Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:26][CH3:27])[C:10]([N:12]1[C:20]2[C:15](=[C:16]([Cl:22])[C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:23]([OH:25])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([NH:32][C:23]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:26][CH3:27])=[O:25])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)c(Cl)c2CC1C(=O)O
Product: CCCCNC(=O)C1Cc2c(ccc(Cl)c2Cl)N1C(=O)[C@H](CC)NC(=O)OC(C)(C)C

Procedure:
This compound was prepared from 1-(N-t-butoxycarbonyl-2-(S)-aminobutyryl)-4,5-dichloroindoline-2-(R/S)-carboxylic acid as described in Example 1, using butylamine instead of trifluoroethylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:32]=3[F:31])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)[nH]c3c3c2OC(C)(C)C3)c(F)c1
Yield: 29.3 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.200 g, 0.512 mmol), thionyl chloride (2.0 mL), 2-fluoro-4-methylaniline (0.128 g, 1.025 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 2.29 (s, 3H), 3.10 (s, 2H), 7.00 (d, J=8.1 Hz, 1H), 7.15 (d, J=12 Hz, 1H), 7.24 (m, 1H), 7.42 (m, 1H), 7.53 (d, J=8.1 Hz, 2H), 8.33 (t, J=8.4 Hz, 1H), 9.99 (s, 1H), 11.00 (s, 2H); MS [M+H]+: 500.39.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[N:5][N:6]2[C:11]([CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].[C:33]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[N:5][N:6]2[C:11]([CH2:12][N:13]([CH3:33])[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CNC(=O)C(F)(F)F)ccnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(Cc1ccnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn12)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of N-((3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)-2,2,2-trifluoroacetamide (40 mg, 0.091 mmol) in 5 mL of acetone was added K2CO3 (50 mg) and CH3I (0.5 mL). After stirring at rt for 4 hr, the mixture was concentrated. The residue was partitioned between 10 mL of water and 10 mL of DCM. The organic layer was concentrated and purified by Pre-TLC (DCM/MeOH=20/1) to give a yellow solid (30 mg, 73%). MS (ESI) m/e [M+1]+ 451.9.
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=[O:31])[C:24](=[O:30])[C:25]=3[O:26]C(C)C)[CH:9]=2)[O:4][C:3]1([CH3:33])[CH3:32]>C1COCC1.Cl>[OH:31][C:23]1[C:24](=[O:30])[C:25](=[O:26])[C:22]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][C:3]([CH3:33])([CH3:32])[C@@H:2]([OH:1])[C@@H:11]2[N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21]
Reactant: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(-c3c(O)c(=O)c3=O)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 50 °C
Yield: 40.8 %

Procedure:
A solution of 303 mg (0.676 retool) of 3-[trans-3-hydroxy-2,2-dimethyl-4-(1- oxo-1,3-dihydroisoindol-2-yl)-chroman-6-yl]-4-isopropoxy-cyclobut-3-ene-1,2-dione in THF (5 mL) containing 1.13 mL (6 N HCl) was heated at 50° C. for 48 h. The reaction mixture was diluted with 2 N HCl and extracted into 20% THF-CH2Cl2. The combined organic extracts were dried (MgSO4), concentrated, and recrystallized from THF to give 112 mg of the title compound as a tan solid, mp>250° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ7.84 (dd, 1 H), 7.81 (d, 1 H), 7.52-7.64 (m, 3 H), 7.51 (s, 1 H), 6.93 (d, 1 H), 5.3 (br s, 1 H), 4.4-4.5 (br d, 1 H), 3.8-4.1 (br, 2 H), 1.47 (s, 3 H), and 1.26 ppm (s, 3 H); IR (KBr) 3400, 1785, 1720, 1670, and 1600 cm-1 ; mass spectrum (DCI+), m/e 406 (M+H). Anal. Calcd. for C23H19NO6. 0.5 H2O: C, 66.66; H, 4.86; N, 3.38 Found: C, 66.67; H, 4.60; N, 3.34.
Reaction SMILES: [NH2:1][C:2](=[O:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:8]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O.[ClH:42]>O1CCCC1.C(OCC)(=O)C>[ClH:42].[ClH:42].[NH2:20][CH2:19][C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:6][C:5]([O:4][CH2:3][C:2]([NH2:1])=[O:34])=[CH:14][CH:13]=2
Reactant: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of tert-butyl [6-(2-amino-2-oxoethoxy)-2-isobutyl-4-phenylquinolin-3-yl]methylcarbamate (0.10 g, 0.21 mmol) in tetrahydrofuran (5 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and 10% aqueous potassium carbonate solution (100 ml). The aqueous layer was separated and extracted twice with ethyl acetate-isopropanol (10:1, 25 ml). The organic layer and the extract were combined and washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give a colorless oil. The obtained colorless oil was dissolved in ethyl acetate (2 ml) and 4N solution of hydrogen chloride in ethyl acetate (1 ml) was added. The reaction mixture was concentrated and the obtained residue was crystallized from diisopropyl ether-methanol to give the title compound (0.062 g, yield 67%) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].CS([C:12]1[N:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=2)[C:14](=[O:23])[C:15]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)=O.O>O1CCCC1>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:12]1[N:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=2)[C:14](=[O:23])[C:15]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1
Reactant: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCc2c(nc(OCC(F)(F)F)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reaction time: 0.08 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (0.472 mL) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.184 g). The reaction mixture was stirred for 5 min, 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.88 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.80 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][S:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].[N:25]1([CH2:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)O)[CH:29]=[CH:28][N:27]=[CH:26]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:25]1([CH2:30][C@@H:31]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][S:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20][CH3:21])=[O:19])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: COC(=O)c1cccc(SCc2c(O)ccc3c2CCCC3=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 94 %

Procedure:
Using the method in Example 154, this compound was prepared from methyl 3-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate (1.81 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3 mmol), Ph3P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g, 8.0 mmol) and purified by a silica-column (eluting with dichloromethane-MeOH 20:1) as a solid-foam, 2.56 g, 94% yield; mp 65° C. NMR spectrum was consistent with structure. Calcd. For C30H28N2O4S.0.5H2O:
Reaction SMILES: C(N1C2C=CC(N[C:17]3[CH:21]=[C:20]([S:22][CH3:23])[S:19][C:18]=3[C:24]([NH2:26])=[NH:25])=CC=2C2C1=CC=CC=2)C.[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38](NC3C=C(C(OC)=S)SC=3C)=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28].C[Al](C)C.[Cl-].[NH4+:58]>C1(C)C=CC=CC=1>[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38]([NH:58][C:21]3[CH:17]=[C:18]([C:24]([NH2:26])=[NH:25])[S:19][C:20]=3[S:22][CH3:23])=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28]
Reactant: CCn1c2ccccc2c2cc(Nc3cc(C(=S)OC)sc3C)ccc21
Reactant: [NH4+]
Reactant: CCn1c2ccccc2c2cc(Nc3cc(SC)sc3C(=N)N)ccc21
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(Nc3cc(C(=N)N)sc3SC)ccc21
Yield: 70 %

Procedure:
4-[((9-Ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine: The same procedure as in Example 253, step (b) was followed using 80 mg (0.21 mmol) of methyl 4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxylate (as prepared in previous step), 2 mL of trimethylaluminum (2.0 M in toluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 mL of toluene, and purified on a 2-g silica SPE column with 5% MeOH—CH2Cl2 to afford 56 mg (70%) of the title compound as a yellow foam. 1H-NMR (DMSO-d6, 400 MHz) δ 1.31 (t, 3H, J=7.0 Hz),2.50 (s, 3H), 4.42 (q, 2H, J=7.0Hz), 7.14 (m, 1H), 7.27 (dd, 1H, J=8.7,2.1 Hz), 7.43 (m, 1H), 7.56 (m, 2H), 7.82 (d, 1H, J=2.0 Hz), 7.87 (s, 1H), 7.92 (s, 1H), 8.10 (d, 1H, J=7.7 Hz), 9.11 (br s, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H20N4S2, 381.1 (M+H), found 381.3.
Reaction SMILES: [CH3:1][C:2]([OH:12])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[C:3]#[CH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:12][C:2]([CH3:1])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[C:3]#[CH:4])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C#CC(C)(O)CCC(C)=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C#CC(C)(CCC(C)=C(C)C)OC(C)=O
Temperature: 40 °C

Procedure:
650.0 g of 3,6,7-trimethyl-6-octen-1-in-3-ol and 0.63 g of p-toluene sulfonic acid in water are mixed and heated up to a temperature of 40° C. 479.3 g of acetic acid anhydride are added within 2 hours. After ca. 20 hours the reaction mixture is cooled down and distilled to obtain 3,6,7-trimethyl-6-octen-1-in-3-yl acetate.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=1>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=2)=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1F
Yield: 8.4 %

Procedure:
Crude (4-tert-butyl-3-fluorophenoxy)acetic acid (124 mg, crude), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (90 mg, 0.55 mmol), triethylamine (0.35 ml) and-N[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (127 mg, 0.5 mmol) were mixed in the same procedure described in Example 2(b) to give 18 mg (7.8% yield) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]([CH2:12][CH2:13][O:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:19][S:16]([CH2:15][O:14][CH2:13][CH2:12][N:9]1[C:8]2[CH:20]=[CH:21][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)(=[O:17])=[O:18]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCOCS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)COCCn1cnc2cc(C(=O)O)ccc21
Reaction time: 1 h
Yield: 83.8 %

Procedure:
1-(2-Methanesulfonylmethoxyethyl)-1-H-benzimidazole-5-carboxylic acid methyl ester (1.0 g, 3.2 mmoles) was dissolved in THF (5 mL). A solution of LiOH (0.38 g, 16 mmol) in water was added and the mixture stirred vigorously for 1 h. The reaction was acidified with 2N HCl to pH 2 at 5-10° C. It was then filtered to give 0.8 g (84%) of 1-(2-methanesulfonylmethoxyethyl)-1H-benzoimidazole-5-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 2.9 (s, 3H), 4.2 (t, 2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.75 (d, 1H), 7.9 (dd, 1H), 8.25 (d, 1H), 8.35 (s, 1H), 12.7 (s, 1H)
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13].C(N([CH:21]([CH3:23])[CH3:22])C(C)C)C.Cl.[CH2:25]([O:27][C:28](=[O:33])[C@H:29]([CH2:31][SH:32])[NH2:30])[CH3:26]>CCO>[O:14]=[C:10]([CH:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][CH:2]1[CH3:1])[CH2:11][CH:12]([NH:30][CH:29]([CH2:31][S:32][CH:12]([CH2:11][C:10](=[O:14])[CH:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:23][CH:21]1[CH3:22])[CH3:13])[C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH3:13]
Reactant: CC=CC(=O)C1C(C)C=CCC1(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CSC(C)CC(=O)C1C(C)C=CCC1(C)C)NC(C)CC(=O)C1C(C)C=CCC1(C)C
Yield: 64.1 %

Procedure:
A solution of 1-(2,6,6-trimethylcyclohex-3-enyl)but-2-en-1-one (83.0 g, 0.50 mol, 2 equiv.), ethyl diisopropylamine (32.3 g, 0.25 mol, 1 equiv.) and L-Cystein ethyl ester hydrochloride (46.5 g, 0.25 mol, 1 equiv.) in EtOH (600 ml) is heated to 60° C. during 44 h. The solvent is removed in vacuo and the residue dissolved in methyl t-butyl ether. The solution is washed with dilute aq. NaCl, dried over MgSO4 and concentrated. The residue is purified by chromatography on SiO2 to yield 85.5 g (71%) of the title compound as orange oil.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:17](=[O:24])[CH:16]=2)=[CH:9][CH:8]=1.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH:14][C:15]2[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:17](=[O:24])[CH:16]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C=Cc2cc(=O)cc(C(=O)O)o2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(=O)cc(C=Cc2ccc(O)cc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boron tribromide (2.5 ml) was added to a stirred suspension of 6-[2-(4-methoxyphenyl)ethenyl]-4-oxo-4H-pyran-2-carboxylic acid (1.4 g) in methylene chloride (140 ml) and the mixture was stirred for 3 hours at room temperature and 1 hour under reflux. Water (30 ml) was added to the stirred mixture and the solid product was crystallised from ethanol-water to give the title product (mp 256° C. with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[C:20]5[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=4[S:19][CH2:18]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=5)[CH2:13][CH2:14]2)=[CH:27][CH:26]=1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)COc4ccc(F)cc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 211 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=80-81° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.09 (m, 3H), 6.95 (m, 2H), 4.85 (s, 1H), 3.98 (brm, 6H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H), 1.99 (m, 2H), 1.80 (m, 2H); LCMS: 500 [M+H].
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.ClCCO[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=1>CN(C=O)C>[N:7]1([CH2:1][CH2:2][O:4][C:20]2[CH:21]=[CH:16][C:17]([C:22]3[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)=[CH:18][CH:19]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC(c2ccccc2OCCCl)=NN1
Reactant: c1c[nH]cn1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCn3ccnc3)cc2)=NN1
Reaction time: 0.08 h
Yield: 316.6 %

Procedure:
Potassium-t-butoxide (0.56 g, 0.5 mmol) is added to a solution of imidazole (0.34 g, 0.5 mmol) in dry DMF (10 ml) under N2. The resulting mixture is stirred until homogeneous and then five minutes longer. A solution of 4,5-dihydro-6-(2-chloroethoxyphenyl)-3(2H)-pyridazinone (1.27 g, 0.5 mmol) in dry DMF (20 ml) is added in one portion and the resultant mixture is heated and stirred at 60° for 12 hours. The DMF is then distilled off and the residue taken up in chloroform. The chloroform solution is extracted with 5% aqueous HCl. The aqueous extract is made basic with 10% aqueous sodium carbonate and extracted several times with methylene chloride. The methylene chloride is evaporated, leaving behind 0.45 g of the product 4,5-dihydro-6-[4-(2-(1H-imidazol-1-yl)ethoxyphenyl]-3(2H)-pyridazinone as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]([C:41]1[CH:46]=[CH:45]C(O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:46][C:41]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:42][CH:43]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4ccc(C(C)(C)C)cc4)cc3C)c2cc1OC
Yield: 45.4 %

Procedure:
4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-(tert-butyl)phenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (35 mg, yield 44%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]#[N:14])=[CH:7][C:6]=1[Cl:15].[BH4-].[Li+]>C1COCC1.CCOCC>[Cl:15][C:6]1[CH:7]=[C:8]([C:13]#[N:14])[C:9]([O:11][CH3:12])=[CH:10][C:5]=1[CH2:4][CH2:3][OH:2]
Reactant: COC(=O)Cc1cc(OC)c(C#N)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CCO)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl(2-chloro-4-cyano-5-methoxyphenyl)acetate (200 mg, 0.835 mmol) in THF (5 mL) was added 2M lithium borohydride (0.835 mL, 1.67 mmol) and the reaction was stirred at RT for 16 hours. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product mixture was separated by MPLC (40+S; 20-60% ethyl acetate/hexanes) to afford the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 3.04 (t, J=6.4 Hz, 2H), 3.93 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 6.927 (s, 1H), 7.536 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:36]=[CH:35][C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:35][CH:36]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.11 g, 0.352 mmol) and 4-(4-bromobenzoyl)morpholine (0.095 g, 0.352 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][C:3]=1[CH3:16].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)cnc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 2-(6-chloro-5-methylpyridin-3-yl) acetate 86-6 (7.8 g, 32 mmol) and TFA (32 mL) in DCM (32 mL) was stirred at room temperature for 3 hours. The solution was adjusted to pH around 12 by sodium carbonate and extracted with dichloromethane. The aqueous phase was acidified to pH 3 by 1N HCl aqueous solution and stirred for 15 minutes. The suspension was extracted with dichloromethane (100 mL X3). The combined organic phases were washed with water and brine, dried over Na2SO4 and then dried to give 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 86-7 as pale yellow solid. MS m/z 186.1 (M+1); 1H NMR 400 MHz (CD3Cl) δ 8.17(d, 1H, J=2.0 Hz), 7.55(d, 1H, J=2.0 Hz), 3.63(s, 2H), 2.38(s, 3H).