Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[C:4]2[O:9][CH2:8][C@@H:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]3[CH:16]=[C:17]([C:32]([OH:34])=[O:33])[C:18](=[O:31])[C:19]([C:20]=1[NH:21]CC1C=CC(OC)=CC=1)=[C:5]23.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C:20]1[C:19]2[C:18](=[O:31])[C:17]([C:32]([OH:34])=[O:33])=[CH:16][N:6]3[C@H:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:2]=1[F:1]
Reactant: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@H](c2ccccc2)CO3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@H](c1ccccc1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of (R)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (366 mg, 0.614 mmol) in CH2Cl2 (10 mL) was added TFA (2.0 mL, 26.9 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The solution of the residue in DMSO (3 mL) was added water and 2M aq. NaOH to adjust pH=7. A precipitate formed and was collected by filtration. The cake was added EtOH (10 mL), and boiled on water-bath. A precipitate was collected by and then dried to give (R)-8-amino-9-fluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (124 mg, 42%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([SH:9])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:23]([Cl:24])=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=1[Cl:26].C(OCC)C>CN(C=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([S:9][CH2:17][C:18]2[C:19]([Cl:26])=[CH:20][CH:21]=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:4]=1
Reactant: Cc1ccnc(S)n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccnc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
4-methylpyrimidine-2-thiol hydrochloride (200 mg, 1.2 mmol) and potassium carbonate (357 mg, 2.6 mmol) was stirred for 30 minutes in anhydrous DMF (4 mL) at room temperature. Then, 2-(bromomethyl)-1,3,4-trichlorobenzene (345 mg, 1.3 mmol) in anhydrous DMF (1 mL) was added, and the mixture was stirred overnight at room temperature. The solid was removed by filtration and filtrate evaporation. The residue was dissolved in DCM and purified on silica gel using 5% DCM/MeOH to afford, after trituration with diethyl ether, 4-methyl-2-{[(2,3,6-trichlorophenyl)methyl]sulfanyl}pyrimidine as a white solid (88 mg, 22% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.44 (s, 3H), 4.75 (s, 2H), 6.09 (s, 1H), 7.17 (d, J=5.1 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H); LRMS (ES+) m/z 319 (100%, M+1), 321 (100%, M+3), 323 (35%, M+5).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)(O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N+:30]([O-:32])=[O:31])(=O)=O>>[CH3:29][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:23]([CH2:22][CH2:21][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[S:10][N:9]=3)[CH2:3][CH2:4]2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc(C)c2[N+](=O)[O-])cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: Cc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1[N+](=O)[O-]
Yield: 11 %

Procedure:
3-{4-[2-(3-Methyl-2-nitro-phenyl)-ethyl]-piperazin-1-yl}-1,2-benzisothiazole was prepared according to the general method as outlined in Preparation 2 starting with 3-piperazin-1-yl-benzoisothiazole hydrochloride (1.71 g, 6.7 mmol) and 3-methyl-2-nitrophenethyl tosylate (1.8 g, 5.37 mmol). The product was isolated via column chromatography to afford 290 mg of brown oil. Yield 11%; MS (APCI): 383 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][C:26](O)=[O:27])([OH:24])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][C:26]([NH:31][CH3:30])=[O:27])([OH:24])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 60 °C

Procedure:
To a solution of 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoic acid, 60d, (0.032 g, 0.076 mmol) in MeCN (1.6 mL) and DMF (1.6 mL) was added HATU (0.058 g, 0.152 mmol), Methanamine (0.154 mL of 2 M solution, 0.305 mmol) and iPr2NEt (0.053 mL, 0.305 mmol). The reaction was heated to 60° C. overnight then concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Water/HCl:MeOH). Pure fractions were combined and concentrated in vacuo to give 29 mg of 751 as the HCl salt.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][C:22](=[O:35])[NH:23][C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:25]=2[O:33][CH3:34])[C:11]1=[O:36])(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].CCOC(C)=O>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][C:22]([NH:23][C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:25]=2[O:33][CH3:34])=[O:35])[C:11]1=[O:36]
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCNC(=O)OC(C)(C)C)c(=O)c3ccccc32)cc1Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCN)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-{1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-ethyl)-carbamic acid tert-butyl ester (100 mg, 1.88 mmol) is taken up in DCM (2 ml) and treated with TFA (2 ml). The reaction is stirred at RT for 2 hours and then treated with EtOAc (20 ml). After 5 minutes, the white solid present is filtered, washed with EtOAc, ether and dried under vacuum to give the title compound as a white solid; [M+H]+ 433,
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[C:4]([N+:14]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>[Zn].C1COCC1.O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[C:4]([CH:3]=1)[NH2:14]
Reactant: CN(C)CCOc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1ccc(Br)cc1N
Reaction time: 4 h
Yield: 51.7 %

Procedure:
Zinc dust (4.52 g, 69.2 mmol) was added to a stirred solution of 2-(4-bromo-2-nitrophenoxy)-N,N-dimethylethanamine (4 g, 13.8 mmol), ammonium chloride (3.7 g, 69.2 mmol), THF/Water (40/40 mL) at RT. Reaction completed in 4 hours. The RM was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water, dried over sodium sulfate, concentrated to get the crude mass which was washed with hexanes to afford titled compound 1.85 g (51.67% yield) as solid. 1H NMR (DMSO-d6, 300 MHz): δ 6.74-6.70 (m, 2H), 6.59-6.56 (m, 1H), 4.99 (s, 2H), 3.97-3.93 (t, 2H), 2.59-2.56 (t, 2H), 2.18 (s, 6H). LCMS: m/z=260.8 (M+2).
Reaction SMILES: N1[CH2:5][CH2:4][CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([CH3:29])=O)=[CH:22][C:21]=1[Br:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:5]=[C:4]3[C:2](=[CH:3][CH:4]=[CH:5][CH:2]=[CH:3]3)[CH:29]=2)=[CH:22][C:21]=1[Br:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: C1CCNC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: Brc1cc(Cc2cc3cccccc-3c2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Pyrrolidine (1.9 ml) and magnesium sulfate (2.74 g) were added to a solution of 1-[4-(benzyloxy)-3-bromophenyl]acetone (3.65 g) in diethyl ether (30 ml) and the mixture was stirred at room temperature for 12 hours. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure and dissolved in ethanol (30 ml). 2H-cyclohepta[b]furan-2-on (0.5 g) was added to the solution and the mixture was refluxed with heating for eight hours. The reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 2-[4-(benzyloxy)-3-bromobenzyl]azulene (0.84 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[NH:14][C:13](=[O:23])[C@:12]([CH2:25][C:26]([O:28][CH3:29])=[O:27])([CH3:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C=O)C>[NH2:30][N:14]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C@@H:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH2:11][C@@:12]([CH2:25][C:26]([O:28][CH3:29])=[O:27])([CH3:24])[C:13]1=[O:23]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(N)C1=O
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A suspension of 60% sodium hydride in mineral oil (0.953 g, 23.82 mmol) was added to solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 429, step A, 4.84 g, 11.9 mmol) in DMF (25 mL). The resulting mixture was stirred for 15 min at 23° C. O-(2,4-dinitrophenyl)hydroxylamine (4.74 g, 23.82 mmol) was added at room temperature. The solution was stirred for 1 h at room temperature then quenched with MeOH (1 mL). Excess solvent was removed under reduced pressure and the residue was purified by chromatography on silica (eluent: 0 to 5% MeOH in DCM; stepwise gradient) to give the title compound.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OCC)C.[Br:18][C:19]([F:24])([F:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>O>[Br:18][C:19]([F:24])([F:23])[C:20]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:21]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)C(F)(F)Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)Br
Temperature: 0 °C
Yield: 95 %

Procedure:
A 200 mL, three-necked flask was charged with 4.76 g (31.8 mmol, 1.11 equivalents) of 1-adamantane methanol and 55 g of diethyl ether, followed by stirring to obtain a suspension. Then, 6.15 g (28.6 mmol, 1.0 equivalent) of bromodifluoroacetic chloride were added thereto. The resulting suspension was cooled down to 0° C. by using an iced bath, followed by adding 5.78 g (57.2 mmol, 2.0 equivalents) of triethylamine in a slow dropwise manner. This reaction liquid was allowed to stand with stirring to reach room temperature, followed by stirring at room temperature for 1 hour. Then, 50 g of water were added to wash the reaction liquid. The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence. Then, it was dried with magnesium sulfate, followed by distilling the solvent off, thereby obtaining 8.78 g of the target adamantane-1-ylmethyl bromodifluoroacetate (yield: 95%, purity: 100%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29](Br)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:30]=[C:31]([CH3:32])[C:26]([NH2:25])=[N:27][CH:28]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 2-amino-5-bromo-3-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (210 mg, 46%). MS (ISP) 444.3 [(M+H)+]; mp 194-195° C.
Reaction SMILES: C([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[S:9][C:8]=1[C:19](O)([CH3:21])[CH3:20])C=C.CC([O-])(C)C.[K+]>C1COCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[S:9][C:8]3[C:19]([CH3:20])([CH3:21])[O:23][C:5](=[O:4])[NH:6][C:7]=3[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C=CCOC(=O)Nc1cc(-c2cccc(Cl)c2)sc1C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2cc(-c3cccc(Cl)c3)sc21
Reaction time: 0.25 h

Procedure:
To a solution of [5-(3-Chloro-phenyl)-2-(1-hydroxy-1-methyl-ethyl)-thiophen-3-yl]-carbamic acid allyl ester (0.12 g, 0.34 mmol) in anhydrous THF (5.0 mL) was added KOtBu (0.076 g, 0.068 mmol) and stirred for 15 minutes, quenched with H2O, and in situ crystallization was carried out by adding minimal amount of MeOH to the solution. The white crystals were collected on a Büchner funnel, mp 123-125° C. 1H NMR (DMSO-d6) δ1.64(s, 6H), 7.05(s, 1H), 7.37-7.48(m, 2H), 7.53-7.56(s, 1H) 7.67-7.68 (m,1H), 10.41(s, 1H); MS(EI) m/z 293/295(M+H); Anal. Calc. For C17H18ClNO3S: C, 57.24; H, 4.12; N, 4.77. Found: C, 56.93; H, 3.92; N, 4.97.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][C:14]=1[F:23].C1COCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:14]=1[F:23]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)(C)O)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Yield: 20.8 %

Procedure:
The methyl 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylate prepared as described in Step 5 was treated with THF (8 mL), MeOH (8 mL) and 1.0 M aq. NaOH (8 mL, 8 mmol) at room temperature for 1 h. The volatile solvents were removed under reduced pressure. The residue was neutralized to pH around 6-7 with 1 M HCl. The precipitates were filtered, rinsed with water and dried to give the sub-title compound as a white solid (0.332 g, 20.8%). LCMS calc. for C15H13F3NO3 (M+H)+ m/z=312.1. found: 312.1.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:32]1[C:40]2[CH:39]=[C:38]([CH:41]=O)[N:37]=[CH:36][C:35]=2[O:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.CO.ClCCl>[ClH:1].[S:32]1[C:40]2[CH:39]=[C:38]([CH2:41][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:6][CH2:5]3)[N:37]=[CH:36][C:35]=2[O:34][CH2:33]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCS3)CC1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (165 mg, 0.441 mmol) in chloroform (10 ml) and methanol (0.4 ml) at room temperature under argon was treated with triethylamine (0.184 ml, 1.323 mmol) and stirred for 0.25 h (the suspension turned into a solution). [1,3]Oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144 Example 61) (73.7 mg, 0.441 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (280 mg, 1.323 mmol) was then added and the reaction was stirred at room temperature. After 1.5 h LCMS showed that there was still some imine present in the mixture so 1 eq of sodium triacetoxyborohydride was added. After 1 h saturated NaHCO3 (50 ml) was added followed by 20% methanol/dichloromethane (80 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/dichloromethane (2×80 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated to afford 215 mg of crude product which was purified by silica chromatography using a 0-20% methanol/dichloromethane gradient to afford the free base of the title compound as a yellow solid (185 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23]S[C:21]4[N:25]=[CH:26][C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:28][C:20]3=4)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O.OO.[OH:38][S:39]([O-:41])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][S:39](=[O:41])(=[O:38])[C:21]4[N:25]=[CH:26][C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:28][C:20]3=4)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CCSc2ncc(N3CCOCC3)cc21
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CCS(=O)(=O)c2ncc(N3CCOCC3)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine (40 mg, 0.084 mmol) in EtOAc (2.5 mL) was added disodium tungstate (24.8 mg, 0.084 mol) and water (0.3 mL). The reaction was cooled at 0° C. and then H2O2 (25.9 μL, 0.84 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (7 mg) was added followed by H2O2 (0.4 mL, 30%) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (15 mL). The separated organic layer was washed with brine (15 mL), dried over MgSO4, filtered and evaporated in vacuo to give 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.64-8.81 (1H, m), 7.87-7.95 (4H, m), 7.74 (1H, dd, J=9.1, 5.8 Hz), 7.36-7.45 (2H, m), 5.59 (1H, s), 4.21-4.26 (2H, m), 3.63-3.72 (6H, m), 2.88-3.01 (4H, m), 2.46 (3H, s). Mass Spectrum (ESI) m/e=506.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][CH:18]=[CH2:19])[CH:9]([CH2:14][CH:15]=[CH2:16])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>[OH:11][CH2:10][CH:9]([N:8]([CH2:17][CH:18]=[CH2:19])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCC(C(=O)OC)N(CC=C)C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCC(CO)N(CC=C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a mixture of methyl 2-[(tert-butoxycarbonyl)(prop-2-en-1-yl)amino]pent-4-enoate (5.0 g) produced above and tetrahydrofuran (100 mL) was added 1M diisobutylaluminum hydride/toluene solution (60 mL) at 0° C., and the mixture was stirred at the same temperature for 15 min. The reaction mixture was diluted with aqueous potassium sodium tartrate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.76 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(Cl)Cl.CO>C1COCC1.CN(C)C1C=CN=CC=1.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: NNc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)NNc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 4-fluorophenylhydrazine hydrochloride (2 g, 12.05 mmol) in THF (60 mL) is added DIPEA (6 mL, 34.40 mmol), ethyl chloroformate (1.2 mL, 12.55 mmol) and 4-dimethylaminopyridine (0.16 g, 1.31 mmol). The mixture is stirred at RT for 4 hours. The reaction is diluted with water and extracted with EtOAc, the organic phase is washed with saturated aqueous sodium chloride, dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel, eluting with DCM then DCM:MeOH (80:1) to afford the title compound (1.92 g, 80.5% yield). MS (m/z): 199 (M+H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH3:11]>CC(N(C)C)=O>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:21][CH2:22]1)[CH3:11]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(C#N)cn3)CC2)ccc1OC
Yield: 4 %

Procedure:
A solution of 6-chloro-nicotinonitrile (20.8 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (1.5 mL) was heated by microwave irradiation to 180° C. for 10 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.2 mg (4%) of the title compound. MS (ISP): 367.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[K])(C)(C)C.C(O)(=O)C(O)=O>CN(C)C=O>[C:19]([O:18][C:16]([CH2:15][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)O[K]
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c2ccccc2c2ccccc21
Yield: 46.9 %

Procedure:
100 g of carbazole, 117 g of t-butyl bromoacetate, and 67 g of t-butoxy potassium were dissolved in 1,000 g of dimethylformamide. The mixture was reacted overnight at room temperature. After the addition of 300 g of 5 wt % oxalic acid aqueous solution, the reaction mixture was extracted with 2,000 g of n-hexane. Precipitate obtained by crystallization in a mixed solvent of 500 g of dimethylformamide and 500 g of n-hexane was dried under vacuum to obtain 79 g of N-(t-butoxycarbonylmethyl)carbazole as a white solid. This compound is indicated as “other dye (D-2)”.