Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH2:8])([O-:4])=[O:3].[CH3:13][C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>CO>[CH:14]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[N+:2]([O-:4])=[O:3])([CH3:16])[CH3:13]
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-nitrobenzylamine hydrochloride (500 mg, 2.65 mmol) and acetone (0.39 ml, 5.30 mmol) in methanol (13 ml) was added sodium cyanoborohydride (500 mg, 7.95 mmol) at 0° C. The temperature was warm up to room temperature. After stirring for 3 hr, the mixture was concentrated in vacuo and extracted with dichloromethane. The combined organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give N-isopropyl-2-nitrobenzylamine as yellow oil. This compound was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]2[C:28]=1[N:27]1[C:29]([CH3:32])=[N:30][N:31]=[C:26]1[CH2:25][CH2:24]2>COCCOC.O>[CH:8]1([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[C:21]2[CH:22]=[C:23]3[C:28](=[C:19]([F:18])[CH:20]=2)[N:27]2[C:29]([CH3:32])=[N:30][N:31]=[C:26]2[CH2:25][CH2:24]3)[CH2:10][CH2:9]1
Reactant: Cc1nnc2n1-c1c(F)cc(B(O)O)cc1CC2
Reactant: Fc1cncc(Br)c1C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc2n1-c1c(F)cc(-c3cncc(F)c3C3CC3)cc1CC2
Temperature: 25 °C

Procedure:
3-Bromo-4-cyclopropyl-5-fluoropyridine (462 mg, 2.14 mmol) was dissolved in a mixture of DME (3.55 mL) and water (3.55 mL). Sodium carbonate (226 mg, 2.14 mmol), (9-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)boronic acid (1-6, 176 mg, 0.71 mmol) and tetrakis triphenylphosphine palladium catalyst (4.11 mg, 3.6 mop were added. The mixture was deoxygenated under reduced pressure, flushed with nitrogen and heated under reflux for 18 h. After cooling to room temperature, ethyl acetate (10 mL) and water (10 mL) were added and the organic layer was separated. The water phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered over a short plug of Celite® and evaporated under reduced pressure. The crude compound was purified using preparative thin layer chromatography (ethyl acetate/ethanol 6:4) in order to yield the title compound as a white solid; 1H NMR (CD3SOCD3, 500 MHz) δ 8.49 (d, J=2.5 Hz, 1H), 8.35 (s, 1H), 7.60 (dd, J=1.8, 12.0 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 3.80 (br. s, 4H), 2.54-2.52 (m, 3H), 1.96-1.95 (m, 1H), 0.89-0.87 (m, 2H), 0.68-0.67 (m, 2H); MS (ESI): m/z=338.97 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16]>>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]2[C:15](=[O:16])[CH:14]=1
Reactant: COC(=O)c1cnc(N)s1
Reactant: CCOC(=O)CC(=O)CCl
Product: COC(=O)c1cn2c(=O)cc(CCl)nc2s1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-amino-thiazole-5-carboxylic acid, methyl ester (5 g) was reacted with ethyl 4-chloro-acetoacetate (10.6 g) in polyphosphoric acid (25 g) under stirring at 100° C. for 4 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was extracted with ethyl acetate and purified over a SiO2 column using n-hexane/ethyl acetate as eluent. Crystallization from isopropyl ether gave 7-chloromethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester, m.p. 139°-141° C. (2.75 g) which was reacted with triphenylphosphine (3.15 g) in acetonitrile (100 ml) under stirring at reflux temperature for 16 hours. After cooling the precipitate was filtered and washed with acetonitrile to give (2-carbomethoxy-5-oxo-5H-thiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenyl-phosphonium chloride, m.p. 180°-181° C. dec. (3.35 g) which was added under stirring to a suspension of 75% NaH (0.3 g) in dimethylsulphoxide (60 ml) and dichloroethane (40 ml) and reacted with 3-pyridine carboxaldehyde (1.4 g) at room temperature for 20 hours. The solution was then diluted with ice water and the crude precipitate was extracted with dichloroethane: the organic phase was separated and evaporated in vacuo to dryness. The crude residue was crystallized from isopropyl alcohol to give 7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (1.3 g) which was hydrolyzed by treatment with a mixture 37% HCl:acetic acid=1:1 (50 ml) at the reflux temperature for 40 hours. After cooling the reaction mixture was diluted with ice water and neutralized with 37% NaOH: the precipitate was filtered and washed with water until neutral. Crystallization from CHCl3 -ethanol gave 0.87 g of 7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 264°-267° C., N.M.R. (CDCl3 -CF3COOD) δp.p.m.: 6.95 (s) (1H, C-6 proton), 7.53 (d) (1H,β-ethenyl proton), 8.02 (d) (1H,α-ethenyl proton), 8.20 (dd) (1H, C-5 pyridyl proton), 8.60-9.03 (m) (2H, C-4 and C-6 pyridyl protons), 8.90 (s) (1H, C-3 proton), 9.11 (bs) (1H, C-2 pyridyl proton), JHαHβ =16 Hz.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[C:16]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=2)=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:14][C:15]1[C:16]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:13][C:10]3[CH:11]=[CH:12][C:7]4[CH2:6][NH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:8]=4[CH:9]=3)[N:27]=2)=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CN1CCNCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)N(C)CCNC3)ncc1Cl
Temperature: 120 °C
Reaction time: 1 h
Yield: 2.2 %

Procedure:
1-Methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (271 mg, 1.53 mmol) and 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (425 mg, 1.28 mmol) were combined in 2-Methoxyethanol (10 mL) and 4.00 M of Hydrogen chloride in 1,4-Dioxane (1.0 mL) was added. The reaction was warmed to 120° C. for 6 h, then the reaction was cooled to room temperature for 1 h before Macroporous carbonate resin (3.16 mmol/g loading; 2.2 g, 6.95 mmol) was added and stirred at r.t. for 1 h, filtered then conc. in vacuo to give an oil. The material was chromatographed on an ISCO column (40 g, 0-15% (5% NH4OH:MeOH):DCM, celite dry load). Product eluted impure with 15% polar solvent, so it was purified by RP-HPLC (5-25% acetonitrile:water). Clean material concentrated followed by formation of the free base with Macroporous carbonate resin to afford 3-Chloro-2-[5-chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (13 mg, 2%) as an orange film. LCMS (m/e) 472 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.82 (s, 1H), 7.57 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=7.7 Hz), 7.04 (s, 1H), 6.91 (m, 3H), 6.07 (s, 1H), 3.88 (s, 2H), 3.48 (s, 2H), 3.06 (m, 2H), 2.94 (m, 2H), 2.72 (d, 3H, J=4.6 Hz), 2.68 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][C:16]([C:18](O)=[O:19])=[CH:17][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:24][C:25]1([F:31])[CH2:30][CH2:29][N:28]([C:18]([C:16]2[S:15][C:14]3[CH:21]=[CH:22][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:12][C:13]=3[CH:17]=2)=[O:19])[CH2:27][CH2:26]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3sc(C(=O)O)cc3c2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2ccc3sc(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Yield: 64.7 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (0.128 g, 0.333 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.063 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.181 g, 1.23 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.225 mL) in 1.3 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=4/96) produced 0.091 g of the title compound as light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][C:23]1[CH:24]=[C:25](OB(O)O)[CH:26]=[CH:27][CH:28]=1)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][CH:24]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOc1cccc(OB(O)O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Reaction time: 17 h
Yield: 65 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-propoxyphenylboric acid (536 mg), cupric acetate (271 mg), MS 4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 17 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) as a light yellow, oily substance.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:37])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:36])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:29]1[C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:25]2[NH:24][C:23](=[O:37])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(N)(=O)=O)c3)c1)=N2

Procedure:
The title compound was prepared from 3′-(8-methyl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid tert-butylamide (Example 2) (220 mg, 0.39 mmol) and TFA (5 mL) in DCM (1 mL) according to the general procedure I step 2. Obtained as a light yellow solid (136 mg, 73%). MS (ISP) 473.9 [(M+H)+]; mp 235-239° C. (dec).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH2:18]C)=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:20]/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1)#[CH:20]
Reactant: CCOC(=O)c1cc(-c2ccc(C=O)cc2)ccn1
Reactant: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(-c2ccnc(C(=O)OC)c2)cc1
Reaction time: 5 h
Yield: 33.7 %

Procedure:
To a stirring solution of compound 2.5 (12.7 g, 50 mmol) in CH3OH (300 mL) was added the Bestmann reagent (14.4 g, 75 mmol) followed by K2CO3 (20.8 g, 150 mmol) and the reaction was stirred for 5 hr. The reaction mixture was diluted with water (500 mL) and extracted with Et2O (3×300 mL). The combined organic layers were dried and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE:Et2O 10:1-5:1) to give methyl 4-(4-ethynylphenyl)picolinate (2.6, 4.0 g, 33.9%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.O.O.[OH-].[Li+]>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COCc1cnc(C(=O)OC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 5-(methoxymethyl)pyrazine-2-carboxylate, 8-(1), (55 mg, crude) was dissolved in 1,4-dioxane (1 mL) and water (1 mL) was added followed by lithium hydroxide monohydrate (50 mg). After stirring at RT for 1 h, water (20 mL) was added and the mixture was extracted with ether (20 mL). The aqueous portion was acidified to pH 2 and extracted with EtOAc (2×25 mL). The combined EtOAc layers were dried over MgSO4 and evaporated to afford the title compound (19 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.58 (s, 3H), 4.77 (s, 2H), 8.80 (br. s., 1H), 9.38 (br. s., 1H)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[C:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:19]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCOC(C)=O.CO>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[CH:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 2.75 h
Yield: 99.2 %

Procedure:
To a solution of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl)ethane-1, 2-dione (250 mg, 0.54 mmol) in EtOAc (6 mL) and MeOH (2 mL) at 0° C. was added NaBH4 (20 mg, 0.54 mmol). After 2.75 hours at 0° C., more NaBH4 (20 mg, 0.54 mmol) was added. After 1.25 hours at 0° C., the reaction was quenched with HOAc (few drops) and H2O (2 mL). The pH was adjusted to 5 (by pH paper) with HOAc and partitioned between H2O (25 mL) and EtOAc (25 mL). The organic layers were dried over Na2SO4 and concentrated to provide 0.25 g (99%) of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)1H-pyrrol-3-yl]-2-hydroxy-ethanone as a crisp foam.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([NH:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:15])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: NCCc1cccnc1
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCCc1cccnc1

Procedure:
3-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 3-(2-aminoethyl)pyridine essentially according to the procedure of Example 1, Step K. It was characterized as the hydrochloride salt. Mass Spectrum: Found: (M+1) 429.2.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[C:4]([NH2:6])=[O:5].[C:9]([O-])(=O)[CH3:10].[Na+].[CH2:14](Cl)Cl.CCOC(C)=O>C(OC(=O)C)(=O)C>[CH2:14]([N:6]1[C:1](=[O:8])[CH:2]=[CH:3][C:4]1=[O:5])[C:9]#[CH:10]
Reactant: NC(=O)/C=C\C(=O)O
Reactant: ClCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: C#CCN1C(=O)C=CC1=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of maleic anhydride (19, 2.5 g, 25.5 mmol) and propargylamine (20, 1.75 mL, 25.5 mmol) in glacial acetic acid (50 mL) was stirred in the dark overnight. The reaction mixture was concentrated to dryness and the residue was recrystallized from a mixture of isopropyl alcohol and water. This gave 21 (3.079 g, 20.1 mmol, 79%) as white crystals. Compound 21 (1.49 g, 9.70 mmol) was suspended in acetic anhydride (7 mL) and sodium acetate (437 mg, 5.33 mmol) was added. The resulting suspension was stirred at 65° C. for 2 h, cooled down to room temperature, and then poured into ice-cold water (75 mL). The aqueous solution was extracted three times with diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Column chromatography (CH2Cl2/EtOAc=1/1) provided 22 (755 mg, 5.59 mmol, 58%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 2.21 (t, 1H, J=2.6 Hz, ≡C—H), 4.30 (d, 2H, J=2.6 Hz, CH2), 6.76 (s, 2H, ═C—H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:20])[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[O:5]1)[N:12]=[CH:11][CH:10]=[CH:9]3.[CH3:21][NH:22][CH3:23]>>[ClH:1].[CH3:21][N:22]([CH3:23])[CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:20])[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[O:5]1)[N:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2ccc3ncccc3c2C1=S
Product: CN(C)CCC1CN(C)C(=S)c2c(ccc3ncccc23)O1
Product: Cl

Procedure:
Following the procedure of Example 31, 4-(2-chloroethyl)-3,4-dihydro-2-methyl-[1,4]-oxazepino[6,7-f]quinoline-1(2H )-thione is reacted with dimethylamine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]([C:16]([O:18][CH3:19])=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>CO>[O:8]=[C:5]1[NH:4][C:3](=[O:9])[C:2]([NH:1]/[C:11](=[CH:10]/[C:16]([O:18][CH3:19])=[O:17])/[C:12]([O:14][CH3:15])=[O:13])=[CH:7][NH:6]1
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(/Nc1c[nH]c(=O)[nH]c1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
To a suspension of 5-aminouracil (275 g, 2.16 mol) in dry methanol (5.5 L) was added dropwise dimethyl acetylene dicarboxylate (344 g, 2.42 mol) at room temperature. After the end of the addition, the mixture was stirred at room temperature for 24 hours. The precipitate was filtered off, washed with MeOH (500 mL) and dried under vacuum to afford the title compound (430 g, 74%) as a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1>ClCCl>[Br:21][C:20]([Br:24])=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.2 %

Procedure:
To a stirred solution of triphenylphosphine (155.6 g, 0.59 mol) in dry dichloromethane (870 mL) at 0° C. was added carbon tetrabromide (100.86 g, 0.304 mol) portionwise. The mixture was stirred at RT for 30 min and then cooled to −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (30 g, 0.15 mol) in CH2Cl2 (90 mL) was added dropwise and the reaction was stirred at −78° C. for 30 min and then at RT overnight. The mixture was filtered and the filtrate was evaporated to dryness. Diethyl ether was added and the mixture was filtered again. The filtrate was evaporated to dryness to give the title compound (64 g). 1H NMR (500 MHz, CDCl3): δ 3.44 (m, 4H), 2.46 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:14]=3[S:23]([NH:26]C(C)(C)C)(=[O:25])=[O:24])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.O>C(Cl)Cl>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:14]=3[S:23]([NH2:26])(=[O:24])=[O:25])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(Cn3ccnc3)cc2)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1ccc(S(N)(=O)=O)c(-c2ccc(Cn3ccnc3)cc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-imidazol-1-ylmethylphenyl)-4-iso-butyl-N-tert-butylbenzene-sulfonamide (0.211 mmol, 90.0 mg, see step (c) above) in CH2Cl2 (5 mL) was added BCl3 (1.5 mL, 1M, 1.5 mmol) under N2 (g). The mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[F:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[F:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Reactant: NCCCF
Agent: Cl
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCCF)nn23)s1

Procedure:
Prepared as in example 5.6.3 from 1-[5-(6-fluoro-imidazo[1,2-b]pyridazine-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and 3-fluoropropylamine hydrochloride [64068-31-1] (43 mg, 0.4 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 6H) 2.12-2.25 (m, 1H) 2.54 (s, 1H) 3.66-3.72 (m, 1H) 4.72 (t, J=5.51 Hz, 1H) 7.21 (s, 2H) 7.63-7.67 (m, 1H). LRMS (ESI) m/z 319.1 [(M+H)]+, calc'd for C15H15FN4OS: 318.38.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:15]=[C:14]([Sn](CCCC)(CCCC)CCCC)[O:13][N:12]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:14]2[O:13][N:12]=[C:11]([CH3:10])[CH:15]=2)=[CH:7][N:6]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(F)c(F)c2)on1
Temperature: 100 °C
Yield: 55.4 %

Procedure:
A 330 mL pressure vessel was charged with 5-chloro-2,3-difluoropyridine (5.00 g, 33.4 mmol), 3-methyl-5-(tributylstannyl)isoxazole (14.9 g, 40.1 mmol), XPhos (2.23 g, 4.68 mmol), PdOAc2 (0.526 g, 2.34 mmol), and 1,4-dioxane (167 ml, 33.4 mmol), flushed with argon, sealed, then heated at 100° C. for 16 hours. The mixture was concentrated; the black oil was absorbed onto silica gel and purified by MPLC, eluting with 20% EtOAc in hexanes isocratic to yield an orange solid; this was triturated with hexanes to give 2,3-difluoro-5-(3-methylisoxazol-5-yl)pyridine (3.6278 g, 55.3% yield) as a yellow solid.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:3][CH2:2]2.[CH2:24]([O:26]C=O)C>>[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH:24]=[O:26])=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:3][CH2:2]2
Reactant: CCOC=O
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Product: O=CNc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1

Procedure:
A mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone (0.50 g; 1.6 mmol) and ethylformate (30 ml) was stirred at reflux for 9 days. The mixture was evaporated. Aqueous sodium hydroxide (20 ml; 1M) was added followed by extraction with dichloromethane (3×20 ml). The crude mixture was purified by silica gel chromatography, using a mixture of dichloromethane:methanol (9:1) and 1% methanol as eluent. The product was isolated as the free base. Yield 0.29 g (53%). Mp. 236° C.