Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)([C:13]2[N:14](COC)[CH:15]=[CH:16][N:17]=2)[OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.Cl.C>C(OCC)C.C(O)(C)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)([C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)[OH:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(O)(c2ccc(Cl)cc2)c2ncc[nH]2)cc1

Procedure:
A mixture of 13 g (0.034 mol) of α-(p-tert.-butylphenyl)-α-(p-chlorophenyl)-1-(methoxymethyl)imidazole-2-methanol, 150 ml. of glacial acetic acid, 15 ml. of concentrated hydrochloric acid and 15 ml. of water was refluxed for 31/2 hours. The reaction mixture was treated with active charcoal and concentrated. The residue was dissolved in diethyl ether and the solution was washed with water. To the ethereal phase an ethereal solution of oxalic acid was added. The precipitate thus formed was crystallised from ethanol with a small amount of methanol. The base was liberated by addition of sodium hydroxyde and extraction with diethyl ether. The ether was distilled off and the residue was crystallised from isopropyl alcohol. As the product obtained contained crystal isopropyl alcohol, it was dissolved in diethyl ether. The ethereal phase was washed with water and dried over sodium sulphate and the ether was distilled off. α-(p-tert.-Butylphenyl)-α-(p-chlorophenyl)imidazole-2-methanol was obtained. Melting point 95°-110° C. The melting point was not sharp but the NMR and IR spectra, the titrations and the elementary analysis were in conformity with the desired structure. Thin layer chromatography revealed only one component.
Reaction SMILES: C[O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][C:4]=1[C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][CH:23]=[CH:22][CH:21]=2.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C.O>[OH:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]([C:6]2[CH:5]=[C:4]([C:18]3[NH:19][C:20]4[C:25]([C:26]=3[CH3:27])=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:3](=[O:2])[NH:8][N:7]=2)=[CH:10][C:11]=1[CH3:17]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2cc(-c3[nH]c4ccccc4c3C)c(=O)[nH]n2)cc(C)c1O
Temperature: 80 °C

Procedure:
6 mg of 4-[6-Methoxy-5-(3-methyl-1H-indol-2-yl)-pyridazin-3-yl]-2,6-dimethyl-phenol is suspended in 2 ml acetonitrile and 6.5 mg of trimethylsilyl chloride and 9.96 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h. The reaction solution is diluted with water and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 3.8 mg. LC-MS (ES+) 346 (M+H)+.
Reaction SMILES: CC(OC)(C)C.C(Cl)Cl.[F:10][C:11]1[CH:12]=[C:13]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:14][C@H:15]([NH:32][C:33](=[O:35])[CH3:34])[C@H:16]([OH:31])[CH2:17][NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][CH3:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1.Cl>CCOCC.CO>[F:10][C:11]1[CH:12]=[C:13]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:14][C@H:15]([NH:32][C:33](=[O:35])[CH3:34])[C@H:16]([OH:31])[CH2:17][NH:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][CH3:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1
Reactant: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCO2
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCO2
Temperature: 25 °C

Procedure:
To a MTBE (20 ml), CH2Cl2 (5 ml), MeOH (0.5 ml) solution of N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-ethyl-3,4-dihydro-2H-chromen-4-yl]amino}-2-hydroxypropyl)acetamide (0.2 g, 0.5 mmol) was added 1N HCl in Et2O (0.38 ml) and the mixture stirred at room temperature. The final white solid was isolated by removing the solvent and tritration with Et2O. HRMS (ESI+) calcd for C23H28F2N2O3 m/z 419.2146 (M+H)+. Found 419.2166.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19].CCCCCC.CCOC(C)=O>C1C=CC=CC=1.C1COCC1.CCOCC>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=Cc1ccccc1NC(=O)CCl
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-aminobenzaldehyde (0.969 g, 8 mmol) and pyridine (1.618 mL, 20.00 mmol) in benzene (8 mL) was stirred at 5° C. under a dry nitrogen atmosphere. A solution of chloroacetyl chloride (0.765 mL, 9.60 mmol) in benzene (4 mL) was added dropwise to the reaction mixture. When the addition was complete, the reaction mixture was allowed to warm to 20° C., then was stirred at that temperature for 15 minutes. The reaction mixture was then washed with water (3×20 mL). The combined aqueous layers were extracted once with EtOAc (15 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid. The solid was checked by TLC (9:1 hexane/EtOAc). A new spot with Rf lower than the starting material was evident. The crude solid was treated with THF/Et2O to provide the intermediate, 2-chloro-N-(2-formylphenyl)acetamide, as an off-white solid (892 mg, 56.4%) that was collected by filtration. 1H NMR (300 MHz, d6-DMSO) δ 11.43 (s, 1H), 10.01 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.94 (dd, J=7.7, 1.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.39 (dt, J=7.5, 1.0 Hz, 1H), 4.47 (s, 2H). MS (DCI—NH3) m/z=198 (M+H)+, m/z=215 (M+NH4)+, m/z=232 (M+NH4+NH3)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[OH-:22].[NH4+]>>[CH3:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]([NH2:15])=[O:22])=[CH:9][C:8]=1[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1
Reactant: [OH-]
Reactant: Cc1nc(-c2cc(C#N)c(=O)[nH]c2C)cs1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1nc(-c2cc(C(N)=O)c(=O)[nH]c2C)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
C-3. 1,2-Dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide--To an ice cold stirred 150 ml portion of concentrated sulfuric acid was added over a 5 minute period 64.2 g of finely powdered 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarbonitrile and the resulting mixture was stirred in an ice bath for 30 minutes and then allowed to stand at room temperature overnight. The reaction mixture was poured onto ice (800 ml beaker half filled) and then neutralized by adding aqueous ammonium hydroxide solution. The tan solid that separated was collected, washed with water, recrystallized from dimethylformamide and dried in an oven at 90° C. for 2 days to produce 59.2 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide, m.p. >300° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(C(C)C)C(C)C.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[OH:30]>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[OH:30][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:21]=1[NH:20][C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[C:25]([OH:27])=[O:26]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: Cc1ncccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)O)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
2-methyl nicotinoyl chloride (0.2 g, 0.00128 mols) is dissolved in 30 ml dry DCM and N,N′-Diisopropylethylamine (0.994 g, 0.00769 mols) is added slowly to the acid chloride solution at 0° C. under nitrogen atmosphere. A solution of 4-Amino-3-hydroxybenzoic acid (0.196 g, 0.00128 mols) in 10 ml dry THF is slowly added to the above solution at 0° C. The solution is then stirred at 0° C. for 30 mins and then at RT overnight. The reaction mixture is then diluted with 100 ml Ethyl acetate and stirred for 30 mins. The precipitated tarry material is filtered off over celite bed and the organic phase given 4×20 ml water wash, 2×10 ml brine wash dried over sodium sulfate and rotary evaporated to get the crude amide (140 mg) which is taken for the cyclisation step without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[C:5]2[C:9](=[O:10])[N:8]([CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7](=[O:28])[C:6]=12.C(O)C.C(O)(=O)C.Cl>[Zn].C(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7](=[O:28])[C:6]=12
Reactant: CCCCCCCCC(CCCCCCCC)N1C(=O)c2c(Br)sc(Br)c2C1=O
Agent: Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(CCCCCCCC)N1C(=O)c2csc(Br)c2C1=O

Procedure:
1,3-Dibromo-5-(heptadecan-9-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (9.43 g, 20.04 mmol) and zinc (1.31 g, 20.04 mmol) were placed in a 3 neck round-bottom flask equipped with a water condenser with ethanol (130 mL), acetic acid (40 mL) and 1 M HCl (2.5 mL). Mixture was refluxed for one hour after which an aliquot was taken for NMR analysis, which indicated reaction was complete. After cooling, the solution was filtered through fritted glass to eliminate remaining Zn particles and solvent was evaporated under vacuum. Product was obtained by silica chromatography, using a 100% hexane to 100% CHCl3 gradient.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:47][O:48][C:49](=[O:57])[C@H:50]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[NH2:51].C(N(CC)CC)C>CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([NH:51][C@H:50]([C:49]([O:48][CH3:47])=[O:57])[CH2:52][C:53]([O:55][CH3:56])=[O:54])=[O:30])[N:27]=4)[CH:21]=3)[C:5]3[CH:33]=[CH:34][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)cs2)c(=O)[nH]c1=S
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)c1csc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=S)[nH]c2=O)n1)C(=O)OC
Reaction time: 8 h

Procedure:
The product from example 8(0.4 g) was dissolved in dry dimethylformamide (15 ml) and treated with N,N-carbonyldiimidazole (0.16 g). After 30 minutes L-aspartic acid dimethyl ester (0.32 g) was added followed by triethylamine (0.5 ml). The mixture was stirred overnight and partitioned between ethyl acetate and 2M HCl. The organic phase was washed with brine, dried (MgSO4), evaporated and purified by chromatography eluting with 50% ethyl acetate in dichloromethane. Used directly in the next step.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:26])([CH3:25])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)C>[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
157 g of N-carbobenzoxy-L-phenylalanine in 500 ml methylene chloride and 300 ml absolute diethyl ether is treated at 15°-18° C. with 85.5 g L-proline tert.-butyl ester in 100 ml diethyl ether over 5 minutes, and then with 114 g of dicyclohexylcarbodiimide in 150 ml of diethyl ether over 15 minutes, both additions being at such a rate that the reaction mixture temperature does not rise above 18° C. The resultant mixture is stirred for a further hour at room temperature, and filtered, the solid residue being washed with ether. The filtrate is washed with, in turn, 2N hydrochloric acid, water, potassium bicarbonate, and then water, each washing being extracted with diethyl ether. All the organic phases are combined, dried over sodium sulphate and concentrated to yield an oily residue. The oily residue is taken up in methylene chloride, filtered, concentrated and dried in a high vacuum to yield the heading compound as a yellow oil.
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(C3C=CC(O)=CC=3)[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.CN1CCN(C)C1=O.[OH-].[Na+].Cl>O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCC(O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: Oc1ccc(C2=CCC(O)CC2)cc1
Yield: 69.3 %

Procedure:
The phenol adducts of 4,4-bis(4-hydroxyphenyl) cyclohexanol obtained as described above were reacted in toto in a manner similar to that described in Example 1 of Japanese Patent Application No. 89890/1987. Namely, the phenol adducts of 4,4-bis(4-hydroxyphenyl)cyclohexanol were added as a whole to a mixture of 100 ml of 1,3-dimethyl-2-imidazolidinone and 1 ml of a 50% aqueous solution of caustic soda. They were then reacted at 200°-220° C. for 3 hours. In the course of the reaction, the reaction system was depressurized after an elapsed time of 0.5 hour so as to draw phenol-containing 1,3-dimethyl-2-imidazolidinone out of the system. After completion of the reaction, the residue in the reaction tank was dissolved in caustic water and then acidified with hydrochloric acid to precipitate crystals. The crystals were collected by filtration, washed with water, dried under reduced pressure and then recrystallized from acetonitrile, thereby obtaining 22.3 g of 4-(4-hydroxyphenyl)-3-cyclohexen-1-ol. Purity: 99.1%. Purity-converted yield: 69.3% based on 4,4-bis(4-hydroxyphenyl)cyclohexanol.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[CH3:41].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([F:34])[CH:36]=4)(=[O:43])=[O:44])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-fluoro-4-methylbenzene-1-sulfonyl chloride (37.5 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 36 mg (50%); 1H NMR (DMSO-d6, 300 MHz): δ 9.4 (s, 1H), 7.92-7.98 (m, 3H), 7.784-7.7.812 (d, 2H, J=8.4 Hz), 7.67-7.74 (m, 3H), 7.59-7.64 (m, 1H), 6.72-6.726 (d, 1H, J=1.8 Hz), 2.17 (s, 3H), 1.74 (s, 6H); MS: m/z 579 (M+).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][Si:9]([CH3:17])([CH3:16])[C:10]#[C:11][C:12](=[O:15])[CH:13]=[CH2:14].CO.Cl>C1COCC1.C(OCC)C>[CH3:8][Si:9]([CH3:17])([CH3:16])[C:10]#[C:11][C@H:12]([OH:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)C#C[Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C[C@@H](O)C#C[Si](C)(C)C
Temperature: 25 °C
Yield: 98.7 %

Procedure:
(R)-Me-CBS reagent (1.0 M Toluene, 2.14 mL, 2.14 mmol) was transferred into a freshly flame-dried flask, and the toluene was removed in vacuo over 1 day. The CBS reagent was diluted with a THF solution of 5-trimethylsilyl-1-penten-4-yn-3-one (163 mg, 1.07 mmol), and the resultant solution was cooled to −30° C. At −30° C., BH3-Me2S (0.589 mL, 1.18 mmol) was slowly added over 10 min. After addition of BH3-Me2S, TLC analyses indicated that the reaction was complete. Methanol was slowly added, and reaction mixture was slowly warmed to room temperature. The reaction mixture was diluted with diethyl ether, and the resultant organic phase was washed with 2:1 (v:v) NaOH/saturated NaHCO3 solution until the aqueous phase was clear, and then washed with brine. After being dried over MgSO4, the organic phase was removed, diluted with diethyl ether, and to this was added a solution of 0.5 M HCl in methanol (4.5 mL, 2.14 mmol). Precipitates were removed by filtration. The crude product in the solvent mixture was purified by flash column chromatography (hexane/ether 5:1) to provide (3R)-5-trimethylsilyl-1-penten-4-yn-3-ol (0.163 g, 100% yield) as a colorless oil: Rf: 0.4 (hexane/dichloromethane 2:1); [α]D20.0°: −24.1 (c=1, CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.95 (ddd, 1H, J=17.0, 10.1, 5.29 Hz), 5.46 (d, 1H, J=7.0 Hz), 5.21 (d, 1H, J=10.1 Hz), 4.86 (d, 1H, J=3.87 Hz), 2.17 (br s, 1H), 0.16 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 137.0, 116.8, 104.9, 91.3, 63.9, 0.2; IR (neat) v: 3368.7, 2961.3, 2927.0, 2855.3, 2174.4, 1250.9, 843.7 cm−1; HRMS: calculated 154.28, found 154.0817 for [M]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl>CC#N.CN(C1C=CN=CC=1)C.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1cc(I)ccc1F)N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-iodobenzoic acid (2 g, 0.0088 mol) was dissolved in MeCN (44 ml) and the mixture cooled to 0° C. Morpholine (0.929 ml, 1.2 eq) followed by EDCI.HCl (2.03 g, 1.2 eq) and DMAP (108 mg, 0.1 eq) were added and the mixture stirred overnight. The mixture was diluted with EtOAc, washed with NH4Cl(sat), dried (MgSO4), and concentrated. The resulting residue was then purified by silica gel chromatography (0-30% EtOAc in hexane) gave 2 g of M1-5. LCMS MH+=336.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].S(Cl)(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][C:15](=[O:17])/[CH:14]=[CH:13]/[C:5]2[CH:6]=[CH:7][C:8]([S:9](=[O:11])(=[O:12])[NH2:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cc(/C=C/C(=O)O)ccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(/C=C/C(=O)Nc2cccc(Cl)c2)ccc1S(N)(=O)=O
Yield: 26.5 %

Procedure:
A solution of (E)-3-(3-methoxy-4-sulfamoyl-phenyl)-acrylic acid (0.291 g, 1.13 mmol) and thionyl chloride (0.100 mL, 1.36 mmol) in dry THF (15 mL) was stirred at reflux temperature for 1 h. Then a further aliquot of thionyl chloride (0.050 mL, 0.68 mmol) was added and the mixture was stirred at reflux temperature for additional 2 hrs. The mixture was then concentrated under reduced pressure, taken up with dry THF (3 mL) and added dropwise to a solution of 3-chloro-phenylamine (0.109 mL, 1.03 mmol) and diisopropylethylamine (0.705 mL, 4.12 mmol) in dry THF (13 mL). After stirring at RT for 16 hrs, the reaction mixture was concentrated under reduced pressure, taken up with DCM and washed with aqueous sodium hydrogencarbonate, and brine. The organic layer was then dried over sodium sulphate and evaporated. The resulting raw material was purified by column chromatography over silica gel (eluant DCM/acetone 9/1) to give 100 mg of the title (E)-N-(3-chloro-phenyl)-3-(3-methoxy-4-sulfamoyl-phenyl)-acrylamide as a white powder.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.C(/C(O)=O)=C\C(O)=O.N.N>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]3[C:4]=2[CH2:3][N:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[C:23]2=[O:28])=[CH:15][CH:16]=1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)c(CCl)n2c1
Reactant: Cc1ccc[nH]c1=O
Agent: Cl
Agent: N
Agent: O=C(O)/C=C/C(=O)O
Product: Cc1cccn(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)c1=O

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridine hydrochloride and 3-methylpyridin-2(1H)-one. 1H-NMR (CDCl3, 400 MHz, δ) 8.43 (dd, J=2.4, 4.1 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.58 (dd, J=5.0, 9.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.17 (m, 1 h), 7.13 (m, 1H), 6.65 (dd, J=1.4, 6.9 Hz, 1H), 5.93 (t, J=6.8 Hz, 1H), 5.63 (s, 2H), 2.16 (s, 3H) ppm; m/e368 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:53][O:54][C:55](=[O:73])[C@@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=2[CH3:71])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:20])[NH:72][C@H:56]([C:55]([O:54][CH3:53])=[O:73])[CH2:57][C:58]2[CH:59]=[CH:60][C:61]([C:64]3[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=3[CH3:71])=[CH:62][CH:63]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (150 mg) was taken in 2 mL of anhydrous DCM and EDCI (64 mg), HOBT (47 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (91 mg) and stirred for 5 minutes. Reaction mixture was cooled to 0° C. and DIEA (164 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction is complete, it was purified by silica gel column chromatography (1:3 EtOAc/hexanes to 2% MeOH in 1:1 EtOAc/hexanes) (152 mg). LCMS (m/z): 853.