Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccccc2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.6 mg, 0.166 mmol) in CH2Cl2 (2 mL) was added phenyl isocyanate (0.20 μL, 0.184 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 145 as a colorless solid (45.3 mg, 69%). LCMS m/z (%)=394 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.64 (bs, 1H), 8.59 (bs, 1H), 7.48-7.41 (m, 4H), 7.37 (d, J=2.71 Hz, 1H), 7.29-7.23 (m, 2H), 7.09 (d, J=8.97 Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, J=1.85 Hz, 1H), 3.97 (t, J=6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-:2].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:1](=[O:2])[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: COc1ccccc1Nc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1-n1c(=O)oc(=O)c2ccccc21
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a suspension of 24.44 g (0.177 mole) of potassium carbonate in 119 ml of toluene and 238 ml of water, stirred at 20°-40° C., was added 28.61 g (0.1176 mole) of 2-(2-methoxyphenylamino)benzoic acid, and phosgene was bubbled through the mixture for a period of 3.5 hours. The reaction was allowed to stand overnight with stirring, and the solid material was collected by filtration. The latter was dissolved in ethyl acetate and added to the toluene layer separated from the filtrate. The solution was washed twice with 200 ml 1N potassium hydroxide and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to yield 7 g of N-(2-methoxyphenyl)isatoic anhydride.
Reaction SMILES: [O:1]=[C:2]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:19])[CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:6]=2[N:5]=1.O.[OH-].[Li+]>CO.O>[O:1]=[C:2]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[O:19])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:6]=2[N:5]=1
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(CC(=O)N3CCCC3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1cc(C(=O)O)c2nc(CC(=O)N3CCCC3)[nH]c2c1)c1ccccc1C(F)(F)F
Yield: 83.6 %

Procedure:
A solution of methyl 2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylate (74 mg) and lithium hydroxide hydrate (66 mg) in MeOH-water (1:1, 2 mL) was stirred at 50° C. for 30 minutes. The solvent was removed under reduced pressure, water was added, and the residue was neutralized by 1N hydrochloric acid under ice-cooling. The precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain the titled compound (60 mg) as pale yellow powder.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.Br[CH2:14][CH2:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18]Br.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:20]1([CH:16]2[CH2:17][CH2:18][N:2]([CH:3]3[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]3)[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1CCC(N)CC1
Reactant: BrCCC(CCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1CCC(N2CCC(c3ccccc3)CC2)CC1

Procedure:
A solution of 3.896 g (20.117 mM) of methyl 4-aminocyclohexanecarboxylate hydrochloride, 6.77 g (22.1 mM) of 1,5-dibromo-3-phenylpentane, and 14.0 ml (80.5 mM) of N,N-diisopropylethylamine in 100 ml of acetonitrile was refluxed for one day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[CH2:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:21][C:22]#[CH:23]>CCCCCCC.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ncn2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(C#CCCCc2ccccc2)ncn1

Procedure:
This product was prepared from toluene-4-sulfonic acid 6-methyl-pyrimidin-4-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (36.6 mg, 31%); 1H NMR δ (CDCl3): 9.01 (s, 1H), 7.31-7.25 (m, 2H), 7.22-7.16 (m, 4H), 2.78 (t, J=7.18 Hz, 2H), 2.51 (s, 3H), 2.41 (t, J=7.17 Hz, 2H), 1.93 (p, J=7.22 Hz, 2H); LCMS m/z: 236.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.O>CN(C)C=O.[Al]>[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:12][C:11]=1[Br:1]
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Cc2ccncc2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A solution of N-bromosuccinimide (1.4 gm) in 10 mL dimethylformamide was added in a dropwise manner to a solution of 4-(4-aminobenzyl)pyridine (1.5 gm) in 10 mL of dimethylformamide. The reaction flask was wrapped in aluminum foil to prevent exposure of the reagents to light. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by thin-layer chromatography. When the reaction was completed, the reaction mixture was combined with 100 mL of H2O with stirring. A reddish brown precipitate was formed, filtered out of solution, washed with H2O, and air dried. The solid was dissolved in ethyl acetate, back washed with saturated NaCl, dried over MgSO4 and triturated with ethyl ether. The solid was filtered from the solution and air dried yielding 1.6 gm of 4-(4-amino-3-bromobenzyl)pyridine as reddish/tan crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: NCc1ccccc1Br
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccccc1Br
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from 2-bromobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. [M+H] calc'd for C13H11BrN2O2, 307, 309; found 307, 309.
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[N:72]=[CH:71][N:70]=[C:69]([NH:73][CH:74]([CH3:76])[CH3:75])[CH:68]=1>>[Cl:37][C:35]1[CH:34]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]3[CH:68]=[C:69]([NH:73][CH:74]([CH3:76])[CH3:75])[N:70]=[CH:71][N:72]=3)[CH2:44]2)=[O:41])[CH:32]=[C:31]([Cl:30])[CH:36]=1
Reactant: CC(C)Nc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: CC(C)Nc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 142 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 6-chloro-N-isopropylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (t, J=1.89 Hz, 2H), 6.48 (d, J=1.89 Hz, 3H), 5.72 (s, 1H), 3.78-4.05 (m, 5H), 3.42-3.60 (m, 3H), 1.90-2.08 (m, 2H), 1.80 (td, J=3.59, 8.97 Hz, 3H), 1.65 (td, J=3.21, 8.03 Hz, 2H), 1.13-1.39 (m, 13H). EIMS (m/z): calcd. for C20H26O2N6O (M+1H) 437. found 437.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:34]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][C:10]2[N:11]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.O.NN>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:34])[CH2:9][C:10]2[N:11]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: NC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
2-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethyl)isoindoline-1,3-dione (Intermediate 87) (1.78 g, 3.00 mmol) and hydrazine hydrate (0.204 mL, 4.19 mmol) in methanol (30 mL) were refluxed for 3 hours. The resulting clear solution was left to cool to room temperature overnight then filtered. The filtrate was applied to a 20 g SCX cartridge and eluted with methanol followed by 2N NH3(MeOH). Product-containing fractions were combined and concentrated by evaporation then purified by flash silica chromatography, elution gradient 2 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanamine (0.942 g, 67.8%) as a colourless solid.
Reaction SMILES: [C:1]([C@H:4]1[CH2:13][C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[NH:5]1)([OH:3])=[O:2].[CH3:21][C:22](=[CH2:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl.S(=O)(=O)(O)O>[CH3:18][O:17][C:15]([CH2:14][C@@H:12]1[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[NH:5][C@@H:4]([C:1]([O:3][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:2])[CH2:13]1)=[O:16]
Reactant: C=C(C)C
Reactant: COC(=O)C[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C[C@H]1C[C@H](C(=O)OC(C)(C)C)Nc2cc(Cl)cc(Cl)c21

Procedure:
Trans-2-carboxy-4-methoxycarbonylmethyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (Example 156) (4 g) was suspended in dichloromethane (50 ml) and isobutylene (50 ml) was condensed at 0° C. Concentrated sulphuric acid (10 drops) was added and the reaction mixture was shaken for 3 days under a nitrogen atmosphere of 30 p.s.i. The solution was poured into saturated sodium hydrogen carbonate solution and diluted with a further amount of dichloromethane (100 ml). The organic layer was separated and the aqueous solution was washed with diethyl ether (100 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue obtained was purified by chromatography on silica gel with 20% hexane in dichloromethane as eluent to give the title compound as a colourless oil (4.07 g); δ (250 MHz, DMSO) 1.45 (9H, s, (CH3)3C), 1.64 (1H, ddd, J=13.0, 12.4 and 4.0 Hz, CHACHBHCCHD), 2.10 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 2.49 (2H, m, CHECHFCO2CH3), 3.44 (1H, m, CHACHBHCCHDCHEHFCO2CH3), 3.65 (3H, s, CO2CH3), 3.97 (1H, dd, J=12.4 and 3.4 Hz, CHACHBHCCHD), 6.63 (2H, m, 6-H or 8-H and NH), 6.79 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e (FAB) 374 (M+1); Found C, 54.93; H, 5.67; N, 3.69. C17H21Cl2NO4 requires C, 54.56; H, 5.66; N, 3.74%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[O:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:53][C:52]2[CH:54]=[CH:55][CH:56]=[C:50]([O:49][C:40]3[C:39]4[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=4)[N:43]=[CH:42][N:41]=3)[CH:51]=2)=[O:19])[N:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C4CCCCC4)c3)c2cc1OC
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg), N,N-Diisopropylethylamine (67 mg, 0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (80 mg, 0.26 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (55 mg, 10% over two steps) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.57-7.60 (m, 2H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.93 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.94 (m, 1H), 1.62-1.82 (m, 8H), 1.24-1.35 (m, 2H), 1.24 (s, 9H); LC-MS (ESI) m/z 545 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1)[CH3:27]
Reactant: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CCOC(=O)Cc1ccccc1-c1ccc(-c2onc(C)c2NC(C)Cc2ccc(OC)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[C:15]([C:16]([O:18]C)=O)=[CH:14][C:13]3[CH:20]=[CH:21][S:22][C:12]2=3)=[CH:5][CH:4]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[NH:27][CH2:24][CH2:25][N:26]2[C:16](=[O:18])[C:15]2[N:11]([C:12]4[S:22][CH:21]=[CH:20][C:13]=4[CH:14]=2)[CH2:10]3)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc2ccsc2n1CC(=O)c1ccc(OC)cc1
Reactant: NCCN
Solvent: C1COCCO1
Product: COc1ccc(C23Cn4c(cc5ccsc54)C(=O)N2CCN3)cc1
Yield: 73.7 %

Procedure:
To a solution of methyl 6-[2-(4-methoxyphenyl)-2-oxoethyl]-6H-thieno[2,3-b]pyrrole-5-carboxylate (100 mg, 0.30 mmol) in 1,4-dioxane (10 mL) was added ethylenediamine (0.78 mL, 12 mmol) and the mixture heated at reflux. The reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (1 to 6% methanol-dichloromethane) to yield 11a-(4-methoxyphenyl)-2,3,11,11a-tetrahydro-1H,5H-imidazo[1,2-a]thieno[3′,2′:4,5]pyrrolo[1,2-d]pyrazin-5-one (75 mg, 73% yield) as a white solid. ESI-MI m/z [M+H]+ 340.25. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=8.7 Hz, 2H), 7.14 (s, 1H), 6.96 (d, J=5.3 Hz, 1H), 6.82 (d, J=5.3 Hz, 1H), 6.78 (d, J=8.7 Hz, 2H), 4.52 (d, J=11.7 Hz, 1H), 4.25 (d, J=11.7 Hz, 1H), 4.02-3.89 (m, 1H), 3.73 (s, 3H), 3.64-3.51 (m, 1H), 3.37-3.26 (m, 1H), 3.08-2.94 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22][CH3:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:31].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:23])=[O:31])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-methyl-3-{3-[(methylthio)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.740 g, 1.90 mmol) in methylene chloride is treated with 3-chloroperoxybenzoic acid (0.580 g, 60%, 2.00 mmol), stirred at room temperature for five minutes, diluted with additional methylene chloride, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% ethyl acetate in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:9]([CH2:30][CH3:31])[CH2:10][C@:11]([OH:29])([C:25]([F:28])([F:27])[F:26])C=NC2C=CC=C3C=2C=CC(=O)N3)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.[C:38]([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([CH:9]([CH2:30][CH3:31])[CH2:10][C:11]([OH:29])([C:25]([F:27])([F:26])[F:28])[CH:38]=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])O
Reactant: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Temperature: -30 °C

Procedure:
and 2.3 g of (2R,4R/S)-4-(,4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal 300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 140 mg (0.88 mmol) of 5-aminoquinolin-2(1H)-one are dissolved in 19 ml of toluene and the solution is admixed with 0.55 ml (1.75 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 539 mg of (5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 44 ml of CH2Cl2 and the solution is cooled to −30° C. 8.9 ml (8.9 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the mixture is allowed to warm to room temperature over 22 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 134 mg of the title compound.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])([CH3:20])([CH3:19])[CH3:18]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc(CS)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 3-(mercaptomethyl)benzoic acid (12 g, 71.43 mmol, 1.00 equiv) in acetonitrile (200 mL) was added tert-butyl acrylate (60 mL) and DBU (21.7 g, 142.76 mmol, 2.00 equiv) and the solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 200 mL of water and then adjusted to pH 2˜3 with 10% hydrochloric acid. This was extracted with 3×200 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (50:1) to afford 10.5 g (47%) of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid as red oil. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.08 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.46 (t, 1H), 3.81 (s, 2H), 2.68 (t, 2H), 2.50 (t, 2H), 1.48 (s, 9H). MS (ES, m/z): 295 [M−H]−.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.Cl>CS(C)=O.O>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[O:1][CH2:2][CH3:3])[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 40 %

Procedure:
Sodium ethoxide (232 mg, 3.4 mmol) was added to a solution of 6-chloro-7-fluoro-8-nitro-9H-β-carboline (200 mg, 0.76 mmol) in DMSO (4 ml) and the reaction mixture allowed to stir overnight. The reaction mixture was diluted with water and the pH of the solution was adjusted to about 4 by adding 1N HCl. The aqueous solution was extracted (3×) with EtOAc. The combined EtOAc layers were dried and evaporated. The crude product was purified by flash chromatography to give the desired product in 40-60% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.44 (t, 3H), 4.24 (q, 2H), 8.21 (d, 1H), 8.46 (d, 1H), 8.91 (s, 1H), 9.02 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 2.37 min. MS (M+H+): 291.9.