Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[CH:25]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOC2=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a suspension of 60% sodium hydride (106 mg, 2.6 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (327 mg, 2.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.27 mmol) and 1,1′-carbonyldiimidazole (87 mg, 0.55 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (25 mg, 20%) as a white solid: LC/MS m/e calcd for C24H27N3O5S (M+H)+: 470.53, observed: 470.4.
Reaction SMILES: [NH2:1][C:2]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]([CH2:6][C@H:7]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[Cl:33].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:46][CH2:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[NH:42][C:41]2=[O:51])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][C:5]([CH2:6][C@@H:7]([CH2:8][C:9]([N:34]2[CH2:35][CH2:36][CH:37]([N:40]3[CH2:46][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[NH:42][C:41]3=[O:51])[CH2:38][CH2:39]2)=[O:11])[C:12]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)=[O:13])=[CH:4][C:3]=1[Cl:33]
Reactant: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)O)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 6.3 g (12.8 mmol) of (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo-butanoic acid, 3.16 g (12.9 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 4.66 g (14.5 mmol) of TBTU, 1.96 g (14.5 mmol) of HOBt, 9.45 mL (68 mmol) of triethylamine and 300 mL DMF was stirred for 12 h at RT. The reaction mixture was evaporated down i. vac., the residue was distributed between EtOAc and saturated NaHCO3 solution. The org. phase was separated off, dried and evaporated down i. vac. The residue was purified by chromatography on silica gel. The yellow oil obtained was triturated with ether and suction filtered. The desired product was obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([C:13]1[NH:14][C:15](=[O:18])[O:16][CH:17]=1)[CH3:12].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:11]([C:13]1[N:14]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:15](=[O:18])[O:16][CH:17]=1)[CH3:12]
Reactant: CCc1coc(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCc1coc(=O)n1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of o-chlorobenzoyl chloride (1.93 g.) and 4-ethyl-4-oxazolin-2-one (1.13 g.) in 30 ml. of benzene is cooled to 10° C. and reacted with 1.21 g. of triethylamine dissolved in 5 ml. of benzene. The reaction mixture is stirred at room temperature for 1 hour. The excess triethylamine and benzene is removed under reduced pressure to leave a light yellow oil (2.4 g.) which is triturated with ethanol whereupon a crystalline solid separates. The solid is removed and washed with a small amount of cold ethanol and dried. Yield 0.3 g.; m.p. 110°-112° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]1)[CH3:27].C(C1C=CC(C2C=NN(C3C=CC(C(O)=O)=CN=3)C=2O)=C(C)C=1)#N>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[C@H:30]([CH3:34])[CH2:29]1)[CH3:27]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CCN1CCN[C@H](C)C1
Agent: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)[C@H](C)C1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-3-methylpiperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.33 Hz, 3H) 1.38 (d, J=7.07 Hz, 3H) 2.33 (d, J=2.53 Hz, 3H) 2.95-3.26 (m, 4H) 3.34-3.55 (m, 2H) 3.73-4.28 (m, 3H) 7.64 (br. s., 1H) 7.71-7.78 (m, 1H) 7.93-8.68 (m, 4H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[Br:25]Br>C(Cl)Cl>[Br:25][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1

Procedure:
To 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.00 g) in CH2Cl2 containing CHCl3 (1.0 mL) and Cl4 (1.0 mL) was added bromine (0.614 g). After shining light for 1 h, the reaction was quenched with Na2S2O4, extracted with CH2Cl2, dried over Na2SO4 and evaporated to yield the title compound which was used as such for the next step (1.10 g).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([O:21][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (648 mg, 1.93 mmol) (obtained as described in Reference Example 2(6)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.31 ml, 3.95 mmol) and triethylamine (0.55 ml, 3.95 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from a mixture of n-hexane and ethyl acetate to afford 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (789 mg, yield 99%) as a white solid.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]1([C:20]2[S:29][C:28]3[NH:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[NH:24][C:23](=S)[C:22]=3[N:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH:15]1([C:20]2[S:29][C:28]3[NH:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[N:24]=[C:23]([N:13]4[CH2:12][CH2:11][NH:10][C@@H:9]([CH2:1][CH2:2][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:14]4)[C:22]=3[N:21]=2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Solvent: c1ccncc1
Product: c1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C5CCCC5)nc43)CCN2)cc1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Combine (S)-2-phenethyl-piperazine (0.537 g, 3.0 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.451 g, 1.5 mmol) in 10 ml of pyridine, and heat to 85° C. for 20 hour. Cool to room temperature, remove pyridine, the residue purify on silica gel using 2N ammonia in methanol/dichloromethane (1:10) as the eluent to give 265 mg of title compound as yellow solid. Mass spectrum (electrospray) (m/e): C27H31N5S, Cacl. Mass: 457.2; Found: 458.3 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm: 7.31–7.27 (m, 2H), 7.24–7.16 (m, 3H), 7.05–6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz), 6.62 (dd, 1H, J=7.8 Hz, J=1.0 Hz), 5.00 (br, 1H), 4.25 (br, 1H), 3.25 (t, 1H, J=7.8 Hz), 3.02–2.88 (m, 4H), 2.73–2.63 (m, 3H), 2.07–2.03 (m, 2H), 1.77–1.61 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:26]=[CH:25][N:24]=[CH:23][C:14]3=[N:15][C:16]=2[NH:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:7][CH2:6]1.[CH3:32][C:33](C)=[O:34].CC(OC(C)=O)=O>O1CCOCC1.[Pd]>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:26][CH2:25][N:24]([C:33](=[O:34])[CH3:32])[CH2:23][C:14]3=[N:15][C:16]=2[NH:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:7][CH2:6]1
Reactant: CC(C)=O
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(N[C@H]3CCOC3)nc2C1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine (2.0 g, 4.68 mmol) in dioxane:acetone (50 ml; 1.5:1) was added Ac2O (4.8 mL, 50.9 mmol) and Pd/C (400 mg, 3.76 mmol); then, the reaction was stirred at 60° C. under H2 atmosphere (345 kPa) for 72 h. The mixture was filtered through a pad of Celite™ and washed with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into sat. aqueous NaHCO3 (50 ml), then washed with brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by flash column chromatography to yield the title compound (193.4 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-1.89 (m, 4H), 2.05-2.09 (m, 4H), 2.60-2.90 (m, 4H), 3.30-3.40 (m, 4H), 3.55-3.57 (m, 1H), 3.68-3.74 (m, 2H), 3.85-3.95 (m, 2H), 4.38-4.51 (m, 4H), 5.91 (dd, J=6.0, 4.4 Hz, 1H), 7.01 (m, 1H), 7.25-7.31 (m, 2H); ESI-MS m/z [M+H]+ 474.3.
Reaction SMILES: I.[PH2](O)=O.[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)(=O)C.O>[CH3:5][C:6]1[NH:7][C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: O=Cc1ccccc1
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(Cc2ccccc2)c1C
Reaction time: 0.17 h

Procedure:
A solution of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of 50% hypophosphorous acid containing 548 mg of 2,4-dimethyl-3acetyl pyrrole was stirred magnetically while a solution of 0.6 ml of benzaldehyde in 5 ml of acetic anhydride was slowly added over 20 mins. The solution was stirred for 10 mins, then poured into water. The crude product which separated was recrystallized from acetone (thimble) as nearly colourless irregular plates (85%, m.p. 165.5°-167° C. after a partial change to prismatic rods above 165° C. Anal. Cal. for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.22; H, 7.50; N, 6.18.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[NH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CN(C=O)C>[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=3)[C:4]([CH:3]=[N:2][O:1][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=3)=[CH:5]2)=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)COc1ccc2[nH]cc(C=NO)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of the product of step 3 (280 mg, 1.068 mmoles) in DMF (2 ml), cesium carbonate (1.0 gm, 3.2 mmoles), 4-trifluoromethyl benzylbromide (510 mg, 2.13 mmoles were added and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure, The crude product was purified by column chromatography using 15% EtOAC in hexane as eluent to yield 350 mg (56%) of product as solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].[CH3:16][NH2:17].CCO>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5]([NH:17][CH3:16])=[O:6]
Reactant: CN
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 20 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of methyl 2-methoxy-5-nitrobenzoate (389 mg, 1.84 mmol) in THF (3.0 mL) was added 33% MeNH2/EtOH solution (2.0 mL, 16.0 mmol) and the mixture was stirred at 20° C. overnight. The solution was evaporated and the residue was chromatographed (SiO2 230-400 mesh) eluting with 7:3 hexanes/EtOAc to remove 2-(methylamino)-5-nitrobenzoate derivatives. Further elution with EtOAc provided the title compound (268.5 mg, 70% yield) as a yellowish solid: LCMS (ES) m/z 211 (M+H).
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.Cl[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([CH2:13][O:14][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)cc(Cl)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.34 M) solution of (5-bromo-2,3-dichlorophenyl)methanol (1 eq.) from the previous step was added chloro(1,1-dimethylethyl)dimethylsilane (1.1 eq.) and imidazole (1.5 eq.). The resulting yellow solution was stirred at RT for 16 h. The reaction mixture was then diluted with ether and washed sequentially with 10% aq. HCl, water and brine. The ether extract was dried Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH3:11]C1N=C(C=O)C=CC=1>>[CH:1]([C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:2]
Reactant: CCc1cccc(C=O)n1
Reactant: Cc1cccc(C=O)n1
Product: CC(C)c1cccc(C=O)n1

Procedure:
The alkylation of 6-ethyl-2-pyridinecarboxaldehyde from Step 1 was performed as described above for 6-methyl,2-pyridinecarboxaldehyde.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6]([S:8]([O:11][CH3:12])(=[O:10])=[O:9])=[CH2:7]>[I-].[Zn+2].[I-]>[CH:5]12[O:1][CH:2]([CH:6]([S:8]([O:11][CH3:12])(=[O:10])=[O:9])[CH2:7]1)[CH:3]=[CH:4]2
Reactant: c1ccoc1
Reactant: C=CS(=O)(=O)OC
Agent: [I-]
Agent: [Zn+2]
Product: COS(=O)(=O)C1CC2C=CC1O2
Yield: 34 %

Procedure:
To a four-necked flask having a capacity of 300 mL and equipped with a stirrer, a dropping funnel, and a thermometer, 150 g (2.20 mol) of furan and 15.0 g of zinc iodide were added, and 41.5 g (0.34 mol) of methyl vinylsulfonate was added to the flask from the dropping funnel at 25 to 27° C. The resultant mixture was continuously stirred at the same temperature for 2 days, and then the resultant reaction mixture was transferred to a 1 L separatory funnel. The reaction mixture was washed twice with 300 mL of water, and then unreacted furan was removed through evaporation under reduced pressure, to thereby obtain 22.0 g of methyl 7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:18]=[N:19][C:20](=[O:23])[NH:21][CH:22]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[H][H]>C(O)C.[Ni]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH2:22][NH:21][C:20](=[O:23])[NH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(-c2cnc(=O)[nH]c2)cc1OC1CC2CCC1C2
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(C2=CNC(=O)NC2)cc1OC1CC2CCC1C2
Yield: 31.3 %

Procedure:
The pyrimidinone (0.38 g, 1.22 mmol) is dissolved in 20 ml ethanol and treated with 0.5 g Raney Nickel, 40 psi hydrogen and refluxed for 18 hours. The reaction is cooled, filtered through celite, and the filtrate concentrated in vacuo. The residue is crystallized from ethyl acetate to afford 0.12 g (31.8%) of the dihydro pyrimidinone as a crystalline solid comprising a 7:3 mixture of endo/exo norbornyl isomers.
Reaction SMILES: [O:1]=[C:2]1[C:11](/[CH:12]=[CH:13]/[C:14](Cl)=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].C(N(CC)CC)C>O1CCCC1>[C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:14](=[O:15])/[CH:13]=[CH:12]/[C:11]1[C:2](=[O:1])[O:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:26])=[O:25]
Reactant: O=C(Cl)/C=C/c1cc2ccccc2oc1=O
Reactant: Nc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1cc2ccccc2oc1=O)Nc1ccccc1C(=O)O

Procedure:
Prepared analogously to Example 31 from trans-3-(2-oxo-2H-chromen-3-yl)-acrylic acid chloride and anthranilic acid in tetrahydrofuran with the addition of triethylamine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH2:8]Br.[CH2:19]([N:26]1[C@@H:31]2[C@H:32]([C:34]#[N:35])[CH2:33][C@@:27]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:28]([OH:36])[CH2:29][CH2:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([N:26]1[C@@H:31]2[C@H:32]([C:34]#[N:35])[CH2:33][C@@:27]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:28]([O:36][CH2:8][C:7]1[CH:6]=[C:5]([C:4]([F:18])([F:17])[F:3])[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)[CH2:29][CH2:30]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
Sodium hydride (0.3 g, 7.5 mmol, 60% in oil) was added portionwise to a solution of 3,5-bis(trifluoromethyl)benzyl bromide (2.5 g, 8.3 mmol) and (1R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 31; 1.4 g, 4.4 mmol) in THF (20 ml). The mixture was stirred at 50° C. for 18 hours then cooled with an ice-bath and quenched by dropwise addition of water. The mixture was partitioned between brine and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. Chromatography on silica gel eluting with 2.5, 5, 10 and 20% ethyl acetate/iso-hexanes afforded the title compound (2.12 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]3[N:14]=[C:13](Cl)[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]3[N:7]=2)[CH:3]=1.[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:34]=[CH:35][C:36]([C:13]3[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]4[N:7]=[C:8]5[C:4]([CH:3]=[C:2]([Br:1])[CH:10]=[CH:9]5)=[C:5]4[N:14]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Clc1nc2c3cc(Br)ccc3nn2cc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(Br)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Yield: 21 %

Procedure:
1 g (2.9 mmol) 9-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-2), 1.09 g (2.9 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, 322 mg (0.28 mmol) tetrakis(triphenylphosphine)palladium and 886 mg (8.4 mmol) sodium carbonate in 30 mL dioxane and 4.2 mL water were heated over night at 105° C. The reaction mixture was poured on water/dichloromethane and vigorously stirred for 30′. The organic phase was separated, washed with brine, dried, filtered, and the solvent was evaporated. The residue was purified by HPLC yielding 346.4 mg (20.6%) of the title compound.
Reaction SMILES: CS[CH2:3][C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C[I:16]>ClCCl>[I:16][CH2:3][C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CSCc1cc(=O)c2ccccc2o1
Reactant: CI
Solvent: ClCCl
Product: O=c1cc(CI)oc2ccccc12
Reaction time: 96 h

Procedure:
8 g of 2-methylthiomethyl-4-oxo-4H-chromene, 200 ml of methyl iodide and 26 ml of dichloromethane are brought to reflux with stirring for 4 days. The precipitate is filtered off, the excess solvents and reagents are evaporated off, the residue is taken up with ethyl ether and the organic phase is washed with sodium thiosulfate solution, dried and evaporated.