Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][CH:31]=1
Reactant: C[C@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 941.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (240 mg, 0.32 mmol) was reacted with (S)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (3.5 g, 9.7 mmol) to afford the desired product (1.4 g, 32%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[C@H:24]([OH:31])[C@H:23]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.O=C1NC2=NC=CC=C2N1C1CCN(C(O[C@H]2C3=NC=CC=C3[C@@H](O)[C@@H](C3C=CC=C(F)C=3F)CC2)=O)CC1.O=C1NC2=NC=CC=C2N1C1CCN(C(O[C@H]2C3=NC=CC=C3C(=O)C(C3C=CC=C(F)C=3F)CC2)=O)CC1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[C@@H:24]([OH:31])[C@H:23]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[CH2:22][CH2:21]2)=[O:18])[CH2:15][CH2:16]1
Reactant: O=C(O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@@H](O)c2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: O=C(O[C@@H]1CC[C@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: O=C([O-])O
Agent: O=C1c2cccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CCC1c1cccc(F)c1F
Solvent: CO
Product: O=C(O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
(5R,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (example 5); and (5S,6R,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate. In a 100 mL round-bottom flask was dissolved (9R)-6-(2,3-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (44.4 mg, 0.083 mmol) (example 2) in methanol (1 mL) to give a colorless solution. Sodium borohydride (6.30 mg, 0.166 mmol) was added, and the mixture was stirred at room temperature for 30 min. LCMS indicated complete conversion to three components (presumably diastereomers), all with desired MW (M+H=536). The mixture was concentrated and directly purified by prep-HPLC (0.1% TFA-methanol-water system) to afford three compounds (order of elution: example 4>5>6, only pure fractions collected). Direct concentration (acidic solution) under high vacuum gave some decomposition (by LCMS and NMRs). They were individually treated with sodium bicarbonate and concentrated to dryness. The residues were repeatedly washed with methylene chloride to obtain the individual free bases. They were then individually purified by FCC (a gradient up to 10% methanol/methylene chloride) to afford the products example 4 (6.7 mg, 14%), example 5 (5.5 mg, 12%), and example 6 (3.0 mg, 6%) as white solids. The relative stereochemistry was not strictly assigned.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:7]=[CH:6][CH:5]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: CS(=O)(=O)Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 1 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-amino-phenyl)-5-(2-benzyl-2H-Indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and methanesulfonyl chloride as starting materials, 19 mg (1%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1 H), 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.10 (s, 3H); ES-MS m/z 510.27 [M+H]+, HPLC RT (min) 2.85.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([NH2:38])[C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1>>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([CH2:6][NH:38][C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:32]=3[CH:31]=[N:30][N:29]4[C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)([OH:5])[C:7]([F:8])([F:9])[F:10])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: COc1ccc(-n2ncc3c(N)cccc32)cc1
Product: COc1ccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cccc5c4OCC5)C(F)(F)F)cccc32)cc1

Procedure:
Prepared similarly to Example 1 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and 1-[4-(methyloxy)phenyl]-1H-indazol-4-amine (Intermediate 3).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[F:12][C:13](I)([F:18])[C:14]([F:17])([F:16])[F:15]>CN(C)C=O.[Cu]>[F:12][C:13]([F:18])([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11])[C:14]([F:17])([F:16])[F:15]
Reactant: FC(F)(F)C(F)(F)I
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Agent: [Cu]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Temperature: -60 °C
Reaction time: 16 h

Procedure:
A mixture of 2.36 g of 1-iodo-2-methyl-4-nitro-benzene and 2.2 g of powdered copper (Org. Synthesis Coll., Vol. II (1948), page 445 washed with water, acetone and dried under reduced pressure) in 10 ml of dimethylformamide under nitrogen in a sealed vessel was cooled to -60° C. and 11 5 g of pentafluoroethyl iodide were added. The mixture was stirred at 160° C. at a pressure of 3.5 bars for 16 hours and then cooled in ice and returned to room temperature. The mixture was poured into ice and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica (eluant-pentane containing 2 to 3% of dichloromethane) to obtain 1.5 g of 1-pentafluoroethyl-2-methyl-4-nitro-benzene which was hydrogenated in the presence of palladized active carbon to obtain the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH2:15][NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:20]([Cl:30])=[CH:19][C:18]=2[O:31][CH3:32])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CO>C(Cl)Cl>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[C:20]([Cl:30])=[CH:19][C:18]([O:31][CH3:32])=[C:17]([NH:16][CH2:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])[CH:22]=1
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl-4-(2-(5-(2-chlorophenyl)-4-chloro-2-methoxyphenylamino)acetyl)piperazine-1-carboxylate (150 mg, 0.304 mmol) in DCM (2 mL), a solution of HCl in MeOH (10 mL, 29 mmol) was added. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo to afford the crude product which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:6])[CH3:5])[CH3:2].C(N(CC)CC)C.[SH2:33]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24](=[S:33])[NH2:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:5])[CH3:6])[CH3:2]
Reactant: CCN(CC(C)N1c2ccccc2Sc2ccc(C#N)cc21)C(C)C
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCN(CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21)C(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 10-{(2RS)-1-[N-ethyl-N-(1-methylethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (2.3 g) and triethylamine in anhydrous pyridine (46 cc) is treated with hydrogen sulphide and stirred for 16 hours at a temperature in the region of 20° C. The greenish solution obtained is purged with nitrogen, poured into distilled water (200 cc) and extracted with ethyl acetate (200 cc and then 100 cc). The combined organic phases are washed with distilled water (3×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (4 g) is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (750 cc) of ethyl acetate and cyclohexane and collecting 60-cc fractions. The combined fractions 6 to 10 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-((2RS)-1-[N-Ethyl-N-(1-methylethyl)-amino]-2-propyl}-2-phenothiazinecarbothioamide (2.5 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[O:2].[OH-].[Na+].Cl>CO>[CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:2]
Reactant: CCOC(=O)COc1cccc(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
ethyl 2-(3-formylphenoxy)acetate (47)/(1 eq) was taken in MeOH and cooled to 0° C. when NaOH (2 eq) solution was added drop wise. After completion of addition the reaction mixture was stirred at rt for 30 min. The reaction mixture was cooled to rt and acidified with dil HCl to attain pH 3 when a precipitate appeared which was filtered and washed well with water and dried well to yield a white solid (49%). NMR: δ 4.754 (s, 1H), 7.23-7.27 (m, 1H), 7.349 (s, 1H), 7.449 (d, J=4.8 Hz, 2H), 9.938 (s, 1H), 13.07 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:23])[CH2:3][CH2:2]1.O.NN>CO.[Ni]>[NH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:10]([CH2:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:11](=[O:23])[CH2:12][CH2:13]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCOCC1
Temperature: 25 °C

Procedure:
1-(3-morpholinopropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (78 mg, 0.244 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (76 uL, 2.44 mmol) at room temperature and the resulting mixture was refluxed for 30 minutes. The reaction was cooled to room temperature, filtered through a celite bed and the bed washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5). Yield: 64 mg of yellow oil (90%). 1H NMR (CDCl3) δ: 6.86 (d, J=8.4 Hz, 1H), 6.56 (dd, J=2.7, 8.4 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 3.93 (t, J=7.2 Hz, 2H), 3.71 (t, J=4.5 Hz, 4H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.44-2.36 (m, 6H) 1.83-1.65 (m, 2H). MS (ESI): 290.2 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:24])[CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>[Pd].C(OCC)(=O)C>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:3])[CH:5]([CH3:24])[CH2:6][N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)C(C)CN(c1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CN(c2ccccc2)c2nc(Cl)ncc2NC1=O
Yield: 3.8 %

Procedure:
A solution of 1.44 g (0.00395 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenyl-amino]-2-methyl-propanoic acid ethyl ester (IV-51), 0.35 g of 10% palladium on carbon and 30 mL of ethyl acetate was stirred under an atmosphere of hydrogen for 1 day. The mixture was filtered, and then concentrated under reduced pressure. The residue was dissolved in 10 mL of a 20:80 mixture acetic acid—ethyl acetate and heated to reflux for 18 hours. The mixture was then cooled, concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate and then brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hot ethyl acetate and dried to give 0.043 g of (rac)-2-chloro-7-methyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-51) as white powder.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:2]=[CH2:3].[N:18]1([S:23]([C:26]2[CH:27]=[C:28]([CH:32]([CH2:36][CH:37]=[CH2:38])[C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.O>[CH2:1]([N:4]([C@@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:33](=[O:34])[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([S:23]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:25])=[O:24])[CH:27]=1)[CH2:36][CH:37]=[CH2:38])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: C=CCN[C@H](CN1CCCC1)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCC(C(=O)N(CC=C)[C@H](CN1CCCC1)c1ccccc1)c1cccc(S(=O)(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 44 h
Yield: 92.9 %

Procedure:
To a stirred solution of allyl-(1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl)-amine (1.00 g, 4.34 mmol) in dichloromethane (22 cm3) at ambient temperature was added 2-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pent-4-enoic acid (1.34 g, 4.34 mmol) followed by 2-Chloro-1-methylpyridinium iodide (2.22 g, 8.68 mmol) and triethylamine (1.82 cm3, 13.0 mmol) to afford a yellow slurry. The mixture was stirred at ambient temperature for 44 hours to afford a brown solution. The solution was diluted with ethyl acetate (50 cm3) and poured into water (100 cm3). The aqueous was extracted with ethyl acetate (3×30 cm3) and the combined ethyl acetate extracts were washed with 1M sodium bicarbonate (2×50 cm3), brine (1×50 cm3), dried over sodium sulfate, vacuum filtered and the volatile fractions removed in vacuo to a crude brown oil. The crude product was purified by column chromatography (silica, eluting with dichloromethane-methanol 99:1 to 95:5 to afford the title compound as a tan viscous oil (2.10, 92.9%) with a positive ion ESI (M+H)+522.3.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>CN(C=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:4]2[C:5](=[O:6])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:1]2(=[O:2])=[O:3])=[CH:22][CH:23]=1
Reactant: Clc1ccc(OCCCCBr)cc1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccc(Cl)cc1
Yield: 57 %

Procedure:
The title compound was synthesized analogously to 83.8 (see experimental below), using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 1-(4-bromobutoxy)-4-chlorobenzene (158 mg, 0.6 mmol) in anhydrous DMF (1 mL). The crude product obtained after workup was purified by flash column chromatography on silica gel (25% ethyl acetate-petroleum ether) to give 83.7 as a white solid (m p 85-88° C.) in 57% yield (104 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si](C)(C)C#CC=C1CCNCC1.Br[C:34]1[CH:35]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[N:41]=2)[CH:37]=[CH:38][CH:39]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[C:16][C:38]3[CH:39]=[CH:34][CH:35]=[C:36]([C:40]4[O:44][N:43]=[C:42]([CH3:45])[N:41]=4)[CH:37]=3)[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: Cc1noc(-c2cccc(Br)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CC=C1CCNCC1
Agent: [F-]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cccc(-c4nc(C)no4)c3)CC2)n1
Yield: 61 %

Procedure:
The title Compound was prepared from Compound 274c following the procedure described for the compound of Example 274 using 5-(3-bromophenyl)-3-methyl-1,2,4-oxadiazole instead of 1-bromo-3,5-difluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from 9:1 to 7:3 affording the title product. Yellow oil. Yield: 61%.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:18]([O:22][C:23](=[O:40])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[C:14]1[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:13]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester gives “A81”; method 1: HPLC/MS: 1.38 min, [M+H]=406;
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](Cl)([Cl:16])=[O:15].CN(C)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:16][C:14]([O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[O:15]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,6-Diisopropylphenol (8.9 g; 0.05 mole) was dissolved in 35 mL benzene and cooled to -3° C. after which liquid phosgene (7.0 mL condensed at -70° C.) was added dropwise maintaining a temperature range of 0° to 3° C. N,N-dimethylaniline (6.0 g; 12.2 m mole) was added dropwise and stirred at 0° C. for 15 minutes. The yellow green suspension was quenched with 5 mL water and the layers were separated. The organic portion was washed with HCl (1N, 5 mL), saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated to dryness to give a green liquid which was distilled affording 2,6-diisopropylphenyl chloroformate as a yellow liquid. ##STR13##
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([C:5]2[CH:4]=[C:3]([OH:2])[N:7]([C:8]3[N:9]=[CH:10][CH:11]=[CH:12][N:13]=3)[N:6]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ncccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ncccn1
Yield: 92 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 48 of Example C-22 was used in place of Compound 27 of Example C-1.
Reaction SMILES: N1C=CC=N1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[CH3:16][C:15]1[C:10]2[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)=[N:8][CH:7]=[N:12][C:11]=2[S:13][C:14]=1[CH3:17]
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c2c1C
Agent: c1cn[nH]c1
Product: Cc1sc2ncnc(NCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-pyrazol-1-yl)-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2ccccc2)cc1
Yield: 94 %

Procedure:
From 4-methoxy-bromobenzene and phenyl boronic acid, yield 94%; mp 85-88° C. (lit.,8 90-91° C.); IR: 1604, 1582, 1520, 1486 and 1286; 1H NMR (400 MHz; CDCl3): 7.57-7.52 (4H, m), 7.42 (2H, t, J 7.9), 7.31 (1H, t, J 7.3), 6.99 (2H, d, J 8.8) and 3.86 (3H, s); 13C NMR (CDCl3): 159.1, 140.8, 133.8, 128.7, 128.1, 126.6, 115.7, 114.2 and 55.3; m/z (EI) 184 (100%, M+), 141 (60) and 69 (40)(Found: M+, 184.088. C13H12O2 requires M, 184.088).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[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][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][N:35]=[CH:34]3)O1>>[NH:36]1[C:37]2[C:33](=[CH:32][C:31]([C:2]3[C:3]([F:22])=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]4=[O:21])=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]ncc4c3)c(F)cn2c1=O
Yield: 78.9 %

Procedure:
Ethyl 8-(1H-indazol-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.15 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (45.2 mg, 0.19 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (48 mg, 77%).