Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O.CCOC(C)=O>[CH3:19][C:11]1([CH3:20])[O:10][C:9](=[O:21])[N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:29])[N:7]=2)[C@H:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC1(C)OC(=O)N(c2ccnc(Cl)n2)[C@H]1c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)n1)c1ccccc1
Yield: 85 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (33.9 mg, 0.112 mmol) and (S)-(−)-1-phenylethanamine (0.15 mL, 1.2 mmol, 10 equiv) in DMSO (1 mL) was heated at 110° C. for 140 min. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)-5,5-dimethyl-4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl) oxazolidin-2-one (37.0 mg, white solid) in 85% yield. 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J=5.8 Hz, 1H), 7.43 (d, J=5.8 Hz, 1H), 7.31-7.24 (m, 3H), 7.19-7.11 (m, 5H), 7.01 (br s 2H), 5.48 (s, 1H), 4.86-4.80 (m, 1H), 1.65 (s, 3H), 1.43 (d, J=7.0 Hz, 3H), 0.98 (s, 3H); HRMS(B) m/z 389.1987 (M+H)+.
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:19][CH:20]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Product: Cc1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
The 4′-methyl-salicylanilide was prepared by condensing phenyl salicylate with 4-toluidine then purified as described in Example 2a. A ligand mixture was then prepared from 4′-methyl-salicylanilide and binaphthol using the procedure described in Example 5a. 31P NMR (121.77 MHz): several peaks between 117.1-117.8 ppm.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C1(=O)CCCC1>[Br:14][CH2:15][CH2:16][CH:17]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: BrCCCCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCC1
Product: CC(CCBr)Oc1ccccc1
Yield: 49.3 %

Procedure:
A mixture of 329 g of phenol, 484 g of dry potassium carbonate, 756 g of 1,4-dibromobutane and 1,000 ml of cyclopentanone was refluxed for 24 hours, while stirring. The solid constituents were filtered off and the filtrate was then concentrated under reduced pressure; the oily residue was taken up in 1,500 ml of methylene chloride, and the solution was extracted with 10×200 ml of 15% strength by weight aqueous sodium hydroxide solution. The organic phase was then extracted with twice 300 ml of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Distillation of the residue gave, at 92°-98° C./0.4 mbar, 395 g of colorless 1-bromo-3-phenoxybutane, which solidified in the receiver; melting point 33°-36° C.
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]1[CH2:44][O:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>CO>[N:48]1[CH:49]=[CH:50][CH:51]=[C:46]([O:45][CH2:44][CH:32]2[CH2:33][NH:34][CH2:35][CH2:36][N:31]2[C:23]2[O:22][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(OCC2CNCCN2c2nc3ccccc3o2)c1
Reaction time: 1 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(benzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (74 mg, 0.14 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure. The material was dissolved in EtOAc (40 mL), washed with 1 N NaOH (2×20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 34.7 mg (79%) of the desired product as a thick yellow oil. LC-MS: RT=4.00 min, [M+H]+=311.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([OH:14])=O)[N:9]=[CH:10][C:5]2=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[C:20]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)([C:22]1NC=CN=1)=O.NC1C=CC=CN=1>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([NH:28][C:27]3[CH:20]=[CH:22][CH:29]=[CH:30][N:31]=3)=[O:14])[N:9]=[CH:10][C:5]2=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1nc(-c2ccco2)c2cnn(CC(=O)O)c2n1
Agent: Nc1ccccn1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2cnn(CC(=O)Nc3ccccn3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A solution of 6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-1-ylacetic acid (200 mg, 0.77 mmol) in DMF (3 mL) was treated with carbonyl diimidazole (125 mg, 0.77 mmol), stirred at room temperature for 2 h, treated with 2-aminopyridine (72 mg, 0.77 mmol), heated to 50° C. for 3 h, cooled and diluted with water. The resulting white solid was filtered, suspended in MeOH, treated with HCl in dioxan (4-M, 1 mL) diluted with diethyl ether and filtered to give the title compound (187 mg, 59%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([OH:35])=O)[C:30]([O:36][CH3:37])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][NH2:46])=[N:43][CH:44]=1.CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([NH:46][CH2:45][C:42]5[CH:41]=[CH:40][C:39]([F:38])=[CH:44][N:43]=5)=[O:35])[C:30]([O:36][CH3:37])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cn1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)O)n3)cc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)NCc4ccc(F)cn4)n3)cc12
Reaction time: 3 h
Yield: 35 %

Procedure:
To a solution of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-methoxypicolinic acid (50 mg, 0.09 mmol), (5-fluoropyridin-2-yl)methanamine (200 mg, 1.58 mmol) and Et3N (0.2 mL) in THF (50 mL) was added T3P (0.05 mL) dropwise at 0° C. and the mixture was stirred for 3 h. After being diluted with water and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by prep-TLC (PE:EtOAc=1:2) to give the pure product of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-((5-fluoropyridin-2-yl)methyl)-3-methoxypicolinamide (20 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.60 (t, J=4.8 Hz, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.99 (s, 1H), 7.92˜7.95 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.24˜7.42 (m, 2H), 7.17˜7.22 (m, 2H), 5.91 (d, J=3.6 Hz, 1H), 4.73 (d, J=5.6 Hz, 2H), 4.01 (s, 3H), 3.18 (s, 3H), 2.97 (d, J=4.8 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 636.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].[Cl-].[Cl-].[Al+3].[C:19]1([CH:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>ClCCCl.O>[OH:28][CH2:29][CH2:30][CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:26]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:27]
Reactant: C1CCCNCC1
Reactant: O=C1OCCC1c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C(CCO)c1ccccc1)N1CCCCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2,3,4,5,6,7-Hexahydro-1H-azepine (3.36 g, 33.9 mmol) in 1,2-dichloroethane (10 ml) was added to a cooled (ice/water) solution of triethylamine (4.68 g, 46.2 mmol) and aluminium trichloride (4.52 g, 33.9 mmol) in 1,2-dichloroethane (70 ml). A solution of 2-phenylbutyrolactone (5.00 g, 30.8 mmol) in 1,2-dichloroethane (50 ml) was added to the cooled reaction mixture and stirring continued overnight. The reaction mixture was poured into water (150 ml), basified with 2M-NaOH, and washed with ethyl acetate (3×80 ml). The combined organic phases were washed with brine (80 ml) and water (80 ml), dried (MgSO4), and concentrated in vacuo to afford a brown oil which partially solidified on standing. The crude product was chromatographed on silica gel, eluting with ethyl acetate to give the title compound as an oil (2.68 g, 33.3%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 6.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.1 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 16:1:0.1) and crystallization (diethyl ether/MeOH) yielded the title compound as a white solid (6 mg, 3%). MS (ISP) 477.1 [(M+H)+]; mp 237.5° C.
Reaction SMILES: C([N:8]1[CH2:56][CH2:55][C:11]2[N:12]=[C:13]([C:35]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:36]=3[C:37]([CH3:54])=[CH:38][N:39]4[S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[C@H:18]([CH3:34])[CH2:17]3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(Cl)(=O)OC(Cl)C>CC#N>[CH3:54][C:37]1[C:36]2[C:40](=[CH:41][CH:42]=[CH:43][C:35]=2[C:13]2[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[C@H:18]([CH3:34])[CH2:17]3)[C:10]3[CH2:9][NH:8][CH2:56][CH2:55][C:11]=3[N:12]=2)[N:39]([S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:51])=[CH:52][CH:53]=2)(=[O:45])=[O:46])[CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(=O)(=O)c7ccccc7[N+](=O)[O-])[C@H](C)C6)n4)CN(Cc4ccccc4)CC5)cccc32)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(=O)(=O)c7ccccc7[N+](=O)[O-])[C@H](C)C6)n4)CNCC5)cccc32)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-6-benzyl-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.17 g, 1.47 mmol) in MeCN (15 mL) was added 1-chloroethyl carbonochloridate (0.18 mL, 1.62 mmol), and the mixture was stirred for 15 minutes at which time the mixture was concentrated in vacuo. The resulting residue was dissolved in a 2:1 mixture of dichloromethane:methanol (15 mL) and heated at 40° C. for 1 hour and then placed at room temperature for ca. 15 h. The mixture was then diluted with dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (3-12% MeOH/DCM) to provide (R)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 702.3 (M+H)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1.Cl>O>[O:14]=[C:11]1[C:10]2[CH:15]=[CH:16][C:7]([CH2:6][CH:2]=[O:1])=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: O=C1OCc2cc(CC3OCCO3)ccc21
Agent: Cl
Solvent: O
Product: O=CCc1ccc2c(c1)COC2=O
Temperature: 40 °C

Procedure:
5-(1,3-Dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one (61 g, 280 mmol) was combined with water (2.2 L) in a 5 L round bottomed flask equipped with a Claisen adapter, thermocouple, stir bar and nitrogen bubbler. Aqueous HCl solution (2M, 1.14 L, 2.29 mol) was added and the resulting mixture was heated at 40° C. for 8 h. Then the mixture was stirred overnight at room temperature. The mixture was extracted three times with 2 L of ethyl acetate. The combined organic layers were concentrated to give (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 177 (M+1)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:12]=2)=[O:9])[N:6]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[S:3][CH:4]=[C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[O:9])[N:6]=2)=[CH:28][CH:27]=1
Reactant: O=C(Nc1cccc(CN2CCCCC2)n1)Nc1csc(Br)n1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)Nc3cccc(CN4CCCCC4)n3)cs2)cc1
Temperature: 25 °C

Procedure:
A stirred suspension of N-(2-bromo(1,3-thiazol-4-yl)){[6-(piperidylmethyl)(2-pyridyl)]amino}carboxamide (2.23 g, 5.64 mmol), 4-methoxyphenylboronic acid (0.94 g, 6.21 mmol), PdCl2(dppf)2 (0.46 g, 0.56 mmol) and Na2CO3 (2.10 g, 17.0 mmol) in ethylene glycol dimethyl ether (25 ml) and H2O (8 ml) was heated at reflux for 12 h. After cooling to RT the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (3:1, EtOAc:acetone) to yield the title compound as a pale yellow amorphous solid. MS m/z: 424 (M+H). Calc'd for C22H25N5O2S: 423.17.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](OC)=[O:6].[Na].Cl.[CH:19]([NH2:21])=[NH:20]>CO>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:5]([OH:6])=[N:20][CH:19]=[N:21][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1
Reactant: N=CN
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Oc1ncnc(O)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
A solution of 2-(4-bromophenyl)-malonic acid dimethyl ester (11.73 g) in methanol (100 mL) is added at 0° C. to a solution of sodium (2.83 g) in methanol (100 mL). The mixture is stirred for 18 h at rt before formamidine hydrochloride (4.10 g) is added. The suspension is stirred at rt for 4 h. The solvent is removed and the residue is suspended in 10% aq. citric acid (100 mL) and stirred for 10 min. The white precipitate is collected, washed with 10% aq. citric acid, water, evaporated three times from CyHex and dried under high vacuum at 40° C. to give 5-(4-bromophenyl)-pyrimidine-4,6-diol (9.90 g) as a pale beige powder. LC-MS: tR=0.61 min, [M+H]+=267.07; 1H-NMR(D6-DMSO): 7.43-7.48 (m, 2H), 7.50-7.55 (m, 2H), 8.13 (s, 1H), 12.1 (s br, 2H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:23]=1[NH2:35].C(OCC)(=O)C>CN(C)C=O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH:35][C:23]1[C:24]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[F:21])=[O:11]
Reactant: O=C(O)CC1CC2CCC1C2
Reactant: Nc1c(F)cc(F)cc1N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC1CC2CCC1C2)Nc1c(F)cc(F)cc1N1CCOCC1
Reaction time: 0.03 h
Yield: 51 %

Procedure:
Bicyclo[2.2.1]hept-2-yl-acetic acid (0.20 mL), N,N-diisopropyl-ethylamine (0.50 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.55 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2,4-Difluoro-6-morpholin-4-yl-phenylamine (0.20 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 60° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 0.17 g (51% yield) of the title compound as a white solid. LC-MS (m/z) 351 (MH+); tR=2.94, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.12 (m, 4H), 1.41 (m, 4H), 1.87 (m, 1H), 1.99 (d, 2H), 2.13 (dd, 1H), 2.20 (m, 1H), 2.27 (dd, 1H), 2.88 (t, 4H), 3.70 (t, 4H), 6.72 (m, 1H), 6.89 (dt, 1H), 9.10 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N(C)C)cc3)ccn2c1=O
Yield: 39.8 %

Procedure:
Methyl 8-(4-(dimethylamino)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-(dimethylamino)-phenyl)-boronic acid (56 mg, 0.34 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (39 mg, 31%).
Reaction SMILES: COC1C=CC(COC([NH:11][NH:12][C:13]([C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[C:16]=2[CH3:25])=[O:14])=O)=CC=1.Cl>O1CCOCC1>[CH3:25][C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[CH:24][C:15]=1[C:13]([NH:12][NH2:11])=[O:14]
Reactant: COc1ccc(COC(=O)NNC(=O)c2ccc3c(c2C)OCCO3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C(=O)NN)ccc2c1OCCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
In a 500 mL volume flask, was combined 18.6 g (0.0499 moles) of N′-(5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazinecarboxylic acid 4-methoxy-benzyl ester, 72 mL of concentrated HCl, and 108 mL of dioxane. The flask was placed into an 80° c. oil bath and mechanically stirred for 2 hours. The reaction mixture was cooled with ice water, then poured onto ice water and transferred to a separatory funnel. The reaction mixture—H2O solution was then extracted twice with 150 mL of CH2Cl2 to remove the acids and neutrals (the starting material). The aqueous phase was made basic (pH 12) with a 20% NaOH solution and extracted 4 times with 150 mL of ethyl acetate. The ethyl acetate extract was dried over MgSO4 and concentrated to yield 4.5 g of 5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.0 (s, 1H), 6.85 (d, 1H), 6.74 (d, 1H), 4.28 (m, 4H), 2.781 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=NO)c3ccccc32)cc1)c1ccccc1Cl
Solvent: c1ccncc1
Product: CC(=O)ON=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2)c2ccccc21

Procedure:
A solution of 5-hydroxyimino-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.06 g) in acetic anhydride (10 ml) and pyridine (10 ml) is stirred at room temperature overnight. After completion of the reaction, the reaction solution is concentrated. To the resulting residue is added water and the mixture is extracted with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=80:1), and recrystallized from ethanol/petroleum ether to give 5-acetyloxyimino-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.75 g) as colorless prisms, m.p. 142°-144° C.
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][C:6]([CH2:7][C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[C:11](=[O:16])[N:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([NH:24]C(OCC4C=CC=CC=4)=O)=[C:19]([Cl:35])[CH:18]=2)[C:9]3=[O:36])=[CH:5][CH:4]=1)#[N:2]>Br>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[C:11](=[O:16])[N:10]([C:17]2[CH:18]=[C:19]([Cl:35])[C:20]([NH2:24])=[C:21]([Cl:23])[CH:22]=2)[C:9]3=[O:36])=[CH:37][CH:38]=1)#[N:2]
Reactant: N#Cc1ccc(CC23CCCN2C(=O)N(c2cc(Cl)c(NC(=O)OCc4ccccc4)c(Cl)c2)C3=O)cc1
Agent: Br
Product: N#Cc1ccc(CC23CCCN2C(=O)N(c2cc(Cl)c(N)c(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
The compound from Example 131 (100 mg) was dissolved in HBr (2 mL, 30% in AcOH). The resulting solution was stirred at room temperature for 30 minutes. The solution was extracted with EtOAc/H2O. The combined organic layers were dried over Na2SO4, filtered and evaporated. The product was purified by preparative TLC to yield the titled compound (52 mg). MS (m/z) 415 (MH+). mp. 103° C.