Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:22])=[CH:18][N:17]=3)[C:14]=2[OH:15])[C:5]([CH3:25])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1COCCN1
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)N3CCOCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and morpholine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H) 3.40-3.87 (m, 8 H) 7.79 (d, J=7.07 Hz, 1 H) 7.88 (d, J=10.86 Hz, 1 H) 8.10 (dd, J=8.59, 2.02 Hz, 1 H) 8.27 (br. s., 1 H) 8.44 (br. s., 1 H) 8.57 (dd, J=2.27, 0.76 Hz, 1 H) 13.47 (br. s., 1 H); ESI-MS m/z [M+H]+408.3.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1C.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[O:55]=[C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58](=[O:65])[N:57]1[CH2:66][CH2:67][CH2:68][C:69]1[CH:70]=[C:71]([CH:74]=[CH:75][CH:76]=1)[CH:72]=O>C1COCC1.C(Cl)Cl>[CH3:2][C:3]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:4]=1/[CH:5]=[CH:72]/[C:71]1[CH:70]=[C:69]([CH2:68][CH2:67][CH2:66][N:57]2[C:58](=[O:65])[C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:56]2=[O:55])[CH:76]=[CH:75][CH:74]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Cc1ccc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2C)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(C)c(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the crude 2,5-dimethylmethylbenzyltriphenylphosphonium bromide in THF (10 mL) and CH2Cl2 (5 mL) were added potassium tert-butoxide (0.163 g, 1.45 mmol) and 18-crown-6 (0.163 g, 1.45 mmol). The mixture was stirred at room temperature under argon for 30 min then sonicated for 1 min. A solution of phthalimide 29 (0.193 g, 0.658 mmol) in CH2Cl2 (2 mL) was added and the mixture stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between EtOAc and saturated aqueous NH4Cl. The combined organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (20 to 50% EtOAc-hexanes) gave (E)-2-(3-(3-(2,5-dimethylstyryl)phenyl)propyl)isoindoline-1,3-dione as an oil. Yield (0.225 g, 86%), trans-/cis-isomer 1:1.5. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.69-7.76 (m, 4H), 6.91-7.44 (m, 7H) 6.63 (d, J=12.0 Hz, 1H), 6.57 (d, J=12.0 Hz, 1H), 3.81 (t, J=7.2 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H), 2.44 (s, 3H), 2.39 (s, 3H), 2.08-2.17 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13](=[O:27])[C@@H:14]1[CH2:18][CH:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:27])[C@@H:14]1[CH2:18][C:17](=[O:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 9.63 mL (7.2 mmol) of oxalyl chloride in 10.6 mL of CH2Cl2 stirred at −78° C. was added a solution of 0.94 mL (13.2 mmol) of methyl sulfoxide in 15 mL of CH2Cl2. The solution was stirred at −78° C. for 30 min. A solution of 1.47 g (6 mmol) of N-Boc-4-hydroxyproline methyl ester in 19 mL of CH2Cl2 was then added dropwise. The mixture was stirred at −78° C. for 1.5 h, and 3.34 mL (24 mmol) of triethylamine was added. The solution was allowed to warm up to room temperature and stirred overnight. It was then diluted with 100 mL of CH2Cl2, washed successively with 100 mL of water, 100 mL of 1N HCl, and 100 mL of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluted with ethyl acetate/hexanes, 1:3), to afford 1.294 g (89% yield) of N-Boc-4-oxo-proline methyl ester. 1H NMR (500 MHz, CDCl3) δ 1.45 (m, 9H), 2.60 (m, 1H), 2.95 (m, 1H), 3.75 (m, 3H), 3.90 (m, 2H), 4.80 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13]([OH:15])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH2:45][CH:46]1[CH:53]2[CH2:54][C:49]3([OH:56])[CH2:50][CH:51]([CH2:55][CH:47]1[CH2:48]3)[CH2:52]2>ClCCl.CN(C=O)C.O>[OH:56][C:49]12[CH2:54][CH:53]3[CH2:52][CH:51]([CH2:55][CH:47]([CH:46]3[NH:45][C:13]([C:7]3[CH:6]=[N:5][N:4]([CH:1]4[CH2:2][CH2:3]4)[C:8]=3[C:9]([F:10])([F:11])[F:12])=[O:15])[CH2:48]1)[CH2:50]2
Reactant: O=C(O)c1cnn(C2CC2)c1C(F)(F)F
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cnn(C2CC2)c1C(F)(F)F
Reaction time: 2 h

Procedure:
1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (Intermediate 6, 100 mg, 0.45 mmol) was dissolved in a mixture of dry dichloromethane (4 mL) and dry DMF (1 mL). DIPEA (0.5 mL, 2.9 mmol) and TSTU (165 mg, 0.5 mmol) were added to the above mixture. After the mixture was stirred for 2 h, the appearance of active ester was detected by LC-MS. Then 4-amino-adamantan-1-ol (77 mg, 0.46 mmol) was added. After another 4 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried under vacuum. The crude mixture was purified by C-18 reversed phase preparative-HPLC with a gradient of 10-100% acetonitrile/water to give 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide (79 mg, 48%. Mass spectrum: m/z: 370.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CO>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
2.6 g. (0.02 mole) of 5-fluorouracil and 1.52 g (0.011 mole) of anhydrous potassium carbonate were suspended in 50 ml. of dioxane and then 2.53 g (0.022 mole) of methanesulfonyl chloride in 20 ml. of dioxane was dropwise added thereto. After stirring at 80°C. for 10 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in a small amount of methanol and allowed to stand at 0°C. overnight. There was obtained 1.48 g (45.4% yield) of 5-fluoro-1 -methanesulfonyluracil. Recrystallization of the product from methanol gave leaflets melting at 223°-224°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:34])[NH:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:14])[F:15])[CH:7]=2)=[O:4])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1cccc(OC(F)(F)F)c1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(OC(F)(F)F)c2)c1
Yield: 37.2 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3-trifluoromethoxyphenyl)acetamido]acetate (3.4 g) and 3-methylphenyl isocyanate (1.4 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(3-trifluoromethoxyphenyl)acetamido}acetate (1.75 g), m.p. 125° C., is obtained.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:18])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Fe]>[ClH:1].[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[O:18])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CN1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Product: Nc1ccc(C(=O)CN2CCN(Cc3ccccc3)CC2)cc1
Yield: 60 %

Procedure:
N1-benzyl-N4-(4-nitrophenacyl)piperazine dihydrochloride (IV-9) (2 mmol) was reduced by reductive iron in a procedure similar to Example 12 to give compound (IV-16), yield 60%, mp 286-288° C. M+ 309.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[N:19]#[C:20]Br.[OH-].[K+]>C(O)(C)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:20]2[NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CBr
Reactant: Nc1ccccc1NCCCN1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1nc2ccccc2n1CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 20.0 g. (0.086 mole) of N-[3-(1-piperidinyl)propyl]-o-phenylenediamine in 80 ml. water, 20 ml. of isopropanol was added to obtain a homogenous solution. With continued stirring, 21.2 g. (0.200 mole) of cyanogen bromide was added in portions over a one hour period. Room temperature was maintained throughout the addition. After stirring for an additional 2 hours the reaction mixture was allowed to stand overnight. The mixture was then poured into ice-water, made strongly alkaline with KOH and extracted with methylene chloride. The extracts were evaporated to a red oil which crystallized from ether, 7.9 g. (36% yield), m.p. 176°-178° C. An analytical sample of 1-[3-(1-piperidinyl)propyl]-2-amino benzimidazole was obtained by crystallization from benzene-cyclohexane, m.p. 179°-181° C.
Reaction SMILES: O[CH2:2][C@H:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1.[F:25]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>O1CCCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[C:11]3[C@H:3]([CH2:2][F:25])[CH2:4][CH2:5][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[C@H](CO)CC3)CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[C@H](CF)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
(R)-tert-Butyl 4-(5-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (30.0 mg, 0.0897 mmol) was dissolved in tetrahydrofuran (0.080 mL). Perfluoro-1-butanesulfonylfluoride (0.0644 mL, 0.359 mmol) and triethylamine trishydrofluoride (0.0584 mL, 0.359 mmol) were added to this solution, followed by triethylamine (0.150 mL, 0.726 mmol). The reaction mixture was allowed to stir for 12 hours at room temperature. The reaction was concentrated, and the material was subjected to chromatography on SiO2 and eluted with 10% MeOH/DCM. The desired 4-((R)-5-fluoromethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (25.0 mg, 83%) was isolated. LC/MS (APCI)+ m/z 337.2.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[S:56][S:55][C:54](=[S:57])[CH:53]=2)=[CH:48][CH:47]=1>CN(C)C=O.C(OCC)(=O)C>[S:57]=[C:54]1[S:55][S:56][C:52]([C:49]2[CH:48]=[CH:47][C:46]([O:9][C:8](=[O:10])[CH2:7][C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[NH:11][C:12]3[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:18])=[CH:51][CH:50]=2)=[CH:53]1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc(-c2cc(=S)ss2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To the solution of 1 (diclofenac, 890 mg, 3.0 mmol) in 50 mL of N,N-dimethylformamide, hydroxybenzotriazole (445 mg, 3.3 mmol) and DCC (680 mg, 3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 5-p-hydroxyphenyl-1,2-dithiole-3-thione (2; 678 mg, 3 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure and the oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 3 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which [2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (3) was obtained (1.1 g, 74% yield).
Reaction SMILES: Br[C:2]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[C:34]([Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])#[CH:35].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH:30]1([N:27]2[CH2:26][CH2:25][N:24]([C:23]3[C:2]([C:35]#[C:34][Si:36]([CH:37]([CH3:39])[CH3:38])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])=[CH:3][C:4]4[C:16](=[O:17])[C:15]5[C:14]6[C:9](=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=6)[NH:8][C:7]=5[C:6]([CH3:21])([CH3:20])[C:5]=4[CH:22]=3)[CH2:29][CH2:28]2)[CH2:33][CH2:32][CH2:31]1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: CC1(C)c2cc(N3CCN(C4CCC4)CC3)c(Br)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)[Si](C#Cc1cc2c(cc1N1CCN(C3CCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O)(C(C)C)C(C)C
Yield: 74.5 %

Procedure:
Under nitrogen atmosphere, to the MeCN (8 ml) suspension of 9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 200 mg, 0.397 mmol), ethynyltriisopropylsilane (268 mg, 3.0 eq.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (39 mg, 0.2 eq.), Pd(CH3CN)2Cl2 (11 mg, 0.1 eq.) and cesium carbonate (518 mg, 4.0 eq.) were added and the mixture was stirred and heated under reflux condition until the reaction is completed. Upon the completion of the reaction, distilled water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-[(triisopropylsilanyl)-ethynyl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (179 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:20])[N:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:1][C:2]1[N:3]=[C:4]([CH3:20])[N:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(Cn2c(C)nc(O)cc2=O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C)nc(OCc3ccc(F)cc3F)cc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of methyl 4-[(4-hydroxy-2-methyl-6-oxopyrimidin-1(6H)-yl)methyl]benzoate (0.2 g, 0.00073 mol, from step 2), potassium carbonate (0.15 g, 0.001 mol), 2,4 difluorobenzylbromide (0.15 g, 0.00073 mol), and 18-crown-6 (0.011 g) in DMF is stirred at room temperature for 1 h under argon atmosphere. The DMF was distilled in vacuo and the residue is partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase is washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel flash chromatography using 35% EtOAc in hexanes to afford the title compound (0.20 g, 69%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.98 (d 2H, J=8.4 Hz), 7.54 (m, 1H), 7.27 (d, 2H, J=8.4 Hz), 6.98 (m, 2H), 5.78 (s, 1H), 5.38 (s, 2H), 5.32 (s, 2H), 3.88 (s, 3H), and 2.44 (s, 3H); ES-HRMS m/z 401.1308 (M+H calcd for C21H19N2O4F2 requires 401.1307). 19F NMR (CD3OD/400 MHz) −111.77 (m), 116.06 (m).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@@H:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:24]([F:27])([F:26])[F:25])[C:6]=2[NH:5]1.Cl.F[C:30](F)(F)C1C2NC(=O)[C@@H]3CNC[C@@H]3C=2C=CC=1.IC>C1COCC1>[CH3:30][N:5]1[C:6]2[C:7]([C:24]([F:27])([F:25])[F:26])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH:13]2[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3NC(=O)[C@@H]2C1
Reactant: O=C1Nc2c(cccc2C(F)(F)F)[C@H]2CNC[C@@H]12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C2CN(C(=O)OC(C)(C)C)CC2c2cccc(C(F)(F)F)c21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (40 mg of 60% dispersion in mineral oil, 1.0 mmol) in 5 mL of THF was added (±)-cis-tert-butyl 4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate, the intermediate from Example 3 (80 mg, 0.22 mmol) in 3 mL of THF. The mixture was stirred for 30 min and then there was added iodomethane (0.10 mL, 1.6 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was filtered through a pad of silica gel and concentrated. The residue was purified by chromatography (ISCO, elution with 1-10% EtOAc in hexane) to afford tert-butyl 5-methyl-4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate. To this material in 4 mL of hexane was added HCl (4 mL of a 4N solution in 1,4-dioxane, 16 mmol) and the resulting solution was allowed to stir at ambient temperature overnight. The solvents were removed in vacuo and the residue was purified by HPLC (C18 reverse phase, elution with gradient H2O/CH3CN+0.5% TFA). Pure fractions were combined and concentrated. The residue was partitioned between aq NH4OH and CHCl3, the organics were washed with brine, dried (K2CO3) and concentrated to afford 12 mg (60%) of the title compound of Example 4. 1H NMR (CDCl3): δ 7.60 (d, 1H), 7.42 (d, 1H), 7.18 (t, 1H), 3.81 (dd, 1H), 3.39 (s, 3H), 3.37-30 (m, 2H), 3.22-3.18 (m, 1H), 3.05-2.98 (m, 1H), 2.81 (t, 1H). LRMS (ESI): 271.16 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:31])=[C:17]([C@:19]2([CH3:30])[CH2:24][S:23](=[O:26])(=[O:25])[C:22]([CH3:28])([CH3:27])[C:21]([NH2:29])=[N:20]2)[CH:18]=1>>[NH2:29][C:21]1[C:22]([CH3:27])([CH3:28])[S:23](=[O:25])(=[O:26])[CH2:24][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:31])([CH3:30])[N:20]=1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC1(C)C(N)=N[C@](C)(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)CS1(=O)=O
Yield: 67 %

Procedure:
Prepared from 5-cyanopicolinic acid (57.1 mg, 386 μmol, Eq: 1.1) and (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (105 mg, 351 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (101 mg, 235 μmol, 67.1% yield) as a white foam. MS (ISP): m/z=430.3 [(M+H)+].
Reaction SMILES: N[C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([Br:18])[CH:9]=2)=[C:5]([CH3:7])[N:6]=1.N(OCCC(C)C)=O>C1COCC1>[Br:18][C:10]1[CH:9]=[C:8]([C:4]2[S:3][CH:2]=[N:6][C:5]=2[CH3:7])[CH:13]=[CH:12][C:11]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: Cc1nc(N)sc1-c1ccc(OC(C)C)c(Br)c1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Cc1ncsc1-c1ccc(OC(C)C)c(Br)c1
Yield: 45.2 %

Procedure:
A solution of 118 mg (0.361 mmol) of 2-amino-5-(3-bromo-4-isopropoxyphenyl)-4-methylthiazole (from Example 230, Step B) in 3.6 mL of THF was added to a solution of 0.107 mL (93 mg, 0.80 mmol) of isoamyl nitrite in 2.4 mL of THF. The resulting solution was refluxed for 1 h. The cooled mixture was partitioned between 25 mL of dichloromethane and 10 mL of water, and the aqueous layer was extracted with 2×25 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, decanted, and evaporated. The crude product was purified by flach column chromatography, eluting with 5% ethyl acetate in hexane, to give 51 mg of the title compound as a yellow solid. Mass spectrum (NH3/CI): m/z=312 (M+1).
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl[CH:24]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH3:35])[C:25]#[N:26]>O1CCCC1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:24][C:25]#[N:26])=[C:29]([CH3:35])[CH:30]=1
Reactant: Cc1cc(F)ccc1CC(Cl)C#N
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C=CC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 195.2 %

Procedure:
18.2 g (0.12 mole) of diazabicycloundecene in 150 ml of tetrahydrofuran are added dropwise, with stirring at room temperature, to 21.7 g (0.11 mole) of 2-chloro-3-(4-fluoro-2-methylphenyl)-propionitrile in 100 ml of tetrahydrofuran, and when the addition is complete, the mixture is stirred at room temperature for 15 hours and filtered, the filtrate is evaporated in vacuo, the residue is taken up in ethyl acetate, washed consecutively with 1-normal hydrochloric acid and water and dried over sodium sulphate, and the solvent is removed in vacuo. 34.6 g (96% of theory) of 3-(4-fluoro-2-methylphenyl)-acrylonitrile of melting point 86° C.-87° C. are obtained.