (m, 2H), 1.19 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2].[CH3:23][NH:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27]>ClCCl.O1CCCC1>[CH2:1]([O:3][P:4]([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])([CH2:14][CH:15]([C:16](=[O:18])[NH:27][C@H:26]([C:25](=[O:32])[NH:24][CH3:23])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)CNC1=O
Reactant: CNC(=O)[C@@H](N)CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CNC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
0.22 g (0.64 mmol) of 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1-imidazolidinyl)methyl]phosphinyl]methyl]-4-methylvaleric acid and 0.116 g (0.81 mmol) of L-leucine methylamide were taken up in 5 ml of dichloromethane and 2.5 ml of tetrahydrofuran. The solution was treated at -8° C. with 0.3 g (1.2 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline. The mixture was stirred at room temperature for 24 hours and was then left to stand at 0° C. for 48 hours. The solvent was removed by evaporation. The residue was taken up in 50 ml of chloroform. The solution was washed in sequence with 5% citric acid solution, 5% sodium hydrogen carbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a gum. This gum was chromatographed on silica gel using chloroform/methanol (19:1) for the elution to give 0.08 g of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester as a gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[N:13]=1>O.C(#N)C>[O:22]([C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)=[N:13]2)=[CH:18][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 51.7 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3-bromobenzoic acid (6 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (5.9 g). The product obtained by precipitation in water (9.8 g; m.p. 188°-192° C.) is dissolved in acetonitrile (300 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-bromobenzamide (5.4 g), m.p. 194° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CCN(CC)CC.Cl.CN>CN(C)C=O>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2C)n1C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a stirred solution of 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (600.0 mg, 1.36 mmol) in dimethylformamide (10 mL) were added HBTU (O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) (772.74 mg, 2.04 mmol) and triethylamine Et3N (0.942 mL, 6.78 mmol). The mixture was stirred for 30 min., then methylamine hydrochloride salt (274.88 mg, 4.07 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with ice cold water and then extracted with ethyl acetate. Then combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-02) (140.0 mg, 22.64%) as an off white solid.
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][P:38](=[N:40][C@@H:41]([CH3:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:39].CO>C1COCC1>[CH:45]([O:44][C:42](=[O:43])[C@@H:41]([N:40]=[P:38]([O:37][C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:39])[CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(Cl)ccc2ccccc12
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Agent: CC(C)(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(OC[C@@]2(F)O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 539 μmol) prepared in Preparation 6 in THF (24 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (1.35 mL, 1.35 mmol) dropwise. The mixture was stirred at room temperature for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate (2.7 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for 1 h, then additional THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.68 mL, 0.68 mmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate (1.35 mL, 0.68 mmol) were added. The reaction mixture was then stirred at room temperature for 3 h. Methanol (6 mL) was added to quench the reaction. The mixture was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (0.2 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)([O-:22])=[O:21]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1nc(-c2ccccc2)cs1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 2-amino-4-phenylthiazole (12.5 g, 80.9 mmol), 1-fluoro-2-nitrobenzene (12.5 g, 89.0 mmol), potassium carbonate (13.4 g, 97.1 mmol) was stirred at 150° C. for 24 h. Water (100 ml) was added and the mixture was extracted twice with 1,2-dichloroethane (50 ml). The crude extract was purified by chromatography on silica gel using toluene as eluent. The product was isolated as the free base. Yield 7.95 g, 33%. M.p. 114-116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(O)(=O)C.C([BH3-])#N.[Na+].[CH3:36][C:37]1[N:42]=[C:41]([CH:43]=O)[CH:40]=[CH:39][CH:38]=1>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][CH2:43][C:41]6[CH:40]=[CH:39][CH:38]=[C:37]([CH3:36])[N:42]=6)=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: Cc1cccc(C=O)n1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(CNC2=c3ccc4c5c([nH]c(=O)c-5c3N(C)C=C2)=CCN4c2ccc(F)cc2)n1
Yield: 43.5 %

Procedure:
A stock solution of Example 23e (0.164 M in N,N-dimethylacetamide, 255 mL, 0.042 mmol), acetic acid (4 M in methanol, 200 mL, 0.84 mmol), sodium cyanoborohydride (0.31 M in methanol, 200 mL, 0.063 mmol) and 6-methylpicolinaldehyde (0.40 M in N,N-dimethylacetamide, 156 mL, 0.063 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 50° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0085 g (44%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 10.85 (s, 1H), 8.41 (d, J=1.83 Hz, 1H), 7.96 (s, 1H), 7.81 (dd, J=8.24, 1.83 Hz, 1H), 7.38 (m, 2H), 7.04 (s, 1H), 6.87 (m, J=9.00, 9.00 Hz, 3H), 6.58 (m, 3H), 4.58 (m, 2H), 4.06 (s, 3H), 3.90 (s, 3H), 3.17 (s, 2H). MS (APCI+) m/z 466.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>CC(N(C)C)=O>[F:16][C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([N:1]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:7][CH2:6]2)=[N:11][C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]([F:27])([F:28])[F:29])=[N:13][CH:14]=1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2F)CC1
Reactant: BrCCCCBr
Solvent: CC(=O)N(C)C
Product: Fc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 100 °C

Procedure:
N4-[(trans-4-aminocyclohexyl)methyl]-5-fluoro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (71 mg, 0.17 mmol) was dissolved in DMA (2 mL). To this solution was added 1,4-dibromobutane (81 μL, 0.68 mmol) and NaCO3 (72 mg, 0.68 mmol). The reaction was heated in the microwave at 100° C. for 20 min. The volatiles were removed and the reaction was diluted with EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude product was purified by twice running on a 1000 micron SiO2 Prep TLC plate, eluting with 10:1 CH2Cl2:MeOH (1% NH4OH) to afford 36 mg (45%) of the title compound, m/z 468.6 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][OH:26])[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:1]([N:8]([CH3:27])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 31.8 %

Procedure:
To a solution of 9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid benzyl-methyl-amide (28) (36 mg, 0.1 mmol) in dichloromethane (2 mL) was added pyridine (7.91 g, 1.0 mmol, 8.1 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (57 mg, 0.5 mmol, 0.04 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×10 mL) and water (2×10 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (20-80% B, 4 g, 45 CV, 18 mL/min) to afford 14 mg (32%) of methanesulfonic acid 2-[4-(benzyl-methyl-carbamoyl)-1,2,3,4-tetrahydro-carbazol-9-yl]-ethyl ester as a yellow oil. The structure was confirmed by 1H NMR (CDCl3) δH 1.10-2.40 (5H, m), 2.51 (1.5H, s, OSO2CH3), 2.54 (1.5H, s, OSO2CH3), 2.70-2.90 (2H, m), 3.08 (1.5H, s, NCH3), 3.15 (1.5H, s, NCH3), 3.40-3.70 (1H, m), 4.10-4.80 (4H, m), 7.00-7.50 (9H, m).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(OCCN3CCOCC3)cc12
Yield: 15 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.359 g, 0.760 mmol) and morpholine (1.0 mL, 11 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5% methanol in chloroform. After drying in vacuo at 57° C. for 20 minutes, 3-benzenesulfonyl-5-(2-morpholin-4-yl-ethoxy)-1H-indazole as an off-white foam (0.0443 g, 15.1%) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75° C. for 16.5 hours to yield the hydrochloride as a light orange foam (0.0411 g). Mass Spectrum (+EI, [M+H]+) m/z 388. 1HNMR (300 MHz, DMSO-d6): δ14.31 (s, 1H), 10.82-88 (br, 1H), 8.03-8.07 (m, 2H), 7.62-7.76 (m, 4H), 7.49 (d, 1H, J=2.10 Hz), 7.26 (dd, 1H, J=9.14 Hz and 2.28 Hz), 4.54 (s, 2H), 4.02 (d, 2H, J=11.71 Hz), 3.80-3.87 (m, 2H), 3.51-3.73 (m, 4H), 3.19-3.31 ppm (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[CH3:16][O:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:20]
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 43 %

Procedure:
6.0 g (29.8 millimoles) of 2-(p-aminophenyl)- 3,4-diazabicyclo[4.1.0]hept-2-en-5-one and 3.9 g (35.9 millimoles) of methoxyacetyl chloride in 150 ml of absolute tetrahydrofuran were refluxed for 4 hours, while stirring. The product was filtered off under suction at 10° C., washed first with tetrahydrofuran and then with water and recrystallized from propanol. 3.5 g (43%) of 2-[p-(methoxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one were obtained as colorless crystals. Mp.: 206° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[N+](CC)([O-])=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (2.3 g, 13 mmol) in nitroethane (20 mL) was added aluminum chloride (3.5 g, 26 mmol) followed by fluorobenzene (1.2 mL, 13 mmol). The mixture was stirred at rt for 4 h, then quenched carefully with 6M HCl. The reaction mixture was washed with dilute aqueous NaOH and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the crude product as a light yellow solid. The solid was purified by recrystallization from hexanes to give (4-fluoro-phenyl)-(4-nitrophenyl)-methanone (2.0 g, 65%). 1H NMR (CHCl3-d) δ 8.41-8.32 (m, 5H), 7.90 (m, 1H), 7.84 (m, 1H), 7.20 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.C(N(CC)CC)C>C(O)CCC>[S:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:2][CH2:3]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCSCC2)nc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a round bottom flask was added thiomorpholine 8-1 (3.6 g, 34.8 mmol), 6-chloronicotinonitrile 8-2 (4.0 g, 29 mmol), triethylamine (8 mL, 58 mmol) and butanol (10 mL). The reaction was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction formed a solid cake. The cake was triturated in 50 mL H2O at 100° C. After cooling, the solid was collected by filtration to give 6-thiomorpholinonicotinonitrile 8-3 as an off-white solid. MS m/z 206.1 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:29])[N:11]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[N:12]([CH2:15][C:16]#[N:17])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[CH2:1]([N:5]1[C:9]2[C:10](=[O:29])[N:11]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[N:12]([CH2:15][C:16]#[N:17])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[N:47]1[CH2:48][CH2:49][CH2:50][C@@H:45]([NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:46]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(Cl)nc2c(=O)n(CC#N)n(Cc3ccc4ccccc4n3)c(=O)c21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(CC#N)n(Cc3ccc4ccccc4n3)c(=O)c21

Procedure:
A solution of 0.14 g 1-(but-2-ynyl)-2-chloro-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, 0.15 g potassium carbonate and 0.07 g (R)-3-tert-butoxycarbonylaminopiperidine in 2 ml dimethylsulphoxide is stirred for 5 h at 60° C. Then water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and then the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1).