Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]([CH2:16]O)([CH2:14]O)[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:13][C:12]([CH3:16])([CH3:14])[CH2:11][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1cccc(Br)c1
Product: CC1(C)COB(c2cccc(Br)c2)OC1
Yield: 86 %

Procedure:
The title compound (86%, crystals) was prepared from 3-bromophenylboronic acid and neopentylglycol.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([S:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH2:3]1>CO.[Pd]>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([S:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH2:3]1
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)cc2)C[C@H](C)N1
Yield: 105 %

Procedure:
A solution of 298 mg (0.951 mmol) of cis-3,5-dimethyl-1-(4-nitro-phenylmethanesulfonyl)-piperazine (as prepared in the previous step) in MeOH (15 mL) was treated with 20 mg of 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% by weight water) and H2 (1 atm) at RT for 18 h. The mixture was filtered through Celite, and the filter cake was washed with MeOH. The solvent was removed in vacuo to afford 283 mg (100%) the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 7.14 (d, 2H, J=8.4 Hz), 6.66 (d, 2H, J=8.4 Hz), 4.08 (s, 2H), 3.75 (br s, 2H), 3.52-3.50 (m, 1H), 3.48 (s, 4H), 2.88-2.76 (m, 2H), 2.23-2.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][N:21]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[CH:22][N:21]=1)=[O:19]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Reactant: COC(=O)c1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)noc2C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.7 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (854 mg, 4.1 mmol) in THF (40 mL) was added 5-hydroxy-pyridine-2-carboxylic acid methyl ester (691 mg, 4.5 mmol) and triphenylphosphine (1.61 g, 6.1 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (2.82 mL, 40% solution in toluene, 6.0 mmol) was added and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was evaporated and then purified by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) to afford the title compound (1.53 g, 76%) as an off white solid. MS: m/e=344.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([C:8]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[O:10])[CH:11]=1
Reactant: COc1cc(C(=O)O)c(C)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCOCC2)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0 g, 9.47 mmol) in DCM (50 mL) was added DIPEA (8.3 mL, 47 mmol) and HATU (3.96 g, 10.4 mmol) followed by morpholine (0.83 mL, 9.47 mmol). The mixture was allowed to stir at RT for 5 h and then water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (3×25 mL) and the combined organic phases were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (2.5 g, 94%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=281 at 3.17 min. 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 6.90 (s, 1H), 3.94 (s, 3H), 3.85-3.76 (m, 4H), 3.61 (dd, 2H), 3.23 (dd, 2H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:12][CH2:11][C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=[C:2]([Cl:1])[CH:10]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CO)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(COS(C)(=O)=O)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methanol (2.5 g, 8 mmol) and triethylamine (3.34 mL, 24 mmol) in dichloromethane (120 mL) at 0° C. was added methanesulfonyl chloride (1.25 mL, 16 mmol). The reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of water, stirred 5 min, and poured into water. The layers were separated and the organics washed with brine, dried over magnesium sulfate, and concentrated to give 3.25 g (quant.). 1H-NMR (CDCl3, 500 MHz) δ 8.09 (s, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 5.68 (s, 2H), 5.59 (s, 2H), 3.60 (t, J=8.2 Hz, 2H), 3.06 (s, 3H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 145.4, 127.5, 127.4, 125.0, 123.0, 122.8, 120.5, 82.1, 67.8, 67.4, 38.0, 17.9, −1.4. Mass spec.: 391.14 (MH)+.
Reaction SMILES: C(OC([C:6]1[N:15]([C@H:16]([CH3:26])[CH2:17][NH:18][C:19](OC(C)(C)C)=[O:20])[C:9]2=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.C(OCC)(=O)C>[Cl:14][C:11]1[N:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[CH:7]=[C:6]1[N:15]2[C@H:16]([CH3:26])[CH2:17][NH:18][C:19]1=[O:20]
Reactant: CCOC(=O)c1cc2ccc(Cl)nc2n1[C@H](C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC(=O)c2cc3ccc(Cl)nc3n21
Reaction time: 2.5 h

Procedure:
A solution of 6.70 g (17.5 mmol) (R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 80 ml dichloromethane was cooled to 0 deg C. and 27 ml (0.35 mol) trifluoroacetic acid were added over 4 min. The cooling bath was removed and after 1 h the volatile components were removed on a rotary evaporator. The residue was dissolved in 40 ml methanol and 9.70 g (70.2 mmol) potassium carbonate was added. After stirring for 2.5 h the reaction mixture was diluted with water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. After evaporation, the residue was taken up in 50 ml tert-butyl methyl ether upon which the product started to precipitate. The solid was collected by filtration, washed with 20 ml of tert-butyl methyl ether and dried under high vacuum to afford the product as a pale yellow powder. The concentrated mother liquors were purified by flash chromatography over silica gel (0.032–0.063 mm) with ethyl acetate as eluant to yield another batch of product (86.6% total).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([CH3:16])=C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:20]CC1>O.CCOC(C)=O.O=[Os](=O)(=O)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](=[O:20])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CC1CCN(Cc2ccccc2)C1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CC1CCN(Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
To a rapidly stirred solution of 1-4 (7.0 g, 33 mmol) in THF (200 mL) and H2O (150 mL) was added NaIO4 (21 g, 100 mmol) followed by addition of OsO4 (10 mL; 2.5% solution). After 16 hrs, an additional amount of OsO4 (10 mL) was added, and the reaction was stirred for 6 hrs. The reaction was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 1-5 as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH:11]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:12]([OH:14])=O.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:19]1(=[O:20])[N:15]([CH:11]2[CH2:10][CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:12]2=[O:14])[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]12
Reactant: Nc1ccccc1CCCC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2CCCC1N1C(=O)c2ccccc2C1=O

Procedure:
A solution of 5-(2-aminophenyl)-2-phthalimidopentanoic acid (3.5 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.9 g) in dimethylformamide (85 ml) is stirred at room temperature under a nitrogen atmosphere for 65 hours. The solvent is removed under high vacuum and the residue distributed between ethyl acetate (250 ml) and water (150 ml). The organic phase is washed with 2N sodium hydroxide (100 ml) and water (100 ml), and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue recrystallized from methanol/ethyl acetate to give 3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one, mp 229°-230° C., used without further purification in the next synthetic step.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37](O)=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)O)ccc32)cc1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCCc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)Nc4ccccc4OCCCC(=O)O)ccc32)cc1

Procedure:
224 mg of compound 36 was obtained in a similar manner to those described in the Examples 1 and 2 using 513 mg of ethyl 4-(2-aminophenoxy)butyrate and 400 mg of 3-[1-(4-butylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[C:23]#[N:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[C:23]#[N:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C#N)CC1
Reaction time: 3 h

Procedure:
4-(2-Cyano-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (587 mg, 1.77 mmol) was dissolved in methanol (50 mL) and to this solution was added ammonium chloride (945 mg, 17.66 mmol) and zinc (1155 mg, 17.66 mmol). The mixture was magnetically stirred for 3 hr and the mixture was filtered through a pad of celite. The solids were rinsed with methanol and the combined filtrate was concentrated to a yellow solid. This crude intermediate was dissolved in ethyl acetate (400 mL) and the resulting solution was washed with water (400 mL) and brine (200 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to give 4-(4-amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:1][CH2:2][C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:20][CH:21]=1)([CH3:5])[CH3:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(CN)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Product: CC(C)(CNCc1ccccc1)c1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Using a method similar to example 35, using 6-[4-(2-amino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide (example 193), and benzaldehyde affords the title compound: HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 6.01 minutes, Purity: 95.6%; mass spectrum (ion spray): m/z=376.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](Br)[CH:8]=1.[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[F:10])[N:18]([CH3:21])[C:17](=[O:22])[CH2:16][CH2:15]3)[CH:6]=[N:5][CH:4]=1
Reactant: NCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Product: CN1C(=O)CCc2cc(-c3cncc(CN)c3)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of example 45, reaction of 3-aminomethyl-5-bromopyridine and 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22) gave the title compound as a light yellow solid. MS: 286.7 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2.Br[C:30](Br)([CH2:33][CH3:34])[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH:8]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)=[CH:18][CH:17]=2)=[O:15])[CH2:7][CH2:6]3)[CH2:34][CH2:33][CH2:30][CH2:31][CH2:32]1
Reactant: CCC(Br)(Br)CC
Reactant: NCc1ccc2c(c1)CCC(NC(=O)c1ccc(-c3ccc(F)cc3)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CCc2cc(CN3CCCCC3)ccc2C1)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
A mixture of 4′-fluoro-biphenyl-4-carboxylic acid (6-aminomethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, 4, (0.054 g, 0.14), dibromopentane (0.022 mL, 0.16 mmol) and K2CO3 (0.099 g, 0.72 mmol) in DMF (2 mL) is stirred at room temperature for 18 hours. The reaction solution is filtered and the filtrate concentrated in vacuo to leave a crude residue which is purified by reversed prep-HPLC using CH3CN—H2O (0.1% TFA) to afforded 36 mg (57% yield) of the desired product as a foaming solid. 1H NMR (300 MHz, CD3OD) δ 7.94 (d, J=8.4 Hz, 2H), 7.72 (m, 4H), 7.25 (t, J=9.6 Hz, 5H), 4.33 (m, 1H), 4.24 (s, 2H), 3.44-3.56 (m, 3H), 3.16-3.24 (br, 1H), 2.84-3.07 (m, 4H), 2.20-2.35 (br, 1H), 1.67-2.02 (m, 6H), 1.54 (m, H1); 13C NMR (75 MHz, CD3OD) δ 168.4, 164.8, 143.4, 137.4, 137.0, 130.9, 131.5, 130.0, 128.9, 128.8, 128.5, 127.9, 126.8, 115.8, 115.5, 60.5, 52.7, 46.6, 35.0, 28.9, 28.3, 22.9, 21.6; 19F NMR (282 MHz, CD3OD) δ 46.3; LRMS: 443.6 (M+H); HRMS: calcd for C29H32FN2O: 443.2499 (M+H), found: 443.2506.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[CH:25]([CH:36]([CH3:38])[CH3:37])[CH2:26][N:27](C)[C:28](=O)OC(C)(C)C.[ClH:39]>CCOCC>[ClH:39].[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[CH:25]([CH:36]([CH3:38])[CH3:37])[CH2:26][NH:27][CH3:28]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CN(C)C(=O)OC(C)(C)C)C(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Product: CNCC(c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1F)C(C)C
Yield: 70 %

Procedure:
Following General Procedure D1, tert-butyl 2-(2-fluoro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)-3-methylbutyl(methyl)carbamate (100 mg, 0.18 mmol) was reacted with HCl in ether (6 mL) to afford the desired product (55 mg, 70%) as an off-white solid: ESI MS m/z 439 [C25H27FN2O2S+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c(C)c1

Procedure:
201.6 mg of the target compound (0.57 mmol, 69.0%) was obtained using 1-(2,4-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[CH2:16]([N:23]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27](Br)[CH:28]=[CH:29][CH:30]=2)[CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:35]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:28]=[CH:29][CH:30]=2)[CH2:25]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Product: Cn1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 96 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 96% yield, starting from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole and (2R)-N,N-dibenzyl-8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine: MS (ESI) m/z 408[M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C[CH2:10][N:11](CC)CC.CN>C1COCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:11][CH3:10])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Clc1cc(Cl)ncn1
Agent: CN
Solvent: C1CCOC1
Product: CNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-bath cooled solution of 4,6-dichloropyrimidine (3 g, 20 mmol) in THF (5 mL), NEt3 (5.6 mL, 40 mmol) was added followed by slow addition of N-methylamine (2 M in THF, 10 mL, 20 mmol). The mixture was warmed to RT and stirred overnight. The mixture was concentrated in-vacuo, the residue suspended in Et2O and solid collected to give the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:27]=[CH:26][N:25]([CH2:2][CH2:3][CH:4]3[C:9](=[O:10])[NH:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[S:5]3)[CH:24]=[CH:23]2)=[CH:20][CH:21]=1
Reactant: O=C1Nc2ccccc2SC1CCBr
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2SC1CCN1C=CN(c2ccc(F)cc2)C=C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In 20 ml of ethyl acetate were dissolved 1.36 g of 2-(2-bromoethyl)-2H-1,4-benzothiazin-3(4H)-one and 1.8 g of 1-(4-fluorophenyl)piperazine. The solvent was evaporated off, and the residue was stirred at 110° C. for one hour. The reaction product was extracted with ethyl acetate, and the extract was washed with water and dried over MgSO4. The crystals obtained by evaporation of the solvent were recrystallized from methanol to give 2-[2-[4-(4-fluorophenyl)-1-pyrazinyl]ethyl]-2H-1,4-benzothiazin-3(4H)-one as prisms, m.p. 158°-159° C. The yield was 0.94 g (50.5%).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:19]O>>[CH3:19][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1
Reactant: NC(CCCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)CCCc1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of Compound 4 (7.1 g, 29.8 mmol) in MeOH (120 mL) at 0-5° C. was saturated with HCl (g) for 2 h, at which time the mixture was allowed to ambient temperature and then was stirred for 24 h. The resulting mixture was concentrated in vacuo to provide technically pure product 5 (7.4 g, 98%) as an acidic salt. 1H NMR (D2O, 300 MHz) δ 1.50-1.93 (m, 4H), 2.67 (t, J=7.1 Hz, 2H), 3.68 (s, 3H), 4.03 (t, J=5.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 8.03 (d, 2H, J=8.2 Hz, 2H); 13C NMR (D2O, 300 MHz) δ 25.50, 29.26, 34.16, 52.66, 53.50, 123.30, 129.18, 145.50, 149.96, 170.37.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH3:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)(=[O:16])=[O:15]>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:21]3[CH:22]=[C:17]([S:14]([NH:13][CH3:12])(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=3)[C:6]=2[N:7]=1
Reactant: CNS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1ncc2scc(Br)c2n1
Product: CNS(=O)(=O)c1cccc(-c2csc3cnc(N)nc23)c1
Yield: 64.6 %

Procedure:
3-(2-Aminothieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (180 mg, 64% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromothieno[3,2-d]pyrimidin-2-amine (200 mg, 0.87 mmol) and N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (260 mg, 0.87 mmol).